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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 14, 2015; 21(42): 12083-12090
Published online Nov 14, 2015. doi: 10.3748/wjg.v21.i42.12083
Management of hepatitis B virus infection after liver transplantation
Miguel Jiménez-Pérez, Rocío González-Grande, José Mostazo Torres, Carolina González Arjona, Francisco Javier Rando-Muñoz
Miguel Jiménez-Pérez, Rocío González-Grande, José Mostazo Torres, Carolina González Arjona, Liver Transplantation and Hepatology Unit, UGC de Aparato Digestivo Hospital Regional Universitario, 29010 Malaga, Spain
Francisco Javier Rando-Muñoz, Department of Abdominals Diseases, Hospital Nij Smellinghe Ziekenhuis, 9202 NN Drachten, The Netherlands
Author contributions: Jiménez-Pérez M, González-Grande R, Mostazo Torres J, González Arjona C and Rando-Muñoz FJ contributed equally to this work.
Conflict-of-interest statement: The authors have no conflict of interest to report.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Miguel Jiménez-Pérez, MD, Liver Transplantation and Hepatology Unit, UGC de Aparato Digestivo Hospital Regional Universitario, Avenida Carlos Haya, 29010 Malaga, Spain. mjimenezp@commalaga.com
Telephone: + 34-6-1095935 Fax: + 34-95-1291941
Received: April 18, 2015
Peer-review started: April 20, 2015
First decision: June 23, 2015
Revised: July 4, 2015
Accepted: September 14, 2015
Article in press: September 14, 2015
Published online: November 14, 2015

Abstract

Chronic hepatitis B virus (HBV) infection is responsible for up to 30% of cases of liver cirrhosis and up to 53% of cases of hepatocellular carcinoma. Liver transplantation (LT) is the best therapeutic option for patients with end-stage liver failure caused by HBV. The success of transplantation, though, depends on receiving prophylactic treatment against post-transplant viral reactivation. In the absence of prophylaxis, liver transplantation due to chronic hepatitis B (CHB) is associated with high rates of viral recurrence and poor survival. The introduction of treatment with hepatitis B immunoglobulins (HBIG) during the 1990s and later the incorporation of oral antiviral drugs have improved the prognosis of these patients. Thus, LT for CHB is now a universally accepted option, with an estimated 5 years survival of around 85% vs the 45% survival seen prior to the introduction of HBIG. The combination of lamivudine plus HBIG has for many years been the most widely used prophylactic regimen. However, with the appearance of new more potent oral antiviral agents associated with less resistance (e.g., entecavir and tenofovir) for the treatment of CHB, new prophylactic strategies are being designed, either in combination with HBIG or alone as a monotherapy. These advances have allowed for more personalized prophylaxis based on the individual risk profile of a given patient. In addition, the small pool of donors has required the use of anti-HBc-positive donors (with the resulting possibility of transmitting HBV from these organs), which has been made possible by suitable prophylactic regimens.

Key Words: Hepatitis B virus, Liver transplantation, Recurrence, Prophylaxis, Hepatitis B immunoglobulin

Core tip: The current success of liver transplantation in patients with chronic hepatitis B (CHB)-related cirrhosis is mainly due to the use of prophylaxis with hepatitis B immunoglobulins (HBIG) and oral antivirals against post-liver transplant recurrence of CHB. The combination of low-dose HBIG plus antivirals forms the current standard prophylaxis. The use of newer antivirals (entecavir and tenofovir), coupled with better understanding of the predisposing factors for recurrence of CHB, has led to new perspectives for prophylaxis regimens, aimed at withdrawal of HBIG or the use of HBIG-free regimens, oriented toward a strategy of individualized prophylaxis.



INTRODUCTION

Chronic hepatitis B virus (HBV) infection is responsible for up to 30% of cases of liver cirrhosis and up to 53% of cases of hepatocellular carcinoma[1]. Liver transplantation (LT) is the best therapeutic option for patients with end-stage liver failure caused by HBV. The success of transplantation, though, depends on the need to receive prophylactic treatment against post-transplant viral reactivation. In the absence of prophylaxis, LT due to chronic hepatitis B (CHB) is associated with high rates of viral recurrence that negatively influence survival[2,3]. The introduction of treatment with hepatitis B immunoglobulins (HBIG) during the 1990s[4] and the later incorporation of oral antiviral drugs have led to improvements in the prognosis for these patients, resulting in LT for CHB now being a universally accepted option, with an estimated 5 years survival of around 85% vs the 45% survival seen prior to the introduction of HBIG[2,3,5]. The combination of lamivudine (LAM) plus HBIG has for many years been the most widely used prophylactic regimen. However, with the appearance of new more potent oral antiviral agents associated with less resistance [entecavir (ETV) and tenofovir (TDF)] for the treatment of CHB, new prophylactic strategies are being designed, either in combination with HBIG or even alone in monotherapy. This has resulted in the development of more personalized prophylaxis based on the individual risk profile of a given patient[6]. In addition, the small pool of donors has required the use of anti-HBc-positive donors (with the resulting possibility of transmitting HBV from these organs), which has been made possible by suitable prophylactic regimens[7]. Table 1 reflects the risk of recurrence of hepatitis B in recipients of anti-HBc-positive organs according to the serological status of the recipient.

