INTRODUCTION — Despite advances in treatment of chronic hepatitis B virus (HBV) infection, liver transplantation remains the only hope for many patients with end-stage liver disease due to HBV. In a study of the natural history of HBV-related cirrhosis in the pre-nucleos(t)ide analogue era, the five-year survival was 71 percent for the entire group of patients, but only 14 percent for those with decompensated disease (figure 1) [1].

The initial results with liver transplantation for chronic hepatitis B in the 1980s were disappointing, with graft reinfection rates approaching 80 to 100 percent [2-4]. In many patients, reinfection was associated with severe and rapidly progressive liver disease, resulting in two-year graft and patient survival of 50 percent compared to 80 percent in those transplanted for other types of chronic liver disease [5]. With these poor results and limited supply of donor organs, many centers and third-party payers abandoned liver transplantation for patients with chronic hepatitis B [6].

Since the late 1980s, the introduction of effective measures to prevent and treat reinfection using strategies involving hepatitis B immune globulin (HBIG) and subsequently nucleos(t)ide analogues have significantly improved the outcome of liver transplantation [7-10]. The overall survival of patients transplanted for HBV-related cirrhosis exceeds 85 percent at one year and 75 percent at five years [7,10-14]. Furthermore, rates of transplantation for HBV-related end-stage liver disease have dropped substantially, with a 24 percent decrease in liver transplantation waiting list registrations since 2010 [15,16].

HBV REINFECTION AFTER LIVER TRANSPLANTATION — The high rate of hepatitis B virus (HBV) reinfection after liver transplantation is probably due to enhanced virus replication resulting from immunosuppression and direct stimulatory effects of steroid therapy on the glucocorticoid-responsive enhancer region of the HBV genome [17,18]. Extrahepatic reservoirs of HBV, such as peripheral blood mononuclear cells, spleen, and other organs, may also contribute to graft reinfection [19].

Risk factors for reinfection — Patients with HBV-related cirrhosis who are eligible for transplantation can be conceptually divided into those with high versus low risk of reinfection.

●High-risk patients include patients with cirrhosis who are hepatitis B e antigen (HBeAg) positive or HBeAg negative but with high serum HBV DNA levels, and patients with antiviral drug-resistance prior to transplant [19-21].

●Low-risk patients include patients with fulminant HBV, coinfection with HDV, and patients with cirrhosis and low serum HBV DNA levels either spontaneously or as a result of nucleos(t)ide analogue therapy [13].

The cutoff for high versus low HBV DNA levels in the transplant setting has not been determined. One study of 177 patients reported that HBV recurrence occurred in 50, 7.5, and 0 percent of patients whose serum HBV DNA at the time of transplant were higher than 100,000, 200 to 100,000, and less than 200 copies/mL, respectively [21]. The authors concluded that serum HBV DNA higher than 5 log₁₀ copies/mL at the time of transplant was associated with significantly higher risk of HBV recurrence.

It should be emphasized that this study included patients transplanted between 1990 and 2002 when hepatitis B immune globulin (HBIG) monotherapy and subsequently combination of hepatitis B immune globulin (HBIG) and lamivudine were the only prophylactic therapies available, and HBV recurrence rate in the high-risk group was 50 percent [21]. The authors concluded that serum HBV DNA higher than 100,000 copies/mL (~20,000 IU/mL) at the time of transplant was associated with significantly higher risk of HBV recurrence.

De novo HBV infection/reactivation — The risk of a hepatitis B surface antigen (HBsAg)-negative recipient acquiring HBV infection following liver transplantation from a hepatitis B core antibody (anti-HBc)-positive donor is generally low, but rates as high as 80 percent have been reported [22,23].

The risk of acquiring HBV infection may be higher from donors who are HBsAg negative but anti-HBc positive [24,25]. One of the largest studies to address this issue found that hepatitis B (HBsAg-positive hepatitis) developed in 18 of 23 (78 percent) recipients of liver transplants from anti-HBc-positive donors, compared with only 3 of 651 (0.5 percent) recipients of livers from anti-HBc-negative donors [26]. The HBV infection was mild in most cases; 50 percent of patients had normal serum aminotransferases, while 85 percent had no or only mild inflammatory activity on liver biopsy one year after transplantation. Nevertheless, liver transplantation from an anti-HBc-positive donor was associated with a decreased four-year survival.

A second study looked at 64 patients who were anti-HBc negative and received a liver from a donor who was HBsAg negative but anti-HBc positive [27]. De novo HBV infection developed in nine patients (14 percent). De novo HBV infection was not associated with an increased risk of death or graft rejection at one and five years, and no graft loss or death was attributed to de novo HBV infection.

Eliminating livers from anti-HBc-positive individuals could result in a significant reduction in the potential donor pool, particularly in countries where HBV infection is endemic. Optimal strategies to prevent de novo infection in this setting have not been established. Reserving livers that are anti-HBc positive for recipients with chronic hepatitis B is one potential approach, since such patients will be receiving hepatitis B antiviral prophylaxis [26,28]. Recipients who have hepatitis B surface antibody (anti-HBs) and/or anti-HBc at the time of transplantation are also less likely to develop de novo infection after receiving a graft from an anti-HBc-positive donor [22,24-26,29-34]. The lowest risk of de novo infection is in recipients who are anti-HBs and anti-HBc positive. Intermediate risk is seen in recipients who are anti-HBs positive and anti-HBc negative (mean 21 percent) or are anti-HBs negative and anti-HBc positive (mean 12 percent). The highest risk is seen in patients who are both anti-HBs and anti-HBc negative (mean 76 percent).

Various prophylactic regimens have been reported to prevent de novo HBV infection when livers from HBsAg negative, anti-HBc-positive donors are transplanted into HBsAg-negative recipients. Many were based upon regimens that included lamivudine monotherapy [35]. However, most studies involved small numbers of patients with short duration of follow-up. In a systematic review looking at patients who received livers from donors who were HBsAg negative and anti-HBc positive, the rate of de novo HBV infection in 110 patients given lamivudine prophylaxis was 3.6 percent after a mean follow-up of 25 months [36]. Entecavir and tenofovir, which are associated with lower rates of drug resistance, may be more appropriate as life-long treatment will be required [37].

HBIG prophylaxis has been studied for recipients who are HBsAg negative. One study included 56 HBsAg-negative patients who received livers from HBsAg negative, anti-HBc-positive donors [38]. HBV infection occurred in 8 of 45 (18 percent) recipients who received prophylaxis compared with 7 of 11 (64 percent) recipients who did not. The rate of infection was highest among HBV-seronegative patients who did not receive prophylaxis (five of five patients) and was intermediate among HBV-immune recipients (two of six patients; 33 percent). HBV-seronegative patients who received prophylaxis also had an intermediate rate of infection (6 of 19; 32 percent). Recipients who were HBV-immune and received prophylaxis had low rates of infection (2 of 26; 8 percent). These data confirm a high rate of transmission of HBV infection from liver grafts of HBsAg negative, anti-HBc-positive donors. The low efficacy of HBIG in preventing HBV transmission is not surprising because HBIG is not effective in inhibiting HBV replication in the liver.

HBIG prophylaxis has also been combined with lamivudine with improved results compared with HBIG monotherapy. A systematic review examined patients who received livers from donors who were HBsAg negative and anti-HBc positive. The rate of de novo HBV infection in the 73 patients who received HBIG and lamivudine prophylaxis was 3.6 percent after a mean follow-up of 31 months [36]. However, the de novo infection rate for combination therapy with HBIG and lamivudine was similar to that seen for lamivudine monotherapy (2.7 percent), suggesting that the addition of HBIG to the regimen does not provide any added benefit.

De novo HBV infection has also been reported after liver transplantation from donors who are serologically negative for HBV markers [22,39,40]. These donors are thought to have occult HBV infection because of the presence of HBV DNA in their sera or liver tissue. Although the risk of reactivation appears to be low [40], routine HBV vaccination prior to liver transplantation may prevent this problem and should be recommended to all liver transplant candidates. Unfortunately, the success of hepatitis B vaccination in this group of older individuals with poor immune response secondary to cirrhosis has been disappointing. (See "Hepatitis B virus immunization in adults".)

Reactivation of HBV replication has also been reported in recipients who are HBsAg negative, anti-HBc positive pretransplant, and received liver grafts from donors who are HBsAg and anti-HBc negative. In one study of 22 patients, HBV DNA was detected in the liver in five (23 percent) HBsAg-negative, anti-HBc-positive patients pretransplant, and in two of these five patients post-transplant [41]. However, none of the patients became HBsAg positive or developed clinical hepatitis post-transplant. These data have not been confirmed by other studies, and there is no evidence that prophylactic antiviral therapy is necessary in this setting.

Transplantation of livers from HBsAg positive donors is not recommended because of the high risk of transmitting infection even if the recipient has immunity to HBV. However, in countries where HBV infection is prevalent, livers from HBsAg positive donors have been used in emergency situations, including some cases where the recipient is HBsAg negative [42,43]. For recipients of HBsAg positive livers, a nucleos(t)ide analogue has been given indefinitely to prevent HBV reinfection. In some reports, biopsy of the donor liver was performed to exclude moderate/severe inflammation or fibrosis and to exclude HDV infection. Although the reported outcomes were generally favorable, the number of HBsAg negative recipients was small and publication bias cannot be ruled out. Furthermore, some studies reported higher rates of HBV reinfection for recipients of HBsAg positive livers compared with HBsAg negative livers [43].

Diagnosis and clinical course — HBV reinfection has traditionally been diagnosed by the reappearance of HBsAg in the serum. Most reinfected patients are also HBeAg positive and have high levels of circulating HBV DNA [44]. Immunohistochemical staining of liver biopsies for HBsAg and hepatitis B core antigen (HBcAg) usually shows intense staining.

Studies using PCR assays have demonstrated that HBV DNA can be detected in serum prior to the reappearance of HBsAg or elevation of aminotransferases [45]. Conversely, studies in which a nucleos(t)ide analogue without HBIG is used to prevent HBV reinfection found that some patients remained HBsAg positive but had undetectable HBV DNA in serum [46]. These findings suggest the need to re-examine the definition of HBV reinfection and the criteria for initiating rescue therapy.

Reinfection is almost always accompanied by recurrent liver disease, which is often severe and rapidly progressive [2-5]. If untreated, cirrhosis occurs within one to two years of reinfection.

An unusual form of liver disease with severe cholestasis and rapidly progressive liver failure (picture 1) [44,47,48], termed fibrosing cholestatic hepatitis, characterized by prominent cholestasis and extensive fibrosis, was observed in the 1990s. Liver injury in this condition is believed to be a result of direct cytopathic effects of HBV since liver biopsies usually show very high levels of both HBsAg and HBcAg expression. This condition is rarely seen now as a result of early diagnosis of HBV reinfection and availability of effective antiviral therapies.

Some patients have detectable levels of HBV DNA in liver or peripheral blood mononuclear cells when tested by sensitive PCR assays but remain HBsAg negative [49-53]. Most of these patients do not have clinical or histologic evidence of recurrent hepatitis B. Whether these patients will eventually develop overt reinfection and recurrent liver disease remains to be determined. These observations underscore the importance of continuous prophylaxis.

PREVENTION OF HBV REINFECTION — Prevention of hepatitis B virus (HBV) reinfection includes use of antiviral therapy pre-transplant and continuation of antiviral therapy with or without hepatitis B immune globulin (HBIG) post-transplant. This strategy has led to a reduction in HBV reinfection rate to less than 10 percent.

Goal — The ideal goal of antiviral therapy in patients awaiting liver transplantation is to reverse cirrhosis complications and the need for liver transplant. However, liver failure may continue to progress since clinical improvement takes three to six months and hepatocellular carcinoma (HCC) can still develop in patients who have clinical improvement. In patients who present late, the goal is to achieve viral suppression, thereby stabilizing liver disease, allowing the patient to receive a liver transplant, and (in those who proceed to transplant) decreasing the risk of HBV reinfection.

Choice and timing of therapy — Antiviral therapy should be started as soon as possible in patients with HBV-related decompensated cirrhosis and detectable serum HBV DNA, regardless of HBV DNA and alanine aminotransferase levels. Although early studies used lamivudine, the high rate of drug resistance and the need for life-long treatment make this a suboptimal therapy.

Entecavir is attractive as a first-line antiviral agent in nucleoside-naïve transplant patients because it is more potent, has a low rate of drug resistance, and is not associated with nephrotoxicity (figure 2) [46]. (See "Entecavir in the treatment of chronic hepatitis B virus infection".). Lactic acidosis in patients with severe liver dysfunction had been reported in case series, but the incidence is unclear, and in some cases, other factors such as sepsis may be contributory [54,55]. One series compared six patients with decompensated cirrhosis receiving entecavir with six patients with non-HBV-related decompensated cirrhosis who were not receiving entecavir. Among the patients receiving entecavir, lactic acidosis was seen in one patient who was suffering from septic shock. No lactic acidosis was seen among the patients not receiving entecavir. Lactic acidosis may be a class effect of nucleos(t)ide analogues.

