Muscle Disorders (including Heart)

“mice were treated with AZT for 35 days (10 mg/kg/day) in drinking water. Animals treated with antioxidant vitamins were fed the same diet as controls but supplemented with vitamins C (ascorbic acid, 10 g/ kg diet) and E (alpha-dl-tocopherol, 0.6 g/kg diet) for 65 days before sacrifice…Cardiac mitochondrial DNA (mtDNA) of mice treated with AZT had over 120% more oxo-dG (8-oxo-7,8-dihydro-2'-deoxyguanosine, which is a biomarker of oxidative damage to DNA) in their mitochondrial DNA than untreated controls. AZT treatment also caused an increase in mitochondrial lipid peroxidation and an oxidation of mitochondrial glutathione…The oxidative effects of AZT are probably due to an increase in production of reactive oxygen species by mitochondria of AZT-treated animals, raising the possibility that oxidative stress may play an important role in the cardiotoxicity of AZT.”

“A 52-year-old male developed slowly progressive proximal muscle weakness of his arms and legs beginning in September of 1999. He was known to be HIV-1 positive since 1996, which was acquired through unprotected intravenous drug use. He was treated with 200 mg of AZT twice daily in 1996…He began to complain of myalgias [muscle pains] in his thighs and calves with occasional burning pain in his feet and palms in the fall of 1999. This was accompanied by weakness in his lower extremities, which progressed to involve his upper extremities and facial muscles over the next several months. By January of 2000, he was unable to climb stairs and had difficulty sitting up in bed…Medications included AZT 200 mg BID [twice daily], indinavir 400 mg BID, naproxen 250 mg TID [three times a day], 3TC 150 mg BID, pyridoxine 25 mg OD [once daily], isoniazid 300mg OD, and ranitidine 150 mg BID…His AZT was discontinued. A muscle biopsy was performed which revealed an inflammatory myopathy…The patient was subsequently started on 100mg of prednisone OD for one month, which resulted in improved strength by March of 2000. He was able to ambulate with a walker…His strength continued to improve and a second muscle biopsy was performed (six months after the first biopsy) showing resolution of the inflammatory myopathy and ragged red fibre pathology. Selective type II fibre atrophy was noted, and this was felt to be secondary to his corticosteroid [prednisone] use”

“antiretroviral treatment with AZT amplified cardiac dysfunction and worsened ultrastructural features of AIDS CM [cardiomyopathy - damage to heart muscle] in TG [transgenic mice, including some genetic material believed to be from HIV]...AZT damaged cardiac mitochondria in WT [wild-type mice (not genetically engineered)], with destruction, swelling, cristae dissolution, and fragmentation. Similarly, hearts from AZT-treated TG showed increased mitochondrial damage, but with greater intensity”

“Myopathy [muscle damage] in long-term therapy with ZDV [AZT] due to mitochondrial damage has been described by several investigators”

“All [92] HIV patients suffering from an unexplained weight loss greater than 10% of body weight, seen in a tertiary university hospital [in Barcelona, Spain] were prospectively evaluated…[in patients who fulfilled the wasting syndrome definition] the final diagnosis was an AZT-related or an HIV-related myopathy in 13 patients (43%) [only two were ascribed to AZT based on muscle biopsy but without a group of untreated patients it is very difficult to say that none of the others were related to AZT]”

“AZT seemed to be the most potent inhibitor of cell proliferation [cell killer]…AZT, ddI and ddC [all nuceloside analogs] all exert cytotoxic [cell killing] effects on human muscle cells and induce functional alterations of mitochondria due to mechanisms other than the sole mtDNA [mitochondrial DNA] depletion. Our results provide only a partial explanation of the fact that AZT, but not ddI and ddC, can induce a myopathy [muscle damage] in HIV-infected patients.”

