Mild improvement in mitochondrial function after a 3-year antiretroviral treatment interruption despite persistent impairment of mitochondrial DNA content

Objective: The ability of a prolonged antiretroviral treatment interruption to reverse mitochondrial toxicity was evaluated in a sub-study of TIBET, a prospective trial examining antiretroviral treatment interruption guided by CD4+ cell count. Patients and Methods: The study population was composed of patients from the TIBET study who had been followed for 96 weeks and whose peripheral blood mononuclear cells (PBMCs) had been collected at baseline and throughout the study period. Of the 201 patients included in the TIBET study, 38 were selected for the mitochondrial sub-study; 18 patients discontinued antiretroviral therapy for 96 weeks and 20 maintained therapy. Mitochondrial DNA (mtDNA) and RNA (mtRNA) were measured in PBMCs using real-time polymerase chain reaction, and mitochondrial function relative to mitochondrial content was assessed using the cytochrome c oxidase and citrate synthase ratio (COX/CS). Results: Whereas mtDNA content showed a similar progressive decrease throughout the study period in both arms, the mtRNA amount remained stable in both groups and the COX/CS ratio improved significantly in patients who interrupted therapy. Conclusions: Mitochondrial function improved during a prolonged antiretroviral treatment interruption despite a decrease in mtDNA levels in PBMCs, probably because of the existence of a mitochondrial transcriptional and translational upregulation mechanism or the reversion of mitochondrial toxicity by a mechanism that is independent of DNA polymerase gamma. The reduction in virus-related mitochondrial damage should be considered another relevant benefit of antiretroviral therapy.