Making Clinical Trials of PrEP More Inclusive of Women, No Matter Their Pregnancy Status
Three new trials of HIV prevention drugs seek to answer directly a question that researchers inside and outside the field of HIV have explicitly avoided for years: How do drugs work -- and are they safe -- in pregnant and breastfeeding women?
In launching the studies, researchers are building a model for how to navigate the complexity of such research. And they are making a bid to change the paradigm for how researchers think of studying pregnant women, said Kristen Sullivan, Ph.D., M.S.W., M.B.A., of the PHASES Study, which is examining the bioethics of HIV research and pregnancy.
"It's a shift in mindset from protecting pregnant women and their future offspring, not from research, but through research," Sullivan said at the 2018 U.S. Conference on AIDS (USCA) in Orlando, Florida.
One of the studies, the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) 2009 study, will start by dosing a small group of pregnant women with emtricitabine/tenofovir disoproxil fumarate (Truvada) for pre-exposure prophylaxis (PrEP) until they find the optimum dose for pregnant women. Then, once the dose is established, they will begin a large trial of pregnant women who are not living with HIV, studying the safety, feasibility, and acceptability of the drug among these women.
The two other studies, MTN-042 and MTN-043, will be randomized, open-label safety trials that will assign two women to the dapivirine ring for HIV prevention for every one pregnant woman taking emtricitabine/TDF. The trials are expected to start showing data several years from now.
From Sojourner Truth to the NIH Revitalization Act
In sub-Saharan Africa, about 1.5 million women are pregnant or breastfeeding at any one time. And all of them are at increased risk of acquiring HIV. A study out of the Conference on Retroviruses and Opportunistic Infections (CROI) this year found that women had a 2.19 to 2.97 times increased risk for acquiring HIV during pregnancy. After giving birth, that risk increased to 4.18 times the risk they faced when not pregnant or breastfeeding.
"Especially in areas with high HIV incidence, women spend a considerable amount of time pregnant," said Katherine Bunge, M.D., of the University of Pittsburgh and investigator of the MTN-042 (DELIVER) trial. "Just in Malawi, the average woman's life span is 60 years. Most women have five children…. That means those women are going to be pregnant or breastfeeding for nine years of her life."
That's 15% of a woman's lifetime and more than a quarter of her reproductive years.
For the vast majority of women, pregnancies have also been a time of deep medical and social disenfranchisement. At USCA, Morenike Giwa, the first woman of color member of the global advisory board for the AIDS Clinical Trials Network, started her presentation by quoting Sojourner Truth: "I have borne 13 children and seen most of them sold off to slavery. And when I cry out with my mother's grief, none but Jesus heard me. And ain't I a woman?"
"Think about what that does to your body and your psyche" to give birth to 13 children, Giwa said. "And then think about the trauma and loss. And then think about the fact that this was the norm for so long, for so many people, to create free labor. You were not a person, not human. You were property. Think about the fact that, particularly for women of color, that was your reality, that was your life."
She went on to name court case after court case in which women were robbed of the right to make decisions about their own bodies and own pregnancies: eugenics laws that the U.S. Supreme Court upheld, giving the state the right to forcibly sterilize women they felt would not contribute to society. These include Native American women who were sterilized against their will -- between a quarter and half of women during one span of time; single women threatened with losing custody of their existing children if they refused to let the state sterilize them -- or sterilize their children; African-American women in the 1970s who were told their daughters should be on birth control to protect them when they were young, only to have them actually sterilized.
Then, add in the complete silence of science when it comes to what happens to medicines in women's bodies during pregnancy. Until the mid-1990s, almost all studies of medical interventions were based on research in white men, said Sullivan.
"There were a number of reasons given for why women were excluded from research categorically," Sullivan said. "Among them was that women's physiology complicates science. I mean, they have menstrual cycles. So, what do we do with that, right? It's too complicated for us to deal with."
Sullivan added, "This is rooted in the idea of protecting women and fetuses and the argument that women were difficult to recruit or retain in studies."
The National Institutes of Health Revitalization Act of 1993 changed this in regard to women as a group, Sullivan said. But the avoidance of studying pregnant women remains largely unchanged.
Getting to Vetted Science
Consequently, when new HIV drugs are approved, they've almost universally not been tested in pregnant or breastfeeding women. That's how you get situations like the early signal from the Tsepamo study in Botswana of a potential neural tube defect for children born to women taking dolutegravir (Tivicay, DTG). Some African countries responded to the news of four babies born with neural tube defects by suggesting that women of reproductive potential and living with HIV not be given dolutegravir, the first-line treatment with better odds of viral suppression. This, in turn, led to intensive protests at AIDS 2018 by African women who insisted on the right to make rational decisions for themselves and their children.
"This highlights the difficult decisions women, providers, and policymakers must make in the absence of complete data," Sullivan said. "And it highlights the critical importance of research and surveillance done ethically, early, and systematically to inform these discussions."
A Potential Road Map for Future Pregnancy Trials
So, bearing in mind the complexity of creating trials that take into account the rights of pregnant women and the health of their fetuses, Bunge and colleagues came up with what they hope will be a model for "safe, efficient" research into medicines in pregnant women.
The study, called DELIVER (a study of PrEP and the dapivirine ring in pregnant women), aims to go about determining drug safety by taking a stepped approach to research. The study is divided into four cohorts. The first, of 150 women, will start at week 36 or 37 of pregnancy.
"We're starting with the lowest-risk pregnant group," Bunge said. "When someone's at 36 weeks, the baby is pretty well developed. We aren't worried they are going to have 28-week delivery, because she's at 36 weeks by the time she's enrolled."
These women will be assigned either the dapivirine ring or emtricitabine/TDF and followed for the rest of their pregnancy. Then, the team will do a safety review. And if the drugs appear safe, it will start on the next cohort, which will be another 150 women who are between 30 and 35 weeks into their pregnancy. Then, the team will repeat the process.
If it's safe again, it will start on the next cohort, and the next. If all the cohorts are safe, then it will enroll the biggest cohort: 300 women between 12 and 19 weeks of pregnancy.
"Truthfully, this is where the bulk of our safety data will come from because we will have the most women for the longest time of exposure," Bunge said. "We don't just want to jump in and do it with those women, because we want to make sure that it's safe first."
All of the infants will be followed through their first year of life.
The Next Steps
When Renee Heffron, M.D., Ph.D., was working on the PARTNER Demonstration Study, it took so long for the ethics committee to allow them to give women a choice of whether to continue on emtricitabine/TDF once they got pregnant that, by the end of it, they had data on only 30 women.
So, Heffron's thrilled to see new research that could confirm the safety that she and colleagues found in their studies.
"These studies designed to work with pregnant women are the best way to get robust data and enough to really show and confirm that there aren't any safety issues," said Heffron, who is not involved in the new studies. "And if there is something going on, they are going to get a signal."
But she said she didn't think that the existence of these studies should make providers hesitant to prescribe emtricitabine/TDF to women who are pregnant and could benefit from it. The Centers for Disease Control and Prevention, for instance, recommends emtricitabine/TDF as an option for women throughout their pregnancies.
"These studies are billed as confirming what the guidelines say, what expert groups have synthesized from the available data, and as completing the body of literature on this," she said. "However, it doesn't show any cause for concern. So providers can feel comfortable prescribing PrEP during pregnancy, as it's hugely beneficial to preventing the mom from getting HIV and transmitting it to the baby."