Perinatal Exposure to Antiretroviral Therapy Is Associated with Increased Blood Mitochondrial DNA Levels and Decreased Mitochondrial Gene Expression in Infants

Background. The effects of perinatal antiretroviral therapy (ART) on infant mitochondrial function are not well known. We compared blood mitochondrial DNA (mtDNA) levels and mtDNA gene expression (mtRNA) in human immunodeficiency virus (HIV) --uninfected, ART--exposed infants born to HIV--positive mothers with mtDNA levels and mtDNA gene expression in control infants born to uninfected women. Methods. In this prospective cohort study, longitudinal mtDNA: nuclear DNA and mtRNA: beta--actin mRNA ratios were compared in blood samples obtained at various time points from birth to 8 months, using generalized estimating equation linear regression models. Results. Log(10) mtDNA levels at birth were higher in ART--exposed infants, compared with levels in control infants, although the difference did not reach statistical significance (P = .07 for comparison of samples obtained 0 --3 days after birth). ART--exposed infants' mtDNA levels increased further during the zidovudine prophylaxis period from age 4 days to age 6 weeks -(P = .001) and remained significantly higher than the levels observed in control infants until the end of the study. In contrast, log(10) mtRNA levels at birth were lower in ART--exposed infants than in control infants (P = .03), but were not statistically different later. Conclusions. When control infants and ART--exposed infants were compared, the mtDNA level was increased but mitochondrial gene expression was decreased in ART--exposed infants. These differences persisted after zidovudine was discontinued, suggesting that changes in mitochondrial proliferation and/ or expression take place during and after ART exposure. These changes are likely the effects of the antiretroviral drugs on mitochondria. The clinical relevance and long--term impact of these alterations must be studied.