Can You Use Descovy™️ for PrEP 2-1-1/On-Demand Dosing?

1/6/22 (Author’s note, contact)

Introduction

(Molina F-TAF PrEP tweet 3/9/19)

“Agree with @CarlosdelRio7 we should not use on demand TAF/FTC for PrEP until we have data since rectal tissue concentration of TVF-DP seem lower than with TDF/FTC according to #CourtneyFlechtner at #CROI2019”

Jean-Michel Molina, via Twitter, 3/9/19

…And so it is that the question of efficacy of Descovy™️ for HIV prevention with nondaily oral pre-exposure prophylaxis (PrEP) dosing has come to be asked over and over again. That’s been the case at least since initial DISCOVER trial results were announced in Spring 2019, followed by limited F-TAF daily-only PrEP approval by the US Food and Drug Administration (FDA) four months later.

“The U.S. Food and Drug Administration today approved Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg) in at-risk adults and adolescents weighing at least 35kg for HIV-1 pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection from sex, excluding those who have receptive vaginal sex. Descovy is not indicated in individuals at risk of HIV-1 infection from receptive vaginal sex because the effectiveness in this population has not been evaluated.”

FDA news release dated 10/3/2019

[CAVEAT: This F-TAF 2-1-1 oral PrEP conversation excludes many who would benefit from more flexible PrEP offerings. In fact, the bolded emphasis added above is due to the fact that cis women and many Trans women, Trans men, other folks assigned female at birth, people who inject drugs, people of color, and youth have already largely been left out of this early F-TAF oral PrEP efficacy research. This exclusion explains in part why the approval was not a fuller one like F-TDF’s oral PrEP approval. A related critical conversation is ongoing. Accordingly, Gilead – the company that makes Descovy™️ – has committed to correcting this erasure and started some such inclusion. However, time will tell whether or not the question of F-TAF 211 oral PrEP efficacy addressed herein will apply meaningfully to ANY of these priority groups vulnerable to HIV acquisition.]

Definitions

Tenofovir (TFV), Tenofovir Disoproxil Fumerate (TDF), and Tenofovir Alafenamide (TAF) (figure courtesy of Ray et al 2016)

The specific drug in question is Gilead’s slightly chemically updated Descovy (Tenofovir-alafenamide/Emtricitabine), a combo HIV antiretroviral treatment component pill launched to replace the 2017-patent-expiring Truvada [Tenofovir-disoproxil fumerate (TDF)/Emtricitabine, or F-TDF]. TAF is just a prodrug or derivative of TDF. (Some argue that it’s merely an evergreened derivative at that, thus the newly-patented-product launch.)

Truvada™️ vs Descovy™️ (image courtesy of PrEPAccessNOW)

(The current US HIV treatment guidelines draw the distinction between TDF and TAF as such, “TAF and TDF are two forms of TFV [Tenofovir] approved by the FDA. TAF has fewer bone and kidney toxicities than TDF, whereas TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.” Liver-, bone-, and kidney health – factors identified above – are important considerations for people taking therapeutic ARVs over long periods, especially as those people age.)

In addition to its patent-related F-TDF-to-F-TAF sales switch strategy for PrEP consumers, Gilead has also marketed Descovy to care providers as a preferable option for PrEP patients on ARVs as preventatives for long periods as they age. (This switch to the newly-patented prodrug means for Descovy a period of time with no price-lowering competition from generic versions.) Thus, the distinction mentioned above in current US HIV treatment guidelines helps explain why some PrEP users (and their care providers) opt for one (or the other) drug for oral Tenofovir-based PrEP.

From a consumer perspective though, I suspect that deciding whether to opt for or switch from/to daily- vs 2-1-1 PrEP generally overlaps with rationales (‘economical, safe, effective, simple, and flexible’) asserted among some PrEP users who have resorted to the Ts and Ss PrEP approach. (Ts and Ss PrEPping is another 4-pill-based, nondaily oral PrEP dosing strategy adapted among cis MSM, involving “weekly-base” dosing or more aptly “routine-plus-event-based” dosing on Tuesdays, Thursdays, Saturdays, and Sundays regularly).

The specific nondaily PrEP dosing approach in question herein is the popularly-coined “2-1-1” dosing strategy (also referred to sometimes as event-based/event-driven/intermittent dosing, on-demand dosing, pericoital dosing, or IPERGAY dosing). This approach using oral F-TDF has been demonstrated as highly effective in multiple trials among cisgendered men in the receptive position during penetrative, condomless anal sex (IPERGAY, IPERGAY OLE, AmPrEP, the San Francisco study, PREVENIR, etc). It starts with two pills 2-24hrs before sex, a 3rd pill 24hrs after the 1st two pills, and a 4th pill 24hrs after the 3rd pill (see diagrams below).

Starting PrEP for cis men [from AIDES’ “PrEP: Instructions for Use” (2021) , pg 17]

Starting PrEP for cis men [from AIDES’ “PrEP: Instructions for Use” (2021) , pg 18]

As the diagrams above also show, the approach allows for flexibility of switching back and forth with daily- and 2-1-1 dosing if needed. This is true as long as there are the post-sex doses 24hrs then 48hrs after last sexual contact, and even with a single pre-sex loading dose instead of two if there was any drug dosing within the previous 7 days. (Though the World Health Organization recently warned that, through experience, the French had to simplify that restart to the usual two pills, regardless of whether or not the gap is less than 7 days or more than 7 days.)

TL:DR

Now, it should be pointed out that the idea of less-than-daily dosing was hinted at indirectly in the FDA application for Descovy™️’s PrEP approval back in 2019. The rationale for the regulator’s rejection of the idea can be surmised from the following excerpt relevant to cis women:

“As part of its rationale for utilizing systemic drug exposure data to support a PrEP indication in cisgender women, the Applicant also states that TAF can quickly (within 2‐3 hours following a single dose) achieve TFV‐DP concentrations of 40 fmol per million cells in PBMCs of both men and women, a clinical threshold demonstrating a level of adherence reportedly associated with a greater than 90% reduction in HIV acquisition (EC90) in prior PrEP trials of Truvada {Anderson et al. 2012a; Anderson et al. 2012b}. However, while this target concentration may be valid for MSM receiving F/TDF, it may not apply to F/TAF due to the differences between TDF and TAF in the correlation between PBMCs and mucosal tissue concentrations for TFV‐DP.”

FDA briefing document, 8/7/2019, pg 26

In other words, as Molina pointed out earlier, “rectal tissue concentration of TVF-DP [with TAF/FTC] seem lower than with TDF/FTC.” Indeed, with IPERGAY™️ trial lead investigator Jean-Michel Molina’s response to the query again via Twitter in early 2020 (screenshotted below), the question of F-TAF 211 PrEP efficacy had again percolated up to one of the most authoritative voices on the topic of 211 PrEP efficacy.

Molina event-driven F-TAF PrEP efficacy question screengrab

Molina’s response, “…[T]here is not [data to support event-based- or timed F-TAF PrEP] and I would not recommend event-driven TAF/FTC until we have good data” just about sums up any TL:DR one could offer with the very same reason why F-TAF 2-1-1 PrEP approval could not be advanced by the FDA.

And yet, the question has popped up more and more frequently in the U.S.-based PrEP Facts Facebook group and elsewhere online as Descovy™️ (F-TAF) has taken more and more market share from Truvada™️ (F-TDF). In other words, there is definitely demand for this (and almost certainly execution already too). Thus, a more nuanced but still reasonable TL:DR to such a question in the category of challenging-because-there’s-no-authoritative-data might read as such:

‘We just can’t say for sure now whether or not the 2-1-1 oral PrEP protocol works with F-TAF to prevent HIV acquisition since A.) F-TAF oral PrEP is only known to be effective/approved/recommended as a daily regimen for people assigned male at birth (AMAB) and B.) there’s no such 2-1-1 F-TAF oral PrEP randomized control trial data yet in humans. Nevertheless, since there are some encouraging bits of animal challenge trial data and human pharmacology data, it’s obviously your-body-your-choice for those people who will do what they will do regardless of the admonitions like that from the esteemed authority quoted above. So, in such cases, it’s best that they try to get balanced, unbiased, comprehensive evidence-based information and discuss it with their care providers for making health and medical decisions that fit their own lives.’

Roadmap

Now, you, dear reader, might be wondering why I am still interested in this topic (or why you should be) beyond the TL:DRs articulated above. Well, if you’re at all like me, then you can’t help but see the demand-but-no-data dilemma. You might also, like me, be excited about new biotechnologies (TAF) and new related approaches TAF-based PrEP, 2-1-1 PrEP), especially when they’re begun or at least based in the community as opposed to the academy. You might even have an eye to the harm reductionist care provider’s approach of shared decision-making by telling-what-you-know and applying the info collaboratively to a patient’s needs. Or, you might just like deep dives that give greater background, context, and detail on such topics. So, with that, feel free, if you’d like, to review with me some of the lead-in (the terms and history), the logic (inferential data), and the limitations (data/guidance gaps) that cause an intrepid few to take a more optimistic (some say permissive) view of people considering experimenting on their own with F-TAF 2-1-1 PrEP while causing many others to dismiss this whole idea as speculative at best. For, in reviewing such information, we might cover some of the balanced, unbiased, comprehensive evidence-based tangential information necessary in order to address the dilemma of such demand-but-no-data drug dosing decisions.

THE LEAD-IN (BACKGROUND)

In order to understand how we got to the point where there were two PrEP pills, multiple dosing strategies, and a desire/need to use one of those pills like the other but without corresponding evidence of efficacy, we’ve got to go back to about 1999. That’s when TAF was just a TDF-offshoot lab compound codenamed GS-7340, sloshing around in vitro. (A quick-n-dirty enumeration on PrEP’s overall history can be found here.) It would take two years, until 2001, for first published papers introducing TAF to the world, while TDF was already making its market debut for HIV treatment. This was soon followed by the start of TAF human testing in 2002 for HIV treatment and the 1st TDF testing as a daily prevention pill in people as well in 2003.

Meanwhile, 2004 brought a curious TAF research pause just as the FDA approved a combined F-TDF pill for HIV treatment. The F-TDF pill approval dove-tailed well, two years later, with animal research showing better preventative power in the combined F-TDF approach rather than either ARV alone and led to a research shift in the form of a combined/comparative approach in the subsequent daily oral TDF-based PrEP trial launched in 2008.

(It doesn’t go without notice also that 2005 saw a TAF-focused expression of hope acknowledging that “better intracellular distribution of the oral prodrug [TAF] … [leads to] extremely potent in vitro activity and selective targeting to lymphoreticular tissues and PBMCs in vitro and in vivo … [and perhaps] effect[s] on latently infected cells …[and] latent cellular reservoirs …leading to the conclusion that it may … be possible to eradicate [HIV].” In other words, some scientists were initially so impressed with TAF’s targeted cellular penetration and potency, that they thought it might have a role to play in reaching the HIV viral reservoir in its many nooks and crannies, thereby helping totally eradicate HIV from the body.)

Where HIV hides (Avettand-Fenoel 2016)

A series of news articles in 2003, 2005, 2006, 2007, and 2008 warned of intrepid street pharmacists, permissive care providers, and risk-oriented (some might say desperate) healthcare consumers experimenting with nondaily oral TDF-based prophylaxis at this same time that TDF was gaining a bit of a reputation for taxing the kidneys of people taking it daily for HIV treatment (and it was pointed out later, taxing their bones too). This burgeoning infamy harkened back in the psyche of the AIDS generation to the toxicity and related controversy surrounding the initial dosing of the ubiquitous 1st HIV treatment ARV known as Zidovudine/ZDV or Azidothymidine/AZT (as well as other similarly troublesome ARVs no longer marketed or commonly recommended to certain groups). That perception – fed by class action lawsuits targeting longterm safety of oral TDF-based HIV treatment regimens – later informed consumer interest in TAF as a safer oral PrEP alternative to TDF. (Though it’s worth pointing out that TDF-based oral PrEP was found to be comparatively safe to placebo as far as serious adverse events in a meta-analyses of almost 16,000 oral TDF-based PrEP research participants spanning 4mos to 4yrs from the earliest West African- and US Safety studies all the way through IPREX, PARTNERS PrEP, and the Bangkok Tenofovir Study right upto IPERGAY and PROUD.)

Subsequent to all the media attention to “the streets,” (documented from a cultural anthropological or communications perspective as a consumer demand in all the “MTV,” “Taking a T,” “the 3 Vs,” “party packs,” and “disco dosing” jargon captured in the media throughout the mid 2000s), 2-1-1 PrEP dosing was finally hitting the research/development pipeline agenda in earnest after a late 2009 researcher confab acknowledging, perhaps euphemistically, that “[T]here is considerable interest in intermittent use of PrEP (iPrEP)…People at risk of contracting HIV cannot afford to let biomedical and behavioral PrEP research be delayed.” Next, in 2010 and 2011, largescale, definitive evidence of daily, oral F-TDF’s HIV prevention power finally emerged from the R-&-D pipeline (after a series of fits-and-starts obstacles).

This F-TDF PrEP proof news was just in time, conveniently, for TAF’s 2011 R-&-D relaunch (and combining with emtricitabine). And, as the famous French IPERGAY trial launched in early 2012 with F-TDF among cis-MSM (and one trans woman), F-TDF daily PrEP was greenlighted by the US FDA. The IPERGAY trial ended surprisingly early (and successfully) about two-and-a-half years later in late 2014. Then, its Open Label Extension about two-and-a-half years hence in 2016 (around the same time as Descovy’s approval for HIV treatment and its market positioning as a more kidney-/bone favorable ARV combo compared to F-TDF and launch of DISCOVER, the only completed F-TAF PrEP trial to date, whose early (and successful) unblinding at the beginning of 2019 preceeded the limited 2019 US FDA Descovy PrEP approval excerpted early herein. (More on its results below.)

In summary – from TAF as a TDF prodrug, to TAF’s R&D pipeline entry, to TAF’s TDF coattail-riding on ARV combo-partner FTC, to related HIV treatment approvals and subsequent PrEP research positionings, to safety concerns (some primarily residual from earlier ARVs) and related consumer-driven dosing innovation demands, to treatment- and prevention trial successes followed soon by FDA approvals – this is how we got to the question of whether or not F-TAF can be used like F-TDF for this particular nondaily dosing approach.

THE LOGIC (INFERENTIAL DATA)

For many people prescribed oral F-TAF for PrEP, the 2-1-1 dosing regimen question is one of convenience, “Can I do that with what I’m already on if the drugs are similar?”

The New ‘New Thing’

Some users may just get excited about being on the vanguard of technology (like the so-called “early adopters” from the Diffusion of Innovations theory discussed by IPREX lead investigator Dr. Robert Grant). In other words, these “early adopters” may prize F-TAF as a status symbol.

Great Things … Small Packages

The tiny pill form of F-TAF may create a sense of cuteness. That cuteness often evokes the same sense of joy, whimsy, ornate decoration, and delight expounded upon recently by NPR’s This American Life yarnster Bim Adewunmi on a episode called “#687: Small Things Considered,” all about our glee in such delicate things. The tiny cuteness of F-TAF may also evoke a sense of discreteness, discreetness, and discretion that dovetails well with the taking-control-in-tiny-increments nature of the 2-1-1 PrEP dosing approach. (There could even be an overlapping “echo” of intimacy from the sex itself to the safety method of 2-1-1 via the small pill size and this simple wraparound dosing method.)

Packing A Potent (Pharmacological) Punch

Regardless, what’s clear is that F-TAF packs a powerful punch in a petit preventative/therapeutic pill package. Specifically, the comparison of Tenofovir inclusion is roughly an order of magnitude (10-fold) smaller in Descovy (25mg of TAF) vs Truvada (300mg of TDF). TAF does this by delaying its metabolism or transformation until it gets inside circulating- and stationary immune cells, the very groups that HIV targets primarily for copy-hijacking and cell-to-cell hopping systematic distribution and establishment.

(Fig. 3 from Antelaet al, 2016, “The role of tenofovir alafenamide in future HIV management”

In addition to many fewer mg TAF than TDF needed to penetrate and protect immune cells, TAF seems to do that cellular penetrating and protecting molecularly faster (1-2hrs vs. 3-4days), at higher levels (404 fmol vs. 49 fmol) and for longer (16 days vs 10 days than TDF).

(Table 1: Key HIV Prevention Clinical Pharmacology Parameters: TFV-DP with F/TAF and F/TDF from Spinner et al, 2019, “DISCOVER study for HIV pre-exposure prophylaxis (PrEP): F/TAF has a more rapid onset and longer sustained duration of HIV protection compared with F/TDF”)

That potency is why oral F-TAF pills are relatively so small and why some are speculating (optimistically even in certain corners) about F-TAF 2-1-1 dosing. Indeed, the biochemical angle (outlined in key documents and slide presentations for the FDA’s F-TAF oral PrEP approval proceedings) forms the greater heft of logic underpinning the speculation that oral F-TAF might be a better fit with those for whom daily adherence is impossible or not preferable otherwise.

(Slide #106 from Brainard, 2019, “Descovy for PrEP” FDA Ppt)

(As a ‘potency/packaging pun intended’ aside, it’s rather curious that Descovy is marketed in single-serving “Day Tracker” blister packs that, ironically, promise longer home shelf-life and ease of portability suitable to 2-1-1 dosing than a 30-pills-for-daily-use bottle, as has been the common commercial container for its counterpart Truvada.)

The Add-On Emtricitabine

Emtricitabine’s rapid cellular onset in anal tissues also plays an important (perhaps independent) but often overlooked role in 2-1-1 PrEP dosing. FTC does this by offering initial local protection therein, early after dosing. AIDSMAP’s Gus Cairns characterized IPERGAY investigator Jean-Michel Molina this way on the matter shortly after confirmatory pharmacological data was published: “…in previous studies, 96% protection from HIV was reached after just three doses of Truvada PrEP and 99% after five doses. Adequate concentrations in blood of both of the drugs in Truvada, tenofovir and emtricitabine, were reached as soon as two hours after taking a pill but that while similar levels of emtricitabine were reached in rectal secretions in the same timespan, tenofovir did not become detectable in rectal secretions until 24 hours after the first dose. This may mean, Molina commented, that emtricitabine offers the sole protection against HIV very early on after a first dose [emphasis added].”

(The FTC finding above dovetails well with more recent complementary pharmacological data. That more-recent, relevant data broke ground on longstanding questions of PrEP drug concentrations in local penile tissues as well as questions of the relative contributions of FTC vs. TDF in local vs systemic protection. As such, these newer data echo the same Molina FTC-local PrEP “sole protection” observation. They also suggest that the protective contribution of TDF or TAF to the two-drug oral PrEP combo may be more systematic than previously supposed, unlike FTC [or its own sister-compound, lamivudine/3TC as the case may be]. Many avid readers will remember this latter local-vs-systemic question as a driving force justifying the launch and execution of the controversial DISCOVER trial, whose results – one might also now reasonably conclude in light of this newer data – also support and advance the supposition of systemic TDF/TAF PrEP protection put forth in the newer data.)

Evidence from Animals?

A few among the bold have taken to citing the limited-but-helpful role that relevant animal data can play where gaps exist otherwise; in this case, F-TAF-based event-driven PrEP efficacy data among macaques. The study actually involved a series of comparisons among variously-timed F-TAF PrEP- and PEP regimes, with- and without the addition of bictegravir (BIC). The relevant regime among them – intermittent F-TAF administered 2h prior to viral exposure and then again 24h post exposure – demonstrated significant protection in the rectal exposure model. The findings also referenced and echoed earlier F-TDF intermittent PrEP animal data that paved the way for IPREX and IPERGAY as well as other animal data that led to DISCOVER, which might explain in part how it started popping up in related discussions online.

(“Figure 1. Study-1: emtricitabine/tenofovir alafenamide (FTC/TAF) and FTC/TAF + 25 mg bictegravir (BIC) two-dose.” from Bekerman et al, 2020, Two-dose emtricitabine/tenofovir alafenamide plus bictegravir prophylaxis protects macaques against SHIV infection)

The Proof is in … Well, the Proof?

Ever since Gilead first introduced the world to DISCOVER trial F-TAF oral PrEP data in early 2019 with “Compared to TDF, tenofovir alafenamide (TAF) has higher intracellular tenofovir (TFV)-DP levels, lower plasma TFV levels, and improved renal and bone safety when used for HIV treatment,” it’s been putting its resources behind positioning Descovy as the new-and-improved replacement for Truvada for PrEP (much like its Apple-self-cannibalizing strategy for its updated treatment products). The stunning DISCOVER trial results sure seemed to capture the imagination too.

(DISCOVER trial HIV incidence)

(DISCOVER trial bone- and renal safety outcomes graphs)

Among the trial’s roughly 5,400 matriculating participants (larger than any other PrEP trial to date), there were only 22 total seroconversions, 15 in the F-TDF arm and seven in the F-TAF arm (“53% reduction in HIV incidence for Descovy over Truvada” the company pointed out several times in its filing with the FDA). What’s more, the trial uncovered markedly improved bone- and renal safety outcomes in the F-TAF arm, all while delivering similar outcomes generally on side effects and adverse events. [Though it’s worth pointing out that Descovy was associated with weight gain and higher lipids/cholesterol in the trial, perhaps, perversely another reason why a sparing approach to dosing would be attractive to some consumers.] Such outcomes in safety and efficacy – especially given the pharmacological differences between the two forms of Tenofovir – underline not only how easily Descovy has found its way into the “superior” position in the minds of some consumers but also how easily they could make the logical leap from “superior product” to “effective even if untested.”

A ‘Superior’ Product?

“In the results presented at CROI there had been seven HIV infections in the Descovy arm and 15 in the Truvada arm. Since then, one more infection was seen in participants taking Descovy… this means that there were 46% fewer infections in the Descovy arm… [T]he 95% confidence interval of the study (its “fuzziness”) means that if one were to rerun the study 20 times, random effects would mean that the result could have turned out to be anything between 77% fewer infections on Descovy to 26% fewer on Truvada. So we can’t say Descovy has superior effectiveness as PrEP, though there is a trend in that direction [emphasis added].”

Gus Cairns in “96-week results of DISCOVER PrEP trial presented at European AIDS Conference,” 11/4/19, AIDSMap

The US NIAID Division of AIDS Director Carl Dieffenbach summarized those preliminary results with the “superiority” slip of tongue; “What we saw in the study was superior safety data from the use of TAF, but also a surprisingly small number of HIV infections as you’d expect because Truvada is pretty powerful as PrEP. TAF was superior … proven non-inferior to the standard. So, it’s looking good.”

(Dr. Carl Dieffenbach and Anne Rancourt in “Promising New PrEP Findings and More: Dr. Dieffenbach’s HIV Research Highlights from Day 3 of CROI 2019,” 3/7/2019, min.-mark 1:33)

In seizing on the fewer infections in the F-TAF arm of the trial, VOICE trial lead investigator Jeanne Marrazzo tweeted out from CROI 2019 “Eagerly awaited results of DISCOVERY [sic] trial demonstrates F/TAF nearly reached superiority over F/TDF as PrEP in MSM/TGW…”

(Marrazzo DISCOVER trial tweet)

Gilead’s own Mike Elliot even got in on the Descovy-‘superiority’-same-sentence hyping tease action, telling the UK’s Gay Star News that week “It didn’t get to that superiority (over Truvada) but showed very good efficacy and numerically fewer transmissions than Truvada…And then there are those important measures on renal and bone…improved renal and bone safety.”

(The connotative effect of all this repeated positioning of the words ‘Descovy’ and ‘superior’ or ‘superiority’ [and ‘safe/safety’] so closely in communication, almost certainly, is not lost on any marketing professional worth their salt, regardless of the meaning of sentences uttered therein.)

THE LIMITATIONS (DATA/GUIDANCE GAPS)

No Good Data

Despite the encouraging inferential animal data, pharmacological data, trial data, and related fanfare, there are still data gaps as well as some pharmacological data that has given experts pause as to whether or not F-TDF could reach sufficiently protective levels in rectal tissues (or other local vulnerable tissues) when administered in an on-demand fashion like the 2-1-1 approach.

To repeat IPERGAY trial lead Jean-Michel Molina yet again, there just isn’t any clinical efficacy data on TAF-based 2-1-1 oral PrEP like there is with TDF-based 2-1-1 oral PrEP (IPERGAY, IPERGAY OLE, AmPrEP, the San Francisco study, PREVENIR, etc.). Indeed, it’s not at all clear:

• who would be doing that clinical research,
• with what demographic population, or even
• where F-TAF nondaily PrEP would be studied.

Nor are there any such completed/ongoing/pending HIV-related F-TAF-based intermittent prophylaxis clinical studies in the pipeline if you go by the recent listings in the US’ database of clinical trials. Indeed, it’s hard to overemphasize how big a limitation the lack of clinical efficacy data is for those intrepid few forging ahead on deploying F-TAF for 2-1-1.

Puzzling PK Data

And if that weren’t enough, the animal challenge trial data that informed the DISCOVER F-TAF PrEP trial had the curious finding of lower rectal mucosal drug levels than F-TDF PrEP. The finding was echoed in preliminary human pharmacological data among both HIV positive- and HIV negative human subjects. It raised the question anew of the systemic-vs-local protection Tenofovir-based PrEP provides via drug levels in rectal-, vaginal-, and penile tissues (usually the 1st contact points of HIV in the body) vs lymphatic cells/tissues and other related blood cells (the systems wherein HIV travels, lodges itself, hides, and replicates). The question and concern formed the basis of warnings from Robert Grant against premature deployment of F-TAF daily PrEP (warnings not unlike those of Molina later concerning 211 F-TAF PrEP) as Grant justified and embarked upon the (ultimately successful) DISCOVER trial.

No Guidance

Moreover, if those data gaps and inconsistencies weren’t enough, then further pause might be provided by the fact that no national- or international health authority has endorsed, recommended, or provided guidance for F-TAF 2-1-1 oral PrEP dosing: US Centers for Disease Control’s (CDC) 2021 PrEP recommendations

• Not the San Francisco AIDS Foundation’s (SFAF) San-Fran-did-intermittent-PrEP-1st-on-US-soil-and-coined-the-term-2-1-1-PrEP 2019 Pre Exposure Prophylaxis Health Program Magnet Clinical Protocol,
• Not the World Health Organization’s (WHO) 2-1-1-PrEP-specific 2019 Technical Update or even its hot-off-the-presses 2021 Updated HIV prevention, infant diagnosis, antiretroviral initiation and monitoring 2021 recommendations,
• Not the International Antiviral Society–USA’s (IAS-USA) 1st-in-America 2-1-1 PrEP-inclusive 2020 Recommendations for Antiretroviral Drugs for HIV Treatment and Infection Prevention,
• Not the European AIDS Clinical Society’s (EACS) HIV treatment/prevention 2020 guidelines,
• Not the vanguard-on-continent, South Africa’s 2020 recommendations.
• Not France’s latest glossy, popular AIDES 2021 PrEP 2-1-1 guide, and
• Not even the long-awaited US Centers for Disease Control’s (CDC) 2021 PrEP recommendations.

Thus, without convincing F-TAF 2-1-1 PrEP-specific preclinical- and clinical data and/or even said institutional guidance, some intrepid health care providers and consumers can only be described as getting ‘out over their skis’ with this innovation.

CONCLUSION

TL:DR

In the final analysis, we just can’t say for sure quite yet whether or not Descovy is effective with the 2-1-1-/event-based-/event-driven-/intermittent-/on-demand-/IPERGAY dosing protocol. This is because – even though there is some encouraging circumstantial evidence – we’ve seen no published large-scale clinical safety/efficacy data so far on oral F-TAF-PrEP 2-1-1 dosing. Hence, despite encouraging PK data suggesting F-TAF could allow for PrEP 211 dosing and or at least more forgiving daily dosing, the F-TAF daily oral PrEP FDA approval last year was limited, and such premature 2-1-1 F-TAF PrEP use otherwise has been prominently discouraged by the 2-1-1 expert.

Simple Solution: Study it?

The current COVID-19 pandemic underlines the need for rigorous scientific data upon which to base our public health decisions (though, ironically, it has also interrupted HIV treatment- and prevention research). Accordingly, the simple solution would be just to do a double-blind, randomized, head-to-head- or placebo-controlled clinical trial in order to answer the question of F-TAF 2-1-1 PrEP dosing efficacy.

However, given Gilead’s initial legal hesitance toward any TDF-based oral PrEP and the company’s articulated financial rationale against seeking approval for F-TDF 2-1-1 PrEP, it may never pursue study/approval of Descovy 211 PrEP. Indeed, it doesn’t take a stretch of the imagination to see that tighter dosing margins of error could be perceived by the company as opening it up once again to legal liability if seroconversion occurs “in the wild.” Similarly, the option of less TAF used per-consumer could be perceived as cutting into company profits.

Victim of PrEP’s Success?

Furthermore, another reason we may never get data to definitively answer this question is the complicated nature of completing PrEP trials in a clinical research landscape that includes safe-and-highly-effective TDF-based oral PrEP as part of the standard of care for trial participants. In other words, the more effective tools we have for preventing HIV, the more of these tools must be offered to future prevention trial participants to meet ethical standards. Also, the more effective these tools, the more future trial participants and/or time needed to meet statistical requirements for definitive trial outcomes.

Beyond that trial-design hurdle, getting funding from federal sources for this kind of research would be a long shot in a crowded pipeline under shifting research priorities. For instance, paradigm-shifting “Biomedical Prevention Era” developments including “PrEP 2.0” technologies LAI CAB, the DapiviRing, and AMP exiting the research/development pipeline recently, plus game-changing “PrEP 2.0” Phase III ISL (MK-8591) PrEP monthly oral pill trials along with the Phase II PrEPVacc and Phase III MOSAICO HIV vaccine trials having already crowded into that same pipeline. Such advancements and potential advancement as research funding competitors make it hard to justify such a relatively retrograde and niche technology as F-TAF 211 oral PrEP for cisMSM only. This is especially true in the face of NIH funding shifts away from including locally active PrEP technologies (gels, inserts, douches, suppositories, etc.) and toward only supporting systemic PrEP agents (pills, injections, implants, etc.).

A Glimmer of (Research) Hope?

Given this lacking information and funding, you might be as fascinated as I was to find a tantalizingly opaque assurance communicated by the San Francisco AIDS Foundation (SFAF) that there is some such TAF-based 2-1-1 oral PrEP research already underway…. At least if you believe SFAF’s recent rundown on TAF/FTC vs TDF/FTC oral PrEP.

(Resource: Side-by-side comparison: Truvada and Descovy for PrEP, San Francisco AIDS Foundation,” Medical review by Janessa Broussard, NP, November 2019)

(I had reached out to the SFAF to learn more about its posted “Descovy for PrEP 2-1-1 … being studied,” but, sadly, was given no such information. However, I’d encourage anyone else similarly-interested to reach out to SFAF as well about its “Resource: Side-by-side comparison: Truvada and Descovy for PrEP, San Francisco AIDS Foundation,” Medical review by Janessa Broussard, NP, November 2019, Prep@sfaf.org, https://www.sfaf.org/contact/https://www.sfaf.org/contact/.)

Final Words of Wisdom

In all honesty, the repeated posing of this question about TAF-based 2-1-1 oral PrEP should itself be taken as a market demand signal. In fact, actual use has even already been documented among trans men. As such, some may call this whole conversation one of irresponsible messaging. However, since we may never have the necessary data to answer the question definitively, we would do best to take a harm reductionist’s approach while integrating a shared decision-making model. That means being honest about what we do and don’t know in order to support patients own deliberations. That reminds me of the advice Bob Grant gave when discussing how to help patients navigate the tricky issue of sex planning and how long till protective drug levels; “ … In our effort to do no harm and be conservative, we may end up doing harm. And so, I think in the end, we’re better off just focusing on what we know, what we don’t know, and being very curious about what our patients are really asking [minute-mark 78;54].”

Now, this doesn’t mean that, in the case of F-TAF 2-1-1 oral PrEP, we follow in the footsteps just yet of maverick medical pros like Marcus Conant, Mike Youle, and Pietro Vernazzo when they prescribed TDF-PrEP off-label over a decade ago. However, it does mean we acknowledge that we know TAF produces higher drug levels than TDF in some places (but not others) and that it does also work as one component of a daily PrEP combo pill (for some populations). We don’t know if that translates to the same outcomes for 2-1-1 F-TAF oral PrEP, nor is that currently recommended.

Thus, it’s your-body-your-choice when it comes to how you protect yourself, but the ole caveat emptor is definitely in order that Descovy users who deploy it for 2-1-1 are doing so at their own (calculated) risk. So, it’s always a good idea to consult with your care provider and consider the relevant facts before you decide on the HIV prevention approach or approaches that work best for you.

PrEP in Pop Culture: Memorials

8/9/21 (Author’s note, contact, and the rest of this PrEP pop culture series.)

Among the many people who have participated in the history-making that is PrEP, some themselves, sadly, now, are also history. Some of these dearly departed contributors are listed below in order of last name, with brief contribution explanations and approximate death notice dates. So, let’s take a moment to acknowledge their contributions to what is known as PrEP in the popular imagination and to mourn their untimely passings.

Timothy Ray Brown 9/29/20 PREP- and HIV treatment/cure advocate (1st person cured of HIV)

Timothy Ray Brown (courtesy of Getty Images via BBC News)

Brad Crelia 11/19/14 Early/active PrEP Facts Facebook group member and HIV writing advocate

Brad Crelia (courtesy of Poz.Com)

Geoff Honnor 6/23/20 ACON former Director of HIV & Sexual Health who helped launch Australia’s “Ending HIV” campaign and adoption of biomedical prevention

Geoff Honnor (courtesy of the Kirby Institute)

Bonus Makanani 8/6/21 groundbreaking PrEP Dapivirine Ring / Truvada pregnancy researcher

Bonus Makanani (courtesy of the Microbicide Trials Network)

J Jeff McConnell 1/25/14 IPREX Investigator and inspiration for PrEP Facts Facebook group

J Jeff McConnell (courtesy of AVAC)

Noel Offer 7/9/19 owner of generics (including PrEP) online international import pharmacy Green Cross

Noel Offer (courtesy of Facebook)

Mags Portman 2/6/19 pioneering British PrEP renegade care provider/campaigner

Mags Portman (courtesy of The Economist)

Paul Duncan Quick 11/3/18 HIV advocate and avid PrEP Facts participant

Paul Duncan Quick (courtesy of Facebook)

Gita Ramjee 3/31/2020 dedicated women’s PrEP Tenofovir gel researcher

Gita Ramjee (courtesy of University of Sunderland via The Lancet)

Zena Stein 11/7/21 pioneering 1990s advocate of PrEP rings as “HIV Prevention… Methods Women Can Use”

Zena Stein (courtesy of the British Medical Journal)

Mark Wainberg 4/11/17 creator of 3TC (forerunner to PrEP agent FTC) and seminal PrEP concept research author 2001 / 2003 / 2003

Mark Wainberg (courtesy of NEJM Journal Watch)

When can we expect long-acting injectable Cabotegravir PrEP approval?

5/6/2021, Author’s note, contact

12/20/21 Update: Under the brand name “Apretude,” U. S. Food and Drug Administration approved long-acting, injectable Cabotegravir PrEP for adults and adolescents 35kg (77lbs) at risk of acquiring HIV. The approval actually happened a month ahead of schedule. Approvals in several other countries are now under consideration.

Introductory TL:DR

Long-acting, injectable Cabotegravir (LAI CAB) PrEP’s approval date is a good question and a fairly frequently asked one these days too. Indeed, many of us share that interest and impatience. In countries where LAI CAB PrEP trials HPTN 083 and HPTN 084 were launched and are ongoing, we should begin seeing LAI CAB PrEP approvals for all populations as soon as this coming winter hits the Northern Hemisphere …Target date January 23, 2022 in America as of the 9/28/21 US FDA Priority Review Application granting (given the good trial data, ViiV Healthcare’s recent approval plan timeline articulation, the resolution of manufacturing issues, recent LAI CAB-based treatment approvals, and their recent LAI CAB PrEP approval application submission strategy successes). [See video transcript excerpt at bottom of this page as postscript.]

LAI CAB PREP TRIAL DATA

This all started accelerating to our projected Winter 2021/2022 approval date event back in Spring and Fall 2020, when, respectively, HPTN 083 and 084 unexpectedly reported data demonstrating positive results for LAI CAB PrEP trials including cisgender man, transgender women, and cisgender women, all who have sex with men. In mid-May 2020, the US National Institutes of Health (NIH) announced preliminary HPTN 083 findings that:

“…the HIV drug cabotegravir injected once every 8 weeks safely and effectively prevents HIV acquisition in men who have sex with men and transgender women who have sex with men. This finding, from a planned interim analysis of study data, marks the first time a large-scale clinical trial has shown a systemic, long-acting form of HIV prevention to be highly effective…Among the 50 people in the trial who acquired HIV, 12 were receiving long-acting cabotegravir and 38 were receiving daily oral Truvada. This translated to an HIV incidence rate of 0.38% (95% confidence interval [CI] 0.20%-0.66%) in the cabotegravir group and 1.21% (95% CI 0.86%-1.66%) in the Truvada group…Consequently, the DSMB recommended that NIAID stop the blinded phase of the trial, which was originally expected to continue until 2021, and share the results…”

This great news was soon followed up with a similarly astonishing NIH announcement about HPTN 084 findings among cisgender African women in early November 2020:

“…In a planned interim review meeting on Nov. 5, 2020, the independent data and safety monitoring board (DSMB) for HPTN 084 found that the study data indicated that long-acting injectable cabotegravir [once every eight weeks] had superior efficacy to Truvada at preventing HIV in the study population. Among the 38 women in the trial who acquired HIV, four were receiving long-acting cabotegravir and 34 were receiving daily oral Truvada. This translated to an HIV incidence rate of 0.21% (95% confidence interval [CI] 0.06%-0.54%) in the cabotegravir group and 1.79% (95% CI 1.24%-2.51%) in the Truvada group. While both PrEP methods were highly effective at preventing HIV acquisition, the protective effect of cabotegravir met the statistical criteria for superiority (hazard ratio, 0.11; 95% CI 0.04-0.32). Both cabotegravir and Truvada were well-tolerated among women in the study, and the DSMB found no safety concerns…Based on their review, the DSMB recommended that NIAID stop the blinded phase of the trial, originally designed to continue until 2022, and share the results…”

APPROVAL TIMELINE/PREDICTION

With those sets of discoveries, announced months and years ahead of schedule, ViiV Healthcare was off to the races. The company’s Kimberly Smith, in early November 2020, immediately thereafter revealed that the best estimate for approval would be just in time for the winter holiday season in late 2021 with store shelf-stocking and sales starting in early 2022. She came up with an approximate timeline on PrEP injectables’ availability to the public that included 6 months for first completing the U. S. Food and Drug Administration (FDA) approval application (further data collection, -quality control, -crunching, and -collation, along with paperwork, Ps-n-Qs on the legal end, presentation preparation, and any public relations full court press, etc.) and then about 6 more months for the application’s analysis by authorities (biding our time before the FDA’s Byzantine and bureaucratic balancing, balloting, and business back-n-forth). The company would have also had to add about 4 months to that if the application hadn’t gotten get the ole paradigm-shifting FDA November 2020 priority fast-tracking status razzle dazzle (which was followed by a further granting of Priority Review on September 28, 2021). In total, that could have meant anywhere from 12 to 16 months from November 2020 without the fast-tracking. [See video transcript excerpt at bottom of this page as postscript.]

MANUFACTURING ISSUE RESOLUTION

Meanwhile, US manufacturing scale-up issues delayed Cabenuva’s FDA treatment approval in late 2019. These LAI CAB manufacturing issues have also lead to insufficient supplies for unblinded LAI CAB PrEP access in HPTN 083/084 for trial participants who hadn’t already been getting LAI CAB PrEP due to being randomized to the active control arm of placebo LAI CAB + real daily oral FTDF PrEP.

However, the US LAI CAB treatment application was put back on track and succeeded two months ahead of the March 2021 outside prediction, thus paving the way for long-acting injectable Cabotegravir-based treatment approvals.

INTERNATIONAL TREATMENT APPROVALS

In fact, if the injectable Cabotegravir-for-HIV-treatment approvals below are any indication, it’s only a matter of (a short but more) time.

For instance, Health Canada approved injectable Cabenuva™️ (CAB+Rilpivirine/RPV) for treatment in late March 2020 with widespread access via public benefits programs following in mid-September 2020, followed by European Commission authorization in late December 2020, and U.S. Food and Drug Administration approval in late January 2021.

In particular, the European Medicines Agency recommended in mid-October 2020 the granting of marketing authorisation for long-acting, injectable Rekambys™️ (RPV) and Vocabria™️ (CAB) for treatment to be sold together there, which paved the way for that European Commission approval in late December 2020 followed by individual EU member state pricing and reimbursement formulations thereafter.

The US finally followed suit through the FDA in late January 2021.

LAI CAB PREP APPROVAL STRATEGY SUCCESSES

Buoyed by these positive LAI CAB PrEP trial results and LAI CAB treatment approval successes, ViiV Healthcare took the bold step of applying for Breakthrough Therapy Designation status with the FDA. The request was granted in mid-November 2020. And, by early May 2021, the company had announced it was initiating a rolling submissions approach (instead of waiting until every single component of the application was completed) for it LAI CAB PrEP application to the FDA in order streamline the process even further. The latest strategic advancement includes a September 28th 2021 Priority Review Application grating that gives the company a target date of January 24th 2022 for its US approval decision.

Subsequently, ViiV Healthcare plans to begin filings with global regulatory authorities by the end of this year with its first such local filings elsewhere in-country where HPTN 083 and HPTN 084 are currently wrapping up.

CONCLUSION

All of those recent developments – the robust LAI CAB PrEP data from HPTNs 083/084, the company’s articulated approval timeline plan/prediction, manufacturing process improvements, the growing slew of LAI CAB treatment approvals (Canada, Europe, the US), and the company’s LAI CAB PerEP application strategy success – bode well for LAI CAB PrEP approvals starting in January 2022 … If not a 2021 holiday early surprise before then 😉. (While Poz Magazine’s Liz Highleyman also pegs the approval at late 2021, as recently as April 2021, AVAC’s betting money was on earliest expected approvals starting in 2022.)

In fact, we’re finally even starting to see US and European LAI CAB treatment retail price guesses of $4000/mo and $4000/yr respectively too now with PrEP shot prices being pegged around those of branded oral TAF/FTC and/or TDF/FTC on different countries’ respective public benefit schemes (PBS).

Time will tell.

*********

POSTSCRIPT – TRANSCRIPT EXERPT

HPTN 084 Study Update Press Briefing, HIV Prevention Trials Network, 11/9/2020

19:04 KIMBERLY SMITH: “…Our intention is to file beginning in the first half of 2020. We’ll begin with a filing to the FDA and move on to other regulatory agencies around the world, and it is our intention that we will include data from both 083 and 084. And so that the indication for Cabotegravir for PrEP would include really all populations, men (19:29) and women, both trans and cisgender [emphasis added].

So we have a real ambition to make this drug very widely available to those who are vulnerable and may benefit from it…

[The time frame] is still a bit up in the air (20:00), but I can tell you the best estimate. So, if we are able to get the submission done within the first half of 2021, the review period for the FDA typically would be 10 months. However, if it is given a priority review, it could be reduced to six months. And so, if that’s the case, we could see an approval as early as the end of 2021, and then we would intend to make the product available (20:30) beginning in early 2022. Now, that’s just starting with the FDA, other regulatory agencies would typically follow, and their timelines tend to be a bit longer, but this is still in the works.”

PrEP in Pop Culture: A Lexicon of Vocabulary, Jargon, Slang, and Neologisms

2/10/21 (Author’s note, contact, and the rest of this PrEP pop culture series.)

INTRODUCTION

Perhaps you’ve heard references to people being “on PrEP” (Pre-Exposure Prophylaxis) or “on Truvada” for HIV prevention. Maybe you’ve heard someone use slang like they were “on The Pill,” “on The Other Pill,” “on The Other Blue Pill,” or “taking [their] Daily Blue.”

I’ve run into the term “PrEPception” to describe the wonders of magnet couples conceiving children with the help of PrEP and it made me wonder “What are some of the other ways that PrEP (and TasP [Treatment as Prevention]) have expanded our lexicon?” I also knew about “Truvadawhore,” “PrEPWarrior,” and “biomed-sorting” but I was curious what else is out there.

So, out of curiosity, I started collecting the terms that bubbled up in my time “watching over the wire,” so to speak, of PrEP-specific and PrEP-adjacent conversations online. After more actively starting to seek out such neologisms, I stumbled upon some scholarship documenting the role such cultural “key terms” could play in being harnessed to track-the-trends, so to speak, on social media (Twitter to be more specific) in the form of PrEP awareness, expressed opinions, perceived barriers and key discussion points on its adoption. (I even gave myself a few partial credits for helping popularize the term DapiviRing and for helping uncover the origins behind another, Ts and Ss PrEPping.)

Thus, for my latest fun PrEP pop culture pet, I decided to enumerate some of those neologisms in a so-called “PrEP Lexicon” made possible by the advent of biomedical HIV prevention. Indeed, the exuberance and euphoria with which denizens of PrEP (and TasP) approach communicating about their beloved biomedical barriers has fueled, fostered, and facilitated their luxuriant launch into the linguistic liberties catalogued, documented, and detailed herein. (It’s almost as if some even threw terms at the wall just to see which would stick or resonate, but that’s part of the fun of watching these linguistic trends.) In the entries below, you’ll find an alphabetized lexicon of some of the latest new terms of the “Golden Age of Biomedical (HIV) Prevention” that we’re currently in. Where possible, each entry includes the new term, its part of speech, its meaning, the when-where-who-what of the earliest usage I could find, and a “see also” suggestion of related terms.

A few last caveats though, there are definitely more of these terms out there, more are created all the time, and their coinages in some cases may be different than I’ve attributed them (with earlier/different progenitors). (A future PrEP Pop Culture series blog entry will also be dedicated specifically to the related phenomenon of PrEP hashtags.) So, do feel free to let me know if I’m missing or mischaracterizing any terms/definitions, credits, earlier dates, etc. Additionally, this is a work in progress, so be aware that it will be updated periodically.

Hope to hear from you as I take on the terms.

ENUMERATION

211 PrEP dosing

• Part of Speech – noun
• Definition – an Americanized rebranding of the French non-daily, oral, TDF-based PrEP dosing strategy for anal sex among cisgender men that instructs users to take a loading dose of two pills of TDF-FTC with food 2 to 24 hours before sex, followed by a third pill 24 hours after the first drug intake and a fourth pill 24 hours later (or one pill daily if sex continues and then then a post-sex pill 24hrs then 48hrs after last possible HIV exposure during sex). The strategy was validated in the IPERGAY trial (thus, another name sometimes used is “IPERGAY dosing”).
• Context of Earliest Usage – Though the San Francisco Magnet clinic was piloting a visual branding of this handy slang using MEMS cap technology in 2017 (since 2-1-1 imbeds the dosing directions in the name itself), 2018 is the first time the term seems to have appeared in public. ““On-demand” PrEP—also known as PrEP 2-1-1—is an alternative method of dosing that may speak to these concerns, making PrEP an option for more people than ever before. PrEP 2-1-1 is named for its schedule of dosing: 2 pills are taken 2-24 hours before sex, 1 pill 24 hours after the initial dose, and one final dose 24 hours later (find more info about this strategy). Clinicians only recommend PrEP 2-1-1 for people having anal sex, since the drug may not be present in levels high enough with PrEP 211 dosing to protect vaginal tissues.” (Emily Land of SFAF, “For people having anal sex, PrEP 2-1-1 is effective at preventing HIV,” 12/19/18)
• See Also – event-based dosing, IPERGAY dosing, non-daily dosing, on-demand dosing

active arm

• Part of Speech – noun
• Definition – a group in any clinical research context where participants are put together and all receive “something,” in other words either all given the same experimental treatment or the same proven treatment for comparison. It’s a long-established concept but took on new significance in the so-called “Post-Placebo Era” of biomedical HIV prevention research as oral TDF-based PrEP was proven/validated and became the required standard-of-care for new PrEP research.
• Context of Earliest Usage – “Active arm [of a trial] is the group of participants receiving a proven or experimental strategy. There can be one or more active arms in a trial. There can be an “active control” arm (see below) or an “active experimental arm”. The difference is whether the efficacy of the active strategy is known or not. Outcomes (like rates of HIV or rates of pregnancy) in people in the experimental active arm are compared to outcomes in people in the control arm.” (AVAC’s Px Wire, “An Advocate’s Guide to Research Terms in the Post-Placebo Era,” 5/11/17)
• See Also – active control arm, double-dummy double-blind trial

A placebo-controlled trial with one active arm, two double-dummy double-blind trials both with two active arms, and an open label trial with two active arms (each active arm is circled in red)

active control arm

• Part of Speech – noun
• Definition – the group receiving a proven treatment in a clinical trial in order to compare with a different group receiving an unproven or experimental treatment in order to understand if and/or how well that experimental treatment works. It’s a long-established concept but took on new significance in the so-called “Post-Placebo Era” of biomedical HIV prevention research as oral TDF-based PrEP was proven/validated and became the required standard-of-care for new PrEP research.
• Context of Earliest Usage – “Active control arm [of a trial] is usually a group of trial participants who are receiving a known effective strategy or intervention that participants in the experimental arm are not receiving. For example, in trials of long-acting injectable PrEP, people in the active control arm are receiving daily oral PrEP, a known effective strategy.” (AVAC’s Px Wire, “An Advocate’s Guide to Research Terms in the Post-Placebo Era,” 5/11/17)
• See Also – active arm, double-dummy double-blind trial

Two double-dummy double-blind trials both with a single active control arm, and an open-label trial with a single active control arm (each active control arm is circled in red)

being on The (Other) (Little) Blue Pill

• Part of Speech – adjective
• Definition – a phrase used to describe anyone taking Truvada for HIV prevention while also referencing Viagra, the blue erectile dysfunction pill, as well as related branding/marketing– and illicit sales controversies around sex and pharmaceuticals
• Context of Earliest Usage – “There’s a very big difference between the real world implications of the iPrEx results and the results from the tenofovir vaginal gel study reported earlier this year—the vaginal gel won’t be made available until researchers can confirm its protective effect and work out some of the complications in assessing adherence and rolling it out. Truvada, however, is already approved in most countries around the globe, and provided that a person can score a prescription and pay for it, he or she could start taking that little blue pill today.” (David Evans, “PrEP Works: The Little Blue Pill That Could,” Poz Magazine, 11/23/10) However, the nucleus of the phrase had already been deployed at least as early as 2008 in reference to maraviroc, an antiretroviral licensed by Pfizer, the maker of Viagra, which, ironically, had, itself, also been associated with the very self-same sobriquet at least as early as February 1999, just months after FDA approval.
• See Also – being PrEPared, cum PrEPared, on PrEP, PrEPared, PrEPpie, PrEPster, PrEPtected, taking Truvada

being on The Pill

• Part of Speech – adjective
• Definition – a phrase used, sometimes jokingly, to describe anyone taking Truvada for HIV prevention, sometimes also referencing common controversies associated with oral contraception
• Context of Earliest Usage – (Conversations online stretch back at least as far as 11/14/14 identifying the term as one in a list of many new ways of referring to PrEP users, H/t JA.)
• See Also – being PrEPared, cum PrEPared, on PrEP, PrEPared, PrEPpie, PrEPster, PrEPtected, taking Truvada

being PrEPared

• Part of Speech – adjective
• Definition – a phrase used (often in promotional campaigns) to describe anyone taking Truvada for HIV prevention
• Context of Earliest Usage – (Conversations online stretch back at least as far as 11/14/14 identifying the term as one in a list of many new ways of referring to PrEP users, H/t DM/ZH.)
• See Also – being on The Pill, cum PrEPared, on PrEP, PrEPared, PrEPpie, PrEPster, PrEPtected, taking Truvada

biomed-matching

• Part of Speech – noun
• Definition – the HIV transmission risk reduction practice where, akin to serosorting, a person using TasP or PrEP chooses to have sex exclusively with or primarily with other TasP– and/or PrEP-using sexual partners
• Context of Earliest Usage – “Finally, some MSM [men who have sex with men] reported a novel seroadaptive behavior, which we call “biomed-matching,” and is indicated by endorsement of “I also have an UVL [undetectable viral load]” or “I am also on PrEP.” These MSM reported they had CAS [condomless anal sex] because both they and their partners were using a biomedical prevention strategy (either PrEP or UVL), thus substantially reducing transmission risk.” (Newcomb et al, Epidemiology and Prevention Journal, 7/9/2015)
• See Also – biomed-sorting, bio-sorting, pharmasorting

biomed-sorting

• Part of Speech – noun
• Definition – the HIV transmission risk reduction practice where, akin to serosorting, a person chooses to have sec exclusively or primarily with TasP– and/or PrEP-using sexual partners regardless of their own corporal biomedical HIV prevention usage
• Context of Earliest Usage – “Whereas “biomed sorting” (a term that we do not believe has yet been used in the literature) more broadly describes individuals who seek out partners who are using a biomedical strategy, regardless of whether that strategy is PrEP or TasP (i.e., men on PrEP having sex with partners on PrEP or virally suppressed HIV-positive men, and vice versa).⁴⁸ In contrast to biomed matching, one can biomed sort without using a biomedical strategy themselves (i.e., someone not on PrEP seeking out partners who are on PrEP or using TasP).” (Grov et al, AIDS Behavior Journal, 8/1/2018, also H/t to MM/AB for 6/29/15 mention in PrEP-neologisms conversations online)
• See Also – biomed-matching, bio-sorting, pharmasorting

bio-sorting

• Part of Speech – noun
• Definition – the practice of choosing to have sex with only partners who disclose that they are Undetectable or on PrEP
• Context of Earliest Usage – “How “Bio-Sorting” on Gay Hook-Up Apps Is Leading to Condomless Sex…Gay men who hook up for sex on mobile apps are discussing biomedical prevention methods with their partners, and some are then going at it without a condom, a new study shows.” (David Heitz, HIVEqual.Org, 9/25/15, also H/t to MM/AB for 6/29/15 mention in PrEP-neologisms conversations online)
• See Also – biomed-matching, biomed-sorting, pharmasorting

blinded trial

• Part of Speech – noun
• Definition – a trial where the facts of which participants are in the experimental treatment group vs. which participants are in the control group are hidden from trial participants themselves and from researchers conducting the trial so as not to influence their behavior in a way that might conflict with measuring the true effect of the experimental treatment during the trial (the term is an established one, but has taken on new and specific relevance as the validation/proof of TDF-based oral PrEP has fostered the “Post-Placebo Era” in PrEP trials)
• Context of Usage – “Blinded trials are ones in which the participants don’t know what they are receiving. A double-blinded trial is one in which neither the participants nor the trial team know which participants are receiving the experimental product and which ones are receiving something else—either a placebo or another product. Blinding protects against bias. If participants or trial staff know who is getting the active experimental product they might act differently. Participants who know they got the experimental product might take more risks if they believe the experimental product provides protection; people who got the placebo might use more condoms.” (AVAC, 5/11/17)
• See Also – double-dummy double-blind trial, Post-Placebo Era

A placebo-controlled trial and two double-dummy double-blind trials that are all blinded trials (each active control arm circled in red)

CAB LA (pronounced “cab L-A”)

• Part of Speech – noun
• Definition – an acronym used to refer to Cabotegravir Long-Acting or long-acting injectable cabotegravir, an intramuscular antiretroviral technology used for combination HIV treatment as well as for the 3rd and most recently validated (2020) PrEP agent/modality after 1st TDF-based oral PrEP (2011) and 2nd Dapivirine-based vaginal rings (2016)
• Context of Earliest Usage – “Brief Summary: This study will evaluate the safety and efficacy of the injectable drug cabotegravir (CAB LA), for pre-exposure prophylaxis (PrEP) in HIV-uninfected cisgender men and transgender women who have sex with men (MSM and TGW).” (ClinicalTrials.gov, 3/21/16)
• See Also – LAI CAB

capoteur/capoteuse (pronounced kah-po-TUR [masculine] or kah-po-TUZ [feminine])

• Part of Speech – noun
• Definition – a French term identifying people based on their exclusive or primary reliance on condoms for HIV prevention, it comes from the word ‘capote’ which means hood, cap, or hat and is used colloquially for condom or prophylactic
• Context of Earliest Usage – “Les enquêté·e·s nous ont rapporté que certaines applications de rencontre (qui ciblent majoritairement un public gay) donnent la possibilité de renseigner sur son profil personnel, si on est prepeur·se, taspeur·se ou capoteur·se. [GOOGLE-ASSISTED TRANSLATION: The respondents told us that certain dating apps (targeting a gay audience mainly) offer the possibility of providing information on their personal profile with identifiers including PrEPer, TasPer, or capoteur•se.” (Ahmed et al, Normalisation de la PrEP, confiance et moralisme., 6/13/17)
• See Also –

control arm

• Part of Speech – noun
• Definition – the group of participants in a trial who are given an already proven treatment or a placebo for the purpose of comparison with those in the experimental treatment group, who are given the untested agent or procedure that is the focus of the trial (the term is an established one, but it has taken on new and specific relevance as the validation/proof of TDF-based oral PrEP has fostered the “Post-Placebo Era” in PrEP trials)
• Context of Usage – “Control arm [of a trial] is the group of participants that are not receiving the experimental product or strategy. This group receives the same prevention package …as the experimental arm.” (AVAC, 5/11/17)
• See Also –

cum dumpster

• Part of Speech – noun
• Definition – a derogatory reference to people who use PrEP and forgo condoms
• Context of Usage – (Conversations online stretch back at least as far as 11/14/14 identifying the term as one in a list of many new words spurred by the advent of PrEP, H/t NEA. However, the term is an established one that has taken on new and specific relevance as validation/proof of TDF-based oral PrEP has fostered the “Era of Biomedical (HIV) Prevention.”)
• See Also –

(I) Cum PrEPared

• Part of Speech – verb
• Definition – to have sex while using PrEP while referencing (“come prepared” pun intended)
• Context of Earliest Usage – (Conversations online stretch back at least as far as 11/14/14 identifying the term as one in a list of many new words spurred by the advent of PrEP, H/t SM. However, as pointed out back then, the cri-de-Gays was already being plastered on tee-shirts.
• See Also –

Disco dosing

• Part of Speech – noun
• Definition – the practice of taking oral TDF or TDF/FTC only around the time of sex rather than daily, the term harkens back to the morphologically and semantically similar term, “disco napping,” which refers to a brief rest before going out dancing and appeared in print at least as early as 1990 in reference to heyday of the Disco Music Era in the 1970s and early 1980s as well as the queer community’s connection thereof, the term could also connote the nondaily or “discontinuous” nature of the dosing practice
• Context of Earliest Usage – “Individuals may also engage in “disco dosing” – taking a pill just before going out for a big evening, and disregarding instructions on daily use, even though the efficacy of irregular use remains unknown.” (AVAC, “Will a Pill a Day Prevent HIV?” 3/1/05) ““I have used tenofovir to protect myself,” Youle tells me over the phone. “I’m not the only HIV doctor in the world who has done that.” Youle says he used condoms when he took the drug, and he’s only done it intermittently, which some researchers have called discontinuous, or “disco,” dosing. He of course knows that PrEP is unproven and that the tenofovir may harm him, but says he has had condoms break, and he knew he was going out for fun. “When you go out for drinks, you leave the car keys at home,” he explains.” (Jon Cohen, “Project T: The Promise of PrEP,” 11/8/19 and 1/22/06)
• See Also –

double-blinded trials

• Part of Speech – noun
• Definition –
• Context of Usage – “However, the term is an established one over the last 60 or so odd years that has taken on new and specific relevance as validation/proof of TDF-based oral PrEP has fostered the “Era of Biomedical (HIV) Prevention.”
• See Also – blinded trial, Post-Placebo Era

double-dummy double-blind trial

• Part of Speech – noun
• Definition – a trial where two active treatment agents are compared head-to-head, but participants in the respective groups groups are a given one active agent and a placebo of the other agent or a placebo of the one agent and an active form of the other agent so no one knows which participant is receiving which agent
• Context of Usage – “Double-dummy double-blind trials are a way to compare two strategies that can’t be made to look identical, without revealing who’s receiving what. Imagine a trial seeking to compare an injection and a pill. They don’t look alike, right? In a double-dummy double-blind trial design, all of the participants would get both a pill and an injection. One group of participants would get an active pill and a dummy injection; the others would get an active injection and a dummy pill. Neither the staff nor the participants would know who had which active strategy.” (AVAC, 5/11/17) However, the term is an established one over the last 60 or so odd years that has taken on new and specific relevance as validation/proof of TDF-based oral PrEP has fostered the “Era of Biomedical (HIV) Prevention.”
• See Also – blinded trial, Post-Placebo Era

dummy (pill)

• Part of Speech – noun
• Definition – a synonym for a placebo treatment, often used in the context of double-dummy double-blind trials
• Context of Earliest Usage – “Dummys are the same thing as placebos. A dummy version of an experimental product looks exactly like that product (e.g., vaccine, injection, infusion, pill or ring) except that it doesn’t have any active ingredient. Examples include a sugar pill or a saline injection or a ring without any drug inside it.” (AVAC, 5/11/17) However, the term is an established one over the last 60 or so odd years that has taken on new and specific relevance as validation/proof of TDF-based oral PrEP has fostered the “Era of Biomedical (HIV) Prevention.”
• See Also –

Episodic/Epi-PrEP

• Part of Speech – noun
• Definition –
• Context of Earliest Usage – “Detailed Description: This proposed study is designed to investigate the acceptability, perceived need and uptake of short-term episodic Pre-Exposure Prophylaxis for HIV prevention among men who have sex with men (MSM). Long-term PrEP may be unnecessary for the many HIV-uninfected men who have episodic contextually defined high-risk periods, particularly when away from their home setting. Alternative dosing strategies, such as short-term fixed-interval episodic PrEP (Epi-PrEP), may be a more realistic, feasible, acceptable, and useful option with high public health impact for the majority of MSM. The overall objective is to determine the feasibility of a clinic-based Epi-PrEP implementation pilot project for 50 MSM (25/each of the 2 study sites) who report occasional condomless sex and who anticipate a period of high-risk while away from home (e.g. vacation) during the study period.” (ClinicalTrials.Gov, “Feasibility of Short-Term PrEP Uptake for MSM With Episodic High-Risk for HIV,” 7/10/15)
• See Also – Periodic dosing, Holiday PrEP

Era of Biomedical Prevention

• Part of Speech – noun
• Definition – a label to describe the current time period where HIV prevention technology now includes safe, effective medicines (antiretrovirals) and corresponding, complimentary medicine delivery devices (pills, injections, rings, etc.)
• Context of Earliest Usage – “Given the number of complex issues related to HIV transmission prevention in this new era of combination prevention options, it is important to identify the kinds of information and support that could assist YBMSM in making the best sexual health decisions for their individual needs over time.³³ While PrEP is a novel tool that can be useful for HIV prevention, it is important to bear in mind that we now have a larger toolbox that still contains other useful biomedical, structural, and behavioral tools. In addition, it is important to ensure that people are using the right tool for them. When we asked YBMSM about PrEP, their conversations inevitably included their thoughts about PrEP in relation to other prevention tools such as condoms and partner selection. Therefore, our purpose in this article is to explore their thoughts about PrEP use in the context of the larger toolbox for HIV prevention that will be increasingly available nationally and globally.” (Mutchler et al, 2015, Getting PrEPared for HIV Prevention Navigation: Young Black Gay Men Talk About HIV Prevention in the Biomedical Era, Journal of AIDS Patient Care STDS. 2015 Sep; 29(9): 490-502)
• See Also –

Era of Biomedical Prevention

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Era of oral PrEP

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Era of oral PrEP

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Era of PrEP

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

event-based dosing

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

EVENT‐BASED DOSING

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Golden Age of Biomedical Prevention (on text for definition)

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Golden Age of Biomedical Research

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Golden Age of Biomedical Research

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Golden Age of Biomedical Research

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Golden age of HIV Prevention

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

HIV Prevention Trial Lexicon

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

holiday PrEP

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

holiday PrEP

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Holiday prep (vacation prep, epi-prep)

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

intermittent dosing

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

IPERGAY dosing

• Part of Speech – noun
• Definition –
• Context of Earliest Usage – “Jean-Michel Molina concluded his talk with an important clarification: “Clearly the effectiveness of the IPERGAY dosing strategy in people having frequent sex taking multiple pills cannot yet be extrapolated to people who have less frequent sex”. He also noted that he hoped that additional follow-up from the ongoing open label phase might provide additional data to address this issue.” (Simon Collins, “The PrEP experience: IAS 2015 and beyond,” 10/1/15, quoting IPERGAY trial lead Molina at IAS 7/19/15
• See Also –

IPERGAY dosing

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

IPERGAY dosing

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

iPrEP

• Part of Speech – noun
• Definition – an acronym which stands for ‘intermittent Pre-Exposure Prophylaxis’ and refers to the use of PrEP on a nondaily basis, sometimes as-needed/on-demand around the time of sex, other times for extended but relatively brief periods like holidays or vacations or work-related travel
• Context of Earliest Usage – “van Griensven F, et al.: Sex predictability, sex spacing and the feasibility of intermittent pre-exposure chemoprophylaxis (iPrEP) to prevent HIV infection among men who have sex with men (MSM) in Bangkok, Thailand. Poster Exhibition, XVII International AIDS Conference, August 2008, LBPE1164” (Mascolini et al, Journal of the International AIDS Society, 2009)
• See Also –

LAI CAB (pronounced “L-A-I cab”)

• Part of Speech – noun
• Definition – an acronym representing long-acting injectable cabotegravir, an intramuscular antiretroviral technology used for combination HIV treatment as well as for the 3rd and most recently validated (2020) PrEP agent/modality after 1st TDF-based oral PrEP (2011) and 2nd Dapivirine-based vaginal rings (2016)
• Context of Earliest Usage – (Conversations online stretch back at least as far as 10/17/19 utilizing the term as shorthand for the focus of then-pending Cabotegravir PrEP trial. H/t MM.)
• See Also – CAB LA

morning after pill

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Morning after pill / ”Morning after” pill

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

morning-after pill

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Morphus Blue

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

MTV: Meth, Tenofovir, Viagra

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

non-inferiority trial

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

nondaily dosing

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

On prep

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

on-demand dosing

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

ONCE‐DAILY DOSING

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Open label extension

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Open label trial

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Party drug

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Party pack

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Periodic Dosing

• Part of Speech – noun
• Definition – the use of oral PrEP on a daily basis but for shorter blocks of time (often less than a month at a time and targeted around travel and/or cultural events that extend a week or longer) rather than indefinitely,
• Context of Earliest Usage – “PERIODIC DOSING[:] Tenofovir or Truvada taken orally, based on any one or more than one of the dosing strategies above during periods of potential sexual or IV exposures. Disruptions in access to a regular partner or partners, voluntary or involuntary periods of abstinence, carefully planned periods of serosorting, including seroconcordant monogamy, or other life events may effectively reduce or avoid exposure, even among individuals frequently at high risk for exposure to HIV. Animal model data may indicate how long before or after exposure prophylactic efficacy is required and may be informative for planning periodic dosing studies.” (AVAC, A Lexicon of Intermittent PrEP Possibilities, February 2009)
• See Also – Episodic PrEP/Eli-PrEP, Holiday PrEP

Periodic PrEP

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

pharmasorting

• Part of Speech –
• Definition –
• Context of Earliest Usage – (also H/t to MM/AB for 6/29/15 mention in PrEP-neologisms conversations online)
• See Also – biomed-matching, biomed-sorting, bio-sorting

Pocket pep

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Post-Placebo Era

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also – blinded trial, double-dummy double-blind trial

Prep DapiviRing

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Prep DapiviRing

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Prep DapiviRing

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Prep DapiviRing

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Prep DapiviRing

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Prep DapiviRing

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Prep persistence

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Prep persistence

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEP refusenik

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEP-landia

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEPagation

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEPamins

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEPared

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEPception

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEPducation

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEPducator

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEPenamas

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEPenamas

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

prepeur·se

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

prepoconcerné·e

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

prepocurieux·se

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

prepophobe

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Prepophobe

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Prepophobe

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

prepophobe

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEPpies

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEPruminations

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Prepson

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEPster

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEPster

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEPtected

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

PrEPWarrior

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

prevention package

• Part of Speech –
• Definition – https://www.avac.org/sites/default/files/resource-files/prevention_lexicon.pdf
• Context of Earliest Usage –
• See Also –

ROUTINE PLUS EVENT‐BASED DOSING

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Safer Sex pills

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

séro-concerné·e

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

séro-exposé·e

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

séro-indifférent·e

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

sérophobe

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

serosorting

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

sérotriage

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

short term, fixed interval PrEP

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Slut pill

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Slut pills

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

stigpain

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Superiority trial

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Taking a T

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Taking Truvada 

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

taspeur·se

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

TelePrEP

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

“Three Vs “”””””the 3V’s””””: Viread, Viagra and Valium”””

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

“Three Vs “”””””the 3V’s””””: Viread, Viagra and Valium”””

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Time-limited prep

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

timed dosing

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

ToyotaWhore

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Trail mix

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Truvadawhore

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Truvalue

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Truvotter

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

vacation PrEP

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Vacation prep

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

WEEKLY‐BASED DOSING

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

Whore pills

• Part of Speech –
• Definition –
• Context of Earliest Usage –
• See Also –

TLDR: Origins of PrEP

9/14/2020 Author’s note and contact

(This TLDR forms summary and motivational publishing for me to get done with a deep dive I’ve been thinking about for a loooong time and working on actively for about a month.)

HIV PrEP as we know it has a pedigree thread that runs through:

• Ancient China, Turkey, Africa, and India pioneering biomedical prevention via small-pox variolation,
• the popularization of Germ Theory in the second millennium,
• Colonial-Era Onesimous/Cotten Mather/Edward Jenner with earliest mass small-pox vaccination data in the 18th century,
• Benjamin Franklin’s 1735 American-as-Apple-pie pragmatist’s proverb about preventing pounds of problems,
• tribes in Sierra Leone (among others) demonstrating quinine’s prophylactic potential against malaria for Bryson in 1847,
• Baikie following up with focused study of anti-malarial quinine as a preventative along the Niger Delta in 1854,
• the dawn of virology around the turn of the 20th century,
• related biomedical prevention advancements through antibiotics in the early decades of the 20th century,
• US military research/deployment of said technologies as far back as WWII in order to address STI epidemics in the ranks by emphasizing “prophylaxis” and “safe sex,”
• the ensuing sexual revolution in the US facilitating informal prophylactic use of antibiotics in the queer community,
• rapid vaccine discovery successes during the Cold War decades,
• queer community/care responses to STIs including Hepatitis B Virus (HBV) as emerging health threats to the “gains of the (sexual) revolution“ in the 1970s,
• the gay community’s critical role in birthing the HBV vaccine in 1980,
• the post-exposure prophylactic (PEP) application of HBV vaccination for needle-exposed healthcare workers (HCWs),
• the dawn of the AIDS pandemic in the US national consciousness in 1981,
• community-based and institutional responses to AIDS in the early 1980s,
• the queer community’s collective self-care and activism in response to institutional inaction as the 1980s wore on,
• the proliferation of antivirals in the 1980s and 1990s,
• the application of virology to the new problem of AIDS including discoveries of HIV ARVs starting in 1987,
• the early hope that ARVs might offer a “morning after pill” PEP option for people exposed to HIV,
• the pioneering call for a biomedical HIV approach that empowered women (and by inference queer men/other receptive sex partners),
• the rise of informal ARV-sharing as community self-care among PLwHA,
• the rise of ARV black markets,
• research/recommendations of ARVs as a PEP biomedical prevention strategy among needle-exposed HCWs and mothers/babies in the late 1980s and early 1990s,
• the HIV fear fatigue of the mid-1990s,
• the discovery of PMPA in 1993 and its preventative potential as a “morning-after pill” (later fashioned into TDF),
• validation of triple combo HAART in 1996,
• the approval of Viagra in 1998,
• the condom fatigue coupled with mounting TasP/U=U evidence and treatment optimism in the 1990s and the 2000s,
• the pressure to expand PEP guidelines/access outside of occupational exposure contexts in the late 1990s and early 2000s,
• the rise of circuit parties coupled with crystal meth at the close of the 20th century,
• the approval of TDF for HIV treatment in 2001,
• evidence that began to accumulate on the efficacy of lamivudine (3TC or XTC) as a PrEP drug for prevention-of-mother-to-child-transmission (PMTCT) in 2002,
• the black market bundling of TDF for PrEP/PEP and Viagra with other drugs for recreational use at circuit parties,
• use of TDF intermittently for PrEP with TasP among magnet couples for safer conception in the mid-2000s,
• activism around funding and stopping biomedical prevention research in the early 2000s, and
• media reports of off-label medical prescribing plus black marketing of TDF as PrEP via “MTV,” “Taking a T,” “the 3 Vs,” “party packs,” “disco dosing,” etc. in the mid 2000s…

All helping set the stage for PrEP the idea … Largely before 2005 when:

• much of the animal research started kicking off along with related media buzz for TDF-based oral PrEP and the US’ formal introduction of nPEP guidelines,
• before 2007 when all the many TDF-based oral PrEP human trials large and small began reporting safety and efficacy
• “giving birth” so to speak to PrEP in America via 2012 FDA approval and 2014 CDC PrEP Guidelines
• before the 2015 PEPFAR scientific advisory board concluded that TDF/3TC is an acceptable alternative to TDF/FTC for PrEP,
• before 2016 when WHO expanded its oral PrEP recommendation to include lamivudine (3TC or XTC) as an alternative to Emtricitabine (FTC),
• before the same time in 2016 when large scale trials began to report on Dapivirine (DPV) ring PrEP safety/efficacy,
• before 2019 when results were announced of the FTAF-vs-FTDF oral PrEP trial leading to partial FDA approval that fall, or
• 2020 when the world saw its first evidence of highly effective long-acting injectable Cabotegravir PrEP and
• the European Medicines Agency issued a positive opinion of the DPV PrEP ring…

in a nutshell, where PrEP came from, its origin.

PrEP in Pop Culture: Graphic Arts

5/5/20 (Author’s note and the rest of this PrEP pop culture series.)

INTRODUCTION

Blue is the color chosen for Truvada™️ , the first drug ever approved by the U. S. Food and Drug Administration for PrEP in 2012.

Image courtesy of Drugs.Com

Now, in the world of drug styling and marketing, choosing blue for a pill’s color sends a signal to consumers that the medicine is infused with all of the cool, calming, tranquility of blue skies.

This is because blue, in its many shades, is a color that, in Western art and culture, represents water, life, optimism, authority, cooler temperatures, sadness, security, and serenity among other objects and concepts. In one word, “sublime” is how one might describe it.

So it’s no surprise that the same properties that lend themselves to blue‘s primary-pigment popularity (and PrEP‘s parallel prescription product) project right onto the portfolio of popular graphic arts representations of PrEP that profit-driven (primarily print) media have produced. They, too, are simply sublime. Thus, in no particular order, I document and delightedly describe them below.

Please feel free to peruse and partake of their peacefulness (if not also pathos), to click through to their creators and communications contexts, and to let me know if you too have seen any sublime graphic arts PrEP representations in popular culture worth adding to the collection.

ENCAPSULATED

The image is of a lightly-drawn, steel blue/baby pink/white male-presenting figure in the lower left region surrounded by but set apart from many other silhouetted, steel blue male-presenting figures encapsulated in translucent pods of the same color in the shape of pills. The multi-colored figure is seated, akimbo almost but floating as it were with no discernible ground, hugging one knee with their back to the viewer in a vulnerable but observant fashion. The monochromatic figures lie prone, also floating it seems as there are no ceilings or walls either, but some with flexing joints, contorted limbs, and/or fetal contractions suggesting their own private distress as well. Most of their faces are shaded, shadowed, or otherwise obscured to such an extent as to disembody them and further alienate the seated, multicolored figure. The only dimensional structure lent to the whole image is that of a pencil-thin white trellis pattern interrupting the solid baby pink background.

The article is “Unprepared: Is PrEP, the drug that prevents HIV, bringing revolution or regression?” by Alexander McClelland for Maison Neuve Arts, Opinions, and Ideas Quarterly on March 28, 2019.

The artist is Christian Fowlie.

SLIGHT SILHOUETTES

The image is a series of roughly four illustrated, male-presenting, overlapping, unclothed, translucent, silhouetted busts done in what looks like pen and watercolor on a white background. Each bust, though arms fall to the sides generally, faces a slightly different direction such that a singular consciousness seems to echo throughout each’s slightly differing point of focus. Each figure also has a slightly different shade of grey, the palette of shades trending slightly darker with each pose change from left to right except the middle one. That middle bust is in blue-green with a tiny, similarly-colored, presumably-PrEP pill in its hand suspended contemplatively in front of its face.

The article is “My Struggle to Take Anti-H.I.V. Medicine” by New York Times guest opinion contributor Daryl Hannah on September 21, 2017.

The artist is Xia Gordon.

MAKING NOISE

The image is a matrix of eight pots and pans in almost all of the nine equal tic-tac-toe quadrants of the matrix, most hardware being silver (clockwise from upper left corner wok in position eleven, saucer in one, stockpot in three, sauté pan in five, cookie sheet in nine), some being black (cast iron skillet in position twelve, nonstick pan in seven), and one pot, a teal Dutch oven in the middle matrix square of the image.

The image was posted on ACT-UP London’s blog page for a March 16th 2016 PrEP Noise Demo for a Health Care System for All.

The artist is unknown.

PROPHYLACTIC

The image is a torn-open, shiny, silver condom wrapper off to the the right with an azure “701” PrEP pill tumbling jauntily out of it. On the wrapper read the words “stay safe” in simple, black print all-caps. A black background swallows up the right 2/3 of the image.

The context is unknown.

The artist is unknown.

A TASTE OF THE CAREFREE

The image is a tight shot of a generous handful of cerulean “701” PrEP pills on a white background that peaks out from the right side of the cyan-saturated image. One of the pills centered horizontally toward the top of the image is decorated as if it were an open-air portal or a Sisteen fresco, a window into the serenity of expansive sky blues and voluptuous, softly-brushed, white clouds depicted thereout.

The article is “PrEP: The Story of a Sexual Revolution“ by Gabriel Arana for Them.us on March 16, 2020.

The illustration artist is Wesley Johnson using Getty Images photos.

NEW AND IMPROVED

The image is of a baby blue “701” Truvada pill on the left and a smaller, light blue “225” Descovy pill on the right. The Truvada pill is styled as a barrel bag with two sturdy, baby blue, leather handle straps while the Descovy pill is styled as a petite, sleek clutch purse with an accompanying satin zipper tassel in the same light blue as the Descovy pill. In the background, like a heraldic Bend flag layout, a diagonal line traces from the lower left corner to the upper right, separating a stark white triangular region for Truvada on the left from a highlighting yellow triangular region for Descovy on the right. Four black, hand-drawn, inward-pointing arrows surround the Descovy “clutch” almost like a halo with two such hand-drawn exclamation points further visually highlighting the “new-n-improved” rhetoric surrounding Descovy.

The article is “Your PrEP Is Not a Status Symbol” By Grant Roth for Slate.com on February 6, 2020.

The photo illustration is by Slate with imbedded photos from Gilead Sciences Inc., the maker of Truvada and Descovy.

CONTROLLED DESCENT

The image is a parachuting deep sky blue “701” PrEP pill slightly askew as it floats gently down through the night sky. The parachute is white, the clouds blue-grey, and the night sky blue-black. A black speckling effect along with side-lighting on the pill and the slow descent of the pill heighten the tranquil, dreamlike late-night feel of the image.

The article is “What Is Safe Sex? The Raw and Uncomfortable Truth About Truvada” by Rich Juzwiak for Gawker.com on March 4, 2014.

The illustrator is Jim Cooke.

INQUIRING MINDS WANT TO KNOW

The image is a giant cobalt blue (presumably) PrEP pill on strings suspended from above with raised hands below holding press conference documentation tools. The background is turquoise. The pill looks like an upside-down blimp or balloon with a multi-planed surface covered in button-sized fasteners distributed throughout as if on a constellations map. There are seven peach-complected hands with blue, orange, yellow, red, mustard, and fuchsia colored jackets over white shirt-cuffs. The tools include several recording microphones, a smartphone, a cassette recorder, and mini-recorders.

The article is APCOM‘s “What Do People Think about PrEP” from September 30, 2015.

The artist is not known.

COVERED… EVEN AND ESPECIALLY IN BED

The image is two Bleu de France “701” PrEP pills snuggling under a black-white reversible blanket in bed together. The pillows are white and the sheet the hue of denim. The area around is almost all black, dropping away the world around and concentrating the eye on the intimacy of the moment.A speckling over everything adds a grey hue with a simple shadow on the left of the bed serve to suggest the wee hours of the night.

The article is “Truvada, Anti-HIV Drug, Has No Harmful Side Effects” from the April 27, 2016 edition of Steth News.

The artist is not known.

A MILLION TINY PRESCRIPTIONS

The image is a hand in silhouette, fashioned of hundreds of spilled baby blue pills, outstretched vertically upward, and filling about one quarter of the visual field. The background – mainly saturating the left side – is a dark orange background. The hand is, at turns, desperate, yearning, and hopeful as it holds up one baby blue PrEP pill. On the right, away from most of the pills, is the initial copy (headline, byline, lead, etc.) for the article, in black typeface.

The article is “Little Blue Hope” by Heidi Koelz from the November 2, 2018 Concord Academy online.

The illustration artist is Chris Gash.

ON THE DOLE/ON THE PILL

The image is of a giant, suited person (though no tie) on the left, cropped from the photo at the head and hips, passing out cerulean presumably-PrEP pills from a piled tray to three tiny people on the right reaching desperately to the heavens for the few that rain down. The overwhelming sentiment in the image is one of two-dimensional gloom as telegraphed by the disembodied donor, the black, grey, and white color pallet, and the clouds stacked to suggest a darkened sky and gathering storm. The macabre theme echoes through a flat or two-dimensional, vaguely Gothic drawing style. The only other color is that of the blue pills, one of which all three people are reaching for at once as two other tiny people flee the scene, hugging tightly what looks like their own relatively giant cerulean PrEP pills.

The article is “Opinion: A Million Americans Need This Drug. Trump’s Deal Won’t Help Enough of Them” from the New York Times editorial board on May 13, 2019.

The illustration artist is Federica Bordoni.

5/5/20 (Author’s note, contact form, and the rest of this PrEP pop culture series.)

