A pretransplant infection with precore mutants of hepatitis B virus does not influence the outcome of orthotopic liver transplantation in patients on high dose anti-hepatitis B virus surface antigen immunoprophylaxis
U Naumann
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorU Protzer-Knolle
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorT Berg
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorK Leder
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorH Lobeck
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorW Bechstein
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorG Gerken
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorU Hopf
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorP Neuhaus
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorU Naumann
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorU Protzer-Knolle
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorT Berg
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorK Leder
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorH Lobeck
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorW Bechstein
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorG Gerken
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorU Hopf
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorP Neuhaus
Department of Surgery, Virchow Klinikum, Humboldt-University, Berlin, Germany
Search for more papers by this authorAbstract
Hepatitis B virus (HBV) infection of the liver graft is a major complication after orthotopic liver transplantation (OLT) for HBV-related cirrhosis. A high viral load before OLT is a known risk factor, whereas the relevance of precore mutants of HBV is a subject of controversy. The aim of this study was to correlate the pretransplantation viral load and a pretransplantation infection with precore mutant HBV (pmHBV) or wildtype HBV (wtHBV) with allograft damage, graft failure, and survival after OLT. Sixty-nine patients with HBV cirrhosis underwent OLT under high dose immunoprophylaxis with anti-hepatitis B surface (HBs) hyperimmunoglobulins (HBIg). A pretransplantation infection with pmHBV and wtHBV was detected by polymerase chain reaction (PCR) and direct sequencing in 30 patients each (pmHBV and wtHBV group). Nine of 69 patients were PCR-negative (noHBV group). Median pretransplantation levels of HBV DNA assessed by hybridization assay were 42 pg/mL for pmHBV and 54 pg/mL for wtHBV patients. HBV recurred in 17 of 30 (57%) of pmHBV and in 14 of 30 (47%) of wtHBV patients and graft failure occurred in 6 of 30 (20%) of pmHBV and 7 of 30 (23%) of wtHBV patients. Neither HBV recurrence nor graft failure occurred in patients in whom no HBV DNA could be detected by PCR using primers flanking the HBV precore region (noHBV) patients. Allograft damage assessed by histology activity index (HAI) scoring was median 6 for pmHBV and 7 for wtHBV patients. Cumulative survival after 5 years was 72% for pmHBV, 74% for wtHBV, and 100% for noHBV patients. In this study, we provide evidence that pretransplantation viral load, but not infection with pmHBV, determines the outcome after OLT in patients on high dose HBIg prophylaxis.
References
- 1 Blumhardt G, Neuhaus P, Bechstein WO, Steffen R, Hopf U, Möller B, Raakow R, et al. Liver transplantation in HBsAg positive patients. Transplant Proc 1990; 22: 1517–1518.
- 2 Todo S, Demetris AJ, Van Thiel D, Teperman L, Fung JJ, Starzl TE. Orthotopic liver transplantation for patients with hepatitis B virus–related liver disease. Hepatology 1991; 13: 619–626.
- 3 O'Grady JG, Smith HM, Davies SE, Daniels HM, Donaldson PT, Tan KC, Portmann B, et al. Hepatitis B reinfection after liver transplantation. Serological and clinical implications. J Hepatol 1992; 14: 104–111.
- 4 Samuel D, Müller R, Alexander G, Fassati L, Ducot B, Benhamou JP, Bismuth H. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med 1993; 329: 1842–1847.
- 5 König V, Hopf U, Neuhaus P, Bauditz J, Schmidt CA, Blumhardt G, Bechstein WO, et al. Long–term follow–up of hepatitis B virus–infected recipients after orthotopic liver transplantation. Transplantation 1994; 58: 553–559.
- 6 Samuel D, Bismuth A, Mathieu D, Arulnaden JL, Reynes M, Benhamou JP, Brechot C, et al. Passive immunoprophylaxis after liver transplantation in HBsAg–positive patients. Lancet 1991; 337: 813–815.
- 7 Müller R, Gubernatis G, Farle M, Niehoff G, Klein H, Wittekind C, Tusch G, et al. Liver transplantation in HBs antigen (HBsAg) carriers: prevention of hepatitis B virus (HBV) recurrence by passive immunization. J Hepatol 1991; 13: 90–96.
- 8 Devlin J, Smith HM, O'Grady JG, Portmann B, Tan KC, Williams R. Impact of immunoprophylaxis and patient selection on outcome of transplantation for HBsAg positive liver recipients. J Hepatol 1994; 21: 204–210.
- 9 Müller R, Samuel D, Fassati LR, Benhamou JP, Bismuth H, Alexander GJM. “EUROHEP” consensus report on the management of liver transplantation for hepatitis B virus infection. J Hepatol 1994; 21: 1140–1143.
- 10 Angus PW, Locarnini SA, McCaughan GW, Jones RM, McMillan JS, Bowden DS. Hepatitis B virus mutant infection is associated with severe recurrent disease after liver transplantation. Hepatology 1995; 21: 14–18.
