Back to Conference Reports
Bruno ROCHE, Didier SAMUEL Centre Hépatobiliaire, Hôpital Paul Brousse, Paris, France
Five to 10% of patients undergoing orthotopic liver transplantation (OLT) has HBV-associated chronic or fulminant liver disease [1,2]. Results of OLT were hampered by recurrent infection. Acute or chronic liver disease on the graft secondary to viral reinfection may lead to graft failure, retransplantation or death [3,4]. The spontaneous risk for HBV reinfection after transplantation is around 80% related to the initial liver disease and the presence of HBV replication at time of transplantation [3,4]. Over the last years, major advances have been made in the management of HBV transplant candidates. The advent of long-term hepatitis B immune globulin (HBIG) administration as a prophylaxis of HBV recurrence and the introduction of new antiviral agents against HBV infection were a major breakthrough in the management of these patients [5,6].
INDICATION FOR LIVER TRANSPLANTATION
Liver transplantation should be considered when the expected medium term survival is below 2 years. Transplantation is indicated in patients with a history of spontaneous bacterial peritonitis, chronic encephalopathy, refractory ascites or recurrent variceal bleeding. Associated hepatocellular carcinoma is also a common indication for liver transplantation.
MECHANISMS OF HEPATITIS B VIRUS RECURRENCE AFTER LIVER TRANSPLANTATION
HBV reinfection is the consequence of either an immediate reinfection of the graft due to circulating HBV particles, of a reinfection of the graft from HBV particles coming from extrahepatic sites or both. In patients receiving HBIG, HBV reinfection may be the consequence of HBV overproduction coming from extrahepatic sites , of a too low protective titer of anti-HBs antibody, or of emergence of escape mutants. This latter mechanism is important since mutations in the pre S/S genome of HBV and in the “a” determinant by immune pressure selection has been described [8-12]. It has been suggested that escape mutation was more frequent in patients receiving HBIG manufactured from vaccines than from patients with post-HBV infection . Escape mutation can reverse when HBIG are stopped . Peripheral mononuclear cells may be implicated: we have shown in a patient that the HBV strain predominant after reinfection was the strain predominating in the mononuclear cells before liver transplantation . This mechanism of escape mutation is not exclusive, since HBV reinfection with a non-mutated form of HBV was described in patients receiving HBIG [8,10].
SPONTANEOUS OUTCOME OF HEPATITIS B VIRUS RECURRENCE AFTER LIVER TRANSPLANTATION
Most cases of HBV reinfection occurred during the 3 first years post-transplantation and rarely thereafter . HBV reinfection is characterized by appearance of HBsAg in serum with high HBV replication level . HBV reinfection has a major impact on graft and patient survival . Indeed in the absence of HBV reinfection, graft histology remains normal . In contrast, almost all patients with HBV reinfection will develop severe graft disease [3,4,16]. This severe evolution is probably related to the high intrahepatocyte amount of HBV antigens suggesting a direct cytopathic effect. A particularly severe form named fibrosing cholestatic hepatitis have been described [17). This high amount of virions particles within the graft is probably the consequence of the immunosuppressive therapy, which enhances HBV replication [15,17-19]. Rapid reduction in the dose of corticosteroids in liver transplant recipients with HBV infection is a common practice [20,21]. Antiviral treatments have dramatically improved the prognosis of HBV graft reinfection.
Back to top
PREVENTION OF HBV RECURRENCE
- Hepatitis B immune globulins.
The mechanisms by which HBIG protects the transplanted liver against HBV reinfection are poorly understood. One hypothesis suggests that HBIG protects naive hepatocytes against HBV released from extrahepatic sites through the blocking of a putative HBV receptor. There is evidence for a dose-dependent response to HBIG treatment [5,16]. HBIG was first administered to an HBsAg positive patient in 1978 . The administration of HBIG during a short-term post-transplantation period gave disappointing results [3-5]. The Hanover group subsequently adjusted HBIG dosages to maintain the anti-HBs titer at greater than 100 IU/L for 6 months after OLT . We and others adopted an indefinite immunoprophylaxis . Patients received 10000 IU/l during the anhepatic phase, then 10000 IU/l daily during the 6 post-operative days, then the level of anti-HBs was assessed weekly and 10000 IU of HBIG were readministered when anti-HBs was less than 100 IU/l. In a European multicenter study there was a dramatic decrease of the rate of HBV recurrence from 75% in patients receiving no or short-term administration of HBIG to 33% in those receiving long-term administration of HBIG (P<0.001) . Recurrence of HBV occurred in 67% of patients transplanted for HBV cirrhosis, 40% of those transplanted for fulminant hepatitis B-Delta, 32% of those transplanted for HDV cirrhosis, and 17% of those transplanted for fulminant hepatitis B . HBV recurrence rate was dependent of the presence of HBV replication assessed by both serum HBeAg and HBV DNA detection using conventional hybridisation technique at time of transplantation . These results were confirmed by others clinical trials in the US and Europe and by long-term follow-up studies (Table 1 and 2) [14,24-30].
