Microbicides

A microbicide is a topical agent that, when applied to a mucosal surface, serves as a barrier to infection. Microbicides can come in the form of a gel, cream, foam, or ring and have various mechanisms of action.

Microbicides can be developed that protect against HIV, against other sexually transmitted infections, and against conception. The microbicides discussed here all have the main goal of preventing transmission of HIV from either vaginal or rectal contact.

Microbicides for anal use may need to have entirely different formulations as the area of mucosal tissue at risk in the rectum is much larger and is open-ended rather than a closed space as in the vagina.

The first generation of microbicides to be developed did not contain antiretroviral drugs, and used a variety of mechanisms to block infection, including raising the acidity of the vagina to limit viral survival or blocking viral cell entry. A number of products, inclduing UsherCell (cellulose sulphate) and Carraguard, have now failed to demonstrate efficacy in large clinical trials, making many researchers pessimistic about the prospect for a non-ARV containing microbicide.^{1 2}

PRO 2000 (naphthalene sulphonate polymer) is a hybrid product combining a buffering agent and an entry inhibitor. This product may also protect against gonorrhoea, herpes, and chlamydia and is safe to use with a condom or diaphragm. A study of over 3000 women in Malawi, South Africa, Zambia, Zimbabwe and the USA reported in 2009,³ and found that PRO 2000 prevented about a third of potential infections in women who used it, compared with women who used a placebo gel or no gel at all. However these results were not statistically significant.

The fact that, despite these modest results, microbicide campaigners were buoyed up by the result is a measure of how disappointing trial results have been in recent years. A larger study of PRO 2000 is due to announce results later in 2009 and will be able to demonstrate efficacy if they find similar reductions in the HIV infection rate.

The second generation of microbicides in development are products that contain antiretroviral drugs in a gel formulation. They are also described as 'topical PrEP', as they use existing antiretroviral drugs whose oral formulations are also being tested for use as pre-exposure prophylaxis.

Women who use non-ARV containing drugs will need to undergo HIV testing regularly in order to minimise the risk of exposure of an infected person to antiretroviral drugs. Leakage of the drug from the vagina into the bloodstream is a crucial issue for antiretroviral-containing microbicides, as the biggest safety concern surrounding these compounds is whether women using them who are HIV-positive but undiagnosed, or who acquire HIV despite using them, could develop drug resistance. One possible solution would be to use combination antiretrovirals in the microbicide.

There are three major programmes of trials which will lead up to phase IIb/III efficacy trials of antiretroviral-containing microbicides for vaginal use:

• First to report will be the CAPRISA 004 study of 1% tenofovir gel in 980 women at two sites in KwaZulu Natal, South Africa. This is the only study looking at ‘coitally-dependent’ use, in which women are told only to use the gel when they think they will have sex. The study may report in 2010. 
• The VOICE (Vaginal and Oral Interventions to Control the Epidemic) study is a trial which, as its name suggests, will directly compare a tenofovir gel with oral tenofovir pre-exposure prophylaxis in 4200 women at 10 sites in South Africa, Malawi, Uganda, Zambia and Zimbabwe. This may report by 2011.
• The International Partnership for Microbicides is co-ordinating a series of studies largely in Africa but also in the USA and Belgium, using the NNRTI dapivirine (TMC120) both as a gel and as drug infused into a silicone vaginal ring which can be left in place for a month: the phase III gel study (IPM 009) is at the planning stage, while the timing of the vaginal ring studies depends on preliminary safety and formulation studies. Study 009 may report by 2012/13.
• In addition to these vaginal studies, there is the U-19 programme using the NNRTI UC-781 as a rectal microbicide.

Further into the future, the International Partnership for Microbicides has negotiated licensing agreements with drug companies to develop the CCR5 inhibitors maraviroc and MRK167 as microbicides.