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

Abstract

Nucleoside reverse transcriptase inhibitors (NRTIs) are effective antiretroviral therapy for the treatment of HIV-infected patients. NRTIs can induce mitochondrial impairment that leads to a number of adverse events, including symptomatic lactic acidosis. In the present review, we describe the underlying mechanism of NRTI-induced toxicity and the main clinical features of this infrequent, but severe, emerging complication. We also summarise experimental data and clinical observations that support the use of L-carnitine supplementation to reverse NRTI-induced mitochondrial impairment.

Figure 1

Mitochondrial electron chain transport and oxydative phosphorylation. Most of the energy produced by metabolic pathways is contained in the reduced form of nicotinamide adenine dinucleotide (NADH) and in the reduced form of flavine adenine dinucleotide (FADH₂), and is transformed in ATP by mitochondria. Reduced mitochondrial coenzymes give their two electrons to carriers that carry them to molecular oxygen, the final electron acceptor, using oxydo-reduction reactions. A protonic gradient allows hydrogen to cross the inner membrane and produce ATP. a-Cu, coenzyme a-copper; a₃-Cu, coenzyme 13-copper; CoA, coenzyme A; CoQ, coenzyme Q; Cyt, cytochrome; F₀, F₀ family ATP synthase; F₁, F₁ family ATP synthase; Fe-S, iron-suphur cluster; FMN, flavine-adenine mononucleotide; H, hydrogen; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase.