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Previous Volume 333:1099-1105 October 26, 1995 Number 17 Next

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ABSTRACT

Background We describe severe and unexpected multisystem toxicity that occurred during a study of the antiviral nucleoside analogue fialuridine (1-(2-deoxy-2-fluoro--d-arabinofuranosyl)-5-iodouracil, or FIAU) as therapy for chronic hepatitis B virus infection.

Methods Fifteen patients with chronic hepatitis B were randomly assigned to receive fialuridine at a dose of either 0.10 or 0.25 mg per kilogram of body weight per day for 24 weeks and were monitored every 1 to 2 weeks by means of a physical examination, blood tests, and testing for hepatitis B virus markers.

Results During the 13th week lactic acidosis and liver failure suddenly developed in one patient. The study was terminated on an emergency basis, and all treatment with fialuridine was discontinued. Seven patients were found to have severe hepatotoxicity, with progressive lactic acidosis, worsening jaundice, and deteriorating hepatic synthetic function despite the discontinuation of fialuridine. Three other patients had mild hepatotoxicity. Several patients also had pancreatitis, neuropathy, or myopathy. Of the seven patients with severe hepatotoxicity, five died and two survived after liver transplantation. Histologic analysis of liver tissue revealed marked accumulation of microvesicular and macrovesicular fat, with minimal necrosis of hepatocytes or architectural changes. Electron microscopy showed abnormal mitochondria and the accumulation of fat in hepatocytes.

Conclusions In patients with chronic hepatitis B, treatment with fialuridine induced a severe toxic reaction characterized by hepatic failure, lactic acidosis, pancreatitis, neuropathy, and myopathy. This toxic reaction was probably caused by widespread mitochondrial damage and may occur infrequently with other nucleoside analogues.

Source Information

From the Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases (R.M., B.S., S.E.S.), the Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (M.W.F., R.S., H.C., A.M.D., J.H.H.), the Department of Nursing, Clinical Center (Y.P.), the Department of Pathology, National Cancer Institute (D.K., M.T.), and the Electromyography Section, National Institute of Neurological Disorders and Stroke (C.L.), National Institutes of Health, Bethesda, Md.; the Department of Surgery, University of Virginia Medical Center, Charlottesville (T.P.); and Lilly Research Laboratories, Indianapolis (J.L.S.).

Address reprint requests to Dr. Hoofnagle at the Liver Diseases Section, Bldg. 10, Rm. 9B07, Bethesda, MD 20892.

Full Text of this Article

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Severe Toxicity of Fialuridine (FIAU)
Bari A., Josephson L., Prince A. M., Lewis W., Perrino F. W., Gordon M., Hoofnagle J., McKenzie R., Straus S., Swartz M. N., Stotka J. L.
Extract | Full Text  
N Engl J Med 1996; 334:1135-1138, Apr 25, 1996. Correspondence

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