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IAS 2017: Experts Agree that Intermittent Oral PrEP Probably Won't Work for Women

Two presenters at the recent International AIDS Society Conference on HIV Science (IAS 2017) in Paris told delegates that both trial results and analysis of drug levels support the idea that event-related or "on demand" pre-exposure prophylaxis (PrEP) might not be sufficiently powerful to prevent HIV infection in women and trans men via vaginal sex.

[Produced in collaboration with aidsmap.com]

Infections and Adherence in Women on PrEP

Robert Grant, principal investigator of the pioneering iPrEx PrEP study of gay men and transgender women, said that although that there was abundant evidence that PrEP did protect cisgender women from infection, it looked like 6 to 7 doses a week, i.e., daily PrEP and good adherence, would be needed to fully protect them.

Grant said that whereas in studies of PrEP for gay men and transgender women there had never been a case of HIV infection in a trial participant who had drug levels consistent with even moderate adherence to PrEP, there were such cases in women.

He cited 24 cases of HIV seroconversion in women in PrEP trials where drug levels were measured either shortly before infection, shortly afterwards, or both. In 9 cases, drug levels either before or after infection were consistent with the women taking 4 to 5 doses of PrEP a week. In another 3 cases, levels both before and after infection were consistent with taking 4 to 5 pills a week. This is a level that has been associated with almost complete protection in men who have sex with men (MSM). No infections have been seen in women whose drug levels were consistent with their taking 6 or 7 pills a week.

Grant said that the few studies of intermittent or on-demand PrEP found levels of adherence considerably below this, and lower than people's adherence to daily PrEP. The Kenya/Uganda iPrEP study randomized heterosexual serodiscordant couples, female sex workers, and MSM to take either daily PrEP or a twice-weekly regular dose plus an immediate post-sex dose if sex happened.

In the heterosexual couples, most of the negative partners took both the daily and the twice-weekly doses correctly, with adherence of 97% and 91% respectively, but they struggled to take the post-sex dose, with adherence of 45%. Among MSM and female sex workers, daily PrEP adherence was adequate (83%, equivalent to nearly 6 doses a week), but adherence to twice-weekly PrEP was only 55% and adherence to the post-sex dose was 26%.

"Being away from home" was the most common reason given for missing the post-sex dose, followed by "just forgetting" -- as one of the gay man in the study said, people tend to fall asleep after sex.

Another study of intermittent PrEP that included women was the ADAPT study, presented at the International AIDS Society conference in 2015. In brief, the women in the study, who were enrolled at its Cape Town site, had just about adequate adherence to daily PrEP (75%, or just above 5 pills a week), but only 56% adherence to a twice-weekly regular dose and 52% adherence to "event-driven" PrEP, which was 1 pill before and 1 pill after sex.

Drug Levels in Animal Studies

Angela Kashuba of the University of North Carolina looked at the biological reasons PrEP adherence might need to be higher and more consistent in women. It has been known for some time that intracellular tenofovir levels in the female genital tract after a single dose of tenofovir/emtricitabine (the drugs in Truvada) are 100 times lower than in rectal tissue, and emtricitabine levels 50 times lower.

Studies in monkeys show that after repeated doses, tenofovir levels in the female genital tract actually reach levels considerably higher than in the rectum -- but only by about the eighth day; peak drug levels are reached in rectal tissue after just 1 or 2 doses. Emtricitabine levels, on the other hand, never reach a level in vaginal tissues anything near as high as in rectal tissues; even after 8 days, levels in the vagina are 7 times lower than in the rectum.

Kashuba advanced a possible biological mechanism behind this. The nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) drugs like tenofovir and emtricitabine work by replacing the bases -- the individual letters in the DNA of HIV -- with fake or defective bases that act as stop commands for further lengthening of the DNA chain. However, they have to compete with the real bases circulating in the blood and present in the cell.

Kashuba said that in vaginal tissue, levels of 2 natural bases, deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate (dCTP)m are 50 to 100 times higher than they are in rectal tissue. In terms of the ratio of dATP to the PrEP drug, this is the same in both rectal and vaginal tissues, with 1.8 times more emtricitabine than dATP.

However, the ratio of tenofovir to dATP is about 350 times higher in rectal than in vaginal tissues; tenofovir is 17 times higher than dATP in rectal tissues, but 20 times lower in vaginal tissue. Drug levels of tenofovir and emtricitabine are both related to dATP and dCTP levels: the higher the natural base level, the lower the drug levels.

What this means is that optimal drug levels (i.e., levels that should guarantee 100% efficacy in preventing infection) both take longer to reach in the female genital tract and that some women never develop them. Optimal rectal concentrations of tenofovir plus emtricitabine, taken together, could probably be reached in 100% of people by the second dose of Truvada, whereas it takes 7 doses of Truvada for 85% of women to reach optimal concentrations in vaginal tissue -- and some never do.

Furthermore, inside the cell, the optimal levels of intracellular tenofovir remain in rectal tissues for at least 5 days after the last dose of PrEP, and are still at 90% of optimum after 10 days. In the vagina, on the other hand, intracellular tenofovir levels start falling immediately and are at 85% of optimum after 3 days. Emtricitabine levels fall much more quickly, within hours.

Implications

What does this imply for PrEP in women?

It shows that there is no reason oral PrEP should not work well for women having vaginal sex, but only as long as they take PrEP daily and have pretty good adherence at 6 to 7 pills a week. It means that women may need to start taking PrEP several days in advance of possible HIV exposure, though nothing like as long as the 3 weeks or so suggested by some recommendations.

It also implies that, for extra reassurance, women may want to combine oral PrEP with other prevention methods both old (condoms) and new (vaginal rings, etc).

It also implies that more research needs to be done on women and PrEP -- the dATP and dCTP levels, for instance, imply that inflammatory responses and gene activation might influence drug levels in the female genital tract -- and thought needs to be given to drugs that could work in other sites such as the lymph nodes.

9/21/17

Sources

RM Grant. Review of clinical studies of intermittent PrEP. 9th International AIDS Society Conference on HIV Science.Paris, July 23-26, 2017. Presentation MOSY0804.

ADM Kashuba. Does pharmacology support on demand PrEP? 9th International AIDS Society Conference on HIV Science.Paris, July 23-26, 2017. Presentation MOSY0803.