Table 1 Risk of de novo hepatitis B in recipients of anti-HBc-positive organs.
Recipient statusNaiveAntiHBc+AntiHBc+AntiHBc-
AntiHBs-AntiHBs+AntiHBs+
No prophylaxis> 40%13%< 2%10%
With prophylaxis12%< 4%< 2%< 2%
High riskIntermediate riskLow riskIntermediate risk
PROPHYLAXIS FOR HBV RECURRENCE AFTER LT

Various strategies have been suggested to aid in the prevention of HBV recurrence after LT.

HBIG monotherapy

HBIG was the first effective drug used as prophylaxis for recurrence of CHB in transplant patients. It led to great advances, as it reduced the rates of recurrence to around 20%-30% and significantly improved survival rates[4]. However, the use of HBIG as prophylaxis in monotherapy has certain complications, such as the potential for mutations in the surface gene that determines resistance and loss of efficacy, the inability to reach sufficiently protective anti-HBs titers in all patients[8,9], and the high economic cost and difficulties associated with their parenteral administration[10]. These inconveniences, together with the appearance of new oral antiviral nucleos/tide analogues (NAs) and the confirmation of their synergistic effect, mean that HBIG is no longer used in monotherapy, and the standard treatment for prophylaxis against CHB recurrence is now combined therapy with HBIG plus NAs[10].

NAs in monotherapy

LAM: LAM was the first effective oral antiviral used against CHB. Its safety and efficacy, even in patients with decompensated hepatic cirrhosis, enabled patients to have a negative viremia at LT, thus reducing the probability of post-LT viral recurrence[11].

Perrillo et al[12], using LAM monotherapy both before and after LT, reported a recurrence rate of around 30%, very similar to that seen with HBIG monotherapy[4]. Furthermore, it was also noted that most recurrences were due to the development of HBV DNA polymerase mutations that led to drug resistance. These patients who experienced recurrence had higher viral loads at the time of LT than those who did not have recurrence, similar to patients treated with HBIG monotherapy.

Because of the high rate of resistance with LAM after prolonged use the resulting risk of recurrence, and the introduction of ETV and TDF with their high genetic barrier to resistance, LAM monotherapy has fallen into disuse.

Adefovir: The commercialization of adefovir (ADV) in 2003 represented an alternative for patients with resistance to LAM. Schiff et al[13] studied a group of 60 patients, of whom 24 received ADV with or without LAM with no HBIG as prophylaxis against post-LT hepatitis B, and found that none developed recurrent hepatitis B after a follow-up of 36 mo. However, because of the potential nephrotoxic effect associated with ADV and the risk of developing resistance ADV is not the first choice for prophylaxis against post-LT CHB recurrence.

ETV and TDF: The recent availability of these highly effective, well-tolerated antivirals with their high genetic barrier to resistance has resulted in changes in the approach to CHB in relation to LT. Accordingly, prophylactic strategies are now being reconsidered (see below).

Combined prophylaxis with HBIG plus oral antivirals

Various studies and meta-analyses[14-18] on the synergic effect of combination HBIG and NAs in prophylaxis for CHB recurrence have found general recurrence rates < 10%, which is noticeably lower than those seen with HBIG or NAs in monotherapy. This reduction in recurrence has led to combined prophylaxis (mainly HBIG plus LAM) becoming the standard of care in LT due to CHB. The possibility of resistance with long-term use of LAM encouraged a trial on the use of combination HBIG and ADV. A systematic review by Cholongitas et al[19] found that the combination of HBIG plus ADV was more effective than prophylaxis with HBIG plus LAM (2% vs 6.1%, P = 0.024).

However, relatively few studies have examined combined prophylaxis with HBIG plus ETV or TDF. Overall, these studies have found recurrence rates ranging from 0% to 4%[20-26]. Nevertheless, no randomized studies have yet compared the efficacy of combined prophylaxis with HBIG + LAM vs HBIG + ETV or TDF, although a recent systematic review noted a higher recurrence rate with the combination HBIG + LAM than with HBIG + ETV/TDF (6.1% vs 1%, P = 0.0004)[27].

Prophylaxis with alternative dosing schedules of HBIG

The high economic cost of prophylaxis schedules combining HBIG plus oral antivirals, together with the high efficacy and safety of the more recent oral antivirals (ETV/TDF), have led to the study of different prophylactic strategies aimed at lowering or eliminating HBIG in order to reduce costs and the inconveniences associated with its administration.

Additionally, other possible routes of administration of HBIG have been assessed. Several studies[28,29] have shown that low-dose intra-muscular (IM) administration of HBIG when combined with NAs is a cost-effective alternative to its intravenous (IV) administration. Recently the subcutaneous administration of HBIG has been found equally effective, well-tolerated, and accepted by patients[30,31].

