What is a microbicide?

An International Working Group on Microbicides (IWGM), which has sought to stimulate research and build consensus on future directions, was set up in 1994. IWGM is an inter-agency coordinating body which works to facilitate the development and approval of safe, effective, affordable and acceptable microbicides to prevent the sexual transmission of HIV and other STIs.

Advocacy has been pursued by the Global Campaign for Microbicides (http://www.global-campaign.org/) which is mobilising agencies and individuals concerned for women's health and HIV/AIDS together with International Family Health and other partners including the UK's National AIDS Trust (Forbes).

The need for a microbicide received powerful endorsement in the 2001 declaration issued by the UN General Assembly Special Session on AIDS.

There are many barriers to the development of a successful microbicide. To maximise access, a product would need to be sold cheaply or distributed widely without medical supervision. This militates against the involvement of major research-based pharmaceutical companies that are geared to developing prescription medicines. There has been even less private investment in microbicides than in vaccines. A lobbying group, the Alliance for Microbicide Development, brings together those companies that are involved with interested scientists and activists. It monitors the progress of microbicide projects that are being pursued by research groups and biotech companies and produces regular surveys of the state of the field (http://www.microbicide.org/).

Microbicide research has mainly been pursued by academic and charitable organisations, and a few small companies. The main funders have been the US National Institutes of Health (Reichelderfer) and private philanthropists, although increasing interest is being shown by other governments and the European Commission. The UK's Department for International Development and the Swedish International Development Agency have both funded work. Private funding has come from the Gates Foundation, the American Foundation for AIDS Research and the Rockefeller Foundation among others.

By 2002, the Rockefeller Foundation - an early supporter of the International AIDS Vaccine Initiative - had ushered a comparable new agency, the International Partnership for Microbicides, into being. IPM, headed by Dr Zeda Rosenberg and based in the USA, is setting out to create public-private partnerships to expand the pipeline of products in development, ultimately licensing them to industry in return for guarantees of access for users in developing countries. Early funding has included US $15 million from the Rockefeller Foundation and $60 million from the Bill and Melinda Gates Foundation, together with governmental support from Denmark, Ireland, the Netherlands, Norway and the UK (http://www.ipm-microbicides.org/).

The microbicide development process

The earliest stages of microbicide development can be carried out in cell cultures and small animals. Increasingly elaborate models of the tissues that are exposed to HIV containing a mixture of different cell types, some vulnerable to HIV, are being constructed.

CONRAD and the Global Microbicides Project (http://www.gmp.org/) have collaborated on a screening system with investigators at the Pennsylvania State College of Medicine. This uses cell-cultures to test the ability of microbicides to interfere with binding by two distinct strains of HIV-1, one binding to CXCR4 and one to CCR5 receptors. It tests cell-free virus inhibition and cell-to-cell transfer of HIV. It also tests mammalian cell toxicity. Compounds that pass all of these tests are then assessed for their ability to protect human peripheral blood monocytes from clinical strains of HIV. It is then possible to use a wider range of tests to measure possible protection against other (non-HIV) pathogens, before taking products forwards into clinical trials (Claypool).

Mice are susceptible to herpes (HSV-2) and this can be used for studies of broad-spectrum microbicide candidates. Another mouse model has been developed, using immunodeficient animals implanted with human vaginal tissues and allowed to heal (Kish). Some studies have been carried out in female monkeys, using HIV-related virus strains developed for vaccine research.

The two basic questions throughout the process of development:

• is it safe or does it damage healthy tissue?
• can it prevent HIV or other microbes from entering the body?

Phase I and Phase II trials of microbicides address the first of these questions. Initially, a small number of low-risk women, abstaining from sex, are asked to volunteer to expose themselves to the substance and report any reactions they suspect may be related to it. Increasingly detailed protocols have been developed for vaginal and cervical examinations, including standardised systems for reporting injuries and inflammation.

Studies of the safety of microbicides for anal use may be justified at an early stage although for protection, it may be necessary 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.

Can early clinical evaluation be accelerated? A three-day dosing schedule and a seven-day dosing schedule have been compared for C31G, a candidate microbicide that was compared to N-9 and found to be more irritating. Unfortunately, N-9 itself is now considered unacceptable, so any test which makes it look good is of limited value (Bax).

In the later stages of these trials, women who are sexually active with regular partners may be enrolled, along with their partners.

Discussion of efficacy trials for microbicides has emphasised their potential value in protecting HIV- negative women from infection by men, but the fact that they would be used by HIV-positive women must be considered in designing clinical trials. Involvement of HIV-positive people in these early tests of the safety of the product is therefore important.

Where microbicide trials differ from vaccine trials and even drug efficacy trials is that there is no obvious 'surrogate marker' for efficacy, in line with immune responses that can be measured for a vaccine or blood levels of a drug that can be compared with those that block the virus in cell cultures.

For this reason, microbicides need to progress relatively early to full-scale ('Phase III') trials of their effectiveness.

Phase III trials of microbicides (to test efficacy) are complex and expensive, and raise many of the same ethical issues as preventive vaccine trials. Microbicides must be provided alongside and in combination with other means of protection, including counselling, condom provision and medical treatment of infections. The COL-1492 study, greeted with dismay because it showed nonoxynol-9 did not work, showed admirably that these challenges can be met.

There is a full review of the issues raised by such trials in Elias (see references).

References

Bax R et al. Use of a rapid screening study to predict long term tolerance.  XIV International AIDS Conference, Barcelona, abstract TuPeF5305, 2002.

Carballo-Dieguez A et al. Frequent use of lubricants for anal sex among men who have sex with men: the HIV prevention potential of a microbicidal gel. American Journal of Public Health, 90: 1117-1121, 1999.

Claypool LE et al. Evaluating the in vitro anti-HIV-1 activity and cytotoxicity of compounds for potential use in topical microbicides: the CONRAD/GMP algorithm. XIV International AIDS Conference, Barcelona, abstract MoPeD3649, 2002.

Elias L et al. Challenges for the development of female-controlled vaginal microbicides. AIDS 8: 1-9, 1994.

Forbes AS. Microbicide advocacy and mobilization: three models from the global north.  XIV International AIDS Conference, Barcelona, abstract MoPeG4270, 2002.

Kish TM et al. Human Immunodeficiency Virus-1 Infection in Human Vaginal Xenografts in a Small Animal Model. XIV International AIDS Conference, Barcelona, abstract MoPeA3045, 2002.

Mayer KH. Methodological challenges in the evaluation of rectal microbicides. Microbicides 2002, Antwerp(http://www.itg.be/micro2002/downloads/presentations/3Tuesday_May_14_2002/Track_B_sessions/Kenneth_Mayer.pdf)

Population Council and International Family Health. The case for microbicides: a global priority. New York and London, 2000.

Ramjee G et al. Challenges in the conduct of vaginal microbicide effectiveness trials in the developing world. AIDS 14: 2553-2557, 2000.

Reichelderfer PS et al. National Institutes of Health microbicide development. XIV International AIDS Conference, Barcelona, abstract TuPeF5304, 2002.

Rosenberg Z. The International Partnership for Microbicides. Microbicides 2002, Antwerp (http://www.itg.be/micro2002/downloads/presentations/3Tuesday_May_14_2002/FHI_Rockefeller_Foundation_Symposium/Zeda_Rosenberg.pdf), 2002.

Watts C et al. The public health and economic benefits of microbicide introduction: model projections. XIV International AIDS Conference, Barcelona, abstract TuPeF5307, 2002.