For HBV-DNA positive patients, the rate of HBV reinfection could be reduced by using higher HBIG doses and maintaining serum anti-HBs level > 500 IU/L or by using pre and/or post-OLT supplemental antiviral therapy. Several reports using very high doses of HBIG, and maintenance titers over 500 IU /l showed promising results [24,31]. HBV recurrence occurred in 0 to 15 % and 16 to 35% of patients transplanted for non replicative and replicative HBV cirrhosis, respectively (Table 1 and 2) [14,31-34].
Taking into consideration the inter- and intra-patients variations in pharmacokinetics of HBIG, monitoring of serum anti-HBs levels is required. An alternative approach has been proposed by Terrault in which a fixed monthly 10000 IU dose of HBIG is delivered intravenously, irrespective of preoperative viral replication status .
Most data support long-term intravenous administration of HBIG. Efforts to use intramuscular HBIG have been motivated by substantial cost benefice and unavailability of intravenous HBIG, but experience with the intramuscular route of HBIG is limited.
HBIG administration had a very satisfactory record of safety and adverse events observed are usually minor and rare. Mercury poisoning has been reported anecdotally in patients receiving an intramuscular form of HBIG via the intravenous route . Some cases of immune reactions have been reported but are easily prevented by infusion of steroids, antihistaminic drugs and longer duration of perfusion. Long-term HBIG administration had several drawbacks: a) HBIG administration is expensive, but the cost is highly variable depending on the country and on the manufacturer ; b) HBIG administration remains constraining because of the need for close monitoring of the level of anti-HBs antibody and frequent reinjection; c) HBV reinfection rate remains high in patients with HBV replication at time of transplantation.
- Antiviral therapies.
Until recently the presence of HBV replication was considered as a contraindication to OLT by most centers [36,37]. Thus an antiviral treatment in order to clear HBV DNA from serum before OLT is logical. However, patient candidates to OLT are difficult to treat because of the severity of the liver disease. An ideal treatment in this setting should have a rapid potent antiviral action without provoking deterioration of liver function.
A major limitation of using interferon before OLT has been its poor tolerability in cirrhotic patients . In a controlled study we used interferon in 22 cirrhotic patients awaiting OLT compared with 26 non treated patients. HBIG were used after OLT. Interferon failed to reduce the rate of HBV recurrence . However, in those patients who were HBV DNA negative by PCR in serum the risk of viral B recurrence was low. In one report the use of interferon prior to OLT was shown to reduce the rate of HBV reinfection . In a few studies, interferon treatment before OLT has been associated with stabilisation of liver disease and postponement of need for transplantation [39,41].
Famciclovir has modest activity against HBV  and was used successfully in a small study before and after OLT in combination with HBIG .
Lamivudine is well tolerated even in decompensated cirrhosis, and is effective by achieving a negativation of HBV DNA by molecular hybridisation in 90% of patients [44-52]. However, viremia will occur in 80% following cessation of therapy and development of mutations in the YMDD motif of the HBV DNA polymerase gene increased with treatment duration . Villeneuve  reported on 35 patients with severely decompensated HBV cirrhosis and replicative HBV infection, who were treated with lamivudine 100 or 150 mg daily. Within 6 months of treatment initiation, 7 patients underwent liver transplantation and 5 patients died. In 23 patients who were treated for at least 6 months, there was a slow but marked improvement in liver function in 22. The rate of development of resistance to lamivudine was 25% at 2 years. Other studies confirmed the slow improvement of hepatic function in patients with decompensated cirrhosis and replicating HBV treated with lamivudine [47,48,50], which may confer a survival advantage . Fontana  in a multicentric study found that lamivudine did not improve overall pre-OLT or OLT-free survival, however suggesting that a subset of patients with less advanced liver failure may derive clinical benefit from lamivudine treatment. A question that emerges is whether to delay OLT in patients who have improved on lamivudine, or to proceed with OLT because of the potential risk for YMDD mutation and subsequent deterioration. New antiviral agents such as adefovir dipivoxil may serve as « rescue » therapy for patients with lamivudine resistance . Cases of liver transplantation in patients with YMDD mutants were reported with controversial results. In 2 cases, recurrence of HBV can be successfully prevented by administration of a prophylaxis combining HBIG and lamivudine [55,56]. In contrast, Rosenau reported 2 cases of HBV recurrence after transplantation in 2 patients with YMDD mutants despite the same combining prophylaxis . This suggests that transplantation should be either contraindicated or performed only after use of new antiviral treatment in case of emergence of HBV escape mutations before transplantation,
Back to top
Lamivudine monotherapy post-transplantation.
The administration of lamivudine alone pre and post-OLT gave promising results at one year with only 1 case of HBV recurrence out of ten patients , however, a longer follow-up showed a rate of recurrence of 5/10 due to the emergence of escape mutations in the YMDD part of the polymerase gene . These mutations were observed mainly in patients with high level of viral replication prior to transplantation . Similar results were reported in other studies with HBV recurrence in 22.6 to 50% of patients [50,61,62] (table 3). These patients developed HBV recurrence with YMDD mutants and sometimes had a severe clinical outcome . Thus, the administration of lamivudine alone as a prophylaxis after liver transplantation is probably insufficient particularly in replicative patients.
Combination of lamivudine and HBIG.
Several groups developed a more rationale approach by giving lamivudine pre-transplantation and a combination of lamivudine and HBIG post-OLT. The initial results were very encouraging demonstrating disappearance of HBV DNA prior to OLT and absence of HBV recurrence . In these studies, the HBV recurrence rate at 1-2 years were less than 10% [45,57,64-72] (table 4). In addition HBV DNA was found to be negative by PCR in most cases at one-year post-OLT. Lamivudine co-administration may reduce the overall amount of HBIG given post-transplantation [57,64]. The good results of combination treatment may be the consequence of a synergistic effect with reduction of the production of HBsAg by lamivudine and with a decrease rate of escape mutations in the preS/S and YMDD regions.
Guidelines and future prospects.
Patients who are considered OLT candidates should be subdivided into patients who have active viral replication and those who do not. For patients without viral replication, there is no evidence that preoperative antiviral therapy is useful. These patients should receive HBIG 10000 IU given daily for 7 days, including the anhepatic period and then indefinitely every 6-8 weeks to maintain anti-HBs titers > 100-150 IU/L. For patients with viral replication, lamivudine therapy should be started before OLT. Patients who developed resistance to lamivudine may respond to adefovir dipivoxil. Transplantation could be done for negative HBV DNA (by molecular hybridisation) patients. After transplantation, these high risk patients should receive a combination of HBIG 10000 IU daily for 7 days and then indefinitely to maintain anti-HBs titers > 500 IU/L especially during first years and antiviral therapy (lamivudine +/- adefovir)(fig 1).
Discontinuation of HBIG:
Future prospects, especially in patients without replication before transplantation, are the possibility to stop HBIG and to replace it by lamivudine or vaccination or both. The aims are to reduce the long-term costs and the constraint of HBIG administration. In a recent study, HBIG administration was discontinued in a select group of 17 patients and replaced by anti-HBV vaccination . The authors claimed good results with anti-HBs production and absence of HBV reinfection. However, the antibody level was low and declining with time in most patients. These results were confirmed with a longer follow-up  and in one other study . Conflicting results were reported by Angelico using a triple course of hepatitis B vaccination in 17 patients transplanted for HBV cirrhosis after cessation of HBIG . Anti-HBs titer greater than 100 IU/L was observed in only 2 patients (12%). Patient populations, methodologies and definitions of vaccine response were different in these studies.
Two studies comparing HBV reinfection rate in a group of transplanted patients randomised to receive HBIG or lamivudine after a period of administration of HBIG were published [77,78]. In the study of Naoumov  24 patients were selected on a low risk HBV reinfection basis (i.e., absence of detectable HBV DNA at time of transplantation and no HBV reinfection after a minimal follow-up of 6 months after transplantation). At one year, HBV reinfection rate was not significantly different: 2 of 12 and 1 of 12 in the lamivudine and HBIG group, respectively. However, HBV DNA was detected by PCR in the serum of patients without HBV recurrence in 2 of 11 patients in the HBIG group and in 5 of 10 patients in the lamivudine group. This should keep us alert. Indeed, the follow-up of these studies is limited, around 1-2 years, and it has been clearly shown that the risk of escape mutations with lamivudine increase with time.
It is important to determine which patients should be chosen to stop HBIG: patients without replication at time of transplantation, minimum delay of several months post-transplantation, negative detection of HBV DNA by PCR before stopping HBIG. The drawbacks of the discontinuation of HBIG are: a) the possibility of recurrence of HBV infection after cessation of HBIG and the irreversibility of reinfection; b) the persistence of HBV DNA in serum, liver or peripheral blood mononuclear cells in 50% of HBV transplanted patients who are HBsAg negative on HBIG long-term therapy at 10 years  or on combination prophylaxis with HBIG and lamivudine [64,78,80] ; c) the absence of possibility to identify patients who have cleared HBV post-transplantation.
