Zidovudine myopathy: A distinctive disorder associated with mitochondrial dysfunction

Abstract

Muscle biopsy specimens were obtained from 48 human immunodeficiency virus-infected patients suffering from various neuromuscular symptoms. Microscopic examination by conventional and electron microscopy revealed a characteristic structural myopathy associated with mitochondrial changes in 13 patients, all of whom had received long-term zidovudine therapy. The mean cumulative dose they had received (498 +/- 145 gm) was significantly higher than that of the other 14 zidovudine recipients of the study. They suffered from a progressive, usually painful, proximal myopathy with pronounced wasting, normal-to-moderately elevated creatine kinase levels, and a myopathic electromyographic pattern. The condition usually improved after withdrawal of the drug. Assay of mitochondrial enzymes, including succinate-cytochrome c reductase, cytochrome c oxidase, and citrate synthase, showed a decline in respiratory chain capacity. Southern blot analysis of mitochondrial DNA showed no abnormality. It is likely that mitochondrial dysfunction, probably resulting from drug-induced inhibition of the mitochondrial DNA polymerase, is implicated in the pathogenesis of this complication of zidovudine therapy.

3′-Azido-3′-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: A possible mechanism of AZT hepatotoxicity

“…During the pre-highly active antiretroviral therapy (HAART) era, AZT monotherapy in AIDS patients was closely associated with myopathy, cardiomyopathy, and hepatotoxicity [1][2][3][4][5][6][7][8][9][10]. Subsequent work in HIV negative rat models treated with AZT confirmed the presence of the same type of toxicities in the rat [11,15].…”

“…When given in monotherapy at high doses over long periods of time, AZT is known to cause damage to many tissues, including a mitochondrial skeletal muscle myopathy, a dilated cardiomyopathy, and hepatotoxicity [1][2][3][4][5][6][7][8][9][10][11]. These conditions are related to AZT use and not to the progression of AIDS since when patients experiencing one or more of these adverse effects discontinued AZT therapy, the adverse effects would resolve [8,9]. In modern therapy regimens, AZT is given at much lower doses and in combination with other drugs.…”

Maternal and Infant Factors Associated With Failure to Thrive in Children With Vertically Transmitted Human Immunodeficiency Virus-1 Infection: The Prospective, P2C2 Human Immunodeficiency Virus Multicenter Study

“…This association has been found in other studies. 4,7 ZDV, in particular, alters mitochondrial metabolism 42 and may have direct nutritional effects in addition to acting as a surrogate marker for more advanced HIV-1 disease. Additional studies should focus on the effects of ZDV and other antiretroviral therapy on nutritional status.…”

Metabolic abnormalities in skeletal muscle of patients receiving zidovudine therapy observed by 31P in vivo magnetic resonance spectroscopy.

“…Histological, ultrastructural, biochemical, and molecular studies in humans and experimental animals have suggested the myopathy induced by AZT is due to a mitochondrial toxicity (1)(2)(3)(4)(5)(6)(7)(8). The myopathic symptoms often begin after the first 6 mo of therapy and include fatigue, muscle weakness, and elevation of muscle enzymes.…”

“…These symptoms occur in at least 17% of patients and are often reversible when AZT therapy is discontinued. The diagnosis is established by muscle biopsy, which on enzyme histochemistry shows characteristic ragged-red muscle fibers by modified Gomori trichrome staining ( 1,2), and accumulation of neutral lipid droplets (4,5). Ubiquitous abnormalities in muscle mitochondrial structure are always identified by electron microscopy (3).…”