- 11 Davies SE, Portmann B, O'Grady J, Aldis PM, Chaggar K, Alexander GJM, Williams R. Hepatic histology following transplantation for chronic hepatitis B virus infection including a unique pattern of fibros–ing cholestatic hepatitis. Hepatology 1991; 13: 150–157.
- 12 Fang JW, Tung FYT, Davis GL, Dolson DJ, Van Thiel DH, Lau JYN. Fibrosing cholestatic hepatitis in a transplant recipient with hepatitis B virus precore mutant. Gastroenterology 1993; 105: 901–904.
- 13 Fang JW, Wright TL, Lau JY. Fibrosing cholestatic hepatitis in a patient with HIV and hepatitis B [Letter]. Lancet 1993; 342: 1175.
- 14 Booth JCL, Goldin RD, Brown JL, Karayiannis P, Thomas HC. Fibrosing cholestatic hepatitis in a renal transplant recipient associated with the hepatitis B virus precore mutant. J Hepatol 1995; 22: 500–503.
- 15 Chen CH, Chen PJ, Chu JS, Yeh KH, Lai MY, Chen DS. Fibrosing cholestatic hepatitis in a hepatitis B surface antigen carrier after renal transplantation. Gastroenterology 1994; 107: 1514–1518.
- 16 McLvor C, Morton J, Bryant A, Cooksley WG, Durrani S, Walker N. Fatal reactivation of precore mutant hepatitis B virus associated with fibrosing cholestatic hepatitis after bone marrow transplantation. Ann Intern Med 1994; 121: 274–275.
- 17
Carman WF,
Jacyna MR,
Hadzyanis S,
Karayiannis P,
McGarvey MJ,
Makris A,
Thomas HC.
Mutation preventing formation of hepatitis B e antigens in patients with chronic hepatitis B infection.
Lancet
1989;
ii:
588–590.
10.1016/S0140-6736(89)90713-7 Google Scholar
- 18
Laras A,
Aygidis J,
Koskinas J,
Hadziyannis SJ.
High incidence of HBV precore gene translation initiation mutations in e antigen negative patients [Abstract].
Hepatology
1995;
22:
269A.
10.1016/0270-9139(95)94801-5 Google Scholar
- 19 Kaspa R Tur, Klein A, Aharonson S. Hepatitis B virus precore mutants are identical in carriers from various ethnic origins and are associated with a range of liver disease severity. Hepatology 1992; 16: 1338–1342.
- 20 Lindh M, Horal P, Dhillon AP, Furuta Y, Norkrans G. Hepatitis B virus carriers without precore mutations in hepatitis B e antigen–negative stage show more severe liver damage. Hepatology 1996; 24: 494–501.
- 21 Hopf U, Neuhaus P, Lobeck H, König V, Küther S, Bauditz J, Bechstein WO, Blumhardt G, Steffen R, Neuhaus R, Huhn D. Follow–up of recurrent hepatitis B and delta infection in liver allograft recipients after treatment with recombinant interferon–alpha. J Hepatol 1991; 13: 339–346.
- 22
Haller G,
Bechstein WO,
Neuhaus R,
Raakow R,
Berg T,
Hopf U,
Neuhaus P.
Famcyclovir therapy for recurrent HBV infection after liver transplantation.
Transpl Int
1996;
9:
475–477.
10.1111/j.1432-2277.1996.tb01611.x Google Scholar
- 23 Neuhaus P, Blumhardt G, Bechstein WO, Platz KP, Jonas S, Mueller AR, Langrehr JM, Lohmann R, Schattenfroh N, Knoop M, et al. Comparison of FK506 and cyclosporine–based immunosuppression in primary orthotopic liver transplantation. A single center experience. Transplantation 1995; 59: 31–40.
- 24 Neuhaus P, Bechstein WO, Blumhardt G, Wiens M, Lemmens P, Langrehr JM, Lohmann R, et al. Comparison of quadruple immunosuppression after liver transplantation with ATG or IL–2 receptor antibody. Transplantation 1993; 55: 1320–1327.
- 25 Butterworth LA, Prior SL, Buda PJ, Faoagali JL, Cooksley WGE. Comparison of four methods for quantitative measurement of hepatitis B viral DNA. J Hepatol 1996; 24: 686–691.
- 26 Protzer U, Goergen B, Hopf U, Neuhaus P, zum Büschenfelde KH Meyer, Gerken G. Pre–core mutants of hepatitis B virus in patients receiving immunosuppressive treatment after orthotopic liver transplantation. J Med Virology 1996; 50: 135–144.
- 27 Gerken G, Paterlini P, Manns M, Housset C, Terre S, Dienes HP, Hess G, et al. Assay of hepatitis B virus DNA by polymerase chain reaction and its relationship to pre–S and S–encoded viral surface antigens. Hepatology 1991; 13: 158–166.
- 28 Hultman T, Stahl S, Homes E, Uhlen M. Direct solid phase sequencing of genomic DNA using magnetic beads as solid support. Nucleic Acid Res 1989; 17: 4937–4946.