Survival of patients transplanted for HBV cirrhosis
In the absence of prophylaxis of HBV reinfection, the 5-year survival is low between 40 and 60%. In 206 patients receiving adequate immunoprophylaxis, results of OLT for HBV infection in Berlin are similar to those results achieved with other indications. Survival rates at 1, 5 and 10 years were 91%, 81%, and 73% respectively . In the multivariate analysis for patient survival, presence of hepatocarcinoma and HBV recurrence were associated with a lower survival. In our own series, The 5 year survival of patients transplanted for HBV cirrhosis and HDV cirrhosis was 80% and 87.8% respectively .
Back to top
Liver transplantation in patients with HDV liver cirrhosis
Patients chronically infected with HBV and HDV are less at risk of HBsAg reappearance than patients infected with HBV alone. The rate of HBsAg reappearance in patients with viral B-Delta cirrhosis was around 50-60% in patients who did not received long term HBIG [4,82], and 17% in those receiving long term HBIG . The overall lower HBV recurrence rate in these patients is probably due to the fact that almost all patients are HBV DNA negative at time of liver transplantation and that HDV has an inhibitory effect on HBV replication .
In contrast, HDV reinfection is frequent and was observed in 80% of cases in the first post-transplant months . The course of HDV reinfection is different if HBsAg reappears or not. In the few cases where HBsAg reappeared, it was associated with a combined HBV-HDV replication, the development of an acute, then chronic hepatitis [84,85]. HBV-HDV recurrence is in general less severe than HBV recurrence alone . In the patients who remained HBsAg negative after transplantation, the amount of HDAg in the liver graft was low and the liver graft remained histologically normal. At long-term, HDV markers progressively disappeared from liver and serum . The hypotheses for explaining the presence of HDV replication in HBsAg negative patients are: a) HBV markers could be present, but not detectable. b) HDV is present in the hepatocytes in the absence of HBsAg but cannot replicate or have a low replication level; c) the level of HDV RNA in the liver is much lower in patients without HBsAg than with HBsAg and this low level of delta virus may explain the absence of liver graft lesions.
In conclusion, the risk of HBsAg reappearance after liver transplantation in viral B-Delta cirrhotic patients who received long term HBIG is low.
Over last decade, major advances have been made in the management of HBV transplant candidates. The advent of long-term HBIG administration as a prophylaxis of HBV recurrence was a major breakthrough. Using lamivudine before transplantation and a combination of lamivudine and HBIG after transplantation it is possible to reduce the rate of HBV reinfection in HBV replicative cirrhotic patients. Future research should: a) test new protocols using lower HBIG doses given intravenously or intramuscularly alone or in combination with additional antiviral agents; b) identify patients in whom HBIG prophylaxis can be stopped safely; c) develop new antiviral agents with activity for patients with lamivudine resistance.
Back to top
Back to top
- Seaberg EC, Belle SH, Beringer KC, Schivins JL, Detre KM. Liver transplantation in the United States from 1987-1998: Updated results from the Pitt-UNOS liver transplant registry. In: Cecka JM, Terasaki PI, eds. Clinical transplants 1998. Los Angeles: UCLA Tissue Typing Laboratory, 1999:17-37.
- European Liver Transplant Registry – ELTR. Registry for the european liver transplant association, data analysis, 05/1968-12/2000, http://www-eltr.vjf.inserm.fr.
- Todo S, Demetris AJ, Van Thiel D, Teperman L, Fung J, Starzl TE. Orthotopic liver transplantation for patients with hepatitis B virus related liver disease. Hepatology 1991;13:619-626.
- O'Grady JG, Smith HM, Davies SE, Daniels HM, Donaldson PT, Tan KC et al. Hepatitis B virus re-infection after orthotopic liver transplantation. Serological and clinical implications. J Hepatol 1992;14:104-111.
- Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou JP et al. Liver transplantation in European patients with the hepatitis B surface antigen. New Engl J Med 1993;329:1842-1847.
- Shouval D, Samuel D. Hepatitis B immune globulin to prevent HBV graft reinfection following liver transplantation: a concise review. Hepatology 2000;32:1189-1195.
- Feray C, Zignego AL, Samuel D, Bismuth A, Reynes M, Tiollais P et al. Persistent hepatitis B virus infection of mononuclear cells without concommitent liver infection: transplantation model. Transplantation 1990;49:1155-1158.