FDA Descovy-PrEP 8.7.19 Advisory Committee Meeting Archiving Dump

(Author’s note)

8/18/19

United States Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Advisory Committee Meeting

Antimicrobial Drugs Advisory Committee

August 7, 2019

08:30 AM EDT – 04:30 PM EDT

FDA White Oak Campus

10903 New Hampshire Avenue

Building 31 Conference Center

The Great Room (Rm. 1503)

Silver Spring, Maryland 20993

https://www.fda.gov/advisory-committees/advisory-committee-calendar/august-7-2019-antimicrobial-drugs-advisory-committee-meeting-announcement-08072019-08072019

****OUTLINE

1. EVENT MATERIALS
2. WRITTEN COMMENTS
3. AGENDA
4. AUDIO RECORDING LINKS
5. TRANSCRIPT 1
6. TRANSCRIPT 2
7. TRANSCRIPT 3
8. TRANSCRIPT 4

****1. EVENT MATERIALS

Event Materials

Lindsey Baden, M.D. – 18 U.S.C. 208(b)(3) Waiver for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (361.57 KB)

https://www.fda.gov/media/129235/download

Lindsey Baden, M.D. – Disclosure Document for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (49.87 KB)

https://www.fda.gov/media/129236/download

Barbara Gripshover, M.D. – 18 U.S.C. 208(b)(3) Waiver for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (197.43 KB)

https://www.fda.gov/media/129237/download

Barbara Gripshover, M.D. – Disclosure Document for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (52.15 KB)

https://www.fda.gov/media/129238/download

Errata to the FDA Briefing Information for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (111.42 KB)

https://www.fda.gov/media/129608/download

FDA Briefing Information for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee

https://www.fda.gov/media/129607/download

Gilead Sciences Briefing Information for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee

https://www.fda.gov/media/129609/download

Webcast Information for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (80.04 KB)

https://www.fda.gov/media/129614/download

Committee Roster for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (28.58 KB)

https://www.fda.gov/media/129610/download

Final Agenda for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (23.97 KB)

https://www.fda.gov/media/129919/download

Final Questions for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (13.07 KB)

https://www.fda.gov/media/129920/download

Final Meeting Roster for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (28.16 KB)

https://www.fda.gov/media/129921/download

FDA Presentations for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee (906.50 KB)

https://www.fda.gov/media/129922/download

Gilead Sciences Presentations for the August 7, 2019 Meeting of the Antimicrobial Drugs Advisory Committee

https://www.fda.gov/media/129923/download

---

****2. WRITTEN COMMENTS

Antimicrobial Drugs Advisory Committee; Notice of Meeting; Establishment of a Public Docket; Request for Comments; Docket ID: FDA-2019-N-2779

https://www.regulations.gov/docketBrowser?rpp=25&so=ASC&sb=postedDate&po=0&dct=PS&D=FDA-2019-N-2779

Comment from (Dr.) Peter Havens (Medical College of Wisconsin)

https://www.regulations.gov/document?D=FDA-2019-N-2779-0002

OPINION: FOR (“in adolescents, if F/TAF is approved for PrEP in adults…to avoid the bone toxicity caused by F/TDF use in adolescents and young adults”)

Comment from Jonathan Winston ()

https://www.regulations.gov/document?D=FDA-2019-N-2779-0003

OPINION: FOR (“favorable renal safety profile compared to Truvada”)

Comment from (William McColl) AIDS United

https://www.regulations.gov/document?D=FDA-2019-N-2779-0006

OPINION: FOR (“concerned that PrEP be widely extended to gay men of color, to women especially women of color and pregnant women, transgender men and women, adolescents, to communities, especially in the South, that experience HIV health disparities, and all communities at greatest risk for HIV infection…AIDS United has recently engaged in working on the issues related to HIV and Aging. Improvements to renal and bone density would create significant advantages for people seeking to prevent HIV to maintain use for longer periods of time.”)

Comment from Damon L. Jacobs

https://www.regulations.gov/document?D=FDA-2019-N-2779-0005

OPINION: FOR (“Two … friends … older adults … discontinued on Truvada because of … interact[ion] with their other medications. Their providers … interest in … Descovy … awaiting FDA approval …[also] International AIDS Conference … data … indicat[ing] that Descovy has a longer half-life than Truvada, and therefore could be more forgiving with missed doses”

Comment from (Dr. Christopher Hall) San Francisco AIDS Foundation

https://www.regulations.gov/document?D=FDA-2019-N-2779-0004

OPINION: FOR (“as an additional PrEP option will expand the number of individuals who will choose to use PrEP as an HIV prevention method…[and] in the DISCOVER trial…F/TAF … shown to be non-inferior or.. at least as good as Truvada for preventing HIV acquisition… in addition…Black and African Americans face over three times the rate of kidney failure in the U.S. compared to Caucasians5, choice of a PrEP alternative with marginally improved renal safety profile may predispose engagement — based on both real and perceived advantages…[also] a more streamlined renal function monitoring algorithm with use of F/TAF for PrEP, and in turn an ability to follow more individuals on PrEP with decreased laboratory expenditures, less intensive lab monitoring, and fewer staff resources dedicated to closer follow-up demanded by present use of Truvada”

Comment from (Craig E. Thompson) APLA Health & Wellness

https://www.regulations.gov/document?D=FDA-2019-N-2779-0007

OPINION: FOR (“F/TAF … an additional option …[to] increase the number of at-risk individuals who decide to use PrEP, and thereby contribute to national, state and local efforts to end the HIV epidemic…APLA Health believes the results of the DISCOVER trial will encourage greater uptake of PrEP among a broad range of populations including young gay and bisexual men, women of color, transgender individuals and older at risk individuals, all of whom are concerned with taking medications for longer periods of time”)

Comment from (Moises Agosto) NMAC

https://www.regulations.gov/document?D=FDA-2019-N-2779-0009

OPINION: FOR (Concerns about … side effects … discourage many individuals who would greatly benefit from PrEP … especially true in communities that already have great distrust of the medical industry.Descovy provides another tool in our HIV prevention toolkit and can avoid the impact of harmful side effects from current medications… would help to reduce barriers to widespread use of PrEP …”)

Comment from (Dr.) Karam Mounzer (University of Pennsylvania)

https://www.regulations.gov/document?D=FDA-2019-N-2779-0008

OPINION: FOR (“The advantages of TAF vs TDF for PrEP may be more prominent among older candidates, especially among those with osteopenia/osteoporosis and/or chronic kidney disease (CKD)…(also) pharmacokinetic analysis showed that the uptake of PBMCs with TFV-DP was faster, higher and longer with FTC/TAF compared to FTC/TDF, rendering TAF a potentially more forgiving PrEP agent for individuals with intermittent compliance”)

Comment from (Bruce Richman) Prevention Access Campaign

https://www.regulations.gov/document?D=FDA-2019-N-2779-0011

OPINION: FOR (“F/TAF … as effective …Truvada… for PrEP, but with fewer side effects: smaller changes in kidney biomarkers and slightly less bone loss. F/TAF will offer an important option for people… considering PrEP but … concerned about the perceived side effects of FTC/TDC, especially those who have compromised renal function.”)

Comment from (Prof. Quarraisha Abdool Karim) Centre for the AIDS Programme of Research (CAPRISA)

https://www.regulations.gov/document?D=FDA-2019-N-2779-0013

OPINION: FOR (“Adherence to daily, oral formulations of tenofovir/emtricitabine and monthly dapivirine rings have proven to be challenging for young women … access to new more potent drugs and formulations that are less user dependent is urgently needed. One such option is FTC/TAF (Descovy®) – a potent and safer alternative to Truvada® (FTC/TDF)….[and] In the absence of clinical trial PrEP efficacy data of Descovy® in women, on balance, the combination of safety data of FTC/TAF from treatment trials that included women; comparable Descovy® and Truvada® non-human primate efficacy data with vaginal exposure; and protective drug level data in women provide evidence in support of the prophylactic use of Descovy® in cis-women. Due to its potency, smaller drug load, longer intracellular half-life and lower systemic circulation of the parent drug tenofovir (TFV), FTC/TAF offers an improved systemic safety profile…. Lastly, iiii Descovy® in the medicines patent pool …will enable rapid access at affordable prices for women in Africa and other developing countries within a relatively short space of time following licensure for PrEP … in … USA.”)

Comment from (Dr.) Elizabeth Bukusi (University of Washington)

https://www.regulations.gov/document?D=FDA-2019-N-2779-0014

OPINION: FOR (“For the women …Descovy may offer some important advantages over Truvada. Complaints … from women on Truvada … included … concerns about the size of the pill and the stigma associated with…connection to ART for HIV treatment …[and]With the shifting funding cycles, … cost of …pill[s] …important reason for investment of Governments who have to carry more of the funding of drugs for ART for both HIV positive and negative individuals. The lower costs for Descovy would offer an advantage for already constrained budgets within the Ministries of Health. (plus) From … pharmacological and medical point of view, … evidence show[s] possible better bone and renal safety which may further reduce care cost”)

Comment from (Prof.) Nelly Mugo (University of Washington)

https://www.regulations.gov/document?D=FDA-2019-N-2779-0015

OPINION: FOR (“The Kenya National PrEP Scale up Program data shows high PrEP initiation among young women and very low retention after month one and worse still at month 3. Women …[in] qualitative interviews speak of the challenge of using … large tablet, … resemblance to ARVs, … blue color contributing to stigma and making it difficult to comfortably use PrEP in the community….FTAF …an option that [could] overcome… these barriers.”)

Comment from (Dr.) Sharon Hillier (University of Pittsburgh)

https://www.regulations.gov/document?D=FDA-2019-N-2779-0010

OPINION: FOR (“Even though Truvada has an excellent safety profile, Descovy does have a superior profile in ways that matter to women-both in safety and pill size. Treatment studies of Descovy have included women and there were not gender disparities in response to HIV treatment. …women should not be left behind. If Descovy is approved for men, it should also be approved for women.”)

Comment from (Prof. Quarraisha Abdool Karim) Centre for the AIDS Programme of Research (CAPRISA)

https://www.regulations.gov/document?D=FDA-2019-N-2779-0012

OPINION: FOR (see above)

Comment from Lynda Dee

https://www.regulations.gov/document?D=FDA-2019-N-2779-0021

OPINION: AGAINST (“Thirty-two years after the approval of AZT in 1987… It is an outright disgrace that [cisgender] women are once again so blatantly excluded from HIV trials…the Sponsor did not study cisgender women at risk for HIV in the DISCOVER trial…It should also be noted that insignificant numbers of transgender women and African-American MSM were included in DISCOVER even though these are the populations that are at the highest risk for HIV transmission….the FDA…is also at fault here for not requiring the sponsor to study cisgender women in DISCOVER…it would be a violation of the agency’s clearly defined statutory mandated duty to approve Descovy at least for cisgender women without sufficient safety and efficacy data. … Truvada provides a reasonable alternative here until the Sponsor actually studies safety and efficacy in significant numbers in this population. Descovy PK data in women has been disappointing from the onset… Claims of Descovys superior safety profile and smaller pill size pale in comparison to the risk of Descovys inferior efficacy in cisgender women.”)

Comment from (Mitchell Warren) AVAC

https://www.regulations.gov/document?D=FDA-2019-N-2779-0019

OPINION: FOR (“The available data presented in the application do, in our opinion, support approval of TAF/FTC as an additional, non-inferior, safe and effective daily oral PrEP option among men and transgender women who have sex with men…if the F/TAF for PrEP label is not extended to include cisgender women, there will be multi-year delays and denial of access of this additional form of oral PrEP … The systemic PK data in the sNDA do, in general, support an initial broader indication of F/TAF for PrEP for cisgender women…..this indication should also be approved but subject to … Phase 4 studies and a robust Risk Evaluation and Mitigation Strategy (REMS)…includ[ing] other populations (e.g., adolescents and transgender men) that were also not part of the DISCOVER trial.”)

Comment from (David C. Harvey) National Coalition of STD Directors (NCSD)

https://www.regulations.gov/document?D=FDA-2019-N-2779-0018

OPINION: FOR “Descovy presents an opportunity to expand PrEP access across the country…

Comment from Drs. Jared Baeten and Connie Celum

https://www.regulations.gov/document?D=FDA-2019-N-2779-0016

OPINION: FOR (“Factors that have decreased PrEP use … include size of the FTC/TDF pill, fear of side effects, challenges with habit formation to daily pill-taking, uncertainty about the need for HIV prevention, lack of access, and stigma in many varieties…. very low level of new infections … in.. DISCOVER trial, and … favorable safety profile of TAF…[it’s] a natural extension of FTC/TDF as PrEP… for anti-HIV activity they are identical and … pharmacology supports FTC/TAF as equivalently effective for HIV prevention regardless of gender or route of sexual HIV exposure…. favorable safety profile of FTC/TAF may be appealing to persons who have been hesitant to take FTC/TDF PrEP, and that profile (and the potential for lower cost of goods with a smaller tablet) may permit even easier PrEP delivery in places like East and Southern Africa where much of our work takes place. ”)

Comment from (David C. Harvey) National Coalition of STD Directors

https://www.regulations.gov/document?D=FDA-2019-N-2779-0020

OPINION: FOR (see above)

Comment from (Prof. Linda Gail-Bekker) The Desmond Tutu HIV Foundation and Centre

https://www.regulations.gov/document?D=FDA-2019-N-2779-0017

OPINION: FOR (“Descovy (DVY) … stands to provide improved bone and renal safety profiles…Despite no direct studies in cis-women, analyses of Gilead clinical pharmacology data demonstrate … no clinically relevant difference in the PK of FTC, TAF, or PBMC-associated TFV-DP between women and men taking DVY…. [and] DVY more rapidly achieves PBMC-associated TFV-DP levels above the protective threshold compared with TVD…in women …higher PBMC and vaginal tissue concentrations of DVY than TVD suggest … there may be … advantage for individuals with less than optimal adherence, which has historically been a challenge for the women enrolled in earlier PrEP trials, such as VOICE and FEMPrEP….safety data … derived from women with HIV-1 taking DVY-containing regimens…support … safety of DVY for PrEP in women at risk of HIV-1…Unique to women is a finding of less nausea among those treated with DVY-containing products than among those treated with TVD-containing products, suggesting … potential additional benefit of increased tolerability for DVY over TVD in women…In addition, the smaller, non-blue colour is important in young women …[for whom] size and colour of the TVD PrEP has negative, stigmatising impact.”)

****3. AGENDA

https://www.fda.gov/media/129919/download

FOOD AND DRUG ADMINISTRATION (FDA)

Center for Drug Evaluation and Research (CDER)

Antimicrobial Drugs Advisory Committee (AMDAC) Meeting

FDA White Oak Campus, Building 31

Conference Center (Rm. 1503)

10903 New Hampshire Avenue,

Silver Spring, Maryland

August 7, 2019

8:30 a.m.- Call to Order and Introduction of Committee

Lindsey Baden, MD Chairperson, AMDAC

8:35 a.m. – Conflict of Interest Statement

Lauren Tesh Hotaki, PharmD, BCPS, BCIDP Designated Federal Officer, AMDAC

8:40a.m. – FDA Opening Remarks Jeffrey Murray, MD, MPH Deputy Director Division of Antiviral Products (DAVP )Office of Antimicrobial Products (OAP) Office of New Drugs (OND), CDER, FDA

8:50a.m. – APPLICANT PRESENTATIONSG ilead Sciences, Inc. Introduction

Diana Brainard, MD Senior Vice President HIV and Emerging Viruses Gilead Sciences, Inc.

DISCOVER Study Design, Treatment Population, and Efficacy Results

Scott McCallister, MD Executive Director HIV and Emerging Viruses Gilead Sciences, Inc.

DISCOVER Safety and Extrapolations

Moupali Das, MD, MPH Executive Director HIV and Emerging Viruses Gilead Sciences, Inc.

Clinical ContextR ichard Elion, MD Director of Research Washington Health Institute

Clinical Professor of Medicine George Washington University

10:15a.m. – BREAK

10:25a.m. – Clarifying Questions

11:05a.m. – FDA PRESENTATION NDA 208215/S12 –Descovy PrEP

Peter Miele, MD Medical Officer DAVP, OAP, OND, CDER, FDA

11:45a.m. – Clarifying Questions

12:25 p.m. – LUNCH

1:30 p.m. – OPEN PUBLIC HEARING

2:30 p.m. – Questions to the Committee/Committee Discussion

3:00 p.m.- BREAK

3:15 p.m. – Questions to the Committee/Committee Discussion (cont.)

4:30 p.m. – ADJOURNMENT

****4. AUDIO/VIDEO RECORDING LINKS

A recording of the webcast can be found at the following address:

•Start of Meeting to Morning Break: (corresponds to Transcript 1)

https://collaboration.fda.gov/p02b424sg3c4/

•Morning Break to Lunch Break: (corresponds to Transcript 2)

https://collaboration.fda.gov/ponp3o5rrn6k/

•Lunch Break to Afternoon Break: (corresponds to Transcript 3)

https://collaboration.fda.gov/p6cwctro9plz/

•Afternoon Break to End of Meeting: (corresponds to Transcript 4)

https://collaboration.fda.gov/p8xr2oc44100

****5. TRANSCRIPT 1

I would like everyone to mute your microphones if you’re not

already done so.

If there questions for the press please address them to Allison and Charlie.

My name is Lindsay Baden and I will be sharing today’s meeting.

I will now call up the Antimicrobial Drugs Advisory Committee Meeting .

We will start from the left to

go around the table.

John Farley, Debbie, Jeff Murray, Jeffrey Murray, MD, Deputy Director, Division of antiviral products, DAVP, Office of Antimicrobial Products, OAP, Office of New Drugs, OND, CDER, FDA , Wendy

Carter, Pete Neely, training

team, Jenny thing

, Laura Cheever

, Shawn,

George,

Barbara,

Michael Green,

[ Indiscernible ], Lauren Tesh Hotaki, PharmD, BCPS, BCIDP, Designated Federal Officer, AMDAC , Lindsey Baden, MD, Chairperson,

AMDAC,

[ Indiscernible ], Tim Burgess ,

Jennifer lie,

Tom Giordano,

Dimitri,

Sally,

Don Smith

, Matthew gets

Moupali Das, MD, MPH, Executive Director, HIV and Emerging Viruses, Gilead

Sciences, Inc.

, [ Indiscernible ],

.

>> I believe we have someone on the phone.

There is some feedback >> Can you hear me back.

>> This weekend.

Thank you.

For topic such as those being discussed at today’s meeting there often a variety of opinions some of which are quite strongly held.

Our goal is that today’s meeting will be a fair and open forum for discussion of these issues and that individuals can express their views without interruption.

Thus is a gentle reminder individuals will be allowed to speak into the record only recognized by the chairperson.

We look forward to a productive meeting.

In the spirit of of the federal

community act in the sunshine act and react that the advisory committee members take care that their conversations are at the topic at hand take place in the open form of the meeting.

We are aware that members of the media are anxious to speak to the FDA about these procedures however FDA will frame from discussing the details of this meeting with the media until its conclusion.

The committee is reminded to please refrain from discussing the meeting topic during breaks or lunch.

Ink you >> And I think everyone for making the time to be here to participate in this discussion.

We know how busy everyone is.

I will ask Dr.

Lauren Tesh Hotaki to read the conflict of interest statement.

>> The FDA is committing

today’s meeting under — all members and temporary members are special government or federal employees from

different agencies.

The following information on the status of this committee is combined to federal ethics and conflict of interest was covered by but not admitted to these 18 section 208.

FDA’s determined that members in voting members of the committee are in compliance with this

conflict of interest laws.

Members and temporary voting members of the committee have been screened for potential financial conflicts of interest of their own as well is sold imputed to them and their

spouses and minor children.

Based on the agenda for today no financial interest supported by the committee members are temporary voting members conflict of the suits interest has been issued in accordance

with 18,

—

[ Indiscernible ]

>>

Take you.

We will proceed with the FDA opening remarks from Dr.

Marie >>

Good morning.

The division of extend this warm welcome to the committee and to the audience to discuss our new supplemental

application for DESCOVY for HIV infection and we are happy to be talking about expanding the HIV convention [ Indiscernible ] today.

Some of you on the panel and perhaps in the audience may have been here in 2012 in this very room when the advisory committee voted on

whether Truvada should be

approved for prep.

That’s for seven years and that brings us to today’s topics.

There are similarities in differences between the two products.

Both are [ Indiscernible ] that contain

emtricitabine 200 mg and tenofovir alafenamide 25 mg tablets).

Both are approved for HIV treatment and also approved a single agents for the treatment of chronic hepatitis the uncle however there are also differences specifically as they relate to the bioavailability of tenofovir alafenamide 25 mg tablets) in the fixed dose combination.

They deliver lower levels of plasma and lower

level, higher levels of — there is also difference in tissue in order to submission.

This is a safety profile but did not result in efficacy difference for HIV treatment.

The other difference is true but is already approved for prevention and DESCOVY is not.

To support that applications of

the clinical trials — which allowed for a broad and the case and for at risk individuals.

Today were dealing with one clinical trial.

What are some of the regulatory considerations about the basis of supporting and approval.

The number of clinical trials needed to support and approval depends on the regulatory situation.

For new molecule entering the market general two or more drugs are expected or two or more trials are expected.

However for a new and related indication for previously approved obvious only one trial is needed to support approval.

Likewise if there is a new [ Indiscernible ] twice-daily to once daily and you cannot make up form of kinetic link is supported by one trial.

Or for new population were PK is different usually we rely on one clinical trial.

For DESCOVY FDA’s initial drug element advice was that clinical trials should be conducted in a relevant populations and that of PK link alone would not be possible.

So for this application I said we have one trial in MSM and transgender women and none in women at risk.

So the primary issue for today and what you will be asked is a question is given the uncertainty around the protective Korolev can extrapolation be used to further expand the indicated

population?

With that being said this application is a special case in the development of for HIV prevention.

I have the following caveat the approach for DESCOVY may not apply to molecular entities because at

this point — can be leveraged.

We asked the committee today for their advice on how this data can be

assessed.

Ink you >> We will now move to the applicant presentations.

Of the FDA and the public believe in a transparent process for information gathering and precision making.

To exercise transparency the advisory committee and FDA believes that it is important to understand the context of the individuals hesitation.

For this reason FDA encourages all participants including the applicants nonemployee presenters to advise the committee of any financial relationship that may have in a sponsor including entity, equity interest and

those based on the meeting.

Advise the committee at be do not have any such financial relationships.

If you choose not to address this issue or financial relationships at the beginning of your presentation you will not preclude you from thinking.

Will now proceed with Gilead presentation at the Brainerd.

>> Good morning.

Ending the HIV epidemic requires not just highly effective treatments for people have already been

impacted.

It also additional options for preventing new

infections.

My name is Diana Brainard and I leave the HIV and emerging viruses group at Gilead Sciences, Inc.

infectious disease physician and I have worked as a clinician and scientist in both the U.

S for people living which is IV and tackle the the epidemic.

It is a pleasure and honor to be here today to work with this committee to bring forward another HIV prevention option that will help us achieve our shared goal of HIV elimination.

Seven years ago as Dr.

Murray mentioned about it was approved to prevent sexually acquired HIV infection.

And remains today the only approved therapy

for HIV preexposure prophylaxis.

Provider is the fixed dose combination of two HIV reverse [ Indiscernible ] inhibitors.

Emtricitabine 200 mg and tenofovir alafenamide 25 mg tablets).

Provider is approved as part of the complete regimen for the treatment of HIV and adults and adolescents.

As well as for prep.

[ Indiscernible ] for the treatment of chronic hepatitis Be.

DESCOVY is the fixed rate tablet of

— is approved as a single agent for treatment of chronic hepatitis B.

We are proposing an indication for DESCOVY co-for adults and adolescents based on the data we are discussing today.

Tenofovir alafenamide 25 mg tablets) and do not revere but they have vastly different metabolisms.

TFS does that one 12th of TDF because of the difference in half-life.

TDF is rapidly converted to TFE

resulting in high plasma

.

>> DESCOVY lower level of circulating not revere translate of your chronically revenant adverse

renal.

The half-life of pre-exposure prophylaxis allows more time to enter perverse

blood and — intracellularly TAF — where it achieves higher

levels of

on the level of interest to all correlates with antiviral activity.

The kinetic differences between Trent 27

TAF and — after a single dose DESCOVY achieves intracellular Tenofovir Disphosphate above PBMC within two hours.

This threshold is relevant for prep based on his correlation using Truvada data from a trial in men who have sex with men with a 90 % reduction in risk of HIV acquisition as compared to the Siebel.

In contract Truvada takes approximately three days

for the mid-level to recess [ Indiscernible ].

And the state levels remain lower than those for DESCOVY.

One steady-state is achieved with either DESCOVY or Truvada drug is stopped Tenofovir Disphosphate start to decline at a similar rate.

However since levels are so much higher with DESCOVY as compared with

Truvada they remain above this EC 9460 days with DESCOVY compared with 10 days with Truvada.

This suggested to us that DESCOVY could be highly effective for prep and the safety advantages observed in people living with HIV taking this cove could also be realized among those at risk for HIV infection.

In 2015 when the Discover study design was coming together there was uncertainty around whether drug levels in the genital tract or peripheral blood nuclear cells vest correlated with protection against HIV.

The higher levels of Tenofovir Disphosphate and PDMs these with this cove could potentially confer in efficacy advantage and offer a more forgiving regimen for prep provided these levels correlated for protection.

However if genital tract tissue levels drive of up efficacy DESCOVY could be less effective for prevention.

Data from healthy volunteers so that rectal tissue levels are tenfold lower following DESCOVY administration compared to turnabout up.

All hypothesis was that prevention at efficacy for oral drugs would be best measured by prefer for your blood mononuclear cells drug levels rather than tissue how much of it levels.

And that therefore this cove would be at least as efficacious as Truvada.

In spite of this difference in rectal tissue levels.

This hypothesis was based on advances and the understanding of mucosal transmission of HIV.

HIV must first reach the epithelium to reach the sub epithelium and it is general belief that a single cell first becomes effect did and initiates

subsequent events.

Kemah kinds [ Indiscernible ] attracts PDMs

the — circulation to the tissue.

This then results in a small population

of initially affect did CD4 T cells located in the sub epithelium.

The recruitment of target cells for HIV, the CD4 cells from the periphery is critical in order for systemic infection to occur.

Dissemination of these recruited and now infected CD4 positive T cells occurs as they entered the prophetic system to travel to regional infidels and spread throughout the body.

Detection against systemic HIV infection can occur via both topical and systemic modalities.

Topical anti-retro virus such as investigational do not revere gel allow for the diffusion of drugs into tissues within the genital tract.

Efficacy depends on reaching therapeutic levels intracellularly within the local city for positives T cells.

These methods had generally been less effective in prop delivered systemically.

To her body and DESCOVY distribute rightly throughout the body and can offer a greater degree of protection.

They can both reach the genital tissues through the blood supply where they can then access resident lymphocytes and importantly as well PBMC is that contain the active metabolite of both Truvada and DESCOVY Tenofovir Disphosphate also can reach the genital tract and can be among the cells recruited to the site of initial infection as well as into the regional training Cliff notes so as to prevent systemic infection.

While there is no been clear evidence of a correlation of her Benton efficacy of Truvada for up with tissue levels efficacy strongly correlates with drug levels of

Tenofovir Disphosphate within tran33s.

A subset of participants in the iPAQ study and then men who have sex with men of to bottle versus placebo

have Tenofovir Disphosphate — because of the wide range of adherence in the tried and due

to correct comparison could be made it was possible to construct a relationship between PBMC, Tenofovir Disphosphate and risk reduction with respect to HIV incident.

It was with these data that Dr.

Anderson established the correlates of protection for 90 % risk reduction for Tenofovir Disphosphate levels at 40 fmol and show that there is a range of protection above and below that level.

These data are not well recognized and have cited in the most recent CDC prep guidance issued on July 18th of this year.

When the DESCOVY study was being designed the scientific and clinical understanding of HIV prevention was less mature.

At that time Truvada for prep was only approved in adults.

DESCOVY was under review by the FDA for the treatment of HIV.

We knew that rectal tissue levels with DESCOVY were tenfold lower than those achieved with Truvada.

If the primary driver for prevention efficacy with orally administered to not for their prodrugs is local level tissue levels in Truvada should be better than DESCOVY F preventing HIV infection.

However if obtaining high levels in tran33s is important at the DESCOVY should be at least as effective as Truvada.

This question was addressed in the phase 3 discovered trial.

To discover trial, a phase 3 study was conducted to assess the state the and efficacy of DESCOVY for HIV prevention.

This was a double-blind active comparator noninferiority trial comparing DESCOVY to the standard of care for prevention Truvada.

The study and rolled over 5000 men and transgender women who have sex with men.

It was designed and conducted in close collaboration with FDA and the community.

Importantly the study met its primary endpoint demonstrating noninferiority of DESCOVY to Truvada through the prevention of HIV infection.

Among individuals randomized to DESCOVY seven acquired HIV infection.

For an incidence rate of 0.

16 per 100 person-years.

And the Truvada group there were 15 infections resulting in an evidence incident rate of 0.

34 per 100 person-years.

The incident rate ratio, the prespecified method for determining noninferiority was 0.

47 with an upper bound of the confidence interval less than the prespecified margin of 1.

62 prespecified control secondary safety endpoints were met.

Demonstrating superiority of discovery to defraud the with

respect to markers and renal toxicity.

These data demonstrate that DESCOVY is highly effective at preventing HIV acquisition and demonstrates safety benefits over Truvada.

What we know now is that both the body and DESCOVY are highly effective for prep if taken.

Adherence is the key determinant of efficacy.

A correlate of protection has been established for Tenofovir Disphosphate

levels in tran33s.

The discover trial that lower levels of Tenofovir Disphosphate with DESCOVY versus Truvada are not relevant for HIV protection.

And that the seven fold higher Truvada Michael for a potential — these results support the conclusion that PBMC drug levels are the efficacy of orally administered to not revere prodrugs.

This finding is an important consideration for the extrapolation of the discover results from six men and transgender women to women.

Today clinical trials within men have had heterogeneous is efficacy results reflecting highly variable adherence.

Data from clinical trials demonstrate that when controlling for adherence Truvada is equally efficacious in women and men.

There is a biologic rationale for this finding.

The biology of HIV as well as the intracellular antiviral activity of Tenofovir Disphosphate are independent of gender .

HIV replicates within CD4 positive lymphocytes with must be recruited to the site of initial infection in order to successfully lead to specific systemic transition.

Adequate drug levels within the recruited cells are necessary and sufficient to mediate detection against HIV infection.

Multiple lines of evidence support reaching the efficacy results for DESCOVY for prep from the men and transgender women in discover to assist women.

The efficacy and therapy have been well established in over 2000 women and are comparable to results in men.

DESCOVY and Truvada both inhibit HIV replication and CD4 T cells to the same active metabolites, Tenofovir Disphosphate.

Extensive pharmacology assessments have demonstrated that the levels of Tenofovir Disphosphate are similar irrespective HIV status or gender.

Taken together this data support the use of DESCOVY for HIV prevention in women.

There is similar support for the extrapolation to adolescence.

DESCOVY and the three other DESCOVY obtaining single tablet regimens are all indicated for HIV treatment in adolescence.

Based on the safety and efficacy established in this group.

HIV behaves similarly independent of age and therefore the extension of safety and efficacy of discovery for prep can be based on similar former code Connecticut and adolescence as

well as a similar mechanist with the stress.

HIV infection status has no relevant impact on these parameters.

Taken together these data support the use of discovery for HIV prevention in adolescence.

Based on the data from the discovery studied the established safety and efficacy of DESCOVY for HIV treatments across men, women and adolescence and pharmacokinetic bridging the following additional indications is proposed for DESCOVY.

DESCOVY is proposed for the the reduce risk of HIV at at risk adults and adolescents wing at least 35 kg.

You will hear from Dr Scott McCallister who will

provide an overview of the phase 3 discovered trial and

efficacy results.

Then Dr Moupali Das, MD, MPH, Executive Director, HIV and Emerging Viruses, Gilead Sciences, Inc.

to have Dr.

Rick Elion has a long-standing history of providing HIV treatment and prevention services to individuals in the DC area for marginalized communities.

He will provide clinical context

for the results of the DISCOVER trial.

We have Gilead professionals to address these questions.

In addition we are pleased that Dr.

Peter Anderson is here today to address questions around adherence.

Dr Anderson is a professor of pharmaceutical sciences at the University of Colorado.

His laboratory specializes in the assessment of drug levels in dried blood splashed and they performed nearly 4000 dried blood spots in discover as part of our adherence discussions.

I would like to welcome Scott

McCallister.

>> Thank you Diana and everyone.

I am in infectious to lease infectious with a long history of clinical care with patience of HIV.

The section I will describe is a tree on

population and efficacy results.

Each of the nearly 2700 MSM or transgender women receive one tablet of active drug and one placebo tablet.

The primary efficacy endpoint analysis was time phase and was conducted when all participants completed 48 weeks in the study and how that completed 96 weeks.

The primary endpoint will the HIV incidence rate for 100 person-years study.

The study was blinded to investigators and study participants until the final person enrolled completed 96 weeks.

At the next scheduled visit individual participants are unblinded and offered to switch to open label to Scobee, blinding is ongoing

and not yet complete.

Eligibility criteria was decide to ensure that the study enrolled population at high risk HIV infection.

All participants required to have at least one of the two

followings risk criteria.

Two or more episodes of condom was a no sex with more than one partner in the 12 weeks before enrollment or diagnosis of rectal gun a real, rectal for media, or syphilis, in the 24 weeks before enrollment.

All needed to be HIV and hepatitis B negative prior or current use

of PrEP and a washout of drugs

was required.

DISCOVER are mostly urban and specifically chosen to be in Logan location

— able to enroll people with significant sexual risk of HIV acquisition.

We also selected size with the cultural competence to enroll and retain people of color and transgender

women.

Ultimate 35 DISCOVER , summer hospitals and some private practices and some local transmit infection

clinics.

The site was responsible to determine the best recruitment practice within their own community.

All of those who met eligibility criteria were allowed to enroll.

It was our goal to allow each person to be a risk of HIV infection to participate.

When we designed to DISCOVER — that included the right design

elements, comparable sexual risk criteria, optimal HIV testing and SDI testing.

So our study would yield reliable results.

We also discuss design issues with both site investigators and with community members in North America and Europe to ensure that the study was practical and aligned with existing clinical this.

Community members encouraged us to establish advisory boards for ongoing dialogue with them.

As a result three community advisory boards were set up, one that was DISCOVER specific and two that with broader HIV issues.

We drew valuable input from the interactions during the trial, during the design phase and recruitment and during the study conduct.

The primary efficacy endpoint was based on the number of HIV infections diagnosed in this cover divided by person-years of exposure in the study.

Noninferiority of DESCOVY was assessed by instance rate divided by the rate in the

Truvada.

Read derived 890 40 margin of 1.

62 of the TBD affect in three prior our CTS.

If the upper bound of the incidence rate racer in discover was less than 1.

62 DESCOVY would be noninferior to

Truvada.

The incidence rate ratio analysis of primary endpoint was a robust means of evaluating the effectiveness of DESCOVY ensuring that the result was due to the drugs used in the buddy and that the treatment population was a sufficient risk of HIV.

At each visit we assessed general safety, including graded adverse events, adverse events leading to discontinuation, serious adverse events and general safety labs.

There was renal lab testing at each visit, bone mineral testing

every 48 weeks and SDI testing from three anatomic sites also at each visit.

We used an analysis cascade or six prespecified safety endpoints where there was a possible difference between the arms due to lower levels of plasma TF the and those untapped.

The safety cascade began with changes from baseline in bone

mineral density in both the hip and spine.

If there were significant differences favoring DESCOVY on each of these we then evaluated the

specific renal proteins, the

data to microglobulin [

Indiscernible ].

With continue significant differences favoring to Scobee we moved to evaluate [ Indiscernible ] with

general urine proteins, all

purchases

—

at each visit all participants received HIV risk reduction education, adherence support and condoms and lubricant from site staff.

In addition opt in and opt out text messaging could be used to remind the individual to take their study minutes daily.

With actual words used in the text chosen by site participants.

Adherence is a critical determinant of prep efficacy so we measured it in multiple ways.

We employed two subjective test, the company to iPad-based questionnaires and counts from returned bottles.

Both at each visit.

We used one objective test, of dried blood

spot to determine TFV-DP provide of chronic adherence in the

past eight weeks before the collection date and we looked at a randomly selected subset of 540 participants about 10 % of the discover population.

In addition to the randomly selected subset we also analyzed dried spots in a case control the amount of analysis of the diagnosed with HIV and DISCOVER with matching controls for each.

In our case control study we compared every individual diagnosed with HIV on study and match them with

five uninfected controls.

The matched controls were specifically chosen to be geographically linked, to have similar time on study drugs in DISCOVER and to have comparable sexual exposure as evidenced by the on study diagnosis of a rectal STI.

From the group of uninfected study participants who were a match for each case five were randomly selected.

Once all controls were selected dried blood spot analysis of the Tenofovir Disphosphate were tested on the date of HIV diagnosis and also on one visit prior.

More than 5800 people were screened for discover.

364 did not meet eligibility of criteria including 49 tested HIV-positive.

5399 were randomized but six in HR were

not treated leaving 26 94 treated in the disco the arm

and 2694 2693 in the two but

arm.

Of those who were randomized and treated in the buddy the

median age was 34.

12 % of the population were emerging adults below age 25 and not jet

at peak own mass.

The racial breakdown across the 11 North American and European countries 84 % self identified as white,

nine % as black.

25 % reported being of Hispanic or Latin

ethnicity.

74 participants or 1 to 2 % of the population self identified as a transgender woman.

From responses on the confidential cost questionnaire the self-reported sexual orientation was or homosexual

in 91 to 92 % bio sexual in 6 to 8 % and heterosexual in one

%.

Baseline sexual behavior data from the confidential cost now showed that the treatment population was a significant risk of HIV infection.

50 % to 60 % had at least two condom was receptive and sex partners and the 12 weeks prior to study entry.

9 to 13 % reported rectal gonorrhea, rectal comedy

chlamydia or syphilis in the past 24 weeks.

Two thirds of discover participants had you dressed to be additional drugs and nearly 1/4 reported binge drinking.

Defined as six or more drinks on at least one occasion and occurring at least

monthly.

A total of 23 % had used Truvada for prep in the past and 16 to 17 % were on it at study entry.

While on study discover participants maintain this high level of sexual behavior on all risk levels.

The average under for condom was receptive and sex partners at baseline and continuing throughout the study.

Similar between the arms.

They also had high rates of sexually transmitted infections.

57 % of those on the study were diagnosed with gonorrhea or chlamydia from at least one of the three anatomic sites tested.

And including syphilis the overall rate on study or any one of these STI is range

from 139 two 145 per 100 person-years in DISCOVER.

Overall 42 % of participants had a rectal STI on the study.

Most likely due to condom was

receptive sex and 60 % had a urethral STI associated with condom was inserted of sex.

At the time of the primary endpoint analysis 16 to 17 % of participants discontinue study

drug in DISCOVER.

The most common reason for discontinuation from study drug

war participant decision, or loss of follow-up 6 to 7 % each.

Only 1 to 2 % of study participants contacted you’d drug to to an adverse event and the other reasons for discontinuation work less than one % each.

As Diana described the study met its primary efficacy endpoint for noninferiority.

Over 8700 person-years on study across the two arms a total of 22 HIV infections were diagnosed.

Seven in the disco we arm, 15 in the Truvada on.

Corresponding to HIV incidence rate of .

16 and person-years respectively.

The rate ratio where point 16 is

divided by .

34 is primary endpoint analysis the rate ratio of .

47 represents a 53 % reduction in HIV instance for the discovery arm relative

to the trip are arm.

The upper bound of the confident interval around .

47 is 1 lower than the lower point six to speak specified noninferiority margin thus establishing the noninferiority of discovery through to about

four prep.

We category —

prior to unwinding a three position panel concluded that five of the 22 HIV diagnoses most likely occurred prior to Tenofovir Disphosphate entry between the screening and randomization business.

The five with suspected baseline infection are shown here in the back section at the bottom of each bar.

Just above our the 17th individuals, six in disco we and 11 you to AVITA required HIV while on study.

The impact that the five suspected baseline infections had on the primary efficacy endpoint we went on to to conduct a sensitivity analysis.

By excluding the five individuals with suspected baseline infection one in discovery arm and the towbar arm the incidence rate ratio in the sensitivity analysis is 0.

55 The confident interval around it extends to 1.

48 which is still low the prespecified 1.

62 noninferiority margin.

Therefore even excluding the suspected baseline infections and the sensitivity analysis the incidence rate in the

DESCOVY arm noninferior to the Truvada aren’t.

We next looked at efficacy analysis by baseline subgroups.

In this forced plot the HIV instance for the two arms are shown again at the top in just left of center.

The rate ratio and surrounding 95 % interval is

show shown on the far right.

There incidence rates for both demographic and baseline risk behavior subgroups.

For each of these subgroups the incidence rates are low and consistent

with the race that the rates of the overall study.

The incidence rate ratio demonstrate that the effect of DESCOVY or Truvada was consistent with the rate ratio in the overall study across all demographic and baseline risk behavior subgroups.

In this diagram are genotypic resistance data of the 22

individuals diagnosed with HIV.

19 has samples that could be successively amplified and evaluated.

Of these 19 only for had genotypic resistance detected to either of the study drugs.

All four occurred in the Truvada arm, all forward M1 84 with resistance to FTC and all four occurred with the suspected race line infection.

Each of the four individuals of in 184 were able to be successfully suppressed on ART,

three with the DESCOVY regimen.

Our adherence results demonstrate that there was a very high level of adherence across the arms.

With self-reports from the confidential cost questionnaires about 80 % reported that they took their study miss more than 95 % of the time across all study business and similar across arm.