“Although the association of AZT with decreased cardiac contractility [cardiomyopathy=heart muscle damage] has been debated, our data indicates a strong correlation between treatment with AZT and the development of a decrease in left ventricular performance in children with HIV infection. The fact that 17 of the 19 patients in the study in whom cardiomyopathy developed had received AZT suggests that the observed decreases in left ventricular performance could have had clinical consequences…AZT withdrawal should be considered in any child in whom cardiomyopathy develops”

“HIV-associated myopathies [muscle diseases] include HIV-polymyositis and HIV-associated acquired nemaline myopathy. HIV-polymositis is much less frequent than zidovudine [AZT] myopathy…Zidovudine (AZT), the first-line antiretroviral therapy in patients with AIDS can induce a reversible toxic mitochondrial myopathy in patients who have received high cumulative doses of the drug…some authors are still reluctant to accept the diagnosis of zidovudine myopathy…[perhaps because] muscle biopsies from patients with muscle symptoms receiving zidovudine may show no abnormality and may lack the typical features of zidovudine myopathy. As mitochondrial dysfunction related to zidovudine is associated with impaired activity of COX [cytochrome c oxidase], we evaluated the COX histochemical reaction for the diagnosis of zidovudine myopathy…on the muscle of 10 patients with biopsy-proven zidovudine myopathy (Group 1). 10 myopathic zidovudine recipients without typical histopathological features of zidovudine myopathy (Group 2), and 10 HIV-infected patients not treated by zidovudine who had an immunhistological profile of HIV-associated myopathy or other neuromuscular disorder…partial COX deficiency was found in 10/10 patients from Group 1 and 7/10 from Group 2. No COX deficiency was observed in patients not treated by zidovudine…Most patients [but not all] with COX deficiency that could be evaluated clinically after muscle biopsy improved after withdrawal of zidovudine (5/7 in Group 1, 5/5 in Group 2).”

“The immunopathogenesis of HIV-associated PM [polymyositis - muscle wasting of unknown origin] was studied by Illa et al, Lamperth et al, and Leon-Monzon and Dalakas [interestingly all published at least 3 years after AZT was approved]…The clinical features of AZT myopathy are those of a generic myopathy, characterized by proximal limb weakness, myalgia predominantly in the thighs and calves, fatigue, myopathic changes on the electromyogram, and hyperCKemia which often worsens with exercise. In a follow-up of 30 patients with AZT-myopathy, myalgia resolved, strength improved or became normal, and spontaneous activity on the EMG decreased or disappeared 4 to 6 weeks after AZT was discontinued.”

“Cultured muscle cells exposed to zidovudine (0 to 10 to 50 to 100 to 200 kmol/I,) showed a remarkable decrease in cell proliferation [replication]. In controls, the cells number increased from one million at day 0 to about 270 million at day 25 and about 7 billion at day 45. After a 4-day exposure to zidovudine, the proliferation decreased significantly at concentrations of 50 to 200 µmol/L and also after 8 days at a zidovudine concentration of 10 µmol/L…Longer exposure to zidovudine resulted in a decrease of growth to virtually zero”

“Myopathy and hepatic toxicity are important complications of zidovudine (3'-azido-3'-deoxythymidine therapy) in patients infected with the human immunodeficiency virus (HIV) both may also occur in HIV infection in the absence of zidovudine therapy. We report 2 cases of myopathy caused by zidovudine, occurring within 16 wks of initiation of therapy, and a case of concurrent hepatic and muscle toxicity. In one case, electron microscopy demonstrated characteristic enlarged mitochondria with paracrystalline inclusions. This technique can distinguish the myopathies caused by either HIV or zidovudine. Both zidovudine-induced myopathy and hepatoxicity require discontinuation of the drug if severe.”

“we obtained 31P magnetic resonance spectra from the calf muscles of AZT-treated patients and age-matched control subjects at rest and during an exercise protocol with a 12-second time resolution. The recovery of phosphocreatine following exercise reflects mitochondrial oxidative function and was significantly delayed in the AZT-treated patients…These findings support the hypothesis that the myopathy associated with chronic AZT results from the inhibitory effects of AZT on mitochondrial DNA synthesis and, secondarily, on the inhibition of mitochondrial oxidative metabolism.”

