The Dangers of Excluding Women From HIV Prevention Drug Tests

When Dázon Dixon Diallo began working to prevent the spread of HIV among women in 1985, she first had to convince them that they could get the infection. Even some HIV activists didn’t fully appreciate that women needed to be included in prevention efforts. Diallo founded an Atlanta-based organization called SisterLove to promote reproductive justice and to support women with or at risk of getting HIV/AIDS, expanding it to a program in South Africa, where today two-thirds of the people living with HIV are women. In the US, almost one in five new HIV diagnoses are among women.

Yet after 35 years, Diallo is still waiting for gender equity in the research for drugs that could prevent HIV infection. The underrepresentation of women in all kinds of medical research—from heart disease to sexual dysfunction—is a longstanding concern among women’s health activists. With HIV, inequity not only leaves women vulnerable to a life-altering disease, but it also thwarts efforts to stop its spread. According to the Centers for Disease Control and Prevention, more than 260,000 women live with HIV in the US, and in 2018, 6,000 women received a new diagnosis of infection.

Transmission is more common in some US communities than others. HIV disproportionately affects African American and Latinx women, and about half of new HIV cases each year are in Southern states. (The CDC provides a tool for learning about risk. AIDSVu, an interactive map created by public health researchers at Emory University with support from the pharmaceutical company Gilead Sciences, shows HIV cases and rates by zip code for about 40 US cities.) And although the Trump administration has launched a national goal of ending the HIV epidemic by 2030, “You never get to ‘end the epidemic’ as long as you keep leaving women behind,” says Diallo.

Gender disparity in HIV treatment and research dates back to the earliest days of the epidemic, when it was viewed almost exclusively as a disease of young, white, gay men. AIDS testing and diagnosis were often triggered by the appearance of opportunistic infections, such as Karposi’s sarcoma. Diseases associated with AIDS in women were different—which meant they had more difficulty getting diagnosed and accessing housing aid, disability payments, and other social services.

In 1993, the CDC expanded the case definition for AIDS to encompass conditions that were common among women, including cervical cancer and pulmonary tuberculosis. “It required changing the science in order to be included from a social, political, and economic perspective,” Diallo says. “To some degree, we are still in that same kind of scenario.”

In the absence of an HIV vaccine, today the primary tool to stop transmission is known as pre-exposure prophylaxis, or PrEP. For the infection to take hold, the virus must wrest control of the DNA in immune cells and make copies of itself. Daily PrEP pills stop the virus from commandeering the cells by blocking a viral enzyme. (Drugmakers are also studying making PrEP medications injectable, or in the form of an intravaginal ring that releases the antiviral drug dapivirine.) PrEP has been hailed a success story, because it gives both men and women a way to protect themselves without negotiating with their partners to wear a condom.

But so far, PrEP studies have a mixed track record for including women. There are two drugs already approved by the US Food and Drug Administration for PrEP: Truvada (emtricitabine and tenofovir disoproxil fumarate) and Descovy (emtricitabine and tenofovir alafenamide). The pills, made by Gilead, are as much as 99 percent effective in preventing HIV infection if taken every day.

Women were well-represented in studies of Truvada for PrEP. (The drug had been in use since 2004 as a form of treatment for people who already have HIV infections.) With between 20 and 52 percent cisgender women, the successful PrEP trials were strong enough to establish its effectiveness and enable its broad approval.

And in May, promising results emerged from a clinical trial for a long-lasting injectable form of PrEP that also works by blocking an enzyme the virus needs to replicate. Cabotegravir is made by ViiV, a pharmaceutical company that is majority-owned by GlaxoSmithKline. An independent panel of experts overseeing the cabotegravir study, known as a data and safety monitoring board, ended the trial early after it showed the injectable was at least as protective as Truvada for men and transgender women. (In fact, there were 12 new HIV infections in the cabotegravir group versus 38 in the Truvada group. Based on the rate of infection, a GlaxoSmithKline press release calls the injectable 69 percent more effective than daily pills, but the results have not yet been published in a journal.)

A parallel cabotegravir trial among about 3,000 cisgender women in sub-Saharan Africa began a year later and is ongoing. The data and safety monitoring board recently examined preliminary results and allowed it to continue—considered a sign that the drug is safe and showing promise. Another review is expected in November. (The Covid-19 pandemic has made it more difficult for women to visit clinics for injections and health monitoring, but so far the trial has not been disrupted, as has happened with many clinical trials.)