With pill counts from returned bottles of study drugs about 70 % appeared to be using their study miss more than tiny more than 90 % of the times.

The levels of TFV-DP from red blood cells from dried spot tested also demonstrate that was a high level of adherence in Ciswomen you both study arms.

On the nearly or thousand blood spots tested in the random subsets 80 to 90

percent had TFV-DP consistent with taking four more tablets per week for both arms.

In contrast very few, just 5 to 9

% at any visit had TFV-DP associated with taking less than two pills per week.

In the 22 HIV cases were compared with uninfected control the dried spot data analysis there provides a clear explanation for the difference between those with HIV and their matched controls.

Low or no adherence was the most significant risk factor are associated with HIV in the study for both arms.

In the case-control study drug adherence as measured in tried spots was significantly lower among those who became infected as compared to match controls.

Most cases had TFV-DP in red blood cells consistent with using the study drug wasn’t two doses per week while more than 20 % of the controls had TFV-DP associated with higher levels of adherence.

Finally less move from the TFV-DP in red blood cells which provided this measure of adherence.

Over to the levers in tran33s which provides a measure of efficacy.

The data from dried blood spot showed a high and comparable level of adherence across both arms.

The levels of activated drug, TFV-DP in PBMC was not across the arms.

One study state was achieved the medium TFV-DP in PBMC was sixfold higher in the

disco we TFV-DP then in the

Truvada arm.

The amount of activated drugs in the PBMC was consistent with established PK data from multiple clinical studies with TAF and TFV-DP treatment.

Given that 40 Fenton Mills represent the 90 percent concentration or EC 90 of TFV-DP 98 % in the DESCOVY arm

was above — in the Truvada arm hello was about this mark.

In summary that DESCOVY was

conducted in — over the course of the study.

Only 87 hundred person-years to HIV incidence rates were only very low and

the noninferiority of DESCOVY or Truvada was established.

Low adherence was the most significant risk factor associated with each HIV diagnosis.

While M1 84 mutations occurred in the towbar arm there was no resistance to study drugs

reported in the DESCOVY arm.

There was no resistance observed in the discovery arm, for cases of M1 84 reported in the Truvada arm.

Significantly more participants in the discovery arm — I would like

to turn the presentation to

Dr.

Mobile DOS Moupali Das.

>> Good morning everyone.

I am an infectious disease physician.

My career has been devoted to helping and that HIV epidemic by increasing prep

uptake.

For the last six years I have worked exclusively on clinical trials comparing the efficacy and safety of the two to enough of your prodrugs.

The discover trial is the largest discover trial with a single comparison of TAF with TDF.

It offers a unique opportunity to

compare both.

The safety and tolerability of DESCOVY and Taft have been Doorly

established in over 26,000 person years of experience in clinical trials and over 1.

6 million person-years in clinical experience.

DESCOVY has a superior there improve renal and bone safety profile compared with the bottle

variable renal bone and biomarkers correlate with fewer

clinical events.

DISCOVER come from similar safety benefits and HIV uninfected people.

They are the first demonstration that these well understood renal and bone safety advantages of DESCOVY compare with Truvada are also true of HIV uninfected population.

There is a meeting exposure of 86 to 87 weeks in disco we and Truvada.

Verbal mineral sub study had 96 weeks of exposure.

Both DESCOVY and Truvada were safe and well tolerated.

The type frequency and severity of their first events were similar between the DESCOVY and Truvada arm.

Most adverse events work grade one or two in severity.

There was a low percentage of study drug related serious adverse events where adverse events needing to discontinuation in DESCOVY and Truvada.

During treatment one person died in each arm.

The most common adverse events in the DESCOVY or sexually transmitted infections.

Six of the nine most common Aedes were bacterial sexually transmitted

exposure.

This is

—

will come back to the general safety data.

The race of SDI were high and persistent

throughout the trial.

About 50 % of participants had lab diagnose gonorrhea or chlamydia at any of the three anatomic sites at baseline and throughout the study.

Were no differences between DESCOVY and provide a.

Two of the most common AE were rectal gonorrhea and chlamydia.

Approximately 10 % of participants had right of Ghana radio or gonorrhea at baseline.

There were no differences between DESCOVY and Truvada.

The by visit positively race reflect high and persistent sexual behavior with the persistent STI race

reflective of high rates

.

There were different from our treatment trials.

Four of the most seven most commonly prescribed medications are and abide out used to treat SGI’s.

More than half of the

participants received — returning back to general safety the common study drug related adverse events reflect the most common adverse events in the discovery treatment

trial.

20 % of participants in DESCOVY and 23 % enter about a half study drug related adverse events.

, Related adverse events were low in frequency and similar between arms.

The majority were mild G.

I and headache.

Laboratory abnormalities were also in

common in the study.

Greater higher lab abnormalities occurred at a low frequency and number clinically significant.

In the HIV treatment trial and in the Truvada adherence subset the lipid-lowering effect of Truvada has been well documented.

In discover Truvada was also associated with a reduction in lipid parameters.

Total cholesterol, HDL and LDL cholesterol all declined.

The magnitude of these declines is not clinically significant.

Were as total cholesterol, LDL and HDL levels of were generally unchaste in participants taking DESCOVY.

Importantly these changes resulting in no difference in the total cholesterol to HDL levels between arms which is strongly associated with cardiovascular risk.

While both this cove and Truvada were safe and well tolerated DESCOVY was superior to do about it in all

sex renal and points.

Reviewed cases including proximal to be a lot of P including

thank only syndrome.

, We also evaluated total protein area by

dipstick and — in discover after 80 person-years of disk exposure

to study grog —

DESCOVY had significantly — the prespecified time point for the assessment of secondary safety and points.

At week 48 discovery participants also had to the can’t lower —

>> At week 48 20 per percent of participants on DESCOVY paired with 24 % on Truvada developed dipstick put in your area.

One % compared to Truvada, to present develop clinically significant quantitative protein area as defined by the kidney foundation as a urine protein to creatinine ratio of greater than 200 mg.

Graham DESCOVY had superior

—

on the left panel the Truvada group had a look 20 % increase from baseline in tubular

written area while discovery —

>>

The superior real safety of DESCOVY was demonstrated in participants

who are on about at baseline who switch to DESCOVY compared to those who remained on

Truvada.

The discover trial included participants taking Truvada for prep at baseline and do not require a washout of Truvada.

Were a large number of, 905 people who were on Truvada at baseline.

We prespecified sensitivity analysis of the participants on baseline Truvada for renal and points.

As overall discover population those on baseline Truvada were switched to DESCOVY had improvements in renal function to to those who remained on Truvada.

The improvements in JFR and those that switch to discovery was apparent as early as week four and persisted through week 48.

The improvements with DESCOVY

in tubular function.

Those who switch to discovery has significant decline in tubular proteinuria approved tubular function while those who remained under by the had 11 %

increase in rental binding [ Indiscernible ].

These changes became apparent as early as week four and continue to week

48.

Discovery was superior to Truvada on all prespecified biomarkers of renal function.

This was demonstrated in both overall population as well as the Truvada switchers.

We evaluated bone safety with the bone density study.

The median age was 34 so approximately half of the participants were still building to peak bone mass which is achieved in the early to mid 30s.

DESCOVY participants headed increase in bone mineral density from about [ Indiscernible ] from baseline in stable help bone density bubbles on Truvada had declines of one % in both bone mineral density from baseline through week 48.

DESCOVY was statistically superior to Truvada in both the specified and points.

Using the T-scores from the baseline participants were classified into the clinically relevant categories

of bone mineral density, and osteopenia and osteoporosis.

29 % of participants either had osteopenia or osteoporosis in the arms.

After 48 weeks after patients on DESCOVY — SGOT show you there were safety endpoints.

Discovery was superior to do about it in all six prespecified Alpha control bone in real safety endpoints at the week 48 endpoint.

We continue to follow long-term renal and bone safety in the

discover study participants.

Both DESCOVY and Truvada were safe and well tolerated.

The rates of serious adverse events or adverse events leading to discontinuation study drugs were low and balance between RM.

The magnitude of the differences in the early safety endpoints between arms is similar to what is observed in HIV and help be comparing DESCOVY to Truvada.

Confirm that the DESCOVY superior safety in PrEP .

This is a significant development from a clinical perspective so we can now offer a similarly efficacious and safer drug as another choice for HIV uninfected people were simply at risk for HIV acquisition.

The efficacy and safety of DESCOVY for women, men to have sex with men.

The excessive clinical

—

we have over 108 thousand person-years into about a for prep and 6500 person-years for DESCOVY for prep for discover

trials.

Both drugs were highly effective for treatment and prevention.

Efficacy is driven by Tenofovir Disphosphate or PBMC.

The 90 % lower plasma levels for DESCOVY compared with Truvada is associated within an improved bone and renal safety profile.

The pique of DESCOVY or Truvada is independent of in transit and extras it factors this means that the pique of plasma to not

for fear is not affected by sex at birth, gender identity, or sexual orientation.

HIV infection status also does not

affect pique.

Tenofovir Disphosphate levels

are comparable with DESCOVY in

DISCOVER and the level in SI Ciswomen in contrast the

Tenofovir Disphosphate — efficacy is high in both women and men on PBMC regimens for treatment.

Also with Truvada.

The key metabolite for both Truvada and his cove associated with safety is plasma to

nonsevere.

Plasma TFV-DP

—

these renal improvements are consistent with the trial results on those on baseline Truvada who switch to DESCOVY.

Women continue regimens who switch to DESCOVY at clinically significant improvements in osteopenia and osteoporosis within 48 weeks.

At baseline a third of women on Truvada based regimens for HIV treatment had osteopenia or osteoporosis.

When he switched to DESCOVY have a spine osteopenia and less osteoporosis at week 48 compared to those who continued on to Rodda.

These results were statistically significant.

Discovery is also an efficacious and safe treatment for HIV and adolescence.

DESCOVY is approved for eight IV treatment in adolescence when at least 35 kg in combination with third agents and discovery Regimens.

It has similar safety benefits compared with Truvada in adolescents with HIV.

Truvada has been approved for (PrEP .

To this .

As a sub for HIV infection status is not affect PK so we would expect high levels in adolescence if they were taking for prep .

50 adolescence who initiated or DESCOVY for HIV

treatment were also evaluated.

The mean age in the study was 15 years and over half of the participants were female.

Discovery was highly efficacious in adolescence for

HIV treatment.

With DESCOVY the levels in adults without HIV adults and adolescents with HIV are similar across all three populations shown on the

left.

Plasma TFK PK is consistent with results from prior studies.

Truvada has — importantly due to the 90 % lower plasma

—

Allison participants continue to build bone mineral density similarly to an eight sex and race match population.

DESCOVY is noninferior to Truvada in HIV treatment and prevention

efficacy.

There comparable to Ciswomen and adolescence.

The efficacy and safety of DESCOVY for prep can be inferred for Ciswomen .

Taken together and the excessive efficacy and safety data support the purposely inclusive indication.

We have planned multiple effectiveness studies of

discovery for prep.

We consider numerous approaches to studying the efficacy of DESCOVY in 2015 we were discarding the trial.

Ciswomen

.

A superiority trial for DESCOVY over Truvada was also not reasonable as both are oral daily pills differentiated primarily although not exclusively on safety.

Lastly we considered a noninferiority trial.

Unlike discover where we pulled effects from three

randomized trial with similar efficacy the five randomized controlled trials in women lacked a consistent treatment of fact from which we would contact a noninferiority margin.

Using only the two trials with the highest efficacy in women taking Truvada who were able to estimate that a non-inferiority trial would require enrollment of about 22,000 women in the high incidence reason.

This would require approximately 8 to 10 years to conduct.

The design of the trans-35 DISCOVER was not approved for adolescence until 2018 so we would be comparing the safety and efficacy of two investigational agents.

More importantly we had different data that adolescence require a higher visit frequency to maintain adherence and made benefit from age-appropriate targeted intervention to maximize recruitment and

potential in clinical trials.

The efficacy and safety of discovery for prep in women and adolescent can be inferred from the totality of evidence for HIV prevention are extensive safety database for HIV treatment.

Clinical data are now needed to inform providers and individuals at risk for HIV regarding the clinical effectiveness of DESCOVY for PrEP.

We’re dedicated to generating this data and will

be supporting in over 3400 women in the United States and Africa.

They include the evaluation of the safety for prep in pregnant and breast-feeding women and how the improve safety tolerability and smaller size DESCOVY could improve uptake and persistence.

We are strongly committed to understanding how having an additional choice for PrEP with this cove which has an approved renal ample safety profile and pharmacologic profiles consistent with an earlier and longer protection from HIV can help address our shared goals of increasing PrEP uptake in helping to end the HIV epidemic.

Thank you please to invite Dr.

Richard L in to talk about the clinical context.

>> Good morning.

My name is Dr Rick Elion.

My financial conflicts of interest are I do

research with Gilead and [ Indiscernible ].

I am a member of the advisory panel for Gilead and I have no stock or financial interest.

I have been active in the carriage it be patient since I left residency in 1983.

I began in Brooklyn in 1985.

At the time of the HIV testing of that year I have been continuous at the front line for caring HIV patients are seeking solutions and improvements in care for over 30 years.

I watched countless men and women die in my first 10 years of practice.

Advances in treatment and prevention have transformed a hearing job to one of satisfaction.

And director of Caesars at the Washington health Institute to serve low-income population in the district.

And a clinical Professor George Washington University.

We were the site for one of the first prep

demonstration in 2013.

I worked at the Department of Health in the wellness program in DC which of the center of care of

those with SDIs.

I also continue to follow patients as a Washington health Institute some of which I have cared more for 20 years or more.

Am grateful and honored to have the chance to share my first active and my DESCOVY is important to our prevented toolbox.

It is estimated that up approximately 95 % who either don’t know their diagnosis or have been diagnosed and not enclosed engaging care.

While treatment is successful at preventing new infections the bulk of new infections will not be prevented with just treatment alone.

We need multiple options for patients who choose their ideal method of treatment is.

When consumers have more choices at least two greater

treatment.

PrEP is critical to prevent

new infections.

The variety of options throughout each person to choose what is right for them.

Choice is critical for patients as they are much more comfortable and committed to the choices they make rather than being told what to do.

Biomedical interventions including treatment as prevention and PrEP are among the most useful.

Treatment as prevention is helping the decline of 80 % of new cases in the United States.

Is a future synergies of these apartments treatment for HIV-infected individuals and PrEP for infected individuals.

The announce shown here look at the change in new diagnosis of HIV over five year period in states by PrEP use.

This data is control for rates of Biologics oppression and the states with low prep use at the finding of three %.

You can see about a one % increase in HIV diagnosis.

These are compared to the high prep use group with 11 % of PrEP where you see a five % reduction in new cases.

These race of PrEP are still quite low considering the risk of profiles in the communities.

And could be greater if there greater [ Indiscernible ].

The CDC report makes clear that communities in need are receiving prep.

This demonstrates the imbalance between the potential need for PrEP in certain communities and the use of PrEP.

Don Smith reported on the disparities between the potential members of various populations that were qualified for versus those who are using.

differences are staggering in the communities and can be seen in the slide go roast differences exist for only a fraction of the communities who are benefiting from props ranging from racial disparities in Blacks and Hispanics and men and women.

Adolescence, 15 to 25 years of age who are sexually act of art facing the same disparities.

We know that Truvada for PrEP efficacious in sis men interested in women.

DESCOVY pharmacology consistent across ages.

This notion of forgiveness is critical to this population.

Aside from the potential benefits of a better DISCOVER DESCOVY will be a better medication for people who are building bone mass.

There depositing bone as part

of the normal growth and the loss could potentially have a lasting effect in adolescence were after losing using to about it may not ever reach bone density.

We is the notion of a Z score.

A lo Z score below two is a warning sign that you have less bone mass and/or may be losing bone more rapidly than expected for someone of your age.

Consideration of The scone for age, race and sex is most important during adolescence when Gohmert is that the variability increases.

The scores are stable over three years of rapid bone decline which you can see after stopping PrEP especially in the younger participants is a concern in finding of these analyses.

Disease for individuals on Truvada, told body during the 48 week period of prep and covered with the comparable time.

The clinical significance of this is twofold.

The first is that the bone mineral density based on the Z score does not recover the baseline 48 weeks after PrEP has been discontinued.

Second.

It is a better choice therefore for adolescence.

Offering them the medication that allows the bone to grow at a normal fashion is an important consideration selecting the best medicine for HIV prevention for adolescence.

It is equally important for women.

I previously mentioned the PK event for adolescence.

The PK data that was presented earlier reflect a higher interest are loyal level of TAF and longer period that the level stay above the threshold of efficacy.

60 days versus 10 days.

These represent a significant difference between

TAF and TDF that PBMC have been correlated with level the protection.

This continues to evolve.

The Ciswomen that the failure of higher tissue levels for men was on a detriment to the overall efficacy.

It was likely German by the higher drug levels in the barest components of the PBMC.

The higher levels in the subsequent longer time to load levels fall below threshold infections could [ Indiscernible ] and mirror to

further study.

This would be very important for both adolescence and for women who

are starkly have a greater [ Indiscernible ] due to poor adherence.

PrEP has been approved for women when adequate adherence has been

maintained.

Women make up approximately nine % of new infections I have a great deal of unsafe infection

through unprotected contact.

Women therefore make up an important part of the population for controlling HIV infection.

Are underrepresented in the low use of PrEP.

In 2015 only two % of women who are eligible for prep were on prep.

I work with colleagues at the Washington Hospital Center in the Department of Health in the same by engaging women in PrEP in the STI program known as the wellness clinic and the family planning at Washington Hospital.

We screened nearly 1000 women who are at high risk of sexual practices and only less than one % opted to

initiate that despite free medications and pure support.

Despite her numerous efforts to explain and encourage the adoption of more tools for HIV prevention for women we have been lagging behind.

This data of HIV incidence for demonstration products show the comparable rates of new infections in men and women.

There should be little doubt that PrEP was Truvada was equally well in men and women when appropriate.

This demonstrates real-world efficacy.

There is no data to suggest that this efficacy is different between genders when adherence is somewhere.

These data from world experience support the fact that women benefit from the same fashion with men for help with Truvada in the world world by adjusting clinical trial settings.

As mentioned earlier women had not adopted up in significant numbers.

The reasons for this are complex and involve multiple issues.

The study of African women and men is a

clinical issue for women as well as side effects and if the treatment will work.

Other service pointed out the mistrusts of providers, stigma and fear being out is as needing HIV protection, partner notification and lack of support once partner cost, access to medicine remain key drivers for women’s reluctance start PrEP.

There are multiple reasons in the this is a

mission exercise by women for adopting treatment.

We want to help women make a better informed decision.

DESCOVY bone safety data is clear.

Increase rich increased risk of fraction and people living with HIV who have taken Truvada-based

regimens.

Approximately one in two women over the age of 50 will break a bone because of osteoporosis.

A woman’s risk of breaking a help is equal to her combined risk of breast, uterine and a wearying cancer.

HIV-positive women have a 15 % higher risk of osteopenia at age 50 than men and a comparable age.

DESCOVY is a safe or alternative for women that Truvada who at any risk for risk for bone health and treatment settings.

I have switch women trying to write a

two TAF regimens to alleviate problems.

We know that Truvada for PrEP is equally effective in men and women.

We know that PBMC levels are associated with efficacy for HIV prevention.

There is no established regimen — the low tissue levels were not predictive of us to sex scene

in Ciswomen and success —

the key issue is that hearing the based on the evaluation of DESCOVY for prep and whether the indications to the extent the on the participants within the DISCOVER trial.

There is a history of conflicting data regarding the role of tissue levels.

Versus the role of systemic protection through components of the blood.

This is obviously one of the key questions before the committee today establishing efficacy and safety in HIV prevention for all committees.

The data from the Ciswomen that systemic protection tries efficacy in MSN and transgender women.

There is a call for —

we do know that DESCOVY was safer in men and transgender women and we do know that the improvements in safety with TAF versus TDF as well and we can debate is a significant clinical and if it.

I believe they do from a safety

perspective for both adolescence and women based on the data that has been shown today.

The differences in PK between TDF and the improve profile might improve outcomes by mitigating suboptimal adherence.

This evidence supports the extension of efficacy data for Ciswomen for

women and adolescence.

At the end of the day as a position counseling women for the need for HIV prevention and prep I cannot stress enough how detrimental it would be to give men a choice of what they for medicine not offer the same choice to Ciswomen who should have the same options available to CSS men and trans women.

They should not have to wait for approval which could take at least four years for TAF for PrEP.

That women decide if the — there is reasonable certainly based on the Truvada prevention to extend the certainty for the mail and transgender men in

discover — I’m certain that women in adolescence do not have the choice and cannot use

the safer medical and medicine.

I hope we don’t give those vulnerable populations that message.

And to allow them the option to choose what will be best for them.

I have talked clinicians, in Uganda and they look to the U.

S recommendation without indications for medications.

Providing a safe and effective medication were women make up half of the cases is fundamentally important.

The decisions today have implications not just in the

United States.

Please allow me to keep doing my job of guiding and helping patients to make the best decisions.

Don’t take the choice out of our hands.

The totality of the evidence and the failure will Evan support making this drug available to all those who need it.

Thank you >>>> I would like to thank the applicant for a very thorough presentation on a tremendous amount of data.

Before we have clarifying questions for the presenters we will take a 10 minute break.

Please remember there should be no discussion of meeting topics during the break amongst yourselves with any members of the audience.

We will resume at 10:25.

****6. TRANSCRIPT 2

We have about 50 minutes for clarifying questions for the applicants presentation.

We may not complete all of the clarifying questions, in which case we will resume after lunch, after we have a chance to have the agencies

presentations.

In the clarifying question process, for those of you who are new to joining us, what I like to do is try to build on themes.

I really asked for committee members to please use the honor system and how we do the clarifying question process.

When we start, if you’re interested in asking a question, signal Lauren or I who will add you to the list.

If the question is asked and there is a follow-on that builds on the theme, very much

like to build on the theme

, please take your card and turn it on its side.

That will indicate you want to build on the theme so we can have a series of questions on the same topic and not be bouncing around with every other question going back and forth between topics.

I just asked the committee members to build on the theme and not put that away so you can ask another question faster.

We will try very hard to get to all the questions as quickly as possible.

I would like to, as much as possible, build on themes because that’s more efficient.

So we will start with I think the member on the phone.

The first clarifying question.

>> Yes or.

The question is, what if any are the laws determining bone density, and renal safety related to the adherents and failure?

>> I am going to ask the doctor to come to the podium and speak to the longer-term bone and

Ringel, renal effects of DESCOVY use .

If you have an additional question we will take it from there.

>> Basically, the ability to steer on multiple incidences, occurring multiple incidences.

>> The failure to what to adhere.

>> Okay .

We will present the safety data first in terms of the long-term effects, then we will talk about adherence, our, how

adherence is related to efficacy.

>> [Echo] >> To the colleague on the phone if you can mute, we are getting feedback.

>> The bone mineral density biomarker in the renal tubular biomarker is a function by markers chosen for evaluation in DISCOVER are associated with clinically meaningful differentiation over the long-term.

First we will look at own and then we will look at

renal .

slide one up please The early declines in bone mineral density between weeks 24 and 48, widen over time through three years of follow-up.

In a representative example of BMD from twofold trials in regiments in HIV treatment.

On the right you can see the separation in the BMD curves is associated with increase in discontinuations

due to to bone adverse events.

This is over a three-year time.

of data from the HIV treatment literature.

Slide two an analysis from the euro Sita

cohort with 619 fractures in

86,118 P why a follow-up.

This was adjusted for demographics in the HIV specific variables and comorbidities, having ever been

on TDF versus never been on TDF, was associated with a 40% increase of fracture risk.

Being currently on TDF versus never being off of it, was associated with a 25% risk.

You may ask what does this mean for

people on prep like PrEP ?

This is data from published earlier this year in terms of an

analysis of trials done to support the US services preventative task force recommendation with a grade A from PrEP for HIV prevention.

Here we see both TDF trials and

Truvada trials.

The follow-up was significant shorter than we have in the treatment literature, however there was an increased trend towards fractures in those receiving

TDF or Truvada.

Now we will switch to renal situations with bio markers.

A similar pattern exists for the tubular markers which are early markers of proximal tubular dysfunction.

The early changes, as early as before, and the line separate over time with longer-term follow-up to weeks 48 and week 96.

They continue to separate through week 144 .

On the right-hand side you can see there were no

discontinuations on people on DESCOVY containing regimens but the toxicity is evidenced by increasing adverse events from renal causes leading to discontinuations in a stepwise faction through week 48 through week 144.

With respect to how this is relevant for people with PrEP, we turn to this year earlier.

Here we see that either TDF or Truvada PrEP is associated with an increased risk of renal a ease

.

In summary , AE’s, we chose these biomarkers because we are aware of the clinical meaningful differentiation in terms of renal and bone safety over long-term follow-up .

And continue to follow the Testaments and discover to follow them over long-term.

>> With respect to the adherents question, I will say there have been multiple clinical trials as well as real-world data sets demonstrating the close correlation between efficacy to Truvada for PrEP and outcome .

Slide five.

This figure demonstrates across multiple different clinical trials and will world data sets that the higher the adherents within the study or within the [indiscernible] within the trial looking at adherence

participants based on plasma, levels, intercellular drug levels, the higher the advocacy with respect to risk reduction for HIV acquisition.

We saw a similar relationship within the discovered trial with respect to nonadherence to either

Truvada or transient, DESCOVY being the primary factor associated with HIV infection.

>> If I may, on the bone, do you have any follow-on questions?

If not we will have some follow-on in the room.

Dr alien on slide 105 showed TDF in adolescent bone development.

Do you have similar for TAF quick >> To review the data we have with task, TAF containing regimens in adolescents.

>> So first I will show you the data in adolescents with HIV.

Slide one up.

DESCOVY or TAF does not have the same impact on bone marrow density as does Truvada.

Here is bone safety in adolescents , adolescents with HIV.

You see both the spine and total body

cut continue to increase and grow and there is minimal changes in disease force which reflect age, race and gender matched populations.

In the Tran 12 study we included

people who were 18 and older did the age range was 18 to 76 .

however we did look at the bone mineral density in participants stratified by age less than 25.

Slide number two up.

This is comparative data between DESCOVY and Truvada ,

less than 25 years and then greater than 25 years with spine.

You can see the participants on DESCOVY continue to have the same

increase in spine bone mineral density where those on Truvada had significant declines which is particularly relevant to this population .

similar trends were observed with hip in terms of continued growth on DESCOVY or stable on DESCOVY but declines on Truvada .

>> Is this consistent with the findings and PrEP that Elian showed .

>> With this data compared to age matched controls, HIV uninfected, not on a compound, is the bone development on TAF equal , or is there a difference?

Because comparing it to TDF, one may accept the

decline in say it is not [indiscernible].

>> If we go back to slide number one.

These are participants with HIV.

So there is that consideration.

But this is people who are on Truvada .

You are asking about the Testaments on TAF .

>> Persons on TAF and am interested in the TAF comparison, not on a tenofovir

dear compound.

Because we don’t have any data

without HIV, this is with HIV.

The dotted line are the matched by age, race, gender and population.

You can see in the dotted lines between zero and week 48, there is no difference in the blue dotted line which is a spine score and the pink dotted line which is total body.

>> Those would be age matched control that’s what I thought you said, I just wanted to make it clear that best as we can tell there is no aggregation of normal bone development, as best as you can tell realizing they are HIV-infected, to be on this for long-term.

>> Exactly, thank you.

>> Was there a follow-on question?

>> My follow-up was related to the adherents question rather than bone.

The previous slide, the backup 32 showed the relationship between adherents

and efficacy.

One of the, one of the considerations is the relationship between the adherents and the efficacy on Truvada continued regimens versus TAF .

Sing in women and men, that informative thoughts as to the local tissue concentrations.

So looking at the film PrEP , versus the [indiscernible] populations, if you can go into how levels of adherence which then presumably correlate with PBMC concentrations, correlating in women versus men.

>> So the level of adherence, measured across the studies varied.

They were not all uniformly assessing adherence through the same mechanism.

However the Association between adherents and efficacy by these measures, whether it was Tenofovir, Plaza levels or Tenofovir within the peripheral blood cells, that relationship held on across men and women.

The study shown here represent some of the larger studies conducted to date.

But since Truvada the prep was approved seven years ago, there is an even larger data set that had accumulated.

The slide one please.

The CDC recently updated their website with new data on efficacy and analyses across all available data.

And concluded that adherents is highly correlated with outcomes for both men and women.

And that the efficacy of Truvada for prep is estimated to be 99% for men and for women, who are using Truvada for PrEP consistently .

>> If I can follow up on that , I guess my question goes into people who are partially adherence, to the degree it is

knowable, as partial adherents, as effective in women as in men?

I think indirectly the question as partial adherents you would think from pharmacokinetic, some of the concentrations of TF V and [indiscernible] which may not be sufficient, will it protect men and women equally.

There may be concerns about tissue.

Again partial adherents protecting women as equal as men?

Certainly there will be a relationship in adherence.

>> There was some recent data presented just a few weeks ago at the IAF conference from the [indiscernible] study which was a larger study conducted in Africa in men, looking at, it was looking at different interventions to increase adherence.

But in terms of the clinical outcomes of that trial, slide three please.

Among the 400 women aged 16 to 25, enrolled in this study, there were four infections with overall incidence rate of one, per 100 person-years.

They use dried blood spots which is the methodology from the study, as well as from Discover trials and they found that the

infections have closely correlated to these measurements of adherence using the dried blood spots, which is to say two of the infections occurred with no detectable blood level and the other two occurred in the setting of adherence consistent with less than two doses per week.

So this suggest that in the setting of low adherence there is no relationship.

>> The adherents question relates to the other question, the argument that there is high levels of Tenofovir active component and that is a correlate of protection.

My understanding is the data, those data were generated from people who were less adherent

and more adherent to the Tenofovir drug.

Is it the PMC data, are they not simply adherence if you measure Tenofovir and hair or some other body component, and do not arrive at the same conclusion that Heyer is a core elective protection for HIV

protection.

It gets to the strength of those data which are critical to this argument the company is making.

>> Sewed Tenofovir knife estate when measured in red blood cells as the stem would be dried blood, is a measurement of adherence alone.

And can be analogous to measuring Tenofovir and hair levels or

plasma, the advantage of the Tenofovir in blood cells is it

allows for an integrated affect of efficacy over a longer period of time, similar to a hemoglobin A-1 C did nevertheless it doesn’t speak itself to efficacy.

But we know for Tenofovir prodrugs to be administered, the drug is acting within the T cells which are component of peripheral mononuclear cells .

we also can draw the correlation between the level of Tenofovir by phosphate within the red blood cells, and with the

corresponding level is within PBMC based on phase 1 studies and healthy volunteers that Dr.

Anderson did to validate that analysis.

And so the dried blood spot data adherence data can hit thresholds of adherence, and based on the phase 1 study done where they did, were able to match the adherents bands exactly to how many doses were given per week, they can then correlate that to the expected intracellular PBMC levels.

We correlate that with efficacy because that’s where we know the diet

, the virus replicates.

>> Only based on adherence as I understand it.

How do we know that somebody with the exact same adherence, let me ask you differently.

How do we know that the levels in PBMC are the critical determinant of prevention, not of treatment efficacy of someone with HIV, but have prevention.

You have an established that in my mind.

>> So we know that Tenofovir ,

Truvada for PrEP is equally effective in men and women.

And adherence is the primary driver

of that efficacy.

When we look at the vegetal and rectal

tissue levels of Truvada .

I will try to slow you that slide in one minute, what we can see is the rectal levels of Tenofovir by phosphate following Truvada use are 100 fold higher than they are in vegetal tissue.

If genital tissue, rectal tissue, I will put slide one up.

These are the data I just spoke to with the 100 fold higher rec tool Tenofovir levels as compared to vegetal levels in the setting of Truvada , with healthy female volunteers.

So if genital tissue levels were driving efficacy, then you wouldn’t expect to see equal efficacy in men and women.

You would see disproportionate efficacy but we don’t.

We also know from the DISCOVER trial that DESCOVY is highly effective at preventing HIV acquisition in men who have sex with men, and transgender

women.

And slide to add in the DESCOVY data in the vegetal and rectal compartments.

What you can see is for DESCOVY , rectal compared to vegetal, told levels are tenfold higher and within the rectal compartment Truvada achieves higher levels

than DESCOVY .

So again comparing Truvada to DESCOVY, if rec told levels were driving efficacy, you would expect Truvada would be better than DESCOVY .

But that is not what we saw in the trial.

We saw they were non-inferior.

And we saw that adherence was the primary driver of efficacy.

So we know that we have these high rectal levels, we know that

vegetal levels with Truvada are lower.

But we know Truvada is highly effective in women who take the drug.

And therefore that provides evidence if you

will, that the active Tenofovir by phosphate and the circulating PBMC is driving the efficacy, and not the tissue level within the homogenate of the tissue.

>> We have several more follow-on questions.

Dr >> I actually thought was follow-on but related to the size.

A couple of statements regarding the size between Truvada and DESCOVY , how much difference in size, having an impact on, you know somebody taking it easy to take it somewhere else.

>> So DESCOVY is substantially smaller than Truvada because it catches a smaller dose.

25 milligram versus 300 milligram.

Slide one please.

Obviously not to size, but you get the relative comparison between the size of the two pills.

Size has been cited in patient surveys as a factor that is seen as favorable.

>> We are still doing follow-on’s.

>> My follow on his back to the PBMC question .

I think the data we have seen where you tried to show the correlate with efficacy was based on the [indiscernible] study with men.

We get into the Tran 12 study trial with DESCOVY.

And then where we didn’t see Truvada being effective do we know that also works for women in other trials or just in those two drugs?

>> There are other trials besides partners prep, that showed efficacy in women.

For example TDF number two was a study conducted in both men and women.

In the TDF to study if you look at the as treated population that sensors people after they have no longer been taking the drug, for at least 30 days, then the efficacy and the men and in women is comparable.

>> Actually my question was do

you have the TFE PBMC data and women know the marker Rebecca Sissy was in the trials, of efficacy was in the trials, that was my question.

>> Within partners PrEP , we had adherents but I don’t believe there was Tenofovir by phosphate levels with the Tenofovir levels .

We can take a look and see if we can find a specific data regarding Tenofovir by phosphate levels in clinical studies within women.

What I would say, I want to reemphasize that the connection between adherents and the Tenofovir by phosphate is in TDM sees, made based on, in PBMC is on the dried

blood’s not assay.

I will have Dr.

Anderson come up to speak to this so he can walk through the connection how the Tenofovir by phosphate corresponds to the level.

Because it seems like what we are talking about is Tenofovir

bi-phosphate in the PBMC’s driving efficacy.

You don’t actually measure the PBMC during the study for adherence, you measure the dried blood spot and then we know from the validated assays what that level correlates to with respect to Tenofovir bi-phosphate in PBMC .

>> I will also say we know across men, women, HIV affected, HIV unaffected that the Tenofovir bi-phosphate levels are consistent .

>> Good morning, [indiscernible] consulting honorary for my time here but I do not have a financial interest .

in the outcome of this meeting.

I wanted to explain the relationship between DBS concentrations and efficacy as well as PBMC concentrations in efficacy , if I could have slide number two up.

DBS was used in the Discover study.

As an adherents biomarker.

What we measured is enter cellular red cells.

The reason is the halfway in the red cell is 17 to 20 days.

So that means the concentration will be proportional to exposure to the drug adherence.

A proportional relationship.

So it’s a wonderful marker for assessing and quantifying adherence.

If I could have slide three please.

The way that we operationalize this is dried blood spots coming to the lab we take a punch.

So we normalize the amount we essay.

And then validate the method, to get it

resolved.

And then we have to understand what that resolve means.

To do that we conducted several observed dose in PK studies and how participants with DESCOVY versus Truvada

and gave them very and , varying adherence rates.

We could tell then the concentration, what the adherence, when we first made that standard relationship.

And then we wanted to know do these bands of adherents relate relate with this one.

And they do.

So these results are from the open label extension that show HIV incidence in the dried blood spot level.

And the difference adherence bands along the top, less than two doses per week on average .

2 to 3, and then greater than for.

People that have blood spot levels greater than four, people that had blood spot levels from 2 to 3 had approximately 90% reduction in HIV incidence related to not being on PrEP .

Holding those dosing categories in mind, this is very similar to what we see

in PBMC’s , slide to please.

So these now just switching the mind from diet, dried blood

spots, these are the active site now.

Case-control from the randomized controlled trial.

And the relationship between drug concentration and PBMC , and efficacy compared to placebo.

Now looking at the bands along the top, these are PBMC concentrations from directly observed dosing

studies showing two doses per week as well as four or more doses per week.

And we saw approximately the same efficacy relationship in the PBMC’s .

Those that were in the roughly 2 to 3 dose range, 90% reduction.

Those in the for more essentially 100% reduction.

HIV incidence is sort of the connection that we make through adherence us, through adherence is the point brought up earlier, making a connection through the adherence.

The differences we know that is the active side.

>> [indiscernible] >> You’ve sort of drawn a line between >> Please talk closer to the microphone >> You’ve drawn a line between the levels from the dried blood spot test, and PBMC levels .

And the correlation with

efficacy data.

And I guess, sort of my thesis is, because PBMC’s or T cells are the site

of replication in the virus, and that TAF has good intracellular levels in PBMC’s that the efficacy would be

expected as good or better.

But the connection between the PBMC levels in previous PrEP trials, depends on the fact, the pharmacokinetics of Truvada .

So whatever the actual target cell that is necessary for effective PrEP is, we know it correlates with the PBMC levels .

Not that PBMC’s are the actual target that makes PrEP efficacious.

How do we know that the correlation between PBMC levels and sell X, is the same with regard to the pharmacokinetics of these two different drugs?

>> So we know cell X is APB for positive T cell.

That is the only cell in which HIV will replicate to spread infection.

Now that CD positive T cell could be within the tissues.

Or it could be within the peripheral blood mononuclear cells recognizing that these are not distinct subsets, but that there is circulation around the body in trafficking of cells in and out of tissues.

I will put slide number two up

please.

And then cc 15 and back please .

just reviewing again how infection is established.

Infection is the initial established in postal transmission by the infection of a local cell.

But in order for infection to disseminate, two different things need to happen.

CD4 T cells need to be recruited to that site of initial infection, so a founder population can be established.

And then the founder population

needs to disseminate the of the lymphatic system.

And we know from nonhuman primate studies, that these CD4 T cells that form the founder population are coming from the peripheral

blood mononuclear cells.

So, we know that when you’re talking about systemic oral drug, that systemic drugs load both peripheral blood on mononuclear cells, but also drug circulating throughout the plasma.

Slide to please understanding how that infection is occurring with

systemic therapy or oral Tenofovir Pro drugs, drugs are

loaded in this peripheral blood mononuclear cells that are circulating in the body in trafficking to different locations, including the lymphatic tissue and including tissue particularly when there’s a chemo kinetic sentinel .

but also TAF in the case of DESCOVY and Tenofovir in the case of Truvada are also circulating throughout the blood and distributing throughout the body .

And so as those drugs get into the tissues, they are also able to load resident cells.

And provide protection that way.

So there are really two different ways that systemic oral agents should provide protection against HIV

infection.

Topical agents can also provide protection, but the way they do that is not by sitting on top but diffusing into the [indiscernible] and in the case of Tenofovir gel for example, they still have to get

into that CD4 T-cell.

That is the only place that HIV replicates.

That is independent of female, male, Regina or rectum.

>> I would agree with most of what you say.

I just have to disagree with the idea that there is an instant tastiness, instantaneous dynamic with cervical and other submucosal populations.

The phenotype of resident memory T cells in different tissues has been demonstrated to be different.

And there are high CCR five resident lymphocytes in vegetal tissues for example that is different, cervical vegetal tissues, and the subregional tissue is also thought to play a role.

And all I’m saying is unless one actually knows what the pharmacodynamics of G these different compounds intracellularly, different resident populations, there is not recruitment until after the virus gets there.

And there is infection locally of cells to come into the site of infection.

So the level of intracellular drug in the lymphocytes that are going to be affected immediately after exposure, is what is relevant .

that, no one has really been able to measure from what I understand.

>> Unfortunately, it is 11:07 AM

.

We need to go to the agency’s presentation.

I would have you respond but this is a longer discussion.

I think as I anticipated we almost got through one round of questions, one question.

So I will be very interested as all of the committee members on further discussion of this, I think you understand the key issue and perhaps over lunch you will further clarify how to educate us on the rationale.

We need to move to the agency’s

presentation.

And clarifying questions to the agency.

If there is time we will come back to further clarifying questions, of the applicant, after lunch.

>> Thank you very much.

>> Dr Millet thank you for presenting on the agency perspective on some of these key issues.

>>

Good morning.

I am Peter merely.

I will be presenting on behalf of the FDA review team far [indiscernible] for DESCOVY , preexposure and PrEP indication.

Here is my agenda A brief discussion is proposed by this application then move on to subcontracts and background.

In particular discussion of the issues we have been having here with regard to the role of the tissue concentrations in HIV prevention.

I will summarize the FDA findings in the DISCOVER trial with women who have sex with men.

And what’s being proposed in this application as part of [indiscernible] and data submitted for that approach.

>> This application proposes a new application for DESCOVY or

TAF , for up Rolexes to reduce the risk of sexually acquired HIV one and at risk adults and adolescents.

>> To be clear there is indication applying to adult and adolescent men who have transit and gender sex with men.

And women who have sex with men.

The indication is similar to the currently approved indication for PrEP

for Truvada .

