Recurrence of occult hepatitis B virus infection in a recipient of a liver transplant for HCV-related cirrhosis: full length genome, mutations analysis and literature review

Tahar Bajjou, Mohammed Rida Tagajdid, Safae Elkochri, Rachid Abi, Nadia Touil, Jalila Rahoui, Fatima Zahra Kandoussi, Yassine Sakhsoukh, Hicham El annaz, Saad Mrani


The outcome of liver transplant recipients in HCV chronic carriers with Anti-HBc only concerning occult HBV infection is unknown. We report here the case of a patient who underwent liver transplantation (LT) for cirrhosis post chronic hepatitis C who received an allograft from a donor with no marker of hepatitis B infection. After LT, HBV DNA was detected in the serum in the absence of HBsAg while HCV RNA remained negative. To determine the origin of this occult HBV infection, we retrospectively examined stored serum and liver tissue, pre and post-transplantation, for HBV DNA by PCR. A stored liver biopsy of the donor before transplantation was also tested. HBV DNA was detected in the pre-transplant liver but not in the donor liver. HBV viral load quantified by real time PCR after LT ranged from about 102 to 5x103 HBV DNA copies/mg of liver, while in sera, concentrations ranged from 102 to 3x103 HBV DNA copies/ml. All PCR products in the S gene from liver and sera were sequenced. Analysis of sequences showed the presence of an HBV strain genotype D. The nucleotide homology between the patient’s HBV strains before and after LT was 96 % across the analyzed regions. Full length HBV genomes were amplified from the sera using Rolling Circle Amplification and then sequenced. Analysis of sequences confirmed the genotype D, but did not show obvious mutations that could contribute to HBsAg seronegativity and low HBV viral replication. Factors leading to occult HBV infection are still unclear, but it is well establish that occult HBV infection is frequent in HCV patients. This underlines the role of extra hepatic sites for HBV replication, potentially lymphocytes acting as “reservoirs”.  



Occult HBV infection, Chronic hepatitis C, HBV-DNA, HBsAg, Liver transplantation

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D. Samuel, C. Feray, H. Bismuth, Hepatitis viruses and liver transplantation. J Gastroenterol Hepatol. 1997;12(9-10):S335-41.

Curry MP. Hepatitis B and hepatitis C viruses in liver transplantation. Transplantation. 2004;78(7):955-63.

Brechot, C, Minami M, De Mitri S, Paterlini P. Hepatitis B and C viruses in hepatitis B surface antigen negative hepatocellular carcinoma patients. Princess Takamatsu Symp, 1995;25:199-209.

Chemin I, Zoulim F, Merle P, Arkhis A, Chevallier M, Kay A, et al. High incidence of hepatitis B infections among chronic hepatitis cases of unknown aetiology. J Hepatol. 2001;34(3):447-54.

Cacciola I, Pollicino T, Squadrito G, Cerenzia G, Orlando ME, Raimondo G. Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease. N Engl J Med. 1999;341(1):22-6.

Squadrito G, Pollicino T, Cacciola I, Caccamo G, Villari D, La Masa T, et al. Occult hepatitis B virus infection is associated with the development of hepatocellular carcinoma in chronic hepatitis C patients. Cancer. 2006;106(6):1326-30.

Fukuda R, Ishimura N, Niigaki M, Hamamoto S, Satoh S, Tanaka S, et al. Serologically silent hepatitis B virus coinfection in patients with hepatitis C virus-associated chronic liver disease: clinical and virological significance. J Med Virol. 1999;58(3):201-7.

Hu, KQ. Occult hepatitis B virus infection and its clinical implications. J Viral Hepat. 2002;9(4):243-57.

Chemin I, Trepo C. Clinical impact of occult HBV infections. J Clin Virol. 2005;34(Suppl 1):S15-21.