HBIG dose reduction: Two differing strategies have been tried: (1) Low-dose IM administration of HBIG (400-500 IU) at fixed intervals with oral antivirals. Two studies endorse these results; Gane et al[29] found recurrence rates of 1% during the first year and 4% in the fifth year, using doses of 400-800 IU per day for the first week and then monthly in combination with LAM. Zheng et al[32] used doses of 800 IU at first weekly and then monthly, recording recurrence rates of 15% at 2 years. In both studies, the rates of recurrence were significantly higher in those patients with HBV-DNA values > 105 copies/mL at the time of transplantation; and (2) “On demand” use of HBIG doses to maintain anti-HBs titers between 50-100 IU/L, considered protective when administered together with oral antivirals. Although this strategy can be more cost effective, it requires repeated monitoring of anti-HBs titers, as the amount of HBIG needed to reach a certain level of anti-HBs varies greatly from patient to patient. Using this strategy plus LAM, Jiang et al[33] found recurrence rates of 2.3% the first year, 6.2% the third year, and 8.2% the fifth year. As before, pretransplant HBV-DNA levels > 105 copies/mL were associated with greater recurrence.

These studies[29,32,33], therefore, show that IV administration of high doses of HBIG is neither necessary nor cost-effective when given together with oral antivirals and also highlight the importance of pretransplant levels of HBV-DNA as a predictive factor for recurrence.

Withdrawal of HBIG after combined prophylaxis: Studies of this strategy vary greatly in design, type of antiviral agent used, and time from LT to HBIG withdrawal. In addition, most of the studies are observational and from a single center[34-44], with just three randomized studies[45-47]. The overall rates of recurrence in these studies ranged from 0% to 17%[34-47].

Using this strategy, it is necessary to note that although the results during the initial years after withdrawing HBIG are good, the risk of recurrence can increase over time due to the appearance of resistance and, in particular, to lack of adherence[48]. The problem of the appearance of resistance may be of little importance if high genetic barrier oral antivirals are used, such as ETV or TDF. To date, only four studies have been published[34,37,42,43], none randomized, analyzing recurrence after withdrawal of HBIG using TDF or ETV. A systematic review by Cholongitas et al[27] that included the patients in these four studies found a recurrence rate of 3.9% vs 1% in the case of combined prophylaxis with HBIG and ETV/TDF, although the difference was not significant (P = 0.17).

This therapeutic strategy seems to be associated with a greater risk of recurrence in those patients with high HBV-DNA levels at the time of transplantation. One study found that detection of low and transitory HBV-DNA levels was not necessarily associated with recurrence, and only those patients who had persistently high hepatitis B surface antigen (HBsAg) and/or HBV-DNA levels had a high risk of experiencing recurrence[44].

Prophylaxis without HBIG: Experience using regimens of prophylaxis without HBIG and just oral antivirals is very limited[25,49-54]. Fung et al[52] studied 80 patients who received ETV monotherapy as prophylaxis, and the rate of HBsAg positivization was 22.5%, where only one patient (1.2%) was positive for HBV-DNA after the 26 mo follow-up period. Likewise, they found that the patients with HBV-DNA < 5 log copies/mL and HBsAg values < 3 log IU/mL pretransplant had an accumulated rate of HBsAg negativization at 18 mo of 100% vs 78% in the patients who did not fulfill these criteria. A more recent study by these same authors[53] showed that recurrence in patients treated with ETV (n = 142) was 0% at 3 years, whereas recurrence in those patients treated with LAM (n = 176) was 17% (P < 0.001). A study by Wadhawan et al[49] using different antivirals in regimens without HBIG (ETV, n = 42; LAM + ADV, n = 19; TDF, n = 12; and ETV + TDF, n = 2) noted recurrence (defined as HBV-DNA positivity) in 6/75 (8%) patients, five of these related to lack of treatment adherence. Cholongitas et al[34], in a systematic review, noted a significantly higher recurrence rate among patients who received prophylaxis completely free of HBIG, using ETV or TDF, compared with those who received combined therapy with HBIG plus LAM, with recurrence defined as HBsAg positivity [26% (29/112) vs 5.9% (109/1834), P < 0.0001]. Considering recurrence as HBsAg positivity and detectable DNA, the recurrence rates were 0.9% with HBIG-free therapy vs 3.8% with combined therapy, although the difference was not statistically significant (P = 0.11). No differences were found in relation to the antiviral used or the use of double-antiviral prophylaxis.

No studies are yet available concerning the combined use of two ANs (e.g., ETV + TDF or TDF plus emtricitabine) as prophylaxis without HBIG.

Vaccination against HBV

Active immunization with recombinant anti-HBV vaccines could be an attractive alternative to the indefinite administration of HBIG, particularly in patients with a low risk of recurrence. However, the few studies available provide contradictory results; and, at the present time, their generalized use cannot be recommended, at least as an isolated prophylactic strategy for post-LT CHB[55,56].

Individualized prophylaxis against HBV

In recent years, growing scientific evidence supports the possibility of reducing or even completely withdrawing HBIG from prophylaxis regimens against post-LT HBV, especially in patients with a low risk of recurrence. When considering the prophylactic regimen, it is necessary to consider all those factors that may affect viral recurrence, including virus-dependent factors [DNA-HBV and HBsAg levels at the time of transplantation, antiviral resistance, coinfection with hepatitis delta virus (HDV), human immunodeficiency virus], patient-related factors (treatment adherence, coexistence of hepatocarcinoma), or those related with the particular antiviral used (antiviral potency, genetic barrier). The pretransplant DNA-HBV levels and the existence of antiviral resistance are considered the most important predictive factors for post-transplant recurrence[29,53,57]. The presence of pretransplant hepatocarcinoma, especially if there is post-transplant recurrence of CHC, is associated with a greater risk of HBV recurrence[58,59]. On the other hand, fulminant hepatitis B is associated with a low risk of HBV recurrence[60], as is coinfection with HDV[10].

