By: Gina Edwards

Imagine a scenario where a pregnant woman comes to her physician seeking an HIV prevention method. Instead of the clinician saying things like, ‘Well, it was safe for pregnant mice.’ or ‘It's safe in non-pregnant people.’, they can say with confidence, ‘This product was studied in pregnant people just like you, and there were no safety issues identified.’

This ideal scenario is the goal, as pregnant people need safe HIV prevention products. Yet, historically pregnant and breastfeeding people have been excluded from clinical trials, which is a big problem: pregnancy represents a period of increased HIV risk for both hormonal and behavioral reasons. In fact, pregnant people are three times more likely to acquire HIV than their non-pregnant counterparts.

The Microbicide Trials Network (MTN), under the direction of MWRI researcher Sharon L. Hillier, PhD, set out to address this problem directly by proposing a safety trial of a novel HIV prevention product in pregnancy. The DELIVER trial is evaluating the safety of both the dapivirine vaginal ring (DVR) and oral pre-exposure prophylaxis (PrEP).

DVR is a silicone ring containing an HIV medication called dapivirine. It is inserted into the vagina and stays there for one month, at which point the old ring is replaced with a new ring. Over the course of the month, the ring slowly releases the anti-HIV medication, which protects women from acquiring HIV through vaginal sex. Currently, it is only approved for non-pregnant, non-breastfeeding individuals, ages 18 to 45.

Breaking the Traditional Study Design Mold

It is highly unusual to actively study the safety of a drug in a pregnant population. Typically, a drug is approved for non-pregnant people, and when a pregnant patient needs the medication, the doctor and patient must assess the risk-benefit ratio based on limited safety data in humans.

Dr. Katherine Bunge, an MWRI researcher and protocol chair of the DELIVER study, says she understands why many people would assume that such a study could not be done.

“In my experience, pregnant people don’t want to take any medication –– let alone a medication that has not been studied thoroughly in pregnancy,” Dr. Bunge says. “The truth is though, people who have enrolled in the trial recognize that they are at risk for HIV and are looking for a prevention method that fits into their life.”

Because of the complexities of studying the safety of a then-investigational drug in a pregnant population, MTN held a large stakeholder meeting to seek support and input on the study design with key decisionmakers from the countries in which the study was to be conducted: South Africa, Malawi, Uganda, and Zimbabwe. Follow-up meetings also engaged community leaders and local Institutional Review Boards (IRBs).

The DELIVER study operated in a stepwise fashion — enrolling one group at a time and submitting data to be analyzed and approved by an independent safety review panel before moving onto the next stage. They began the trial with women late in the third trimester who used either DVR or oral PrEP until delivery, and then moved onto the second group, who were early in their third trimester. Finally, DELIVER moved into the last group of women in the second trimester. At each step, staff members carefully explained the study to prospective participants and worked with the community at large to address any concerns.

Ultimately, the DELIVER study found that women can safely use the dapivirine vaginal ring for HIV PrEP in the third trimester of pregnancy. A sister trial evaluated and confirmed that DVR is also safe to use during breastfeeding. Dr. Bunge presented the pregnancy outcomes and complications from the first two groups at the 30th Conference on Retroviruses and Opportunistic Infections (CROI), a national HIV conference. MTN’s methodical study design on an investigational product in a pregnant population could be used as a model for other drugs.

“This is a Game Changer.”

Several African countries have approved DVR and it has been recommended by the World Health Organization for women at high risk of acquiring HIV. Other products that have been approved for HIV prevention include a daily pill and an injectable medication administered every two months.

DVR is a landmark advancement in HIV prevention products, particularly as it is the first woman-controlled method.

“Many women do not have the ability to negotiate condom use with their partners, so this is a game changer,” Dr. Bunge says. “The dapivirine vaginal ring is discreet — nobody needs to know you are using it — comfortable, and inexpensive to scale up. Because the medication is released exactly where it is needed but not absorbed into the blood stream in significant quantities, the risks of systemic side effects and HIV drug resistance are almost nonexistent.”

For years, pregnant people have been excluded from clinical trials. But MWRI researchers are at the forefront of women's health research: pushing boundaries, imagining the unimaginable, and prioritizing the health of women. The DELIVER trial is an example of this commitment to change.

“A lot of people will say that studying the safety of an investigational product in pregnancy is too hard and too expensive,” Dr. Bunge says. “The DELIVER trial demonstrates that it can be done.”