Sixth International Congress Drug Therapy in HIV Infection 17-21 November, 2002 Glasgow, UK

Purpose of the study: Nucleoside reverse transcriptase inhibitors (NRTIs) are being increasingly associated with mitochondrial (MT) toxicity. We aimed to assess MT content and function in peripheral blood mononuclear cells (PBMCs) of HIV-infected patients previous to the development of clinically evident body fat changes.

Methods: Methods We studied one control group of antiretroviral naïve patients (n=25) and four (n=42) on different highly active antiretroviral therapies (HAART) consisting on AZT+3TC or d4T+ddI plus either nelfinavir (NFV) or nevirapine (NVP) for at least 6 months. Groups were comparable in age and gender. The relative mitochondrial/nuclear (MT/n) DNA ratio was determined by real time PCR and MT abundance was estimated by means of citrate synthase activity. Enzyme activity of complexes III and IV of the electron transport chain (ETC) was spectrophotometrically determined; oxygen consumption was polarographically measured in intact PBMCs and in the presence of complex I and III substrates. The decrease of cis-parinaric acid fluorescence due to lipid peroxidation reactions was used to indirectly monitor the oxidative damage of PBMCs membranes.

Summary of results: Only those groups of HIV-infected patients on HAART including d4T+ddI exhibited significant MTDNA depletion. MT abundance was significantly lower in all treated groups, showing NFV-containing HAART groups the greatest decrease. Antiretroviral regimens containing either d4T+ddI or NFV were associated with a significant decrease of enzyme activity of complex IV of ETC, being the greatest decline found when both d4T+ddI and NFV were combined in the same schedule. All oxidative activities remained normal. None HAART regimen was associated with increased lipid peroxidation; even those groups receving d4T+ddI exhibited less oxidative damage of lipids from PBMCs membranes than others groups.

Conclusions: Conclusions Three main conclusions arise from our data. First, PBMCs can be used to detect different degrees of mitochondrial toxicity of HAART regimens, even before adverse effects occur. Second, all HAART regimens seem to exert toxic effects on mitochondria and different patterns are observed, suggesting the presence of different HAART pathogenic mechanisms on mitochondria. And third, despite MTDNA depletion was present in asymptomatic patients on d4T+ddI-containing HAART, functional capacity of MRC remained normal and the oxidative damage was not increased. Accordingly, we recommend caution on interpreting isolated abnormal genetic mitochondrial analyses and encourage simultaneous genetic and functional approach previous to attribute any pathogenic conclusion.

Presenting author: S López

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1 Muscle Research Unit, Internal Medicine Department.

2 Infectious Unit, Hospital Clínic of Barcelona, Spain.

3 HIV Unit, Hospital Fundació-Asil de Granollers, Spain.

2002-11-17
PL14-1
1a

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