Thus, those patients considered to be at low risk for recurrence (negative pretransplant viremia, prior absence of antiviral resistance) could be considered for HBIG-free prophylaxis or with HBIG just given for a limited time (1-6 mo), using antivirals with a high genetic barrier (ETV/TDF) and provided there are no treatment adherence problems. On the other hand, patients at high risk for recurrence, as well as those with limited options for treatment if prophylaxis fails (e.g., patients with delta coinfection) would benefit more from a long-term regimen based on the combination of HBIG plus antivirals.

ANTI-CORE-POSITIVE DONORS

The imbalance between the high demand for transplant organs and the paucity of donors has necessitated the use of serum HBV-positive organs (anti-HBc positive, HBsAg negative). These represent the main risk factor for the de novo development of hepatitis B in transplant patients[7]. Several studies have shown equal survival for anti-HBc positive and anti-HBc negative organ recipients[61-63]. The risk of developing de novo hepatitis B in anti-HBc-positive organ recipients depends mainly on the serological status of the recipient at the time of transplantation and the adoption of effective prophylactic measures. A systematic review by Cholangitas et al[7] found that if recipients were negative for both anti-HBc and anti-HBs the risk of recurrence was 48%, if the recipient was anti-HBc positive the risk was 13%, and if the recipient was anti-HBc positive and anti-HBs positive, the risk was reduced to < 2%. With prophylaxis, the risks were 12%, < 4%, and < 2%, respectively (Table 1). This prophylaxis is specifically for: (1) patients with no immunity against the virus (HBsAg negative, anti-HBc negative, anti-HBs negative); (2) patients with acquired immunity (vaccinated: anti-HBs positive, anti-HBc negative and HBsAg negative); and (3) patients who are anti-HBc positive and anti-HBs negative. Prophylaxis is not generally advisable in patients with natural acquired immunity (HBsAg negative, anti-HBc positive with anti-HBs positive) given the minimum or null risk of reinfection[7,64].

Prophylactic strategies for de novo hepatitis B in recipients of anti-HBc organs have traditionally consisted of HBIG with or without LAM. Diverse studies have shown that HBIG monotherapy is inferior to that of HBIG combined with LAM, and that combination therapy with HBIG and LAM is no more efficient than monotherapy with LAM to prevent resistance[7]. The systematic review by Cholongitas et al[7] found that the rate of de novo hepatitis B with monoprophylaxis with LAM was < 3%. The high cost of prophylaxis with HBIG and the introduction over recent years of new antivirals with a high genetic barrier (ETV/TDF) has resulted in many transplant centers ceasing to use HBIG as passive prophylaxis[7,64,65]. Nevertheless, the heterogeneity of studies concerning prophylactic strategies with the use of anti-HBC positive organs necessitates large, well-designed multicenter studies to provide a high level of scientific evidence.

TREATMENT OF POST-LIVER TRANSPLANT HEPATITIS B

Hepatitis B in the LT patient can appear through transmission from a risk contact, transmission from an anti-HBc positive organ with no adequate prophylaxis (de novo hepatitis B), or by reactivation of a prior hepatitis B when prophylaxis fails (recurrent hepatitis B). Whatever the reason, treatment of established hepatitis B in the LT patient is based on the same recommendations as for immunocompetent patients.

The most commonly accepted definition of recurrent hepatitis B is the reappearance of circulating levels of HBsAg after transplantation, with or without HBV-DNA positivization or histological evidence of disease. Nonetheless, a few authors, such as Lenci et al[66], suggested that the definition of recurrence should include one or more of the following at some time after transplantation: (1) HBsAg positivity; (2) detectable serum levels of HBV-DNA; (3) detectable levels of covalently closed circular DNA in liver tissue; (4) increase in alanine aminotransferase; or (5) liver damage seen in a liver biopsy. Whilst this definition would seem more useful from the practical point of view, it is not yet universally accepted. Those patients who, years after transplantation, are still HBsAg-positive with negative HBV-DNA may have a high risk for a clinical, histological, and biochemical recurrence of hepatitis B. Accordingly, it is not advisable to stop HBIG in these patients.

CONCLUSION

LT for patients with hepatic cirrhosis due to CHB is now a universally accepted treatment. The magnificent results have been made possible in great measure by the use of HBIG and oral antivirals for prophylaxis against post-LT recurrence of CHB. The combination of low-dose HBIG plus antivirals is now considered the standard prophylaxis for post-LT recurrence of hepatitis B. The use of the newer antivirals (ETV and TDF), together with our better understanding of the factors that predispose patients to recurrence of CHB, has allowed for new focus to be placed on prophylaxis regimens. These efforts are aimed at withdrawing HBIG or the use of HBIG-free regimens from the outset, using only oral antivirals, especially in patients at low risk of recurrence, thus applying a strategy of individualized prophylaxis. In addition, the efficacy of these prophylactic regimens has enabled the use of grafts from anti-HBc positive donors without these being considered a risk, thereby increasing the donor pool.

