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Rhabdomyolysis after cerivastatin–gemfibrozil therapy in an HIV-infected patient with protease inhibitor-related hyperlipidemia

2001; Lippincott Williams & Wilkins; Volume: 15; Issue: 6 Linguagem: Inglês

10.1097/00002030-200104130-00029

1473-5571

Claudio Maria Mastroianni, Gabriella d’Ettorre, Gabriele Forcina, Miriam Lichtner, Angela Corpolongo, S Coletta, Vincenzo Vullo,

HIV Research and Treatment

Fat redistribution and lipid abnormalities are increasingly being recognized with the use of protease inhibitors (PI) in HIV-1 [1]. The optimal management of PI-related hyperlipidemia remains to be defined [2]. Possible interventions include dietary modification and exercise, the discontinuation of PI, or the use of lipid-lowering agents. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and fibric acid analogues are becoming increasingly common for the treatment of PI-associated lipid abnormalities, but their use is complicated by the potential for adverse drug interactions. Here, we report a case of severe rhabdomyolysis and acute renal failure in an HIV-1-infected patient taking a combination of cerivastatin and gemfibrozil concurrently with PI based-therapy. A 57-year-old heterosexual HIV-1-seropositive man with a CD4 T cell count of 262/μl and a viral load of 6.1 log10 copies/ml had been started on antiretroviral treatment with zidovudine (300 mg twice a day), didanosine (200 mg twice a day) and indinavir (800 mg three times a day). Because of the onset of severe hyperlipidemia (cholesterol, 383 mg/dl; triglyceride levels, 1100 mg/dl) that was refractory to dietary therapy, a combination of cerivastatin (0.6 mg a day) and gemfibrozil (600 mg a day) was given. Four weeks after the addition of cerivastatin–gemfibrozil to PI-based treatment, the patient was hospitalized because of fever, bilateral lower extremity weakness, acute muscle pain and dark urine. On admission, he had myalgia on pressure and was unable to walk. His temperature was 39°C. Laboratory studies were as follows: serum creatinine, 2.73 mg/dl; blood urea nitrogen, 119 mg/dl; sodium, 142 mEq/l; potassium, 5.8 mEq/l; creatine phosphokinase, 76 000 IU/l; lactate dehydrogenase, 5465 IU/l; aspartate aminotransferase, 1263 IU/l; alanine aminotransferase, 637 IU/l; bicarbonate, 19 mEq/l; white blood cells, 3.18 × 109/l; platelets, 247 × 109/l. An arterial blood gas determination revealed a pH of 7.33, partial pressure carbon dioxide of 32 and partial pressure oxygen of 70. The urine was positive for myoglobin. Serology for antinuclear antibodies, anti-smooth-muscle antibodies and rheumatoid factor was negative. The cholesterol level was 200 mg/dl; triglyceride levels were 200 mg/dl. The CD4 T cell count was 527/μl and the plasma viral load was less than 2.30 log10 copies/ml. Electromyography revealed severe muscular damage. No clinical or radiological evidence of active infections was documented. All antiretroviral drugs as well as lipid-lowering agents were immediately discontinued. The patient was treated with steroids, massive hydration and urine alkalinization. Clinical symptoms and laboratory abnormalities gradually improved, and within 14 days the patient fully recovered with normal muscle enzymes. Electromyographic study became normal within 8 weeks. After 2 months, antiretroviral treatment with stavudine (40 mg twice a day), lamivudine (300 mg twice a day) and nevirapine (200 mg a day for 14 days and 400 mg a day thereafter) was introduced with no side-effects. Acute rhabdomyolysis may occur during HIV-1 infection, and it has been attributed to HIV-1 itself, opportunistic infections, or drug toxicity. Drug-induced rhabdomyolysis has been reported in HIV-1-infected patients taking pentamidine, trimethoprim–sulfamethoxazole, sulfadiazine and antiretroviral agents such as didanosine, zidovudine, indinavir and ritonavir [3,4]. Recently, lipid disorders have been seen in a significant proportion of HIV-1-infected patients receiving PI-based antiretroviral therapy, but potential drug interactions complicate the treatment of hyperlipidemia. The two main classes of lipid-lowering agents are fibrates and statins. Fibrates, such as gemfibrozil, are able to decrease serum triglyceride concentrations but do not affect serum cholesterol concentrations. On the other hand, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins are able to decrease both serum cholesterol and triglyceride concentrations. A recent pharmacokinetic study showed that the metabolism of most statins and fibrates, including atorvastatin, simvastatin, lovastatin, benzafibrate, ciprofibrate, fenofibrate, and gemfibrozil, are affected by PI, probably through effects on cytochrome P450 (CYP)3A4 [5]. As a consequence, levels of these drugs may increase by five- to 30-fold in the circulation, with the risk of severe toxic effects. Patients receiving lovastatin or simvastatin concurrently with PI experienced myopathy and rhabdomyolysis, whereas the administration of atorvastatin and pravastatin was found to be safe [6]. In the case reported here, we used cerivastatin, a new synthetic 3-hydroxy-3-methylglutaryl-reductase inhibitor, which has been metabolized by cytochrome CYP3A4 and CYP2C8 hepatic isoenzymes. Because of this dual metabolic pathway, it was believed that the drug had a low potential for interactions with CYP34A inhibitors, including HIV-1 PI. It is likely that in our case the combination of cerivastatin and gemfibrozil was the precipitating factor that induced severe rhabdomyolysis associated with renal failure. On the other hand, cases of rhabdomyolysis and renal failure have been reported in HIV-1-negative patients taking cerivastatin–gemfibrozil combination treatment [7–9]. In conclusion, because of its severe toxic effects, the simultaneous administration of statins, including cerivastatin, and fibrates should be avoided for the management of HIV-1 PI-related hyperlipidemia. Claudio M. Mastroianni Gabriella d'Ettorre Gabriele Forcina Miriam Lichtner Angela Corpolongo Simona Coletta Vincenzo Vullo