Background:  Mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTI) has been reported to be responsible for many of the associated adverse effects. The relative impact of NRTI on mitochondrial DNA of HIV-1-infected children receiving HAART is unknown.

Methods:  We selected 31 HIV-1-infected children from PACTG 382 receiving 1 to 2 NRTI, nelfinavir, and efavirenz on the basis of sustained undetectable plasma HIV-1 RNA ≥2 years. The mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) were quantified from peripheral blood mononuclear cells using real-time PCR. The mtDNA: nDNA ratios were compared longitudinally before and during HAART. Clinical markers including plasma HIV-1 RNA, HIV-1 intracellular DNA, CD4⁺ T-cell counts and percents, lipid profiles, physical parameters and the incidence of adverse effects were compared to mtDNA levels.

Results:  The median mtDNA levels increased from 137 copies/cell at baseline to 179 copies/cell at week 48 (p = 0.01) and 198 copies/cell at week 104 (p <0.001). Children who received regimens containing didanosine (ddI) had persistently lower mtDNA levels compared to those in children who received regimens not containing ddI at baseline (106 vs 140 copies/cell, p = 0.008), at week 48 (155 vs 182 copies/cell, p = 0.04) and week 104 (158 vs 214 copies/cell, p = 0.01). When we analyzed the subjects based on the use of other NRTI, no statistical significant differences in the mtDNA levels were observed at weeks 48 and 104 (p = 0.27 to 0.40). The mtDNA levels were negatively associated with the HIV-1 intracellular DNA levels at the early stage of HAART (p = 0.02). Plasma HIV-1 RNA, CD4⁺ T-cell counts and percentages, lipid profiles, physical findings and the incidence of adverse effects were not associated with the mtDNA levels.

Conclusions:  ddI significantly lowers the mitochondrial DNA levels in peripheral blood mononuclear cells of children before and during HAART. Children receiving ddI 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 ddI has been widely used for treatment of HIV-infected children.