Update on mitochondrial toxicity: where are we now?
Long-term alterations to body metabolism have become apparent with the prolonged use of antiretroviral nucleoside analogue reverse transcriptase inhibitors (NRTIs). The NRTIs differ in the mechanisms, potency and probably also tissue specificity of mitochondrial toxicity. One group of NRTIs, the so-called "d-drugs" (zalcitabine> didanosine>stavudine) are relatively strong inhibitors of g-polymerase and thus cause a time- and dose-dependent decrease in the intracellular levels of mitochondrial DNA (mtDNA). The most important target organs of d-drugs are the liver, skeletal muscle, peripheral nerves and probably also the subcutaneous adipose tissue of lipoatrophic subjects. Hyperlactataemia may be observed. Zidovudine is an inhibitor of the mitochondrial adenine nucleotide translocator, binds to adenylate kinase and may also be converted into stavudine triphosphate in vivo. Persistent hyperlactataemia, mtDNA depletion and isolated cases of mitochondrial encephalomyopathies have been observed in babies under perinatal exposure with zidovudine. Nucleotide analogues such as tenofovir are avidly taken up into renal tubular epithelia. Isolated cases of renal failure and Fanconi syndrome require further investigation. Mitochondrial toxicity cannot yet be adequately monitored and predicted. Drugs with potential additive or synergistic toxicity, such as valproate, should be used with caution. Didanosine interacts with allopurinol, hydroxyurea and ribavirin. In established mitochondrial toxicity, cessation of the offending NRTI remains the most effective therapeutic intervention because vitamin cocktails and l-carnitine have, at best, only a marginal effect.
Walker
Ulrich A
UA
Medizinische Universitätsklinik, Department of Rheumatology and Clinical Immunology, Hugstetterstrasse 55, D-79106 Freiburg, Germany.
D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000473:pathology; D009705:Nucleosides / Q000009:adverse effects* / Q000627:therapeutic use; D011247:Pregnancy; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use
D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors