Sixth International Congress Drug Therapy in HIV Infection 17-21 November, 2002 Glasgow, UK

[ABSTRACT:] NRTIs act as false nucleoside substrates for Polymerase-g, which mediates mitochondrial DNA synthesis, and this may result in NRTI-related DNA depletion and clinical manifestations of mitochondrial dysfunction. The ability of a specific NRTI to induce mitochondrial depletion depends on its affinity for polymerase-g and pharmacodynamic factors that influence its access to the mitochondrial compartment. Mitochondrial polymerase-g inhibition may also affect the fidelity of mitochondrial DNA synthesis, with increased risk of mitochondrial DNA mutations and associated clinical syndromes—although this is a rare cause of clinical disease.

NRTI therapy is an independent risk factor for lipoatrophy, and depletion of mitochondrial DNA has been observed in adipose tissue and cells from affected patients. Modifying or stopping NRTI therapy is associated with very modest reversion of lipoatrophy in the first 24 to 48 weeks, so it is prudent to focus on identifying regimens with a low risk of inducing the condition in the first place. The risk of peripheral neuropathy also correlates with a specific NRTI’s affinity for mitochondrial polymerase-g.

Hyperlactatemia represents a spectrum of disease, ranging from ”compensated” asymptomatic hyperlactatemia to life-threatening lactic acidosis. Early recognition of clinical manifestations and prompt discontinuation of offending NRTIs remain the cornerstone of management.

The limited and slow reversal of many tissue-specific toxicities following removal of the offending agent (eg, fat wasting, neuropathy) suggests that it is far more prudent to prevent these syndromes through the use of relatively nontoxic drugs, rather than to attempt to treat and reverse them once they are established.

Presenting author: Simon Mallal

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1 Royal Perth Hospital, Perth, Australia

2002-11-17
PL13-2

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