An injectable form of PrEP could boost HIV prevention among women—whether because it’s easier to have a shot every two months than to take a pill every day, or because it would remove the potential stigma of having a PrEP bottle in the medicine cabinet, says Kimberly Smith, an infectious disease physician who is head of research and development for ViiV. “We need more options for prevention for women, period. We need it for the field broadly, but in particular for women,” she says. “This study is so critical to that.”

But the path to new PrEP options for women has been fraught. Last fall, Gilead drew the ire of health advocates when the FDA approved Descovy, the company’s second PrEP drug, only for men and transgender women. In this case, the drug had not been tested in cisgender women.

Descovy had been approved by the FDA for HIV treatment in 2016, after Phase 3 studies that included about 15 percent women. But designing a Descovy PrEP trial for women was complicated. To establish that Descovy was “non-inferior” to Truvada, the approved drug, its efficacy needed to be compared with the results from at least three other well-conducted studies of Truvada’s efficacy.

That wasn’t possible, because two all-women Truvada trials for PrEP had not shown efficacy, possibly because the participants didn’t actually take the pills every day as instructed. (Adherence to a drug regimen is an issue in PrEP trials, and failing to take the drug every day may lessen its effectiveness.) That left only two other studies. To make a comparison statistically acceptable, a trial that aimed to show Descovy was as good as Truvada for prevention in women would need to establish that “non-inferiority” by a wide margin, FDA officials concluded. In fact, meeting the FDA’s requirements would have required testing in about 22,000 women, Gilead officials said.

And for that reason, Gilead decided to take a different approach based on a trial in men and transgender women only. “We discussed alternative trial designs with the FDA and with physicians in Africa who care for at-risk women. With their input, we concluded that a trial that was not adequately statistically powered would not be sufficient to demonstrate the efficacy of (Descovy) for PrEP in cisgender women,” Gilead spokesperson Chris Ridley wrote in an email to WIRED.

Unable to reach agreement with the FDA on the design of a study in cisgender women, Gilead officials chose to extrapolate the results from the study of men and transgender women—noting that Descovy had been tested and used successfully in women, and blood levels of the metabolized form of the active ingredient are similar in men and women. The Descovy trial showed the new PrEP drug led to smaller changes in blood markers related to bone and kidney health compared to Truvada, which may make it safer for people with kidney problems or at risk of osteoporosis. (In a rare side effect, Truvada can cause an increase in levels of creatinine, a metabolic substance filtered by the kidney. It also can cause a small but reversible loss of bone density.)

But when the study results came before the FDA’s Antimicrobial Drugs Advisory Committee, the panel decried making a choice between recommending approval of a drug for women based on a study that excluded them, or approval for men and transgender women only. “We have failed women,” said Lindsey Baden, the committee chair and an infectious disease physician at Harvard Medical School, at the panel’s August 2019 meeting. “To be at this point and not have the data to guide decisionmaking is a shame on all of us.”

In keeping with the panel’s 8–10 vote against finding that Gilead had shown Descovy to be safe and effective for cisgender women, the FDA ultimately approved Descovy with an exclusion for “receptive vaginal sex.” The agency required Gilead to conduct an additional study among cisgender women but allowed a different study design (comparing the drug to a background incidence of new HIV infections among African women) that would make it feasible.

The public response was harsh. News stories led with the exclusion of women from the study. “Where Were the Women?” asked the headline of a perspective piece in the New England Journal of Medicine. Its authors, Robert Goldstein and Rochelle Walensky, infectious disease physicians at

Massachusetts General Hospital, wrote that the outcry from the scientific and advocacy communities “suggests that they expected and deserved better; they are all watching for remediation.”

In an accompanying letter, Diane Brainard, an infectious disease physician who is senior vice president for HIV and emerging viral infections at Gilead, and Scott McCallister, executive director of clinical research, responded, citing the FDA’s recommendation of a new study design. “This innovative framework now allows us to conduct an efficacy study of [Descovy] for PrEP in several thousand cisgender women; we are working actively with community members and clinical trial experts to finalize the design,” they wrote. “We appreciate the importance of responsibly conducting this trial without delay so that cisgender women will have the potential to benefit fully from the same PrEP options available to cisgender men and transgender women.”

