American Foundation for AIDS Research, April 2003
Kristen Kresge

"People started calling me the diaphragm lady," remarked Nancy Padian, Director of International Programs at the University of California, San Francisco's AIDS Research Institute. Padian spent much of the last eight years on a spirited quest to study diaphragms' power to prevent HIV transmission. With tens of millions in new funding for trials, she is no longer so easily dismissed.

Women for decades have carried around rubber diaphragms in their handbags as a convenient and unobtrusive barrier method of birth control. This old mainstay maynow have a promising new role in the global fight against HIV. Vaccine researchers may view this as a reversion to the Stone Age, but Padian finds it intriguing. "The fact that you have an approved device that might be preventive … it's sort of elegantly simple," she said.

A properly fitted standard diaphragm costs about $25, and an experimental one-size-fits-all version will cut the price dramatically. Once positioned over a woman's cervix, the diaphragm can comfortably remain in place for an entire day and protect during repeated sexual acts. A diaphragm can also be used without sexual interruptions or the partner's knowledge. This becomes especially useful among sex workers in Africa and other regions where women are paid less if a protective device is used.

Padian hopes that the diaphragm will reduce HIV infection rates by 30% or more, the same goal sought for the first HIV vaccines, which are years away from practical use. Even this low rate of protection could have a major impact on HIV's spread.

Padian considers the female condom, the only other attempt at creating barrier prevention for women as highly disappointing. This barrier device fails as a good alternative to the male condom because it requires cooperation from the woman's partner. Female condoms are also quite expensive for women in developing countries because they cannot be reused. How much protection the female condom providesBesides, amount protection they provide is still unknown.

The Research Jackpot
Funding agencies initially dismissed the idea that women would be willing to use a diaphragm, even if proven effective in preventing HIV transmission. Finally, CONRAD, a small contraception research agency based at the Eastern Virginia Medical School, supported Padian's pilot study in Zimbabwe to measure women's willingness to use the diaphragm. In that country, HIV infects an estimated 34% of adults aged 15 to 49. Padian presented this study's results at the XIV International AIDS Conference last summer in Barcelona.

Zimbabwean women first took part in a two-month program to encourage and teach male condom use. Those still unable to convince their partners to regularly employ condoms were enrolled in the diaphragm acceptability phase. Padian found that 98% of the 156 women in this study were willing to use the diaphragm as an alternative method, knowing that its effectiveness against HIV remains undetermined. Only 1% of the women in the study had ever used a diaphragm before.

That preliminary study paid off. At the end of the summer, Padian's proposed diaphragm efficacy trial in southern Africa received $28 million in funding from the Bill & Melinda Gates Foundation. One reason that the Gates Foundation grew interested in the diaphragm's benefits was its own focus on preventing the spread of the disease. The foundation released a report at the International AIDS Conference this summer detailing a comprehensive plan to prevent 29 million HIV infections by 2010. Padian received the bulk of the funds made available to investigate available technologies.

Padian, who is a major recipient of National Institutes of Health funding for other projects, could never obtain government backing for diaphragm research. "The simplistic approach to an AIDS problem is not looked at with great enthusiasm," said AIDS pioneer Dr. Jay Levy, a colleague of Padian's at the University of California, San Francisco. "It was too simple for the NIH to sponsor. The Gates Foundation listened and agreed to give it its day in court."

The study itself is hardly simple. Collecting enough data to analyze the diaphragm's influence on HIV transmission will take at least four years. Padian's trial will follow 4,500 women at two sites in South Africa and one in Zimbabwe. It will last four years, with participants randomized to either the control group or the diaphragm group. Both groups will receive safe sex/condom counseling to satisfy ethical concerns.

Since the condom is the most effective prevention tool available, Padian does not want the diaphragm perceived as its replacement. "I don't think we're looking for just one prevention device," said Padian. The ethically necessary safe sex counseling, which promotes condom use even as the diaphragm is tested, will complicate and further retard the data analysis.

A nettlesome analytical issue will arise if members of the trial's control group utilize condoms more often than the diaphragm group. This will weaken diaphragms' observed effect. Then too, the study must rely on information provided by the participants to determine the results, which decreases its analytical precision. Some women may report using a diaphragm when they did not or some may use a condom and a diaphragm together without mentioning this dual use.

"There are many things that make these trials difficult to show what they're trying to show, even if they work," said Thomas Moench, the Medical Director of the microbicide research firm ReProtect in Baltimore. "You could have 40 or 50 percent prevention with the diaphragm and the study wouldn't show it."

The Original Science
The cervix has long been identified as a focal point for sexually transmitted disease. Although they can shift during sex and leave the cervix exposed, diaphragms usually block fluids from ever reaching the cervix or the upper genital tract. Researchers have found that diaphragms offer strong protection against chlamydia and gonorrhea, which may be due to the associated spermicide as well as to the physical barrier that diaphragms provide.

The concept of employing diaphragms against AIDS was an extension of these observations. Jay Levy first proposed the idea back in 1989. Levy's laboratory was studying the transmission of HIV from men to women. He found that a woman's cervix, and not her vagina, is probably the most susceptible location for infection during heterosexual transmission.

He also found that a main source of infection was not free-floating virus in semen, but cells already infected by HIV. For these HIV-infected cells to infect the woman, Levy knew they had to come into contact with immune cells.

Cervical tissue is full of immune cells, much more so than vaginal tissue. Levy observed that it was also easy for the HIV-infected cells to reach the cervical immune cells because the cervix has a very fragile and thin lining. Also, contractions that occur during sex cause fluids to be drawn up into the uterus and upper genital track, another vulnerable region.

It makes sense that the majority of women with HIV contract the virus through the cervix, and the diaphragm's ability to block the cervix should offer protection. "I'm fairly certain there will be an effect," Levy predicted.

Levy called the cervix the "hot spot" for transmission of HIV, but it is not the only place where infection can occur. Thomas Moench pointed out that female monkeys can still contract HIV even if they have had complete hysterectomies.

"Transmission can occur across the vagina, but the vagina is kind of like skin – it's made of many layers of cells. The cervix is very fragile. It's most susceptible," said Moench.

Bolstering the Diaphragm
No one expects the diaphragm to be as protective as the condom. Condoms are the most proven method available for protection against HIV and AIDS, with an efficacy rate estimated by several studies to be 90% to 95%. Getting people to incorporate them into their sex lives has been the big problem.

Moench says that in the United States, condom use occurs in less than 15% of heterosexual sex. It is dramatically lower in countries where infection rates are higher. The Joint United Nations Programme on HIV/AIDS claims that condom use is below 5% in hard-hit Botswana, where 40% of all adults aged 15 to 49 are infected with HIV.

"This epidemic would be over if we didn't have problems with condom acceptability. Condoms are the best thing we've got," said Moench. "But we need a method women can control themselves."

Moench worries that many people will trade in the safer condom for the more convenient diaphragm if the trial results are good, a trend that he refers to as "condom migration." Conversely, he wonders whether the public will dismiss the diaphragm entirely if the desired protective effect is not evident. This could have an unwelcome impact on microbicide research.

He foresees combining microbicides and diaphragms as the ultimate protection strategy for women. But because a female-controlled device is urgently needed, Padian does not want to wait until a microbicide receives approval.

"It's proven difficult to get at this in a way that's satisfying to everyone," Moench remarked. "One is more likely to work [diaphragm with microbicide] and one is simpler [just diaphragm]. But it could be years until a microbicide is approved. That's driving them to want to explore the diaphragm by itself."

Moench agreed that diaphragms are a sound option for women who cannot convince their partners to regularly use condoms. "You don't have to be going after 100% efficacy. A partially effective strategy, used widely, could be tremendously beneficial."

As Padian works out the final design of the study, both she and Levy remain confident that the diaphragm will show significant protection against HIV. "I think it will work. We're hoping for a 30% to 40% effect, but we may do even better," said Levy.

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