Is gestational exposure to HIV and protease inhibitors associated with timing of pubertal onset?

Background: Few studies have evaluated the influence of gestational HIV/antiretroviral exposure on pubertal onset in children who are HIV-exposed but uninfected (CHEU). Methods: CHEU in the Surveillance Monitoring for ART Toxicities study and children HIV-unexposed uninfected (CHUU) in the Bone Mineral Density in Childhood Study with Tanner staging at age 9 years were included. Pubertal onset was defined as Tanner stage >2 for each sex-specific puberty indicator. Log-binomial regression models were fit to estimate relative risks (RRs) of pubertal onset in CHEU vs. CHUU, adjusted for exact age and other covariates. Among CHEU, models were fit to assess the association of pubertal onset with maternal protease inhibitor exposure, CD4 count, and earliest HIV viral load (VL) in pregnancy. Results: 227 CHEU (114 female, 113 male) and 344 CHUU (182 female, 162 male) were included. Among male CHEU, the adjusted likelihood of pubertal onset by age 9 years was 2.07 times higher [95% CI 0.89, 4.79] for genitalia and 3.55 times higher [95% CI 0.92, 13.81] for pubic hair compared to male CHUU. Pubertal onset was similar in female CHEU and CHUU. Among male CHEU, a maternal VL >400 copies/mL was associated with a greater likelihood of pubertal onset (adjusted RR:12.6 [95% CI 1.56, 102] for genitalia and 9.85 [95% CI 1.17, 83] for pubic hair). Conclusions: Gestational HIV exposure and exposure to higher maternal HIV viral load was associated with greater likelihood of pubertal onset by age 9 years in male CHEU. Further confirmatory and mechanistic studies are warranted.