- Trautwein C, Shrem H, Tillmann HL, Kubicka S, Walker D, Boker KHW et al. Hepatitis B virus mutations in the pre-S genome before and after liver transplantation. Hepatology 1996;24:482-488.
- Ghany MG, Ayola B, Villamil FG, Gish RG, Rojter S, Vierling JM et al. Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis. Hepatology 1998;27:213-222.
- Protzer-Knolle U, Naumann U, Bartenschlager R, Berg T, Hopf U, Meyer Zum Bushenfeld KH et al. Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high dose hepatitis B immune globulin after liver transplantation. Hepatology 1998;27:254-263.
- Carman WF, Trautwein C, Van Deursen FJ, Colman K, Dornan E, McIntyre G et al. Hepatitis B virus envelope variation after transplantation with and without hepatitis B immune globulin prophylaxis. Hepatology 1996;24:489-493.
- Terrault NA, Zhiou S, McCory RW, Pruett TL, Lake JR, Roberts JP et al. Incidence and clinical consequences of surface and polymerase gene mutations in liver transplant recipients on hepatitis B immunoglobulin. Hepatology 1998;28:555-561.
- Brind A, Jiang JJ, Samuel D, Gigou M, Feray C, Brechot C et al. Evidence for selection of hepatitis B mutants after liver transplantation through peripheral blood mononuclear cell infection. J Hepatol 1997;26:228-235.
- Samuel D, Roche B, Feray C, Arulnaden JL, Gigou M, Bismuth A et al. Long-term results of liver transplantation in HBsAg positive patients receiving anti-HBsAg passive immunoprophylaxis (Abstract). Hepatology 1998;28:A313.
- Phillips MJ, Cameron R, Flowers MA, Blendis LM, Greig PD, Wanless L et al. Post-transplant recurrent hepatitis B viral liver disease. Viral-burden, steato-viral, and fibroviral hepatitis. Am J Pathol 1992;140:1295-1308.
- Samuel D, Bismuth A, Mathieu D, Arulnaden JL, Reynes M, Benhamou JP et al. Passive immunoprophylaxis after liver transplantation in HBsAg-positive patients. Lancet 1991;337:813-815.
- Davies SE, Portmann BC, O'Grady JG, Aldis PM, Chaygar K, Alexander GJ et al. Hepatic histologic findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis. Hepatology 1991;13:150-157.
- Lau JYN, Bain VG, Davies SE, O'Grady JG, Alberti A, Alexander GJM et al. High-level expression of hepatitis B viral antigens in fibrosing cholestatic hepatitis. Gastroenterology 1992;102:956-962.
- Demetris AJ, Todo S, Van Thiel DH, Fung JJ, Iwaki Y, Sysyn G et al. Evolution of hepatitis B virus liver disease after hepatic replacement. practical and theoretical considerations Am J Pathol 1990;137:667-676.
- Tur-Kaspa R, Laub O. Corticosteroids stimulate hepatitis B virus DNA, mRNA and protein production in a stable expression sytem. J Hepatol 1990;11:34-36.
- Gish RG, Keefe EB, Lim J, Brooks LJ, Esquivel CO. Survival after liver transplantation for chronic hepatitis B using reduced immunosuppression. J Hepatol 1995:22;257-262.
- Johnson PJ, Wansbrough-Jones MH, Portmann B. Familial HBsAg positive hepatoma: treatment with orthotopic liver transplantation and specific immune globulin. BMJ 1978;1:278.
- Lauchart W, Muller R, Pichlmayr R. Long-term immunoprophylaxis of hepatitis B virus (HBV) re-infection in recipients of human liver allografts. Transplant Proc 1987;19:4051-4053.
- Terrault NA, Zhou S, Combs C, Hahn JA, Lake JR, Roberts JP et al. Prophylaxis in liver transplant recipients using a fixed dosing schedule of hepatitis B immunoglobulins. Hepatology 1996;24:1327-1333.
- Lerut JP, Donataccio M, Ciccarelli O, Roggen F, Jamart J, Laterre PF et al. Liver transplantation and HBsAg-positive postnecrotic cirrhosis: adequate immunoprophylaxis and delta virus co-infection as the significant determinants of long-term prognosis. J Hepatol 1999;30:706-714.
- Blumhardt G, Neuhaus WD, Bechstein L, Steffen R, Hopf U, Moller B et al. Liver transplantation in HBsAg positive patients. Transplant Proc 1990;22:1577-1578.
- Muller R, Gubernatis G, Farle M, Niehoff G, Klein H, Wittekind C et al. Liver transplantation in HBs antigen (HBsAg) carriers. Prevention of hepatitis B virus (HBV) recurrence by passive immunisation. J Hepatol 1991;13:90-96.
