In 2010, the CAPRISA 004 clinical trial demonstrated that a gel containing an antiretroviral (tenofovir) could be used vaginally around the time of sex to reduce the risk of HIV and HSV-2. This provided proof of concept that a vaginal microbicide could work. In fact, it was the first trial to show that ARVs could reduce the risk of HIV—even before the string of oral PrEP trial results, and before the treatment-as-prevention trial results (HPTN 052, PARTNER). It was an incredibly exciting finding, coming after a string of disappointing trial results and years of research and advocacy that often faced neglect, ridicule and hostility.
Since then, two trials have tried to replicate those findings in order to get sufficient evidence to apply for regulatory approval. One of those trials was VOICE, which ended in 2013 after being unable to demonstrate that the gel worked. It turned out that too few participants were using the gel consistently. The other trial trying to replicate the results was FACTS 001. All of these studies were conducted among women in Sub-Saharan Africa, where the need is greatest for products that women can use to reduce their risk of HIV.
As was the case with previous large-scale clinical trials, participants in both arms were offered a standard prevention package that included STI testing and treatment as needed, condoms, and risk reduction counselling. On top of that, participants were randomised to receive either tenofovir gel or a placebo gel.
Findings in a nutshell
The rates of HIV were identical in both arms of the study (tenofovir gel vs placebo gel), so the microbicide gel did not lower the risk of HIV among this group of young African women. Much like VOICE, too few participants used the gel consistently enough to demonstrate that the gel worked. Results on the effect of the gel on the risk of HSV-2 will be available later.
For more complete results, check out these resources:
This is very disappointing to say the least. It is abundantly clear that women in general, and young African women in particular, need a range of options to lower their HIV risk. But it’s pretty clear that a vaginal microbicide gel is not going to be a workable option, especially for young African women.
That does not mean that a gel containing tenofovir does not lower HIV risk when it’s used consistently. CAPRISA 004, VOICE and FACTS 001 all had similar findings: among the subset of women who used the product consistently around the time of sex, their risk of HIV was lowered by around 54-66%. However, that was among a relatively small proportion of participants. Most women were unable to use the product consistently enough to make a significant difference.
It may be a different story for HSV-2. In CAPRISA 004, the women who received the gel had a 51% lower risk of acquiring HSV-2 than women who received the placebo—and that was when comparing both arms of the trial, not just the consistent users. The risk is likely lowered even more if the gel is used consistently. We will have data on HSV-2 from FACTS 001 soon.
So does this spell the end for vaginal gels as a microbicide? Will gels containing the next generation of ARVs still be moved forward? What about the non-ARV-based gels? Is the future of vaginal microbicides now entirely in the hands of the next generation of products—vaginal rings and long-term injectables? Or will the HSV-2 data be sufficiently compelling to seek regulatory approval? The gel was shown to be safe in all three trials, and as a bonus we know that the most consistent users would get al least moderate protection from HIV, on top of significant protection from HSV-2. And we know that HSV-2 increases HIV risk. Another option to consider: could the gel be combined with a diaphragm to boost the protective effect of both products?
There is now a similar tenofovir gel being tested for rectal use in a phase 2 study. If the results are positive when they are available next year, will that be sufficient to move it forward into a large-scale efficacy trial? Or do we need to re-think the whole idea of a gel for rectal use as well? On the one hand, the ability of participants in vaginal microbicide trials to use gels consistently has been mixed. On the other, many people are accustomed to using a product for anal sex (lubricants, enemas/douches), so perhaps adherence will be easier, despite the fact that applying the rectal gel in its current form is quite different from how people currently use douches or lubes.