It started Wednesday, Sept. 28 when the Microbicide Trials Network—a clinical trials network funded by the U.S. National Institutes of Health (NIH)—announced that one arm of its VOICE study was being discontinued for futility. VOICE follows 5000 sexually active, HIV-negative women in Uganda, South Africa and Zimbabwe, testing the safety and effectiveness of HIV prevention strategies involving antiretroviral drugs. Each of these two strategies has shown promise in other research: antiretroviral pills (pre-exposure prophylaxis or “PrEP”) and a vaginal gel microbicide. Originally VOICE contained five arms: (1) a 1% tenofovir gel microbicide, the same one that showed efficacy in the CAPRISA 004 study, but used daily instead of just before and after intercourse; (2) a placebo gel; (3) tenofovir pills; (4) Truvada pills (a combination of tenofovir and emtricitabine); and (5) a placebo pill.
After a recent peek at the ongoing data, the study’s data safety monitoring board recommended closing the oral tenofovir arm. While the other two ARV arms continue, indicating at least a chance that those products are working as expected, the announcement evoked bad memories of last April, when Family Health International (now FHI 360) announced that the FEM-PrEP study was being closed early for futility. In that study—another large, well-funded and apparently well-run trial—oral Truvada could not demonstrate efficacy in preventing HIV acquisition among women. The FEM-PrEP result has widely been considered an outlier, not enough to convince anybody that PrEP doesn’t work among women—but, while VOICE could still show efficacy for Truvada, the closure of the tenofovir arm is not good news for PrEP as a possible strategy in women.
Less than a week later, The Lancet Infectious Diseases published the results of a study (affiliated with the Partners PrEP study, one of the two trials which provided encouraging data earlier this summer on PrEP as a strategy for couples in which one partner is infected and the other isn’t) indicating that using hormonal contraceptives may double a woman’s risk of acquiring HIV (if she’s negative) or transmitting HIV (if she’s positive). These data had been presented at IAS over the summer, but the appearance in the Lancet and a discussion in the New York Times have prompted broader concern. While other research has indicated an association between hormonal contraceptives and HIV, these data are the strongest. And these data are particularly dispiriting because they most directly implicate long-acting injectable contraceptives like DMPA, a method popular in sub-Saharan Africa (and elsewhere) for its ease of use.
We should note the disclaimers: a study stopped for futility doesn’t prove that the intervention didn’t work, it just means that the data couldn’t show that it did work; and the contraceptives data don’t meet the gold standard of a randomized clinical design. Plus, it’s been a great couple of years for biomedical HIV prevention research overall: after a decade in which condoms were the sole technology for preventing HIV, the last two years have seen proof of concept for vaginal microbicides (CAPRISA 004) and PrEP in men who have sex with men (iPrEx) and young heterosexual men and women (TDF2), plus the effectiveness of PrEP or early treatment for men and women in discordant couples (HPTN 052, Partners PrEP), as well as the large scale rollout of adult male circumcision as a cost-effective, cutting-edge (as it were) prevention strategy in several countries.
But consider how the news has differed for women as opposed to straight men. (Pardon my bracketing the MSM perspective in this post.) If you’re an HIV negative man, you can go get circumcised and reduce your risk of acquisition (from any female partner) by at least 60%. If your primary female partner is HIV positive and starts ARV therapy, the odds of your getting HIV from her are practically zero. Plus the data so far on PrEP efficacy are stronger in men. Oh, and as always, you could just use a condom when you have sex.
If you’re an HIV negative woman, condom negotiation—that is, whether you can get a male partner to use one—is commonly a problem. Hence the demand for “female-controlled” methods of contraception (such as hormonal) and HIV prevention (PrEP and microbicide), which don’t necessarily require a male partner’s consent. One downside of hormonal contraception, though, is that it may weaken your position in negotiating condom use, since your male partner is no longer concerned about unintended fatherhood. And now it appears that the contraceptives themselves may increase your HIV risk. Of course, you really don’t want to stop using contraceptives if you don’t want to get pregnant—an even higher-stakes decision in settings where maternal mortality is high. In principle PrEP could offset some of this risk, but the efficacy data for PrEP in women are starting to look erratic.
So vaginal microbicides stand out as particularly important products for women, and good news from the gel arm of VOICE would be a big deal, especially since it could provide enough additional data for FDA approval of vaginal tenofovir. But if all goes well, and vaginal microbicides are ready for roll-out in a couple of years, there will be tough questions about how to prioritize resources. In particular, how should investment in a women-only product compare to investment in a gender-neutral product like an HIV vaccine? While an effective preventive vaccine is still years behind microbicides, an expert panel of economists recently ranked investment in an HIV vaccine atop its list of favorable cost-benefit solutions. (Microbicide investment didn’t make the list.) And while of course the choice is not “either-or,” consider the economic climate for global health spending and where it will be in two years.
What values should guide these decisions? Arguments for vaginal microbicide emphasize the position of individual women as well as the scope of the epidemic in women (60% of new infections in sub-Saharan Africa occurring among women). Microbicides may well be a highly cost-effective intervention on a population level, but there’s more to the argument than this. In contrast, arguments for vaccines usually focus on their maximum population-level impact, a more traditional “public health argument.” Both sides can make strong claims in favor of greater fairness and equity, but they’re often different kinds of claims. For instance, economic cost-benefit analyses offer a certain kind of neutrality, but is neutrality even a virtue in this case?
There’s no doubt, anyway, that the landscape of these decisions will depend on how the evidence turns out and how the technologies develop…all the more reason to follow the news from VOICE and other prevention research.
*Interested readers may also wish to follow the O’Neill Institute’s cutting-edge work on global preparation for PrEP rollout.
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The views reflected in this blog are those of the individual authors and do not necessarily represent those of the O’Neill Institute for National and Global Health Law or Georgetown University. This blog is solely informational in nature, and not intended as a substitute for competent legal advice from a licensed and retained attorney in your state or country.