|| || || || || ||

Nucleoside Analogues and Mitochondrial Toxicity

Ubonvan Jongwutiwes, M.D.

ABSTRACT
The availability of durable, effective antiretroviral therapy for HIV-infected patients has
fundamentally altered the prognosis of this disease and has also increased awareness that long-term drug
toxicities have the potential to cause significant morbidity and even mortality in this patient population.
Nucleoside analogue reverse transcriptase inhibitors (NRTIs) represent key components of the antiretroviral
combinations used to manage HIV infection. Many of the important and treatment limiting side-effects of
nucleoside analogues have been suggested to be related to the impact of these agents on mitochondrial DNA
polymerase gamma. The long-term use of nucleoside analogue reverse transcriptase inhibitor (NRTI) drugs
has been associated with a number of clinically relevant toxicities including hyperlactataemia and lactic
acidosis, neuropathy, pancreatitis and lipoatrophy. At present there is no reliable method of detecting subclinical
mitochondrial toxicity in patients exposed to NRTIs. Clinical awareness of this problem is therefore important
to ensure the early detection of significant side effects and to allow timely consideration of changing therapy
in those affected. There is no proven, effective therapy for NRTI-associated mitochondrial toxicity other
than ceasing the implicated agent, and even with this strategy, resolution of symptoms may be incomplete.
(J Infect Dis Antimicrob Agents 2006;23:27-45.)