The Facts About HIV Microbicides

Dapivirine intravaginal ring. Courtesy Microbicide Trials Network (MTN)

You would think that it would be a simple thing to do: create a topical gel or cream that you could apply before sexual intercourse to effectively kill HIV on contact. After all, if something like nonoxynol-9 can reduce the risk of pregnancy by killing sperm, how difficult could it be to develop something for HIV, right?

The truth is that the development of microbicidal agents has been fraught with challenges and complications since it was first proposed more than 25 years ago. In some cases, the agent's ability to disable HIV has inadvertently led to the deterioration of mucosal tissues of the vagina or rectum—facilitating rather than preventing HIV transmission.

In other cases, the agents were simply ineffective in preventing HIV infection or resulted in intolerable side effects for those on treatment.

To date, there is no HIV microbicide either available or recommended for use. However, a significant number of candidates are being actively researched, including a tenofovir-based gel, long-acting intravaginal rings, and rectal microbicides.

Why Are Microbicides Considered Important?

Microbicides are neither envisioned to replace condoms nor supplant safer sex practices, but rather to provide an additional protective barrier during sex—particularly in anal-receptive or vaginal-receptive intercourse where transmission risk is higher.

However, from an even broader picture, microbicides are seen as means by which to reduce the spread of HIV among people who are most at risk. These include women who are vulnerable to sexual violence or abuse, or for whom sexual abstinence is simply not realistic (either because of the desire to bear children, or cultural constraints that limits their autonomy and power).

It is envisaged that microbicides might eventually be able to provide women-at-risk an effective means of self-protection while affording users an added safeguard should a condom burst or slip off during intercourse.

Early Setbacks in Microbicidal Research

Much of the early microbicidal research focused on the use of either detergents or agents that could alter the vaginal pH to effectively kill (or inactive) HIV.

Among the earliest candidates was the aforementioned nonoxynol-9, an organic surfactant used both as a spermicide and in facial/sports creams. Alarmingly, a meta-analysis conducted in 2002 concluded that the use of nonoxynol-9 actually increased the risk of HIV in women by some 50%, with higher incidences of vaginal lesions contributing to the risk.

Other agents designed to maintain high, protective vaginal acidity (including the much-researched BufferGel) were shown to be well tolerated in women, but ultimately demonstrated no reduction in HIV transmissions.

Strategies for Development

There are a number of possible approaches to the development of an effective HIV microbicide, which can be broken down into two general categories.

The first can be classified as non-antiretroviral microbicides, the agents of which either act as decoy receptors to HIV (preventing the attachment of the virus to target cells of the vagina) or utilize macromolecules called dendrimers that actively bind to HIV to prevent infection.

While early efforts have proven largely unsuccessful (PRO 2000, Carraguard, cellulose sulphate), a number of newer agents are being explored—including the dendrimer microbicide VivaGel, and the synergistic use of dendrimers and the CCR5 entry inhibitor Selzentry (maraviroc) used in combination antiretroviral therapy (ART).

The second, and arguably more prominent, category are antiretroviral microbicides. The development of these agents is based on research into the use of tenofovir and other antiretroviral drugs in topical gels, rings, lubricants, and other delivery systems.

The CAPRISA 004 Study in 2010 was the first to demonstrate the effectiveness of the approach, employing the use of 1% tenofovir gel before and after vaginal sex in 889 HIV-negative women. Overall, infection rates were reduced by 39 percent in the non-placebo group, while participants with high levels of adherence (greater than 80 percent) had a 54 percent reduction.

By contrast, the VOICE Trial was seen as something of a setback. Following on the heels of CAPRISA, the Voice Trial studied the two different HIV prevention models—the daily use of an antiretroviral drug (either Viread or Truvada) or the daily use of a tenofovir gel—in 5,029 women. The trial was terminated when none of the methods were found to be effective.

The post-study analysis determined that the failure was due not to the therapies, but to a widespread lack of adherence among participants (especially among young, unmarried women). Further research will help better elucidate the behavioral causes.

The Way Forward

Following the setback of the VOICE trial, an aggressive push was made to explore alternative approaches to the development of microbicidal agents. Results have been largely mixed. Among the Phase II and III trial recently completed:

  • The FACT 001 Trial, which recruited 2,900 women in South Africa, provided participants the same regimen as that used the CAPRISA 004 (1% tenofovir gel before and after sex). According to the post-trial results, there was no reduction in the number of HIV infections among users.
  • The ASPIRE (MTN-020) evaluated the efficacy of an intravaginal ring containing dapivrine (a highly potent, experimental antiretroviral drug) when used for a period of one month in 3,476 women in Africa. Results in 2015 demonstrated an overall 27 percent reduction in HIV risk among women using the dapivirine ring, primarily in women over the age of 21. Little or no protection was seen in women under the age of 21, primarily due to inconsistent usage of the device.
  • Similarly, the RING (IPM 027) Study also investigates the dapivirine ring in 1,650 women in Uganda and South Africa in a randomized, Phase III trial. Participants will use their rings for a period of two years. Results were slightly better than those seen in the ASPIRE study, with an overall reduction of 37%. Again, results were better among women aged 21 and over. No benefits were seen in women aged 18-21.
  • Meanwhile, the MTN 017 will explore the use of a tenofovir-based rectal gel alongside the daily use of Truvada in a group of 186 men who have sex with men (MSM) and transgendered women. The Phase II study was conducted over eight weeks, with high levels the acceptability and adherence to the multi-pronged regimen.Future studies will likely focus on the efficacy and usage of the rectal gel a means of protection before and after sex.
  • Finally, in March 2014, an animal study conducted by the Centers for Disease Control and Prevention (CDC) showed that a topical gel using the antiretroviral Isentress (ratelgravir) might effectively prevent HIV infection in women after sexual exposure. No word yet on whether the study will be expanded beyond the current proof of concept.

Other facets of research are investigating the development of paper-thin, quick-dissolving vaginal films, as well as various antiretroviral formulations (or co-formulations) for topical gels or rings.

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Article Sources

  • Abdool Karim, Q.; Abdool Karim, S.; Frohlich, J.; et al. "Effectiveness and Safety Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women."Science. September 3, 2010; 329(5996):1168-1174.
  • Dobard, C.; Sharma, S.; Parikh, U.; et al. "Postexposure Protection of Macaques from Vaginal SHIV Infection by Topical Integrase Inhibitors." Science Translational Medicine. March 12, 2014. 6(227):227ra35.
  • Microbicide Trials Network (MTN). "About Microbicides Fact Sheet: Microbicide Trials Network." Pittsburgh, Pennsylvania. Fact sheet issued March 25, 2014.