Impact of nucleoside reverse transcriptase inhibitors on mitochondria in human immunodeficiency virus type 1-infected children receiving highly active antiretroviral therapy

Abstract

Mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTIs) has been reported to be responsible for various adverse effects. The relative impact of NRTIs on the mitochondria of human immunodeficiency virus (HIV) type 1 (HIV-1)-infected children receiving highly active antiretroviral therapy (HAART) is unknown. Mitochondrial DNA (mtDNA) levels were quantified longitudinally from peripheral blood mononuclear cells (PBMCs) in 31 HIV-1-infected children from Pediatric AIDS Clinical Trial Group Study 382 who were receiving HAART, including nelfinavir, efavirenz, and different NRTIs, and who had had undetectable plasma HIV-1 RNA levels for >2 years. The median mtDNA levels in PBMCs increased from 137 copies/cell at the baseline to 179 copies/cell at week 48 (P = 0.01) and 198 copies/cell at week 104 (P < 0.001). Before the initiation of HAART, children who received regimens containing didanosine had mtDNA levels persistently lower than those in children not receiving didanosine (106 versus 140 copies/cell; P = 0.008). During HAART, the median increase in the mtDNA level from the baseline to week 104 was the lowest in children who received regimens containing didanosine (+26 copies/cell) compared to those in children who received other regimens (+79 copies/cell) (P = 0.02). A multivariate analysis also demonstrated that didanosine, as part of HAART, was the only NRTI associated with the change in mtDNA levels (P = 0.007). Children receiving didanosine-containing antiretroviral regimens have the lowest mtDNA levels in PBMCs and may be at greater risk for long-term adverse effects due to mitochondrial toxicity. This may be of particular importance in resource-limited countries where didanosine is widely used for the treatment of HIV-infected children.

Figures

FIG. 1.

Changes in mtDNA levels from the baseline to week 104 between children who received specified NRTI and those who did not receive specified NRTI during HAART. Squares, median values of the changes in mtDNA levels from the baseline to week 104; bars, IQRs of changes in mtDNA levels from the baseline to week 104. The Wilcoxon sum rank test was used to compare the mtDNA levels between the two groups.

FIG. 2.

Changes in mtDNA levels from the baseline to weeks 8, 48, and 104 on the basis of the NRTI regimens received during HAART. The different symbols indicate the median values of the changes in mtDNA levels from the baseline to each week in children who received (i) d4T (⧫), (ii) ZDV plus 3TC (▴), (iii) d4T plus 3TC (•), and (iv) ddI-containing regimens (▪). Bars indicate the IQRs of changes in mtDNA levels from the baseline to each week. The Wilcoxon sum rank test was used to compare the mtDNA levels in two groups.