Chamorro AJ, Casado JL, Bellido D, Moreno S. Reactivation of hepatitis B in an HIV-infected patient with antibodies against hepatitis B core antigen as the only serological marker. Eur J Clin Microbiol Infect Dis. 2005;24(7):492-4.

Orlando R, Tosone G, Tiseo D, Piazza M, Portella G, Ciancia R, et al. Severe reactivation of hepatitis B virus infection in a patient with hairy cell leukaemia: should lamivudine prophylaxis be recommended to HBsAg-negative, anti-HBc-positive patients? Infection. 2006;34(5):282-4.

Margeridon S, Carrouée-Durantel S, Chemin I, Barraud L, Zoulim F, Trépo C, et al. Rolling circle amplification, a powerful tool for genetic and functional studies of complete hepatitis B virus genomes from low-level infections and for directly probing covalently closed circular DNA. Antimicrob Agents Chemother, 2008 Sep;52(9):3068-73.

Galy O, Petit MA, Benjelloun S, Chevallier P, Chevallier M, Srivatanakul P, et al. Efficient hepatitis C antigen immunohistological staining in sections of normal, cirrhotic and tumoral liver using a new monoclonal antibody directed against serum-derived HCV E2 glycoproteins. Cancer Lett. 2007;248(1):81-8.

Wang JT, Lee CZ, Chen PJ, Wang TH, Chen DS. Transfusion-transmitted HBV infection in an endemic area: the necessity of more sensitive screening for HBV carriers. Transfusion. 2002;42(12):1592-7.

Liu ZJ, Li SW. Prophylaxis of HBV reinfection by immune therapy after liver transplantation. Zhonghua Gan Zang Bing Za Zhi. 2006;14(4):294-5.

Ghisetti V, Marzano A, Zamboni F, Barbui A, Franchello A, Gaia S, et al. Occult hepatitis B virus infection in HBsAg negative patients undergoing liver transplantation: clinical significance. Liver Transpl. 2004;10(3):356-62.

Abdelmalek MF, Pasha TM, Zein NN, Persing DH, Wiesner RH, Douglas DD. Subclinical reactivation of hepatitis B virus in liver transplant recipients with past exposure. Liver Transpl. 2003;9(12):1253-7.

Larghi A, Leffler D, Frucht H, Rubin M, Semrad CE, Lefkowitch JH, et al. Hepatitis B virus reactivation after kidney transplantation and new onset lymphoma. J Clin Gastroenterol. 2003;36(3):276-80.

Hino K, Basuni AA, Ireland J, Newell A, Mphahlele J, Smit EJ, et al. Reappearance of hepatitis B surface antigen in immunocompromised individuals: reinfection or reactivation? Dig Dis Sci. 2002;47(2):415-8.

Brechot C, Thiers V, Kremsdorf D, Nalpas B, Pol S, Paterlini-Bréchot P. Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: clinically significant or purely “occult”? Hepatology. 2001;34(1):194-203.

Uchida T, Kaneita Y, Gotoh K, Kanagawa H, Kouyama H, Kawanishi T, et al. Hepatitis C virus is frequently coinfected with serum marker-negative hepatitis B virus: probable replication promotion of the former by the latter as demonstrated by in vitro cotransfection. J Med Virol. 1997;52(4):399-405.

Lowell JA, Howard TK, White HM, Shenoy S, Huettner PC, Brennan DC, et al. Serological evidence of past hepatitis B infection in liver donor and hepatitis B infection in liver allograft. Lancet. 1995;345(8957):1084-5.

Dickson RC, Everhart JE, Lake JR, Wei Y, Seaberg EC, Wiesner RH, et al. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. The National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Gastroenterology. 1997;113(5):1668-74.

Berenguer M. Natural history of recurrent hepatitis C. Liver Transpl. 2002;8(10 Suppl 1):S14-8.

Shiffman ML, Vargas HE, Everson GT. Controversies in the management of hepatitis C virus infection after liver transplantation. Liver Transpl. 2003;9(11):1129-44.

