In utero nucleoside reverse transcriptase inhibitor exposure and signs of possible mitochondrial dysfunction in HIV-uninfected children

Abstract

Our study suggests that first exposure to 3TC or ZDV/3TC in the third trimester may be associated with the occurrence of possible MD. Further studies that rigorously assess MD and better control confounding are needed.

Neurologic Outcomes in HIV-Exposed/Uninfected Infants Exposed to Antiretroviral Drugs During Pregnancy in Latin America and the Caribbean

“…While some studies have reported less than 1% prevalence, 4,5,19 most studies have reported prevalence rates of 1%-3%. 6,8,14,15,20 Although our prevalence is higher, this may be because the NISDI study was designed specifically to detect both adverse and serious adverse events among HEU infants, and thus, the neurologic outcomes included were much broader (including head circumference to ascertain microcephaly) compared to previous studies that looked only at MD as an outcome. In fact, excluding microcephaly, our observed prevalence of other specific neurologic diagnoses was only 2.4%, which is more in line with the 1%-3% prevalence frequently reported.…”

“…The findings of this investigation are consistent with those of previous studies that found no association between in utero ARV exposure and neurologic outcomes, such as MD, [10][11][12][13]20,21 neurologic events, 14,21 and congenital abnormalities 15 among HEU infants. However, there are other studies that did find associations between in utero ARV exposure and MD, 4,8 hyperlactatemia, 22 febrile seizures, 6 and neurologic dysfunction. 7 Our analysis examined differences by specific ARV drug among all cART-exposed infants, while other studies compared cART-exposed infants to those unexposed.…”

“…Using this logic, one explanation for the findings from the PACTG 219/219C study, that demonstrated that initiation of 3TC or ZDV/3TC in the third trimester was associated with neurologic/neurodevelopmental abnormalities, could be that uncontrolled HIV infection earlier in pregnancy, rather than a toxic effect of the ARVs started in the third trimester, was the contributing factor for the findings in these children. 8 With regard to covariates, the odds of NC was higher among male infants and those with lower birth weight, lower Apgar scores, maternal infectious disease, and infant infections themselves. These findings are not unexpected and are in line with previous studies finding higher rates of microcephaly and more NCs associated with these risk factors.…”

“…7 Data from the PACTG 219/219C included 20 cases of possible MD among 1,037 HEU subjects, 19 of whom had neurologic/neurodevelopmental signs, including 9 with seizures, and found an increased risk of MD associated with maternal initiation of 3TC or ZDV/3TC in the third trimester of pregnancy. 8 While the overall prevalence of possible MD in the PACTG 219/219C cohort was higher than that seen in the French cohort (0.3% in the FPCS, 1.8% in 219/219C ARV-exposed HEU subjects, and 2.9% in 219/219C ARV-unexposed HEU subjects), 8 more recent data from the US IMPAACT P1025 cohort reported a 0.3% prevalence of possible MD, but the number of cases was too small (n = 3) to analyze the association between ARV exposure and the clinical findings. 9 Beyond the IMPAACT P1025 results, findings from the initial FPCS were not supported by results from many other groups, including investigators from several US cohorts who reviewed >20,000 HEU subjects and found no deaths due to MD.…”

Evaluation and Management of the Infant Exposed to HIV-1 in the United States

“…Mitochondrial dysfunction should be considered in children with perinatal ARV exposure who present with severe clinical findings of unknown etiology, particularly neurologic findings. [67][68][69][70][71][72][73][74] Information regarding in utero and/or neonatal ARV exposure should be part of the ongoing permanent medical chart of the child, particularly for uninfected children. Children with in utero ARV exposure who develop significant organ-system abnormalities of unknown etiology, particularly of the nervous system or heart, should be evaluated for potential mitochondrial dysfunction.…”