1st International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 26–28 June 1999 - San Diego, CA, USA

MITOCHONDRIAL TOXICITY OF NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS

Antiviral Therapy 1999; 4(Suppl. 2):15 (abstract no. 9)

K Brinkman
Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands

Although every NRTI seems to have its own spectrum of toxicity, there are several lines of evidence that the common pathway of all these toxicities is the induction of mitochondrial dysfunction: NRTIs inhibit DNA polymerase, the only enzyme that is responsible for mitochondrial DNA (mtDNA) replication, leading to mtDNA depletion. In fact, NRTI-related toxicities can be regarded as a compilation of the clinical features of genetic mtDNA defects: myopathy, cardiomyopathy, neuropathy, lactic acidosis, exocrine pancreas failure, liver failure and bone marrow failure. The large interindividual variation and the tissue-specific toxicity of the individual NRTIs is not clearly understood, but different, tissue-specific, pharmacodynamics of the NRTIs seems to play a role. Screening tests for the development of mitochondrial dysfunction are not available. We found that random analysis of lactate concentration and lactate/pyruvate (L/P) ratios showed higher values in persons who had NRTI related toxicity, but several confounding factors make these measurements less reliable. Glucose loading in a standardized fashion resulted in a pathological increase in L/P ratio in most of NRTI using patients (n=11) in contrast to controls (n=4), but this test will be too laborious for routine screening. Other tests have to be developed to demonstrate mitochondrial dysfunction in asymptomatic patients. To definitely demonstrate mitochondrial failure, invasive procedures like muscle or liver biopsies remain the gold standard, but impractical for routine use. The most serious presentation of mitochondrial toxicity is (fatal) lactic acidosis, presenting with abdominal discomfort, nausea and vomiting, followed by tachypnoea and rapid deterioration. This toxicity occurs after months of NRTI therapy, and persons who have suffered other NRTI toxicity appears to be at increased risk. Early recognition is essential and NRTIs have to be stopped immediately. Co-factor supplements, like riboflavin, co-enzyme Q and L-carnitine can be beneficial.

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