Learning from Microbicides

A Young Field's Experience Working with High-Risk Women

By Emily Bass

AIDS vaccines and microbicides share many key goals. Both seek to develop prevention strategies that will stem the tide of new HIV infections around the world, and both share a keen awareness of women’s vulnerability to HIV. But despite these similarities, the two fields have evolved separate strategies for mobilizing funds, political will and scientific support for their goals.

Today, however, microbicides and vaccines are starting to converge on common ground. Both are pursuing trials in the developing world, and as they do so, microbicides—long considered a “little sister” to vaccines—are taking on a new role as a font of insights regarding the challenges facing both fields.

This has been catalyzed by exciting developments in the microbicide arena, with 2002 having several highlights. The New York-based Population Council completed a Phase II trial of a seaweed-based microbicide called Carraguard in high-risk women in South Africa and Thailand, and is now preparing for a 6,600-woman Phase III study scheduled to start in early 2003. The UK’s Department for International Development unveiled a five-year, US$23.5 million microbicides project that will draw collaborators from South Africa, Tanzania, Uganda, Cameroon and Zambia. Another big step was the formation of the US-based International Partnership for Microbicides (IPM), a new public-private partnership with pledges of nearly $30 million from governments and private sector funders over the next five years. The IPM plans to use these funds to speed research and spearhead planning on the manufacturing, regulatory and access fronts.

This activity has been a long time in coming. Microbicides are a novel concept that was slow to receive widespread support from politicians or AIDS researchers, some of whom have falsely categorized them as “kitchen-sink” contraceptive research. Save for a few small biotech companies, the private sector has stayed away from developing microbicides.

In spite of these hurdles, a dedicated group of advocates and researchers has made steady progress. Earlier this year, many of these players collaborated on a series of expert papers, produced with funding from the Rockefeller Foundation’s Microbicides Initiative, that explored a range of issues around economics, acceptability and access. The papers also included modeling studies which demonstrate the strong impact even a partially effective microbicide could have on reducing the numbers of new infections and saving health-care expenditures, even excluding antiretrovirals. These papers helped identify priorities for the newly-formed IPM.

This flurry of activity, and the new impact analyses, have captured the attention of even the most seasoned players in the field. “For the first time—and I get goose bumps as I say this—we have the hard data to make a strong case for investments in microbicides,” said Geeta Rao Gupta, President of the Inter-national Council for Research on Women, at a Microbicides Initiative event this past February.

Good news for microbicides is good news for AIDS vaccines, too. Microbicides are moving forward with trials in some of the same populations AIDS vaccine developers will also need to engage, which include commercial sex workers (CSW), adolescent girls and other women at high risk, especially in developing countries. Roughly 4,000 high-risk women have already participated in microbicide studies—significantly more than for AIDS vaccines, where the two Phase III trials to date have involved cohorts that are roughly 95% male.

Finding points of comparison

Overall, the microbicide field has conducted 14 studies of vaginal microbicides in humans, including several large trials in women at high risk. There are 50-60 different compounds in various stages of development, and they can be grouped into about five categories based on their mode of action. Products also vary in their scope—some aim to protect not only against HIV but also other STDs, while some are potential contraceptives.

In recent years, funding shortages have kept many of these candidates idling in pre-clinical development instead of entering human trials. But those which have moved forward are progressing towards Phase III studies more rapidly than AIDS vaccines are. One reason: Early microbicides studies can determine product safety, but they yield no data (such as immunogenicity) that hint at efficacy. Without a way to evaluate products in Phase I or II trials except for safety, microbicide investigators tend move more quickly to Phase III trials. (Carraguard, which enters Phase III trials this year, had equal numbers of infections in the gel and placebo arms of its Phase II trials.)

Because of this rapid pace, the microbicides field—although relatively young—has already conducted several large trials in the developing world. These differ from vaccine studies in the type of commitment needed from volunteers, since participation entails regular gel use over months or years, providing detailed information about sexual practices, and use of a product that may be noticed by male partners, opening the door for conflicts over trial participation. Yet these demands also mean that planners must find highly effective ways to engage women in trials.

Many of the lessons from these trials apply to vaccines—lessons that were center stage at Microbicides 2002 (12-15 May, Antwerp, Belgium), the field’s major biannual meeting. There, several hundred participants gathered to discuss the victories and setbacks of the previous two years, including an in-depth look at two of the field’s most significant trials to date: COL-1492, a Phase III study of Nonoxynol-9 (N-9) completed in 2000; and this year’s Phase II Carraguard study.

Recruitment and retention

Leopold Zekeng (Laboratoire de Santé Hygiène Mobile, Cameroon) reported on two successive N-9 trials in Cameroon, each of which enrolled approximately 1,200 women. The first, which tested a film formulation, enrolled commercial sex workers; the second tested an N-9 gel, in high-risk women not engaged in commercial sex work.

Both cohorts were followed for two years, with a 20% loss to follow-up in CSWs and a 5% loss in non-CSWs. The study employed an all-female enrollment and outreach staff, who obtained volunteers’ permission to make home visits if they failed to appear for scheduled appointments. Zekeng said that having a female team was important, since it avoided suspicions that might be aroused by women receiving unfamiliar male visitors. A physician was also available for house calls to participants.

