Mitochondrial toxicity in advanced HIV disease

Although it is widely accepted that toxicities tend to be more severe in people with advanced HIV disease, nobody has been able to explain why. In a review of the literature on nucleoside analogue toxicity, pharmacologist Dr Peter Anderson of the University of Colorado and colleagues offer a potential explanation for the greater severity of nucleoside analogue toxicities in advanced HIV disease and during treatment of hepatitis C infection.

The authors note that people on therapy with CD4 cell counts below 100 tend to have more problems with NRTI-associated toxicities such as peripheral neuropathy, pancreatitis and fat wasting. They cite evidence for the association of higher intracellular NRTI phosphate levels with severity of HIV disease. A few studies also suggest that women have higher concentrations of phosphorylated NRTIs than men, which may explain epidemiological findings that women also have a greater susceptibility to developing NRTI toxicity. Finally, they make a link between cellular activation and NRTI side-effects, pointing to increased levels of chemical markers of activation such as interferon (IFN) and tumor necrosis factor (TNF) found in people with advanced HIV disease. What is missing from the literature, though, are data showing a direct correlation between increased levels of cellular activation markers and increased intracellular levels of phosphorylated NRTIs or increased NRTI toxicity.