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Background:  Nucleoside reverse transcriptase inhibitor (NRTI) induce mitochondrial toxicity, resulting in damage of the respiratory chain. Our objective was to evaluate the in vivo effect of several NRTI-combinations on the respiratory chain by selective exploration of muscle and liver lactate metabolism in HIV-infected patients.

Methods:  This cross-sectional study enrolled HIV-infected patients who were untreated (Group 1), on stable triple-combination with at least 1 drug (zidovudine, zalcitabine, stavudine, didanosine; Group 2), or with a backbone of abacavir and lamivudine (Group 3). Venous lactatemia was measured at rest. Muscle lactate metabolism was assessed during a standardized non-ischemic exercise-test, and liver lactate metabolism was evaluated during intravenous lactate perfusion.

Results:  We enrolled 70 patients (87.5% men), median age 41 years, and a median 9-year-history of HIV infection, in the study (Group 1: 17 patients, Group 2: 34 patients, Group 3: 19 patients). None of the patients had hyperlactatemia symptoms. Group 3 patients had been pre-treated with drugs for a median of 7 years, and were switched for less toxic NRTI for a median of 18 months. Despite ranging within normal values in all patients, the median blood lactate level at rest was significantly higher in treated patients (G2: 1.30 mmol/L, G3: 1.50 mmol/L) than in untreated patients (0.90 mmol/L, p = 0.0005). Muscle lactate metabolism showed that lactate production (normalized by the mechanical energy production and peak of lactatemia) was not different between the three groups, but lactate clearance, measured by the ratio peak lactatemia on lactatemia 10 minutes after the exercise, was decreased in both treated groups (Group 2 ratio: 1.60, Group 3 ratio: 1.80) in comparison with untreated patients (Group 1 ratio: 2.15, p = 0.0232). In contrast, liver lactate metabolism evaluated during lactate intravenous perfusion (lactate production and clearance) was similar in the 3 groups.

Conclusions:  These results suggest that NRTI-containing regimens induce damage in lactate metabolism at the muscular level, even in HIV-infected patients with no hyperlactatemia symptoms, with a significant decrease in lactate clearance in muscle. Conversely, NRTI-containing regimens had no impact on liver lactate metabolism. Whether the absence of difference in muscle lactate clearance between Group 2 and Group 3 could be attributed to lingering effect of lengthy previous exposure of Group 3 to D-drugs warrants further investigations.

Keywords: mitochondrial toxicity; lactate; nucleoside analog