4/2/18
3rd entry of 8 (1. Intro, 2. Definition, 3. Research, 4. Origins, 5. Rationales, 6. Critiques, 7. Implications, 8. Conclusion)
What data explains the approach?
“The evidence from studies that 4+ pills a week provides good protection for cis men is pretty clear…”
Ts and Ss PrEP dosing has not been studied in its own right; rather, it represents an interpretation and application of the relevant PrEP trial data accumulated to date. The main relevant data is that of at least 4 pills per week offering substantial protection in IPREX, IPREX OLE, and IPERGAY trials. However, other informative data exists in trials stretching as far back as preclinical animal data from a decade ago and into more recent smaller trials and demonstration projects (summarized in the chart below) in the early and mid years of this decade as well. Indeed, it even echoes in data revealed in late 2019 from among cisgender women in HPTN 082, 3P, and POWER, plus 2021 data from HPTN 084.
[Chart]
In 2008, the US Centers for Disease Control’s (CDC) Gerardo García-Lerma published some of the first preclinical/animal data demonstrating that short but potent intermittent PrEP (single doses right before and after exposure) could protect macaques rectally in a manner comparable to a daily PrEP regimen. Interestingly, the results also helped shift the research agenda away from Tenofovir (TVF or TDF) alone as a PrEP agent and toward the combination of TDF and Emtricitabine (FTC) that we now use for PrEP. That trial was soon followed up in 2010 by even more encouraging intermittent PrEP data authored by Garcia Lerma on animal rectal exposures. Combined, the two trials opened the door to the possibility of nondaily PrEP dosing in humans and also underlined the importance of timing of post-exposure doses in non-daily PrEP strategies. In fact, they’re cited by both IPREX and IPERGAY as well as a number of other important PrEP human trials large and small since then.
Published in 2010, IPREX was the first large scale, randomized control trial to demonstrate daily oral PrEP efficacy in humans. It tested a PrEP regimen of TDF/FTC among several thousand cisgender men who have sex with men (cMSM), transgender women (TGW), and transfeminine individuals assigned male at birth (AMAB). Being that, at the time, PrEP was an unproven strategy, the trial documented varying adherence levels of participants to the daily pill. In one of those twists of circumstances that later turn out to have important historical consequences, this created an adherence spread (some following the regimen of daily doses, some taking most doses, and some taking few if any at all). Fortunately, the trial was a success, and its efficacy results were hailed as groundbreaking at the time. The study’s lead investigator (and PrEP ‘founding father’ … or ‘midwife’ if you respect self-appointed titles) Dr. Robert Grant even made Time Magazine’s list of the World’s 100 Most Influential people in 2012.
That same year, a small pharmacological study called STRAND helped establish which level of drug corresponded with which level of adherence in IPREX. Those established drug adherence levels were then compared to records of seroconversions in IPREX, revealing the prevention equivalent of a dose-response relationship. In other words, the more drug participants took, the more their risk of HIV acquisition was reduced. Analyzed IPREX blood samples showed that:
- 2 pills per week led to a 76% risk reduction,
- 4 pills per week led to a 96% risk reduction, and
- 7 pills per week led to a 99% risk reduction among trial participants.
Soon after, several smaller trials hinted to likely user preferences and practices around nondaily PrEP when compared to daily dosing among participants. IPREP in Kenya in 2012 reported that a twice weekly fixed dose with a booster dose 2hrs after sex was just as acceptable among MSM and female sex workers (FSW) though it was adhered to significantly less frequently, especially the post-sex dose. Close on its heels the next year, 2013, IPREP Uganda released similar results outlining the relatively challenging nature of nondaily PrEP strategies among serodiscordant heterosexual couples. In the IPREP Uganda trial, however, the addition of texting services as pill reminders led to greater adherence across the groups. These two small trials highlight the difficulty of forming a habit of post-sex dosing with nondaily approaches to PrEP.
By electronic monitoring, median adherence for daily dosing was 80 %. Median adherence for intermittent dosing was 71 % per a “relaxed” definition (accounting for off-prescription dosing) and 40 % per a “strict” definition (limited to the prescription). Factors associated with lower adherence included travel, transactional sex, and longer follow-up; higher adherence was associated with daily dosing and an income. The definition of intermittent dosing strongly affects interpretation of adherence. These findings suggest interventions should address challenges of mobility, sex work, and long-term PrEP.
