Mitochondrial studies in HAART-related lipodystrophy: from experimental hypothesis to clinical findings.
Chronic use of antiretrovirals (ARVs) to treat HIV infection, along with more prolonged patient survival, has been associated with an increase in adverse drug effects in HIV-infected patients on treatment. It has been proposed that some of these adverse effects (including myopathy, cardiomyopathy, anaemia, hyperlactataemia/ lactic acidosis, pancreatitis, polyneuritis and lipodystrophy) could be mediated by mitochondrial (mt) toxicity. From the experimental data, it has been proposed that nucleoside analogue reverse transcriptase inhibitors (NRTIs) also inhibit gamma-polymerase, the enzyme devoted to replicate (and, to a lesser extent, repair) mtDNA. It is now widely accepted that the use of most NRTIs in HIV-infected patients is associated with mtDNA depletion. Although cross-sectional studies suggest that certain ARVs, especially stavudine, are more toxic to mitochondria, the differences among different highly active ARV therapy (HAART) schedules detected in the analysis of longitudinal studies are not so clear. These types of study in previously untreated individuals suggest that the greatest mtDNA loss appears at the beginning of the treatment. Conversely, in ARV-experienced patients, the potential beneficial effects of HAART changes in terms of mtDNA content remain controversial and must be further investigated. Functional studies accompanying genetic investigations are needed for the correct pathogenic interpretation of the mtDNA abnormalities.
Miró
Oscar
O
Mitochondrial Research Laboratory, Department of Internal Medicine, Hospital Clinic, IDIBAPS, Barcelona, Catalonia, Spain. omiro@clinic.ub.es
López
Sónia
S
Cardellach
Francesc
F
Casademont
Jordi
J
D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D003430:Cross-Sectional Studies; D004272:DNA, Mitochondrial / Q000032:analysis; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D039682:HIV-Associated Lipodystrophy Syndrome / Q000139:chemically induced*; D006801:Humans; D008137:Longitudinal Studies; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology
D004272:DNA, Mitochondrial