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Background We describe severe and unexpected multisystem toxicity that occurred during a study of the antiviral nucleoside analogue fialuridine (1-(2-deoxy-2-fluoro-
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.
-d-arabinofuranosyl)-5-iodouracil, or FIAU) as therapy for chronic hepatitis B virus infection.
There is no completely satisfactory therapy for chronic hepatitis B. Interferon alfa is now approved for use in this disease, but a four-to-six-month course produces long-term remissions in only one third of patients.2,3,4,5 Furthermore, interferon must be given parenterally, is often poorly tolerated, and is expensive. Clearly, better antiviral therapies are needed.
Among antiviral agents, the nucleoside analogues have been most widely evaluated as potential therapies for chronic hepatitis B. Adenine arabinoside (vidarabine)6 and its monophosphate,7 acyclovir,8 didanosine,9 zidovudine,10 and ribavirin11 have been studied in chronic hepatitis B, but all were either ineffective or too toxic for prolonged use. Recent in vitro and in vivo models of HBV infection12,13 have permitted the identification of several new, orally bioavailable antiviral agents with marked inhibitory activity against HBV. These second-generation nucleoside analogues include 3'-thiacytidine (lamivudine),14 famciclovir,15 and fialuridine (1-(2-deoxy-2-fluoro--d-arabinofuranosyl)-5-iodouracil, or FIAU).16,17
In two preliminary dose-finding studies, two- and four-week courses of fialuridine led to prompt and marked suppression of serum HBV DNA levels by 65 to 95 percent.18,19 However, there was sustained loss of viral DNA in only a few patients. The possibility that longer courses would be more efficacious led to a trial of a six-month course of fialuridine, an investigational drug. This study was begun in March 1993 but was terminated on an emergency basis 13 weeks later when hepatic failure and lactic acidosis suddenly occurred in one of the patients. In this report, we describe the clinical features of this toxicity, which, despite immediate discontinuation of the medication, eventually led to hepatic failure, lactic acidosis, and pancreatitis in seven patients, of whom five died. Two others survived after emergency liver transplantation.
Methods
This phase 2 trial was designed to evaluate the safety and efficacy of a six-month course of fialuridine in 24 patients with chronic hepatitis B. Patients were randomly assigned to receive either 0.10 or 0.25 mg of fialuridine per kilogram of body weight per day given orally in two or three divided doses. Fialuridine was provided as a liquid formulation by Oclassen Pharmaceuticals (San Rafael, Calif.) and administered under an Investigational New Drug Application held by Eli Lilly and Company (Indianapolis) for use in chronic hepatitis B.
Entry criteria included the presence of chronic hepatitis B without hepatic decompensation or other serious medical illnesses. All patients had histologic evidence of chronic hepatitis B on the basis of liver biopsy (performed within one year of entry), persistent elevations in serum aminotransferase activities, and the presence of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV DNA in serum for at least six months. Exclusion criteria included serologic evidence of hepatitis C, hepatitis D, or human immunodeficiency virus (HIV) infection.
While receiving therapy, the patients were seen in the outpatient clinic every one to two weeks, were questioned regarding symptoms and side effects, and underwent a physical examination and a battery of blood and urine tests. The blood tests included measurements of serum alanine and aspartate aminotransferases, creatine kinase, alkaline phosphatase, bilirubin, albumin, blood urea nitrogen, and creatinine; a complete blood count; and assays for HBV markers. Radioimmunoassays (Abbott Laboratories, North Chicago, Ill.) were used to test for HBsAg, HBeAg, anti-HBs, and anti-HBe, and liquid-phase hybridization was used to test for HBV DNA (Genostics, Abbott) (limit of detection, approximately 2 pg per milliliter).20
Details of the protocol were approved by the institutional review board of the National Institute of Diabetes and Digestive and Kidney Diseases, and all patients gave written informed consent.
Results
Characteristics of the Patients
Between March 24 and June 16, 1993, we enrolled 15 patients (13 men and 2 women) in the trial, ranging in age from 29 to 64 years (mean, 44). Twelve were white, two Asian, and one black. The source of hepatitis was believed to be sexual contact in seven, occupational exposure in three, and familial exposure in two and was unknown in three. The patients had had documented chronic hepatitis B for 1.1 to 11.7 years (mean, 5.2). Eleven had participated in a study involving a 4-week course of fialuridine and had completed therapy 7 to 13 months earlier. Eight patients had previously received recombinant interferon alfa, and six had received other nucleoside analogues without sustained beneficial responses.