Cabrerizo M, Bartolomé J, Caramelo C, Barril G, Carreno V. Molecular analysis of hepatitis B virus DNA in serum and peripheral blood mononuclear cells from hepatitis B surface antigen-negative cases. Hepatology. 2000;32(1):116-23.

Stoll-Becker S, Repp R, Glebe D, Schaefer S, Kreuder J, Kann M, et al. Transcription of hepatitis B virus in peripheral blood mononuclear cells from persistently infected patients. J Virol. 1997;71(7):5399-407.

Torii N, Hasegawa K, Joh R, Hayashi N. Configuration and replication competence of hepatitis B virus DNA in peripheral blood mononuclear cells from chronic hepatitis B patients and patients who have recovered from acute self-limited hepatitis. Hepatol Res. 2003;25(3):234-43.

Chazouilleres O, Mamish D, Kim M, Carey K, Ferrell L, Roberts JP, et al. “Occult” hepatitis B virus as source of infection in liver transplant recipients. Lancet. 1994;343(8890):142-6.

Webster A, Brenner MK, Prentice HG, Griffiths PD. Fatal hepatitis B reactivation after autologous bone marrow transplantation. Bone Marrow Transplant. 1989;4(2):207-8.

Yamamoto K, Horikita M, Tsuda F, Itoh K, Akahane Y, Yotsumoto S, et al. Naturally occurring escape mutants of hepatitis B virus with various mutations in the S gene in carriers seropositive for antibody to hepatitis B surface antigen. J Virol. 1994;68(4):2671-6.

Kreutz, C. Molecular, immunological and clinical properties of mutated hepatitis B viruses. J Cell Mol Med. 2002;6(1):113-43.

Jeantet D, Chemin I, Mandrand B, Tran A, Zoulim F, Merle P, et al. Cloning and expression of surface antigens from occult chronic hepatitis B virus infections and their recognition by commercial detection assays. J Med Virol. 2004;73(4):508-15.

Ireland JH, O'Donnell B, Basuni AA, Kean JD, Wallace LA, Lau GK, et al. Reactivity of 13 in vitro expressed hepatitis B surface antigen variants in 7 commercial diagnostic assays. Hepatology. 2000;31(5):1176-82.

Hass M, Hannoun C, Kalinina T, Sommer G, Manegold C, Günther S. Functional analysis of hepatitis B virus reactivating in hepatitis B surface antigen-negative individuals. Hepatology. 2005;42(1):93-103.

Chaudhuri V, Tayal R, Nayak B, Acharya SK, Panda SK. Occult hepatitis B virus infection in chronic liver disease: full-length genome and analysis of mutant surface promoter. Gastroenterology. 2004;127(5):1356-71.

Chen SY, Kao CF, Chen CM, Shih CM, Hsu MJ, Chao CH, et al. Mechanisms for inhibition of hepatitis B virus gene expression and replication by hepatitis C virus core protein. J Biol Chem. 2003;278(1):591-607.

Shih CM, Lo SJ, Miyamura T, Chen SY, Lee YH. Suppression of hepatitis B virus expression and replication by hepatitis C virus core protein in HuH-7 cells. J Virol. 1993;67(10):5823-32.

Schuttler CG, Fiedler N, Schmidt K, Repp R, Gerlich WH, Schaefer S. Suppression of hepatitis B virus enhancer 1 and 2 by hepatitis C virus core protein. J Hepatol. 2002;37(6):855-62.

Raimondo G, Balsano C, Craxì A, Farinati F, Levrero M, Mondelli M, et al. Occult hepatitis B virus infection. Dig Liver Dis. 2000;32(9):822-6.

Zhang YY, Hansson BG, Kuo LS, Widell A, Nordenfelt E. Hepatitis B virus DNA in serum and liver is commonly found in Chinese patients with chronic liver disease despite the presence of antibodies to HBsAg. Hepatology. 1993;17(4):538-44.