Digestive Diseases and Sciences, Vol. 37, No. 3 (March 1992), p. 478
LETTER TO THE EDITOR
ACTIVATION OF HEPATITIS C VIRUS FOLLOWING IMMUNOSUPPRESSIVE TREATMENT
To The Editor: Activation of hepatitis B virus (HBV) infection during immunosuppressive and/or cytotoxic treatment has been reported (1, 2). Although accentuation of active hepatitis consistent with type non-A, non-B (NANB) infection following such treatments has been reported (3, 4), this has not been demonstrated unequixrocally. Moreover, whether the enhanced hepatitis seen in these situations is actually due to viral activation or some other mechanism has not been documented. Recently, we have seen three patients with well-established chronic C hepatitis that occurred as a result of repeated blood transfusions administered as part of the treatment of acute leukemia. Two of these three developed fulminant hepatic failure following a rapid withdrawal of cyclosporin A (CsA) immunosuppression administered following allogenic bone marrow transplantation (Table 1). Serial determinations of HCV RNA in blood using a two-stage polymerase chain reaction (5) revealed an activation of HCV infection after the initiation of the CsA therapy. This observation suggests that replication of HCV may be influenced by immunological state of the host or at least as a consequence of cyclosporine therapy. What was particularly striking in these two cases, however, was the observation that two weeks after the termination of cyclosporine therapy, fulminant hepatic failure occurred in both cases. In only eight of the TABLE 1. HCV RNA AND ANTI-HCV IN TWO HEPATITIS C PATIENTS RECEIVING CYCLOSPORIN A (CsA) P r i o r to s t a r t
o f CsA therapy
Case 1 HCV RNA Anti-HCVt (OD) Case 2 HCV RNA Anti-HCVt (OD)
++$ (0.067) + + (>2.0)
1 m o n t h after s t a r t o f CsA
therapy
At o n s e t o f FH*
++++ + (>2.0) ++ + (>2.0)
(0.012) + + (0.500)
*FH: fulminant hepatitis. tAnti-HCV was determined using Ortho HCV Ab ELISA test. ~ + + + + , + + + , + + , + are approximately equivalent to 104, 103, 102, 10x chimpanzee infectious dose (CID/ml), respectively.
478
20 prior cases in which a more prolonged taper of cyclosporine had been used (four versus two months) did an exacerbation of hepatitis C disease occur. More important is the fact that none of the exacerbations in these eight were severe in nature. This suggests that a rapid taper (two months) as opposed to a longer immunosuppressive weaning period (four months) may have been the critically important variable in the pathogenesis of the FHF seen in these two cases. M. YOSHIBA K. SEKIYAMA F. SUGATA
Division of Gastroenterology Showa University Fufigaoka Hospital Yokohama, Japan H . KANAMORI F . KODAMA
Department of Hematology~Chemotherapy Kanagawa Cancer Center Yokohama, Japan H. OKAMOTO Immunology Division Jichi Medical School Tochigi, Japan REFERENCES 1. Galbraith RM, Eddelston ALWF, Williams R, Zuckerman AJ, Bagshawe KD: Fulminant hepatic failure in leukemia and choriocarcinoma related to withdrawal of cytotoxic drug therapy. Lancet 2:528-530, 1975 2. Hoofnagle JH, Dusheiko GM, Shafer DF, Jones EA, Micetich KC, Young RC, Costa J: Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Intern Med 96:447-449, 1982 3. Locasciulli A, Santamaria M, Masera G, Schiavon E, Alberti A, Realdi G: Hepatitis B virus markers in children with acute leukemia: The effect of chemotherapy. J Med Virol 15:29-33, 1985 4. Lok ASF, Liang RHS, Chiu EKW, Wong K-L, Chan T-K, Todd D: Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Gastroenterology 100:182-188, 1991 5. Okamoto H, Okada S, Sugiyama Y, Tanaka T, Sugai Y, Akahane Y, Machida A, Mishiro S, Yoshizawa H, Miyakawa Y, Mayumi M: Detection of hepatitis C virus RNA by a two-stage polymerase chain reaction with two pairs of primers deduced from the 5'-noncoding region. Jpn J Exp Med 60:215-222, 1990
Digestive Diseases and Sciences, Vol. 37, No. 3 (March 1992) 0163-2116/92/0300-0478506.50/09 1992PlenumPublishingCorporation
