Capping Infection

An ongoing clinical trial is testing whether the contraceptive diaphragm can help lower women's risk of HIV infection

By Sheri Fink, MD, PhD*

An old-fashioned birth control method, the diaphragm, could one day soon make a comeback as a woman-controlled HIV prevention method. That's the hope of researchers conducting a randomized, controlled HIV prevention study funded by the Bill and Melinda Gates Foundation and known as Methods for Improving Reproductive Health in Africa (MIRA) that has enrolled women in Harare, Zimbabwe and in Durban and Johannesburg, South Africa. Investigators from the University of California at San Francisco (UCSF), University of Zimbabwe, Ibis Reproductive Health, Medical Research Council of South Africa, and the Perinatal HIV Research Unit of South Africa are assessing whether latex diaphragms used during intercourse can protect women from contracting HIV.

"Biologically, it's very plausible that it will work," says MIRA Principal Investigator Nancy Padian. Contraceptive diaphragms cover the cervix, the lower opening of the uterus, and prevent access to the upper genital tract, both thought to be key sites of entry for HIV. Cervical tissue is much thinner than vaginal tissue and observational studies have suggested that other sexually-transmitted pathogens, including those causing gonorrhea and chlamydia, preferentially infect cervical as opposed to vaginal cells and that diaphragms used with spermicide can prevent the transmission of some sexually-transmitted infections (STIs). Analogous to the male foreskin, the cervix also contains some of the same target cells for HIV-Langerhans cells, a type of antigen-presenting dendritic cell. A recent prospective study in South Africa showed that male circumcision removing the foreskin may significantly reduce men's chances of acquiring HIV.

Although women can still acquire HIV after hysterectomy, these other findings suggest that shielding the cervix with a diaphragm might lower the risk of a woman contracting the virus. In addition, because relatively high amounts of HIV are shed by cervical cells, covering the cervix during intercourse might decrease a woman's infectiousness if she already has HIV.

Current prevention methods fall short

With effective AIDS vaccines and microbicides still years away, male and female condoms remain the most reliable method for HIV prevention. But condom use remains extremely low-one study in the US found that condoms were used consistently during heterosexual intercourse only about 19% of the time. Female condoms, comparable in efficacy to the male condom in preventing STIs other than HIV and on the market for more than a decade, have been inadequately supplied and adopted-in 2005, only 14 million female condoms were available worldwide, compared with 6 to 9 billion male condoms.

Male circumcision is showing some promise in trials as an HIV prevention method but, even if proven effective, will require years to implement widely. Female-initiated methods are seen as particularly important in light of the fact that young, married women are the fastest-growing group of new HIV infections in many countries, and they often have difficulty negotiating condom use. Both HIV professionals and at-risk populations have shown a keen interest in expanding HIV prevention options, particularly those that are woman-controlled and already approved for use.

The diaphragm fits both of these criteria but its low usage worldwide and its labor-intensive initial fitting process cast doubt on whether women and health care providers will find the method acceptable. In the US and other countries where oral hormonal contraceptives are affordable and widely available, diaphragms have fallen out of favor as a birth control method. In 1995 only 2% of contraceptive users between the ages of 15 and 44 in the US used the method. Standard diaphragms come in nine different sizes and must be fitted in a health clinic and inserted prior to intercourse. Many health care providers stopped recommending them. "There's somewhat of a provider bias," says Padian. "Health care providers assume women won't use them."

Padian's recent research, however, has been finding the opposite. "They're highly acceptable," she says. Her group conducted a six-month diaphragm acceptability study in Zimbabwe prior to the launch of the HIV prevention study. Nearly all of the 186 participants reported having tried the diaphragm during the study period. At the study's conclusion 96% had used the diaphragm during the previous two months, however consistent diaphragm use between visits was low-only 13-16%.

Zimbabwe study

On a recent afternoon at the MIRA study site in Epworth, a densely-populated suburb of Harare, Zimbabwe, a dozen or so women arrived for their final study visit. Outside in the dusty sunshine, music blared from a saloon next door and peddlers squatted before small piles of tomatoes and carrots. Here in Zimbabwe the researchers have enrolled 2503 women ages 19-49, randomized them into diaphragm and no diaphragm arms (both receive condoms and prevention education), and are following them for at least 12 months. During quarterly visits the researchers test the participants for HIV and STIs and ask them about their experiences with the diaphragms. The women fill out computer surveys and meet with counselors and clinicians. All women completing their final visits are offered a diaphragm. "Most women are accepting it," says Project Director Agnes Chidanyika. "They look forward to using it, especially those in the condom arm who haven't used it."

