Monitoring the safety of ARV therapy during pregnancy

Paige Williams

December 1, 2015 — Paige Williams, senior lecturer on biostatistics at Harvard T.H. Chan School of Public Health, studies the health and development of children whose HIV-infected mothers took antiretroviral (ARV) drugs during pregnancy.

In a study published last year, you found that the overall risk of birth defects was low for women taking ARVs during early pregnancy — in keeping with previous research that has found ARV use in pregnancy to be generally safe. What did you look at in the current study, and what did you find?

The current study focuses on health and developmental problems that might emerge later in life, such as cognitive, hearing, and language impairments, and metabolic problems. We found that taking combination antiretroviral drugs during pregnancy does not increase the overall risk of these adverse outcomes in babies born to mothers living with HIV.

However, one commonly used drug called zidovudine (or AZT) was linked to about 70% higher risk for metabolic problems in these children. We did not anticipate finding this, since this drug has not previously been linked to metabolic problems. In contrast, many drugs in the class of ARVs known as protease inhibitors were linked to lower risk of metabolic problems in this study, even though this drug class has often been linked to higher risk of issues such as elevated cholesterol.

We also found over four-fold higher risk of both neurodevelopmental and language impairments for children whose mothers took didanosine plus stavudine during pregnancy. These particular drugs are now rarely used during pregnancy due to other safety concerns.

In addition, while not linked to antiretroviral drug exposures, the percentage of babies with some type of health or developmental problem — about one in four — was surprisingly high. The high rates, particularly for metabolic problems and language impairment, may be partially attributable to other risk factors that are common in our study population, such as low socioeconomic status.

The basis for your research is the SMARTT study (Surveillance Monitoring of ART Toxicities). What are the goals of that study?

We developed a systematic approach for classifying side effects after birth in children born to mothers with HIV infection. This approach looks for “trigger” events — certain adverse clinical, laboratory, developmental, or cognitive problems— to identify which children require additional follow-up. Confirming these potential adverse reactions to ARVs is costly and may require either a specialized consult or other invasive tests. The SMARTT trigger-based design means not having to conduct these types of tests on every enrolled child.

Using this trigger-based approach, we were able to combine information across multiple domains in which ARV side effects could occur, such as poor growth, neurologic problems, neurodevelopmental problems, hearing or language problems, and metabolic toxicities. This type of study design could serve as a model for other studies aiming to evaluate the safety of ARV exposures during pregnancy.

Why is this research significant and what are the next steps?

Current guidelines by the World Health Organization and other agencies now recommend that women with HIV start combination antiretroviral treatment during pregnancy, if not already receiving ARVs, and then remain on this treatment for the rest of their lives. As a result, a higher percentage of women will be expected to already be on antiretroviral drugs when they become pregnant. Globally, this will vastly increase the numbers of children with intrauterine exposure to such drugs. Overall, our study results support the safety of these recommendations, but they also suggest that continued monitoring of the safety of such exposures is a critical need for the future.

Some of our next steps include evaluating whether the side effects observed in children in our study resolve over time, and whether new adverse outcomes emerge over time. We also need to evaluate newer ARV drugs as they are approved and become more widely used during pregnancy. Finally, given the large number of ARV drugs available, we need to conduct assessments to determine the safest combination of ARV drugs and also the safest time during pregnancy to initiate ARVs. Some of these questions will be discussed by experts at an upcoming ARV Safety Workshop to be held by the Biostatistics Department at the Harvard Chan School early next year.

Amy Roeder