LETTER TO THE EDITOR
ACTIVATION OF HEPATITIS C VIRUS FOLLOWING IMMUNOSUPPRESSIVE TREATMENT
To The Editor: Activation of hepatitis B virus (HBV) infection during immunosuppressive and/or cytotoxic treatment has been reported (1, 2). Although accentuation of active hepatitis consistent with type non-A, non-B (NANB) infection following such treatments has been reported (3, 4), this has not been demonstrated unequixrocally. Moreover, whether the enhanced hepatitis seen in these situations is actually due to viral activation or some other mechanism has not been documented. Recently, we have seen three patients with well-established chronic C hepatitis that occurred as a result of repeated blood transfusions administered as part of the treatment of acute leukemia. Two of these three developed fulminant hepatic failure following a rapid withdrawal of cyclosporin A (CsA) immunosuppression administered following allogenic bone marrow transplantation (Table 1). Serial determinations of HCV RNA in blood using a two-stage polymerase chain reaction (5) revealed an activation of HCV infection after the initiation of the CsA therapy. This observation suggests that replication of HCV may be influenced by immunological state of the host or at least as a consequence of cyclosporine therapy. What was particularly striking in these two cases, however, was the observation that two weeks after the termination of cyclosporine therapy, fulminant hepatic failure occurred in both cases. In only eight of the TABLE 1. HCV RNA AND ANTI-HCV IN TWO HEPATITIS C PATIENTS RECEIVING CYCLOSPORIN A (CsA) P r i o r to s t a r t
o f CsA therapy
Case 1 HCV RNA Anti-HCVt (OD) Case 2 HCV RNA Anti-HCVt (OD)
++$ (0.067) + + (>2.0)
1 m o n t h after s t a r t o f CsA
therapy
At o n s e t o f FH*
++++ + (>2.0) ++ + (>2.0)
(0.012) + + (0.500)
*FH: fulminant hepatitis. tAnti-HCV was determined using Ortho HCV Ab ELISA test. ~ + + + + , + + + , + + , + are approximately equivalent to 104, 103, 102, 10x chimpanzee infectious dose (CID/ml), respectively.
478
20 prior cases in which a more prolonged taper of cyclosporine had been used (four versus two months) did an exacerbation of hepatitis C disease occur. More important is the fact that none of the exacerbations in these eight were severe in nature. This suggests that a rapid taper (two months) as opposed to a longer immunosuppressive weaning period (four months) may have been the critically important variable in the pathogenesis of the FHF seen in these two cases. M. YOSHIBA K. SEKIYAMA F. SUGATA
Division of Gastroenterology Showa University Fufigaoka Hospital Yokohama, Japan H . KANAMORI F . KODAMA
Department of Hematology~Chemotherapy Kanagawa Cancer Center Yokohama, Japan H. OKAMOTO Immunology Division Jichi Medical School Tochigi, Japan REFERENCES 1. Galbraith RM, Eddelston ALWF, Williams R, Zuckerman AJ, Bagshawe KD: Fulminant hepatic failure in leukemia and choriocarcinoma related to withdrawal of cytotoxic drug therapy. Lancet 2:528-530, 1975 2. Hoofnagle JH, Dusheiko GM, Shafer DF, Jones EA, Micetich KC, Young RC, Costa J: Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Intern Med 96:447-449, 1982 3. Locasciulli A, Santamaria M, Masera G, Schiavon E, Alberti A, Realdi G: Hepatitis B virus markers in children with acute leukemia: The effect of chemotherapy. J Med Virol 15:29-33, 1985 4. Lok ASF, Liang RHS, Chiu EKW, Wong K-L, Chan T-K, Todd D: Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Gastroenterology 100:182-188, 1991 5. Okamoto H, Okada S, Sugiyama Y, Tanaka T, Sugai Y, Akahane Y, Machida A, Mishiro S, Yoshizawa H, Miyakawa Y, Mayumi M: Detection of hepatitis C virus RNA by a two-stage polymerase chain reaction with two pairs of primers deduced from the 5'-noncoding region. Jpn J Exp Med 60:215-222, 1990
Digestive Diseases and Sciences, Vol. 37, No. 3 (March 1992) 0163-2116/92/0300-0478506.50/09 1992PlenumPublishingCorporation