“With light microscopy, the muscle specimens of all AZT-treated patients, but none of the five untreated patients, had unique morphologic features characterized by abundant ragged red fibers suggestive of abnormal mitochondria, as previously described. The number of ragged red fibers in the AZT-My[opathy] group…was similar to the number of ragged red fibers counted in 25 muscle biopsy specimens from patients with inflammatory myopathie…All the specimens, including those with abnormal mitochondria from the AZT-treated patients, had histologic features of inflammatory myopathy, as seen in polymyositis, characterized by varying degrees of endomvsial inflammation with necrosis and phagocytosis of muscle fibers…Necrotic [dying muscle] fibers with vacuoles were prominent in the AZT-treated patients…In patients with AZT-My, the most striking abnormality was a marked proliferation of mitochondria, especially in the subsarcolemmal regions, with extreme variations in the mitochondrial size and shape…The mitochondria ranged from 1 µm (normal) to 12 to 15 µm, with changes ranging from marked proliferation to disorganization. disruption, loss of concentric arrangement of the cristae, and occasionally small paracrystalline structures…Structurally, abnormal mitochondria such as those described above may not function normally.”

“A total of 23 patients with myopathy [muscle damage] are reported…AZT Myopathy [17 patients]…In this group of patients with necrotizing myopathy [dying muscle], all muscle biopsies were abnormal, even those obtained from clinically uninvolved muscles…Mitochondrial alterations, which were only conspicuous in degenerating fibers, included enlargement, loss of cristae with granular matrix, bizarre crystal forms, and rarely, paracrystalline arrays. Some fibers with mitochondrial abnormalities showed increased numbers of lipid globules…After stopping AZT, myalgia promptly resolved in all who had this symptom…14 patients had marked improvement…3 improved but still have substantial weakness. Improvement in strength did not begin until 4 to 6 weeks after discontinuing AZT and was slow and steady over the next few months. 2 patients stopped AZT for 3 months with resolution of myalgia and weakness, but with resumption of AZT at one-half dose, myalgia and elevated CK without weakness recurred in both.”

“Striking differences between the AZT-treated hearts and control rat hearts were found ultrastructurally. Myocardial [heart muscle] samples from the AZT-treated group revealed widespread cardiac myocyte mitochondrial disruption and fragmentation of cristae. Some mitochondrial cristae appeared focally dissolved and poorly organized…Other zones showed mitochondrial cristae that were clumped and focally swollen. Mitochondrial findings were consistently present in multiple samples of myocytes from AZT-treated rat hearts and conspicuously absent from samples of hearts of untreated rats.”

“Long term therapy with [AZT] can induce a toxic myopathy associated with mitochondrial changes”

“typical mitochondrial myopathy [muscle damage] has been reported to be expressed among many patients with AIDS treated with long-term azidothymidine (AZT) therapy…for AIDS patients, it is urgently necessary to develop a remedy substituting this toxic substance, AZT”

“A clinically significant myopathy that precedes the development of zidovudine associated mitochondrial myopathy has been a rarity in our experience.”

“Muscle biopsies were classified into four groups on purely morphological grounds…[Most severe was] Group 4 (1 3 patients) included distinctive myopathy, with pronounced structural and mitochondrial changes…Zidovudine had been administered before performing muscle biopsy in 27 of 48 patients including all the 13 patients in group 4…There was a significant link between the evidence of structural and mitochondrial myopathy and the administration of zidovudine (Group 4, 100%; other patients, 40%)…Zidovudine therapy was not stopped in 4 patients; 3 patients rapidly died of AIDS and 1 experienced progressive deterioration of his muscular condition…Withdrawal of zidovudine was attempted in 9 of 13 patients…Partial to complete improvement of symptoms was observed in all 9 patients; myalgia resolved in a few weeks, together with a decrease of CK levels, and progressive improvement of strength was observed over the following weeks or months…mean SCR (an enzyme of the respiratory chain) activity was significantly lower in the patients with zidovudine-associated myopathy than in those in the other groups. The mean activity of CCO (the other respiratory chain enzyme tested) was decreased to a lesser extent…The present study shows that long-term zidovudine administration can cause severe myopathy in HIV-infected [HIV-antibody positive, to be correct] patients, characterized histologically by the distinctive association between structural abnormalities and mitochondrial changes. The lesions were typical in myopathic patients who had received more than 250 gm of the compound. Zidovudine myopathy has comprised about one-third of HIV-associated neuromuscular disorders we have evaluated since 1987 and has been detected in 18% of patients treated with the drug for more than 200 days”

