Understanding Microbicide Development

What progress is being made in the development of vaginal microbicides?

By Kristen Jill Kresge

Since the discovery of HIV nearly 35 years ago, scientists have been pursuing multiple approaches to prevent the virus from spreading. Some of these approaches are highly effective at blocking transmission and have contributed to the steady decline in the number of new HIV infections that has occurred in the past decades in many parts of the world.

In addition to adult male circumcision and risk-reduction counseling, treatment, as researchers long expected, is one of the best forms of prevention. Several studies in different populations have confirmed that if HIV-infected individuals are on suppressive antiretroviral (ARV) therapy they are as much as 96 percent less likely to transmit the virus to others. Based on these findings, the World Health Organization (WHO) now recommends that all HIV-infected individuals be offered ARV treatment at the time of their diagnosis. The organization’s previous guidelines recommended treatment commence once the individual met certain threshold criteria.

The same ARV drugs that are the crux of treatment are also an effective means of prevention when administered orally to uninfected individuals. This strategy, referred to as pre-exposure prophylaxis or PrEP, has been shown to prevent HIV infection in 12 efficacy trials involving multiple populations, including serodiscordant couples (where one person is HIV infected and the other isn’t), heterosexual men and women, men who have sex with men, injection drug users, and transgendered women. Based on the overwhelming effectiveness of PrEP when used consistently, last year the WHO recommended that PrEP be offered as an HIV prevention strategy to all individuals at substantial risk of HIV infection.

Researchers are also interested in microbicides that would deliver ARV drugs directly into the vagina in an effort to prevent sexual transmission of HIV. These ARV-based microbicides are being administered not as vaginal creams or gels that were once the mainstay of microbicide development, but rather via vaginal rings that eliminate the need to apply a gel or take a pill on a daily basis or around sex. This strategy may offer multiple advantages over some of the earlier microbicide candidates that proved unsuccessful in stopping HIV transmission.

ARVs are the way to go

For decades HIV prevention advocates, funders, and researchers viewed development of a vaginal microbicide as a priority. But several microbicide candidates tested in clinical trials failed to work. Two microbicide candidates—the spermicide Nonoxynol-9 and the HIV entry inhibitor cellulose sulfate—were actually shown to increase the risk of HIV transmission because of their disruptive effect on the genital cells that form a physical barrier to HIV particles. SAVVY, another microbicide gel candidate, was ineffective in blocking HIV transmission and was associated with a higher incidence of reproductive adverse events in a clinical trial.

In 2009, however, researchers were buoyed by the results from a clinical trial in South Africa that tested the efficacy of an ARV-based microbicide. This trial, known as CAPRISA 004, evaluated a topical gel formulation of the ARV tenofovir in nearly 900 women and found that it reduced HIV infection rates by 39 percent. At this time oral PrEP was still being evaluated so this trial provided the first positive results that an ARV-based prevention strategy HIV Orange xsectcould be effective.

Researchers then embarked on two confirmatory trials of the tenofovir gel microbicide. The FACTS 001 trial tested the same gel as CAPRISA 004 in a larger cohort of more than 2,000 South African women. Another trial, known as Vaginal and Oral Interventions to Control the Epidemic or the VOICE study, tested both oral and topical PrEP in more than 5,000 women from South Africa, Zimbabwe, and Uganda. Use of the tenofovir gel was not associated with any reduction in HIV infection rates in either of the confirmatory studies, disappointing researchers and advocates alike. The reason for the lack of efficacy was apparently that women failed to use the gels consistently. Adherence, researchers surmised, was the biggest factor in the microbicide’s failure.

Researchers were simultaneously exploring other means of administering an ARV-based microbicide, including development of vaginal rings. These rings, which have been used to deliver hormonal contraception since 2001, slowly release the drug over a month’s time, thereby eliminating the need to take a pill consistently around sex. The rings are made of a flexible silicone material and are inserted into the vagina by the woman. Results from at least one pivotal Phase III trial of a vaginal ring containing the experimental ARV dapivirine are expected in a few weeks when researchers and clinicians gather in the US city of Boston for the annual Conference on Retroviruses and Opportunistic Infections.

Dapivirine is an ARV that was not licensed for HIV treatment by its original developer (Janssen Sciences Ireland UC, formerly Tibotec Pharmaceuticals) because it isn’t absorbed well when given orally. In 2004, Tibotec granted the rights to dapivirine to the International Partnership for Microbicides, which is the organization leading one of the Phase III trials of a vaginal ring containing the drug. This study, known as the Ring Study, involves nearly 2,000 women from South African and Uganda. The other Phase III trial, ASPIRE, is being led by the Microbicide Trials Network and involves 2,600 women from Malawi, Uganda, South Africa, and Zimbabwe.

In addition to vaginal rings researchers are also investigating vaginal films—Band-Aid sized sheets that are inserted into the vagina—containing antibodies against HIV that are capable of inactivating many of the viral strains in circulation. These so-called broadly neutralizing antibodies are the types of antibodies vaccine researchers hope to be able to induce through vaccination. There are also several long-acting, injectable ARVs in development that may be a viable means of HIV prevention.

For microbicide researchers it is very clear that more HIV prevention options are still needed. According to the Joint United Nations Programme on HIV/AIDS’s 2014 Gap Report, nearly half of the 5,000 new HIV infections reported daily across the globe occur in women and girls despite the proven efficacy of oral PrEP and other HIV prevention strategies. g

Based on an article by Mary Rushton in IAVI Report, Vol. 19, Issue 4.