Editorial Response: Hyperlactatemia and Hepatic Steatosis as Features of Mitochondrial Toxicity of Nucleoside Analogue Reverse Transcriptase Inhibitors

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Abstract
The long-term toxicity of highly active antiretroviral therapy (HAART), especially the development of both the lipodystrophy syndrome and hyperlipidemia, has been linked to the use of HIV protease inhibitors in most studies. However, the broad spectrum of toxicities associated with one of the other classes of drugs, the nucleoside analogue reverse transcriptase inhibitors (NRTIs), can display complications almost as serious and with more fatal outcomes. The common pathway of NRTI toxicities is induction of mitochondrial dysfunction [1, 2], because NRTIs inhibit DNA polymerase-γ, an essential enzyme for the replication of mitochondrial DNA (mtDNA). Depletion of mtDNA will follow, successively leading to depletion of mtDNA-encoded proteins and to mitochondrial dysfunction. All long-term side effects of NRTIs that have been described can be attributed to this mitochondrial toxicity, and recently we hypothesized that the HAART-related lipodystrophy is induced via this mechanism as well [3].