- Lemmens HP, Langrehr JM, Blumhardt G, Lohmann R, Knoop M, Verschl J et al. Outcome following orthotopic liver transplantation in HBsAg positive patients using short or long term immunoprophylaxis. Transplant Proc 1994;26:3622-3623.
- 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.
- Konig V, Hopf U, Neuhaus P, Bauditz J, Schmidt CA, Blumhardt G et al. Long-term follow-up of hepatitis B virus infected recipients after orthotopic liver transplantation. Transplantation 1994;58: 553-559.
- McGory RW, Ishitani MB, Oliveira WM, Stevenson WC, McCullough CS, Dickson RC et al. Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with agressive passive immunization. Transplantation 1996;61:1358-1364.
- Gugenheim J, Crafa F, Fabiani P, Militerno G, Goubaux B, Saint Paul MC et al. Récidive du virus de l'hépatite B après transplantation hépatique. Gastroenterol Clin Biol 1992;16:430-433.
- Sawyer RG, McGory RW, Gaffey MJ, McCullough CC, Shepard BL, Houlgrave CW et al. Improved clinical outcome with liver transplantation for hepatitis B related cirrhosis. Ann Surg 1998;227:841-850.
- Nymann T, Shokouh-Amiri MH, Vera SR, Riely CA, Alloway RR, Gaber AO. Prevention of hepatitis B recurrence with indefinite hepatitis B immune globulin (HBIG) prophylaxis after liver transplantation. Clin Transplant 1996;10:663-667.
- Lowell JA, Burgess S, Shenoy S, Curci J, Peters M, Howard TK. Mercury poisonning associated with high dose hepatitis B immune globulin administration after liver transplantation. Liver Transplant Surg 1996;2:475-478.
- Muller R, Samuel D, Fassati LR, Benhamou JP, Bismuth H, Alexander GJ. Eurohep consensus report on the management of liver transplantation for hepatitis B virus infection. J Hepatol 1994;21:1140-1143.
- JURY OF THE INTERNATIONAL CONSENSUS CONFERENCE ON INDICATIONS OF LIVER TRANSPLANTATION. Consensus statement on indications for liver transplantation : Paris, June 22-23, 1993. Hepatology 1994; 20:63S-68S.
- Perrillo R, Tamburro C, Regenstein F, Bolart L, Bodenheimer H, Silva M et al. Low-dose titratable interferon alpha in decompensated liver disease caused by chronic infection with hepatitis B virus. Gastroenterology 1995;109:908-916.
- Marcellin P, Samuel D, Areias J, Loriat MA, Arulnaden JL, Gigou M et al. Pretransplant 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.
- Tchervenkov J, Tector A, Barkun J, Sherker A, Forbes C, Elias N et al. Recurrence-free long-term survival after liver transplantation for hepatitis B using interferon-alpha pretransplant and hepatitis B immune globulin posttransplant. Ann Surg 1997;226:356-365.
- Hoofnagle JH, Di Bisceglie AM, Waggoner JG, Park Y. Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B. Gastroenterology 1993;104:1116-1121.
- DeMan RA, Marcellin P, Habal F, Desmond P, Wright T, Rose T et al. A randomized placebo-controlled study to evaluate the efficacy of 12-month Famciclovir treatment in patients with chronic hepatitis B e Antigen-positive hepatitis B. Hepatology 2000;32:413-417.
- Singh N, Gayowski T, Wannstedt CF, Wagener MM, Marino IR. Pretransplant Famciclovir as prophylaxis for hepatitis B virus recurrence after liver transplantation. Transplantation 1997;63: 1415-1419.
- Bain VG, Kneteman NM, Ma MM, Gutfreund K, Shapiro JA, Fischer K et al. Efficacy of Lamivudine in chronic hepatitis B patients with active viral replication and decompensated cirrhosis undergoing liver transplantation. Transplantation 1996;62:1456-1462.
- Markowitz JS, Martin P, Conrad AJ, Markmann JF, Seu P, Yersiz H et al. Prophylaxis against hepatitis B recurrence following liver transplantation using combination Lamivudine and hepatitis B immune globulin. Hepatology 1998;28:585-589.
- Villeneuve JP, Condreay LD, Willems B, Pomier-Layrargues G, Fenyves D, Bilodeau M et al. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology 2000;31:207-210.
- Yao FY, Bass NM. Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection. J Hepatol 2000;33:301-307.
- Kapoor D, Guptan RC, Wakil SM, Kazim SN, Kaul R, Agarwal SR et al. Beneficial effects of Lamivudine in hepatitis B virus-related decompensated cirrhosis. J Hepatol 2000;33:308-312.