- 29 Sanger F, Nicklen S, Coulsen A. DNA sequencing with chain–terminating inhibitors. Proc Natl Acad Sci U S A 1977; 74: 5463–5467.
- 30 Lai ME, Solinas A, Mazzoleni AP, Deplano A, Farci P, Lisci V, Porru A, et al. The role of pre–core hepatitis B virus mutants on the long–term outcome of chronic hepatitis B virus hepatitis. A longitudinal study. J Hepatol 1994; 20: 773–781.
- 31 Naoumov NV, Schneider R, Grötzinger T, Jung MC, Miska S, Pape GR, Will H. Precore mutant hepatitis B virus infection and liver disease. Gastroenterology 1992; 102: 538–543.
- 32 Knodell RG, Tshak KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981; 1: 431–435.
- 33 Norusis MJ. SPSS® for windows™: Base system User's Guide, Release 6.0. SPSS Inc.,© 1993.
- 34 Ackrill AM, Naoumov NV, Lau JYN, O'Grady J, Portmann B, Eddleston ALWF, Williams R. Molecular changes in the hepatitis B virus (HBV) core gene in liver graft recipients and association with fibrosing chole–static hepatitis (FCH) [Abstract]. Hepatology 1992; 16: 49A.
- 35
Ghany MG,
Villamil FG,
Gish R,
Roiter S,
Vierling IM,
Lok ASF.
Survival after liver transplantation for HBV liver failure is unrelated to precore stop codon mutation [Abstract].
Hepatology
1995;
22:
420A.
10.1016/0270-9139(95)95402-3 Google Scholar
- 36 McMillan JS, Bowden DS, Angus PW, McCaughan GW, Locarnini SA. Mutations in the hepatitis B virus precore/core gene and core promoter in patients with severe recurrent disease following liver transplantation. Hepatology 1996; 24: 1–7.
- 37 Dienes HP, Gerken G, Goergen B, Heermann K, Gerlich W, zum Buschenfelde KH Meyer Analysis of the precore DNA sequence and detection of precore antigen in liver specimens from patients with anti–Hepatitis B e–positive chonic hepatitis. Hepatology 1995; 21: 1–7.
- 38 Tong SP, Li JS, Vitvitski L, Trepo C. Replication capacities of natural and artificial precore stop codon mutants of hepatitis B virus: relevance of pregenome encapsidation signal. Virology 1992; 191: 237–245.
- 39 Chuang WL, Omata M, Ehata T, Yokosuka O, Hosoda K, Imazeki F, Ohto M. Coinfection study of precore mutant and wildtype hepatitis B–like virus in ducklings. Hepatology 1994; 19: 569–576.
- 40 Okamoto H, Tsuda F, Akahane Y, Sugai Y, Yoshiba M, Moriyama K, Tanaka T, et al. Hepatitis B virus with mutations in the core promoter for an e antigen–negative phenotype in carriers with antibody to e antigen. J Virol 1994; 68: 8102–8110.
- 41 Laskus T, Rakela J, Nowicki MJ Persing DH. Hepatitis B virus core promoter sequence analysis in fulminant and chronic hepatitis B. Gastroenterology 1995; 109: 1618–1623.
- 42 Naoumov NV, Thomas MG, Mason AL, Chokshi S, Bodicky CJ, Farza–neh F, Williams R, et al. Genomic variations in the hepatitis B core gene: A possible factor influencing response to interferon alfa treatment. Gastroenterology 1995; 108: 505–514.
- 43 Carman WF, Trautwein C, van Deursen FJ, Colman K, Dornan E, McLntyre G, Waters J, et al. Hepatitis B virus envelope variation after liver transplantation with and without hepatitis B immune globulin prophylaxis. Hepatology 1996; 24: 490–493.
- 44 Protzer U, Naumann U, Knolle P, Berg Th, Hopf U, zum Büschen–felde KH Meyer, Neuhaus P, et al. “Escape”–Mutanten des Hepatitis B Virus (HBV) – ein bedeutendes Problem bei Reinfektion nach Lebertransplan–tation (OLT) [Abstract]. Z Gastroenterol 1996; 34: 71.
- 45 Marcellin P, Samuel D, Areias J, Loriot MA, Arulnaden JL, Gigou M, David MF, et al. Pretransplantation interferon treatment and recurrence of hepatitis B virus infection after liver transplantation for hepatitis B related end stage liver disease. Hepatology 1994; 19: 6–12.
- 46 Laskus T, Rakela J, Steers JL, Wiesner RH, Persing DH. Precore and contiguous regions of hepatitis B virus in liver transplantation for end stage hepatitis B. Gastroenterology 1994; 107: 1774–1780.
- 47 Chazouilleres O, Mamish D, Kim M, Carey K, Ferrell L, Roberts JP, Asher NL, et al. “Occult” hepatitis B virus as source of infection in liver transplant recipients. Lancet 1994; 343: 142–146.