This year’s Carraguard trial also reports encouraging results. The CDC-sponsored site in Chiang-Rai, Thailand retained over 90% of participants. The South African sites also reported high retention (complete data analysis is still underway). Nicol Coetzee (University of Cape Town), a principal investigator at the Guguletu, South Africa site, emphasized the importance of staff committed to intensive follow-up for no-shows, which can involve multiple phone calls or prolonged searches for participants in squatter camps. Looking ahead to the upcoming Phase III study, which will enroll 6,600 women at multiple sites in southern Africa, including 2,000 in Guguletu, Coetzee acknowledged that it will be a challenge to meet the increased level of investment needed for effective recruitment and follow-up.

Informed consent, ongoing education

Barbara Friedland (Population Council) described an extensive back-and-forth with community representatives to revise the Carraguard informed consent form. Key issues: defining terms like speculum, microbicide, anal sex, and randomization in Tswana, Zulu and Xhosa, and finding ways to explain potential adverse events in cultures unused to the exhaustive consent forms used in Western medical information. The first version of the form “did too well” in cataloguing every possible side effect, however rare, Friedland noted wryly—leading participants in a pilot project on informed consent to argue that volunteers for the real study were entitled to greater compensation due to the risks involved.

Significantly, all of the trials were able to enroll women without directly involving their male partners in the informed consent process. Whether or not women in many countries have the autonomy to give independent informed consent is a looming question for trial planners, particularly in resource-poor settings where poverty and societal norms limit women’s access to confidential healthcare services.

This issue becomes even more complex when dealing with adolescents. Although they are disproportionately affected by HIV—15-19 year-old females are up to five times more likely to be HIV-infected than their male counterparts in regions of sub-Saharan Africa—18 is the age at which most can legally consent to participate in scientific trials. They are also socially constrained by families and communities, who may view participation in an HIV-related study as proof of stigmatized, sexual behavior.

While vaccines and microbicides trials are both grappling with when and how to enroll adolescents, microbicides researchers may take the plunge first, since product safety profiles may differ in this young age group. Compared with older women, the cervix of adolescents has more exposed columnar epithelium, a tissue thought to have almost no defenses against invading pathogens, and could theoretically respond differently to topical microbicides.

Regulatory agencies may also require data from adolescents (and a wide range of other women) before they will license a microbicide. Indeed, that was the message of a presentation at Antwerp by Sheena McCormack (Medical Research Council, UK), who summarized a WHO-sponsored meeting in March that discussed regulatory issues related to the approval of microbicides. “We need safety data that represents the general population, and therefore we have to include adolescents,” she said. McCormack also mentioned other groups that should be included, such as HIV-positive and post-menopausal women.

Unfortunately, there are no easy solutions to the challenges of adolescent enrollment. Soon, the upcoming Phase III Carraguard trial will seek to drop the minimum age for enrollment from 18 to 16. Janneke Van de Wijgert (Population Council), a principal investigator on the trial, says that they are working with each local Institutional Review Board (IRB) to determine whether 16-year olds will be allowed to enroll, with or without parental consent, and that the trial will seek parental consent where needed. At two participating sites in Botswana, feedback from focus groups suggests that adolescents at these sites are unlikely to get (or seek) consent from parents, who do not want to believe that their children are sexually active, says CDC study coordinator Dawn Smith. To circumvent this, Smith says the team may recruit teenage girls who have just given birth (25% of whom are HIV-positive)—since their parents will know that they’re sexually active.

Other presentations in Antwerp underscored the difficult truth that people in the hardest hit areas may approach experimental microbicides with false hopes engendered by desperation. For example, Lut Van Damme (Institute for Tropical Medicine, Antwerp) presented a COL-1492 sub-study on beliefs of participants from Thailand, Western and Southern Africa. In South Africa, the epicenter of the AIDS epidemic, 56% of participating women said that protection from HIV was the most important characteristic of the experimental product. This figure dropped—roughly in keeping with HIV prevalence in the regions—to 22.5% in West Africa, and 7.8% in Thailand. Instead, some of these participants emphasized the gel’s lubricant qualities and perceived enhancement of vaginal “cleanliness” as the main benefits of the product.

Van Damme’s colleague Ethel Quana (Medical Research Council, South Africa) followed with results of 15 focus group discussions and 103 interviews conducted with South African sex workers 12-15 months after the COL-1492 trial ended. Many of those interviewed said that they believed the product protected them from STDs—even when not using condoms and when their clients reported having STDs. “Despite provision of information [at monthly clinic visits], participants retained false perceptions of the product,” Quana noted.

CDC’s Dawn Smith says she’s seen a similar tendency to believe that microbicides are effective in focus groups in Botswana. “We’ll start out by explaining that we don’t know whether the compound works. And within 10 to 15 minutes, the group starts talking as if it does work. It’s very, very scary,” says Smith.