The indication is listed for you here.

As you know the date of the agency

reviewed as part of the PrEP indication for Truvada consistent with data from the phase 3 blind placebo-controlled trial in

transgender Wender, women.

An adult heterosexual men and women and HIV discipline relationships as part of the PrEP trial.

As well as data from the phase 2 open label trial and adolescent MSM.

>> As you have heard already there are some differences between TAF and TDF , both drugs have been approved.

But compared to Tenofovir 300

milligrams and TDF of 25

milligram.

It resulted 90% lower plasma levels in the Tenofovir .

These differences in the plasma exposure to Tenofovir that makes those differences and the safety profile observed between

TAF and TDF .

, There is a reduction.

>> That said, there have been published single-dose comedies that suggest that it achieves

lower [indiscernible].

As measured in homogenates.

>> Why is this important, as you have heard in the previous discussions, the relative importance of mucosal tissue versus systemic drug concentrations to PrEP efficacy is unknown .

Importantly the minimum drug concentration in mucosal tissues if relevant would be considered protective against HIV-1 infection is also unknown.

>> That we have some indirect observations that might support a role for mucosal tissue

direct concentrations in PrEP efficacy.

As mentioned before tropical microbicide experience, vegetal mucosal

tissue at high enough levels with very limited systemic exposure can reduce the risk of HIV-1 infection.

As you have heard and other oral doses, exposure and Vaginal tissue versus rectal tissue.

This differential drug distribution has concerns in combination

with adherence may have computed, contributed to mixed efficacy results in the PrEP trials in Cisgender women .

That is a controversial topic.

It has been greatly debated the last few years did the end result is we are not entirely sure to what extent this differential may have on the efficacy.

In other words, suboptimal adherence given in women than in men.

>> These concerns have practical implications.

The CDC PrEP guidelines for example

acknowledge the lack of scientific consensus on protective contribution of drug exposure in specific body tissues.

The CDC addresses this issue by reporting the time to achieve maximum intracellular concentration of TF the DP in

PBMC’s studies and some state guidelines have also followed suit in the tissue differential also discussing the time to achieve protective concentrations.

For example New York state prep guidelines recommend a

seven-day lead-in of oral PrEP use for protection from Angel sex.

In contrast they recommend 20 days of protection with receptive Vaginal six.

And the consensus with the PK was the prime motivator or driver for PrEP efficacy .

>> As we know there are no gender differences with respect

to PK for TDF.

Given that there is a lack of consensus regarding the contribution of level tissue versus the systemic exposure for PrEP efficacy.

And these are lower mucosal tissue concentrations

with oral TAF versus TDF dosing.

The FDA determined that fully powered clinical trials would be needed to support efficacy of [indiscernible] is the active control here >> Back to the application.

The data submitted to support PrEP

for DESCOVY consist of one phase 3 double-blind active controlled RCT in the MSN/TG W DISCOVER study.

>> To support an indication of cyst gender women and adolescence and asked drug collation approach is used it

>>[Captioners transitioning] >> >>

At each follow-up as you heard they receive risk reduction counseling and adherence counseling as well as STI screening at all three anatomical sites, oral, rectal and urine.

>> A primary efficacy endpoint was the essence per 100 person-years one or subject reached a minimum of 48 weeks of follow-up at least 50% had reached 96 weeks of follow-up or permanently discontinued from the trial.

>> For the relative risk analysis #based on historical data from the three clinical

trials for prep and MSM.

Based on equal weighting of trials and HID incidents of 1.

44 was assumed for the control arm of F/TDF with the confidence

interval of 2.

60 4 analysis with the discover trial was a ratio.

The square root of the lower bound of this confidence interval provided the noninferiority margins so

the square root of 2.

64 is 162 5390 subjects were randomized in discover.

Six subjects were randomized but not treated with a safety population of 5387.

Full analysis used for the primary efficacy analysis consisted of subjects randomized in treated HIV-negative and one follow-up HIV test during the trial and

that population was 5335.

The baseline characteristics were the #[ Indiscernible ] 34 years.

99% of subjects were MSM and 1% were transgender women.

84% were white, black or mixed black race made up 9% of subjects and Hispanics 25%.

Baseline 60% of subjects reusing Truvada for prep and 44% were uncircumcised.

Meeting duration of exposure was 86 weeks balanced between the two arms.

Adherence to study was hired by multiple measures in this trial.

>> For the primary efficacy analysis a total of 22 HIV infections were reported.

Seven Indy F/TDF arm with an infection rate of 1.

06 and 50 in the F/TDF arm for HIV infection of .

342 rate ratio was 0.

68 with confidence intervals shown here.

The upper bound of the confidence interval was below the prespecified margin of 1.

62 in the discover trial we received a report of

additional [ Inaudible-Static ]

one more HIV infection inclusion.

>> Data indicates F/TAF provides a similar level of protection as F/TDF of rectal acquisition of HIV.

If we consider other potential HIV

transmission in men we do not have any direct evidence to support the efficacy of F/TAF for this low risk transmission.

We can assume insert if sex was occurring at the trial and subjects reported a mean of four, unprotected inserted anal intercourse partners prior to screening.

60% were diagnosed with gonorrhea and chlamydia likely from unprotected anal intercourse.

Given the low rates of HIV infection >> I’m going to switch gears and talk about safety as

observed in the discover trial.

Both F/TAF and F/TDF were well tolerated and no notable differences between the two arms of adverse events or laboratory abnormalities.

The most common AEs were sexually transmitted infection is [

Indiscernible ] diarrhea at 16%, nausea and 7%, headache at 7% and fatigue at 6% with comparable rates between the

arms.

6% of subjects in the F/TDF arm were considered serious adverse events and 5% in the F/TDF had serious adverse events.

The majority were not considered related to study drug.

We observed low rates of adverse events [ Indiscernible ] into percent Indy F/TDF arm.

The most common adverse events leading to drug discontinuation with gastrointestinal disorders which led to drug withdrawal less than 1% of subjects in each arm.

We look at G events overall and they attended [ Indiscernible ] with the startup syndrome described in previous trials of F/TDF PrEP.

These issues did not have a major impact on bodyweight.

There was a mean increase of weight from baseline of 1.

1 kilograms for F/TAF and essentially no change in weight in F/TDF.

>> Looking at renal safety, when we looked at the meeting absolute change in serum creatinine there was minimal change in either group at weeks 40 way #[ Indiscernible ] the mean change and estimated GFR from baseline.

The blue line shows the changes which essentially stayed consistent with baseline whereas in the F/TDF group there was a decrease from baseline over the course of the trial which became apparent as early as

week four.

The distribution of urine poking to creatinine ratio PCR categories was a key alpha protected safety in point

in this study.

PCR is generally regarded by the empty division of cardiovascular and renal products is a useful laboratory assessment.

The proportion of subjects who had no significant baseline and went on to develop [ Indiscernible ] higher in the

F/TDF group.

Conversely the proportion of subjects who had significant proteinuria at baseline which will only 25 per arm and had improvement in their category was higher in the F/TDF group and 57 versus 44% respectively.

>> These differences were statistically significant at week 48 however the differences were not significant at week 96.

We observed a greater frequency of treatment emergent proteinuria by your dipstick in the F/TDF arm a 24% versus 21 percent for F/TAF.

Most abnormalities were grade 1 and saw no difference in the frequency of potent area between the two arms.

We saw little differences in the frequencies of treatment emergent laboratory abnormalities as it pertains to serum creatinine.

2% for F/TDF and 1% for F/TAF overall and no differences between the groups with respect to hyper phosphatase man.

>> Very little difference between the groups in the frequency of treatment emergent adverse events related to renal safety.

This one case of [ Indiscernible ] syndrome as well as a case of nephrotic syndrome in the F/TDF on.

The cases in the F/TDF arm [ Indiscernible ].

When we looked at other adverse events as grouped by high-level terms whether for renal failure or impairment, electrolyte analysis, renal function and urinalysis, we saw no differences between the groups.

>> There was little difference between the two groups in the renal adverse events that led

to drug discontinuation.

>> In summary, for adverse events treatment emergent lab abnormalities related to renal functional safety we observed no major differences between the groups in this particular subject population.

I remind you as with Truvada approved labeling for discovery carries a warning for the onset of worsening renal impairment.

Moving onto bone safety.

The mean percent change from baseline at week 48 in hip and spine were a key alpha protected safety endpoint.

As shown in the table they were differences between the groups at hip and spine and it weeks 48 and 96 essentially no great change in the trend [ Indiscernible ] at each site for the F/TDF arm.

These differences were statistically significant at both time points.

>> Consistent with other tenofovir product labeling we conducted an analysis of the percent change from baseline using the following cutoffs, 7% for hip and 5% change from baseline for spine as we [ Indiscernible ] considers clinically meaningful.

We saw no difference between the two arms with the hip either decreases or increases and no difference between F/TAF and F/TDF between decreases in spinal BMT but a greater proportion of subjects in the tenant on the had a 5% or greater increase from baseline at week 48.

>> The applicant has shown your results from a categorical analysis regarding the change of the BMD clinical status from baseline to week 48.

We concur there was a greater proportion

of subjects in the F/TDF arm that had status a week 48 and a greater proportion of subjects in the F/TDF on that had an improvement of the BMD status in the hip at week 48.

When we did the same analysis we saw the differences in the proportion of subjects at week 48 and there was a greater proportion of subjects in the F/TDF arm that showed improvement.

>> When we turned to adverse events as reported in the discover trial during the course of the trial was a no differences between the two groups with respect to fractures most of which were traumatic and occurred at a relatively low rate of 2% or pathological fractures as well as in reports of back pain,

spinal pain or bone pain.

Was on the differences between the two groups with respect to what the investigators themselves reported as bone density decrease, bone loss, osteoporosis or hyper phosphatase man.

>> We looked at the meeting change from baseline in passing lipids and an overall trend to decrease it best in cholesterol and LDL in both arms but the magnitude of the decrease from baseline was greater for F/TDF and a spider decrease from baseline and fasting triglycerides with F/TAF.

However is important to note we saw no differences from baseline for the ratio of total cholesterol to HDL either within groups or between

groups.

That said the F/TDF group had a consistently higher incidence of abnormalities related to total cholesterol LDL or triglycerides across all toxicity levels.

>> We conducted a categorical analysis of a shift from baseline LDL categories as adapted from the NIH national cholesterol education program.

We found a greater proportion of subjects in the F/TDF group had worsening LDL category at week 48 compared to the F/TDF group, 17 versus 10% and a good proportion of subjects in the China group had improvement in their LDL category compared to F/TAF, 40 versus 28% respectively.

These findings did not translate to any major differences between the two groups with respect to adverse events and clinical adverse events which were very low in the trial anyway.

While the proportion of subjects who were on lipid modifying agents at study entry was balance between the two arms, a slightly greater proportion of subjects in the F/TDF arm initiated these ages during the study at 2% versus 1% .

In summary both F/TAF and F/TDF were well

tolerated and safe.

Differences between the groups were observed for various indices namely changes from baseline in renal biomarkers, bone mineral density and fasting serum lipids consistent with previous trials that compared TAF to India.

In general F/TAF and F/TDF had similar profiles including low rates of serious adverse events or adverse events leading to drug discontinuation.

>> I will now turn to our discussion of the indication

for PrEP in sis gender women.

Prep indication is challenging.

Previous clinical trials in women have demonstrated

variable efficacy of oral F/TDF .

FDA recommends designs in women because the termination of a not appear any margin is not readily feasible.

>> In this application 2X compilation strategies are proposed.

When is the extrapolation of F/TAF efficacy from MSM in the discover trial to support indication in sis gender women.

One must demonstrate exposures including plasma as well as diphosphate concentrations.

The second approach is to extrapolate efficacy and as you have heard this approach makes use of

published value as derived

[ Indiscernible ].

For this approach one must demonstrate diphosphate concentrations in systemic BK but also in cervical vaginal

tissue.

With respect to the first approach, we don’t expect there is going to be in the clinically relevant differences in the PK PPM say associated

between men and women.

For reasons that have been discussed of any matching systemic drug exposures alone may not suffice because of the unknow contribution of mucosal tissue concentrations to PrEP efficacy .

For the second approach where we try to extrapolate efficacy to support F/TAF, while there is some overlap regarding systemic drug exposures the applicant has

cited [ Indiscernible ] for PrEP efficacy.

Two things to consider.

This threshold concentration was associated with adherence to three to four doses of FTS per week specifically from the IprEx trial.

This concentration has not been validated as a PK surrogate for all populations.

The concern with relying on the PBMC threshold concentration is that may not accurately reflect the drug concentrations at the tissue level.

We know with F/TDF with multiple dosing we can achieve this threshold

concentration of 40 femtomoles.

We know this concentration in PBMC correlates to a rectal tissue concentration of greater than 100 vegetables per milligram or greater than the lower limit of quantification.

In contrast a single dose can reach this PBMC concentration of 40 femtomoles in a matter of hours.

The vaginal tissue concentration can be reported as below the level of quantification.

In both scenarios we achieved this threshold concentration being proposed as a circuit in PBMCs with diverse results in relevant tissues and concentrations.

The more conservative approach is to try to match PK both systemic and tissue to support and extrapolation of F/TDF in women as opposed to F/TAF in the same population.

For the systemic part we know TAF [ Indiscernible ].

With regards to tissue concentrations we know a single dose TAF TDF results and concentrations mostly below the level of quantification.

We don’t know is whether multiple dosing achieved different results at the tissue level and to that end data from an external study

in healthy female volunteers was submitted to support the latter part of the extrapolation.

This is the study design conducted in two parts including a single dose and multiple dose where subjects were treated for 14 days with F/TAF or F/TDF.

We are going to focus only on the approved doses for F/TAF and F/TDF.

Multiple samples were collected for pecan plasma, PBMC, rectal and vaginal biopsies and focus on the biopsies and the evaluations for Dr.

Le diphosphate concentrations.

One thing about this design is each woman contributed cervical vaginal tissue samples and only one given time point.

That is because tissue samples were collected at different clinical sites at different time points.

Rectal tissues were collected four hours post dosing administration.

Vaginal tissues collected at four hours post dose following single dose administration and following 14 the administration.

The measurement were tissue homogenous and assuming it tissue density of one gram per mL final sample concentrations in the lower limit of

quantitation of 0.

3 nanograms >> Here are the results we obtained.

Following single dose administration of F/TAF or F/TDF 83% of tissue samples were below the lower limit of quantitation at four hours.

Following multiple doses a significant proportion of tissue PK samples were also be out here.

Concentrations were higher for oral F/TDF dosing only four hours post dose.

They were mostly unquantifiable at 24 and 48 hours and unclear if this isolated finding it four hours translates to comparable

or higher Dr.

Le diphosphate concentrations in vaginal tissues beyond four hours after administration.

>> This table represents the results from the multiple dose part of the study.

It is busy so I will walk you through it.

If you look at the first row and the column for F/TDF 62% of vaginal tissue samples in the F/TDF arm were below the level of quantification.

None of the tissues in the F/TDF arm were

Dr.

Ofotokun Indiscernible ].

Similar results were seen with cervical tissue biopsies and is for the rectal tissues the results confirmed the previous reports dosing with oral F/TDF results in higher tran [ Indiscernible

].

For 20 hours at 48 hours the majority of the tissue samples for the vaginal cervical tissues were below the level of quantification and we were not able to determine and medium level for these tissues any degree of confidence.

In conclusion, F/TAF and F/TDF

afford similar protection against sexual acquisition of HIV-1 infection.

Both are safe and well tolerated.

F/TDF dosing results are smaller it

changes compared to [ Indiscernible ].

No major differences were noted with respect to the side effect profile during the course of the study.

Clinical data regarding the use of F/TAF in sis gender women are lapping

>> This application proposes a PrEP indication based on efficacy data be tenofovir

diphosphate concentrations.

The relative importance of mucosal tissue versus systemic drip concentrations remains unknown.

>> That concludes my presentation and I will take any clarifying questions from the committee.

>> Thank you.

We will now take clarifying questions for the agencies presentation and I think [ Indiscernible ] has the first question.

>> A question that may also overlap with the question [

Indiscernible ] you state TAF FTC is effective in preventing HIV in MSM and transgender women but we have never seen the transgender female data broken out in any way, do you have a sense of what that looks like or better question for the sponsor?

>> The applicant is free to chime in, first it was a very small proportion of transgender women enrolled.

I believe about dirty percent opted out early during the course of the trial.

None of the HIV infections were seen in the transgender women.

>> Any pharmacokinetic data on tenofovir versus Truvada in regards to whether any of those transwomen were using estrogen?

>> I would defer to the applicant as to concomitant medications being used by the

transgender women in the study.

We have seen reports about the

effect of PrEP with feminizing

hormone therapy.

No clinical action studies

have been conducted with TAF.

I don’t know for clinical pharmacology reviewer would like to discuss this topic further.

>> There is no clinical interaction study being conducted with TAF and feminizing regimens and drug interactions are likely to be minimal however, some studies suggest estrogen can change [ Indiscernible ] of leukocytes and analogs.

The study conducted was [ Indiscernible ]

receiving feminizing regimens that the paper published recently by [ Indiscernible ]

showing minimal changes to an for the transgender woman and

minimal changes [ Indiscernible

].

The sample size is very small.

The study showing the lower concentration of tenofovir diphosphate is mostly driven by the higher the ATP levels in rectal tissues but we don’t tab

any data [ Indiscernible ]

>> I would ask applicant, this is clarifying questions to the agency.

We realize applicant has important data so if you can keep a list of these questions and then we will come back and engage your data set after we clarify with the agency.

>> I will hold for that.

>> If we can see slide 46 again, I just want to make sure you understand, I think it was the last slide in your presentation the one described as complicated.

My question is simplistically for BLQ you want it to be lower because that is the percentage above a level that is quantified and not really telling us what level is present, it is just whether anything can be quantified or not.

I want to make sure I am reading this correctly.

I see at four hours F/TAF in the vagina appears to be better than F/TDF and and cervical tissue it appears to be better

and at 24 hours, F/TAF is not as good but neither one are very good in

both [ Indiscernible ] and have 48 hours basically they are all not good.

We are also demonstrating F/TDF doesn’t have that level of protection overtime either.

If mucosal levels are important, this slide does not demonstrate that because you are not seeing a difference that benefits F/TDF which Artie has a drug indication and has shown to be efficacious, is that correct?

>> I don’t know we can say what is better than the other, the tissue samples were just not quantifiable.

But I agree with you the TDF samples were also not showing much.

It may be an issue with the assay or the cutoffs we used to determine quantifiable.

I don’t know if the clinical reviewer has any other input here.

>> [ Indiscernible ] >> Can you tell me which number

it is?

Slide 79 .

Slide 80.

You can see [ Indiscernible ]

which makes it difficult to

compare across studies.

In this [ Indiscernible ] we

have a higher [ Indiscernible ].

The difference can be due to tissue biopsies and because it is converted from the nanogram per mill to [ Indiscernible ] per gram, if you have a smaller sample size it is possible to

have LLQ values.

Related to the [ Indiscernible ] may not have the long-term stability data

and also [ Indiscernible ].

It is probably related to the

[ Indiscernible ].

>> In thinking about this problem of understanding whether the drug levels in the genital compartment are the actual proxy for protection, have you looked at the trials were the only difference in treatment was TDF [ Indiscernible ] in a difference in plasma, genital discordance and suppression.

We know some women on suppressant therapy can still also have HIV present in the genital tract and that may be an additional way to get a differential

impact of TAF versus TDF in the genital compartment.

Can you come in from the agency perspective about how we should view the appropriate nests of an application for a drug intended all the way out to have an indication in men and women coming in with clinical trial data only for men with an expectation [ Indiscernible ].

I am concerned because often women are excluded because about possible pregnancy and of the reasons in this fee is to make a potentially concerning precedent.

Thanks >> We have not looked at that

data.

At least I am not aware if the company has that information.

The second question, ideally the agency would like to see clinical trials in the populations for which the labeling is going to be indicated.

We recognize conducting trials in women in the current landscape with

Truvada approved is challenging.

I think our first initial hurdle was to agree on

a trial period.

That ultimately was decided to be conducted in MSM and transgender women.

Discussions about a trial with women were had with the applicant and again we noticed there were

challenges and difficulties in the agency itself was struggling with the appropriate study designed to recommend for this population.

It was never really agreed-upon this particular application the way it appeared would support the

indications being requested.

At this point we are trying to work with what was submitted to

see if we can justify an indication across the populations based on a study conducted in one particular

population.

Going forward we are not recommending this particular approach.

As Dr Murray noted, this particular case is unique because we are talking about basically [ Indiscernible ] for the same drug and we have an approved drug already for Truvada and

all those populations but ordinarily we would not rely on a single trial in one population to support an indication across multiple populations.

>> An .

Giving your review of the sum total of the data, what is your impression with the agencies impression of a marker of protection in the vaginal compartment?

Has that emerged or is that still unclear given the state of the data?

>> That remains very much unclear.

I want to emphasize it is not one or the other.

It is not necessarily mucosal tissue versus systemic.

There may be a contribution of both and that is what we don’t understand.

If vaginal tissue concentrations are relevant, are they acting as the primary line of defense in the systemic acting as a backup?

I think that was a theory floated by Dr.

Anderson but we don’t know at this point.

The only thing we can measure are these tissue homogenates.

Some said this have looked at mononuclear cells within the vaginal tissues themselves and have had mixed results with respect to differences with the vaginal compartment and the rectal compartment.

I think the field itself at least to us is a bit mixed or conflicted.

The first question you asked is very much unclear in my opinion.

>> Part of the challenge, and other members of the committee have asked this, the vaginal

compartment, there are menstrual cycle issues, microbiome issues, behavioral issues that are different than other compartments and it may be adherence or PBMC concentration that may be all that matters or there may be an interaction with his other factors in trying to understand from the data available to determine if perhaps adherence is all we need which is in part which is what is being suggested but I am struck by voice and the other trials that did not show even results a protection although explanations, there it always worries me when there are lots of explanations and we are asked to embrace the positive but not worry about the negative and assume it should just work the way we want it to.

I guess my question is, should we just assume the vaginal compartment is an extension of the systemic

compartment in this setting?

This will be asked of the applicants later which is building on the conversation.

>> I think it would be challenging to do that now that we know the pharmacokinetics are very different between TAF and TDF.

I think part of the difference we see systemically may be extended to the compartments in question for various reasons, TDF itself may be cycling in the G.

I and achieve a high protection in the rectal tissue for example.

I don’t know we can confidently say we can extend systemic to tell us what is going on in the vaginal tissue.

>> My other follow-on, I will continue to follow on in this line of questioning.

>> Kind of along this line of

discussion was the significance of the time for achieving

protective concentration that was different with TDF for different populations.

What is different for men and what is different for women.

I think the guidelines varies from different state regions of the country based on the time for protective concentration for

TDF.

Do we have a sense of that variability with TAF?

>> I think the guidelines are being conservative because of this uncertainty around the role of tissue concentration.

I think CDC has presented the data for prescribers to be aware of and some state guidelines have pushed that further into prescribing

recommendations.

And trying to be the most conservative, for TAF we don’t have any information like that.

It depends of whether you believe systemic PK is the driver or protection, in which case you probably don’t need this lead-in time but if you believe it all that tissue may be contributing to PrEP efficacy, I don’t think we have any data to help us with what is going on with TAF, at least in the vaginal tissue.

>> Dr.

Swaminathan? >> These are drugs that stop viral replication, these are not disinfectants.

The applicant has a valid point that it is T

cells that are the issue.

Is it useful to look at drug concentrations of homogenates of biopsies which are primarily

everything but lymphocytes?

>> In retrospect, but probably not, going into this what we had with these single reports out there that was surprising to the community that TAF was acting so differently in local tissue compartments.

It is probably what drove us to be conservative and request a clinical trial to begin with.

If it had been established systemic PK were the main driver, we probably didn’t need the discover trial.

There was a fair amount of uncertainty as I tried to describe to you both in the literature and the guidelines.

conducted and I will say rectal tissue concentrations with TAF are lower compared to TDF in the discover trial shows comparable efficacy results regardless but we don’t know the minimum concentration.

It may be whatever concentration is being achieved with TAF in rectal tissue may suffice, we don’t know.

But you are right I don’t know tissue homogenates is the best measure to give us some valuable information at

this point, I don’t know.

[ Indiscernible ] >> Switching topics, you mentioned the idea that penal transmission or acquisition seemed reasonably protective

against here.

Did the sponsor gather data on types of sex?

Is there any signal the acquisition is more likely in

men who reported [ Indiscernible ] or so much overlap between the two in in the single person you can’t distinguish that?

>> My impression within each individual there is a variety of sexual practices that we can’t decipher if there was a subgroup that was thickly practicing insert effects.

Pretty much all of the HIV zero converters for practicing anal receptive intercourse but they also had reports of inserted sex in their.

There are individuals who reported for the most part inserted sex showed up with rectal STIs.

Again all of these reports are

self-reported.

Like I said I don’t think we had any direct evidence but given the low number of HIV infections and the fact we presumed a lot of these individuals for practicing insert effects the protection did defer to them as well.

>> [ Indiscernible ] >> Just a brief follow-on.

If I remember I think about 60 some percent were uncircumcised, any circumcision signal?

>> It was 44%.

In terms of baseline characteristics and HIV infection we didn’t see any correlation.

>> I do remember the confidence interval outside the U.

S lot higher, is circumcision involved in that?

>> I would have to defer to our statistician.

>> Please state your name at the microphone.

>> [ Indiscernible ] there is no such baseline characters that have a great impact on a final result.

>> [ Indiscernible ] >> A question about a citation you have in your briefing document, a mallet analysis that compares TDF that compares tenofovir and Truvada

versus DESCOVY and the safety data presented talks about statistically significant margins of safety, are any of these from your perspective clinically significant?

>> I think in the clinical setting, probably not but over the long term they might be.

I think the current average use of PrEP at this point is 6-12

months.

We didn’t see anything different between the two arms in terms of clinical events.

>> If you stratus by the adverse events by age is there anything that flushes out in terms of this being more common among older adults?

There are some 60 and 50-year-olds in the study.

>> There was a small number of older participants.

We didn’t see any differences come up on either end of the spectrum.

>> Dr.

gets? >> My question relates to the nature of risk population and the expected rate of HIV in the patient population.

I not was projected at a rate of infection that was somewhat higher and I wonder if someone from the agency could run through the calculations that predict what the expected rate of HIV infection was in

the actions [ Indiscernible ]

.

Having confidence of the projections of what the expected rate of infection is I think is important.

>> You mean without PrEP?

This wasn’t a placebo-controlled trial.

To that and I think you are asking [ Indiscernible ] I think the applicant did do a comparison to local geographic areas in the U.

S epidemiological data looking at concurrent HIV incidence not on PrEP and I think there were four to five incidents per 100 persons.

At least in the U population of MSM in the geographical areas where the study was conducted the incidents was much higher.

>> And the STI rate?

How does that influence your thinking of being in a high risk population?

>> Dr.

Murray has published a meta-analysis looking at various PrEP trials and tried to correlate the STI rate at least four rectal gonorrhea and the predicted HIV incidence would be.

As you heard there was a high amount of STI’s going on in this trial and based on the correlations we have looked at, that should’ve correlated to an HIV incidence of I believe six.

>> Six what? >> Six per 100.

>> So tenfold higher.

I have a follow on to Dr.

send Barry’s comment.

The issue of the trial in cisgender women you mentioned a noninferiority margin so can you help us understand, doesn’t mean it is not possible or how would you frame [ Indiscernible ] what might look like for us to understand the challenges in a [ Indiscernible ] trial.

>> The challenges we have [ Indiscernible ] and then we have one trial that could show statistically significant

protection in the [ Indiscernible ] trial that showed a point estimate that favored efficacy.

When you have such divergent results from historical trials it becomes a challenge to come up with a margin.

I don’t know if the statisticians want to discuss this but that is basically the main conundrum.

We would not be able to adequately construct a margin with such divergent variety in previous trials.

>> So in the MSM trans population we have consistent results with Truvada and it is easier to design a trial that shows consistent results.

In cisgender women where the data are very uneven it is difficult to have a trial but we should assume it should work.

I’m just trying to follow the logic of that being put before us.

>> I think a noninferiority trial would be difficult to construct.

That said there might be other possible study

designs such as comparisons to local HIV incidence in the population of study in the

community a study.

These are novel study designs we are grappling with ourselves in the agency given that we have a product on a market that is highly effective.

>> Dr.

Gripshover? >> What about a switch study?

Is that something the FDA would consider would be appropriate?

We have women already taking Truvada for PrEP.

Would that be a study design that could be

considered.

You may not have a high incidence rate but at least you are comparing it to an already approved drug?

I’m curious what the agency would think if that is the study design that would work.

>> I don’t know what the comparison would be in a switch study other than safety.

We haven’t really considered a switch study.

>> Dr.

Green? >> This is a direct follow-on.

So you can’t easily come up with a strategy to give a noninferiority study but there is no reason to presume if you did a head-to-head it would be superior and it also seems like it would be unethical to do a placebo study so we may be back

to the argument of the sponsor that there is no feasible way to assess it so we have no choice but to make a decision using extrapolation.

I don’t know if that is your intent to say but I’m hearing that.

Tell me why that’s not true.

>> I think you hit the nail on the head.

The question is how confident do we feel the extrapolation approach would be reasonable to extend the

indication?

At this point we hadn’t really discussed in the alternative study designs so that may still be on the table.

It is not a question of whether we think this is appropriate but whether in the absence of other supporting data we feel confident this might work.

>> Dr.

Ofotokun? >> I don’t seem to by the argument we can construct an inferiority margin around the data we have for women because we know from looking at the data and the studies in PrEP in women the reason were efficacy was not demonstrated that way was because of poor adherence so in studies [ Indiscernible ] the drug was effective and we can construct a margin around a study [ Indiscernible ] that

ever been done and construct an inferiority margin in the study design.

I remember the sponsor had a series of planned studies in women so how are they planning to do that if it is clinically

impossible to have a sample size calculation.

>> I will answer your second part first.

We have not seen any of these proposals and agencies the applicant has proposed.

My understanding is these aren’t going to be efficacy comparisons.

They may be safety demonstration projects.

The first question I would defer to our statistician about construct [ Indiscernible ]

>> [ Indiscernible ].

>> Dr.

Smith, you have a follow on?

>> There is a lot of work going on to develop new agents for prep for preexposure prophylaxis.

It is not clear to me whether you are saying from now on no studies will be done in women because we can’t define the margin and therefore we can’t do a noninferiority trial in the current PrEP is so effective .

I don’t understand the implications of the

decision for future trials.

Given that, it may be difficult to find a high incidence population of women in the U.

S It is certainly not the case in the developing world and I think in fact in the world at large, women are the largest number of new infections so the need for effective prevention options for women is even greater than for MSM although

not in this country.

If we are saying from now on we would do the studies and men and some PK studies to extrapolate to women, that doesn’t sound like a good scientific approach so I’m trying to understand the

boundaries you are drawing and how that will apply in the future.

>> We are not saying that at all.

There is a path forward in terms of superior designs.

[ Indiscernible ] the challenges we have drugs that is similar in terms of administration and

dosage.

If you’re looking at long-acting agency can’t do a superiority trial so that is what we have been advocating.

This is a particular circumstance that is complicated because we have two

similar products.

This PK extrapolation being proposed is not meant to be precedent-setting for future trials in women at all.

>> And we do need to remember the business at hand is the current application.

There are broader questions I think are appropriate for us to highlight as we have been doing to set the stage for data in the future that are needed to make informed choices so your points are very well taken.

I’m not sure it will result agency policy going forward but I think the points have been heard.

Sankar Swaminathan, did you have a follow on?

>> Can you clarify from an agency perspective how much of a study needs to be done in the U.

S an indication?

>> The guidance is we can accept clinical data from form studies if the [ Indiscernible ] why the data or applicable to the U.

S case 60% of the subjects were in the U.

S covered.

There is not that preponderance of foreign data but for PrEP in general and for example in women studies will be conducted [ Indiscernible ] the mechanism of transmission of HIV in the mechanism of action for the drug should be the same regardless of the geographical populations.

>> Other questions with the agency about their presentation and their analyses of the data

submitted?

If not, it is 12 20 p.

m are supposed to take a break.

I don’t think we have time to delve into another line of questioning but I think to the applicant I think you have heard issues around and perhaps after, we would do the open public session and come back to clarifying questions to the applicant but data on the efficacy entrance and data on the inserted male partner if you have it was some of the issues raised I think you have the data and we just wait for the committee to see comments around the design issue around

the cisgender female will be helpful for the committee to hear your thoughts.

You touched on them but I think they are central to our discussion.

After lunch we will have the open public session and resume the disk unction with the applicant and the agency after the agency has finished their clarifying component.

We will now take a break for lunch and reconvene in this room at 1:30 PM sharp.

****7. TRANSCRIPT 3

It will allow centers to enroll more clients especially those at higher risk HIV acquisitions.

For I continue for transparency the SAF has received problematic support from Gilead County for less than four % of his annual revenues in the fiscal year.

This statement is to write in my own professional medical review in the position of foundation and leadership and has not been influenced by Gilead was staff.

SAF enrolled 59 participants.

We understand that early Rios demonstrated very low results in the

Truvada group.

In addition preliminary discovery data suggests better renal and bone outcomes for the participants on an act.

But we agreed that the improve outcomes are likely marginal yet based on remote, motivators including those at most at risk may be more likely to engage with PrEP as more ages with improved side effect profiles are approved for

reviews.

Additionally , a strategic priority of the foundation is to center is PrEP services on communities disproportionately based on the incidence rates including black Americans.

And rolling persons in such prep show the need for

treatment.

The approval may enhance problematic capacity to provide standard prep services that CEOs like ours.

Those affected by local or other structural

factors such as depicted here.

Innovation of an express model of screening supporting conical

prep follow-ups in PrEP patients.

Clinical management of Truvada for PrEP patients baseline and episodic

monitoring every 3 to 6 months.

With conventional use of

F/TAF we believe that we can project a more inclined function in turn inability to

follow, lesson to sublet

monitoring and pure staff — with all the social classes held unchanged if approved for use and prescribed for a

portion of our.

Patients .

Thank you for your time and attention.

>> Thank you.

Will speaker numbered two bugs step up to the podium and introduce yourself.

Please state your name and any organization you’re representing.

>> Thank you for the opportunity to speak today on behalf of the national Center for health research.

And Stephanie Fox analyze scientific and medical data to provide objective health information to policymakers.

We do not accept funding for medical device company so I have no conflict

of business.

However it only provides benefit if it is effective and safe Esther Vona for each population for which is indicated.

Otherwise you to can be unnecessarily increased risk for HIV.

The discover trial phone similar rates of protection against HIV infections amongst participants taking both drugs.

While the trial seems well designed to demonstrate comparative effectiveness of the drug it is still a single trial replication is the key to scientific evidence and independent trials can result in different infection rates due to differences in demographic or profiles of

patients or other factors.

For example study participants were more likely to be white, older and better educator than the general U.

S that is at risk for HIV.

Which is the target audience for the drug.

This population may consist with people who are currently using Truvada their questions about the generalize of liability of the population that consider using the drug.

It is important to study the general U.

S at risk for HIV.

The study also found improvements for biomarkers related to kidney health and bone density suggesting that this could be safer than Truvada.

However there is only relevant if it translates into clinical medical difference related to kidneys or bone fractures.

Which were similar in both treatment groups in the

clinical trial.

The trial suggest that the benefits outweigh the risk for men who have sex with men however the benefit risk ratio was muscular for transgender men women.

This into a part of the relatively low number of transit gender might women in the trial.

The high dropout rate.

The FDA is a considering this for transgender women and the efficacy of the drug for transgender women should be analyzed.

This is important considering the recent findings

that formalized therapy can affect trucks.

Similarly there is insufficient evidence that the drug is effective and safe

for prep for ciswomen

gender women.

Similarly the benefits for adolescent boys differs from that of men and should be considered separately.

Finical trials demonstrating effectiveness and safety persists gender women and adolescents are needed if the FDA is considering approval for

them.

We understand the desire to provide a new prep treatment indicator for a broad population.

Especially when the new treatment may be expected to lead to risk for kidneys them bone density.

It is an appropriate and potentially dangerous to approve this drug for subgroups of patients that have not been adequately studied.

The law require substantial evidence that benefits outweighs the risk in the subpopulation and the new indication clinically.

Thank you >> Thank you.

>> Will speaker number threes come to the podium and introduce yourself.

>> Thank you so much.

My name is Jeremiah Johnson and I am the HIV project director at treatment action group in New York.

We appreciate the hearing is being held today considering how centrally Gilead has control this entire process on development all the way to do it laying it for decade for the medication all the way to centrally controlling the DISCOVER trial without the input of the community.

We believe it is a string important that this regulatory agency in the community begin given time to have a transparent discussion about this and to take control of the process again and away from an applicant that has a vested interest in maintaining a $2 billion a year market in biomedical convention in the

U.

S GAGAS.

Within my six remaining minutes I will go over three main points in a small amount of time.

So please pay attention.

To start we are going to be talking about in terms of representation within discover and the broader body of evidence that we have as part of this as DA discussion today.

We have number of concerns about Gilly is active campaign against his own product Truvada and what will

be generic TAF-FTC an overstatement of efficacy and

safety benefits that can be compared to that.

Have a general discussion about the lack of transparency in the

whole process and a rush process when involved in four discusses that clearly the community was not adequately consulting on early on in the process.

I will not go into this like too much.

Obviously the trial participants within the DISCOVER do not represent the broader epidemic that we see in the United States and

around the world.

With 99 paying system under men.

Were not seeing a body of evidence amongst all population that needs to be considered in terms of efficacy safety for scale of a new option.

Right now you’re hearing at the podium and there is a lot of discussion online right now and a lot of debate amounts community advocates about what the does the state of Maine and what should we be advocate and that we don’t have sufficient data.

For no good reason to we have insufficient data.

Some believe that we have to continue to advocate for an

indication for us ciswomen because they are not beneficial to the bottom line to do the follow-up efficacy research in order to get an indication for ciswomen and if we miss the opportunity there will be different PrEP for different populations.

We are concerned that we’re sending a message that we’re sending a message that if we don’t do adequate research within these populations that you don’t have to do that and you can get a broader indication anyway.

That is an enormous problem so it is up to the FDA today and going forward in this discussion whether you believe the information and the evidence presented thus far is indicative of a broader indication or a narrow indication.

What must be clear is that ciswomen cannot be left behind or other populations that are been left behind in the entire process.

If it is not approved there must be guarantee, it there must be requirements that the company

contains the efficacy, exit efficiency so that they are not left behind in the process.

It needs to be contingent on open label studies that continues to give us information for the population.

This must have been and this committee must be responsible for the deficit that has taken place.

We must see that for all of the communities that are highly prioritized within the epidemic.

We’re not prioritized within the treatment.

Will .

They are also trying desperately to even in this

room today boldly assert that it is a safer option when in fact we do not see clinically different outcomes in the DISCOVER trials and continue to downplay increases in weight and challenging issues around lipids that certainly indicate that it is not necessarily a safer option.

It is important that this regulatory body operate with the highest level of scrutiny with the labeling, marketing and educational materials that come out of the applicant should an indication be provided for DISCOVER .

Quickly these are slides that Gilead will not be presenting to date that we saw from the DISCOVER trials that they was a significant increase in

weight.

The stresses the need for additional research in this population considering that the DISCOVER was not representative of these populations.

Ultimately we had to ask what is the Russian this entire situation.

There is not one peer-reviewed publication that is, of the DISCOVER trial.

Their full transparency and we just aren’t as to see some of the information from the trial.

This is coming after a delaying tactic development.

We’re frustrated as community members that Gilead continues to centrally control this process, the FDA does not and the community has not been adequately involved so going forward this body needs to send a clear signal that any manufacturer engaged in the field of biomedical research must do a better job.

If they actually have to adhere to GPC and work with community from the start and they actually have to allow this regulatory body to come up with a robust research protocol that covers all populations and not just their bottom line.

With that I will close and just say that we require a robust post marketing research following this discussion today with the labeling and all materials need to be under high scrutiny and that we need a clear message from the F DA that this process will go better in the future with future modalities.

Thank you >> Thank you.

Will speaker number four speak up to the podium and introduce yourself.

Please state your name and the organization you are representing for the record.

>> Hello my name is [ Indiscernible ] and I’m

cofounder of the

— I wanted to review , next slide please.

DESCOVY is a correlation of two different drugs which was first approved in 2015 as part of Jen Boyer for HIV treatment

and emtricitabine 200 mg.

Act [ Indiscernible ].

This is alleged to convey certain safety benefits compared to PDF.

I think that one of the things that it’s important to realize in the entire process is that TAF is not a do drug despite being FDA

approved

in 2015.

Gilead first file a patent application for TAF cleaning priority all the way back to 2000.

Using the codename at the time was GS 7340.

All the back in 2001 regarding the metabolism of GS 7340 now known as TAF.

What we should be asking ourselves is why in 2019 are we discussing a FDA application for TAF and why don’t we have better data on assist gender women.

Has been developed when it was supposed to be developed we would’ve had

an F/TAF.

Is go through the development of TAF.

As Gilly had begun early phase 1 and two trials in 2001 and 2002 filed in IMD with the agency for the development of TAF back in January of 2002.

In October 21st 2000 force they discontinue development of TAF.

On October 2010 to restart development of TAF.

What was the reason for this top and

start approach to drug development.

You don’t have to look to me or Jeremiah or anyone in this room to actually understand what Gilead was during.