Footnotes

P- Reviewer: Pinero F S- Editor: Yu J L- Editor: Filipodia E- Editor: Ma S

References
1.  Alliance WH. Viral hepatitis Global Policy, 2010.  Available from: http://www.worldhepatitisalliance.org/theWHA.aspx.  [PubMed]  [DOI]
2.  Burra P, Germani G, Adam R, Karam V, Marzano A, Lampertico P, Salizzoni M, Filipponi F, Klempnauer JL, Castaing D. Liver transplantation for HBV-related cirrhosis in Europe: an ELTR study on evolution and outcomes. J Hepatol. 2013;58:287-296.  [PubMed]  [DOI]
3.  Zheng SS, Wu J, Liang TB, Wang WL, Huang DS, Xu X. Prophylaxis and treatment of hepatitis B virus reinfection following liver transplantation. Hepatobiliary Pancreat Dis Int. 2002;1:327-329.  [PubMed]  [DOI]
4.  Samuel D, Muller 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.  [PubMed]  [DOI]
5.  Kim WR, Poterucha JJ, Kremers WK, Ishitani MB, Dickson ER. Outcome of liver transplantation for hepatitis B in the United States. Liver Transpl. 2004;10:968-974.  [PubMed]  [DOI]
6.  Ghaziani T, Sendi H, Shahraz S, Zamor P, Bonkovsky HL. Hepatitis B and liver transplantation: molecular and clinical features that influence recurrence and outcome. World J Gastroenterol. 2014;20:14142-14155.  [PubMed]  [DOI]
7.  Cholongitas E, Papatheodoridis GV, Burroughs AK. Liver grafts from anti-hepatitis B core positive donors: a systematic review. J Hepatol. 2010;52:272-279.  [PubMed]  [DOI]
8.  Shouval D, Samuel D. Hepatitis B immune globulin to prevent hepatitis B virus graft reinfection following liver transplantation: a concise review. Hepatology. 2000;32:1189-1195.  [PubMed]  [DOI]
9.  Terrault NA, Zhou S, McCory RW, Pruett TL, Lake JR, Roberts JP, Ascher NL, Wright TL. Incidence and clinical consequences of surface and polymerase gene mutations in liver transplant recipients on hepatitis B immunoglobulin. Hepatology. 1998;28:555-561.  [PubMed]  [DOI]
10.  Laryea MA, Watt KD. Immunoprophylaxis against and prevention of recurrent viral hepatitis after liver transplantation. Liver Transpl. 2012;18:514-523.  [PubMed]  [DOI]
11.  Fontana RJ, Keeffe EB, Carey W, Fried M, Reddy R, Kowdley KV, Soldevila-Pico C, McClure LA, Lok AS. Effect of lamivudine treatment on survival of 309 North American patients awaiting liver transplantation for chronic hepatitis B. Liver Transpl. 2002;8:433-439.  [PubMed]  [DOI]
12.  Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, Martin P, Dienstag J, Adams P, Dickson R. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology. 2001;33:424-432.  [PubMed]  [DOI]
13.  Schiff E, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, Tillmann H, Samuel D, Zeuzem S, Villeneuve JP. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transpl. 2007;13:349-360.  [PubMed]  [DOI]
14.  Markowitz JS, Martin P, Conrad AJ, Markmann JF, Seu P, Yersiz H, Goss JA, Schmidt P, Pakrasi A, Artinian L. Prophylaxis against hepatitis B recurrence following liver transplantation using combination lamivudine and hepatitis B immune globulin. Hepatology. 1998;28:585-589.  [PubMed]  [DOI]
15.  Chen J, Yi L, Jia JD, Ma H, You H. Hepatitis B immunoglobulins and/or lamivudine for preventing hepatitis B recurrence after liver transplantation: a systematic review. J Gastroenterol Hepatol. 2010;25:872-879.  [PubMed]  [DOI]
16.  Rao W, Wu X, Xiu D. Lamivudine or lamivudine combined with hepatitis B immunoglobulin in prophylaxis of hepatitis B recurrence after liver transplantation: a meta-analysis. Transpl Int. 2009;22:387-394.  [PubMed]  [DOI]
17.  Loomba R, Rowley AK, Wesley R, Smith KG, Liang TJ, Pucino F, Csako G. Hepatitis B immunoglobulin and Lamivudine improve hepatitis B-related outcomes after liver transplantation: meta-analysis. Clin Gastroenterol Hepatol. 2008;6:696-700.  [PubMed]  [DOI]
18.  Katz LH, Paul M, Guy DG, Tur-Kaspa R. Prevention of recurrent hepatitis B virus infection after liver transplantation: hepatitis B immunoglobulin, antiviral drugs, or both? Systematic review and meta-analysis. Transpl Infect Dis. 2010;12:292-308.  [PubMed]  [DOI]