- Fontana RJ, Lok ASF. Lamivudine treatment in patients with decompensated hepatitis B cirrhosis: for whom and when? J Hepatol 2000;33:329-332.
- Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R et al. A multicenter United states-Canadian trial to assess Lamivudine monotherapy before and after transplantation for chronic hepatitis B. Hepatology 2001;33:424-432.
- Yao FY, Terrault NA, Freise C, Maslow L, Bass NM. Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort. Hepatology 2001;34:411-416.
- Fontana R, Keeffe E, Carey W, Fried M, Reddy R, Kowdley K et al. Effect of lamivudine treatment on survival of 309 north american patients awaiting liver transplantation for chronic hepatitis B. Liver Transpl 2002;8:433-439.
- Benhamou Y, Bochet M, Thibault V, DiMartino V, Caunes E, Bricaire F et al. Long-term incidence of hepatitis B virus resistance to Lamivudine in human immunodeficiency virus-infected patients. Hepatology 1999;30:1302-1306.
- Perrillo R, Schiff E, Yoshida E, Statler A, Hirsch K, Wright T et al. Adefovir dipivoxil for the treatment of Lamivudine-resistant hepatitis B mutants. Hepatology 2000;32:129-134.
- Stärkel P, Horsmans Y, Geubel A, Ciccarelli O, Goubau P, Rahier J et al. Favorable outcome of orthotopic liver transplantation in a patient with subacute liver failure due to emergence of a hepatitis B YMDD escape mutant virus. J Hepatol 2001;35:679-681.
- Saab S, Kim M, Wright T, Han SH, Martin P, Busutill RW et al. Successful orthotopic liver transplantation for Lamivudine associated YMDD mutant hepatitis B virus. Gastroenterology 2000; 119:1382-1384.
- Rosenau J, Bahr M, Tillmann HL, Trautwein C, Klempnauer J, Manns MP et al. Lamivudine and low-dose hepatitis B immune globulin for prophylaxis of hepatitis B reinfection after liver transplantation. Possible role of mutations in the YMDD motif prior to transplantation as a risk factor for reinfection. J Hepatol 2001;34:895-902.
- Grellier L, Mutimer D, Ahmed M, Brown D, Burroughs AK, Rolles K et al. Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis. Lancet 1996;348:1212-1215.
- Mutimer D, Dusheiko G, Barrett C, Grellier L, Ahmed M, Anschuetz G et al. Lamivudine without HBIg for prevention of graft reinfection by hepatitis B: long-term follow-up. Transplantation 2000;70:809-815.
- Mutimer D, Pillay D, Dragon E, Tany H, Ahmed M, O’Donnell K et al. High pre-treatment serum hepatitis B titre predicts failure of Lamivudine prophylaxis and graft reinfection after liver transplantation. J Hepatol 1999;30:715-721.
- Lo CM, Cheung ST, Lai CL, Liu CL, Oi-Lin Ng I, Yuen MF et al. Liver transplantation in asian patients with chronic hepatitis B using Lamivudine prophylaxis. Ann Surg 2001;233:276-281.
- Malkan G, Cattral M, Humar A, Al Asghar H, Greig P, Hemming AW et al. Lamivudine for hepatitis B in liver transplantation. Transplantation 2000;69:1403-1407.
- Mutimer D, Pillay D, Shields P, Cane P, Ratcliffe D, Martin B et al. Outcome of Lamivudine resistant hepatitis B virus infection in the liver transplant recipient. Gut 2000;46:107-113.
- Marzano A, Salizzoni M, Debernardi-Venon W, Smedile A, Franchello A, Ciancio A et al. Prevention of hepatitis B virus recurrence after liver transplantation in cirrhotic patients treated with Lamivudine and passive immunoprophylaxis. J Hepatol 2001;34:903-910.
- Yao FY, Osorio RW, Roberts JP, Poordad FF, Briceno MN, Garcia-Kennedy R et al. Intramuscular hepatitis B immune globulin combined with Lamivudine for prophylaxis against hepatitis B recurrence after liver transplantation. Liver transplant Surg 1999;5:491-496.
- Yoshida EM, Erb SR, Partovi N, Scudamore CH, Chung SW, Frighetto L et al. Liver transplantation for chronic hepatitis B infection with the use of combination Lamivudine and low-dose hepatitis B immune globulin. Liver transplant Surg 1999;5:520-525.
- Angus PW, McCaughan GW, Gane EJ, Crawford DHG, Harley H. Combination low-dose hepatitis B immune globulin and Lamivudine therapy provides effective prophylaxis against posttransplantation hepatitis B. Liver Transplant 2000;6:429-433.
