It’s 2021. Where are the women in HIV clinical trials?

A troubling fact was revealed at this year’s International AIDS Society Conference on HIV Science: When it comes to women in HIV-related clinical trials, the numbers even in 2021 remain, as Dawn Averitt, founder of the Well Project, put it, “abysmally low.” In fact, among the studies presented during the conference, women made up as few as 7% of participants.

More commonly, around a third of participants in clinical trials that were presented at the conference were assigned female at birth.

Views on Women in Clinical Trials Are Changing …

Historically, women in large part had been excluded—deliberately so—from clinical trials. In 1977, the U.S. Food and Drug Administration (FDA) prohibited most studies from enrolling women of childbearing age because of concerns about the effect of an investigational substance on the fetus, should a participant become pregnant. That view changed over time, and by 1993, the FDA formally rescinded the 1977 ban.

“We began to understand that no data is not actually protective,” said Eileen Patricia Scully, M.D., Ph.D., an assistant professor of medicine at Johns Hopkins University. “So when we don’t know the impact of a particular drug on women, we also can’t protect them once that drug is approved and is really used.” Scully noted that during her own experience being pregnant, “the first thing you realize is that there is almost no data for almost any medications in pregnancy.” She added, however, that she sees small steps being made toward more inclusion—and Averitt agreed. “I think what we are seeing now is increasingly an understanding that we have to allow women who are pregnant or breastfeeding to participate in clinical studies,” said Averitt.

Back in 2006, Averitt was involved in the Gender, Race, and Clinical Experience (GRACE) study of darunavir (Prezista) and ritonavir, which set out to prove that sufficient numbers of women could be recruited for clinical trials. Ultimately, the study enrolled 287 women, 67% of the 429 participants. However, more women than men dropped out, bringing to the forefront the need for researchers to consider the challenges of not only recruiting women, but retaining them as well. “One of the lessons learned was that retention of women should have been a critical focus from the initial planning stages of the study,” Averitt and colleagues wrote in Journal of Women’s Health in 2011.

Another hurdle: The study’s recruitment success didn’t carry over to current practice. “We really thought that if we pulled off the GRACE study, we could quit having this argument about whether or not women could participate in clinical trials,” said Averitt. Yet, she remains hopeful. “I think this is a moment where we are starting to see some movement,” she said, “and we can’t allow that commitment to be something that people talk about but don’t act on.”

Ten years after GRACE, Natalie A. DiPietro Mager, Pharm.D., Ph.D., a professor of Pharmacy Practice, and Katherine A. Liu, Pharm.D.—both of Raabe College of Pharmacy at Ohio Northern University—reviewed the participation of women of childbearing potential in prescription drug research. In 2009, an average of 37% of enrollees in non-sex-specific U.S. federally funded studies were women. However, 64% of studies reviewed did not report data on sex, nor did they explain why they didn’t do so.

… But We Still Don’t Have Enough Data

“I really don’t think there has been a big change from the time that article was written,” said DiPietro Mager. Case in point: Asked about lenacapavir—a long-acting injectable being investigated for both the treatment and prevention of HIV—in women of childbearing potential, presenter Samir K. Gupta, M.D., M.S., a professor of medicine and vice chair for research for the Department of Medicine at Indiana University School of Medicine, noted: “Unfortunately, I am not aware of any data yet specifically in that demographic subset.”

Tracking data on enrollment of cisgender and transgender women, as well as other underrepresented groups, is the first step in effecting behavior change, said Scully. For one, some researchers simply might not be aware of their study’s demographics. “Mandating reporting will embarrass some people into making sure they enroll women,” she noted. And data is needed to get funding sources to incentivize change. “In the end, behavior modification for this kind of thing is going to be through funding streams,” said Scully.

Aren’t Most Women Living With HIV in the Global South?

At 39%, the SALSA study—which evaluated the efficacy and safety of switching to the two-drug regimen dolutegravir and lamivudine (DTG/3TC, Dovato)—included a relatively robust cohort of participants who were women. The goal had been 50% women; however, enrollment had to be cut short due to the SARS-CoV-2 pandemic, explained Josep M. Llibre, M.D., Ph.D., of the Hospital Universitari Germans Trias i Pujol in Barcelona, Spain. Trials with other regimens haven’t found a difference in efficacy based on sex, so enrolling fewer women than planned is unlikely to be an issue, explained Llibre. “I would not suspect having a different result with dolutegravir/3TC only in women,” he said.

Llibre noted that in industrialized nations, the HIV epidemic is mainly one of men who have sex with men. “If you want to try a study with mostly women, you have to do it in Africa, or recruit only women,” he said. “That has been done.” There are about 1.2 million people living with HIV (PLWH) in the U.S., and with 23% of them women, you have a pool of more than 250,000 women living with HIV who can be enrolled in a trial, countered Averitt. “So this concept that we can’t find 100 women, or 200 women, or 300 women, to participate in a trial,” she said, “is, frankly, lazy.”

Worth noting is that the SALSA study is focused on enrolling older PLWH. In women, that often means there’s the likelihood of menopause—when pregnancy potential is no longer an issue. The study, however, did not track menopausal status. While enrolling women who cannot get pregnant might alleviate concerns about a potential fetus, it’s not a solution to the inclusion imbalance. For one, hormones, especially estrogen, may play a role in HIV latency control. “Yes, post-menopausal women should be included in studies, but they should not be a substitute for all women,” said Scully.

Sometimes It’s the Men Who Are Missing

At IAS 2021, one exception to the missing women problem was the VIBRA trial, evaluating community-based antiretroviral treatment delivery, which enrolled 58% women. It was conducted in rural Lesotho (in southern Africa), where the majority of PLWH are older women, explained study co-author Alain Amstutz, M.D., a postdoctoral scientific collaborator at the Swiss Tropical and Public Health Institute in Basel, Switzerland. “Actually, we were hoping to get more men into our study,” said Amstutz, “as this group is underrepresented and less understood in studies in Lesotho.” In fact, health workers went door to door earlier in the day and did some HIV testing in the fields to encourage men to participate, but had limited success.

Diverse enrollment “includes cisgender women, transgender women, and then cisgender men in specific locations where they are not well represented,” said Scully during her presentation. And diversity doesn’t just start at trial enrollment. “I think that HIV research across the spectrum, from discovery work in animal models to clinical cohorts, should consider sex and gender identity, as appropriate,” she explained. “This will lead us to better outcomes for all people living with HIV.”

What Needs to Be Done to Reach More Women?

To achieve diversity of enrollment, women—and particularly women of color—must be involved in all stages of a clinical trial, starting with its design. Study sites in and of the community, rather than just academic medical centers, in many ways may help build trust, thus resulting in increased participation in trials by women. While these sites require more investment up front, once non-traditional sites have been trained in good clinical practices and research data collection, they could be allowed to recruit more participants than their enrollment goal.

Quotas, such as every third person enrolled must be a woman, would also help. Researchers could institute diversity stop points and time-outs similar to safety reviews to assess the demographic composition of the participant pool during the recruitment period and during the course of the trial. “If you don’t want to start out with [quotas], that’s fine, but there should be a three-month review,” suggested Scully.

Early-morning and weekend clinic hours and help with transportation and childcare could enable women with family and other responsibilities to participate. Outreach at laundromats, stores, and salons could also go a long way to increase awareness of clinical trials among women. A thorough and transparent informed-consent form that includes contraceptive options and information regarding pregnancy—should a participant become pregnant—as well as additional time to review that information, are also needed.

One way to develop more strategies for reaching potential trial participants is to conduct qualitative research among women who screen out of, choose not to participate in, or drop out of a clinical trial. This information could be helpful “not only for enrollment, but for retention, because it’s important to make sure that participants stay in the trial,” noted DiPietro Mager.

Asking research questions that are of interest to women and valuing their participation as partners, not subjects—also by compensating them for their time—will also go a long way toward getting women interested in clinical trials. As Averitt put it: “Participants in clinical research are essential. Without the participants, you don’t get the answers, and you don’t learn what you need to learn. Therefore, we need to elevate what it means to be a part of clinical research and what that contribution looks like.”

By Barbara Jungwirth