Entecavir has been compared with other agents in studies of patients with decompensated cirrhosis who have not yet undergone liver transplantation. In a trial with 191 patients with chronic HBV and decompensated cirrhosis, patients were assigned to treatment with entecavir or adefovir [56]. Entecavir was superior to adefovir with regard to viral suppression to less than 300 copies/mL (approximately 60 international units/mL) at weeks 24 and 48 (49 versus 16 percent and 57 versus 20 percent, respectively). An improvement in the Child-Pugh score of two or more points was seen in 35 percent of patients receiving entecavir and 27 percent of patients receiving adefovir. The mean decreases in Model for End-stage Liver Disease (MELD) score from baseline were 2.6 and 1.7, respectively. The rate of serious adverse events was consistent with advanced liver disease and was similar between those treated with entecavir and adefovir (69 versus 66 percent). There was no significant difference between those treated with entecavir and adefovir with regard to HCC development (12 versus 20 percent) or mortality (23 versus 33 percent). Seven percent of patients treated with entecavir discontinued the medication due to an adverse event, compared with six percent of those treated with adefovir.

Another trial assigned 112 patients with HBV and decompensated cirrhosis to treatment with entecavir, tenofovir, or tenofovir-emtricitabine and found results with entecavir to be similar to those with the other treatments [57]. Viral suppression to less than 400 copies/mL (approximately 80 international units/mL) at 48 weeks was seen in 73, 71, and 88 percent of patients, respectively, a decrease in Child-Pugh score of at least two points was seen in 42, 26, and 48 percent, respectively, and all groups had a median decrease of two points from the baseline MELD score. Treatment was discontinued due to a treatment-related adverse event in 9, 7, and 4 percent of patients, respectively, with a mortality rate at the end of the 48-week study of 9, 4, and 4 percent, respectively.

Many experts have recommended de novo combination therapy, but data in support of this approach are not available and it is unclear if combination therapy is superior to monotherapy with drugs that have a high genetic barrier to resistance such as entecavir or tenofovir. In a report of a study comparing entecavir monotherapy with entecavir plus tenofovir combination therapy in 379 nucleos(t)ide-naïve patients with compensated liver disease, there was no advantage of de novo combination therapy over monotherapy with regard to viral suppression, except in patients who were hepatitis B e antigen (HBeAg)-positive and had very high HBV DNA levels (>10⁸ international unit/mL) [58].

Adefovir is associated with a lower rate of drug resistance than lamivudine, but nephrotoxicity has been observed in up to 20 percent of pre- and post-liver transplant patients [59,60]. While many factors, such as hepatorenal syndrome and concomitant nephrotoxic medications, may contribute to impaired renal function, adefovir is not an ideal first-line antiviral in transplant patients because of its weak antiviral activity and a high rate of primary nonresponse, which is likely to be higher in patients who require dose reductions due to renal insufficiency. (See "Tenofovir and adefovir for the treatment of chronic HBV infection", section on 'Adefovir'.) 

Tenofovir can be substituted for adefovir. The advantage of tenofovir over adefovir is the increased potency resulting in a lower rate of primary nonresponse, and to date there has been no confirmed case of drug resistance. Tenofovir is preferred to entecavir in patients with lamivudine resistance or prior exposure to other HBV nucleos(t)ide analogues and undocumented response. Studies have shown that tenofovir monotherapy is as effective as combination therapy with tenofovir and emtricitabine in patients with prior lamivudine or adefovir resistance [61-63]. (See "Tenofovir and adefovir for the treatment of chronic HBV infection".)

One concern about the use of tenofovir disoproxil fumarate (tenofovir DF) is the risk of nephrotoxicity since renal impairment is common in patients with decompensated cirrhosis and in liver transplant recipients. Tenofovir alafenamide (tenofovir AF), is a newer formulation of tenofovir with better uptake in the liver, less systemic exposure, and lower risk of renal and bone adverse effects, however, data in patients with liver transplantation are not yet available.

Data on telbivudine in this setting are limited, but given the high rate of drug resistance, it is not an ideal treatment and we do not use it. (See "Hepatitis B virus: Overview of management", section on 'Nucleos(t)ide analogs'.)

Interferon should not be used in decompensated cirrhosis due to frequent and serious side effects [64-67]. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection".)

Monitoring — Close monitoring of serum HBV DNA levels is critical to assess response and to detect virologic breakthrough so rescue therapy can be initiated promptly. Virologic breakthrough secondary to drug resistance can be associated with hepatitis flares, worsening liver failure and death, and HBV reinfection post-transplant. Patients who are deemed not to require antiviral therapy at presentation (of note, all patients with decompensated HBV cirrhosis should be placed on antiviral therapy unless HBV DNA is not detected, in which case other causes of liver disease should be evaluated) should also be monitored as HBV DNA may become detectable or increase to higher levels during follow-up. Antiviral drug resistance is extremely rare in patients who are nucleos(t)ide-naïve and started on entecavir or tenofovir de novo. If HBV DNA levels increase during therapy, these patients should be evaluated and counseled about medication adherence. Drug resistance should be confirmed prior to switching therapy.