19.  Cholongitas E, Goulis J, Akriviadis E, Papatheodoridis GV. Hepatitis B immunoglobulin and/or nucleos(t)ide analogues for prophylaxis against hepatitis b virus recurrence after liver transplantation: a systematic review. Liver Transpl. 2011;17:1176-1190.  [PubMed]  [DOI]
20.  Jiménez-Pérez M, Sáez-Gómez AB, Mongil Poce L, Lozano-Rey JM, de la Cruz-Lombardo J, Rodrigo-López JM. Efficacy and safety of entecavir and/or tenofovir for prophylaxis and treatment of hepatitis B recurrence post-liver transplant. Transplant Proc. 2010;42:3167-3168.  [PubMed]  [DOI]
21.  Gao YJ, Zhang M, Jin B, Meng FP, Ma XM, Liu ZW, Su HB, Zhao JM, Li HW. Clinical-pathological analysis of hepatitis B virus recurrence after liver transplantation in Chinese patients. J Gastroenterol Hepatol. 2014;29:554-560.  [PubMed]  [DOI]
22.  Kim YK, Kim SH, Lee SD, Park SJ. Clinical outcomes and risk factors of hepatitis B virus recurrence in patients who received prophylaxis with entecavir and hepatitis B immunoglobulin following liver transplantation. Transplant Proc. 2013;45:3052-3056.  [PubMed]  [DOI]
23.  Lee S, Kwon CH, Moon HH, Kim TS, Roh Y, Song S, Shin M, Kim JM, Park JB, Kim SJ. Antiviral treatment for hepatitis B virus recurrence following liver transplantation. Clin Transplant. 2013;27:E597-E604.  [PubMed]  [DOI]
24.  Na GH, Kim DG, Han JH, Kim EY, Lee SH, Hong TH, You YK, Choi JY. Prevention and risk factors of hepatitis B recurrence after living donor liver transplantation. J Gastroenterol Hepatol. 2014;29:151-156.  [PubMed]  [DOI]
25.  Perrillo R, Buti M, Durand F, Charlton M, Gadano A, Cantisani G, Loong CC, Brown K, Hu W, Lopez-Talavera JC. Entecavir and hepatitis B immune globulin in patients undergoing liver transplantation for chronic hepatitis B. Liver Transpl. 2013;19:887-895.  [PubMed]  [DOI]
26.  Ueda Y, Marusawa H, Kaido T, Ogura Y, Ogawa K, Yoshizawa A, Hata K, Fujimoto Y, Nishijima N, Chiba T. Efficacy and safety of prophylaxis with entecavir and hepatitis B immunoglobulin in preventing hepatitis B recurrence after living-donor liver transplantation. Hepatol Res. 2013;43:67-71.  [PubMed]  [DOI]
27.  Cholongitas E, Papatheodoridis GV. High genetic barrier nucleos(t)ide analogue(s) for prophylaxis from hepatitis B virus recurrence after liver transplantation: a systematic review. Am J Transplant. 2013;13:353-362.  [PubMed]  [DOI]
28.  Angus PW, McCaughan GW, Gane EJ, Crawford DH, Harley H. Combination low-dose hepatitis B immune globulin and lamivudine therapy provides effective prophylaxis against posttransplantation hepatitis B. Liver Transpl. 2000;6:429-433.  [PubMed]  [DOI]
29.  Gane EJ, Angus PW, Strasser S, Crawford DH, Ring J, Jeffrey GP, McCaughan GW. Lamivudine plus low-dose hepatitis B immunoglobulin to prevent recurrent hepatitis B following liver transplantation. Gastroenterology. 2007;132:931-937.  [PubMed]  [DOI]
30.  Singham J, Greanya ED, Lau K, Erb SR, Partovi N, Yoshida EM. Efficacy of maintenance subcutaneous hepatitis B immune globulin (HBIG) post-transplant for prophylaxis against hepatitis B recurrence. Ann Hepatol. 2010;9:166-171.  [PubMed]  [DOI]
31.  Yahyazadeh A, Beckebaum S, Cicinnati V, Klein C, Paul A, Pascher A, Neuhaus R. Efficacy and safety of subcutaneous human HBV-immunoglobulin (Zutectra) in liver transplantation: an open, prospective, single-arm phase III study. Transpl Int. 2011;24:441-450.  [PubMed]  [DOI]
32.  Zheng S, Chen Y, Liang T, Lu A, Wang W, Shen Y, Zhang M. Prevention of hepatitis B recurrence after liver transplantation using lamivudine or lamivudine combined with hepatitis B Immunoglobulin prophylaxis. Liver Transpl. 2006;12:253-258.  [PubMed]  [DOI]
33.  Jiang L, Yan L, Li B, Wen T, Zhao J, Jiang L, Cheng N, Wei Y, Yang J, Xu M. Prophylaxis against hepatitis B recurrence posttransplantation using lamivudine and individualized low-dose hepatitis B immunoglobulin. Am J Transplant. 2010;10:1861-1869.  [PubMed]  [DOI]
34.  Cholongitas E, Vasiliadis T, Antoniadis N, Goulis I, Papanikolaou V, Akriviadis E. Hepatitis B prophylaxis post liver transplantation with newer nucleos(t)ide analogues after hepatitis B immunoglobulin discontinuation. Transpl Infect Dis. 2012;14:479-487.  [PubMed]  [DOI]
