Bench-to-bedside review: Severe lactic acidosis in HIV patients treated with nucleoside analogue reverse transcriptase inhibitors

Nucleoside analogue reverse transcriptase inhibitors (NRTIs) are effective antiretroviral therapies for the treatment of HIV-infected patients. Treatment with NRTIs has been associated with mitochondrial toxicity [1] responsible for adverse events including hepatic steatosis [2], myopathy [3], neuropathy [4], myelotoxicity [5] and overproduction of lactate [1].Symptomatic lactic acidosis following the use of NRTIs was first described by Jolliet and Widmann [6] and by Chatta and colleagues [7] in HIV-infected patients treated with azidothymidine. Several reports since then have established that other NRTIs can induce lactic acidosis [8-30]. This severe adverse event is infrequent but its occurrence may be underestimated [31]. Progression of lactic acidosis can lead to irreversible multiple organ failure despite drug withdrawal [8].In the present review, based on Medline research and using personal data, we describe the pathophysiology and the clinical spectrum of lactic acidosis in an attempt to define a population with a poor prognosis. Based on clinical data and experimental evidence, we discuss the use of L-carnitine as a specific treatment for life-threatening NRTI-induced lactic acidosis.The main function of mitochondria is to produce energy through electron-chain transport and oxidative phosphorylation (summarised in Fig. 1). The core of the pathway is a complex of five subunits (subunits I–V) located on the inner mitochondrial membrane. Electrons pass the chain from various substrates, providing energy to the proton pump that creates an electrochemical gradient between mitochondria and their environment. Different substrates can enter the electron-chain transport at complex I (the reduced form of nicotinamide adenine dinucleotide [NADH]–coenzyme Q oxidoreductase) or complex II (succinate–coenzyme Q oxidoreductase), which provide electrons to complex III (coenzyme QH2–cytochrome oxidoreductase). Complex III then reduces cytochrome c, which passes electrons to c