Maternal combination antiretroviral (ARV) therapy (cART) during pregnancy has been successful in preventing vertical HIV transmission. However, in utero exposure to ARVs, many of which can cross the placenta, could have long term effects on HIV-exposed uninfected (HEU) infants. Some ARVs can cause mitochondrial toxicity and affect mitochondrial DNA (mtDNA) quantity and quality. Previous studies among HEU infants exposed to cART in utero have been inconsistent, with some reporting increased blood mtDNA levels at birth compared to HIV-unexposed uninfected (HUU) infants, while others report a decrease. Our objective was to compare HEU and HUU infant blood mtDNA content at birth and over the first 3 years of life, and investigate any relationship to cART exposure.
Peripheral blood mtDNA content was measured by monochrome multiplex qPCR in 324 HEU (0-3y, of whom 214 had ≥2 blood samples) and 308 HUU children (0-3y, each with a single blood sample) enrolled in the CARMA cohort study. A subset of these children was randomly age- and sex-matched 1:1 for a cross-sectional comparison of mtDNA content over the first 3y of life. Factors showing an association univariately (p<0.1) were considered in multivariable linear regression models.
mtDNA content at birth (0-3d) was obtained for 114 HEU and 86 HUU children. In a multivariable model of mtDNA content at birth (n=200) that included HEU/HUU status, gestational age (GA) at birth, and maternal smoking during pregnancy, lower GA was the only factor independently associated with higher mtDNA content (p<0.001). Among infants born at term (GA>37w, n=168), although HEUs had significantly lower GA at birth (median: 38.9 vs. 39.7, p<0.01), the multivariable analysis revealed that only HEU status (p=0.005) was independently associated with higher birth mtDNA content. In a separate model that investigated maternal cART parameters among HEUs (n=114), neither duration nor type of in utero cART exposure were associated with mtDNA content at birth. Additionally, infant AZT prophylaxis did not affect mtDNA content at 6w vs. birth. Lastly, among age and sex-matched children (n=214:214), HEU children continued to have higher mtDNA content than HUUs (p<0.01) throughout the first three years of life.
HEUs and infants born preterm have higher mtDNA content at birth, an effect that persisted up to age three. This may represent a long-term effect, possibly resulting from adaptive mitochondrial biogenesis in response to in utero stresses.