35.  Park SJ, Paik SW, Choi MS, Lee JH, Koh KC, Kim SJ, Joh JW, Lee SK. Is lamivudine with 1-week HBlg as effective as long-term high-dose HBlg in HBV prophylaxis after liver transplantation? Transplant Proc. 2002;34:1252-1254.  [PubMed]  [DOI]
36.  Yi NJ, Lee KW, Kong SY, Park KU, Lee KB, Hong G, Han SS, Park SJ, Suh KS. Outcome of various treatments for posttransplant hepatitis B virus recurrence. World J Surg. 2013;37:812-819.  [PubMed]  [DOI]
37.  Wesdorp DJ, Knoester M, Braat AE, Coenraad MJ, Vossen AC, Claas EC, van Hoek B. Nucleoside plus nucleotide analogs and cessation of hepatitis B immunoglobulin after liver transplantation in chronic hepatitis B is safe and effective. J Clin Virol. 2013;58:67-73.  [PubMed]  [DOI]
38.  Nath DS, Kalis A, Nelson S, Payne WD, Lake JR, Humar A. Hepatitis B prophylaxis post-liver transplant without maintenance hepatitis B immunoglobulin therapy. Clin Transplant. 2006;20:206-210.  [PubMed]  [DOI]
39.  Neff GW, Kemmer N, Kaiser TE, Zacharias VC, Alonzo M, Thomas M, Buell J. Combination therapy in liver transplant recipients with hepatitis B virus without hepatitis B immune globulin. Dig Dis Sci. 2007;52:2497-2500.  [PubMed]  [DOI]
40.  Yuefeng M, Weili F, Wenxiang T, Ligang X, Guiling L, Hongwei G, Wencai L, Xiaoguang W, Wei M, Zhongyi F. Long-term outcome of patients with lamivudine after early cessation of hepatitis B immunoglobulin for prevention of recurrent hepatitis B following liver transplantation. Clin Transplant. 2011;25:517-522.  [PubMed]  [DOI]
41.  Weber NK, Forman LM, Trotter JF. HBIg discontinuation with maintenance oral anti-viral therapy and HBV vaccination in liver transplant recipients. Dig Dis Sci. 2010;55:505-509.  [PubMed]  [DOI]
42.  Saab S, Desai S, Tsaoi D, Durazo F, Han S, McClune A, Holt C, Farmer D, Goldstein L, Busuttil RW. Posttransplantation hepatitis B prophylaxis with combination oral nucleoside and nucleotide analog therapy. Am J Transplant. 2011;11:511-517.  [PubMed]  [DOI]
43.  Stravitz RT, Shiffman ML, Kimmel M, Puri P, Luketic VA, Sterling RK, Sanyal AJ, Cotterell AH, Posner MP, Fisher RA. Substitution of tenofovir/emtricitabine for Hepatitis B immune globulin prevents recurrence of Hepatitis B after liver transplantation. Liver Int. 2012;32:1138-1145.  [PubMed]  [DOI]
44.  Wong SN, Chu CJ, Wai CT, Howell T, Moore C, Fontana RJ, Lok AS. Low risk of hepatitis B virus recurrence after withdrawal of long-term hepatitis B immunoglobulin in patients receiving maintenance nucleos(t)ide analogue therapy. Liver Transpl. 2007;13:374-381.  [PubMed]  [DOI]
45.  Angus PW, Patterson SJ, Strasser SI, McCaughan GW, Gane E. A randomized study of adefovir dipivoxil in place of HBIG in combination with lamivudine as post-liver transplantation hepatitis B prophylaxis. Hepatology. 2008;48:1460-1466.  [PubMed]  [DOI]
46.  Schmoldt A, Benthe HF, Haberland G. Digitoxin metabolism by rat liver microsomes. Biochem Pharmacol. 1975;24:1639-1641.  [PubMed]  [DOI]
47.  Teperman LW, Poordad F, Bzowej N, Martin P, Pungpapong S, Schiano T, Flaherty J, Dinh P, Rossi S, Subramanian GM. Randomized trial of emtricitabine/tenofovir disoproxil fumarate after hepatitis B immunoglobulin withdrawal after liver transplantation. Liver Transpl. 2013;19:594-601.  [PubMed]  [DOI]
48.  Buti M, Mas A, Prieto M, Casafont F, González A, Miras M, Herrero JI, Jardi R, Esteban R. Adherence to Lamivudine after an early withdrawal of hepatitis B immune globulin plays an important role in the long-term prevention of hepatitis B virus recurrence. Transplantation. 2007;84:650-654.  [PubMed]  [DOI]
49.  Wadhawan M, Gupta S, Goyal N, Taneja S, Kumar A. Living related liver transplantation for hepatitis B-related liver disease without hepatitis B immune globulin prophylaxis. Liver Transpl. 2013;19:1030-1035.  [PubMed]  [DOI]
50.  Genzini T, Dos Santos RG, Pedrosa C, Curvelo LA, Noujaim HM, Crescentini F, Mota LT, Guirro TG, Ferreira FY, Salomão P. Liver transplantation in bearers of hepatitis B associated or not with delta hepatitis in the age of the new antiviral drugs: is hyperimmune globulin still necessary? Transplant Proc. 2010;42:496-497.  [PubMed]  [DOI]
