Background: Inhibition of DNA polymerase gamma by nucleoside reverse transcriptase inhibitors (NRTIs) can cause mitochondrial dysfunction and cellular toxicity. Hyperlactataemia, which is a consequence of a shift in the metabolism of pyruvate, is an indicator of nucleoside-related mitochondrial toxicity.
Methods: We evaluated exercise and oxidative capacities as well as circulatory and ventilatory responses to exercise in 24 HIV-infected patients on NRTIs presenting hyperlactataemia [mean (+/-standard deviation) fasted lactate=3.5+/-1.1 mmol/L]; 27 NRTI-treated patients with normal baseline lactate concentrations were used as controls (mean fasted lactate=1.6+/-0.3 mmol/L).
Results: In the patients with hyperlactataemia, the average peak work capacity (1.7+/-0.6 W/kg) and peak oxygen consumption (VO(2)) (21+/-4 mL/kg/min) were significantly lower (P<0.01) than in control subjects (work, 2.1+/-0.4 W/kg; VO(2), 25+/-4 mL/kg/min). The capacity to increase oxygen extraction during exercise was significantly diminished in the hyperlactataemia group, as shown by a low peak systemic arteriovenous oxygen difference (a-vO(2)) difference compared with controls (11+/-3 vs 14+/-3 mL/dL; P=0.008), and as indicated by a linear correlation between VO(2) and systemic a-vO(2) difference (r(2)=0.76). During exercise, the increases in cardiac output relative to VO(2) (mean Delta cardiac output (Q)/DeltaVO(2)=8+/-3.6) and ventilation (mean Delta ventilation (VE)/DeltaVO(2)=48.6+/-13.2) were significantly higher in hyperlactataemia patients compared with controls (mean cardiac output Delta(Q)/DeltaVO(2)=6+/-2; mean DeltaVE/DeltaVO(2)=42+/-12.7; P=0.03).
Conclusions: The degree of exercise limitation in patients with nucleoside-related mitochondrial toxicity correlates directly with the severity of impaired muscle oxidative phosphorylation, as indicated by the capacity for muscle oxygen extraction. Exaggerated circulatory and ventilatory responses to exercise are direct consequences of the level of impaired muscle oxidative phosphorylation.