The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs

Abstract

The Surveillance Monitoring for ART Toxicities (SMARTT) cohort of the Pediatric HIV/AIDS Cohort Study includes over 3,500 HIV-exposed but uninfected infants and children at 22 sites in the US, including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARVs) and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental (ND), behavior, language, and hearing. SMARTT employs an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger) undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain) with exposure to combination ARVs (cARVs), any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a ND case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With ND testing at 1 year of age, specific ARVs (atazanavir, ritonavir-boosted lopinavir, nelfinavir, and tenofovir) were associated with lower performance, although all groups were within the normal range. No ARVs or classes were associated with lower performance between 5 and 13 years of age. Atazanavir and saquinavir exposure were associated with late language emergence at 1 year, but not at 2 years of age. The results of the SMARTT study are generally reassuring, with little evidence for serious adverse events resulting from in utero ARV exposure. However, several findings of concern warrant further evaluation, and new ARVs used in pregnancy need to be evaluated.

Management Algorithm for Interrupting Mother-to-Child Transmission of Hepatitis B Virus

“…Generally, pregnancy category B drugs such as TDF and LdT are safe to use during pregnancy, and antiviral treatment with TDF or LdT has no influence on congenital abnormalities or neonatal growth percentiles. However, it should be noted that in a human immunodeficiency virus/acquired immune deficiency syndrome cohort study, 23 in utero exposure to TDF resulted in a 12% reduction in total mean whole-body bone mineral content (56.0 vs 63.8 g, respectively; P ¼ .002). Moreover, the rate of postpartum hepatic flare was reported to be 40% to 50% in mothers who stopped antiviral treatment.…”

Surveillance monitoring for safety of in utero antiretroviral therapy exposures: current strategies and challenges

“…Due to its long-term follow-up, this cohort study is able to address adverse outcomes beyond the early infant period including language and hearing impairment, pre-school and school-aged neurocognitive functioning, metabolic and cardiovascular outcomes, and growth and pubertal maturation. Additional details of study design and key findings have been recently summarized [55]. …”

Emerging evidence from a systematic review of safety of pre‐exposure prophylaxis for pregnant and postpartum women: where are we now and where are we heading?

“…However, we identified few studies evaluating prenatal PrEP exposure and longer‐term infant outcomes. In the SMARTT cohort, TDF use in pregnancy among HIV‐infected mothers was associated with reduced bone mineral content in neonates compared to exposure to other ARVs, though TFV concentrations in meconium were not associated with infant weight, length or bone mineral content . A recent study using DXA suggests that prenatal TDF exposure in HIV‐exposed infants may lead to decrement in neonatal bone mineral density .…”