After N-9, what next? Several potential microbicides are poised to be tested for effectiveness in humans.

Now that the spermicide nonoxynol-9 (N-9) has been ruled out as a microbicide (1) (see article, page 18), attention has shifted to other substances that might be used topically as a protective barrier against HIV and other sexually transmitted infections (STIs). An effective vaginal microbicide would offer a desperately needed option for women at risk of HIV who cannot persuade their partners to use condoms.

More than 50 agents are being studied for their microbicide potential, and about one-third are in clinical (human) trials. (2) While a microbicide is unlikely to reach the market until after 2010, six microbicide products are expected to enter effectiveness trials--the most advanced stages of testing in humans--in 2003 and 2004, says Dr. Zeda Rosenberg, chief executive officer of the International Partnership for Microbicides (IPM) and former FHI scientific director for the HIV Prevention Trials Network (HPTN), a worldwide collaborative research program that evaluates HIV prevention interventions. The IPM was founded in 2002 to accelerate microbicide research, development, and access and has attracted nearly $100 million in support, including a $60 million grant from the Bill and Melinda Gates Foundation.

Those products nearing effectiveness trials act in different ways to prevent HIV and other STI pathogens from infecting cells. Four of them--Carraguard (carageenan, derived from red seaweed), dextrin-2-sulfate, cellulose sulfate, and PRO 2000--are sulfated or sulphonated polymers with large, negatively charged molecules that bind to pathogens or to potential host target cells forming a protective coating.

The other two microbicide candidates poised to enter effectiveness trials kill or inactivate pathogens. C31G, like N-9, damages bacterial membranes and viral envelopes. BufferGel destroys pathogens by maintaining the natural acidity of the vagina in the presence of alkaline semen.

All six compounds have shown some ability to block HIV and other sexually transmitted pathogens in test tubes or in animals. (3) Four of them may also offer protection against pregnancy. The two that do not appear to be contraceptive are Carraguard and dextrin-2-sulfate.

The six candidates have performed well in safety trials designed to detect systemic toxicity or disruption of the epithelial cells that line the vagina. (4) Such trials usually begin by studying the safety and acceptability of the compound among healthy women. Subsequent study populations represent the range of people who might use a microbicide, including HIV-positive individuals. Recognizing that anal sexual intercourse greatly increases the risk of HIV infection for both men and women, researchers are also beginning to assess the safety of rectal microbicide use.

Two of the compounds, Carraguard and dextrin-2-sulfate, have completed expanded safety trials. Results of the Carraguard trials, involving 565 women in South Africa and Thailand, are expected in May of 2003. Preliminary results of those trials and from the first 35 HIV-negative, sexually active women enrolled in an expanded safety trial of dextrin-2-sulfate at St. Francis Hospital in Kampala, Uganda, showed no adverse effects. (5) If the final results of the Uganda trial are equally positive, an effectiveness trial of dextrin-2-sulfate could begin in South Africa, Tanzania, Zambia, and Uganda in 2004. The Population Council hopes to begin an effectiveness trial of Carraguard, involving about 6,000 women in South Africa and Botswana, in 2003.

FHI and the U.S.-based CONRAD Program are also awaiting completion of data analysis--from a recent safety trial involving 54 Cameroonian women--before deciding whether to proceed to an effectiveness trial of cellulose sulfate. CONRAD plans to test the effectiveness of cellulose sulfate in a second trial in Benin, Uganda, and India, and FHI researchers are designing effectiveness trials of another compound, C31G.

HPTN plans to conduct a combined expanded safety and effectiveness trial of BufferGel and PRO 2000. The proposed study design calls for enrollment of more than 3,100 sexually active, HIV-negative women in India, Malawi, South Africa, Tanzania, the United States, Zambia, and Zimbabwe. If this design is approved by a review committee of the U.S. National Institutes of Health (NIH), which is HPTN's sponsor, the trial could begin in 2004. (FHI works with NIH, FHI's Protection of Human Subjects Committee, and local ethical review boards and community groups to ensure that its research is always conducted in compliance with U.S. regulatory requirements and international guidelines designed to protect human research participants and to ensure that study participation is equitable and free of coercion.)

In October 2002, a contraceptive effectiveness trial sponsored by the U.S. National Institute of Child Health and Human Development began enrolling 975 U.S. women who will use a diaphragm with either BufferGel or a conventional spermicide. (Contraceptives do not need to be tested for effectiveness in as many women as do microbicides because the risk of becoming pregnant when one is not using a family planning method is so much greater than the risk of acquiring HIV during each act of unprotected intercourse.) If the results show that BufferGel offers contraceptive protection equivalent to that of the spermicide, it could be sold as a contraceptive in the United States within two years.

Bringing a substance to market as a microbicide is expected to take much longer, even if any of the first-generation candidates are shown to protect against HIV in humans. Most likely, first-generation microbicides will, at best, be only partially effective.

OTHER CANDIDATES

The six leading microbicide candidates act before HIV invades a host cell. Others are being developed that will interrupt the HIV life cycle after it enters a target cell in the vagina or cervix, by inhibiting either initial replication of HIV or further spread of the infection.

One of these postinfection challengers, a topical formulation of the HIV drug tenofovir disoproxil fumarate