Mitochondrial toxicity of nucleoside analogues: mechanism, monitoring and management.
Nucleoside analogues (NRTIs) are potent antiretroviral medications and are central to effective highly active antiretroviral therapy (HAART). Their intended action is to inhibit HIV reverse transcriptase. Nucleoside analogues also inhibit replication of mitochondrial DNA, and the pathogenesis of many of the toxicities associated with HAART is thought to be NRTI-induced mitochondrial dysfunction. Individuals with HIV infection may be particularly susceptible to clinically significant mitochondrial toxicity due to possible effects of HIV itself on mitochondria. 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. Similarly, there are no established methods for preventing mitochondrial toxicity in those on therapy including NRTIs. Micronutrients may have a role, but further study is needed to clarify optimal prevention as well as monitoring strategies.
Cherry
Catherine L
CL
Burnet Institute for Medical Research and Public Health, GPO Box 2284, Melbourne, Vic. 3001, Australia. kate.cherry@med.monash.edu.au
Lala
Luxshimi
L
Wesselingh
Steven L
SL
D000818:Animals; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000187:drug effects; D004259:DNA-Directed DNA Polymerase / Q000187:drug effects; D016903:Drug Monitoring / Q000379:methods*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008928:Mitochondria / Q000821:virology; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000517:prevention & control; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology
D004272:DNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human