Prophylactic therapies post-transplant — Antiviral therapy should be initiated in the rare patient who is not on treatment at the time of transplant, and continued indefinitely in all patients post-transplant.

Antiviral strategies — With the availability of multiple nucleos(t)ides, the role of HBIG is evolving. HBIG immunoprophylaxis alone has been less successful in preventing reinfection in patients with detectable HBV DNA (and particularly those with a viral load greater than 100,000 copies/mL or roughly 20,000 international units/mL) or HBeAg pretransplant [9,21,68]. Antiviral therapy with nucleos(t)ide analogues before transplant decreases the risk of reinfection by decreasing the amount of circulating virus at the time of transplant and by prolonging the half-life of HBIG [69].

While many transplant centers still administer HBIG during the early post-transplant period, the dose and duration of HBIG varies markedly across transplant centers. At our center, HBIG dose regimen is tailored according to the predicted risk of reinfection. High-risk patients receive intravenous HBIG during the first year, and then HBIG is stopped. Low-risk patients, those with undetectable HBV DNA at transplant either in the absence of antiviral therapy or while receiving entecavir or tenofovir (drugs associated with very low risk of resistance) and no evidence of HDV infection do not receive HBIG [45,70,71]. Other centers have evaluated the replacement of HBIG using HBV vaccines or combination therapy with lamivudine and adefovir [72]. Adefovir is a weak antiviral with moderate risk of drug resistance and is now replaced by tenofovir.

Nucleos(t)ide analogues without HBIG have been used as monotherapy or in combination post-transplant and this approach may suffice in preventing recurrent hepatitis B in patients with low or undetectable HBV DNA at transplant (figure 2):

●In a study of 80 patients who all received entecavir monotherapy as prophylaxis, 21 patients (26 percent) had complete viral suppression at the time of transplantation [46]. After a median follow-up of 26 months post-transplant, 18 patients (23 percent) were HBsAg positive, but 17 of those patients had undetectable HBV DNA.

●A second study examined 362 patients who received lamivudine, entecavir, or combination therapy (most often lamivudine and adefovir, many of these patients had prior lamivudine resistance) for prophylaxis [73]. The overall HBV reinfection rates were 5 percent at one year, 10 percent at three years, 13 percent at five years, and 16 percent at eight years. When examined by the specific treatment, the reinfection rate at three years was 17 percent for lamivudine, 0 percent for entecavir, and 7 percent for combination therapy.

●A third study included 75 patients who received a living related donor liver transplantation and had an HBV DNA level at the time of transplantation ≤2000 international unit/mL [74]. The patients received antiviral therapy but no HBIG. All patients were HBV-DNA negative three months after transplantation. Sixty-six patients cleared HBsAg. Cumulative probabilities of clearing HBsAg were 90 and 92 percent at one and two years post-transplant, respectively. All nine patients who remained HBsAg positive had undetectable HBV DNA at last follow-up. HBV DNA reappeared in six patients (8 percent), five of whom had stopped taking oral antivirals and one of whom developed resistance to entecavir. After changing the antiviral regimen, all six patients again became HBV-DNA negative.

●A fourth study included 265 patients, 99 with undetectable HBV DNA, 90 with HBV DNA ≤10,000 IU/mL, and 64 with HBV DNA >10,000 IU/mL at transplant. All patients received entecavir monotherapy with no HBIG and were followed for a median of 59 months. Two hundred forty two patients (92 percent) cleared HBsAg. Fourteen were persistently HBsAg positive but none had detectable HBV DNA in serum. Cumulative rates of HBsAg clearance at one and five years were 90 percent and 95 percent, respectively. All patients including those who remained HBsAg positive had undetectable HBV DNA in serum [75].

Hepatitis B immune globulin — HBIG immunoprophylaxis is based upon the rationale that administered antibody to HBsAg (anti-HBs) will bind to and neutralize circulating virions, thereby preventing graft infection. Anti-HBs also undergoes endocytosis by hepatocytes, interacting with HBsAg within the cells, and decreasing HBsAg secretion [76]. Several studies demonstrated a reduction in reinfection and improved patient and graft survival with strategies involving prophylaxis with HBIG (figure 3) [9,20,77-81]. As a result, long-term, high-dose HBIG became the standard prophylaxis for HBV reinfection in most transplant centers prior to the availability of effective antiviral therapy. With the introduction of effective antiviral therapy, HBIG can often be discontinued after one year in patients at high risk of reinfection, and may not be necessary in patients who are at low risk.

Patients who are regarded as high risk for HBV reinfection include those with detectable HBV DNA, with confirmed antiviral drug resistance, or with hepatocellular carcinoma (HCC) at the time of liver transplant. Patients at high risk for HBV reinfection are given prophylaxis with combination of HBIG plus nucleos(t)ide analogue (entecavir or tenofovir DF) for 6 to 12 months and indefinite nucleos(t)ide analogue monotherapy thereafter.

For patients transplanted for HBV/HDV coinfection, HBIG combined with a nucleos(t)ide analogue is used for prophylaxis because there is no effective treatment for recurrent HDV infection. However, patients who are transplanted for HBV/HDV coinfection generally have low risk of reinfection [82]. (See "Liver transplantation in adults: Prevention and management of hepatitis D virus recurrence after liver transplantation".) .

Dose regimen — HBIG is a polyclonal preparation of human anti-HBs purified from pooled donor plasma. It is usually given intravenously as a 10,000 international unit bolus dose during the anhepatic phase followed by daily doses during the first week. Subsequent doses are either given monthly or in accordance with anti-HBs titers. A trough anti-HBs titer of at least 100 international unit/L is thought to be protective [83]. However, some studies have suggested that the rate of reinfection can be reduced further in patients with anti-HBs titers consistently above 500 international unit/L [20,50]. We use a fixed-dose schedule that routinely results in anti-HBs titers of >500 international unit/L during the first year post-transplant in patients who have high risks for reinfection.

Anti-HBs titers vary not only from patient to patient but also within the same patient even when HBIG is administered as fixed doses [20,50]. Serum HBV DNA level at the time of transplant is an important predictor of the half-life of HBIG [69].

Combined with other antiviral agents — Low-dose or limited duration HBIG appears as effective as long-term high-dose intravenous HBIG in the era of potent nucleos(t)ide analogues and availability of rescue therapies. A meta-analysis of two prospective and four retrospective studies where HBIG alone had been compared with HBIG plus lamivudine concluded that combination therapy was associated with a significantly lower rate of HBV-related deaths and all-cause mortality [84]. In addition, a systematic review of 46 studies found that patients treated with a combination of HBIG plus adefovir (with or without lamivudine) had a lower recurrence rate than patients treated with HBIG plus lamivudine (2.0 versus 6.1 percent) [85].

Other studies have evaluated strategies involving low-dose HBIG with nucleos(t)ide analogues to reduce the high costs associated with HBIG:

●One retrospective study evaluated the risk of HBV recurrence in 42 HBsAg positive patients with pretransplant HBV DNA levels less than 100 international unit/mL who received a short course of HBIG (5000 international unit intravenously in the anhepatic phase and then daily for five days) in addition to antiviral therapy (tenofovir, entecavir or tenofovir/emtricitabine), which was continued indefinitely [86]. The one-, three-, and five-year HBsAg recurrence rate was 2.9 percent (95% CI 0.4-19.1 percent) for all time points.

●In a study of 147 patients who received low-dose HBIG intramuscularly (400 to 800 international unit daily for one week then monthly) plus lamivudine (100 mg daily) following liver transplantation, patient survival was 92 percent at one year and 88 percent at five years [87]. The risk of HBV recurrence was 1 percent at one year and 4 percent at five years. A higher HBV DNA titer at baseline was associated with an increased risk of recurrence.

●In a study of 187 patients, HBV recurrence rates were examined in patients who received various HBIG regimens [70]. HBIG was given to 183 patients (98 percent), and 185 patients (99 percent) received at least one nucleos(t)ide analogue. The most common HBIG regimen was low-dose intramuscular injection (39 percent), followed by high-dose intravenous HBIG (25 percent), low-dose intravenous HBIG (21 percent), and finite duration of HBIG (12 percent; median duration 12 months). Overall, HBV recurrence was seen in 13 patients (7 percent).

Data have suggested that entecavir or tenofovir monotherapy was effective for preventing HBV reactivation and that HBIG can be safely withdrawn one year after transplantation [75,88]. In an observational study including 69 patients who had liver transplantation for HBV monoinfection and were initially given HBIG alone or HBIG in combination with nucleos(t)ide analogues, HBIG was systematically withdrawn, and patients were followed for a median of 69 months [88]. The nucleos(t)ide analogue (entecavir or tenofovir DF) was continued (or added if it had not been started previously), while patients who had initially received lamivudine plus adefovir/tenofovir were switched to tenofovir DF alone. Following HBIG withdrawal, six patients (9 percent) became HBsAg positive (after a median duration of 18 months), but all six patients had undetectable HBV DNA and stable graft function during 30 additional months of follow-up. HBsAg detection was transient in three patients and at low levels in the remaining three patients.  

Side effects — The available formulations with lower protein concentrations rarely cause immune-mediated reactions and premedication is frequently not necessary.

HBIG preparations available for use in the United States do not contain thimerosal.

Cost and supply — Protocols that use high-dose intravenous HBIG as described above are expensive (total charges of $80,000 to $200,000 in the first year, including the costs of intravenous infusion sets and monitoring). In addition, the supply of HBIG is unreliable [20]. To reduce the costs of HBIG therapy, attempts have been made to increase the interval between intravenous HBIG dosing, substitute maintenance intravenous HBIG with intramuscular administration of 5 mL (approximately 1000 units) HBIG, or to discontinue HBIG after the most vulnerable period.

Novel formulations of HBIG are being tested that appear to have longer lasting levels of circulating antibodies, and thus may require less frequent administration and thereby reduce costs [89]. The half-life of one of these preparations (OMRI-Hep-B) was significantly longer than standard therapy (22 versus 13 days) in a study involving 15 patients in which the two preparations were directly compared [89]. Further studies are needed to confirm these results.

Monoclonal anti-HBs — Results of early studies with monoclonal anti-HBs were unsatisfactory, with a high rate of breakthrough infection [90,91]. Several new formulations of humanized monoclonal anti-HBs are in clinical testing.

HBIG-induced escape mutants — Reinfection in patients receiving maintenance HBIG immunoprophylaxis may be due to inadequate dosing or to the emergence of mutant virus that can escape neutralization [92-95]. Most of the mutations involve substitutions of one or more amino acids in the predominant epitope of HBsAg, the "a" determinant. Some of these mutations result in decreased binding to anti-HBs and may therefore escape neutralization by HBIG.

In one report, there was a significant correlation between the development of "a" determinant mutations and the duration of HBIG therapy; cessation of HBIG resulted in reversion to pretransplantation sequences in most instances [94]. In a second study, variants with amino acid changes at residue 144 or 145 were most common; patients infected with these variants had adverse clinical outcomes compared to those who received high dose long-term HBIG but were not infected with these mutant virus (graft failure in 44 and 23 percent, respectively) [95]. These findings underscore the need for combination prophylaxis.

HBIG escape mutants are rare in patients who receive combination prophylaxis with HBIG and nucleos(t)ides.

Hepatitis B vaccination — Active immunization using standard hepatitis B vaccines has been studied to reduce the need for life-long HBIG prophylaxis. Most studies have focused on low risk patients who are more than one to two years post-transplant. The results of the first study were encouraging, but subsequent studies found that response rates were variable and often poor (8 to 80 percent), and anti-HBs titers achieved in the responders were low despite the use of higher doses and multiple courses of vaccine [96-100]. More recent studies using new vaccines and adjuvants have been more encouraging but these data need to be confirmed [101].

MANAGEMENT OF RECURRENT HBV INFECTION — The choice of treatment for recurrent hepatitis B (HBV) depends upon prior prophylactic therapy. When possible, antiviral resistance mutation testing should be performed to guide the selection of nucleos(t)ide analogues.

●Rare patients who received no prophylaxis or hepatitis B immune globulin (HBIG) should be treated with entecavir or tenofovir. Entecavir may be preferred because of the lower rate of drug resistance and lack of nephrotoxicity.

●Patients who received lamivudine prophylaxis are most likely to have developed resistance to lamivudine and will require treatment with tenofovir disoproxil fumarate (tenofovir DF), which is effective against lamivudine resistant HBV.

●Patients who received adefovir as initial prophylaxis and developed resistance to adefovir require the addition of entecavir or a change to tenofovir.

●Patients who received adefovir as rescue therapy for lamivudine resistance should undergo resistance mutation testing, if possible, to guide the selection of treatment. Most patients will likely require the combination of tenofovir and entecavir, though some studies suggest that tenofovir alone might suffice.

Interferon alfa — The experience with interferon has been disappointing. No consistent effect on HBV replication or liver disease has been demonstrated [102]. In addition, side effects such as neutropenia are frequent and there are concerns about interferon-induced rejection. Transplant recipients are immunosuppressed and have higher viral loads, factors that probably explain the lack of response to interferon.

Lamivudine — Lamivudine is well tolerated and can inhibit HBV replication and improve liver disease in these patients [45,103-106]. As in the nontransplant setting, a problem with lamivudine is the development of resistance, and it should no longer be used in the transplant setting [104,105].

Several case reports found that patients with recurrent hepatitis B due to combination of lamivudine and HBIG-resistant mutations run a more severe course. In vitro studies showed that combination of these mutations had enhanced HBV replication in the presence of lamivudine [107].

Adefovir — Adefovir is effective in suppressing HBV DNA replication and in improving or stabilizing liver disease in patients with recurrent hepatitis B and lamivudine resistance. Because of its potential for nephrotoxicity and weak antiviral effects, it should not be used in the transplant setting. (See "Tenofovir and adefovir for the treatment of chronic HBV infection", section on 'Adefovir'.)

Entecavir — Entecavir-resistant mutations are more likely to be selected in the presence of lamivudine-resistant mutations. Entecavir should not be used in patients with lamivudine-resistant HBV (see "Entecavir in the treatment of chronic hepatitis B virus infection"). Because of its potent antiviral effects, low rate of drug resistance, and lack of nephrotoxicity, entecavir is an ideal antiviral agent in nucleoside-naïve patients.

Telbivudine — Data on use of telbivudine in the transplant setting are limited. Based on experience in nontransplant patients, telbivudine should not be used as monotherapy because of the high risk of drug resistance.

Tenofovir — Because of the potential for nephrotoxicity, tenofovir DF is not an ideal drug in the transplant setting in nucleoside-naïve patients, but tenofovir DF, alone or in combination with a nucleoside, lamivudine, emtricitabine, telbivudine or entecavir, is recommended for patients with lamivudine resistance or prior nucleoside exposure. Tenofovir alafenamide (tenofovir AF) has less renal toxicity and is an alternative to tenofovir DF in patients with (or at high risk for) renal impairment, although data in the transplant setting are limited.

Reduction of immunosuppression — Immunosuppressive therapy such as prednisone and cyclosporine increases serum HBV DNA levels. Several studies have suggested that rapid withdrawal of prednisone may improve the long-term course of patients with recurrent HBV infection [108,109]. As a result, many centers now withdraw steroid therapy after three to six months in patients transplanted for hepatitis B. Whether cyclosporine or tacrolimus (FK506) immunosuppression is preferable in HBsAg-positive transplant recipients remains unclear [17].

TREATMENT OF PATIENTS COINFECTED WITH HIV — Outcomes of liver transplantation for selected patients with HIV and hepatitis B virus (HBV) coinfection have been favorable [110]. Patients who are coinfected with HBV and HIV may have lamivudine resistance if lamivudine was used as part of a combination regimen to treat HIV infection. The choice of medications used to prevent or treat HBV recurrence in patients who are coinfected with HBV should take into account the medications' activity against both HBV and HIV and the results of antiviral resistance mutation testing of those with prior treatment. (See "Treatment of chronic hepatitis B in patients with HIV", section on 'Approach to treatment'.)

RETRANSPLANTATION — The experience with retransplantation for HBV-related graft failure has been poor [3,9,111]. However, with the availability of multiple antiviral agents, the need for retransplantation for recurrent hepatitis B has diminished markedly. Prudent use of antiviral therapy, close monitoring for drug resistance, and addition of salvage therapy should prevent graft failure and the need for retransplantation.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Liver transplantation".)

SUMMARY AND RECOMMENDATIONS

●Combination of hepatitis B immune globulin (HBIG) and antiviral therapy has reduced recurrent hepatitis B virus (HBV) to less than 10 percent, with resultant improvement in patient and graft survival. With the availability of antiviral therapies that have lower rates of drug resistance and are effective against lamivudine (LAM)-resistant HBV, reinfection rate has continued to decrease.

●Patients with HBV-related cirrhosis who are eligible for transplantation should be started on antiviral therapy with a nucleos(t)ide analogue as soon as possible. Entecavir is preferred for patients who are nucleoside naïve or who had prior treatment with adefovir, while tenofovir is preferred for patients who had prior treatment with lamivudine or telbivudine. (See 'Choice and timing of therapy' above.)

●Entecavir or tenofovir should be continued post-transplant. Patients with undetectable HBV DNA at the time of transplant may not require HBIG post-transplant, while a short course of HBIG is warranted in patients with detectable HBV DNA at the time of transplant.

●The choice of treatment for recurrent hepatitis B following liver transplantation depends upon prior prophylactic therapy and presence of drug-resistant mutants (see 'Management of recurrent HBV infection' above):

•We suggest that patients who received no prophylaxis or HBIG only be treated with tenofovir or entecavir (Grade 2C).

•Patients who received nucleos(t)ide analogue prophylaxis should be tested for antiviral drug resistance mutation to guide the choice of rescue therapy. In general, combination therapy is recommended, and most patients will need a combination of tenofovir with entecavir.