Fung, J

Gavaler, JS

Starzl, TE

Van Thiel, DH

Wright, HI

English

PubMed

Name not available

Interferon therapy of hepatitis following liver transplantation under FK 506 or cyclosporine

D-Scholarship@Pitt

1R/~ Interferon Therapy of Hepatitis Following Liver Transplantation Under FK 506 or Cyctosporine D.H. Van Thiel. H.I. Wright, J.S. Gavaler. J. Fung, and T.E. Starzl V IRAL hepatitis is a major disease indication for liver transplantation. Both fulminant hepatic failure due to any of a number of hepatotrophic viruses such as hepatitis A. B. C. B+D. -E. cytomega!ovirus (CMV). Epstein-Barr (EBV), herpes, or NANBNC and chronic hepatitis associated with cirrhosis and liver failure due to hepatitis B. C. B+D, or NANBNC are among the four or five more frequent specific indications for liver transplan-tation at most transplant centers. For this later group of patients. in particular. with chronic viral liver disease. disease recurrence is an important clinical problem follow-ing successful transplantation. 1-3 Two issues of particular concern relative to viral hepa-titis following liver transplantation are the effects of the required immunosuppressive agent upon viral replication and the role. if any, of interteron therapy upon either rejection induction or persistence. Because of the size of the transplant program at the University of Pittsburgh and the availability of both cycJosporine (CyA) and FK 506 as :..,munosuppressive agents at this institution. experience with both agents has been obtained in liver allograft recipients with either recurrent or de novo viral hepatitis who have been treated with a-interteron. MATERIALS AND METHODS Subjects :\ total of 84 liver allograft reCIpients with viral hepalllls have been treated With a-intertcron. [wenty-two of these indiViduals were reCelVln1! eVA. and 62 were receiving FK 506 as their maJor Immunosuppressive agent. Twenty-eight of these hepallc allograft reCIpients had hepalllls-B. 37 had hepatuis-C. and II} had hepall-IIs-NANBNC as the cause of their hepalllls, Disease Detection Abnonnal liver Injury tests. panlcularly abnonnalities of the aminotransferase levels that were resistant to minor changes an t he immunosuppressIve regtmen. or that were not allnbutable to a reco!ZOIzed drug toxicity. identified an allograft recipient as requIr-ing a liver biopsy. Immedlatelv pnor to each liver biopsy. a ~omplcte panel of Viral serolollic studies. Including assays for HAV, HBV, HCV. HOV. EBV. and CMV was obtained. A pcrcutaneous liver biopsy was obtained from each with a Tru-cut needle and was processed by the Clinical Pathology Department. Therapv and Disease Monitonng Individuals Identified as descnbed above. who were found to have a liver biOpsy consIstent with viral hepatitis consisting of a pattern llf lobular inflammation and patchy hepatocellular necrosIs. as well as a mononuclear cell infiltrate In the ponat areas. but wllhout eVidence of acute cellular rejection t vasculitis or bile duct tnluro. were treated wllh tt-Interteron tSchenngl at a dose of 5 million U. 3 times a week. for 6 months. During the course of interferon therapy, the liver injury parameters (ALT. AST. bili-rubin. and atkaline phosphatase I. as well as hematologic parame-ters (WBC and platelet counts I. were monitored weekly for the tirst month. then twice monthly for a second month. and then monthly until the tennination of a 6-month course of therapy. After 6 months. a second liver biopsy was obtained and the interferon therapy was discontinued. Six weeks later. a third liver biopsy was obtained and the liver injury parameters were assessed monthly thereafter. for an additional 6 months. Response Definitions A full response was defined as a complete nonnalization of the assessed liver Injury parameters tALT and AST levels) and in the case of HOV disease. a seroconversion from HBeAg-posltive to HBeAb-positive. A partial response was defined as a greater than SO% reducuon in the baseline liver injury parameters. but not a complete normalization of these parameters of liver injury, RESULTS The time from date of transplantation to the'time at which the viral hepatitis in liver allograft recipients was docu-mented histologically is shown in Table I. Hepatitis due to the HBV tended to occur earlier than did hepatitis C or NANBNC hepatitis in these allograft recipients. More importantly. (hose receiving FK 506 developed their hep-atitis earlier (han did those who were receiving CyA. regardless of the type of hepatitis. Overall. 10% of the patients treated experienced a complete remtssion: 50% experienced a partial remission. while 40% failed to respond to a 6-month course of a-intert'eron therapy at the dose utilized. The response rates for those IOdividuals receIving FK 506 as their primary immunosuppressive agent were less than those receiving Cy A. and consisted of fewer individuals experi-encing a partIal remission and a slightly greater number of Table 1. Time to HeplitiU. Following fran.pIantatIon VilUl FK !lO8 HBV 381 :!: 53 HeV 564 :t 88 NANBNC 599:!: 162 All S18:!: 102 <;~ 1991 by Appleton & Lange 0041·1345191/$3.001+0 evA PVI/ue 991 % 210 <001 1348 :!: 313 <,002 910 % 235 NS 1082:!: 235 <0001 3052 rrllflStJlantatlOn ProcetK1ttJt}S. Vol 23. No 6 (Decemoerl. 1991: pp 3052-3053 INTERFERON THERAPY OF HEPATmS ALL FOAMS OF HEPATmS Fig 1. The bars show the percentage of patients in each group treated with either FK 506 or CyA expenenang a full. partial. or no response to 6 months of Interferon therapy. nonresponders (Fig I). Despite the normalization (full response) or greater than 50% reduction in the levels of the assessed measures of liver injury (partial response). the liver histology failed to improve in most subjects. Worse yet. as assessed by the Knodell criteria for disease activ-ity.' the histologic disease either remained stable in a third of the subjects studied or worsened slightly in the remain-ing two thirds. DISCUSSION This is the first report of the use of a-interferon in a large group of liver allograft recipients treated for viral hepatitis occurring after successful transplantation. Several obser-3053 vations can be made as a result of this unique experience. First. immunosuppression with FK 506. as compared to CyA. is associated with a statistically earlier onset of posttransplant hepatitis. regardless of the specific type of hepatitis being considered. More importantly. FK 506. as compared to eVA. is associated with a reduced number of clinical responses to a-interferon therapy. Third. despite a good clinical response as assessed by liver injury parame-ters. the histologic evidence for viral hepatitis in liver allograft recipients either remain unchanged or actually worsens as a result or during the period of interferon therapy. Fourth. and importantly. no episodes of acute cellular rejection or cases of chronic rejection were ascrib-able to the use of a-interferon in these allograft recipients. These data suggest that the enhanced immunosuppression associated with FK 506 as opposed to CyA results in an enhanced rate of viral replication and. as a reSUlt. a reduction in the number of responses to a-interferon therapy experienced. Moreover. these data suggest that the use of newer and more powerful immunosuppressive agents such as FK 506 mandate the identification and use of more specific antlviral agents if viral hepatitis is to be successfully treated in liver allograft recipients. REFERENCES I. Starzt TE. Demelris AJ. Van Thiel DH: N Engl J Med 321:1014. 1092. 1989 2. Demelris AJ. Jaffee R. Sheahan DG. el al: Am J Pathol 125:161.1984 3. Demelns AJ. Todo S. Van Thiel DH. el al: Am J Pat hoi 137:667. 1990 4. Todo S. Demelns AJ. Van Thiel DH. el al: Hepalology 13:619. 1991 5. Knodell R. Ishak K. l31ack We. ..:1 al: Hepalology 1:431. 1981 

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Interferon therapy of hepatitis following liver transplantation under FK 506 or cyclosporine

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