Aminotransferase Levels and HBV Markers
Levels of HBV DNA decreased in all patients during therapy, the average decline by week 4 being 92 percent in the group given 0.10 mg of fialuridine per kilogram per day and 93 percent in the group given 0.25 mg of fialuridine per kilogram per day. Among the 10 patients who were treated for at least eight weeks, HBV DNA became undetectable in 6 during therapy (Figure 1). In one patient (Patient 9), HBeAg became undetectable and anti-HBe developed, along with a decrease in serum aminotransferase levels into the normal range. In the other patients, alanine aminotransferase levels were relatively unchanged and HBsAg and HBeAg remained detectable.
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During the first eight weeks of treatment there were few side effects. One patient had intermittent crampy abdominal pain; another had paresthesias in the feet. Thereafter, increasing fatigue developed in six patients, nausea in five, numbness and tingling in the feet or hands in four, crampy lower abdominal pain in three, constipation in two, and mild thrombocytopenia in one. These clinical changes led to a reduction in the dose in four patients between weeks 9 and 11 and discontinuation of the drug in three between weeks 10 and 12. Thirteen weeks into the trial, Patient 2, in whom fialuridine therapy had been stopped 17 days earlier because of paresthesias, was admitted to a local community hospital because of the sudden onset of hepatic failure, shock, and lactic acidosis (Figure 2). The study was terminated immediately. All patients were contacted and told to stop taking fialuridine and to return for evaluation.
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Hepatic Failure and Lactic Acidosis
Follow-up evaluations of the patients in the days after treatment was stopped revealed that seven (including Patient 2) had varying degrees of hepatic failure and lactic acidosis (Table 1). All seven had received fialuridine for at least nine weeks, with cumulative doses ranging from 551 to 1753 mg. Most of the seven patients had fatigue, nausea, constipation, and abdominal pain. All seven had steadily worsening jaundice (Figure 3A), decreasing hepatic synthetic function, gradually worsening prothrombin times (Figure 3B), and increasing serum ammonia and lactate levels (Figure 4). Frank acidosis with hyperpnea and increased anion gaps became evident after lactate levels exceeded 12 mmol per liter.
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The hepatic failure and lactic acidosis were rapidly progressive in Patients 2 and 7, who were transferred to liver-transplantation centers within four days of admission. After initial treatment with a hepatic-assist device23 did not reverse the hepatic failure, these two patients underwent emergency liver transplantation.24 The condition of both was hemodynamically unstable at the time of transplantation, and the patients died 22 and 36 hours later with relentless lactic acidosis, profound hypotension, and little evidence of graft function.
Five patients (Patients 1, 3, 4, 6, and 10) had a more gradual progression of hepatic failure and lactic acidosis (Figure 3A, Figure 3B, and Figure 4). Their condition deteriorated over a period of several weeks, and they were transferred to transplantation centers 10 to 29 days after admission and 13 to 48 days after fialuridine was stopped. In all five, hepatic decompensation and profound lactic acidosis ultimately developed. Two patients (Patients 1 and 4) died of hemodynamic collapse due to pancreatitis and lactic acidosis before liver transplantation could be performed, and a third (Patient 6) died of complications of pancreatitis after transplantation. Transplantation was successful in the remaining two patients, resulting in a prompt reversal of the lactic acidosis as well as other signs of hepatic failure.24 They were discharged from the hospital 16 and 94 days after transplantation. During 24 months of follow-up, they have had no evidence of residual fialuridine-induced toxicity except for a mild peripheral neuropathy. Both have been treated with high doses of hepatitis B immune globulin, and neither has had evidence of recurrence of hepatitis B.
Pancreatitis
All seven patients with severe hepatotoxicity had biochemical evidence of pancreatitis, with progressive increases in serum lipase levels (up to a 50-fold increase). Concomitantly measured serum amylase levels remained normal except in three patients who had severe abdominal pain and clinically apparent pancreatitis, which ultimately contributed to their deaths. All five patients who died had both gross and microscopical evidence of pancreatitis at autopsy.
Neuropathy and Myopathy
Five patients with severe hepatotoxicity had symptoms or signs of peripheral-nerve injury. These consisted of paresthesias and dysesthesias in the feet or toes that were mild to moderate in severity. Clinical findings were subtle, consisting of mild reductions in vibratory sensation and responses to light touch and decreased ankle reflexes. Two patients reported muscle pain or weakness. Muscle and nerve biopsies were performed in two patients with severe hepatotoxicity (Patients 3 and 10). Histologic analysis of muscle showed rare ragged-red fibers, occasional subsarcolemmal cracks, and increased amounts of lipid. These changes are similar to, but milder than, those observed with zidovudine-induced myopathy.25 Nerve biopsies revealed a mild focal loss of myelin and mild interstitial fibrosis.