In a counseling room at the clinic, a young woman in the diaphragm arm of the study demonstrated diaphragm use on a plastic pelvic model. She grasped the latex, cup-shaped diaphragm by its firm, springy lip, squeezed it in two, and inserted it easily into the model. "To be eligible to be in the study you have to be able to insert the diaphragm within five attempts," says Chidanyika. "We had one or two out of those 2500 women who couldn't insert the diaphragm in five attempts. It was fairly easy once they knew how it was done for them to be able to insert it."

The young woman said she found her own diaphragm comfortable and had used it throughout the study period except when she tried to get pregnant. As with all barrier methods, the importance of child-bearing in many societies may be an obstacle to widespread adoption of the diaphragm as an HIV prevention method.

Those championing the diaphragm claim that its great advantage over the condom is the fact that women can typically use it without their partners' knowledge. Chidanyika said that was only partly true in the MIRA study, because participants are asked to use Replens gel when inserting their diaphragms. "There's this myth about dry sex in African countries, so we were worried they might not want to use the diaphragm because they would have to use the gel to ease the insertion," she says. "But we actually found the gel became quite popular." Chidanyika says the diaphragms were acceptable among the male partners of most women, who were happy to let their female partners use a potential HIV prevention method that their partners were responsible for and they could not feel. However, this sentiment was not universal, says Chidanyika. "The problem we did have with some women is the partner would say if she can use it without me knowing, then she can be unfaithful."

Challenging study environment

The MIRA study is being conducted at the epicenter of the HIV epidemic. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) 2006 Report on the Global AIDS Epidemic, HIV prevalence among adults ages 15-49 in Zimbabwe is 20.1% and in South Africa it's 18.8%. If diaphragms prove to be acceptable and effective against the transmission of HIV and STIs at these sites, chances are that they will prove useful in other countries hit hard by HIV/AIDS.

In Zimbabwe in particular, researchers could scarcely have chosen a more challenging situation in which to conduct their study. The country is currently experiencing epic inflation and joblessness. The Epworth study site sits just a few feet away from the rubble of countless shanties destroyed by order of the Zimbabwean government in the summer of 2005 in a campaign called Operation Murambatsvina or "Drive out Trash." According to a UN-Habitat study, an estimated 700,000 people lost their dwellings or businesses in the campaign.

Over a quarter of the MIRA study participants in Zimbabwe were displaced by Operation Murambatsvina. This could have devastated the study, but MIRA researchers temporarily stopped enrolling new participants and channeled all of their energy and resources into tracking participants in order to keep them in the study. "We went to everybody, regardless of whether we just saw them yesterday or we last saw them last year," says Chidanyika. "We just tried to find out if they were going to be evicted by Murambatsvina and, if they were, which places they were most likely to move to."

The researchers managed to retain a stunning 99% of the participants by visiting homes, villages, and displaced persons camps, reaching out to alternative contacts, and launching a radio and poster campaign. The researchers now provide many participants with bus fare to reach the study site from their new locations. Chidanyika says the high retention rate also reflects the enthusiasm of the diaphragm study participants. "The participants themselves, they were very interested in participating in the study and coming back," she says.

A look to the future

Results from the MIRA study are expected in 2007. If diaphragms prove effective at lowering HIV transmission, however, those wishing to promote wide-scale adoption of the method will need to contend with several difficulties.

The major fear with diaphragms and indeed all female-controlled methods is that they will lead to lower condom usage. "I don't think anyone thinks diaphragms will be more effective than condoms," acknowledges Padian, "but we're doing the study in the situation where many women cannot use condoms." There is also a fear that behavioral disinhibition will result from women believing that they can stop worrying about contracting HIV if they are using a diaphragm, but this is a consideration with all HIV prevention mechanisms and even HIV treatment. The potential problem will need to be countered by education.

