Wall Street Journal - July 13, 2007
Marilyn Chase, marilyn.chase@wsj.com

A $37-million clinical trial funded by the Bill and Melinda Gates Foundation in Africa showed that using diaphragms as a barrier to HIV failed to prevent infection, in the latest in a growing list of disappointments in efforts to prevent AIDS.

The Gates Foundation has long given priority to funding efforts aimed at preventing the disease's spread, rather than putting money into drug treatments for those already afflicted. Despite criticism from some in the field that money would be better spent on drugs, the foundation argues that unless the disease's spread is slowed, the tide of five million new infections a year will swamp the world's treatment capacity.

But effective new prevention methods have eluded public-health researchers. In late January, the field was stunned when a microbicide, or virus-blocking gel, also backed by the Gates Foundation failed to work in a clinical trial.

"Prevention [research] isn't a field for someone who wants a guaranteed slam dunk on the first try," said Nicholas Hellmann, interim director HIV, TB and Reproductive Health at the Gates Foundation. "But we'll come up with new technologies that will work. We're going full steam ahead."

The Gates Foundation has a $917 million portfolio of prevention projects, including providing access to proven tools such as condoms, and funding research into new technologies such as vaccines and microbicides.

In the latest setback, researchers found that volunteers using latex diaphragms along with condoms became infected about as often as those using condoms alone. The annual rate of infection was about 4% a year in the two-year study of 5,000 South African and Zimbabwean women, most of whom were married or in steady relationships. The report, by Nancy Padian, leader of the international team of researchers on the study, was published online in the journal Lancet yesterday. Dr. Padian, a professor of medicine at University of California, San Francisco, has studied AIDS since 1983.

The finding is most disappointing "for women who still can't negotiate condom use by men," Dr. Padian said in an interview. Women urgently need methods of AIDS prevention they can control themselves, commentators wrote in an opinion piece in the same issue of Lancet.

In this first major randomized controlled trial of diaphragms as a preventative, researchers had hoped the Ortho All-Flex latex diaphragms, used with lubricant, would shield the cervix from HIV. One problem was biological: diaphragms leave the vagina exposed. Another was behavioral: Despite instructions to use dual protection, the diaphragm users reported lower condom use by their partners.

Of 25 major randomized controlled trials to test different ways to prevent HIV transmission, funded by a variety of sponsors, 19 studies showed no effect, the report notes. Among recent trials, only male circumcision and treating sexually transmitted infections seem to help prevent HIV infection.

Using AIDS drugs during childbirth to prevent mother-to-baby transmission has also had promising results. Now, condoms and abstinence programs are the main tools promoted for preventing HIV/AIDS, which affects nearly 40 million people world-wide.

Until there is a vaccine -- which could be a decade away -- hopes are focused on increasing the practice of male circumcision in poor countries, and on the continuing trial of Gilead Inc. pills Viread and Truvada now being tested in Africa, Asia, the U.S. and Latin America to see whether they can prevent HIV infection.

Male circumcision has recently been shown to reduce risk to men by helping reduce the incidence of inflammations and lesions that increase vulnerability to the HIV virus among men in resource-poor areas.

But circumcision faces cultural and religious barriers. It also requires surgical sterility and weeks of post-operative abstinence to avoid exacerbating risks of infection. Internationally, health officials are still conferring on best practices for expanding opportunities for men at risk to become circumcised.

A potential prevention pill is tricky too, due to concerns it might undermine other "safe sex" efforts.

Scientists said separately in this week's issue of the journal Nature that the field of AIDS prevention can't afford more negative results. "The microbicide field is drinking at the last-chance saloon," John Moore of the Weill Cornell Medical College in New York said in an article in the issue addressing a dispute over the design of a new microbicide trial in South Africa. "If it has many more problems, it's finished."

Microbicides were the talk of an August AIDS conference in Toronto, where Bill Gates and Bill Clinton touted their promise. But in January, a Gates-funded trial of microbicide gel for women was pulled from study after an analysis found more women became infected while using it than a placebo.

It harked back to the failure years earlier of nonoxynol-9, a spermicide that ended up increasing the risk of women contracting HIV because it inflamed cells of the reproductive tract, accelerating infection. Other microbicide tests may yield results this year.

The negative results also raise broad questions about the design of prevention studies. To be ethical to the participants, trials must offer all volunteers condoms -- which have been shown effective in blocking HIV, as well as the methods being tested.

But it is hard to tease out effects of the diaphragm or other tools from the effect of condoms. Finally, prevention trials rely on sticking to a behavior change, which is hard to enforce and test. Rates of condom and diaphragm usage couldn't be objectively confirmed by researchers, who relied on statements of the volunteers themselves.

In Seattle, University of Washington Medical Professor Judith Wasserheit said, "I wouldn't characterize this as the last gasp in AIDS prevention." While not affiliated with the diaphragm study, she serves as vice chair of the university's new department of global health, which is jointly funded by the Gates Foundation and Washington state.

Dr. Wasserheit said studies of new AIDS vaccines by Merck & Co. and the National Institutes of Health are now starting to resuscitate some hope, as have tests to see if treating herpes -- which involves lesions that increase vulnerability -- can help prevent AIDS infection and transmission.

Even hope for diaphragms as a preventative isn't dead yet, insists Christopher Elias president of PATH, the Seattle-based non-profit developing a diaphragm made of a lavender-colored, smooth silicone designed to be easy to use, without requiring the fittings of traditional diaphragms.

"If you have one negative trial of an ulcer drug," Dr. Elias reasons, "you don't give up on ulcer drugs."

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