If STRAND was important for establishing just how often timed (or fixed) PrEP doses are needed for protection, then Cell-PrEP, another small important pharmacological trial, published in 2014, was its sister study. For Cell-PrEP helped flesh out important guidance on how soon daily doses reach maximum concentration in the body and how long they persist at such protective levels after PrEP medications are withdrawn. The trial showed that 7 daily doses was the top-off point and that after 30 days of such dosing, medicine stayed within protective range for 7 additional days if stopped. Just the same, the researchers concluded with a reminder on previous advice for how to stop PrEP:
“PrEP differs from PEP in that early replication is presumably blocked by PrEP, as long as PrEP activity is high, perhaps allowing for a faster HIV clearance rate in the setting of PrEP. Similar efficacy was found in animal studies that compared continued PrEP dosing for 28 days after the last viral inoculation vs discontinued dosing after the last viral inoculation [19]. These considerations suggest that shorter durations of dosing might be adequate for PrEP following the last potential HIV exposure, but not enough information is available to make specific recommendations. This should be an area of future research. Until then, a conservative recommendation would be to continue dosing for 4 weeks after the last potential HIV exposure.”
In 2014, IPREX’s 4-or-more-pill-protection observations were echoed in preliminary analyses of data from the IPREX Open Label Extension (OLE) trial. The OLE had offered PrEP, in a real world setting, to all eligible IPREX participants as well as those from several other smaller PrEP trials completed at the time. So positive were the results that one summer headline blared “Overall PrEP effectiveness in iPrEx OLE study 50%, but 100% in those taking four or more doses a week.” Grant responded to the results by explaining :
“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… [W]e have up till now been very conservative in public statements about how well these things will work when used.”
Following close on the heels of the 2014 IPREX OLE 4-doses-per-week confirmatory efficacy observation mentioned above came the IPERGAY trial. Published in 2015, IPERGAY is the only large-scale, randomized control trial so far to demonstrate efficacy of a nondaily TDF/FTC PrEP regimen in humans. It tested a 4-pill strategy (Sound familiar?) in a 2-1-1 succession of the first two doses 2-24hrs before sex, a third dose 24hrs after the first two doses, then the fourth dose 24hr after the third, like IPREX among MSM. The trial was a success, though at 400, the participant pool was relatively small. In the median, participants had enough sex that they took about 4 pills per week … Thus IWantPrEPNow’s citing IPERGAY as its source for the 4-pills-per-week of Ts and Ss fame.
While some accepted IPERGAY’s results, CDC’s skeptical response gave many users pause about whether or not on-demand PrEP was an option for those seeking an alternative to daily PrEP:
“The IPERGAY results provide the first evidence that an event-driven regimen was effective among high-risk MSM with frequent sex (median of ten sex acts per month and eight partners every two months). CDC cautions, however, that researchers do not yet know if this regimen will work among MSM who have sex less frequently or among other populations at high risk for HIV infection. In this study overall, available data suggest that men were taking PrEP an average of three to four days per week.
CDC continues to recommend daily dosing of PrEP and urges people at substantial risk for HIV infection and their health care providers to continue to follow current CDC guidelines.”
In his analysis of IPERGAY data, Dr. Grant focused more on the real world application of data from trial participants experiencing “seasons of risk” and deploying the short course of PrEP on-demand only for sex they’d deemed risky:
“We know that people go in and out of seasons of risk—times when they’re more likely to be exposed to HIV… [but] Two doses after a potential exposure to HIV appears to provide substantial protection in the Ipergay study if men were taking PrEP before the exposure…If someone’s in a position where they’re sure their risk of exposure to HIV has ended, they do not need to keep taking PrEP indefinitely. The IPERGAY results suggest that they can stop after taking 2 doses over 2 days after the last sexual exposure, as long as they have been taking PrEP before sex, preferably for at least 7 days.”
After IPREX, its OLE, and IPERGAY, it was easy to find data of 4-pills-per-week correlating highly with protection from HIV among those engaged in anal sex. Indeed, in research circles, 4-or-more-pills-per-week became the shorthand yardstick for assessing adequate adherence in such demonstration projects. The report-outs on adherence and efficacy came often as “no seroconversion among participants taking 4 or more pills per week.” Over and over, the pattern repeated:
- in 2015 PrEP demonstrations like the Adolescent Trials Network (ATN) 110 among a small cohort of youth and a few hundred enrolled in the US PrEP Demonstration Project,
- in the 2016 follow-up ATN 113,
- in a Gilead-sponsored aggregation the same year of data from the three rolled in with tens of other ongoing PrEP demonstrations around the world including more than 7,000 cisgendered MSM and trans female participants,
- in a 2017 post trial seroconversion analysis from the ADAPT trial,
- most recently, and most surprisingly, in a 2019 AVAC webinar (slides here) on gaps in PrEP knowledge concerning cisgender women via data from the HPTN 082, 3P, and POWER studies of such cis women in Africa in the wake of the FDA’s 10/3/19 approval of Descovy as PrEP for all populations except those engaged in receptive vaginal (or fronthole) sex, and
- 2021 data from HPTN 084 (where 35 of 36 seroconversions among oral F-TDF arm cisgender female participants were among those taking less than 4 pills per week).
The surprising and more recent echoes in data revealed in late 2019 (from among cisgender women in HPTN 082, 3P, and POWER) as well as in 2021 (HPTN 084 by way of inference) deserve their own explainer by none other than Monica Gandhi, the prevention researcher who helped introduce the world to update in the concept:
… [There’s been a] relatively long period of time where we have [had] the dogma that women had to take higher frequency of TDF/FTC [Truvada] doses than men… And so, that idea that there were lower levels of tenofovir in the cervical/vaginal tract compared to the rectal tract led to a modeling study that said probably women need higher doses, and higher number of doses, of TDF/FTC than men do for the same amount of efficacy. And modeling in the iPrEX OLE study showed, for men at least, that probably four doses a week was okay for PrEP efficacy. And the relative dogma was that women needed seven doses per week for efficacy—full daily adherence—for this to work…”
“It’s when you study a drug in trials or in real life or in demonstration projects—that’s when you get closer to the truth than some of our [mathematical] models...”
“There was very high PrEP uptake in HPTN 082 and, very importantly, very low incidence of HIV despite the fact that women were taking around four doses a week. At three, six, and 12 months, there are low levels of tenofovir diphosphate [as measured] in dried blood spots, but importantly, there were very few seroconverters…“
“The same finding occurred in the 3P study … high-risk young population with STIs and partners suspected of having other partners. And again, the PrEP adherence as assessed by tenofovir diphosphate concentrations in dried blood spots was not seven doses a week. It was more like four doses a week. And importantly, there were no HIV seroconversions here as well,” she said. “And I’m building this argument because, again, the studies were not done with TAF/FTC [Descovy], but maybe we need the host [human] studies before we extrapolate from pharmacokinetic data...”
“Any extrapolation that we want to make for women or men from the pharmacokinetics for TAF and FTC vs. TDF/FTC may not tell us what eventually happens in the real world with men and women, just like those two demonstration projects told us different things from the pharmacokinetics and what happened in demonstration projects…”
Hence, while strictly speaking, the Ts-and-Ss-4-(or-more)-pills-per-week-for-anal-sex strategy hasn’t been studied, there’s a lot of evidence from large- and small trials (IPREX, STRAND, IPREX OLE, ADAPT, IPERGAY, ATN 110/113, US PrEP Demo, HPTN 082, 3P, POWER, HPTN 084, etc.) demonstrating that, on average, this dosing level provides substantial protection from HIV during anal (as well, as of October 2019, vaginal and fronthole) sex. There’s also data (IPREP Kenya, IPREP Uganda) that highlights potential adherence challenges to nondaily approaches.
Finally, a 2016 analysis of PrEP data relevant to nondaily dosing (some of which was discussed above) by pharmacology expert Pete Anderson provides useful concluding insights explaining the particular mechanisms behind the strategy that’s evolved into what some call “PrEPping on the Ts and Ss:”
“It is important that the PrEP agents distribute and adequately accumulate in mucosal tissue (e.g. vaginal, rectal, penile) where these initial virologic events are localized.(13, 14) The possibility of virus escaping to lymph nodes at early time points suggests that systemic drug concentrations may be important as a “back-up” for this potential scenario. …It is possible that “back-up” systemic drug may contribute to PrEP efficacy…Mucosal drug distribution studies have focused on cervicovaginal and rectal tissues as these compartments are more accessible compared with penile tissue. …These agents [current oral PrEP dual drugs] are nucleos(t)ide analogs that require phosphorylation in cells for pharmacologic activation. The resulting intracellular anabolites, tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP), are ion-trapped thereby extending their half-life at the site of action.(23) The longer half-life results in a buildup from the first dose to steady-state concentrations. This build up takes several half-lives to reach the steady state plateau. This is relevant for event-driven dosing because single (or a few) doses will result in low concentrations relative to steady-state concentrations achieved with daily dosing. These lower concentrations suggest a lower margin for error in terms of missed doses for event-driven dosing.”
Prophylaxis 
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