Mild Fialuridine-Induced Toxicity
Mild hepatotoxicity occurred in three patients (Patients 5, 8, and 9) who had received fialuridine for 10 to 11.5 weeks and had received cumulative doses of 420 to 1216 mg, which were comparable to the cumulative doses in the seven patients with severe hepatotoxicity (Table 1). These patients had nausea and abdominal discomfort along with increasing aminotransferase elevations and slight decreases in serum albumin and fibrinogen. These abnormalities were mild, developed two to three weeks after fialuridine was stopped, and generally resolved within 4 to 12 weeks. Patient 5 had mild epigastric discomfort and slight increases in serum amylase and lipase levels that persisted for eight months but ultimately resolved completely. In Patient 9 HBV DNA and HBeAg became undetectable during treatment; the other two patients remained positive for HBV DNA, HBeAg, and HBsAg.
Absence of Fialuridine-Induced Toxicity
Five patients (Patients 11, 12, 13, 14, and 15) received fialuridine for less than four weeks (Table 1), with total doses of less than 200 mg. None had obvious clinical or biochemical evidence of fialuridine-induced toxicity. Serum aminotransferase levels remained unchanged and serum bilirubin, albumin, and lactate levels were normal on multiple occasions. During 24 months of follow-up, these five patients have had no evidence of fialuridine-induced toxicity.
Histologic Evidence of Fialuridine-Induced Hepatotoxicity
Liver tissue was available from the explants of the five patients who underwent transplantation and was obtained at autopsy from the two patients who died without transplantation. Histologic analysis revealed moderate to marked microvesicular and macrovesicular steatosis and cholestasis (Figure 5A). The degree of inflammation and hepatocellular necrosis was largely unchanged from that present in liver-biopsy specimens obtained before treatment. Electron microscopy documented abnormalities of mitochondria and the accumulation of small droplets of fat (Figure 5B). All seven patients with severe hepatotoxicity had evidence of chronic hepatitis, and three had cirrhosis. Immunoperoxidase staining for hepatitis B core antigen was positive in six of the seven patients.
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Discussion
In this phase 2 study of the antiviral agent fialuridine, a severe and progressive form of hepatic failure and lactic acidosis developed in 7 of the 15 study patients. This severe toxic reaction was seen after 9 to 13 weeks of therapy and with cumulative doses of only 551 to 1753 mg of fialuridine. Five patients died of relentless lactic acidosis with or without hemorrhagic pancreatitis. Two patients survived after successful emergency liver transplantation. The syndrome of fialuridine-induced toxicity did not resemble typical fulminant hepatic failure in that serum aminotransferase levels were minimally elevated, bilirubin increases were initially slight, and lactic acidosis was severe and relentless. Instead, the fialuridine-induced toxic reaction resembled the fulminant hepatic steatosis that occurs with Reye's syndrome, acute fatty liver of pregnancy, and toxic reactions produced by high-dose tetracycline and valproic acid.26
The severe toxicity of fialuridine was not predicted by preclinical studies in laboratory animals, which had shown no evidence of hepatic, pancreatic, skeletal-muscle, or nerve damage. Furthermore, pilot studies of fialuridine given for two to four weeks to 43 patients with HIV infection18 and 24 patients with chronic hepatitis B19 had not revealed obvious hepatotoxicity on initial analysis. However, the underlying chronic hepatitis B and HIV infection may have obscured fialuridine-induced hepatotoxicity. Among the 67 patients treated in the pilot studies, 3 died of liver disease and 1 of pancreatitis within six months of completing therapy. Extensive reevaluation of these pilot studies by an expert committee of the Institute of Medicine concluded that some of these events may have represented delayed toxic effects of fialuridine.27 Indeed, three months after a one-month course of fialuridine and several weeks after a cholecystectomy, intractable ascites followed by lactic acidosis developed in one patient. Autopsy revealed microvesicular fat in the liver, which — in retrospect — makes it likely that fialuridine-induced toxicity played a part in the worsening hepatic function. The other patients who died within six months of receiving fialuridine in the pilot studies were infected with HIV; two died of end-stage liver disease attributed to the progression of viral hepatitis, and one died of pancreatitis attributed to didanosine therapy; none had microvesicular fat in the liver on autopsy.