Today, a new Gilead trial that includes women is in the planning stage. Brainard emphasized the company’s commitment to its upcoming trial of Descovy among women in Africa—despite delays caused by the Covid-19 pandemic—in a recent email to women’s health advocates. She noted that the new study has been shaped by input from a global community advisory group. “Consultations with this group have influenced nearly every aspect of our study of Descovy for PrEP in young women and adolescent girls—from determining how demographic data will be collected to improving the consent process to better balancing data collection with participant burden,” she wrote. “Gilead is making progress toward our goal of gender parity in HIV trials because of the engagement of dedicated community partners and stakeholders. We welcome and appreciate your input and look forward to continuing dialogue with you on this priority.”

Gilead officials are meeting with advocates from South Africa and Uganda as well as AVAC, a New York City-based organization that promotes HIV prevention policy and research, Ridley wrote. Gilead also solicited feedback from the South African Health Products Regulatory Authority. The delay “has allowed them to continue the process of hosting meetings and getting input,” he told WIRED. “We’ve been using the time and the additional input to refine the protocol.” The trial is on schedule to start in mid-2021, he said.

The Descovy debate creates a new opening for women’s health advocates, says Diallo of SisterLove. When she and other advocates met with Gilead officials after the FDA decision, Diallo pressed for the principal investigators—the researchers heading the study—to be women of color. She asked for research into the real-world experiences of women who use PrEP to better understand their sense of risk and willingness to take a daily pill. “This is the first time we’ve actually been brought to the table as advisers before the study protocol is even written,” she says. “We’re determining the sites, the elements of the study, and the protocol, and we’ll be involved in creating the informed consent and deciding what the communication to patients will look like.”

The hunt for a new PReP drug is not the first time women have been excluded from drug testing. In fact, exclusion was once US government policy. In 1977, the FDA cautioned that women of “childbearing potential” should not be a part of early clinical trials—those that show safety and initially screen for effectiveness—unless the drug was for a life-threatening condition. Officials feared unknowingly causing harm to fetuses. In practice, women were often excluded from trials completely, and drugs tested only in men were prescribed for women. The FDA reversed that guidance in 1993 and in 2014 expressly advised drug companies to analyze their data to look for sex differences in the drugs’ effects.

The National Women’s Health Network, an advocacy group, has called on the FDA to require drug makers to include enough women in their trials to show that the drugs would be safe and effective if used by women. To add some transparency to the process, since 2015 the FDA has provided “snapshots” of new drugs showing the percentage of women, older adults, and different racial groups in the large Phase 3 clinical trials, which are used in regulatory decisions. With each yearly report, the proportion of women has increased.

Yet the under-enrollment of women persists. FDA researchers published a 2018 study in the Journal of the American College of Cardiology comparing the participation of women in cardiac drug trials with the proportion of women with the target diseases. They found equity in trials related to hypertension and atrial fibrillation (and even over-representation in trials for pulmonary arterial hypertension). But women were underrepresented in trials for drugs to treat heart failure, coronary artery syndrome, and acute coronary syndrome, primarily because they weren’t as likely as men to be screened for eligibility for the studies—even though heart disease is the leading cause of death for women.

“There’s been a lot of work to try to improve inclusion. The Descovy scandal, which I find particularly problematic, shows us that this is not always working,” says Susan Wood, a health policy expert at George Washington University and former director of the FDA Office of Women’s Health.

Even if women are well-represented in studies of newly-approved drugs, prior disparities linger. Nine out of 10 prescriptions in the US are for generic drugs. These are based on older drug formulas that were approved years ago when women were much less likely to be well-represented. When the US General Accounting Office reviewed drugs that had been pulled from the market for safety reasons from 1997 to 2001, eight of the 10 withdrawn drugs involved a greater risk to women than men.

“We can’t just continue excluding women from our knowledge base of medicine and health,” says Alyson McGregor, an emergency medicine physician at Brown University and author of Sex Matters: How Male-Centric Medicine Endangers Women’s Health—and What We Can Do About It. “I think we have a moral obligation to wind the clock back, if we need to, and redo some of these important studies to see how women may be different.”

The Dangers of Excluding Women From HIV Prevention Drug Tests

Author: sgadmin

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