Perhaps the most serious obstacle to future use of diaphragms is the possibility that they will be less acceptable in real settings than they are in the research environment. Over-optimism about the prospects of the female condom, another woman-controlled contraceptive and HIV prevention method, is an important cautionary case. While evidence suggests that the female condom is effective and easy to use, it has taken a long time to increase uptake for this unfamiliar contraceptive method.

On the positive side, however, female condoms have been successfully marketed in some high-prevalence countries. Furthermore, the diaphragm may be more attractive economically for some women; a single diaphragm, though initially more expensive than a female condom, may be used for several years.

The main problem with traditional diaphragms is the cumbersome way they are fitted. The traditional, labor-intensive method uses rings. The MIRA study, instead, has used a method that its directors term a "modified fitting scheme." All women start with one size of diaphragm, then the fit is assessed using digital examination and other sizes are tried as necessary.

Even this simpler method, however, requires a health clinic attendance for a diaphragm fitting, a potentially costly prospect that may be associated with stigma. This limitation has led developers to pioneer alternate forms of cervical barriers. Maggie Kilbourne-Brook, program officer with the group Program for Appropriate Technology in Health (PATH), says a single-sized device is the main improvement needed. "It needs to be 'one size fits many,'" she says, "which will reduce the procurement cost, the training cost, and has the potential to become an over-the-counter device."

This conclusion is based on detailed research that PATH, in conjunction with the Contraceptive Research and Development Program (CONRAD), has conducted on the acceptability of cervical barriers. Women who had used barriers were asked what they did and did not like about them. Providers, too, were asked why barriers were not being used in their clinics and what it would take to bring them into wider use. Donors and those in charge of procurement were also surveyed. The goal was to uncover the roadblocks to greater use of cervical barriers, opening the possibility to create better products. "They'd been around 100 years and hadn't really been improved in that time," says Kilbourne-Brook. "We now understand much more about vaginal anatomy. Manufacturing practices have changed. New materials have been developed."

In addition to needing a one-sized product, the researchers concluded that several other modifications would make diaphragms much more acceptable. "What we need to be able to achieve is to make a device that is easier to insert and remove than standard products, and easier to use and learn to use than the currently available product," says Kilbourne-Brook. "It needs to be comfortable for both partners."

The PATH researchers used this information to develop an improved diaphragm. Their development process was further informed by user feedback from women and their partners in Thailand, South Africa, and the Dominican Republic. The resulting product, SILCS, is a single-sized silicone diaphragm with a nylon or polymer spring that fits most women across all of these countries. The researchers expect to begin testing the product for contraceptive effectiveness in late 2006.

A number of other cervical barriers are also in the process of being developed and approved. The single-sized Lea's Shield is a silicone cervical barrier contraceptive already FDA approved for up to 48 hours of continuous use in the US and Europe. Another product being tested, the BufferGel Duet, is a disposable, one-size diaphragm pre-filled with the candidate microbicide and contraceptive BufferGel.

Indeed, if both microbicides and diaphragms prove to be partially effective at preventing HIV transmission then combining them could well offer higher protection. "We're interested in evaluating whether the use of a physical barrier like a diaphragm could advance the effectiveness of a microbicide," says Sharon Hillier, a microbicides researcher at the University of Pennsylvania. "Thinking of combinations of chemical agents like microbicides with physical barriers may present a real advance in effectiveness."

Kilbourne-Brook believes it is important for advocates of various woman-controlled prevention methods, including cervical barriers, microbicides, and female condoms, to come together and devise strategic ways to look at research questions and procedural and regulatory hurdles. "Anything that we can do for one of these products will strengthen the future prospects for all of these products as well," she says. "All of these products can offer a greater likelihood of protected sex for couples." Padian agrees, "None of the methods we are looking at are 100% effective."

If the MIRA study indicates that traditional diaphragms are protective against HIV transmission, Padian believes there will be ways to extend the results to the new forms of cervical barriers that are being developed. "We'll be able to generalize somewhat," she says. "It would be crazy if you had to do a complete other trial."

Her hope is that even partial protection against HIV by diaphragms will have a powerful effect on the epidemic. "Even though it's not perfect, it's better than nothing," she says, "especially when women can't negotiate male condom use. For many women this is unequivocally one hundred percent out of the question."

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*Sheri Fink, MD, PhD, is a freelance writer whose work has appeared in such publications as The New York Timesand Discover Magazine, and the author of War Hospital: A True Story of Surgery and Survival.