From Pages to Practice
Often, the first question that women living with HIV ask when they discover they are pregnant is, “Are my antiretrovirals safe for my baby?” Most of the time, the answer is yes. In 2018, the U.S. Department of Health and Human Services issued guidelines to reflect no difference in rates of birth defects for a long list of antiretrovirals that are used during pregnancy, including the most common regimens containing zidovudine, lamivudine, tenofovir, darunavir and ritonavir.
However, some concerns have been raised about an association between antiretrovirals and birth defects, particularly with efavirenz, based largely on case reports that suggested an association with neural tube defects. A newer antiviral, dolutegravir, is more effective than efavirenz with a higher barrier to resistance, better side-effect profile, and increased viral suppression. Therefore, the World Health Organization (WHO) recommended dolutegravir as a first-line agent for HIV, and it became the first-line treatment used in Botswana in 2016. Then, in 2018, a review of data alerted the WHO of a potential association between dolutegravir and neural tube defects.
In a prospective observational study, researchers conducted birth-outcomes surveillance among 119,477 deliveries in Botswana between 2014–2019. All abnormalities were documented and photographed. Unexpectedly, dolutegravir exposure at conception was associated with a slightly higher prevalence of neural tube defects than exposure to other antiretrovirals at conception. However, the prevalence of 0.3% reported in this study was lower than the prevalence of neural tube defects reported in previous studies of dolutegravir. Due to dolutegravir’s greater suppression of viral load in pregnancy, it remains an important option for HIV-positive women to manage their disease during pregnancy.
The following NEJM Journal Watch summary explains the study in more detail.
Anna Wald, MD, MPH reviewing Zash R et al. N Engl J Med 2019 Jul 22 Raesima MM et al. N Engl J Med 2019 Jul 22 Havlir DV and Doherty MC. N Engl J Med 2019 Jul 24
Is dolutegravir safe for women of reproductive age to use? Following a potential concern due to increased risk for neural tube defects in the offspring of women who received dolutegravir-based antiretroviral therapy at conception (NEJM JW Infect Dis Aug 2018 and Lancet Glob Health 2018 Jul; 6:e804; [e-pub]), investigators in Botswana prospectively evaluated almost 120,000 more deliveries for adverse birth outcomes with a focus on neural tube defects identified with neonatal surface examination.
Neural tube defects occurred in 0.3% of infants born to 1683 women who received dolutegravir at conception, 0.1% of infants of 14,792 women who received antiretrovirals without dolutegravir, 0.04% of infants of 7959 women who received efavirenz, and 0.08% of infants of 89,372 women who were HIV negative. Additional surveillance data from elsewhere in Botswana also showed a small increase in risk for neural tube defects among newborns of women taking dolutegravir at conception and early in pregnancy.
Comment: These extensive data confirm that, when taken at conception, dolutegravir is likely associated with the slightly (<1%) increased risk for neural tube defects. Nonetheless, this integrase inhibitor remains the preferred first- and second-line antiretroviral because of its high efficacy, ease of administration, infrequent side effects, and high barrier to resistance. In addition, modeling studies have indicated that, compared with other regimens, dolutegravir leads to better outcomes for women and infants because of improved maternal health and fewer perinatal HIV transmissions (NEJM JW Infect Dis May 2019 and Ann Intern Med 2019; 170:614). As such, the WHO has reaffirmed use of dolutegravir for all persons living with HIV, including pregnant women. It remains unknown whether folate supplementation in this setting can mitigate risk for neural tube defects; further surveillance should help answer that question.