The former CEO, Dr John Milligan was one of the reasons we were concerned about development TAF was we were trying to watch to Botta versus [ Indiscernible ] and have our own study was the safest thing

on the market was the best at the time.

We are receiving mixed messages.

For those that take TAF every single day I am highly disturbed by the applicants behavior by delaying a drug that was going to produce some safety benefits to protect their bottom line rather than detect the public health.

I only wish that the FDA would share the same billing but is that the FDA reports Gilead decision to delay.

Worst of all I was quite surprised

Until this year.

Would also recommend the [ Indiscernible ] get the patent term adjustment allowable under U.

S touching the entire period of Gilly as delay as the testing phase.

This will prevent Americans from accessing generic drugs for additional five years.

This is the disturbing presence that the FDA is rewarding the decision of a Corporation to delay the development of a drug that is

now purporting is safer than

TAF-FTC.

We are pleased with a Catch-22.

On one hand we deny the ability for art DESCOVY from telling a

broad indication for and no efficacy data for this population or we choose to deny the extension of that indication and that unfortunately in today’s environment we are basically worked to deny women the choice to make the decision of the drug that they would like to take.

I believe personally and not representing my organization that it is the right choice is to extend the

indication of

F/TAF .

Ciswomen women get HIV.

The idea that the applicant will decide not to provide high-quality evidence supporting efficacy in the population is disturbing.

The fact is that this agency may be forced to grant a broad indication with no efficacy data is also disturbing.

This can never happen again.

I want to make that incredibly clear.

Ciswomen, meant to have sex with men all of us deserve medical technologies that are skimming up to fight one of the deadly police pandemics of our time.

They deserve high quality treatment.

We should not encourage companies to delay high-quality evidence for the the point of ologies.

Thank you.

>> Thank you.

Will speaker number five step up to the podium and introduce yourself.

Please state your name and any organization your representing for the record.

>> Hello.

June Gibson my brothers keeper located in

Jackson Mississippi.

My brothers keeper as a community based organization to reduce health disparity in the United

States by the well-being of minority and marginalized populations through leadership in public and community health like this is collaboration and practices.

We do it through a radio program and services including

our community-based programs and a center for research evaluation and power for change.

One of our most prominence will be open hours healthcare Center.

That is our primary health care clinic.

The center is in and a visit innovative that offers underserved, underserved population with an emphasis on

the LGBTQ+ population.

We offer an array of services including women’s health, family planning, men’s health, HIV care, mental health, preventative screening and transportation and emergency assistance.

When you look at our HIV and PrEP Mississippi we

have struggle but we have been able to accomplish some things.

If you look at our linkage for HIV testing and linkage to care where either exceeding or meeting the national goal.

However we continue to do struggle in retention and care in fire

suppression.

The PrEP data is the open hours healthcare Center.

This is a particular interest because we provide 75 % of all of the PrEP in the state of Mississippi.

As you can tell it is sparse.

We’re not in the entire state.

You can have one rest but that really optimizes and says who we are reaching the we have more to do.

There are multiple reasons why we are not able to do this in Mississippi.

We have done assessment by patients and our staff and of course there is a lack of access.

There is a prevalent thing that is around the country.

We also have stigma which is in every form of care that we provide.

There is also some other cancers that are, route our assessments with our patients.

Not only is there local recession of risk and you would think you Mississippi that is the thing but it is.

There’s a concern about side effects.

When you live in that state like Mississippi side effects are huge because we are already existing with so many other negative health outcomes.

On ways see the commercials that talk about the benefits of the medication and how wonderful they are and that last 50 seconds when they run through all of the side effects

that is what we hear.

And I hear it in particular when you think about Truvada because my dad is on the analysis.

My Alice is on dialysis.

So is my cousin.

We’re living the side of text and we need a safer option.

We need a safer option for no other reason that we have gone through enough.

We have high diabetes race, high blood pressure race, kidney failure, you name it we have it and all of this combined with

HIV.

We need DESCOVY for PrEP so we can increase utilization.

If we gave free pills every month that is accessed but access is not indicative of utilization.

So we need to have a safer option for our community.

In particular with African-Americans.

We live these health disparities.

We live the side effects and we are women in particular who may have a low perception of risk it seems as if we are taking to Botta we are trading illnesses.

I get rid of one to get another.

That is not something that we want.

Particular for adolescence and including

parents with adolescence they generally want the best for their children and they really don’t want to think about their kids having sex but we know that that is the real thing.

If they see the advertisements for Truvada and they see the side effects it gives the impression that they are going to expose their children to something that is going to give them a lifelong problem and when you’re in the state of Mississippi you see your family in a dialysis clinic.

If you had the opportunity to as a stop by the dialysis clinic.

Will see that it is filled with African-Americans.

As it relates to adolescence I actually have a call tomorrow for a parent.

Her six-year-old-year-old came to us and tested positive for syphilis and chlamydia.

She called one month later wanted to take him off of PrEP because she is so concerned with the health issues and the side effects associated with PrEP.

You and I we understand the correlation between syphilis and HIV but that is not her reality.

That is not her perception.

We all live within our perception because that is our true reality.

I will like for PrEP, for DESCOVY to be approved for prep between African-American women and

adolescent.

>> Thank you.

Will speaker number six please step up to the podium and introduce yourself.

Please state your name and the organization you are representing for the record.

>> Good afternoon.

And Kirk Myers in the prosperity in Dallas Texas.

I am the founder and chief executive officer of a AIDS prevention agency.

We provide services that address health, social and economic disparities amongst black Americans with an emphasis on the [ Indiscernible ] community and their families.

I am also a black man who has had sex with women and was living with HIV for over 26 years.

Through my lived experience and managing my disease and managing my agency dedicated to decreasing new incidence of HIV and AIDS through various prevention programs I know the delays and deliberations that are surrounding the prompt approval

of discovery for black women, trends individuals is out of sync with our real-world reality.

This captures the reality amongst my people especially those black women and trends individuals individual overrun by the socioeconomic health disparities they confront daily.

Some people have privilege on their side for time-consuming contemplation

the prompt approval of DESCOVY for the approved use of HIV for PrEP my community makes immediate choices on a day to be basis that ultimately can result in the acquisition or spread of HIV aids.

Therefore I urge the prompt approval of DESCOVY for the proposed use of HIV PrEP because it is right to give lack women, MSM the option to make a safer and effective choice on it daily basis to predict as a go about their

lives as usual.

While I work as a CEO or the street level of a sex worker I will be standing as an authentic voice to compel the advisory committee to consider the fact that I have immediate access to those who would benefit from DESCOVY for the proposed use of HIV.

I have organized community forms, focus groups and one-to-one individuals to speak with authority that this drug is wanted.

The young women gave me and confide in me have expressed [ Indiscernible ] that has the ability to protect them from HIV and AIDS with more side effects.

Finally if anything is right at this historical moment in HIV prevention it is options to go beyond the past practice of normalizing the majority and

ignoring the mud minority.

Without this option expediency , desperation and ignorance will continue to drive up the statistics of new incidence of HIV and AIDS.

With all due respect I am asking the advisory committee members to join me in doing the right thing and insist on the prompt approval of DESCOVY for

prevention of I’ve HIV for

transgender individuals who respect will speak out and share our testimony that this is the right stuff to take.

For the more we implore that this drug be approved not just in men and trans women but women need this drug and it will not be in the interest of public health to have this drug approved without including

women.

For to be stigmatized as a drug everyone deserves the same choice in prevention options as the rest of us.

Is a black man living with HIV in America for the past 26 years there has been this divide between black men and black women and when we look at options this is the best option for all of us possible.

I am not a scientist.

I do not have all the beautiful sliced to compel you to do anything that I can tell you from the grassroots level and street level that this drug is needed and if we only approve it for one indication it will create further stigma that we do not need.

Thank you >> Will speaker number seven step up to the podium.

>> I am into war and I am the executive director of New York-based organization focused

on accelerating the delivery of drugs.

I should note I was a member without any conversation of the independent data committee of the DISCOVER trial .

I stood here as some of you in this room did as well seven

years ago.

The task was easy The data was robust, the evidence was clear and I am delighted that that committee then and the FDA shortly thereafter follow the evidence and approved Tenofovir Disphosphate near .

I wish the task was as easy to date.

While the evidence is clear today we sent in an evidence free zone which has been well discussed

today.

Is the dynamics his face and I hope we don’t to return to ever again.

I have some thoughts about that toward the end.

The data or the data We must act on that most urgent data point presented at that is an epidemic that continues to multiple places in multiple populations.

What we do today matters.

Not just in the United States but particularly for

women at great risk in Africa.

Recognize full well that that is outside of the approval of the FDA and committee.

Your job is to look at safety and efficacy for the U.

S this room today recommendation made in this room by the FDA will resonate and influence the global response.

I realize that is a heavy burden but one that is real.

I am going to stick a few minutes to go through the two courses that you have on

the table.

Is very clear to me and the organization that I believe that the data presented in the application supports a noninferiority claim for PDF for oral propped for men and transgender women.

I emphasize that is noninferiority.

The DISCOVER that we assign for

noninferiority we met the test.

Not only as you make your vote today on the committee but as the FDA works around the labeling for Gilead that this be clearly registered as a non-if the area oral propped option.

Any claims of superiority I think are unfounded.

Yes there is a different safety profile.

I cited to date that it may be safer on some levels but concerns in hours with weight gain.

We need to be very clear so there is no computer to PrEP users today or users of tomorrow that we are somehow promoting one as a safer more effective drug.

This is a noninferior oriole oral drug.

One is more challenging young women.

Data was not collected in the efficacy trial.

We can quarterbacking why that was and

why decisions were made.

The best time to debate that is not sitting in an FDA hearing to consider drug approval.

The should’ve been open conversation that we had with the company, with FDA and community groups far and wide to discuss the best pathway for product development.

I do trust that that is the case and Dr.

Murray described that for next generation new chemical entity

prep agents that is not a change with what we discussed today is not creating a new status quo.

We recognize that this is a [ Indiscernible ] and based prep and I use my comments in that regard.

If F/TAF is not approved for women the only one that will pay the price is women at risk

of HIV.

Gilead will not suffer nor will others.

That said we have to be clear that safety and efficacy matter.

Based on the data is ended today and I just say in addition to not taking money from pharmaceutical companies I am not a status mission, try

list, ethicist or scientists.

There is a very clear rationale for F/TAF to work in women.

I believe that is critical to approve.

That said I believe the prep indication is to come with an incredibly strong robust and enforceable postmarketing surveillance, research agenda and a risk evaluation and mitigation strategy that makes it very clear that over the next 12 to 24 months Gilead will be responsible for collecting in collaboration with other research groups the effectiveness as well discussed efficacy of prep in women is hard to measure currently with oral propped, not impossible but hard to do, let us focus on effectiveness and ensure that FDA postmarketing ensures that we have that.

I will say in our work in Africa particularly as reported in a number of studies the pill size does matter.

It is one of the leading reasons why women in programs in Africa

do not continue the medication.

Your decision will matter and a smaller drug, not necessarily

safer or more effective will be of enormous benefit.

I want to emphasize again in closing that the education prescriber information is afforded materials that are not part of any materials that is monitored by the FDA but with community and put.

In an active way to ensure that the language used to describe this indication as a noninferior product for all populations clearly describe clearly enforced and robustly done.

So we do [ Indiscernible ] to approve for population

F/TAF for PrEP.

This is a signal of delay and distrust of the research community and product development.

At the same time committing together that we are not changing the rules for future products of new PrEP agents that we ensure that we have better conversations early in the process so that products coming to this committee and to the FDA are done with the most robust and complete package possible.

Thank you very much >> Thank you.

Once again the open public hearing speakers have presented us with

incredibly powerful insights.

In the challenge at hand before us and we thank all of the speakers for sharing your thoughts and convictions and insights and balancing this

very difficult problem.

To open public hearing portion of this meeting is now concluded and will no longer take comments from the audience.

Will no turned our attention back to the business at hand which is a evaluating the data presented before us and we will continue with our clarifying activities with the applicant.

Prior to the applicant [ Audio lost ] as I look at all of the materials we have received seem to be defined by a weight greater than equal to 35 kg.

That is not how I have thought of about adolescence.

I want to know if there is an age parameter or simply a way to parameter.

Is a 15 to 17 the end of sufficient weight or is it down to 10 or five.

I just want to know if there are any parameters around the adolescent category.

>> I think we’re sticking with weight.

It becomes tricky to decide what age one should be starting to use — >> 10 then?

>> If it is purely weight it could be a big 10-year-old or 36 kg.

>> We know the safety and have the dose down to 35 kg and exactly in a physician or person of adolescent age should consider it is probably up to them and when you put an age in their it boxes you and.

>> I thought about it was 15 or 17.

Is that purely weight-based? >> Thank you for the clarification.

I wanted to make sure that I was reading weight as the determinant and not other factors.

Okay? Back to the applicant wanted to clarify some of the concepts from this morning that you needed your input and then we will come back to the many questions we have on the list from the panel members.

>> Thank you.

We have for clarifying answers to prior questions.

The first is around the data for DESCOVY in vegetal tissue.

I want to walk through what the available data are and someone has a clear understanding of the dater and the literature.

There been three different studies of DESCOVY in vegetal tissue.

One was a single dose study of DESCOVY and the discussion of that manuscript they compared the results with another study that the same group conducted several years prior with about a.

The second study was done with a single dose of DESCOVY and Truvada within the same study.

The third city was done by the same group and multiple doses of DESCOVY and Truvada looking at

vegetal tissue levels.

Slight to.

Here are the results for most studies.

In the first study looking at DESCOVY best tissue levels following a single dose of DESCOVY the tissue levels of AC was reported as 132,098.

This was compared in across study comparison to the Truvada levels which were noted to be 1.

3 to 1 those with DESCOVY.

The second study that was done with a single dose of Truvada or DESCOVY in the same trial demonstrated that after four hours all of the samples with Truvada Cold War below the quantification and 69 % of the samples with DESCOVY was below the quantification.

The conclusion is that multiple dose data are needed.

In the setting of multiple doses which is indeed the more relevant setting to assess tissue levels for daily administered drug four hours after dosing of DESCOVY or Truvada levels were

2.

6 fold higher with DESCOVY as compared to Truvada.

FDA presented these data in their presentation.

At 24 hours and 48 hours after dosing stopped there were comparable and low levels between DESCOVY and Truvada in the battle tissue.

I would like to now put these special tissue data into context with what we know about

rectal tissue data.

The vegetal tissue or just now a graphical representation of the data I showed you as a four hour time point in the table where you can see that DESCOVY achieve slightly higher levels than Truvada four hours after dosing.

As compared to rectal tissue levels the first thing to note is that Truvada achieves about 10 fold higher levels than DESCOVY in the rectal tissue.

It is also relevant to note that the rectal tissue levels with Truvada are somewhat of an outlier as compared to the vegetal tissue levels with both DESCOVY and Truvada and the rectal tissue with DESCOVY.

This has been hypothesized to be related to the low bioavailability of Truvada and the fact that there may be drug delivered through the directly through the G.

I rectal tissue with Truvada.

If done stone to a lesser extent with DESCOVY which has higher viability Billy.

This is up hypothesis without clinical or scientific proof.

Nevertheless what we know about Truvada is that despite the lower levels in the battle tissue as compared to the rectal tissue levels with Truvada Truvada PrEP is highly and equally

efficacious and then women.

The lower levels in vegetal tissue correlate to having efficacy in the setting of Truvada for PrEP use in women.

Similarly we now know with the Discover co-trial is that despite having tenfold

lower levels of [ Indiscernible ] both drugs demonstrate that they were highly effective and DESCOVY was not inferior to Truvada at preventing HIV acquisition.

These data contribute to increasing body of understanding the systemic drug levels of what is driving efficacy and advocacy is not related to particularly

homogenous tissue levels.

I can keep going to the other issues or we can stop for comments.

>> Thank you.

Your point is well taken.

Since this is such a an important issue comments from the committee to better understand these data since

these are a critical element.

>> Lori.

concern is there are extremely

large small numbers.

I need some help understanding how generalizable these results are to the larger population.

I am unable to that based on the data presented.

>> So in terms of the generalizability all tissue level studies that have been conducted have generally been less than 10 participants per group occasionally somewhere between 10 and 15.

This is just related to the nature of the invasive nature of conducting the studies and the requirements for biopsy.

In addition we haven’t seen any of data looking at tissue level data in prevention studies because taking biopsies in the setting of individuals who are at risk for HIV infection could actually increase their risk and those data are not available nor are they likely to be generated.

So I would agree that the data are variable and that they are not a large amount of data, nevertheless when we think about what the state of Maine in the setting of high amounts of clinical data around efficacy of Truvada for prep in both men and women those data can provide reassurance.

>> A little more clarity would help to.

How is it that states are coming up with guidelines on the amount of time needed to obtain maximum intracellular concentrations and pushing in that direction when we are not able to get, we are able to get 14 participants from this study and I might also ask if it would be appropriate to ask the agency to comment on this as well.

>> Yes.

>> So during the lunch break we try to track down the

data that actually we are behind the timeline of recommendation around 20 days.

The data really came back to very sparse tissue data and there are no data that connected 20 days.

One study showed that when assessing national tissue levels in rectal tissue levels over time it seemed that as attend day time period there were stable and study state levels within the rectal tissue of time with Truvada where is the battle tissue levels were still seeing to be increasing and seems like that is the basis for the extrapolation to 20 days required.

But this is never been validated and we don’t know of any clinical data to speak to the time to protection for women.

>> Would you like agency to comment if anyone is aware of the basis for those recommendations?

>> Also if they could comment on their understanding of the uncertainty associated with the concentrations in the tissues given the small numbers.

>> We actually have concerns about the reliability of the data because of the inconsistency and the small numbers and the differences in methodology.

But that is all we have right now.

This extrapolation which has been proposed.

As to the time to achieve protection I don’t believe the CDC has a recommendation in that regard.

What they are stating is the time to treat maximum concentrations.

Some steak islands have interpreted to mean enter protected levels which make sense but I don’t know that the data is robust to that extent but needs conservative levels.

We have not introduce any of that to the [ Indiscernible ], review the data because as it stands right now PrEP is going to be using combination practices so it is counterproductive or counterintuitive to suggest a lead-in period where you come of condoms for example.

So we have not entertain that and we’re not really use the data.

I pointed out that that concerned about the differential distribution is out there and it has guiding some of these recommendations that are being protected by states.

>> To another — I don’t know one of the statisticians can comment but when I hear a number of a temple in crews in the tissue concentrations that content to stick in everybody’s mind but we have to understand the uncertainty associated with that and has a confidence been after the summated so we don’t get home estimated so we don’t get hung up on that number.

This is pretty important point but I will leave it at that and I just want to make that as a final point.

>> This is Jenny from FDA.

The [ Indiscernible ] that we have four tissues with a small numbers and presented as a median in the [ Indiscernible ] because there are a lot of low limit of connotations was observed in those tissue concentrations so this is something [ Indiscernible ].

>> It is just a minor verification about the [ Indiscernible ] tissue concentrations that generated in the rectal and but China.

Can you confirm or clarify to

me whether but China data of

the but China tissue .

I know there different sometimes for you look at the different aspects as opposed to

rectal drug concentration.

>> There is a range of methodologies used with a compartment study.

This is a method with tissues or cells are washed from the cervix and sometimes with or without scraping.

The data that is shared with you is biopsy data, the slide provides a very high level schematic of how these tissue levels are measured and whether it is in the rectum or the but China force after use to take biopsies generally with rectal tissues or biopsies are taking them with basil sampling where it externally limits want to do.

These biopsies consists predominantly of epithelial

cells and fiber blast which make up the majority of the tissue.

I will point to the limitations of the sampling.

Also contained within that biopsy will be a variety of immune cells including relevant CD4 cells and macrophages, [

Indiscernible ] and the tissue block is intubated with enzymes in order to break up the cells

because the ciswomen is released through enzymes.

The amount is quantified using [ Indiscernible ] so the toll TFK PK level that is reported is the Tenofovir Disphosphate across all of these different cell types recognizing that the predominant cells that are contributing to these levels are epithelial cells and fiber blast and it has been hypothesized that part of the reason these battle tissue levels drop off at 24 hours and 48 hours and why there are so many [ Indiscernible ] of the time measurements is because epithelial cells have a more

rapid turnover and therefore the Tenofovir Disphosphate within the epithelial cells which represent a higher proportion of contribution to the levels are turning over and are no

longer having ciswomen as a 24 hour and 48 hour time for it.

That is just a hypothesis.

>>

[ Captioners transitioning ]

>> We did look at the subset of those participants it had PK sampling done at the week four time pound and found there was no difference in tenofovir diphosphate levels within that

population.

This slide shows data on the 18 women who are part of the study that had tenofovir diphosphate levels

measured at week four.

You can see the concentration of tenofovir diphosphate is similar to what is seen in the MSM population despite being on gender affirming have [ Indiscernible ] hormones.

>> Any questions?

I think these are fairly clear.

>> The third issue was providing additional information [ Indiscernible ] >> Just to remind everyone the eligibility criteria for the discover trial were in two parts.

The first piece was requiring two episodes of condom less anal sex with more than one unique partner in the past 12 weeks prior to enrollment where the second criteria was evidence of rectal gonorrhea, rectal chlamydia or syphilis in the past six months past 24 weeks.

I have proportion people in the study and use all reported going to share the data in the people reporting [ Indiscernible ] in terms of the number of partners at screening prior to baseline.

>> The me number of inserted anal intercourse partners was four which is the same as the report of condomless anal intercourse partners.

There were no differences between arms.

All the people infected in the study, the 22 people who acquired HIV had data and biologic evidence of condomless anal intercourse.

>> Just to clarify, so I am understanding these data and

what is implied, data on men who were inserted the not receptive, so purely insert is and what degree of transmission occurred in that population?

>> We don’t have data who were people who were purely inserted but the criteria required receptive evidence of anal intercourse that was unprotected.

There was [ Indiscernible ] evidence of receptive anal intercourse.

>> Follow-on questions or clarifications?

Please continue.

>> The last topic I would like to proactively follow-up is the question about study design issues in CIS women.

As reported by panelists and community members and FDA, there are challenges with conducting a clinical trial in women and superiority store

report two oral drugs that are placebo-controlled trial are not going to be ethical given Truvada is effective in women and we talked about inferiority and the challenges around establishing a noninferiority margin and the FDA perspective on the inability to construct a non-inferior margin because of

the lack of consistency.

We did look at taking the effect from the two most effective randomized clinical trials in women, partners PrEP which was one of the registration studies for Truvada and a Bangkok study which was a study in injection drug users but most of the HIV acquisition in women was through sexual transmission.

Using the treatment effect from those two studies, we calculated a noninferiority margin using the same methodologic approach we used for discover and came up with a sample size of 22,000 in a high risk population and that would take eight to 10 years to conduct which was part of the reason we didn’t initiate that study particularly in the setting of the ongoing discover study however, we also recognized there is been a lot of discussion since 2015 about this conundrum of what could be done to assess the efficacy of PrEP in women and now where we are because of the discover results and because there is highly effective active comparator in Truvada and now

DESCOVY and men as well.

Dr Indiscernible ] has been one of the leaders in this area and we have and participating in discussions as well as with PrEP experts and community members and are some novel tile design methodologies that don’t fall within the standard rubric but I could ask Dr.

Wilson to discuss some of those approaches from a statistical standpoint.

>> Thank you.

Just to clarify the 22,000 Diana referred to would be a study in Africa so you are dealing but by

incidence rate.

In order to find the base noninferiority designed we selected two of the five women’s studies which had the most benefit from Truvada so we cherry picked the two studies to help us reduce the sample size and the lowest we could get it to was 22,000.

Now we are certainly open to more innovative ideas.

Unfortunately for us, [ Indiscernible ] a great talk a week ago and we are very receptive to some of the ideas Jeff proposed and I would like to go through some of these in terms of how a woman’s study could look.

>> All of these are proposals but it was proposed there should be at least two placebo anchors in order to interpret a woman’s study.

The two that come to mind would first and epidemiologic assessment of the perceivable incidents so we

would envision a study in Africa where it would be based on current epidemiologic data what the incident sees [

Indiscernible ].

The second approach to estimate a placebo incidence could be based on the screening period from the study so knowing how long it was from the last test to beginning treatment, that being the risk period, we can look at the subset of women not on Truvada and assess the incidence and that would be a reference

placebo incidence.

The other thing proposed in order to

assess whether a PrEP drug is effective visit should lower the incidence by five to 10

fold.

The idea came from oral contraceptives and oral contraceptives lower the incidence of about 40 fold but we are trying to be realistic.

Just for reference if you look at the discover study where the adherence was very high, we are estimating Truvada lowered the incidence by 10 to 20 fold based on two ways of estimating

the placebo incidence and [ Indiscernible ] 20 to 40 fold.

These are both effective agents.

I like to bring up slide number one which is the noninferiority study we are talking about.

Just with reference to these five studies, the two best studies, partners PrEP and a Bangkok study which had the lowest risk ratio, in partners PrEP we are lowering incidents threefold and in Bangkok we are lowering incidents fivefold.

These are just the point

estimates.

I would also add in our own demonstration project where we have got a lot of real-world data in women, our estimate we are lowering incidents approximately fivefold based on observing and

incidents of .

8 largely from cohorts in Africa where you would expect and incidents [

Indiscernible ].

The fivefold is as far as we are apparently

getting with adherence rates.

Is potentially possible to improve appearance and get greater effect sizes but

clearly the metric for what constitutes good enough efficacy will need to be tailored to the population and adherence we are getting.

>> And other criteria which is an extra criteria and not a different option is that the incidence rate in the experimental arm should be no more than .

5 higher than the active control which would be Truvada and that seems somewhat

reasonable.

Another separate approach was a part [ Indiscernible ] look at the

adherence subset of a study.

In discover if you look at the individuals who are taking two or more tablets a week, we are only seen two infections, one in each arm so we are observing and incidents of last then one in 1000 in adherence subjects and it was proposed that threshold of one in 1000 is a reasonable measure of what constitutes an effective agent.

These are all good ideas and very innovative approaches that we can leverage and work with

the FDA on to try and design a woman’s study that answers the efficacy question and we are committed to doing this.

>> Thank you.

If [ Indiscernible ] in the placebo groups I’m having trouble understanding how you come to a 22,000 person study when we look at the discover which had a one per hundred person [ Indiscernible ] you have a fivefold increase event rate it a threefold increase in sample size?

I’m having trouble understanding.

>> The main thing driving up the sample size is the weaker performance of Truvada in these women’s studies.

In the design of discover, we estimated based on the three historical controls that we would lower incidents fivefold.

When you pool these two best studies you are lowering incidents threefold so it becomes a lot

harder to attain 50% of a week affect.

>> I see your point but I am still concerned with the assumptions but I see your

point.

Other questions Goetz?

>> I want to come back to what you just said, the weaker performance of Truvada in these

women, are you stating that [ Indiscernible ]

>> It comes back to Dr.

Baden’s question as to why the sample size must be so large.

Are you projecting the women you will enroll will be nonadherent?

>> Our interpretation of the data is adherence is a primary driver of efficacy.

As you have seen presented today, there are several thousand women who have been given PrEP and over 100,000 men that have been given PrEP.

If you look at the literature there is a total of six case reports of individuals getting infected while on treatment.

It is highly unusual to get infected while on

adequate adherence and that is why the threshold of what constitutes good enough is you need to have less than one in 1000 individuals getting infected because that is what the current drugs can deliver.

>> [ Indiscernible ] >> Why did the discover study work?

It is a circular problem we are dealing with.

You expected it 10 hold higher-rated HIV then you saw in both arms.

The adherence was extremely high, higher than it was across the board in the previous studies and yet you ended up with a non-inferior drug statistically proven not inferior in this population.

I don’t get it >> My understanding is that you’re perfectly adherent to both Truvada or discovery there is no advantage to one of the other from it efficacy point of view.

That is a hypothesis data from Truvada is we are seeing, and similarly for

discovery we are seeing 2500 infections and individuals are adherent and to find there is a DBS done every three months showing adequate drug levels.

On the other end of the spectrum if you stop taking the drug completely, there is no difference between what the drug can provide because it is not providing any benefit.

To the extent that is a benefit is in the middle.

The individuals who are not fully adherent but are taking some drug in the PK properties of the drug lead us to believe at least from the PBMC levels there could be an advantage to the efficacy of discovery.

These data are somewhat suggestive.

We don’t have enough data to say even in a subset there isn’t an advantage and certainly the study overall has its own superiority but that is a hypothesis that can be tested in the future as well.

>> Dr.

Walker? >> It may not correlate to the discussion going on at hand, and forgive me if you mentioned this, there has been a lot of information presented but I wanted to know, could you go back and let us know some information about these baseline demographics and exactly how the sites were selected?

I’m curious especially within the U.

S knowing HIV is not evenly distributed among states and regions so I’m curious to know how your sites were selected and if you could just give me some details on the states if they were rule or urban and if that led to the disproportion of African-Americans in this study?

>> I will ask Dr.

McCallister to comment and describe our site selection process.

While he is coming to the podium I will say the discover study enrolled 9% overall African-American subjects within the U.

S proportion was 13%.

As I believe was pointed out earlier today, the population we enrolled into discover was largely reflective of people taking PrEP today.

It was not reflective of the people at highest risk for new infections

right now.

This slide shows the percentage of Blacks and Hispanic and Latino individuals enrolled in the discover trial on the left as compared to the percentage of Blacks and Hispanic or Latino individuals taking PrEP today in the U.

S Our proportions were similar for discover for black participants and we enriched somewhat for participants who self identified as Hispanic or Latino.

I will have Dr McCallister speak to the efforts we took to enrolled a diverse range of sites in the study.

>> We did specifically seek outside and a high background HIV incidence areas.

In the U.

S doing, almost all of them were urban centers and they were hospitals in STI clinics and

health departments.

Within the U.

S in discover, we had a large percentage in the Northeast and the Southeast in particular.

One of the findings that has come out, in an attempt to understand what the background epidemiology was of our site was we used CDC data to get HIV incidence rate in these sites and compared it to places where discover was conducted.

>> These data are incidence

rates over time at 25 metropolitan statistical areas inside the United States that overlapped with discover sites and these are incidence rates in MSM in those locations who

were not using PrEP .

What you see is over time the general incidence rate in both the discover sites as well as non-discover sites has gone down a bit but the discover sites where in places where the incidence was higher consistently over time.

>> >> Can you clarify if that comparison was adjusted for the racial and ethnic distribution of the participants matched for what the distribution is in the MSAs?

>> These data on the screen are all the people at risk with an

indication within these MSAs.

When you do break it down racially, the numbers are very close.

They range from 3 4.

2 >> I’m not sure I understand that.

What I’m asking is does this comparison, where you were saying people in high risk areas, are they from a racial and ethnic group that is at high risk in that area?

Have the HIV in Houston is an African-Americans right now.

If he only enrolled white people in Houston you would get a lower rate of HIV incidence, does this adjust with that difference?

>> It is inclusive of all people in these MSAs so the answer is no it is not specifically adjusted for African-Americans.

The rate an African-Americans were the rate in Caucasians from these locations are very close to these numbers.

>> Am I being obtuse?

>> The point has been made.

Dr Indiscernible ].

Dr >> I will follow up on what I think is his question.

You have presented data on say one metropolitan statistical area [ Indiscernible ] the MSA’s from which you recruited patients have higher rates of HIV

acquisition the other MSAs.

When I think the question is, the patients enrolled in the

study, are they representative of the racial makeup of that MSA and this would be predicted to have the higher rates or were there patients enrolled in this study populations of lower risk?

Which gets back to the question of the risk of the population enrolled in the efficacy of the intervention.

>> What I think your question is driving at is how confident can we be that we were in the right population with a high risk for HIV.

To address that I will ask Dr.

Wilson to come to the podium in the two ways we try to estimate the potential placebo rate to understand whether we were in the right population.

>> Just answer the question directly, we did an analysis where we forest the racial makeup in the MSAs to match that in discover and the rate

went down by .

3 overall in 2017 and 3.

5 when you force it to match the

racial makeup in discover.

We have looked at another method of assessing the placebo rate and that is using the rectal gonorrhea approach which I can show you.

There have been eight different cohorts within controlled trials of placebo controls.

Each of the eight black dots on this graph represent a placebo cohort and what is notable is the higher the rental gonorrhea rates the higher the HIV incidence rate in these placebo cohorts and it is a linear relationship.

On this graph we have superimposed the discover data suggest about 20 on the X axis you will see two little dots and these represent data from discover.

Great for Truvada and blue for DESCOVY .

For both arms we have the rectal gonorrhea incidence as well as the HIV incidence.

These two dots with the vertical confidence intervals which are hard to see because

they are so tight are well below what the projected placebo incidence would have been in the gray area is the

95% prediction interval around the placebo rate.

>> Dr.

Smith, did you have a follow on?

>> I had a question about the

MSA slide.

>> We will pull that up.

>> Remind me the years in which the discover trial was actually happening?

>> It started at the end of 16

and largely in 17.

>> Okay.

So incidence was falling in both sets of communities before the start of the study and you really only

have the last two time points that are presumably related to the discover trial?

>> That’s correct.

If I can have the slide on the increase relative to placebo in Truvada with the MSAs.

When we designed the study relative to the three historical studies used for the design, we expected Truvada to lower

incidents fivefold.

1 expected for Truvada versus 6.

96 in placebo from the three studies.

When you look at the actual data from discover we are noticing Truvada is lowering the incidence might 8.

6 fold if you were to use the MSA data, that is this middle estimate of the placebo rate.

The placebo rate estimate to be 3.

8 during the duration of the study versus the U.

S discover where we observed Truvada incidence of 4.

46 active control was substantially more active than we anticipated.

Using the rectal gonorrhea it is actually 19 fold reduction we are seeing with active control Truvada.

Discover was actually a better test of a new agent then we anticipated it to be.

>> Dr.

Das? >> Was it really a better test or just the prevalence of circulating HIV in the populations test might’ve been lower and therefore exposure to HIV may have been lower?

I think you made the case the at-risk behavior was relatively high but how do we know the gonorrhea curves you showed in the low rates in the discover cohort work just because there

was lower exposure to HIV?

>> If you look at the lower

bound of the interval around HIV incidence we projected for placebo so what we projected an incidence likely up of six, the lower bound is slightly above three.

In looking at the conservative miss, there is a big gap between how placebo would have performed relative to have these two agents are performing.

>> Thank you we are close to our break but before we go to our break, one last question on the cis- women.

Separate from this committees deliberation and the agencies action, what is your commitment to studies in cis- women in terms of generating the data that are absent?

>> We are firmly committed to generating data in women and asked shown we have got a number of studies that we are hoping to initiate within the next year.

Is are not traditionally powered for efficacy studies, these are clinical effectiveness studies and they are planned to be conducted both in the U.

S well as in high incidence settings within Africa to demonstrate the safety as well as the clinical efficacy across a broad range of populations.

In addition, we are committed to generating clinical data

with DESCOVY with PrEP using one of these novel approaches if we can come to an agreement on what that approach should be and Dr.

Wilson walked to some of the ideas in active discussions with investigators and experts on how to best get this done and we are committed to do it and planning to incorporate the feedback we received from FDA and from the panelists in this decision.

>> So whether or not there is the indication that is granted, you will conduct studies in cis- women to determine the effectiveness?

>> Without a doubt.

>> It is that the 10s hundreds or thousands?

>> The indication allows us to go more broadly into clinical effectiveness demonstration projects so it clearly allows us ticket to higher number and reach a higher number of women more quickly because we have endorsement from a regulatory agency that this drug is safe and effective in the population.

If we don’t have an indication, we are still generating then in women but the nature of the data has to be restricted until we get the endorsement from the regulatory bodies that we can do these demonstration projects so we are committed and we are going to generate data and I think the proportion and maybe the velocity of that data depends on where we land but the commitment is there and it will

happen.

The time period is just depends.

>> I understand.

We will take a break and resume at 3:15 PM sharp.

****8. TRANSCRIPT 4

We have several committee members to still have questions from this morning.

I will ask the committee members as well as applicants to be as poignant as possible in the questions and the response so we can cover as much ground in the next 15 or 20 minutes before we have to get to discussion about the questions at hand.

I’m going to start with questions from this morning.

Dr Indiscernible ] you are on the list.

Dr >> I have a question that relates to the slide cc 50 which was the plot looking at

the different subgroups.

I know there has been conversation, I know adolescence had been part of the populations you were contemplating including in your request for indication and I wonder if you could explain.

The closest thing we have to adolescence is age less than 25 and one of the only two data points on this curve that show

a favoring to TBD so maybe you can comment on that.

>> I will first make the point there a wide confidence intervals around the point estimate related to the relatively small sample size as compared to the entire study design.

The incidence rate within the population of participants who are less then 25 are higher than the overall incidence rates.

This is related to the relationship between younger age and lower adherence which has been demonstrated in many prep studies and certainly demonstrated in the adolescent study with Truvada and reflects those participants have lower adherence in that age bracket however both DESCOVY and Truvada were highly effective and substantially lowered the risk of HIV acquisition.

>> Thank you.

A follow on to that, safety in the younger ones, I am learned adolescence is defined by weight of the 35

kilograms.

The data you have on [ Indiscernible ] 10-year-olds on Truvada, 12-year-olds?

I want some sense if we may be giving it to our 10-year-olds.

>> We have Truvada, DESCOVY and state [ Indiscernible ] regimens containing Truvada that are indicated for adolescents to 35 kilograms and indications in younger populations based on the data we generated in treatment trials so we have nearly a large body of evidence to suggest DESCOVY therapy is safe and well tolerated in these younger populations even extending less than 35 kilograms.

>> Is that from zero to 10 years old in treatment?

>> In the setting of HIV treatment I think our lowest weight indication is 25 kilograms.

>> Again any labeling is going to need to take into consideration the absence of data.

>> I’m getting a signal the age cut office six.

>> So you have [ Indiscernible ] with indication.

Dr did you have a follow on? Dr.

Gripshover? from thsi moring

(4:00)
>> GRIPSHOVER: Yes, I had one question about weight gain, we did see one slide from the audience earlier, but I know especially in the HIV treatment world where there is a concern with obesity they think some may be related to TAF some also the integrase inhibitors I think they gained one kilogram in the the men it seems like sometimes women gain more weight so I wonder if we can have any data in women on TAF outside of this is if we are trying to extrapolate this to a broader population?

>>BRAINARD: I will ask Dr. Das to come and discuss the weight gain in the discovery study and place it into context around what we know from other PrEP trials.

I’ll also note that the data we have from other HIV treatment setting suggest there are many factors associated with weight gain and integrase nhibitor therapy being one of them and that is seen across different integrase inhibitors.

TAF in and of itself iss not associated with weight gain.

What we see in the HIV treatment staff is TDF is associated with the weight-suppressive effect and when TDF is switched to either a TAF product or a regimen without TAF that doesn’t contain TDF, that can be associated with weight gain.

>> DAS: The difference in weight in the discovery study was driven by the TDF weight suppressive effect that Diana just discussed.

We’ve known about the potential for Truvada to potentially suppress weight since the IprEx trial.

The U. P.I. has weightloss as a known adverse drug reaction for Truvada based on the IprEx trial.

On the left-hand side you see placebo across the top and Truvada across the bottom and you see with IprEx there was a weight loss through week 48 with Truvada and a weight gain on placebo.

This is in median percent changes in weight.

In discover, the Truvada arm looked similar to the IprEx arm with initial weight loss and a little bit of stabilization toward the end and the discover arm the descovy arm sorry looked very similar to the placebo.

The average amount in American age 18 to 40 gains in the year is one kilogram and the placebo weight gain in the IprEx trial and the weight gain in the discover trial on the descovy are are consistent with that. Further. if you look at HPTN 077 at 48 weeks the placebo armed gained about one kilogram.

The Cabo arm in that trial also gained gained 1.1 kilogram.

I think what we are seeing a trials that compare TDF to TAF is the TDF weight suppression or stabilization affect versus the release of that affect in switch with a lack of that affect in the TAF arm.

(7:31)

>> Thank you. Dr.Lee?

>> Can you please go back to slide cc 50 in the subgroup analysis of los [ Indiscernible ] this may have been where the incidence rate

is a little higher perhaps due

to adherence as a reason.

What was the adherence for that group and was it similar to the treatment trials you see in adolescence?

I’m trying to correlate this for younger people and if we would see the same trends.

>> I will ask Dr.

McCallister to address the issue of adherence by age within the discover trial.

I will say overall we have seen lower levels of adherence within studies of PrEP in adolescence and younger individuals and that was one of the drivers for where we didn’t include adolescence was because of the data suggesting they benefit from an increased visit frequency, they are going to benefit from increased interventions to improve adherence and have age appropriate retention and recruitment methodology.

>> So adherence in individuals less than age 25 was lower than in those above age 25.

This is the kill count data broken down by less than 25 years on the left, 25 to 50 in the middle and above age 50 on the right.

These are as you can see far lower for those less than age 25.

Another way of looking at it is true the [ Indiscernible ] data.

We see the same pattern.

Less than 25 using the tenofovir diphosphate levels and if you are in a range of four tablets per week or higher.

Of the 22 infections in discover, seven of them did occur in this group and all seven did not have technical difficulties.

>> Thank you.

Dr early in the day?

>> My questions have been addressed.

>> Dr.

Jia Donna? >> A question for the agency.

Two questions, is it within your purview to say a registration or study should include an X proportion people in [ Indiscernible ] a certain proportion are black African-American from the U.

S is that something you can say or is it up to the sponsor to design that?

