HIV This Week

Cutler B, Justman J. Vaginal microbicides and the prevention of HIV transmission. Lancet Infect Dis. 2008;8(11):685-97.

Worldwide, nearly half of all individuals living with HIV are now women, who acquire the virus largely by heterosexual exposure. With an HIV vaccine likely to be years away, topical microbicide formulations applied vaginally or rectally are being investigated as another strategy for HIV prevention. A review of preclinical and clinical research on the development of microbicides formulated to prevent vaginal HIV transmission yielded 118 studies: 73 preclinical and 45 clinical. Preclinical research included in-vitro assays and cervical explant models, as well as animal models. Clinical research included phase I and II/IIb safety studies, and phase III efficacy studies. Whereas most phase I and phase II clinical trials have found microbicide compounds to be safe and well tolerated , phase III trials completed to date have not demonstrated efficacy in preventing HIV transmission. Topical microbicides are grouped into five classes of agents, based on where they disrupt the pathway of sexual transmission of HIV. These classes include surfactants/membrane disruptors, vaginal milieu protectors, viral entry inhibitors, reverse transcriptase inhibitors, and a fifth group whose mechanism is unknown. The trajectory of microbicide development has been toward agents that block more specific virus-host cell interactions. Microbicide clinical trials face scientifically and ethically complex issues, such as the choice of placebo gel, the potential for viral resistance, and the inclusion of HIV-infected participants. Assessment of combination agents will most likely advance this field of research.

Editors’ note: This excellent review was conducted before the results of the HPTN035 PRO 2000 trial were announced in February. This phase II/IIb safety/test of concept trial found a statistically non-significant but encouraging 30% protection for women in the experimental arm using the sulfonated polymer naphthalene sulfonate gel (0.5% PRO 2000). Sub-analyses revealed a strong dose-response relationship with the best protection seen in high gel, low condom users. Through their negative charge, anionic polymers interact with HIV’s envelope proteins, interfering with the attachment of HIV to CD4+ cells. A pivotal phase III efficacy trial, the UK Microbicide Development Programme’s MDP-301 trial of 0.5% PRO 2000 involving 9673 women is expected to report findings in late 2009/early 2010 that may confirm or contradict the HPTN035 results. These are interesting days in the microbicide world.