HIV prevention finally in the hands of women

One of the most remarkable research findings over the past 4 months was the success of a tenofovir-based vaginal gel in preventing HIV infection.

The results of the CAPRISA 004 study, which were announced at the International AIDS Conference in Vienna in July and subsequently published in Science, revealed a 39% reduction in new HIV infections in South African women who used a 1% tenofovir vaginal gel before and after sex compared to those who used placebo gel. Among women with the highest adherence, new infections were reduced by 54%. Notably, and also unprecedented, new HSV-2 infections were reduced by 51%, possibly because of anti-HSV activity mediated by tenofovir precursors. In light of the elevated susceptibility conferred by HSV-2 infection, the long-term protective effects of the tenofovir gel against HIV acquisition could be even greater than suggested. The significance of these results is underscored by the standing ovation that followed the presentation of these findings at the Vienna conference.

Women constitute approximately half of newly HIV-infected individuals worldwide.

In sub-Saharan Africa, where the study was conducted, women account for almost 60% of people with HIV.

It is heartbreaking to note that one-quarter of the women screened to participate in the CAPRISA 004 trial were excluded because they already were HIV seropositive. Although condoms are well documented to prevent HIV transmission, and participants enrolled in the CAPRISA trial were counseled to use them, women cannot control whether condoms are used in many situations due to poverty, lack of power and social traditions. Male circumcision has been documented to decrease susceptibility in men, but only affects the susceptibility of women indirectly through fewer infected partners.

The development of a topical microbicide that women can apply themselves, with or without their partner’s knowledge, has been touted as the salvation for women at risk for HIV. Nevertheless, the field has been beleaguered by multiple failed studies of nonspecific microbicides that, at best, did not prevent HIV acquisition, and at worst enhanced it. The tenofovir-based gel used in the CAPRISA 004 trial is the first female-controlled biomedical HIV prevention measure ever demonstrated to reduce new infections in women.

Microbicides fall within the larger category of interventions known as pre-exposure prophylaxis, or PreP.

Antiretroviral therapies administered perinatally are highly efficacious in preventing mother-to-child HIV transmission and constitute the first demonstration of the effectiveness of PreP.

Studies have also convincingly shown that PreP is protective in the SHIV-infected rhesus macaque model. Thus, the concept of PreP is not new, and one might argue – with the benefit of hindsight – it was obvious that PreP would work.

The innovation in PreP, however, is its implementation in an economical and effective manner. Multiple ongoing studies are testing the efficacy of several types of oral PreP — either tenofovir alone or in conjunction with emtricitabine in a variety of populations. These include men-who-have-sex-with-men, injection drug users and heterosexual men and women in sub-Saharan Africa.

Fewer ongoing studies are examining the effects of topical PreP, as the bias in the field before CAPRISA 004 was that the proof of concept would be more easily demonstrated with oral than topical PreP.

Major concerns in the development of PreP include acceptance of the intervention, adherence, increased risk behavior, toxicity, drug resistance and cost. In the CAPRISA 004 study, acceptance of the intervention was high; 97% of participants reported that they found the gel acceptable and 98% reported that they would use it if it prevented HIV infection. Adherence, as determined by returned applicators, was assessed at 72.2% of sex acts. Individualized adherence counseling was performed at monthly visits. There was no evidence for increased risk behavior related to gel usage; in fact, condom usage increased during the course of the study. No significant toxicity was observed in CAPRISA 004 nor was drug-resistant HIV found in women who became infected.

According to the manufacturers, the cost of producing the tenofovir-based vaginal gel for the trial was 32 cents per application, and it is estimated that large-scale production could further reduce these costs through economies of scale. Estimates of the cost of oral PreP have generally been much higher.

Many issues need to be addressed as PreP is developed including:

l identifying the populations that will benefit from PreP;

l determining the effectiveness of various forms of PreP in preventing HIV transmission through different routes including vaginal and anal sex and injection drug use;

l developing optimal counseling strategies to encourage adherence and decrease behavioral disinhibition; and

l identifying optimal dosing schedules and drug formulations. As results from the multiple ongoing PreP studies become available, undoubtedly additional questions will come to the fore. The development of PreP promises to be rewarding, but challenging.

The results of the CAPRISA trial have electrified the prevention field and rejuvenated enthusiasm for an approach that several leading HIV experts had argued needed to be discarded just a few years ago. Nevertheless, much work remains to be done.

First, it is essential that the findings of CAPRISA be validated in larger studies, as the margin of error, based on the number of women in the study, ranged from 6% to 60% efficacy. The VOICE trial is currently enrolling 5,000 women in sub-Saharan Africa to a placebo-controlled study of two forms of oral PreP and a tenofovir-based vaginal gel. This study should provide more definitive information on the efficacy of topical PreP, as well as data on its relative effectiveness compared to oral PreP.

Second, it is critical that the fields of microbicides and oral PreP become better integrated. Although historically they evolved separately, combining efforts through joint conferences and working groups is the logical way to most efficiently advance the development of PreP as researchers grapple with many of the same questions. Indeed, the optimal regimen in some instances might include both topical and oral PreP.

Lastly, it is clear that PreP alone is not enough to achieve HIV prevention, in the absence of an effective vaccine. PreP needs to be tested in combination with other behavioral, socioeconomic and biomedical interventions. Coordination of efforts among the various groups conducting these studies is essential to maximize efforts and minimize redundancies as the field of HIV prevention forges ahead.