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participating institutions:
Johns Hopkins University AIDS Service, New York State DOH AIDS Institute, The CORE Center, Cook County Hospital



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Physiologic basis for hyperlactatemia defined

Changes in Mitochondrial DNA as a Marker of Nucleoside Toxicity in HIV-Infected Patients [Cote HCF et al. NEJM 2002;346:811]: The authors used a novel method to analyze mitochondrial DNA in venous blood to determine the ratios of mitochondrial:nuclear DNA in three patient populations: eight HIV-infected patients with symptomatic hyperlactatemia from nucleosides, 47 HIV-infected patients who were untreated, and 24 controls without HIV infection. The mtDNA:nDNA ratio was reduced by 68% in those with hyperlactatemia compared to controls and reduced by 43% compared to untreated HIV-infected patients. With discontinuation of nucleosides the half-life of mitochondrial DNA ranged from 4.5 to 8 weeks and the time required for lactate levels to return to normal range was 4-28 weeks. The authors conclude that mitochondrial DNA levels are significantly reduced in patients with symptomatic hyperlactatemia due to nucleosides and that these changes resolve when treatment is discontinued.

Comment: It has been previously shown that nucleoside analogs inhibit DNA polymerase gamma leading to depletion of mitochondria DNA and that this appears to be the cause of lactic acidosis, hepatic steatosis, myopathy, cardiomyopathy, peripheral neuropathy, pancreatitis, and possibly lipoatrophy. Hyperlactatemia appears to be the result of mitochondrial toxicity (Nat Med 1995;1:417; JCI 1995;96:126) and is most common in patients receiving stavudine (CID 2000;31:162; CID 2001;33:2072; AIDS 2001;15:717). In the present study all eight of the patients with hyperlactatemia had received stavudine for 33-192 weeks. An important advance in this study was the method to assay mitochondrial DNA. The standard method requires a muscle or liver biopsy, which is obviously impractical for general application. In this study the test was done on venous blood with quantification of nuclear gene and mitochondrial gene by PCR. The authors point out that in inherited mitochondrial diseases, severe symptoms occur when levels of mitochondrial DNA are reduced to 20% of normal, which is similar to the depletion observed in symptomatic patients in this study.





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