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.
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:
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.
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:
“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)
Prophylaxis 
5 thoughts on “Rationales for Ts and Ss PrEP Dosing? (5 of 8)”