51.  Gane EJ, Patterson S, Strasser SI, McCaughan GW, Angus PW. Combination of lamivudine and adefovir without hepatitis B immune globulin is safe and effective prophylaxis against hepatitis B virus recurrence in hepatitis B surface antigen-positive liver transplant candidates. Liver Transpl. 2013;19:268-274.  [PubMed]  [DOI]
52.  Fung J, Cheung C, Chan SC, Yuen MF, Chok KS, Sharr W, Dai WC, Chan AC, Cheung TT, Tsang S. Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation. Gastroenterology. 2011;141:1212-1219.  [PubMed]  [DOI]
53.  Fung J, Chan SC, Cheung C, Yuen MF, Chok KS, Sharr W, Chan AC, Cheung TT, Seto WK, Fan ST. Oral nucleoside/nucleotide analogs without hepatitis B immune globulin after liver transplantation for hepatitis B. Am J Gastroenterol. 2013;108:942-948.  [PubMed]  [DOI]
54.  Ahn J, Cohen SM. Prevention of hepatitis B recurrence in liver transplant patients using oral antiviral therapy without long-term hepatitis B immunoglobulin. Hepat Mon. 2011;11:638-645.  [PubMed]  [DOI]
55.  Tahara H, Tanaka Y, Ishiyama K, Ide K, Shishida M, Irei T, Ushitora Y, Ohira M, Banshodani M, Tashiro H. Successful hepatitis B vaccination in liver transplant recipients with donor-specific hyporesponsiveness. Transpl Int. 2009;22:805-813.  [PubMed]  [DOI]
56.  Bienzle U, Günther M, Neuhaus R, Vandepapeliere P, Vollmar J, Lun A, Neuhaus P. Immunization with an adjuvant hepatitis B vaccine after liver transplantation for hepatitis B-related disease. Hepatology. 2003;38:811-819.  [PubMed]  [DOI]
57.  Marzano A, Gaia S, Ghisetti V, Carenzi S, Premoli A, Debernardi-Venon W, Alessandria C, Franchello A, Salizzoni M, Rizzetto M. Viral load at the time of liver transplantation and risk of hepatitis B virus recurrence. Liver Transpl. 2005;11:402-409.  [PubMed]  [DOI]
58.  Faria LC, Gigou M, Roque-Afonso AM, Sebagh M, Roche B, Fallot G, Ferrari TC, Guettier C, Dussaix E, Castaing D. Hepatocellular carcinoma is associated with an increased risk of hepatitis B virus recurrence after liver transplantation. Gastroenterology. 2008;134:1890-189; quiz 2155.  [PubMed]  [DOI]
59.  Saab S, Yeganeh M, Nguyen K, Durazo F, Han S, Yersiz H, Farmer DG, Goldstein LI, Tong MJ, Busuttil RW. Recurrence of hepatocellular carcinoma and hepatitis B reinfection in hepatitis B surface antigen-positive patients after liver transplantation. Liver Transpl. 2009;15:1525-1534.  [PubMed]  [DOI]
60.  Samuel D, Feray C, Bismuth H. Hepatitis viruses and liver transplantation. J Gastroenterol Hepatol. 1997;12:S335-S341.  [PubMed]  [DOI]
61.  Yu AS, Vierling JM, Colquhoun SD, Arnaout WS, Chan CK, Khanafshar E, Geller SA, Nichols WS, Fong TL. Transmission of hepatitis B infection from hepatitis B core antibody--positive liver allografts is prevented by lamivudine therapy. Liver Transpl. 2001;7:513-517.  [PubMed]  [DOI]
62.  MacConmara MP, Vachharajani N, Wellen JR, Anderson CD, Lowell JA, Shenoy S, Chapman WC, Doyle MB. Utilization of hepatitis B core antibody-positive donor liver grafts. HPB (Oxford). 2012;14:42-48.  [PubMed]  [DOI]
63.  Prieto M, Gómez MD, Berenguer M, Córdoba J, Rayón JM, Pastor M, García-Herola A, Nicolás D, Carrasco D, Orbis JF. De novo hepatitis B after liver transplantation from hepatitis B core antibody-positive donors in an area with high prevalence of anti-HBc positivity in the donor population. Liver Transpl. 2001;7:51-58.  [PubMed]  [DOI]
64.  Huprikar S, Danziger-Isakov L, Ahn J, Naugler S, Blumberg E, Avery RK, Koval C, Lease ED, Pillai A, Doucette KE. Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management. Am J Transplant. 2015;15:1162-1172.  [PubMed]  [DOI]
65.  Lucey MR, Terrault N, Ojo L, Hay JE, Neuberger J, Blumberg E, Teperman LW. Long-term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl. 2013;19:3-26.  [PubMed]  [DOI]
66.  Lenci I, Tisone G, Di Paolo D, Marcuccilli F, Tariciotti L, Ciotti M, Svicher V, Perno CF, Angelico M. Safety of complete and sustained prophylaxis withdrawal in patients liver-transplanted for HBV-related cirrhosis at low risk of HBV recurrence. J Hepatol. 2011;55:587-593.  [PubMed]  [DOI]