Background:  Nucleoside (NRTI) -containing ART can cause mitochondrial (mt) toxicity. We investigated blood mtDNA and mtRNA levels in HIV-uninfected ART exposed infants (born to HIV-infected women and exposed to HAART in utero and zidovudine (ZDV) for ~6 weeks after birth), and compared them to non-ART-exposed control infants born to HIV-uninfected women.

Methods:  A total of 75 ART-exposed and 80 control infants from 2 Canadian sites were studied. Blood was collected longitudinally from ART-exposed infants at 1 to 3 days and an additional 1 to 4 times until ~8 months of age. Control infants, aged 1 day to 8 months, had blood collected once. Blood mtDNA/nuclear DNA (nDNA) ratio was quantified in all samples (n = 316). Mt (cytochrome C oxidase I) mRNA/b-actin mRNA was measured in samples from 1 site (n = 197). Comparisons between ART-exposed and control infants were done on log transformed values, using generalized estimating equations modeling over 4 periods (1 to 3 days, 4 days to 6 weeks, 6 to 16 weeks, >16 weeks).

Results:  ART-exposed infants experienced neutropenia (28%), anemia (57%), and hyperlactatemia (89%). Although blood mtDNA levels were similar at birth (1 to 3 days, p = 0.06), they increased over time until 6 weeks (p <0.0001) in both groups. During the 4-day to 6-week period, mtDNA became significantly higher in ART-exposed infants than in controls (p = 0.0006) and remained so throughout the study period (6 to 16 weeks, p = 0.008; >16 weeks, p <0.0001). In contrast, mtRNA levels were lower in ART-exposed infants than controls at birth (1 to 3 days, p = 0.04). MtRNA increased in both groups over the 4-day to 6-week period (p = 0.009), but tended to remain lower in ART-exposed infants than in controls (4 days to 6 weeks, p = 0.08; >16 weeks, p = 0.07) except in the 6- to 16-week period (p = 0.99), likely due to low number of controls (n = 8) in that age group.

Conclusions:  In this observational study, mild laboratory abnormalities suggestive of mitochondrial toxicity were frequent in ART-exposed infants. The significantly greater increase in mtDNA levels during the first 6 weeks of life in the ART-exposed infants and the persistence of this elevation long after ZDV discontinuation, along with the concurrent decrease in mtRNA, suggest that significant changes in blood mitochondrial proliferation and gene expression take place during and after ART exposure. Although the relative influence of in utero vs postnatal ART exposure remains unclear, it is postulated that these changes are a consequence of the toxic effect(s) of the drugs on the cells and their mitochondria.The impact of these alterations on mitochondrial function and integrity, as well as their potential long-term implications, requires further study.