“15 biopsy specimens were from patients who were being treated with a full dose of zidovudine (AZT) when the myopathy developed, and 6 other specimens were from patients who had myopathy before receiving AZT therapy through prior treatment with AZT may have contributed to the manifestation of myopathy, the AZT-treated patients were included because we found that their inflammatory infiltrates were identical to those occurring in patients with HIV-PM who had not been treated with AZT…Because the majority of HIV-positive patients were receiving AZT, which can also cause myopathy and affect the circulating lymphocyte subsets, the lymphocyte counts in the AZT-treated group were also analyzed separately to evaluate possible differences from the patients who were not treated with AZT…we found that the virus [HIV], although capable of infecting muscle cells in tissue culture, did not exert a cytopathic effect in the muscle and could not be detected within the muscle fibers immunocytochemically”

“In our review of our clinic patients who have received zidovudine therapy for more than 6 months, 16% (14 of 86 patients) have had persistently elevated creatine kinase values. Six percent of these patients (5 of 86) developed symptomatic myalgia and objective proximal muscle weakness. These 5 symptomatic patients had received zidovudine for an average of 45 weeks and had had creatine kinase elevations for several weeks before onset of symptoms. Of these 5 patients, 4 had creatine kinase values return to normal and symptoms resolve after zidovudine was withdrawn...Three patients were rechallenged with zidovudine: each had recurrent creatine kinase elevations at a dose of 600 mg/d. The zidovudine dose was increased to 1200 mg/d in 2 patients: after a few days, both developed recurrent muscle symptoms that again responded to dose reduction. ...Results of quadriceps muscle biopsies done on our patients who responded to zidovudine withdrawal showed severe myopathic changes without evidence of inflammatory infiltrates. Electron microscopy revealed many ultrastructural changes, including destruction of the sarcomere profile with z-band change in the form of streaming and rod bodies. Muscle mitochondria showed wide variation in size, swelling, degeneration and laminar bodies. ...There have been 40 case reports [to 1990] of patients who have developed myopathy while taking zidovudine (including our 5 symptomatic patients). Zidovudine therapy was discontinued in 34 of these patients and 26 improved.”

“Before 1986, when zidovudine (formerly called azidothymidine [AZT]) was introduced…the number of patients with HIV-associated myopathy was small, and myopathy [muscle disorders] was considered a rare complication of HIV infection. During the past two years [1988-1989], an increasing number of patients receiving long-term zidovudine therapy have had myopathic symptoms such as myalgia (in up to 8% of patients), elevated serum creatine kinase levels (in up to 15%), and muscle weakness. These symptoms generally improve when zidovudine is discontinued…We conclude that long-term therapy with Zidovudine can cause a toxic mitochondrial myopathy, which… is indistinguishable from the myopathy associated with primary HIV infection.”

“A severe proximal myopathy, predominantly affecting the legs, seems to be a significant complication of long-term zidovudine therapy, even at reduced doses; it affected 18% of our patients who had received treatment for more than 200 days. Other drugs could not be implicated. The pathogenesis is obscure; the myopathy resolves on cessation of zidovudine, but not on dose-reduction, though there is then a risk of rebound encephalitis.”

“A 24-year-old woman presented in January, 1988, with a 2-week history of progressive leg weakness and difficulty in walking. She had been found to be HIV antibody positive in April 1986, and in October, 1986, Pneumocystis carinii pneumonia developed. After the pneumonia she had been on zidovudine [AZT] 200 mg 4-hourly and had required three blood transfusion for consequent myelosuppression [white blood cell deficiency]. On examination there was proximal weakness but no wasting of the upper and lower limbs, tenderness of the shoulders and thighs, and preserved deep tendon reflexes. Her gait was waddling and she was unable to rise out of a chair without using her arms...7 days after zidovudine withdrawal, her proximal weakness and muscle tenderness had improved significantly, and muscle force was clinically normal at follow-up 2 months later.”

“All [four] patients had an insidious onset of myalgias, muscle tenderness, weakness, and severe muscle atrophy favouring the proximal muscle groups. Physical examinations revealed varying degrees of muscle weakness and grossly apparent atrophy. Weight loss due to muscle loss was uniformly noted; in one patient, the loss was a striking 18 kg…Zidovudine was discontinued in three patients, who subsequently had symptomatic improvement…The patient who continued to receive the drug had persistent [symptoms]”