- Lee PH, Hu RH, Tsai MK, Ho MC, Lai HS, Lai MY et al. Liver transplantation for patients with hepatitis B: prevention of hepatitis B recurrence by intravenous antihepatitis B immunoglobulin and Lamivudine. Transplant Proc 2000;32:2245-2247.
- McCaughan GW, Spencer J, Koorey D, Bowden S, Bartholomeusz A, Littlejohn M. Lamivudine therapy in patients undergoing liver transplantation for hepatitis B virus precoce mutant-associated infection: high resistance rates in treatment of recurrence but universal prevention if used as prophylaxis with very low dose hepatitis B immune globulin. Liver Transpl Surg 1999;6:512-519.
- Han SH, Ofman J, Holt C, King K, Kunder G, Chen P et al. An efficacy and cost-effectiveness analysis of combination hepatitis B immune globulin and Lamivudine to prevent recurrent hepatitis B after orthotopic liver transplantation compared with hepatitis B immune globulin monotherapy. Liver Transplant 2001;6:741-748.
- Anselmo D, Ghobrial R, Jung LL, Weaver M, Cao C, Saab S et al. New era of liver transplantation of hepatitis B: a 17-year single-center experience. Ann Surg 2002;235:611-620.
- Roche B, Samuel D, Roque AM, Feray C, Petit AM, Vasseur B et al. Intravenous anti-HBs Ig combined with oral lamivudine for prophylaxis against HBV recurrence after liver transplantation (abstract). J Hepatol 1999;30:A80.
- Sanchez-Fueyo A, Rimola A, Grande L, Costa J, Mas A, Navasa M et al. Hepatitis B immunoglobulin discontinuation followed by hepatitis B virus vaccination: a new strategy in the prophylaxis of hepatitis B virus recurrence after liver transplantation. Hepatology 2000;31:496-501.
- Sanchez-Fueyo A, Martinez-Bauer E, Rimola A. Hepatitis B vaccination after liver transplantation. Hepatology 2002;36:257.
- Bienzle U, Gunther M, Neuhaus R, Neuhaus P. Successful hepatitis B vaccination in patients who underwent transplantation for hepatitis B virus-related cirrhosis: preliminary results. Liver Transplant 2002;8:562-564.
- Angelico M, Di Paolo D, Trinito M, Petrolati A, Araco A, Zazza S et al. Failure of a reinforced triple course of hepatitis B vaccination in patients transplanted for HBV-related cirrhosis. Hepatology 2002;35:176-181.
- Dodson SF, De Vera ME, Bonham CA, Geller DA, Rakela J, Fung JJ. Lamivudine after hepatitis B immune globulin is effective in preventing hepatitis B recurrence after liver transplantation. Liver Transplant 2000;6:434-439.
- Naoumov NV, Lopes AR, Burra P, Caccamol L, Iemmolo RM, De Man RA et al. Randomized trial of Lamivudine versus hepatitis B immunoglobulin for long-term prophylaxis of hepatitis B recurrence after liver transplantation. J Hepatol 2001;34:888-894.
- Gigou M, Feray C, Roche B, Afonso AM, Shouval D, Bismuth H et al. Residual viral B particles at 10 years post transplantation in patients receiving long-term anti-HBs immunoglobulins (HBIG)(abstract). J Hepatol 2000;32:A31.
- Samuel D. Liver transplantation and hepatitis B virus infection : the situation seems to be under control, but the virus is still there. J Hepatol 2001;34:943-945.
- Steinmuller T, Seehofer D, Rayes N, Muller AR, Settmacher U, Jonas S et al. Increasing applicability of liver transplantation for patients with hepatitis B-related liver disease. Hepatology 2002;35:1528-1535.
- Ottobrelli A, Marzano A, Smedile A, Recchia S, Salizzoni M, Cornu C et al, Patterns of hepatitis delta virus reinfection and disease in liver transplantation. Gastroenterology 1991;101,1649-1655.
- Krogsgaard K, Kryger P, Aldershvile J, Andersson P, Sorensen TL, Nielsen JO. Delta infection and suppression of hepatitis B virus replication in chronic HBsAg carriers. Hepatology 1987;7:42-45.
- Rizzetto M, Macagno S, Chiaberge E, Verme G, Negro F, Marinucci G et al. Liver transplantation in hepatitis delta virus disease. Lancet 1987;ii:469-471.
- Samuel D. Zignego AL, Reynes M, Feray C, Arulnaden JL, David MF et al. Long-term clinical and virologic outcome after liver transplantation for cirrhosis due to chronic delta hepatitis. Hepatology 1995;21:333-339.
Back to Conference Reports