Peripheral neuropathy and antiretroviral drugs

Patients treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) develop a varying degree of myopathy or neuropathy after long-term therapy. Zidovudine (AZT) causes myopathy; zalcitabine (ddC), didanosine (d dI) and lamuvidine (3TC) cause neuropathy; stavudine (d4T) and fialuridine (FIAU) cause neuropathy or myopathy and lactic acidosis. The tissue distrib ution of phosphorylases responsible for phosphorylation of NRTIs relates to their selective tissue toxicity. The myopathy is characterized by muscle w asting, myalgia, fatigue, weakness and elevation of CK. The neuropathy is p ainful, sensory and axonal. In vitro, NRTIs inhibit the gamma-DNA polymeras e, responsible for replication of mtDNA, and cause mtDNA dysfunction. In vi vo, patients treated with AZT, the best studied NRTI, develop a mitochondri al myopathy with mtDNA depletion, deficiency of COX (complex IV), intracell ular fat accumulation, high lactate production and marked phosphocreatine d epletion, as determined with in vivo MRS spectroscopy, due to impaired oxid ative phosphorylation. Animals or cultured cells treated with NRTIs develop neuropathy, myopathy, or cell destruction with similar changes in the mito chondria. There is evidence that the NRTI-related neuropathy is also due to mitochondrial toxicity. The NRTIs (AZT, ddC, ddI, d4T, 3TC) contain azido groups that compete with natural thymidine triphosphate as substrates of DN A pol-gamma and terminate mtDNA synthesis. In contrast, FIAU that contains 3'-OH groups serves as an alternate substrate for thymidine triphosphate wi th DNA pol-gamma and is incorporated into the DNA causing permanent mtDNA d ysfunction. The NRTI-induced mitochondrial dysfunction has an influence on the clinical application of these agents, especially at high doses and when combined. They have produced in humans a new category of acquired mitochon drial toxins that cause clinical manifestations resembling the genetic mito chondrial disorders.