>> We can make the recommendation but we wouldn’t want to hold up a trial or an approval if they didn’t meet with the suggested rate would have been in that certain population.

>> Another question is this request to approve based on essentially drug level

extrapolation for women, do you have other examples of when the agency has allowed that to happen?

Can you get any guidance on when that is appropriate or considered inappropriate at the agency level?

>> I don’t think we have any other examples.

>> The tissue level, we extrapolate efficacy for children all the time so we have matched efficacy in different populations based on systemic PK.

I don’t think we have ever made a regulatory approval decision based on a non-systemic type of PK argument.

>> And that prior decision you inferred the correlate of protection so to speak, let’s say an antibiotic level in blood where there is an understanding of the protective moiety is.

>> We have always tried to

match as much bioequivalence, I use that term loosely to the population that had the clinical data.

>> Dr.

Goetz? >> I want to go back to one of the backup slides which had shown

correlation between dosage [

Indiscernible ].

That was in the IprEx study .

What I was interested in is trying to build this bridge which may or may not be buildable, are there similar data that are inferred based on PBMC or RBC studies in women that correlate the same level of protection of two to three tablets per week as being the cut rate?

>> I will ask Dr.

Anderson to address this question about the thresholds for adherence for women and for men.

>> I would say not this level in formal analysis in women.

We just don’t have that yet.

We do have [ Indiscernible ] there is

a very recent study in women, this study is one of the very few studies in women that have collected blood spots and a marker were you can tell different gradients of adherence and this study did collect those.

They had four infections in the study and none of those infections occurred at the middle with the DBS level.

They all occurred at the low level.

>> So aside from this sparse

data set, there are no data at your disposal that will allow us [ Indiscernible ] based on a

biological measure that correlates with drug levels to protection in women and shows equivalence between the level of protection we expected in minute that level and the level of protection demonstrated in women.

>> I think these results on the screen are consistent with what we saw, it is a smaller data

set that it is consistent.

>> I would also say in the partners PrEP study there was an assessment of adherence based on tenofovir blood levels.

Unlike tenofovir diphosphate in red blood cells was is an integrated adherence

, tenofovir plasma levels were say within the last four days so this is a measurement of adherence and less precise but it does offer an objective assessment and it is referenced in the new CDC guidance as a meaningful assessment of what they call recent PrEP use which the correlate is associated with a 90% protection for both when [ Indiscernible ] partners PrEP where they look at both men and

women who had detectable levels the overall efficacy was 92% and and men it was 89% in in women 94%.

This represents a lower level of adherence and for example we saw in the discover trial nevertheless shows there is no difference

between men and women.

>> Thank you.

We made it to the list.

Other questions from the committee?

We are not all satisfied given the nature of the data but are there other questions that can help inform the committee in our deliberations?

>> If not, we will proceed to the questions to the committee and panel discussions.

It would like to remind public observers, public attendees may not participate except at the specific request of the panel.

I would like to thank Dr.

Brainard and the Gilead team for covering an incredible amount of information given the size of the problem, the amount of data could never approach the magnitude of the problem.

We were able to get through about 50% of the slides you prepared.

You have at least 1600 slides, I think we got 150 to 200 in front of us so thank you for preparing the information and sharing it with us.

>> Now we must turn to the questions at hand.

Before we moved to the questions at hand, I have some guidance I would like from the agency and if others have questions, let me

know.

I would be interested in the agencies guidance,

particularly in the cis- women conundrum.

I want to make sure I understand the Robin correctly.

There are multiple studies with Truvada, at least two showed no benefit in two showed benefit.

One led to the indication.

However these data were not strong enough to allow a determination of the study design with the noninferiority margin yet these data are strong enough to guide us with a bridging study to lead to an indication.

Is that the position we are in as we are reflecting on how to move forward with our deliberations?

>> That’s correct even though we had low efficacy in some studies, it was low or no adherence but we think it women are adherent they should be 90% affect.

>> That wasn’t strong enough to set a noninferiority margin so you can have a female trial analogous to a male trial.

>> Noninferiority studies are tricky and are you supposed to use as much is possible.

The problem with not adhere to studies is you need to assume what you saw in the past is going to be repeated going

forward.

For studies in Africa we are not sure what the adherence rate is going to be and that hampers our ability to noninferiority [ Indiscernible ] based on adherence and things we have never really looked that.

>> What tools do you have it brought indications were given to mandate or require future studies versus goodwill and intent to do future studies?

>> I would say this would be a postmarketing commitment.

Requirements are for pediatric studies and safety.

This is really expanding the indication so it would fall under a legal postmarketing commitment but this studies particularly in the HIV arena are almost always completed especially where they are important like this would be to extend the indication to women.

Anybody else want to comment on that?

>> Dr.

green? >> Again I’m going to be the pediatrician.

On the packet to have it looks like application again does include adolescence weighing at least 35 kilograms but I noticed neither question one or two addressed our opinion on adolescence they are not interested in any opinions on the committee on adolescence?

>> We were willing to extrapolate to adolescence based on what is known for PK and safety for the treatment and the fact there is an indication in adolescence for Truvada.

We are willing to make that late [ Indiscernible ] same gender in adolescence because it is the route of transmission we think it could be the variable.

>> Does an indication have to specify sex or can it specify

behavior?

So approved men who have sex with men or can it be approved for men or does it have to be approved for men?

Do you see the distinction I making?

Is that something within the labeling options?

>> Are you talking about MSM and heterosexual men and those have inserted intercourse with women or men who have sex with men?

>> It gets a little bit tricky but if the indication was limited to MSM we would have to think about how the indication would be worded for men in general.

>> [ Indiscernible ] >> Another labeling question, on a label are you able to say this truck has been studied in these populations, there is a recommendation for use in another population based on extrapolation, is that something that can be explicitly put in the label?

>> I think so.

We do that to a certain extent when we describe certain pediatric data.

>> Dr.

Smith? >> Is a possible to discuss MSM indication separate from the transgender women recommendation cry [ Indiscernible ] I have questions about one but not the other.

>> We didn’t plan to have a question answered that way but you might have that as a

comment after your vote but I think if we are prepared to go ahead with MSM I think the agency was prepared to go ahead with the transgender women as well realizing you’re not going to be up to do a power study in transgender women.

Zero conversions out of 74 are probably indicative of some protection in and of itself in the discover trial.

>> But you’re getting it just the power issue given the population sizes?

>> If you look at the IprEx subset analysis that had 200 transgender women defined slightly differently, there was no evidence of impact, statistically significant evidence of protection.

To me it is an extrapolation question.

They didn’t include enough transgender women in

order to do a separate analysis and now asking to make an indication based on the fact that works for MSM.

It was just my question.

>> I think we’re going to ask to have a vote on a package deal and then you can explain why or why not you voted for it or not and if that is one of issues you can explain that.

>> I think we will vote on the questions as written but I think your point is the guiding principle, we can then explain our concerns or reinforcements of how we look at the different

indications.

After we vote, the agency finds our comments even more helpful than our vote.

It is very important that we will vote which looks yes or no but in reality we can express different elements we find reassuring or concerning and what they should pay attention to.

I will be mindful of time, we have about 50 minutes and we have all been very energetic in this complex arena for all the reasons discussed earlier.

In the other discussion amongst the committee before we moved to the vote?

Any aspects of the data or what we are charged with that would be helpful to

discuss or clarify?

If not, I can read [ Indiscernible ] we will be using an electronic voting system.

Once we begin the vote the buttons will start flashing.

It is a new system so hopefully we won’t get confused.

They will continue to flash even after you have entered your vote.

Press the button firmly and that corresponds to your vote.

If you are unsure or wish to change your vote you may press the corresponding button until the vote is closed.

After everyone has completed their vote the vote will be locked in and then displayed on the screen.

The DFO will read the vote into the record.

Next we will go around the room and each individual who voted will state their name and vote into the record.

You can also state the reason why you voted you did if you want to.

We will continue in the same manner until all the questions have been answered.

We when I moved to the first question and I will ask if there are any questions about the question before we vote.

Has the applicant provided substantial evidence of the safety and effectiveness of DESCOVY were preexposure prophylaxis prep to reduce the risk of sexually acquired HIV-1 infection in men and transgendered women who have sex with men.

If yes provide your rationale, if no provide your rationale and list what additional trials are needed.

Please provide additional comments or thoughts in your vote.

If yes you can still have a rationale about studies that are needed.

Any questions about the question?

If not, let’s proceed to voting.

I assume the voting from our online member is being handled?

Okay.

>> For the record the vote 16 yes, to know zero abstention zero no votes.

>> We went out go around the room and state your name and your vote into the record and if you have comments to the agency please share them.

Dr Goetz?

>> I voted yes.

The discover trial supports the approval of DESCOVY .

And I think the word support is entirely appropriate because it certainly supports the efficacy, I use the word efficacy appropriately as well.

I think what is needed to enhance these trials to show the effectiveness in real world populations that expand

transgendered [ Indiscernible ] and other populations and larger populations and African-American men and populations about all patients to be fully adherent to PrEP the population tested here was a highly adherent of population but the real world I’m afraid includes individuals who are less adherent and it is very important to demonstrate the effectiveness in other populations that may face

challenges and certainly long-term safety outcomes to see whether the biologic

signals representing that task lead to clinical outcomes favorable as well.

>> Dr.

Smith I voted yes because I think there is substantial evidence to support an indication for men who have sex with men.

I am not convinced there is substantial evidence for

transgender women and I think additional studies are going to be necessary as my colleague said to understand how this is actually used in populations that aren’t at the highest risk of HIV acquisition and who stands to benefit from it.

Adolescence like men and women in transgender persons all have documented adherence problems with Truvada generally and I think it will be important to

understand how TAF adds protection or not in those populations.

>> Dr.

read? >> I voted yes and my comments have largely been stated but I think they bear repeating.

The data provided do support the safety and efficacy of DESCOVY by demonstrating [ Indiscernible ] in transgender women.

I think though there were a few infections in the

trial the high rates of STI infections and other indicators to support virus characterization.

DESCOVY appears to be safe is demonstrated in discover as well as the extensive experience in people living with HIV.

I think it has been stated that the study population enrolled and discovered did not represent the populations most at risk for HIV and therefore if DESCOVY is approved for use in MSM and transgender women the applicant should be required to collect postmarketing data on safety and effectiveness in those underrepresented populations including transgender women.

As well as people of color.

I think it is important as was raised in the public comment period the labeling and advertising should only speak to the noninferiority, not the superiority of the effectiveness as well as the safety of DESCOVY.

It is important to note the markers for kidney and bone toxicity were biomarkers only and did not indicate a clinical benefit and I also think it is important to not to disregard some of the potential negative adverse events including weight gain.

>> I also voted yes mirroring some of the prior comments, I think the data presented are very strong for supporting the noninferiority of DESCOVY for preexposure prophylaxis in men who have sex with men.

I do want to state again the importance of selling this is a noninferiority book from it efficacy and safety in overselling the safety could create an environment where drug switches are done in a way that don’t reflect the data and create significant disparities in various populations in men who have sex with men.

My expectation of this approval is that it should be marketed responsibly from the perspective of not creating these disparities and having Truvada be a drug for poor people and DESCOVY be a drug for rich purple [ Indiscernible ] people so it is important we don’t oversell the elements of noninferiority.

From the perspective of transgendered individuals, I think more data are necessary.

I think in the same breath that we are going to probably discuss women we should discuss transwomen and trans men and the need and responsibility to get more robust data.

Historically the answer it is hard to do has created a lot of disparity and mistrust in public health and research among transgender individuals so we need to work with the strategies to go beyond that rather than to stay with that and ultimately I think with the caveat of work to do in the transgender population, I stand by my vote of yes.

>> [ Indiscernible ] I agree

with the comments already made.

I am not convinced we have an updated to say anything about transgender women however he did vote yes on that including that language mainly because the biological similarities, anal receptive sex primarily is the risk factor so I agree there is sufficient evidence that probably would be protected with this non-inferior drug.

>> Laura Dodd, I voted no because the question had the term men and transgender women so my concern is really related to transgender women and I agree with the comments so I won’t articulate further.

>> Dr.

Walker? >> I voted no for other reasons that were expressed.

According to the CDC more than 290,000 African Americans with stage III HAV of died since the inception of the HIV epidemic.

Is African Americans were made disproportionate risk for HIV with and bisexual men and heterosexual women being

affected more than any other race or ethnicity there was not substantial or compelling evidence to indicate the safety and effectiveness of DESCOVY for PrEP to reduce HIV infection among this population so that is why voted

no.

Is a public health researcher and a community advocate and an African-American heterosexual woman I have alarming concerns regarding the safety of DESCOVY as well as the sexual behaviors that will result from individuals taking this drug.

There was a lost opportunity to provide substantial data reflective of the community in which is greatest impacted by HIV.

The data from the discover trial failed to provide an update on the prevention of HIV in transgender women.

>> Dr.

Le voted yes with this for the reason the drug combination has demonstrated noninferiority to Truvada and offers an alternative for PrEP which is critical in the data showing why 7% of the CDC estimate of 1.

1 million people with PrEP indication actually receive PrEP.

DESCOVY may offer potential [ Indiscernible ] despite voting yes I do agree we need more information on transgendered women.

>> Dr.

Burgess? >> Tim Burgess, I voted yes.

I think the data from the discover trial met the

noninferiority to Truvada and just that in men who have sex with men.

>> Dr.

Ofotokun I voted yes for the same reasons that have been expressed by my fellow committee members.

I am convinced DESCOVY is not inferior to Truvada and I think it should be emphasized this is a noninferiority study.

Even though I voted yes I am particularly concerned about the low number of nonwhite disciplines in the study and that should be noted and I think if this moves forward the agency should strongly

recommend a postmarketing study that includes all of this population especially black men who have sex with men who are most affected by this epidemic

in the U.

S expressed there is not enough transgender women to make a strong recommendation but I believe based on the data it would be effective in this is that population that should be studied should this approval move forward.

I think we should also emphasize the side effect related to DESCOVY.

It is sold as a safer drug and it may be safer in some aspects but there are other aspects with the lipid profile is definitely something that should be emphasized and I am still concerned the jury is not yet out on the weight gain issue with TAF.

>> Lindsey Baden, I voted yes.

Highlight some key issues.

The continuum of the body of evidence from the prior studies with Truvada with discover is a continuous set of data that work well together and are very reassuring that in MSM it worked very well.

I share the concerns and the population

I thought the data met the criteria for noninferiority and have the equivalent of not severe safety profile for the impact on lipid metabolism and weight gain might balance out the bone density and renal

benefits.

The caveat the study did not include enough transgender women to allow subset analysis, the study was generally well designed including a large cohort and robust follow-up.

If approved label should highlight the noninferiority performance of

TAF and not [ Indiscernible ] not only the potential benefits in terms of renal and bone density but the potential increased risk related to lipid metabolism and rate gain and obesity.

Thank you >> We have [ Indiscernible ] on the phone.

[ Echo in Audio ]

>> Mute your computer while you speak is the advice I am giving.

What you just did work >> I voted yes.

I have concerns for transgender, I think more dated be [ Indiscernible ] yes to the way it was presented.

>> Dr.

Gripshover voted yes.

I believe the discover trial showed efficacy and safety to reduce the HIV acquisition in men.

I think it is a bit of a stretch for transgender women but I agree it is the same biologic release

method [ Indiscernible ] bone marrow density and renal function may be important in young adults [ Indiscernible ] affecting renal function for

the vast majority of people [ Indiscernible ] we need to emphasize this was a noninferiority study

>> Dr.

Siberry Like many before me I think the trial provided evidence for a claim for noninferiority as an alternative both from an efficacy in a clinical meaningful safety standpoint.

The claim would include adolescents.

I strongly support the use of weight without age down to 35 kilos and except the ability to extrapolate for adolescents.

>> Dr.

Swaminathan I agree there was inferiority as far as efficacy the and MSM but the numbers were insufficient to make a clear conclusion about transgender

women.

Nevertheless because of the number of variables that would have to be controlled for the number of patients that would have been required to be enrolled wouldn’t have been feasible and I agree it may have to depend on postmarketing evaluations but the way the question is phrased I agree they did provide substantial evidence of efficacy.

>> Dr.

Cheever? >> I voted yes I believe there is adequate evidence for noninferiority.

I am disturbed this far into the epidemic in this mini clinical trials we can’t do trials on people most at risk and that we really need to look at African-Americans and I echo other people talking about the lack of transgender women represented in this trial.

Once again that needs to be looked at to better understand the noninferiority in that population.

>> For question when it was 16-to but those who voted no there was a large consent the dated to support efficacy however it is in the population studied and limited power in transgender and [ Indiscernible ] safety signal in wait and lipids and those will all have to be carefully followed and monitored in a postmarketing

setting and expanded in the key at-risk populations and it is not inferiority and not superiority on either of the key issues.

Alec and moved to question two.

Do the data from the discover trial in combination with the available pharmacokinetic data and of the previous HIV-1

prevention trials with Truvada

in cis- gender women [ Indiscernible ] if no provide your rationale and list what additional studies and trials are needed.

Also comment on the trial design that would be adequate to expand the indication.

Please provide any additional comments or thoughts on your vote.

Any questions about the question? Dr.

Siberry?

>> Is not asking whether we would support expanding the indication but specifically saying do we think the data are the reason we would expand, am I reading that right?

>> My read of this in the agency can correct me, do believe there dated establishing substantial efficacy and save the in this population and how the information is provided, is that the intent of the question?

Does that answer your question?

>> Yes.

>> If no other questions, let’s vote.

Our online voter is being handled.

One more person needs to vote.

>> Everyone repress your button.

Just keep voting.

For the record the vote is eight yes and 10 no.

Zero abstention and zero no voting.

>> We state your name and your vote into the record.

Dr Cheever.

>> No.

I think the company demonstrated the difference in metabolism between TDF and TAF and we do not know the protective factors for PrEP and how it works in the mechanisms.

We do know we have differences in immunologic male youth between the [ Indiscernible ] so have concerns about what has been shown.

That said I wanted to vote yes because the thought of not having this indicated for women I think will only further inhibits the implementation of PrEP among women.

From a public health perspective it is more harm than good and not approving it for this indication but that wasn’t the question that was asked so that is how I split that.

We have talked about it all day long, the failure to implement PrEP women is huge and we keep glossing over it and I think that is the wrong conversation to be having.

Is about why women in my transgender persons in youth and what we can do to better get them to have protective effects of prep and women [ Indiscernible ] we weren’t having today.

>> Dr.

Swaminathan no.

I would just go to the reasons.

As far as the question as to what the data allowed you to conclude is what is key.

The sales being affected in the vagina and service versus the rectal and penile mucosa are not clearly defined.

Although virus epithelium must affect cells resident in all tissues, the resident target cell population at the time of exposure is the local pool of lymphocytes.

This pool is relatively static and more so in vaginal tissues than the G.

I and replenished by local

expansion.

The PK in PD in this lymphocytes may not be the same as those in the peripheral blood or other anatomic sites.

We just do not know.

The relative efficacy of TAF and TDF made different between rectal and vaginal tissues and between MSN and cis- gender women.

[ Indiscernible ] is not relevant as unlike with [ Indiscernible ] measured primarily in cells infected by rather in both populations of heterogeneous cells from biopsies.

While there is evidence of the safety profile particularly for long-term use this has to be balanced against the possibility of in peer efficacy.

A relative lack of efficacy may translate to a currently incurable infection.

When has the potential choice between long-term morbidity versus immediate risk.

I do not believe we can state with scientific validity TAF [ Indiscernible ] in cis- women for PrEP.

Extrapolation is defensible if there is no scientific reason there could be pharmacokinetic or pharmacodynamic differences between the groups.

That is not the case here and therefore the basis for extrapolation is not obvious.

The absence of clinical data in this group combined with the potential difference in the sight of exposure and other potential gender-based biological cofactors do not allow me to recommend labeling this drug as effective and I do not believe the drug should be approved or labeled without adequate evidence merely because doing the necessary clinical studies

would be challenging.

The alternative is to expose segments of the population underrepresented in studies to ineffective therapy.

>> Dr.

Siberry I think there is good evidence of a biologic [ Indiscernible ] I remain unconvinced we have a good dialogic Corlett for protection.

The reasons Dr Swaminathan said, I think it is inappropriate to extrapolate to women however I feel like we have field women by letting this implication come in without data from women to begin with and I fear failing them again by having an approval for use in men and not women.

That is why I asked for the clarifying question about the question because I think these are two different things and I would be supportive of an indication that includes women with a strong postmarketing requirement for clinical evaluation.

Thank you >> Dr.

Gripshover? >> Barbara Gripshover, I voted no.

I do not believe the data would support [ Indiscernible ] not studied in that population and I don’t think it is clear just

the level [ Indiscernible ]

.

I believe there is a large unmet need of a women [

Indiscernible ].

While I do not like the idea of approving a drug for single population I also think we are obligated to base our recommendations based on data.

Women deserve our best efforts

[ Indiscernible ].

If the drug is approved for MSM I would require us to have an efficacy study in women as part of the agreement.

>> Dr.

Lupole You are on mute if you are talking.

We may have lost the

connection.

>> I voted no as well.

The lack of data and study participants and conflicting data.

It is my recommendation the trial for

this drug in cis- women and [ Indiscernible ] has not been presented to me that it would be safe and effective.

Thank you.

>> Dr.

Green? >> Michael Green, I voted yes but I almost abstained and I almost voted no.

With regards to [ Indiscernible ] the key concern of the FDA appeared to be relating to the tissue level in the vagina and cervix and those associated with TAF were lower than TDF.

There for the absence of the trial in cis- gender females to determine efficacy they are asking us if we can extrapolate to extend approval based on [ Indiscernible ] population.

The data presented suggests low levels both the four hours and 24 hours and 48

hours and yet F/TDF carries an approval in men, women and analytics for preexposure prophylaxis against HIV and considered effective if those taking it are

compliant.

Is not clear low tissue levels have any impact on the effectiveness of Truvada and seems unlike the to me it would for DESCOVY.

Clearly there is not a concern that intracellular levels would be different between men and women.

We heard the agency stated they feel challenged by developing design for noninferiority studies and no reason to expect a positive outcome in a superiority trial and comparison to placebo would be unethical.

I felt it was appropriate to include cis- gender women in the indication especially given the equity issues that have been discussed during this hearing.

Having said that that would be

important to mandate

postmarketing studies in this indication be undertaken by the sponsor and the subsequent studies did not bear out [ Indiscernible ] the label be modified to reflect this if not having the indication removed.

Thank you >> Dr.

Weina but the answer is really maybe.

The reality is we really don’t have a clue which is the appropriate surrogate marketer use.

Is at the tissue level? Potential the PBMC levels?

Is it adherence or more likely something we haven’t even considered yet because we haven’t bothered to count it in some revelation years from now will finally give us that insight.

Right now it seems like the surrogate marker selected depends on which opinion you would like to have supported and the science behind it itch whichever you select and that seems very whimsical.

I reach back to the FDA mission statement and the mission statement is to promote and protect the public out by helping [ Indiscernible ] reach the market in a timely manner and monitor the products for continued safety after they are in use.

This product is out there for treatment and Artie demanded by patients who are subjected to social media pressures and this is only going to accelerate.

I have no doubt this is already being used in cis- gender women in the United States and it is not being followed.

We should follow the FDA mission statement to get this to the market for the broadest population possible and reasonable and monitor the product for continued safety.

Here of course I’m referring to the efficacy because if it doesn’t work then it is putting the users at risk.

If approved for MSM and transgender women it is definitely going to be used either off label or unable in analytics and cis- gender women just because of the perception of better safety.

We may as will carefully guide the post-market surveillance of this product and how well it works.

Clearly when he carefully prescribed and intensive postmarketing required trials.

>> Dr.

Baden, I voted no The question was, do we have substantial evidence of safety and efficacy?

There are no efficacy data presented.

Data are too strong to allow placebo trial but too weak to allow a noninferiority margin.

When his pieces of data the use to say we cannot study this population and I share the open public hearing speakers as well as [ Indiscernible ] we failed

women to be at this point and not have the data to guide decision-making is a shame on all of us.

I feel like Aerosmith.

We are in a desperate situation therefore let’s do something because we can do something in there are side effects to or interventions.

Our interventions are not benefit with no risk and the presumption we can benefit a not have risk is also shame on us.

We need to generate some data to guide the risk-benefit ratio and the road traveled for prevention in women is uneven with high-quality large studies so far as to presume the good data are the ones we should

hang our hat on his sumptuous.

I think given the mixed historical data the absence of data with this particular agent I cannot support an indication which is efficacy.

On the other hand there should be a mandated study, whether is mandated as part of an approval or mandated to get approval.

Both can be done but it should be mandated.

I think once the risen approval it is impossible to undo even if there is no benefit shown.

If there is no approval the pressure is to do the study but then there are women at risk who don’t have this medication and hence we have this population but I voted no because there were no data in the population in question.

Dr Ofotokun.

>> I voted yes.

Taking a look at the data as a whole.

DESCOVY data and the historical data from Truvada.

Based on data in HIV-infected individuals treated with DESCOVY I am convinced the product is just as safe in men and women and the big question is that of [ Indiscernible ] in cis- women.

I tend to have some confidence in the pharmacokinetic data in the

Corlett of Truvada.

[ Indiscernible ] protection, I

seem to believe that in itself provides a strong compelling

data

that TAF [ Indiscernible ] I agree it is a terrible failure the agency as well as a sponsor would come to this committee with lack of data for

women.

I strongly believe like others have expressed their should be a mandated study to look at

women, cis- women [

Indiscernible ].

I also believe DESCOVY for men who have sex with men alone would create [

Indiscernible ].

The equity issue that already exists that either you were going to prove it for the indication for PrEP in men and women or you’re not going to move forward.

I think treating a two-tier prevention and treatment will not be helpful and we should remind ourselves there are more women living with HIV in the world than there are men and the risk of new infection is significantly higher among women if you look at this globally.

I will stop there >> Dr.

Burgess I voted yes but as others have said I nearly voted no and nearly abstained.

I share their concerns about what we think we understand about the punitive mechanism of protection

depending on route of exposure but my overarching concern was about the public health impact of an indication in one population and not in another

population coupled with the fairly compelling articulation of levels in PBMCs as the primary if not total component of the mechanism of protection

led me to vote yes.

I would like others articulate a strong

recommendation for compelled post-market [ Indiscernible ] in women.

>> Dr.

Le ] largely based on three factors.

Data print dating [ Indiscernible ] some safety data from other studies in making this drug combination available as an available option for women and not just for men.

My vote for yes is contingent upon full commitment from the applicant to incorporate a robust package labeling stating efficacy and effectiveness have not been established in cis- women with the use of this product in the vaginal tissue penetration was low and the approval was based on extrapolation of existing data in the other population.

The applicant should commit to conduct robust postmarketing

studies to allow for us to better understand efficacy and/or effectiveness as well as incorporating safety monitoring for weight gain, renal function, plasma lipid levels.

>> Dr.

Walker? >> It was a strong know for me.

No wavering on the fence.

I most highly appalled.

Is about eight women on the committee in the agency and the applicant [

Indiscernible ] or heterosexual women or women in general.

I was highly appalled that more dedication and passion wasn’t put into the study.

>> Dr.

Dodd? >> I voted no and I was not on the fence.

My concern is about confusion or lack of trust that might be generated by an approval that wouldn’t be supported by strong science.

We can’t approve something just because there is a need.

I want to commend the agency for their good discussion about surrogacy.

I think this is often a confusion in the reviews of studies.

There lots of reasons why good Corlett of protection may fail as a surrogate endpoint for the clinical benefit in point, in this case the endpoint is protection.

The Corlett is not a surrogate make.

We have seen dated to support PBMC is a good marker of protection and women

but we have not seen the data and I thought the agency did a good job of providing reasonable arguments about why PBMCs may not be a good marker of clinical benefit.

There probably should be both data related to the biological mechanism supporting additional surrogacy studies.

This looks like or studies on tissue concentrations and additional studies in cis- women with an actual clinical benefit and point of protection.

I’m not convinced there is not a study design out there that would support this.

I don’t know it would have to be something as large as a 20,000 participants study but I think it is time to put some creative heads together and think of some feasible designs.

>> Dr.

Giordano no.

It pains me to say that believe there is the potential for creating one drug for the rich, one for [ Indiscernible ] that is a horrible precedent.

The FDA approval to me means we know this drug is safe and effective.

I’m convinced we note this drug is safe, no drought about that but is it effective?

That remains a hypothesis.

Given there is different biology involved, I think you need efficacy data and it just boils down to that for me.

I think we are in this position and it is absolutely horrible but that is the position we are in.

I don’t envy the agencies ultimate decision but to me there is no way you can say this drug has efficacy in cis- gender women .

Who is to blame for that is not my decision.

>> Dr.

Daskalakis yes.

There are couple of reasons.

We have had success with topical agents that we know of to prevent HIV and we have seen data and

intracellular levels that seem to be protective so that in combination for the role of PBMC level and intracellular level and prevention made me feel I had enough evidence to recommend you consider approval for this drug for cis- gender women.

I would put the caveat that labeling would be critical.

[ Indiscernible ] I also think it would be important to state there is not been it efficacy study done.

From a safety perspective I agree with what everyone else’s said.

I think safety has been demonstrated.

I don’t think the approval of this drug would increase 15 uptake among women.

That is not the problem, at least in the U.

S the pill and a marginal

improvement.

The problem is the patients and providers are unable to do an appropriate assessment who needs PrEP and I’m concerned creating the tiered system will create even more confusion with providers [ Indiscernible ] that makes me concerned.

I think a mandatory study no matter what, whether it is after approval or preapproval requiring that it is critical and that needs to help answer the question about intracellular level versus mucosal level so good science that looks at the role of mucosal levels of tenofonir in women would be critical.

I would also think about coupling the transgender women study against the women study since they are women and that’s probably it to wait to [

Indiscernible ].

Another thing I want to bring it recently is the precedent for extrapolating

data.

We have U health services recommendations

that PrEP [ Indiscernible ] tenofonir could potentially be used as monotherapy to prevent PrEP in women and heterosexual males and females and injection drug users.

I do not see us having a conversation about using [ Indiscernible ]

so we can [ Indiscernible ].

I would encourage the agency to consider looking back at the Bangkok PrEP study and [ Indiscernible ] and ask if we should be asking the same thing about a drug that could cost last then five dollars a month.

>> Dr.

read with a lot of the same hesitations.

Just to be clear I also agree it is extremely disappointing to be in a situation in which there are no clinical efficacy data in cis-

gender women .

A population [ Indiscernible ] however I felt

in this case it was reasonable to extrapolate data from the [ Indiscernible ].

Although cis- gender women were not included it is reasonable to extrapolate safety [ Indiscernible ] I think it is unlike the safety profile would differ.

In the absence of clinical efficacy data in cis- gender women and the question of the relevance

of PK, extrapolation is not straightforward although the collected data regarding PK levels contain mixed results.

It is reasonable to extrapolate

clinical efficacy [ Indiscernible ] on the basis of the data provided indicated

higher levels [ Indiscernible ].

It is also unclear what levels

are required [ Indiscernible ].

I think it would be problematic to approve an indication who have men with sex with men alone and subsequent delay in access for women would be an

unfair situation and I think should be given to the approval with the broader indication to include women or no approval until adequate efficacy can be achieved in that population.

If an indication is approved like others I recommend strongly [ Indiscernible ] performed trials to collect safety and effectiveness data.

Not only is the effectiveness important but the safety profile needs to be further supported.

It is important the company has attested and pledged they will perform these trials and it is up to the agency to require them to do so.

>> Dr.

Smith like we are moving backwards from the 2012 meeting that approved Truvada in which there was a lot of discussion and concern that we had data [ Indiscernible ] now we don’t have data on women at all.

The decision has been made we would do the trial and MSM and figure out what it means for women rather than studying women

themselves.

I find that bad science but also disrespectful in an issue of research equity.

Women deserve the same quality of data about the safety and efficacy of the drugs they are exposed to that men get and that is not the situation we find ourselves in at the moment.

I also think because we have Truvada approved for women we are not denying women access to PrEP and it is important to remember that.

What we are doing is saying a second drug that is similar in risk and benefit is available to one population but not another yet based on the data we have and I think that is preferable to approving it, doing and efficacy study, and somebody suggested maybe taking it back or modifying it if it doesn’t work out as well.

That’s a recipe for disaster among the African-American community if we get ourselves into a situation where we are proving something and then saying we weren’t right.

I wouldn’t even think about doing that.

The other thing is even though we think about the fact it may be hard to explain [ Indiscernible ] for this group or that group, I think it the proper studies are done in the short term over the next three or four years to get the kinds of data that are missing, we will be in a position to say whatever is appropriate about women, I think we are going to increasingly in the PrEP field have the situation of some rings are for some people and other things are for other people whether that is [ Indiscernible ] if that becomes approved, that is surely not for all populations.

I know we are nervous about what that means when we suddenly have to

start making decisions but I think this is not the occasion in which that should overrule the absence of data on efficacy for women as the basis for our decision.

>> Dr.

Goetz yes.

I think unlike the other eight people who voted yes, I do not hear a ringing endorsement from anyone of

strong data.

I read the statement [ Indiscernible ] is a livable statement [

Indiscernible ] what we know about surrogate markers, correlates of protection, I think quality is a light word in many regards.

The fact of the matter is we will need a face for mandated clinical trial to substantiates this is an alternative and any guidelines or documents produced by other societies the strengths and weaknesses of this, the conditional nature, and this is an alternative needs to be very clear.

I felt strongly that I’m not sure tissue markers are a surrogate either that has been pointed out by many individuals.

First of all we get very limited samples and secondly the sales we sample are not likely relevant cells so we either need robust data showing across levels of different adherents, inevitably some people are less adherent and we need to correlate if are going to substantiate in any way PBMCs show the correlate between PBMC and protection is similar across the relevant risk groups.

I think that would go a long way to demonstrating what we need to show.

I think adherents is a crucial measure.

What we have in this drug, the population that was extraordinarily adherent.

That is wonderful but we need to be clear and really emphasize adherents throughout this drug [ Indiscernible ] but that is

not to be taken [ Indiscernible ]

>> Thank you.

There you have it.

Eight to 10 vote key principles as I hear it is I will summarize the yes and the no together, the correlate is unclear and perceived differently.

The optics of approval for population A but not population problematic as many deleterious effects it done or if not done and everyone agrees there needs to be actual data so the challenge, and I will be

presumptuous [ Indiscernible ] into the agency and applicant, [ Indiscernible ] there should be a way to do some type of study systematically in a reasonable amount of time if there is collective will to generate data expeditiously and that would [ Indiscernible ].

Many of us believe this would work and should work but we cannot guide policy or regulatory pathway.

We have run 15 minutes over.

I would like to thank five minutes to discuss the last question and that will be an open discussion unless the agency advises me otherwise.

The open discussion is pleats is is whether the data from the discover [ Indiscernible ] I will open the discussion and look for

disagreement that have elements that are analogous to MSM in the sense of the biology and how the drug works in the nature of the exposure.

We weren’t able to extract [ Indiscernible ] presumably there would be some of that in the population in the biology in the prior experiences such that I don’t think it is unreasonable to think it is likely to work in that population but I would like other comments from the committee as to if others agree it should likely work in that population or if there are concerns as to why it may not.

>> Were talking about HIV uninfected men having sex with the discordant partner, female partner.

>> And circumcision has not been addressed but other presented strategies would be maximally encouraged.

>> I agree with your general view that this can be extrapolated but I do think the data should be looked at more carefully from the discover trial.

The enrolled people who had condomless anal sex so I think the collective information about practices you may be able to segregate those practice predominately inserted sex from those who didn’t and

see if there was a difference in the levels of infection in the two arms.

The overall infection risks are probably lower in both arms of that group if you limit it to those but we should ask for additional scrutiny of data.

>> And perhaps new data to look at that population.

Dr Gripshover?

>> I do think the fact 44% uncircumcised this means there was a group that it not yet even used that other protective so I think that is helpful.

>> Given the way the trial was enrolled, the data is just not there so I’m not sure you can actually extrapolate anything from that trial.

>> So what is your view on the applicability to men who have vaginal sex?

>> In my patient population I

have individuals that I have in my patient population that are

at high risk in heterosexual relationships and come to me and are actually on Truvada for preventive reasons but the data is not really there to support it.

It just makes sense based upon the data that is out there so there is an extrapolation because the individual is at very high risk and everything we can do to help prevent it is something worthwhile as long as they are properly informed as to the risks associated with taking the medication as well.

>> If you have MSM you have inserted and receptive, presumably the insert if risk would be similar to the [

Indiscernible ] therefore data suggests it works in that population even though it is not specifically pulled out.

That would be suggestive it is likely to work in that population.

>> Like I was talking about before, suggestive and correlates [ Indiscernible ] >> These are human data in men who are in study on drug and not getting affected.

This is not extrapolating from assays that we are not completely sure what they tell us with the Corlett that we are not sure what it tells us and five people.

>> Sure.

Given the potential outcome of not putting the individual on Truvada when they come to me with exceedingly high risky behavior with multiple unknown partners on a

regular basis, I informed them of the risks associated with it [ Indiscernible-Multiple Speakers ]

>> Just teasing this issue with the issue about the need for a study in women, it seems as if there is another for another heterosexual study like a partners PrEP .

>> Part of a challenge there is treatment [ Indiscernible ] >> But there is still an environment where it is feasible so it Mrs.

[ Indiscernible-Multiple Speakers

].

You get have [ Indiscernible ] the sample size will probably have to be bigger and in fact may be smaller.

>> The point is there are parts of the world in which this could be done just like we do malaria studies and other parts of the world because we haven’t got a whole lot of malaria in the United States to get new drugs approved.

>> Dr.

Swaminathan little more you can extrapolate from.

You have data that in discordant couples where the

woman is positive that

tenofonir works and MSM couples it works and we have evidence that TAF works and MSM couples and now you were just sort of bringing in the fourth variable in the mix of those variables to say [

Indiscernible ] and TDF also works for this situation.

You can sort of extrapolate a little bit more from that but you would expect the person that was protected by TDF in the partner study to be protected by TAF in the future.

>> Another piece of supporting

evidence is the incidence of [ Indiscernible ] in the patient population which I think is 15 to 20% so there was substantive

exposure [ Indiscernible ] and yet if I recollect the data properly all the cases of infection were amongst those people who had receptive anal intercourse so what we don’t know [ Indiscernible ] the presence of the [ Indiscernible ] is a strong piece of evidence in favor of the fact there was a risk.

>> Dr.

Smith? >> I think that touches on a lot of the key issues around this question.

Are there any other issues the agency would like us to address?

If not, I would like to thank the applicant were tremendous amount of data being presented and entertaining a lot of discussion in a challenging area.

And agency for sharing your views and the challenge.

The panel members for robust high-energy day in covering a lot of complex issues and the public as well for sharing your thoughts and I was see if the agency has any closing remarks.

>> On behalf of our division at the agency want to thank the committee for their thoughtful discussion and deliberations today.

I also want to thank the speakers who commented during the open public hearing as well.

I want to thank the company for conduct in the discover study and other pertinent research and for committing earlier in the day to conduct a trial or trials in

women.

Also want to thank the trial participants as well.

Lastly I’d like to thank our staff for their dedication and diligence in conducting the reviews and preparing for this committee.

I want to leave you with a couple thoughts before we end.

Our review of this application continues.

We have not made any final determinations as of today and your comments and the discussions will greatly impact

our final determination.

Lastly, I feel like we should dedicate our collective efforts to ensuring the availability of safe and effective medications for all populations so the next time we meet we can definitively state the HIV incidence in the United States has substantially declined in all populations and we are moving closer to defeating this epidemic.

Thank you very much >> Thank you.

I will now adjourn the meeting.

Safe travels.

>> [ Event Concluded ] >>

Rationales for Ts and Ss PrEP Dosing? (5 of 8)

Author’s Note

4/16/18 (updated and posted 6/20/19)

5th entry of 8 (1. Intro, 2. Definition, 3. Research, 4. Origins, 5. Rationales, 6. Critiques, 7. Implications, 8. Conclusion)

Why would people be interested in potentially risking their health by skipping PrEP doses?

INTRODUCTION

There are many practical and personal reasons why some PrEP users are getting ahead of policy/recommendations in interpreting, applying, and experimenting with the data on PrEP in their own lives. Indeed, IPREX principal investigator Robert Grant’s response to adherence data from the trial’s Open Label Extension points to one of the central themes that not only connects the motivations in testimonies given for this series on Ts and Ss PrEPping but that also undergirds the innovative nature of PrEP itself. That theme is user-based control:

“If people were at higher risk they took more PrEP and adhered to it better…it shows that people who are at risk can take reasonable and appropriate decisions on their own behalf…The important thing may be choice.”

Revisiting the exchange between Will Nutland and Darrell Tan last fall at the Vancouver Men’s Health Summit provides a perfect launching pad for witnessing testimonies of rationales from actual Ts and Ss PrEP users. Nutland’s question posits cost and kidney impacts while Tan’s answer speculates that Ts and Ss demonstrates a hesitancy on the part of PrEP users to adopt the IPERGAY on-demand strategy in the face of limited quantity and quality of data.

As you will read in the testimonies below, these reasons do indeed motivate those deploying Ts and Ss PrEPping. However, several other telling reasons emerged as well.

TESTIMONIES I

For example, Juan* (not his real name), echoed Andrew Leavitt’s testimony by covering just about every rationale above as well as a desire for greater control and flexibility given his changing sex life and uncertain/limited PrEP access. He’s a cisgendered, informal, local PrEP advocate in Spain who explained:

I have to order into [the] UK and collect on visits there as [it’s] not legal to import here. Europe is very different and no access programmes….Spain is a bit backward on adopting PrEP…I use 4/wk and fill the blank day if I’ve had a risk so that I get 2 successive doses as per the event-based model. That’s probably unnecessary but I feel happier that way …[I’ve] been on that model 12 months and neg at [my] 9 month test … [it] keep[s] costs down and reduce[s the] load on [my] kidneys …It also allows you to quickly recover to daily dosing if there’s a “special event.”

Davis*, another pseudonymous cisgender male PrEPster, also cited flexibility, cost, and kidney concerns as primary motivators for his Ts and Ss use. An academic and advocate in London, he proffered:

[I did it for] cost (when I was buying it) and doing everything I can to lower possible renal issues (I’m 50, so want to reduce those risks). 4 a week provides a nice steady-state…I use Ts and Ss on a usual basis and move to a daily regime if I’m anticipating some [definite] action. I’m going [abroad] tomorrow so I’ve moved to daily for the week before. … I do talk with people on a peer-to-peer basis about the different ways of using PrEP (and then strongly advise they speak to a[n] MD!).

In fact, that potpourri of user-control concerns echoes in data collected online by Harvard Professor Julia Marcus and colleagues in 2019 among MSM, non-binary people, and other queer folk just in the US. Ts and Ss PrEPping was of high interest, second only to IPERGAY, on-demand/intermittent “2-1-1” dosing among nondaily approaches. In a recent conversation on Twitter, Marcus pointed out that the number of actual participants who chose to complete the survey, close to 10,000 in total, completely dwarfed their expectation of 300 respondents. Marcus also emphasized that not only were almost 2/3 interested in nondaily PrEP, but also that 1 in 20 were already deploying various nondaily dosing strategies, pointing to a duty of more practical leadership on the part of the CDC.

Non-Daily Use of HIV Preexposure Prophylaxis in a Large Online Sample in the U.S., Marcus et al, CROI 2020

SAFETY CONCERNS

Now, at this juncture, a few bullet points are in order concerning PrEP safety data in general and concerning kidney function as well as bone density in particular:

• A 2016 meta-analysis of all major PrEP trials to-date found the pill well-tolerated generally and with few significant safety issues, though most of those which did arise reversed themselves after discontinuation of PrEP use,
• A head-to-head comparison of Truvada-for-PrEP and over-the-counter aspirin that same year found that the HIV preventative compared favorably to the common pain reliever / cardiovascular preventative,
• Reviews of 1-million HIV/HBV treatment years in 2008 then 7.5-million in 2015 showed Tenofovir to be generally safe and well-tolerated. However, some statistically significant but frequently reversible declines in kidney function and BMD plus some rare, serious kidney adverse events were documented,
• Similarly, a more recent, targeted, PrEP renal review by Monica Gandhi and colleagues suggests that 3 factors (age >40, baseline reduced kidney function, and higher adherence) predicted renal impacts. Gandhi responded to a related question about such matters when she presented the data analysis:

(Roughly 29:00)
Smith: Michael Smith, MedPage Today. Are renal issues and creatinine declines clinically significant? Is this something that people should worry about, that they are going to have clinical sequela? Is this reversible if people stop?

(30:20)
Gandhi: I think there’s clinical significance to the renal issues because these are healthy people who don’t need medication for their treatment of HIV. And, so, I think it’s often said, ‘these are such low declines, it doesn’t matter,’  that’s not my opinion as an HIV clinician. I think it matters a lot to monitor for toxicities when you don’t have an infection. So, so … I will take the groups for [which] I think [it] matter[s] the most, which are, you know, older people and people who already had renal issues, and I will monitor. I think it’s absolutely clinically significant to monitor them and take them off the drugs if you have a decline, if they’re falling into dangerous territory. [It’s a] risk versus benefit analysis [as with PrEP and resistance], but you can’t … The reversibility of this is interesting. In IPREX and in PREP Demo, they may have reversed, but in cohort studies, there are people whose Tenofovir-associated damage does not reverse. And, so, I think it’s peculiar to the individual and you just don’t want to be one of those people, so I think it’s significant.

Meanwhile, Albert Liu, in responding to the same question by presenting his own analysis of PrEP Demo Project kidney data, also emphasized closer screening and monitoring among those key groups already mentioned:

31:00

Albert Liu: “Yeah, I would just say that the majority of folks in our studies had small declines and they were nonprogressive, so it’s really … We had about 3% that had a greater than 10% decline and that seemed more clinically significant, so it really [is] … Finding those people who are more likely to have problems and again those are people who have low function at baseline and people who are older.“

• Gandhi and Matthew Spinelli‘s bone mineral density (BMD) analysis from the same IPREX OLE data pool echoed the monotonic BMD impact relationship with dosing that Gandhi spoke of above with respect to kidneys (according to a report on ContagionLive.Com):

“Investigators found a monotonic decrease in BMD with higher weekly PrEP adherence, observing a drop in spine BMD of only approximately 1% and a 0.5% decrease in hip BMD among PrEP users with very high adherence over a median of 24 weeks.

For those with high risk of bone fracture, such as older adults, who are planning on initiating prolonged daily PrEP, the study authors recommend considering alternate PrEP strategies, such as tenofovir alafenamide‐based PrEP once available. In addition, they write that dose‐limiting strategies such as intermittent PrEP use could potentially reduce the risk of bone density loss, although additional research is needed to compare toxicity in daily versus intermittent PrEP use. Based on the study’s findings of only modest BMD declines seen even with very high PrEP adherence, the differences are likely … clinically significant only for individuals at highest risk of bone toxicity. On whether supplements may help PrEP users offset the bone toxicities of HIV prophylaxis drugs, Spinelli says it’s a question worth researching. “PrEP users, at least in my experience, are not given a recommendation for calcium and vitamin D prior to starting PrEP. This is an idea that deserves additional study in a randomized controlled trial.””

(Interestingly, this was despite the fact that, during the US Tenofovir Extended Safety Study and IPREX, participants were informed of possible PrEP BMD impacts and counseled to consider exercise-, diet-, and vitamin D and calcium supplementation in order to mitigate any possible impacts akin to then-little-understood HIV treatment-related Tenofovir BMD impacts. In that vein, there is also some encouraging 2019 PrEP-supplemented-with-Vitamin-D bone health data among cisMSM hot off the presses by Michael Dube and colleagues.)

• One other small bit of related data seems worth mentioning herein, which is that PrEP impacts on 15-19yo youth bone development seem to be irreversible, even 48wks after discontinuation, unlike their older peers according to study author Peter L. Havens, who looked at data from the groundbreaking ATN 110 and 113 trials that, together, paved the way for 2018’s FDA approval of adolescent access to PrEP (The studies also set the standard for youth self-consent in HIV prevention research.),
• It goes without saying that intellectual honesty requires consideration of the point on renal impacts raised by Darrell Tan in his recent review of daily vs nondaily PrEP:

“What other reasons might there be for choosing event- driven dosing instead of daily dosing? Avoidance of drug toxicity might seem another intuitive reason, but during the randomised phase of IPERGAY,1 the active group had more gastrointestinal adverse events (14% vs 5%; p=0·002) and renal adverse events (18% vs 10%; p=0·03) than the placebo group; by contrast, a meta-analysis11 found that adverse event rates with daily PrEP are similar to those with placebo (odds ratio 1·01, 95%CI 0·99–1·03)”

(However, it’s been acknowledged by Tan and others that those conclusions being drawn so far are based on population-averaged adherence levels as low as 30% and in some studies based on self-reported adherence, which are known to be less accurate than blood/tissue/hair sampling.)

In the absence of more/definitive data, some experts (like Gandhi and Spinelli as we can see) and consumers (like those who share personal rationales above and below) will consider a less-is-better approach.

And given the lack of rigorous head-to-head comparison data that would clarify on the matter, it’s probably best to say the only consensus among those experts who have looked at this topic more carefully is that there’s a need for more monitoring of certain PrEP users and more study comparing dosing strategies and side effects … but I digress[ed].

TESTIMONIES II

Meanwhile, for a cis filmmaker and prominent activist in Germany named Nicholas Feustel, a desire for greater flexibility but also hesitancy around IPERGAY data (speculated by Tan) seem to be animating factors:

“I … combine “4 pills per week” with on-demand dosing according to the IPERGAY regimen. Taking PrEP daily doesn’t make a lot of [sense] for me – I just don’t have so much sex. On-demand dosing would be great – if only I could plan sex ahead! We know from iPrEX that no one got infected in that study who took 4 or more pills a week. So, 4 pills should actually be enough to be protected.

So what I do …[is] take 4 pills a week as the ”standard” (Mondays, Wednesday, Fridays, Saturdays)… And I decided to do the consecutive days dosing (Fri/Sat), because those are the days with the highest probability of having sex for me. Now, IF I actually have sex, and if that sex actually requires PrEP, then I “turn on IPERGAY dosing”, and would add in pills on the days that I normally wouldn’t take pills. This way I don’t have to even ask myself that question ‘does IPERGAY dosing work when you don’t do it very often,’ which means ‘does it work when you don’t have any remaining drug levels in your body from [the] last time you took it?’ With the ”4 pills a week“ I always have a certain level of drugs in my system (which should already be enough to protect me), and then I’d even add more if need be.”

Though, for Jamie, a trans man living just outside Birmingham, the second largest city in England, an all too familiar situation of a period of limited supply spurred him to deploy Ts and Ss temporarily to stretch his precious pills for a prolonged period between prescriptions:

I knew about Ts&Ss from the IwantPrEPnow site. I normally take daily as it’s easier to remember to take it. I reduced the dose so that I was still covered for a few weeks whilst waiting for the delivery. I can’t remember but don’t think I was particularly sexually active at the time, and knowing 4 times a week provides the required coverage, this wasn’t really a high-risk strategy… my personal preference is Daily, then [Ts and Ss], then event-based dosing… [for] Reducing risk. If I could, I’d have sex at least weekly so 4 pills a time.  To[o] much room for error on the on[-]demand. Plus it would easily fall into the Ts & Ss. Prefer daily as full coverage and room if I ever miss a pill.

Non-Daily Use of HIV Preexposure Prophylaxis in a Large Online Sample in the U.S., Marcus et al, CROI 2020

What these testimonies have in common are knowledge of the relevant data, a desire to reduce cost and/or manage supply under access-limiting constraints, and a concern about optimizing drug levels in the face of fluctuating sex habits and/or health concerns. In other words, they all are motivated to make PrEP work in their uniquely complicated lives. In fact, that potpourri of user-control concerns echoes in data collected online by Harvard Professor Julia Marcus and colleagues in 2019 among MSM in the US.

CONCLUSION

Given that the U.K. has experienced a rather contentious delay in PrEP approval after its own PROUD study was completed more than 3 years ago, it’s fitting that Brits were overrepresented among people willing to go on record about this topic. As a final note, a return to Dr. Robert Grant and more words of wisdom about PrEP user-based control perfectly summarize the phenomenon being witnessed in Britain (and elsewhere) as larger numbers of interested PrEP users pour into the relative safety and certainty of the NHS IMPACT Trial and the baton is passed from our early innovators quoted above. (Now, mind you, they include the likes of advocates and activists pushing for greater PrEP access via self-sourcing with generics online, via therapeutic drug monitoring of such generics, via agitating against the National Health Service, and via creating other pathways for informal PrEP access in the U.K.) Indeed, Grant‘s analysis of PrEP motivation discussed just months before PROUD’s publication gives further perspective as far as dissemination of PrEP innovations:

21:01

“Albert Liu, my colleague at the San Francisco Department of Public Health published in late 2013 evidence that PrEP … as a concept [Diffusion of Innovation], was being handed off from the innovators … The 2.5% of people who will try anything as long as its new and it has some promise … That those innovators were starting to pass the PrEP concept off to early adopters, who are characterized by people who … will use it but only if they’re sure that it really works and it really works well. So early adopters are very interested in knowing how well PrEP works. They care a lot about whether it’s 99% effective or 100% effective and there’s endless debate online about whether PrEP is 99.5% protective or 99.8% protective. They care that it works and we know that from marketing as well. I mean, if you’re marketing iPhones to early adopters and there’s one little feature buried three tiers below that doesn’t work the way it should, [then] you’re going to hear about it because early adopters are characterized by people who really want it to work and for PrEP, that means it has to work really well when used and the good news is that it does.”

–ACON PrEP Forum A Tale Of Two Cities, published on Oct 6, 2015

Thus, for those who use it, Ts and Ss PrEPping is economical, safe, effective, simple, and flexible most importantly (but probably a bit cool too as a cutting-edge approach to sexual health for innovators and early adopters).

***

Next up, taking a more critical look at the Ts and Ss PrEP dosing approach…

(all entries: 1. Intro, 2. Definition, 3. Research, 4. Origins, 5. Rationales, 6. Critiques, 7. Implications, 8. Conclusion)

Contact

PrEP in Pop Culture: Awareness Campaigns

5/22/19 (Author’s note and the rest of this PrEP pop culture series.)

Raising public awareness is one of the most visual – and pop culture-relevant – of public health endeavors. This can include posters, commercials, billboards, memes, brochures, and many other tangible and digital cultural products with the express purpose of getting the word out. Indeed, one could easily and generally define “campaign” here as health awareness and outreach efforts, usually based on one visual idea and/or a a slogan linked to popular language or even a popular value, analogy, or trope otherwise, and sustained for some period of time to improve the general public’s health or that of specific, vulnerable communities therein.

And what better way to catalog such biomedical prevention related visual culture, in our Internet era, than to start with some of the digital documents of such efforts.

As such, what follows is a snapshot compilation, in chronological order of first appearance, of over 50 efforts at PrEP (and to a lesser extent TasP/U=U) awareness raising that we’ve come to know and love (or hate). After having cataloged them all, a few points jumped out at me. First, the images were culled largely from Facebook (“PrEP Facts: Rethinking HIV Prevention and Sex” in particular). Second, the vast majority of appeals featured here were directed at cisgender men who have sex with other (primarily cis) men. (It’s worth considering the main source I drew from.) However, later emphasis has included trans and cis women, trans men, and other gender nonconformers assigned female and male at birth, and even sex workers and youth. Additionally, the year 2013 – nestled between FDA PrEP approval the year before and complete CDC recommendations that year after – was the the first for campaigns (outside of research). Meanwhile, in 2016, there was an explosion in examples of creative PrEP public health awareness promotions. Finally, there were at least two viral, grass roots campaigns including the one of first non-USA efforts, both reaching international consciousness.

Feel free to comment at the bottom or to contact me directly just if you feel so-moved or if you see something missing, mischaracterized, or amiss otherwise below.

[NBs: Most images and interactive text posted below link to digital galleries and write-ups where more related campaign images and information can be found. Also, some links have expired and thus are substituted with archived versions. Several other posts in this PrEP-in-pop-culture series also cover graffiti, graphic arts, hashtags, memes, music, photography, testimonials, videos, and other media that can sometimes overlap with public health campaigns. Additionally, Building Healthy Online Communities (BHOC) has also collected campaign material samples for their consortium of public health leaders and gay dating website- and app owners who are working together to support HIV and STI prevention online. The FABTASTIC resources they packaged together are now available at their campaign clearinghouse, which includes a variety of search options including topic (hiv / aids and stds), audience (clinicians / providers, general public, persons with hiv / aids, msm, msm of color, youth, seniors, transgender / gender non-conforming folks, etc.), objective (promote PrEP, connect to care, find a clinic, reduce stigma, promote U=U, etc.), format (radio, print, video, digital, billboards and posters) language (english, spanish) and even reprint permission (yay or nay).]

***2013***

Slogan: Keep it real with PrEP.

Originator: San Francisco AIDS Foundation, San Francisco Department of Public Health, Project Inform, Be The Generation, Gilead Sciences and other local health agencies, community-based providers, and PrEP advocates, like Jake Sobo.

Date: 11/20/13

Locale: San Francisco, CA

***2014***

Slogan: “#TruvadaWhore”

Originator: Adam Zebowski / PupBones

Date: 3/28/14

Locale: International (organic/viral/online)

Slogan: Be PrEPared!

Originator: The Stigma Project

Date: 5/30/14

Locale: US (national)

Slogan: “Share the Night, Not HIV.”

Originator: NYC Department of Health and Mental Hygiene

Date: 9/16/14

Locale: New York City, NY (USA)

***2015***

Slogan: I swallow.

Originator: Austin PrEP Access Project

Date: 2/1/15

Locale: metro Austin, TX (USA)

Slogan: “PrEP Up!”

Originator: AIDS Alabama

Date: 4/15/15

Locale: Alabama (USA)

Slogan: “Are you ready for PrEP?”

Originator: CDC – US Centers for Disease Control and Prevention

Date: 5/11/15

Locale: USA (National)

Slogan: “HIV prevention just got easier.”

Originator: New York State Department of Health

Date: 6/22/15

Locale: New York State (USA)

Slogan: “Swallow this!”

Originator: Harlem United

Date: 6/30/15

Locale: New York City, NY (USA)

Slogan: “PrEP Heroes”

Originator: Mike Ruiz / Housing Works Community Healthcare

Date: 7/8/15

Locale: New York City NY (USA)

Slogan: Take PrEP

Originator: Evergreen Health Services

Date: 7/31/15

Locale: western New York (USA)

Slogan: “You can fuck raw!”

Originator: Seeitclearly2020

Date: 9/18/15

Locale: Australia (organic/viral/street)

Slogan: “PrEP is like …”

Originator: APCOM – Asia Pacific Coalition on Male Sexual Health

Date: 9/22/15

Locale: Asia (regional)

Slogan: (Mr. PrEPpy)

Originator: APCOM – Asia Pacific Coalition on Male Sexual Health

Date: 9/22/15

Locale: Asia (regional)

Slogan: “I am PrEP.”

Originator: John Byrne

Date: 11/12/15

Locale: Miami FL (USA)

Slogan: “Do it daily.”

Originator: AIDS Action Committee of Massachusetts

Date: 11/23/15

Locale: Greater Boston MA (USA)

Slogan: Play Sure

Originator: NYC Department of Health and Mental Hygiene

Date: 12/1/15

Locale: New York City

Slogan:

Originator: APCOM – Asia Pacific Coalition on Male Sexual Health

Date: 12/23/15

Locale: Bangladesh

Slogan: “What r u into?”

Originator: Los Angeles LGBT Center

Date: 2015

Locale: Los Angeles County CA (USA)

***2016***

Slogan: “PrEPare for love this Valentine’s Day.”

Originator: AIDS Resource Center of Ohio

Date: 2/10/16

Locale: Ohio (USA)

Slogan: Without Fear

Originator: Test BKK / APCOM – Asia Pacific Coalition on Male Sexual Health

Date: 2/10/16

Local: Bangkok Thailand

Slogan: dOWN it!

Originator: Legacy Community Health

Date: 1/25/16

Locale: greater Houston, TX (USA)

Slogan: Spread Tingle / PrEP for Love

Originator: AIDS Foundation of Chicago ( AFC), Illinois PrEP Working Group

Date: 2/1/16

Locale: Chicagoland IL (USA)

Slogan: “ Black Lives Matter: What’s PrEP Got to Do with It?”

Originator: Black AIDS Institute

Date: 3/31/16

Locale: USA (National)

Slogan: “Suck. F*# k. Test. Repeat.”

Originator: Test Bangkok / APCOM (Asia Pacific Coalition on Male Sexual Health)

Date: 4/29/16

Locale: USA (National)

Slogan: Get PrEP LA / The Protectors

Originator: LA County Department of Public Health

Date: 5/5/16

Locale: LA County, CA

Slogan: Trágate esto! / Swallow this!

Originator: John Byrne/Adrian Mena

Date: 5/27/16

Locale: Miami, FL (USA)

Slogan:

Originator: Delaware HIV Consortium

Date: 6/2/16

Locale: Delaware (USA)

Slogan: PrEP Squad, join the team!

Originator: DC PrEP Squad

Date: 6/7/16

Locale: Washington DC Metro Area (USA)

Slogan: “Join the Movement.”

Originator: The Miltown Movement

Date: 6/11/16

Locale: Milwaukee, WI (USA)

Slogan: Our Sexual Revolution

Originator: San Francisco Department Of Public Health

Date: 6/15/16

Locale: Bay Area, California

Slogan: PrEP for Her

Originator: MAC AIDS Fund, DC Public Health

Date: 6/17/16

Locale: Washington DC

Slogan: PrEP is for…

Originator: AIDS Project of New Haven

Date: 6/24/16

Locale: greater New Haven, CT (USA)

Slogan: “Prevention is reality.”

Originator: Gilead Sciences Inc.

Date: 7/1/16

Locale: USA (National)

Slogan: Trust a different kind of protection.

Originator: Chicago House

Date: 7/7/16

Locale: Chicagoland IL (USA)

Slogan: “Addicted to PrEP.”

Originator: BCN Checkpoint

Date: 7/8/16

Locale: Barcelona (Spain)

Slogan: Get PrEPed!

Originator: Health Initiative for Men

Date: 7/14/16

Locale: metro Vancouver, BC (Canada)

Slogan: How do you pregame…? / #PrEP4Sex

Originator: STAR TRACK Adolescent Health Program at the University of Maryland

Date: 7/19/16

Locale: Baltimore MD (USA)

Slogan: “Prevention you can get behind.”

Originator: Hotel Gaythering / The Pride Center

Date: 8/3/16

Locale: Miami FL (USA)

Slogan: “I missed the bus, but I don’t miss a dose.”

Originator: Gay Men’s Health Crisis

Date: 8/5/16

Locale: New York City Metro Area (USA)

Slogan: “Sexo seguro es fresco./Safer sex is cool.”

Originator: Marcus Sanchez / Kind Clinic

Date: 8/28/16

Locale: Metro Austin TX (USA)

Slogan: Les situations varient… Les modes de protection aussi. / Situations vary… So do prevention tools.

Originator: Santé Publique France

Date: 11/18/16

Locale: France (Europe)

Slogan: #20DaysToStart

Originator: Hive Online / Project Inform

Date: 11/29/16

Locale: USA (online)

Slogan: “Stay Sure.”

Originator: NYC Department of Health and Mental Hygiene

Date: 12/1/16

Locale: New York City, NY (USA)

Slogan: “Stay Sure.”

Originator: NYC Department of Health and Mental Hygiene

Date: 12/1/16

Locale: New York City, NY (USA)

***2017***

Slogan: “F*ck w/out Fear!”

Originator: Los Angeles LGBT Center

Date: 1/6/17

Locale: Los Angeles County CA (USA)

Slogan: “Proud to be PrEPPED. / Orguillosamente PrEPARADO!”

Originator: Proud to be PrEPPED / Colorado Department of Public Health & Environment

Date: 2/1/17

Locale: Colorado (USA)

Slogan: “Being Healthysexual!”

Originator: Digitas Health Life Brands / Gilead Sciences, Inc.

Date: 4/8/17

Locale: USA

Slogan: “PrEP4Love.”

Originator: Equally Georgia

Date: 9/24/17

Locale: Georgia (Europe)

Slogan: “Wish I knew one pill a day could prevent HIV.”

Originator: Onondaga County Health Department

Date: 2017

Locale: Syracuse/central NY State (USA)

***2018***

Slogan: “Living Sure.”

Originator: NYC Department of Health and Mental Hygiene

Date: 3/6/18

Locale: New York City, NY (USA)

Slogan:

Originator: Ending AIDS New Zealand

Date: 4/3/18

Locale: New Zealand

Slogan: 1 Pill Prevention / What is PrEP?

Originator: PrEP Georgia

Date: 4/11/18

Locale: Georgia (Europe)

Slogan: “PrEP’d AF!”

Originator: Los Angeles LGBT Center

Date: 6/3/18

Locale: Los Angeles County CA (USA)

Slogan: “I swallow daily.”

Originator: Apicha Community Health Center

Date: 6/25/18

Locale: New York City (USA)

Slogan: Un comprimé par jour vous protège du VIH. / One pill per day protects you from HIV. / PrEP4Love

Originator: AIDES (France)

Date: 7/3/18

Locale: France (National)

Slogan: “Be proud! Be prepared!”

Originator: Palmetto Community Care

Date: 9/18/18

Locale: greater Charleston NC (USA)

Slogan: “Sister Friends: Get PrEP’d”

Originator: Get PrEP LA / County of Los Angeles Public Health Department

Date: 10/24/18

Locale: Los Angeles County CA (USA)

***2019***

Slogan: “Philly keep on loving without worrying about HIV.”

Originator: City of Philadelphia Department of Public Health

Date: 2/28/19

Locale: Philadelphia PA (USA)

Slogan: “Get PrEP’d!”

Originator: AFAO – Australian Federation of AIDS Organizations

Date: 3/1/19

Locale: Australia

Slogan: Ik slik, slik jij?/I swallow, do you?

Originator: PrEP Netherlands

Date: 4/18/19

Locale: The Netherlands

Slogan: (none)

Originator: NYC Department of Health and Mental Hygiene

Date: 5/10/19

Locale: New York City, NY (USA)

Slogan: “Chill Pill.”

Originator: End AIDS Washington

Date: 5/15/19

Locale: Washington State (USA)

*****

Slogan: “The GayScout’s motto: Be PrEPared.”

Originator:

Date:

Locale: Utah

(the rest of this PrEP pop culture series)

PrEP in Pop Culture: Celebrity Endorsements

4/25/19 (Author’s note and the rest of this PrEP pop culture series.)

When an idea or a tangible thing is mentioned or endorsed by notable people in the media – celebrities as diverse as actors, advocates, musicians, politicians, and the like – it not only raises awareness but also trust levels. PrEP and TasP are no exceptions as the idea and the access level of biomedical prevention expands. As such, listed below in alphabetical order by family name are just a few of the many examples of various popular people speaking positively of prevention via modern marvels TasP and/or PrEP…”The beautiful people” “doin’ it fa da culturah” (NB: For more celebrity/institutional endorsements and/mentions of biomedical HIV prevention approaches, see also the music node and the “PrEP Royalty” node for this pop culture series or the Prevention Access Campaign. This list will be updated periodically, especially if/as you, the readers, share suggestions for inclusion.):

Timothy Ray Brown, HIV treatment/cure advocate and public speaker:

“When I first heard about the introduction of the use of Truvada for PrEP (pre-exposure prophylaxis) in 2012, I did not give it much thought. I had been cured of HIV in 2007, and had been told by my doctors that I am immune to the virus. Therefore, I did not think that PrEP was something I needed for myself. Since the whole reason for all of my work is to help the HIV-positive community and their loved ones by giving hope that HIV can be cured, I eventually decided that PrEP is an important tool in preventing new infections and this is an extremely large part of my mission.” (via Positively Aware Magazine Op-Ed, January/February 2015 issue)

[Editor’s note: On February 11, 2017, Brown revealed that he was, at that time, and, for several years, had been a PrEP.]

Max Cameron, adult film performer:

“The original reason I started taking PrEP, was at the time I was dating someone who is HIV positive and undetectable…At the time, I was still somewhat concerned. I prefer condomless sex, like many gay adults. I wanted to protect myself in case he fell behind in his meds or started to develop a viral load above 200 copies /ml again…I had also been flirting with the idea of doing porn…Treasure Island. All their stuff is bareback. I know the last test results of all my scene partners and you always assume their status is positive. I understand the testing protocols and knew my risk. I wanted to make sure I protect my health. After all condom efficacy ranges between 55-85%, while my PrEP regime protects me beyond 99%efficacy because I’m adhering perfectly…Before I was on PrEP I was pretty risky. You take peoples word, based on their status. I always respect if my partner wants to use condoms during anal sex, or has the idea in their head that they want to have sex with a condom…PrEP is an amazing option…You will see more companies promoting the use of Truvada. Models who are HIV negative will be jumping on board. It will change things in the industry for the better. It’s kind of a trend that porn is going; more barebacking. This is just another tool in our arsenal to help with HIV prevention. If we are practicing bareback sex, we should be promoting safer sex, but using other forms of safer sex, like PrEP.” (via The Homo Culture Magazine interview, 9/3/14)

Milan Christopher, rapper/actor:

“In communities of color, there is so much stigma around sex, being gay, and HIV that people are scared to even talk about PrEP — and many more don’t even know about it…I’ve had friends die of [AIDS complications] and I’ve had scares where I thought I was exposed to HIV. This was happening before PrEP was available. When my doctor told me about a clinical trial for PrEP several years ago, I knew I wanted to try it to protect myself. I’ve been taking it ever since. I get my PrEP from the L.A. LGBT Center. The center offers consultations, testing, and can help people get on PrEP. They can also help people get it at low or no cost.” (via The Advocate Magazine interview, 7/23/18)

Bill Clinton, former US President:

“The most promise of the prevention tools is not the most immediate … if you have microbicides, you’re going to empower women to save their own lives and stop them from being infected,” (via public speech at the XVI International AIDS Conference, 8/13/06)

Cam Christou, adult film performer:

“I first heard about PrEP when I want in to get PEP. My ex-boyfriend was HIV positive and the condom broke…At first, I did it for him, not necessarily myself…He was healthy, on medicine, and his viral load count was low. I was involved in the local HIV/AIDS health clinic in Washington, D.C., and I was comfortable having sex with him, even with using a condom…We’ve come so far with this amazing drug, but it’s still a long, long road ahead…It’s an opportunity to have open dialogue with former and current lovers, and people having sex. Surprisingly, people know nothing about it. The thing I like about Truvada, is that although there is a mask out there that it increases promiscuity, it doesn’t. Either I’m going to have protected or unprotected sex. Either way, I have something to fall back on. I talk to my family members about it, especially the ones who attribute being gay with automatically getting HIV. You have to be careful. This opens doors for education ad to change the stigma out there.” (via The Homo Culture Magazine interview, 11/15/14)

Jason Domino adult film performer / sexual health public speaker:

“I started Porn4PrEP because my first scene, my first partner with HIV positive, and that sort of put me through a learning curve that I wasn’t prepared for. After that, I went on PrEP, and I sort of kept that a bit to myself. While I was dealing with that, a number of my friends became HIV positive, and I realized just how important it was to tell people about this. So, I now dedicate a lot of my time as a PrEP Advocate…Since I started porn, I learned a lot about HIV…like …When people have a well-managed viral load, they can become “Undetectable,” and that is uninfectious, and the scientific community’s been saying that for quite a while. So that can sort of erode some of the fear and increase respect and understanding there.” (via Gay Star News interview, 12/1/16)

Bob the Drag Queen, American Drag performer extraordinaire:

“Okay, PrEPare yourself! What I’m gonna tell you may sound unbelievable but there is a once-a-day pill called PrEP, short for pre-exposure prophylaxis. It’s shown to lower the risk of getting HIV of a more than 90%… I know!” (via Greater Than AIDS PSA video, 6/5/16)

Daniel Franzese, actor/advocate:

“Elizabeth Taylor AIDS Foundation was underwriting the new media playbook on HIV with GLAAD to present to MSNBC, and they were looking for a celebrity to do it, and so they contacted me, and I became an ambassador for the Elizabeth Taylor AIDS Foundation. And when I did the four-hour media training, I learned so many things that I felt, as an educated gay man, I should already have known. And I couldn’t believe where we were in today’s age of prevention and treatment, and how much I didn’t know. And I learned of PrEP for the first time. And I learned of all these things, and I thought, if I don’t know about this stuff, and I’m a person that, you know, reads the news every day and considers himself a healthy sexual person, then I know a lot of people who have a lot less resources than I have don’t know this…[What’s next is] I’m on tour doing my Yass! You’re Amazing!comedy tour. I’m touring colleges, clubs, and theatres throughout the country with my standup tour. And I even include stories about PrEP and things within my comedy, because I have the ear of all these college students — I try to find ways to at least mention it and make them aware about PrEP and other things. It’s been really great!” (via TheBody.Com interview, 4/30/19)

Bill Gates, Microsoft founder:

“A woman should never need her partner’s permission to save her own life…We believe that microbicides and oral prevention drugs could be the next big breakthrough in the fight against AIDS. We are determined to help medical science discover these new drugs and get them to the people who need them.” (via public speech at the XVI International AIDS Conference, 8/13/06)

Jackée Harry, actress:

“Women of color (cis & trans) have disproportionately higher rates of HIV. We also have access to PrEP – a daily medicine that lowers our chances of getting infected. But for some reason, not many of us are taking it. Don’t make the same mistakes I made in the 80’s. Even if you’re straight, even if you’re vanilla in the bedroom, & especially if you don’t want to go celibate: ask your doctor about PrEP & GET ON IT! @BlackAIDS has all the information you need to know: https://blackaids.org/news-and-events/black-women-prep/“ (via Twitter post, 6/10/18)

Luke Hudson, adult film performer:

“I’ve been on [PrEP] for over a year and I would definitely recommend it to anyone … [Especially,] anyone who’s having barrier free sex.” (via HIV Plus Magazine interview, 5/9/17)

Eli Lewis, adult film performer:

“I am a huge advocate for pre-exposure prophylaxis!…PrEP is a preventative measure for the spread of HIV infection, with Truvada being the most commonly known medication. It is prescribed to be used alongside with other safer-sex measures, like using a condom, which further decreases the chances of infection among individuals…The puritanical and fear-mongering idea that the drug created to supplement, improve, and even save the sexual health of individuals was an argument made years ago when birth control was first introduced…I commend those who do their research and decide that PrEP is right for them, especially if they work in the adult entertainment and escorting industries, have casual sex with multiple individuals, or are in a serodiscordant relationship where one partner is HIV-negative and the other his HIV-positive…Recent studies have shown HIV-positive individuals with an undetectable viral load…is [in] virtually no risk of spreading the virus,” said Eli Lewis. “That being said, I would feel more secure filming, or even having casual sex with an HIV-positive individual who is regularly tested and on HIV medication.” (via The Homo Culture Magazine interview, 8/5/15)

Michael Lucas, adult film performer, producer, and advocate:

“My choice to begin taking a highly-potent HIV drug wasn’t an easy one. And the decision to come out publicly as someone who’s on PrEP is not one that I take lightly. But the more I learn about PrEP, the more shocked I’m becoming that gay men are not shouting from the rooftops about this potential game changer in the fight to prevent new HIV infections, which we’re losing badly. I’m ready to shout about it.” (via Out Magazine Op-Ep, 7/24/13)

Paul Morris, adult film producer:

“The number of men who have written to me asking to be the recipient of gallons of semen is virtually uncountable. These aren’t the incidental fantasies of a small fringe of outliers. These speak to the heart of the sexual imagination of most queer men. ..Years ago I stated that all gay men are HIV-positive. That is, every gay man alive today is defined as much by the viral load narrative as by any external homophobia. If you wonder at the meaning of a jar filled with poz loads being poured up the ass of a happy, intelligent, and more-than-willing young gay man, the primary meaning is that there is no reason or excuse for continuing to live in fear of a virus…We’re at a point where it’s altogether possible, given the simple strategies like PrEP, to render HIV a nonissue. And the gay world is panicking because too much money, too many institutions, too much of the gay mainstream has based itself on terror and fear and grief. It’s a cultural identity crisis. It’s a mass version of agoraphobia. A world that’s suddenly free of fear is daunting and very large.” (via VICE Media interview, 5/12/14)

Barack Obama, then-US President:

“My administration implemented our nation’s first comprehensive National HIV/AIDS Strategy, and we’ve updated it through 2020. We’ve invested in research and evidence-based practices that have given us revolutionary tools like treatment as prevention and pre-exposure prophylaxis.  We’ve made critical investments to help eliminate waiting lists for the AIDS Drug Assistance Program.  We’ve continued efforts to support the promise of a vaccine.  And the Affordable Care Act has resulted in millions of individuals gaining affordable, high-quality health coverage – all without denial for pre-existing conditions like HIV. While there is more work to do – the economically disadvantaged; gay and bisexual men, especially those who are young and Black; women of color; and transgender women all continue to face huge disparities – I’m confident that if we build upon the steps we’ve taken, we can finish the job.” (via Whitehouse statement, 6/5/16)

Mr. Pam, adult film director:

“When I first heard about [PrEP], I was really skeptical about it…You take a pill and you won’t get AIDS. Really?…I spoke with models, friends, sluts, etc., and I moderated a discussion panel about it and I was afraid…[Now,] I actually feel like it’s great. It seems like it’s working. I have two friends [on PrEP] … Knowing first hand people who are taking it … is great! This is very exciting….I think it is awesome and it could be the future of HIV prevention. It’s new. It’s a revolution. It’s super exciting.” (via The Homo Culture Magazine interview, 8/27/14)

Danny Pintauro, child star and HIV advocate:

“I’m a huge supporter of PrEP. If you add PrEP to the equation, we virtually have the tools to end new infections and that’s so exciting… [And i]f we can get to a place where HIV-positive men who are undetectable can feel proud to say that — and other people will potentially feel like that’s kind of sexy — then it won’t be about slut shaming because they’ll understand it’s really hard to pass HIV on to someone when you’re undetectable…I can be proud to say I’m taking my medications. I’m taking care of myself. I’m healthy and in turn I’m taking care of the people I spend time with…If everyone knew their status, then we could pretty much eradicate new infections…. What if we could find a way to make it that knowing your status was really cool? If we could create an environment where a person can say they’re proud to know their status, proud to be on top of it, and that makes it a little bit sexier? I think inherently we’d get more people to know.” (via HIV Plus Magazine interview, 12/14/15)

Dan Savage, Love/Lust/Sex/Relationship advice columnist and public speaker:

“If [a] guy is poz and he’s being treated and he’s taking his meds correctly and his viral load is undetectable, he’s not going to infect you with HIV. (Peter Staley: “Undetectable = Uninfectious.”) …[Additionally,] pre-exposure prophylaxis, or PrEP, is a way for people who do not have HIV but who are at substantial risk of getting it to prevent HIV infection by taking a pill every day. The pill (brand name Truvada) contains two medicines (tenofovir and emtricitabine) that are used in combination with other medicines to treat HIV. When someone is exposed to HIV through sex or injection drug use, these medicines can work to keep the virus from establishing a permanent infection. When taken consistently, PrEP has been shown to reduce the risk of HIV infection in people who are at high risk by up to 92%. PrEP is much less effective if it is not taken consistently.

If you have a hard time using condoms correctly and consistently during anal intercourse, … [Y]ou absolutely, positively need to get on PrEP. …Get on PrEP, …There are other STIs to worry about besides HIV, of course. PrEP doesn’t provide protection against syphilis, gonorrhea, chlamydia, etc. But the disease … [Y]ou have the most cause to worry about—is one you can worry about a whole lot less once you’re on PrEP.” (via The Stranger advice column, 2/10/15)

Rocco Steele, adult film performer:

“If a person chooses to bareback, they need to talk to their doctor and see if they can take PrEP. …The important thing is education…We need to be talking about this more. HIV, AIDS, STDs, our status and getting tested.” (via Edge Media interview, 11/29/15)

Scott Weiner, former San Francisco supervisor and current California state Senator:

“Each morning, I take a pill called Truvada to protect me from becoming infected with HIV… I went on PrEP to further protect and take personal responsibility for my health. I’m HIV-negative, and I want to remain that way…As an elected official, disclosing this personal health decision was a hard but necessary choice. After all these years, we still see enormous stigma, shame, and judgment around HIV, and around sexuality in general. That is precisely why I decided to be public about my choice: to contribute to a larger dialogue about our community’s health…We simply need the political will to ensure that the community has accurate information about and access to all prevention methods, including PrEP. I hope my disclosure can play a role in moving us toward these goals.” (via Huffington Post column, 9/17/14)

Owen Hawk, adult film performer:

“In 2019[, stigma] and fear are the main barrier to testing, treatment, and Prep. The path to eradication of new HIV is through those means. So if you are not actively part of ending HIV stigma and fear *you* are part of the problem, standing in the way of [eradication]. So if you are so fearful and afraid of HIV that you cannot have sex with someone who is undetectable, *you* are the one who should not be allowed in porn, *you* are the one who does not deserve a platform, fanbase etc. *you* should leave, not demand to be accomodated. / end rant” (via Twitter tweet, 1/31/19)

Brian Sims, Pennsylvania State Representative:

“PrEP/PEP: Starting this day off smart, proactive, and in control! Think this is an invite to talk about my sex life? It’s not. Think it’s an invite to shame me or anyone else? Grow up. “Stigma” is the thing our enemies want us to be stunted by. It literally kills us. It’s stupid and we control our own fate. No shame in this game. Just Pride. #PrEPsavesLIVES” (via his Instagram account, 4/23/19)

Dimitri Joseph Moise, actor, singer, dancer, producer, and magazine editor:

“I realized I would thrive the day I became undetectable… I don’t have to be scared anymore. I’m undetectable, which means I cannot transmit the virus. So I can live a happy life.” (via HIV Plus Magazine interview, March/April 2019)

Alex Azar, current US Department of Health and Human Services Secretary

“Securing this commitment is a major step in the Trump Administration’s efforts to use the prevention and treatment tools we have to end the HIV epidemic in America by 2030. Under President Trump’s leadership, HHS worked with Gilead to secure preventative medication for individuals who might otherwise not be able to access or afford this important treatment. The majority of Americans who are at risk and who could protect themselves with PrEP are still not receiving the medication. This agreement will help close that gap substantially and deliver on President Trump’s promise to end the HIV epidemic in America.” (via HHS statement, 5/9/19)

Donald Trump, current US President:

“Great news today: My Administration just secured a historic donation of HIV prevention drugs from Gilead to help expand access to PrEP for the uninsured and those at risk. Will help us achieve our goal of ending the HIV epidemic in America!” (via Facebook statement, 5/9/19)

(the rest of this PrEP pop culture series)