Herrero, J.I. (José Ignacio)

Pardo, F. (Fernando)

Prieto, J. (Jesús)

Quiroga, J. (Jorge)

Riezu-Boj, J.I. (José Ignacio)

Sangro, B. (Bruno)

Sola, J. (Josu)

Dadun, University of Navarra

CASE REPORTEffectiveness of Lamivudine in Treatment ofAcute Recurrent Hepatitis B AfterLiver TransplantationJ. IGNACIO HERRERO, MD, JORGE QUIROGA, MD, BRUNO SANGRO, MD, IOSU SOLA, MD,JOSE IGNACIO RIEZU-BOJ, MD, FERNANDO PARDO, MD, and JESUS PRIETO, MDKEY WORDS: lamivudine; hepatitis B; liver transplantation.In spite of long-te rm prophylaxis with hepatitis Bimmune globulin (HBIG), recurrence of hepatitis Bvirus (HBV) infection in the graft constitute s theleading cause of morbidity and mortality among pa-tients unde rgoing liver transplantation (LT) due toHBV-induced live r cirrhosis (1). In many of thesepatients acce lerated HBV replication overcomes theprotective effect of HBIG (2).Inte rferon therapy, which is partially effectiveagainst HBV in immunocompetent patients (3), is oflimited value in post-LT HBV graft infection (4).Lamivudine , a nucleoside analog that inhibits thereverse transcriptase activity of HBV, has shownpromising results in HBV infection in both immuno-competent (5) and HIV-immunosuppre ssed patients(6). Signi® cant improvements in live r histology havebeen demonstrated after one year treatment withlamivudine in immunocompetent patients (7). In-deed, administration of lamivudine before and afterLT has also been effective in preventing hepatitis Brecurrence after LT (8), and this drug lacks the seri-ous side effects found with other nucleoside ana-logues (9).We report on a LT patient in whom lamivudinewas an effective therapy for acute recurrent HBVhepatitis.CASE REPORTA 48-year-old white man received a liver graft in March1995 because of HBV liver cirrhosis. Preoperatively, hepa-titis B surface antigen (HBsAg) and antibodies to the coreand e antigens (anti-HBc and anti-HBe, respective ly) weredetectable in the serum, but hepatitis B e antigen (HBeAg)and HBV DNA (dot blot) were not detectable. He receivedhigh-dose anti-HBs immunoglobulin, according to Samuelet al (10) and standard immunosuppression with cyclospor-ine, azathioprine, and prednisone.Intraoperative and postoperative courses were unre-markable, liver function tests became normal within twoweeks after LT, and serum HBsAg became undetectable.Five months after transplantation he deve loped graft dys-function secondary to HBV infection. Liver function testsrevealed severe cytolysis and progressively declining hepaticfunction (Figure 1). Biliary and vascular complications,rejection, and other viral infections were ruled out. Liverbiopsy showed lobular hepatitis with marked cholestasisand the presence of HBsAg and HBcAg in 100% and 60%of hepatocyte s, respective ly (Figure 2) . Serum HBsAg be-came detectable and serum HBV DNA leve ls, as deter-mined by the Digene Hybrid Capture assay (Digene Diag-nostics, Beltsville, Maryland) were greate r than 2000 pg/ml,demonstrating accelerated viral replication. Famciclovir(500 mg every 8 hr) was initiated; HBIG, azathioprine, andprednisone were discontinued; and the cyclosporine dosewas reduced to maintain blood trough leve ls below 100ng/ml.Despite this treatment, liver function tests continued toworsen, and the patient was switched from famciclovir tooral lamivudine (100 mg/day). Shortly thereafter, liver func-tion improved and aminotransferase levels rapidly dimin-ished, reaching normal levels three months afte r lamivudinewas initiated. Serum HBV DNA leve ls decreased rapidlyand became negative within the ® rst month of lamivudinetherapy. Serum HBsAg remained positive one month afterinitiation of lamivudine, but became undetectable twomonths later. Aminotransferase values remain within nor-mal limits and HBV DNA and HBsAg have remainednegative for two years. Six months afte r starting lamivudine,Manuscript received October 27, 1997; revised manuscript re -ce ived January 29, 1998; accepte d February 5, 1998.From the Liver Unit, Clõ Â nica Unive rsitaria de Navarra, Pam-plona, Spain.Address for reprint requests: Dr. J. Ignacio Herrero, Liver Unit,Clõ Â nica Unive rsitaria de Navarra, Avda. Põ Â o XII, s/n. 31008 Pam-plona, Spain.Digestive Diseases and Sciences, Vol. 43, No. 6 (June 1998), pp. 1186 ± 11891186 Digestive Diseases and Sciences, Vol. 43, No. 6 (June 1998)0163-2116/98/0600-1186$15.00/0 Ñ 1998 Plenum Publishing Corporationthe patient was both HBsAg- and anti-HBs-negative , be-coming anti-HBs-positive six months later; currently, hisserum anti-HBs concentration is 188 mIU/ml. A liver biopsyperformed ® ve months after initiating lamivudine therapyshowed a signi® cant improvement, with only mild to mod-erate lymphocyte in¯ ammatory activity. Immunostainingagainst HBsAg and HBcAg were both negative . This histo-logical improvement was con® rmed in a second liver biopsyperformed after one year of lamivudine therapy. No ad-verse event related to this drug was recorded. Currently, thepatient is still on lamivudine and immunosuppressive ther-apy includes cyclosporine, maintaining trough leve ls at arange of 50 ± 75 ng/ml.DISCUSSIONPassive immunoprophylaxis with HBIG reducesbut does not eliminate the risk of recurrent HBVinfection after LT (2). The natural history of HBVreinfection after LT is usually accelerated because ofimmunosuppression. Moreover, some of the patientsdevelop ® brosing chole static hepatitis, a clinicopath-ological syndrome characte rized by cholestasis, severe® brosis, and marked expre ssion of HBV antige ns inhepatocyte s, which leads to a rapidly progre ssive live rfailure (11) due to a direct cytopathic effect. There isno effective therapy for this condition. The high viralreplication secondary to immunosuppression makesinte rferon therapy of limited ef® cacy (4). Adeninearabinoside monophosphate has shown only a partialand transient effectiveness (12) and may cause neu-rotoxicity (13) . Long-te rm therapy with ganciclovirhas been shown to be partially effective in a pilotstudy (14) . Although this treatment caused signi® -cantly reduced HBV DNA in several patients, ALTvalue s remained increased in most of them and serumHBeAg and liver HBsAg remained detectable in allthe patients, demonstrating the inability of ganciclovirto fully inhibit HBV replication. Furthermore , as itseffect over HBV DNA was transient, ganciclovir hadto be administe red inde ® nite ly. The need for intrave -nous administration precludes the long-te rm use ofthis drug. Recent reports on famciclovir, the oralform of penciclovir, in the treatment of post-LT HBVinfection has shown only partial activity (15) .The patient reported in this pape r had a recurrentHBV infection of the liver graft presenting as a severeacute hepatitis, with remarkably high viral replicationand progre ssive worsening of liver function. Althoughimmunosuppression was markedly reduced and fam-ciclovir was started, live r function deteriorated fur-ther and viral replication remained extremely high. Inthis setting, lamivudine dramatically changed the clin-ical picture . The patient began to feel better, amino-transfe rase and bilirubin value s immediate ly de-creased, and viral replication was fully inhibite d, asdemonstrated by the abrupt fall in serum HBV DNAleve ls, the rapid loss of serum HBsAg, the persistentFig 1. Evolution of serum transaminase (dotted line), bilirubin (solid line), and hepatitis B virus DNA levels (arrowheads) beforeand after lamivudine therapy.LAMIVUDINE IN ACUTE HEPATITIS B AFTER LT1187Digestive Diseases and Sciences, Vol. 43, No. 6 (June 1998)histological improvement, and the loss of HBsAg andHBcAg in live r tissue .The effectiveness of lamivudine in this case and inother preliminary trials warrants furthe r investigationin the transplant setting and in nontransplant HBVinfection. Pre liminary results from a multicenter trialof lamivudine after LT have shown promising results(16) , but several points, such as duration of therapy,need to be clari® ed because short-term treatment (12weeks) has only a transient effect on HBV DNAleve ls (5). Finally, this drug may be useful not only inchronic infection but also in acute hepatitis B, asdemonstrated by the dramatic improvement of thepatient reported here.REFERENCES1. Wright TL: Liver transplantation in patients with chronic hep-atitis B and hepatitis C. In Transplantation of the Liver, 2nd ed.WC Maddrey, MF Sorrell (eds.). Norwalk, Appleton & Lange,1995, pp 477± 5012. Samue l D, Muller R, Alexande r G, Fassati L, Ducot B, Ben-hamou JP, Bismuth H: Liver transplantation in Europeanpatients with the hepatitis B surface antigen. N Engl J Med329:1842± 1847, 19933. Perrillo RP, Schiff ER, Davis GL, Bodenheimer HC, LindsayK, Payne J, Dienstag JL, O’Brien C, Tamburro C, JacobsonMI, Sampliner R, Feit D, Lefkowitch J, Kuhns M, MeschievitzC, Sanghvi B, Albrecht J, Gibas A, Hepatitis InterventionalTherapy Group: A randomized, controlled trial of interferonalfa-2b alone after prednisone withdrawal for the treatment ofchronic hepatitis B. N Engl J Med 323:295± 301, 19904. Terrault NA, Combs Holland C, Ferre ll L, Hahn JA, Lake JR,Roberts JP, Ascher NL, Wright TL: Interferon alfa for recur-rent hepatitis B infection after liver transplantation. LiverTransplant Surg 2:132± 138, 19965. Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, VicaryC, Rubin M: A preliminary trial of lamivudine for chronichepatitis B infection. N Engl J Med 333:1657± 1661, 19956. Lai CL, Liaw YF, Leung NWY, Chang TT, Guan R, Tai DI, NgKY, Wu PC, Dent JC, Gray DF: 12 months of lamivudine (100mg od) therapy improves liver histology: Results of a placebocontrolled multicentre study in Asia. J Hepatol 26( suppl 1) :79,19977. Benhamou Y, Dohin E, Luniel-Fabiani F, Poynard T, HurauxJM, Katlama C, et al: Ef® cacy of lamivudine in replication ofFig 2. Histopathologic appearance of posttransplant hepatitis B at the time of its recurrence (left) and immunostaining againstHBsAg (upper right) and HBcAg (lower right).HERRERO ET AL1188 Digestive Diseases and Sciences, Vol. 43, No. 6 (June 1998)hepatitis B virus in HIV-infected patients. Lancet 345:396 ± 397,19958. Grellier L, Mutimer D, Ahmed M, Brown D, Burroughs AK,Rolles K, McMaster P, Beranek P, Kennedy F, Kibbler H,McPhillips P, Elias E, Dusheiko G: Lamivudine prophylaxisagainst reinfection in liver transplantation for hepatitis B cir-rhosis. Lancet 348:1212± 1215, 19969. McKenzie R, Fried MW, Sallie R, Conjeevaram H, Di Bisceg-lie AM, Park Y, Savare se B, Kleiner D, Tsokos M, Luciano C,Pruett T, Stotka JL, Straus SE, Hoofnagle JH: Hepatic failureand lactic acidosis due to ® aluridine (FIAU), an investigationalnucleoside analogue for hepatitis B. N Engl J Med 333:1099 ±1105, 199510. Samue l D, Bismuth A, Mathieu D, Arulnaden J, Rayne s M,Benhamou J, Brechot C, et al: Passive immunoprophylaxisafter liver transplantation in HBsAg-positive patients. Lance t337:813± 815, 199111. Lau JYN, Davies SE, Bain VG, O’Grady JG, Alberti A, Alex-ander GJM, Williams R: High level expression of hepatitis Bviral antigens in ® brosing cholestatic hepatitis. Gastroente rol-ogy 102:956 ± 962, 199212. Marce llin P, Samuel D, Loriot MA, Are ias J, Bismuth H,Benhamou JP: Antiviral effect of adenine arabinoside mono-phosphate (ARA-AMP) in patients with recurrence of hepati-tis B virus (HBV) infection after liver transplantation. Hepa-tology 12:966A, 199013. Lok ASF, Wilson LA, Thomas HC: Neurotoxicity associatedwith adenine arabinoside monophosphate in the treatment ofchronic hepatitis B virus infection. J Antimicrob Chemother14:93± 99, 198414. Gish RG, Lau JYN, Brooks L, Fang JWS, Steady SL, ImperialJC, Garcia-Kennedy R, et al: Ganciclovir treatment of hepatitisB virus infection in liver transplant recipients. Hepatology23:1± 7, 199615. Rabinovitz M, Dodson F, Rakela J: Famciclovir for recurrenthepatitis B (HBV) infection after live r transplantation(OLTX). Hepatology 24:282A, 199616. Perrillo R, Rakela J, Martin P, Levy G, Schiff E, Wright T,Dienstag J, Gish R, Villeneuve J, Caldwell S, Brown N, Self P,Lamivudine Transplant Study Group: Lamivudine for hepatitisB after liver transplantation (OLT). Hepatology 24:182A, 1996LAMIVUDINE IN ACUTE HEPATITIS B AFTER LT1189Digestive Diseases and Sciences, Vol. 43, No. 6 (June 1998)

Effectiveness of lamivudine in treatment of acute recurrent hepatitis B after liver transplantation

Universidad de Navarra

Effectiveness of lamivudine in treatment of acute recurrent hepatitis B after liver transplantation

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Dadun, University of Navarra

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