Microbicides for sexually transmitted infections

Mechanisms of action

Detergent and surfactant microbicides, such as nonoxynol-9, sodium dodecyl sulfate, and Savvy (1.0% C31G), disrupt the viral envelope, capsid, or lipid membrane of microorganisms. However, these agents also kill host cells and impair mucosal barrier function, and clinical trials have not shown them to be effective against HIV transmission; testing of this class has largely been discontinued. Another class of microbicides works by lowering vaginal pH to kill or inactivate pathogens; BufferGel is one such agent that maintains the natural acidity of the vagina, but candidates in this category have proven ineffective in preventing HIV infection.

Polyanion microbicides, including carrageenans, act as decoy receptors for viral binding because many microbes use heparan sulfate for initial attachment. Carrageenan preparations like 0.5% PRO 2000 and 3% Carraguard have failed to demonstrate efficacy in preventing HIV transmission in phase III trials; PRO 2000 was safe but did not reduce HIV risk in women, and Carraguard was also safe but ineffective.

Formulations

First-generation microbicides were mostly semi-solid systems such as gels, tablets, films, or creams applied vaginally before intercourse. Vaginal rings offer long-term controlled release, requiring replacement only once a month, which could improve proper use; in 2010, the International Partnership for Microbicides began the first study in Africa testing a dapivirine-containing vaginal ring. Systemic administration through injectable or oral formulations, known as PrEP, is also being explored; injectable forms might be given monthly but require close monitoring and carry a risk of ARV-resistant HIV strains.

Many men who have sex with men in developed countries already use lubricants containing nonoxynol-9, suggesting receptivity to rectal microbicides, but development of rectal products lags behind vaginal ones because the rectum has a thinner epithelium, greater surface area, and lower elasticity. In January 2010, the National Institutes of Health awarded $17.5 million to the University of Pittsburgh for rectal microbicide research, including acceptability studies with homosexual men aged 18 to 30.

Successful topical microbicides may eventually combine multiple modes of action, and long-acting formulations like vaginal rings could deliver several active ingredients.

Completed clinical trials

A major breakthrough occurred in July 2010 when the Centre for the AIDS Programme of Research in South Africa (CAPRISA) announced that an ARV-based microbicide gel partially prevented HIV. The CAPRISA 004 trial, conducted among 889 women in South Africa, evaluated 1% tenofovir gel for preventing male-to-female HIV transmission. The study found a 39% lower HIV infection rate in women using tenofovir gel compared with placebo; 38 women using the gel acquired HIV versus 60 using placebo.

No tenofovir-resistant virus was detected in those who became infected. The gel also provided 51% protection against herpes simplex virus type 2 (HSV-2), a lifelong infection that increases HIV risk two-to-three times. Tenofovir is a nucleotide reverse-transcriptase inhibitor (NRTI) developed by Gilead Sciences, approved in tablet form for HIV treatment. CAPRISA 004 was a collaboration among CAPRISA, Family Health International, and CONRAD, funded by USAID and the South African Department of Science and Technology's Technology Innovation Agency.

Current research

Efforts continue to develop safe and effective topical microbicides, with several gel formulations in phase III efficacy trials and about two dozen other products in earlier phases. The CAPRISA 004 results may need confirmation by other trials before tenofovir gel is made available to the public, with regulators, particularly in South Africa, making that decision. In 2013, the VOICE study (MTN 003) is scheduled to release results; it is evaluating three HIV prevention strategies in women: one ARV-based microbicide and two daily oral ARV regimens, testing 1% tenofovir vaginal gel in a once-daily formulation.

Pre-Exposure Prophylaxis (PrEP) products, administered orally or by injection, are also being tested; they contain ARVs to protect HIV-negative people before exposure, offering autonomous use not dependent on timing of sex. Current PrEP candidates include tenofovir and Truvada (tenofovir and emtricitabine). A potential risk of PrEP is that systemic drugs might create ARV-resistant HIV strains over time.

Did You Know?

• Some sub-Saharan African cultures view vaginal lubrication as undesirable, which may pose a barrier to microbicide implementation.
• Condoms are effective against most STIs but not HPV, and social factors like sexual disempowerment of women limit their use.