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Journal of Clinical Oncology, Vol 26, No 28 (October 1), 2008: pp. 4695-4696 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.18.7609
Does Rituximab Really Induce Hepatitis C Virus Reactivation?Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
Department of Medical Oncology and Hematology, Cancer Institute Hospital, Tokyo, Japan
Division of Pathology, The Japanese Foundation for Cancer Research, Tokyo, Japan
Department of Transfusion Medicine, and Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
Department of Medical Oncology and Hematology, Cancer Institute Hospital, Tokyo, Japan To the Editor: We wish to raise several issues regarding the recent case report by Hsieh et al.1 Both the title of the article and its conclusion suggest that rituximab-induced reactivation of hepatitis C virus (HCV) is possible during combination chemotherapy with rituximab. We think it cannot be concluded with certainty whether rituximab alone was associated with HCV reactivation in the case described. The first reason for the authors’ conclusion is that liver dysfunction did not develop during initial chemotherapy and occurred after combination chemotherapy with rituximab. However, it is known that HCV-infected patients first develop liver dysfunction after the second or later cycles of chemotherapy. Indeed, a previous study of liver dysfunction in HCV-positive patients with diffuse large B-cell lymphoma treated with a cyclophosphamide, vincristine, doxorubicin, and prednisolone–like regimen has shown that the incidence of hepatic toxicity tended to increase with the number of chemotherapy courses.2 Reactivation of viruses such as hepatitis B virus (HBV),3 cytomegalovirus,4 and varicella-zoster virus5 is considered to be associated with immunosuppression caused by rituximab treatment. Rituximab targets and depletes CD20-positive malignant lymphocytes along with normal CD20-positive B cells, and previous studies have demonstrated rapid depletion of normal B lymphocytes, whereas immunoglobulin levels remain within normal limits until at least 6 months after treatment.6 Indeed, HBV reactivation during the fourth to sixth (or between the third and fifth) cycles of rituximab treatment has been reported,3 and one study has documented markedly late HBV reactivation at several months after completion of rituximab treatment.7 Therefore we think it is too speculative to conclude that rituximab was responsible for the rapid increase of transaminase levels during the clinical course described. It is difficult to determine whether liver dysfunction is caused by HCV reactivation or chemotherapy toxicity. In fulminant hepatitis caused by HCV reactivation, the level of HCV RNA has been reported to increase during chemotherapy and dramatically decrease at the onset of severe liver dysfunction.8 In fact, we have experienced a case in which the expression of HCV RNA increased during rituximab chemotherapy and dramatically decreased to below the normal limit at the time of severe liver dysfunction.9 The changes in serum HCV RNA and transaminase levels described in the latter two reports suggest that the liver dysfunction may have been caused by the spread of HCV in the liver and the resulting immune reaction against HCV-infected hepatocytes. However, for the patient described, the authors provide no data to suggest HCV viral load before and after liver dysfunction. The authors also consider that a synchronized increase of HCV RNA and transaminases could have accounted for the rituximab-induced HCV reactivation. However, they present no details of HCV RNA levels during the first course of chemotherapy without rituximab, and it is unclear whether the HCV viral load had increased before rituximab administration. A previous study of nine patients with chronic HCV hepatitis has shown that prednisone therapy increased the HCV RNA level in all of them,10 suggesting that anticancer agents may have induced the increase of HCV RNA. Therefore, we think that, in this particular case, it is necessary to clarify how the HCV RNA level changed during the course of treatment. Liver dysfunction during rituximab-containing chemotherapy needs additional investigation, given that rituximab-induced HBV reactivation is a significant clinical problem. If rituximab did, in fact induce severe liver dysfunction through HCV reactivation in the present case, this would have important implications for clinical management. Additional detailed information on the association between rituximab infusion and HCV reactivation is therefore required. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Hsieh CY, Huang HH, Lin CY, et al: Rituximab-induced hepatitis C virus reactivation after spontaneous remission in diffuse large B-cell lymphoma. J Clin Oncol 26:2584-2586, 2008 2. Besson C, Canioni D, Lepage E, et al: Characteristics and outcome of diffuse large B-cell lymphoma in hepatitis C virus-positive patients in LNH 93 and LNH 98 Groupe d’Etude des Lymphomes de l’Adulte programs. J Clin Oncol 24:953-960, 2006 3. Tsutsumi Y, Kanamori H, Mori A, et al: Reactivation of hepatitis B virus with rituximab. Expert Opin Drug Saf 4:599-608, 2005[CrossRef][Medline] 4. Suzan F, Ammor M, Ribrag V: Fatal reactivation of cytomegalovirus infection after use of rituximab for a post-transplantation lymphoproliferative disorder. N Engl J Med 345:1000, 2001 5. Bermúdez A, Marco F, Conde E, et al: Fatal visceral varicella-zoster infection following rituximab and chemotherapy treatment in a patient with follicular lymphoma. Haematologica 85:894-895, 2000[Medline] 6. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998[Abstract] 7. Dai MS, Chao TY, Kao WY, et al: Delayed hepatitis B virus reactivation after cessation of preemptive lamivudine in lymphoma patients treated with rituximab plus CHOP. Ann Hematol 83:769-774, 2004[CrossRef][Medline] 8. Vento S, Cainelli F, Mirandola F, et al: Fulminant hepatitis on withdrawal of chemotherapy in carriers of hepatitis C virus. Lancet 347:92-93, 1996[CrossRef][Medline] 9. Ennishi D, Terui Y, Yokoyama M, et al: Monitoring serum hepatitis C virus (HCV) RNA in patients with HCV-infected CD20-positive B-cell lymphoma undergoing rituximab combination chemotherapy. Am J Hematol 83:59-62, 2008[CrossRef][Medline] 10. Fong TL, Valinluck B, Govindarajan S, et al: Short-term prednisone therapy affects aminotransferase activity and hepatitis C virus RNA levels in chronic hepatitis C. Gastroenterology 107:196-199, 1994[Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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