In Utero Efavirenz Exposure Associated With Microcephaly Risk

People with perinatally acquired HIV face unique challenges. Since the development of combination antiretroviral regimens, occurrence of perinatally acquired HIV has decreased substantially. Progress on this front, however, presents new challenges: children who are exposed to HIV in the womb but do not become infected experience complications, such as microcephaly, which warrant the attention of clinicians.

A new study, published in The Lancet HIV, evaluated the relationship between in utero antiretroviral exposure and microcephaly. The study found that exposure to the antiretroviral efavirenz was associated with 2 to 2.5 times increased risk of microcephaly. Study authors also demonstrated that children exposed to HIV in utero with microcephaly had lower mean scores on neurodevelopmental assessments.

The study evaluated children enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study at 22 clinical sites in the United States. Those evaluated were below the age of 18 years, had been exposed to but were not infected with HIV, and had at least 1 head circumference measurement while enrolled. Microcephaly was qualified as having a head circumference Z score < -2 according to the 2000 US Centers for Disease Control and Prevention growth charts for children 6 to 36 months old.

After 36 months, Nellhaus standards (head circumference < 2^nd percentile) were used. This was referred to as the SMARTT criteria. An alternative definition for microcephaly was developed by applying Nellhaus standards across all ages, referred to by study authors as the Nellhaus criteria.

Relative risks were obtained using Poisson regression models examining associations between in utero antiretroviral exposure and microcephaly status, with adjustments made for potential confounders. Neurodevelopmental functioning was compared between children who were exposed to HIV but infected with and without microcephaly.

A total of 3055 participants enrolled in SMARTT between March 21, 2007 and August 1, 2017 had at least 1 head circumference examination. The cumulative incidence of microcephaly over a median of 5.1 years of follow-up was 70 (2.9%) by SMARTT criteria and 159 (5.2%) by Nellhaus criteria.

Adjusted models showed utero exposure to efavirenz (4.7% exposed) was associated with increased risk of microcephaly when examined using both Nellhaus standards (relative risk 2.02) and SMARTT criteria (relative risk 2.56).

Associations were more pronounced in children who had been exposed to combination regimens of efavirenz with zidovudine plus lamivudine compared to those exposed to combination regimens of efavirenz with tenofovir plus emtricitabine.

Protective associations were observed for darunavir exposure (relative risk 0.50). Children who were exposed but uninfected with microcephaly had lower neurodevelopmental assessment mean scores at age 1 and 5 and a higher prevalence of neurodevelopmental impairment compared to those without microcephaly.

The results ultimately indicated that children whose mothers were on regimens with efavirenz were more than 2 times as likely to have microcephaly, relative to children whose mothers were treated with other therapies.

“Our findings underlie the importance of having alternatives to combination therapy with efavirenz for pregnant women with HIV,” study author Rohan Hazra, MD, chief of the Maternal and Pediatric Infectious Disease Branch of National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, said in a press release.