Dealing with Failure

The microbicides field has already had to learn the hard way how to absorb the impact of an efficacy trial that doesn’t deliver positive results—in this case, COL-1492, the pivotal trial which found that commercial sex workers who used N-9 as a vaginal microbicide had a slight but significant increase in risk of HIV infection as compared to those who used a placebo gel. This is thought to be due at least partly to micro-tears and irritation of the vagina caused by prolonged use of N-9 as a topical microbicide. These data were first presented in 2000 at the International AIDS Conference in Durban. But as multiple presentations and a special symposium in Antwerp illustrated, the field is still examining how to absorb the trial’s lessons and find better ways to evaluate microbicide safety pre-clinically.

The good news: many sites which had been on the starting line for a follow-up study of N-9 (in a film formulation called Conceptrol) were able to switch course in midstream and launch other studies, such as acceptability studies of dummy gels, or condom-use protocols. Field leaders said that, for the most part, the COL-1492 results did not have a significant negative impact on microbicide trial plans, perhaps because N-9 was already an approved product--so the data, while disappointing, did not reflect badly on the field’s overall development.

On a more cautionary note, counselors and care providers reported anger and frustration on their part, and that of their clients, over the shift in messages—now having to tell women not to use N-9 as a lubricant during sex. As one South African counselor pointed out in Antwerp, “We’re concerned about recommending another product and then having ‘something happen’ and we have to come up with new messages again.”

Defining standards and care

The most emotional session discussed standard of care for participants and communities. This is also a difficult topic in the vaccine field, where most of the discussion revolves around whether (and how) to provide antiretroviral medications for volunteers who become HIV-positive during a trial. But, as presenters at Antwerp emphasized, many microbicide trials will take place in settings where providing even the most basic health care services may be a strong inducement for people to enroll in a research study.

Comments from participants in the Phase II Carraguard trial offer dramatic support for this view. Some were so pleased with their care—including Pap smears, GYN exams and STD treatment—that they asked to enroll in the upcoming Phase III study. This posed a challenge to planners who wanted to randomize unbiased participants, but did not want to alienate the community by excluding these eager trial veterans. Ultimately, the decision was made to allow Phase II participants to enroll, but to avoid seeking them out.

Another vivid report from the field came from Cameroon’s Leopold Zekeng, whose microbicide trial provided treatment for STDs and vaginal infections. “In situations where women were clear of STDs, we thought they would be happy,” Zekeng reported. Instead, “They were unhappy because they were not getting drugs that others were getting.” Having never been in a situation where pills were readily dispensed, women wanted to benefit fully, he said. In this case, the researchers decided to give out vitamins to women who did not have STDs.

These problems will only increase as trials get larger, said South Africa’s Coetzee. Guguletu has a 20% HIV prevalence rate. “During the screening process, we’ll uncover high numbers of HIV-positive well women and a lot of women with abnormal Paps who will flow into existing health services. We’re going to need to think about how the community will benefit from and access health care services while we’re doing the trials.”

Sharing fertile common ground

One of the most striking things about the Antwerp meeting, according to some participants, was the attention given to overlaps between AIDS vaccines and microbicides. Peggy Johnston, Assistant Director for HIV/AIDS Vaccines at the U.S. National Institute of Allergy and Infectious Diseases (NIAID), gave a plenary lecture on “Analogies Between Research on AIDS Vaccines and Microbicides;” later in the week, Lori Heise, head of the Global Campaign for Microbicides, delivered a thought-provoking talk comparing advocacy for AIDS vaccines, microbicides and treatment.

These comparisons are being borne out in the field, where there’s more overlap than ever between prevention and treatment, and between vaccines and microbicides. Hlabisa, South Africa is a prime example. This very high-incidence area was the site of extensive community education and mobilization during several years of NIH-sponsored preparedness for Phase III vaccine trials—which are still at least several years away.

This gap has led Hlabisa to move into microbicides trials. In July 2002, the South African Medical Research Council (MRC) and NIH-sponsored HIV Prevention Trials Network (HPTN) will launch a 150-woman feasibility study to lay the groundwork for Hlabisa’s participation in a microbicide trial (HPTN 035), where it will enroll 1000 women. “We’ve spoken truthfully with the community and they understand that there will not be a vaccine for a while,” says MRC’s Gita Ramjee. “So we are going to do a microbicide trial.”

There may also be joint action on policy fronts, as both fields seek to maintain and strengthen the demand for products which do not yet exist, and which may still be years away—even the most optimistic estimates say it will be five years before the first microbicide is approved.

As those gathered in Antwerp agreed, both AIDS vaccines and microbicides will continue to be propelled by the forces that have carried them so far: a mixture of optimism, perseverance and accumulating knowledge. Peggy Johnston was one of several speakers who grappled with the question of how to rally politicians—many of whom have a short tenure in office—to support products that may be years down the road. In answer, she reminded the audience that, centuries ago, cathedral building was thought to be a most noble profession—and that the laborers who worked on them did not know if they would be completed in their lifetime. Johnston urged the crowd to share this message with potential political and private sector allies. “Let this be our cathedral,” she said.