Studies on Newer Antiretrovirals in Pregnancy: Time for a Paradigm Shift

Key Takeaways

• Treatment of pregnant women with HIV should be a balancing act considering both maternal and infant needs.
• For newer antiretrovirals, pregnancy safety studies should be prioritized to avoid providing young women with HIV with outdated treatment strategies.

The treatment of pregnant women with HIV has always been a balancing act that equally considers maternal and infant interests. As healthcare professionals, we would like to offer young women the same antiretroviral treatment (ART) options we use in all our other patients. However, for newer drugs, we face a lack of efficacy and safety data regarding their use in pregnancy. Therefore, most HIV pregnancy guidelines differ from guidelines for nonpregnant adults with HIV. This results in fewer treatment options for pregnant women with HIV and for young women who wish to conceive. Young women with HIV are at risk of being provided with drugs and treatment strategies that are outdated.

The Pregnancy Data Gap
The main reason for the underlying data gap is the exclusion of pregnant women from clinical trials on new drugs since the thalidomide scandal in the 1960s. What was meant as protection for mother and fetus has turned into the opposite. Because data from prospective trials are missing, the use of new drugs in pregnant women is guided by limited evidence from animal studies, case reports, and pregnancy registries.

The Tsepamo Study
Because of the restrictions on efavirenz (EFV) use during pregnancy, we know that data from animal studies cannot easily be transferred to humans. Significantly increased neural tube defects (NTDs) in monkeys exposed to EFV could not be confirmed in humans. Furthermore, EFV turned out to be a drug recommended for pregnant women by the WHO for many years. The Tsepamo study was a surveillance study evaluating NTDs with EFV that was extended to evaluate the use of dolutegravir (DTG) in 2016. Two years later, a signal of an elevated risk of NTDs was observed in women who conceived while receiving DTG treatment. However, thanks to the ongoing prospective study and the consistent analysis of a higher number of pregnancies, we now know that the use of DTG at conception is not associated with a higher risk of NTDs.

Antiretroviral Pregnancy Registries
National and international antiretroviral pregnancy registries also provide important maternal and infant safety data. Nevertheless, it takes time for a reasonable number of pregnancies to be reported and analyzed. In addition, HIV pregnancy registries cannot replace prospective ART studies or studies on the pharmacokinetics and pharmacodynamics of drugs in pregnant and breastfeeding women. These data are usually available with a delay of 6-8 years after approval of a drug.

Protecting Women Through Research: A Paradigm Shift
Driven by the COVID-19 pandemic, with the obvious need to offer the newly approved vaccines to pregnant women, there has been a call to action to accelerate research activities on the use of ART in pregnancy. A paradigm shift is underway, moving from protecting pregnant women from research to protecting them through research. There has been a consensus on a new framework, including early pharmacokinetics studies for all new drugs. So, in the future, by the time a drug gets approved, pharmacokinetics and preliminary safety data should be available. For women who become pregnant in a clinical trial, it should be possible to stay on the study drug. For so-called priority drugs, pregnancy safety studies should be performed during phase III trials or early post approval. Comprehensive and strategic surveillance in pregnant women should be carried out after approval of a drug.

Conclusion
Finally, it should be mandatory to involve women with HIV at all stages of decision-making in the research of antiretroviral drugs. New drugs can make a significant difference for mother and child. We need them, and we need them much faster.

Your Thoughts?
How do you handle the balancing act to meet maternal and infant needs when data are lacking for antiretrovirals in pregnancy? Join the discussion by posting a comment.