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Ribavirin and Use of Clotting Factors in Patients With Hemophilia and Chronic Hepatitis C
To the Editor: Ribavirin has been used in combination with interferon (IFN) alfa to treat chronic hepatitis C. This combination therapy has been reported to be more effective than IFN monotherapy for eradicating hepatitis C virus (HCV),1-3 including that occurring in patients with concomitant hemophilia.4-5 We are unaware of previous reports of reduction in the use of clotting factors in HCV-positive patients with hemophilia treated with ribavirin and IFN.
Methods
Eight consecutive patients with hemophilia were treated as outpatients for HCV infection with IFN and ribavirin between June 2002 and November 2003 at Nagoya University Hospital (Table). All patients were men with a mean (SD) age of 44.8 (10.0) years. Six patients had hemophilia A, and 2 had hemophilia B. Hemophilia was severe in 3 patients, moderate in 2, and mild in 3. Four patients (patients 1, 2, 3, and 5) had been previously treated with IFN alfa-2b alone (Intron A; Schering Plough K. K., Osaka, Japan) (6 MU/d for 2 weeks, followed by 3 times/wk for 22 weeks), but HCV had not been eradicated. During this study, all patients were treated with the same 24-week regimen of IFN. Oral ribavirin (Rebetol; Schering-Plough, Kenilworth, NJ) was administered at a dose of 600 mg/d for patients who weighed 60 kg or less and 800 mg/d for those who weighed more than 60 kg during 24 weeks. The dose of ribavirin was reduced by 200 mg/d if the patient’s hemoglobin concentration decreased to below 10 g/dL due to hemolytic anemia induced by ribavirin; the hemoglobin level did not fall this low from any other causes.
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Table. Patient Characteristics and Treatment Responses*
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The use of clotting factors was assessed by patient logs. Because the patients with mild hemophilia rarely used clotting factors, we compared the average use of clotting factors from the 5 patients with moderate and severe hemophilia before, during, and after treatment. Pairwise comparisons were made by 2-sided t test, with statistical significance defined as P<.05. All statistical analyses were done using JMP version 5.0.1 (SAS Institute Inc, Cary, NC). Ability to perform activities of daily living was assessed by interview. The protocol was approved by the Nagoya University institutional review board and written informed consent was obtained from each patient before treatment.
Results
In the 5 patients requiring clotting factor, the mean (SD) use of clotting factors per month for the 6 months prior to combination therapy was 3783 [2646] U/mo; during therapy it was 1605 [1488] U/mo; and for the 6 months after therapy it was 1667 [1528] U/mo (Figure). The mean use during treatment was significantly lower than before treatment (P = .03). The mean use after treatment was lower than before treatment, approaching statistical significance (P = .06). Seven of 8 patients noted no limitation of life activities before or after the start of IFN and ribavirin. One patient (patient 1) noted slight limitation of daily activities because of fatigue associated with combination therapy. The use of clotting factors in this patient was reduced during treatment but returned to the pretreatment level afterward. The average numbers of bleeding episodes treated per month in the 6 months before combination therapy, during the therapy period, and in the 6 months after therapy, respectively, were 1.7, 0.7, and 1.6 (patient 1); 6.0, 3.0, and 4.1 (patient 2); 4.0, 2.6, and 2.2 (patient 3); 1.0, 0.2, and 0.7 (patient 5); and 3.6, 0.8, and 0.0 (patient 8). Most bleeding episodes were hemarthroses; a few involved mucosal or intramuscular bleeding.
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Figure. Use of Clotting Factor Concentrates 6 Months Before, During, and 6 Months After Combination Therapy With Ribavirin and Interferon for the 5 Patients Requiring Clotting Factor During the Study
Differences in each period were analyzed by paired t test. P = .03 for comparison of pretreatment and active treatment; P = .06 for comparison of pretreatment and posttreatment. Large data markers indicate mean clotting factor use; error bars, SEs.
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Comment
In our hospital, 47 patients with hemophilia who had been treated for chronic hepatitis C with IFN alone had no observed reduction in the use of clotting factor, including 4 of the patients in this study. This strongly suggests that the reduced use of clotting factors was associated with the addition of ribavirin.
The reason for the reduction in the use of clotting factors by these patients with hemophilia is not clear. One suggestion comes from a case report that described an increase in warfarin dose requirement in a patient with a heart valve prosthesis after the start of this combination therapy,6 and a change in coagulation status after starting ribavirin could be associated with our observations.
In 2 patients in this study, the decreased use of clotting factors continued after combination therapy ended. Being able to increase physical activities during treatment might strengthen muscles recovering from atrophy caused by joint bleeding. This increased strength could reduce stress on joints, further decreasing the risk of spontaneous hemarthrosis.
Based on this case series, ribavirin in combination with IFN, and possibly alone, may reduce the use of clotting factors in patients with hemophilia and chronic hepatitis C. Further studies, including replication of these findings and clinical trials, would help to clarify the potential role of ribavirin in these patients.
Financial Disclosures: None reported.
Takashi Honda, MD, PhD;
Hidenori Toyoda, MD, PhD;
Kazuhiko Hayashi, MD, PhD;
Yoshiaki Katano, MD, PhD;
Motoyoshi Yano, MD, PhD;
Isao Nakano, MD, PhD;
Kentaro Yoshioka, MD, PhD;
Hidemi Goto, MD, PhD
Department of Gastroenterology
Nagoya University School of Medicine
Nagoya, Japan
Koji Yamamoto, MD, PhD;
Junki Takamatsu, MD, PhD
jtkmtsu{at}med.nagoya-u.ac.jp
Department of Transfusion Medicine
Nagoya University School of Medicine
1. McHutchison JG, Gordon SC, Schiff ER, et al, Hepatitis Interventional Therapy Group. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med. 1998;339:1485-1492.
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2. Poynard T, Marcellin P, Lee SS, et al, International Hepatitis Interventional Therapy Group (IHIT). Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet. 1998;352:1426-1432.
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3. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
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4. Santagostino E, Rumi MG, Rivi M, Colombo M, Mannucci PM. Sustained suppression of hepatitis C virus by interferon and ribavirin in hemophilic patients not responding to interferon monotherapy. Blood. 2002;99:1089-1091.
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5. Fried MW, Peter J, Hoots K, et al. Hepatitis C in adults and adolescents with hemophilia: a randomized, controlled trial of interferon alfa-2b and ribavirin. Hepatology. 2002;36:967-972.
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6. Schulman S. Inhibition of warfarin activity by ribavirin. Ann Pharmacother. 2002;36:72-74.
ABSTRACT
Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2005;293:1190-1192.
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