The onset of the severe hepatotoxicity in the present study was sudden. In most instances, the results of liver-biochemistry tests remained unchanged from pretreatment values in the one to two weeks before the onset of hepatic failure. Most patients with severe hepatotoxicity, however, had a one-to-two-week prodromal period of increasing fatigue, nausea, and crampy abdominal pain. Despite the discontinuation of therapy, the lactic acidosis, hepatic failure, and pancreatitis worsened relentlessly.
Several features of the multisystem toxicity suggested that it was related, at least in part, to widespread, severe mitochondrial injury. First, the clinical picture of hepatic failure resembled that of Reye's syndrome in its progression of symptoms and in the early appearance of hepatic synthetic dysfunction, hyperammonemia, and lactic acidosis, despite minimal increases in aminotransferase levels and mild jaundice.26 Second, the toxicity predominantly affected organs and tissues that have a slow turnover of cells and a major dependence on mitochondrial function. Finally, light microscopy of liver specimens showed marked accumulation of microvesicular fat, with scant hepatocellular necrosis. Electron microscopy revealed abnormal mitochondria and confirmed the presence of microvesicular fat.
In vitro studies suggest that some toxic reactions induced by the nucleoside analogues may be caused by mitochondrial injury.28,29,30,31,32 Zidovudine, didanosine, and zalcitabine inhibit the DNA polymerase 
of mitochondria. Serving as chain terminators, these drugs block the elongation of the mitochondrial DNA chain and deplete mitochondrial DNA to varying degrees. In contrast, recent short-term in vitro studies indicate that fialuridine has minimal effects on the amount of mitochondrial DNA33 but becomes efficiently incorporated into cellular and mitochondrial DNA and causes increased lactate production by cells.34,35,36 Fialuridine differs from most other antiviral nucleoside analogues in having a hydroxyl group and thus being unblocked at the 3' position of the deoxyribose molecule, which permits its incorporation into nascent DNA chains. Thus, the cellular injury caused by fialuridine may be due to the synthesis of defective mitochondrial DNA, leading to reduced amounts of mitochondrial DNA or to abnormal enzymes encoded by mitochondrial genes.
Clinically, the multisystem toxicity of fialuridine resembles that of several of the other nucleoside analogues. For instance, zidovudine has been associated with a toxic myopathy characterized by the depletion of mitochondrial DNA in myocytes.32 More recently, treatment with zidovudine has been linked to "idiopathic" lactic acidosis and cases of severe fatty liver and hepatic failure.37,38,39,40 A similar syndrome of hepatic failure and fatty liver has been reported after treatment with didanosine41,42 and zalcitabine.37 Finally, pancreatitis as a toxic consequence of didanosine treatment is well known, and "chemical" pancreatitis occurs in as many as 50 percent of patients treated with didanosine for prolonged periods.43
Thus, the multisystem toxicity associated with fialuridine in our patients resembled the recognized but uncommon toxic reactions produced by other nucleoside analogues. This suggests that the toxicity of this class of compounds might be related to generalized mitochondrial injury, with individual agents having a propensity to injure particular target tissues: muscle in the case of zidovudine, peripheral nerves in the case of zalcitabine, pancreas in the case of didanosine, and liver in the case of fialuridine. The greater toxicity of fialuridine may relate to its chemical structure, which permits its incorporation into DNA. Confirmation of this hypothesis and further elucidation of the drug's toxicity may have important implications for patients treated with antiviral nucleoside analogues.
We are indebted to a large number of persons who provided invaluable help and advice during this episode, including the nursing and social service staff of the Clinical Center of the National Institutes of Health, as well as Drs. William Balistreri, John Lake, Roger Williams, William Stevenson, Stephen Caldwell, E. Rolland Dickson, Jr., Michael Gaffey, Forrest Dodson, Hector Ramos, John Fung, Jake Demetrius, Richard Nichols, Thomas Boyer, Robert Gorden, Hyman Zimmerman, Kamal Ishak, Zachary Goodman, Yung-Chi Cheng, Jean-Pierre Sommadossi, Karen Lindsay, Robert Perrillo, Norman Sussman, James Kelly, Bud Tennant, Carlos Lopez, Ronald Browsher, James Balow, Howard Austen, Marinos Dalakas, Edward Cupler, Jean Grem, Daniel Martin, Michael Montello, Mel Sorensen, and Phillip Gorden.
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.
References
-d-arabinofuranosyl)-5-iodouracil in human liver cells. J Clin Invest 1995;95:555-563.
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Related Letters:
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.
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Full Text
N Engl J Med 1996;
334:1135-1138, Apr 25, 1996.
Correspondence
This article has been cited by other articles:
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