Steatosis-lactic acidosis syndrome associated with stavudine and lamivudine therapy

Hepatic steatosis and lactic acidosis have been reported sporadically with the administration of antiretroviral nucleoside analogs (ANA), such as zidovudine, didanosine, zalcitabine, combivir (a combination of zidovudine and lamivudine) and lamivudine. ANA require phosphorylation to the corresponding mono, di-, and triphosphate by cellular host kinases to exert their antiretroviral activity. Triphosphate inhibits the viral reverse transcriptase and terminates the growing viral DNA chain. Triphosphate also inhibits host DNA polymerase, resulting in compensatory glycolysis and lactic acidosis. Abnormal mitochondrial oxidation of free fatty acids causes the accumulation of neutral fat in liver cells, manifesting as severe hepatomegaly with macrovesicular steatosis. There appears to be some degree of intracellular carnitine depletion as a result of abnormal uptake by liver cells. Therapy with oral carnitine and antioxidants such as co-enzyme Q and vitamin C may be beneficial, but experience with these agents is limited. We recently cared for three patients with HIV infection who developed lactic acidosis and hepatic steatosis while receiving stavudine and lamivudine. 63% of the previously reported cases have been women (letter, Glaxo Wellcome). All three of our patients were also women.