Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients

INTRODUCTION — Hepatitis B virus (HBV) infection has been a major risk factor worldwide for hepatocellular carcinoma (HCC) and cirrhosis, and less commonly, for acute liver failure. Despite the availability of effective antiviral therapy, some patients with complications from HBV infection will require liver transplantation. In such patients, it is important to decrease HBV replication prior to transplant and to prevent HBV reinfection after transplant. Preventing HBV reinfection following liver transplantation is critically important because reinfection has been associated with rapidly progressive liver disease, graft loss, and death.

Preventive strategies are also needed to reduce the risk of de novo infection in transplant recipients without chronic HBV infection who are at risk for HBV transmission from a transplanted liver.

This topic will discuss how to prevent HBV infection in liver transplant recipients. Selection of patients for liver transplantation and an overview of pretransplant evaluation and management are discussed separately. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation" and "Hepatitis B virus: Overview of management".)

Prevention and management of other infections following liver transplantation are discussed separately. (See "Infectious complications in liver transplantation".)

The diagnosis, management, and prevention of HBV reactivation in nontransplant patients receiving immunosuppressive therapy are also discussed separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

CHRONIC HEPATITIS B INFECTION

General principles — The availability of effective antiviral therapies with low risk of drug resistance has greatly decreased the need for liver transplantation for hepatitis B infection [1-3]. Detailed information on trends in liver transplantation for patients with chronic hepatitis B infection can be found on the United Network for Organ Sharing (UNOS) website.

For those who do require transplant, medical management focuses on preventing HBV reinfection of the graft (table 1). In liver transplant recipients who are hepatitis B surface antigen (HBsAg) positive, reinfection occurs when hepatocytes in the liver graft from a seronegative donor (HBsAg negative and hepatitis B core antibody [anti-HBc] negative) are infected by circulating HBV in the plasma [4]. Patients who develop HBV reinfection with clinically evident liver disease (referred to as HBV recurrence) following liver transplantation can develop rapidly progressive liver disease, graft loss, fibrosing cholestatic hepatitis (a rare form of cholestatic liver injury that can be rapidly fatal), cirrhosis, and death [5-8].

In the setting of antiviral prophylaxis, HBV reinfection is defined as reappearance of HBV DNA after it has been undetectable because HBsAg may remain detectable for varying periods of time post-transplant. The definition of HBV reinfection has evolved with the availability of antiviral agents. When no prophylaxis or only hepatitis B immune globulin (HBIG) was used for prophylaxis, HBV reinfection was defined as detection of HBsAg in plasma after transplantation. However, since the late 1990s, antiviral prophylaxis is routinely administered. Some transplant centers use nucleos(t)ide analog monotherapy for prophylaxis because of the widespread availability of nucleos(t)ide analogs with negligible rates of antiviral drug resistance and because of the cost and limited availability of HBIG. In the setting of antiviral prophylaxis alone, HBV reinfection is defined as reappearance of HBV DNA after it has been undetectable because HBsAg may remain detectable for varying periods of time post-transplant. (see 'Diagnosis' below)

Pretransplant management — Prior to transplant, all patients with chronic HBV infection should receive nucleos(t)ide analog therapy to minimize further disease progression and to reduce the risk of reinfection post-transplant. (See 'Determining risk of HBV reinfection post-transplant' below.)

Entecavir or tenofovir (ie, tenofovir disoproxil fumarate [TDF] or tenofovir alafenamide [TAF]) is used as first-line therapy in patients with decompensated cirrhosis because they are effective and well tolerated and are associated with low rates of drug resistance [9-11]. Either TDF or TAF should be administered to those with a history of lamivudine use. We prefer TAF formulation of tenofovir because of data supporting its efficacy and reduced risk of renal toxicity [12-14]. (See "Hepatitis B virus: Overview of management" and "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

Determining risk of HBV reinfection post-transplant — Strategies to prevent HBV reinfection depend upon the level of risk. The estimated risk of HBV reinfection after liver transplant is based on patient characteristics and virologic factors (table 1) [15-18]. (See 'Strategies to prevent HBV reinfection' below.)

One of the main risk factors for reinfection of the liver graft is having a detectable HBV DNA (eg, ≥10 to 20 international units/mL) at the time of transplantation [19,20]. The risk is greater in those with high viral loads. As an example, in a study of 177 patients with HBV infection who had liver transplantation, a serum HBV DNA level ≥100,000 copies/mL (approximately 20,000 international units/mL) at the time of transplant was associated with higher rates of HBV reinfection compared with a lower viral load (50 versus 4 percent) [18]. In contrast, none of the patients with undetectable HBV DNA developed HBV reinfection after transplantation. This study was performed during the era when HBIG alone or in combination with lamivudine was used for prophylaxis.

Other factors that increase the risk of HBV reinfection include:

●Hepatitis B e antigen (HBeAg) positivity at the time of transplant

●History of antiviral drug resistance during pretransplant therapy

●Coinfection with hepatitis D virus (HDV)

●History of noncompliance with pretransplant antiviral therapy

●History of hepatocellular carcinoma (HCC)

●Coinfection with human immunodeficiency virus (HIV)

Strategies to prevent HBV reinfection — For patients with chronic HBV infection, the cornerstone of preventing HBV reinfection is use of an antiviral agent (ie, nucleos[t]ide analog) with or without HBIG. For HBsAg-positive liver transplant recipients on a prophylactic regimen, the HBV reinfection rate has been reduced to <10 percent [21], and survival rates have exceeded 85 percent at one year and 75 percent at five years [1,19,22-25]. (See 'Use of antivirals' below and 'Immunoprophylaxis for high-risk patients' below.)

Prior to the use of a prophylactic regimen, rates of HBV reinfection in the liver graft had been up to 80 percent [5,26]. The high rate of HBV reinfection after liver transplantation was probably due to enhanced virus replication resulting from immunosuppression and direct stimulatory effects of glucocorticoid therapy on the glucocorticoid-responsive enhancer region of the HBV genome [27,28].

Use of antivirals — Patients with chronic HBV infection should receive antiviral therapy to reduce the risk of reinfection. The use of immunoprophylaxis is discussed below. (See 'Immunoprophylaxis for high-risk patients' below.)

●Most patients with chronic HBV will continue their existing nucleos(t)ide analog after transplantation. However, after transplant, some centers may not use TAF because it has not been approved in the post-transplant setting due to lack of data. In addition, there may be certain drug interactions with TAF that are not seen with TDF (eg, rifamycins, certain anticonvulsants).

It is important to make sure that patients who had impaired renal function pretransplant and were receiving reduced doses of nucleos(t)ide analog pretransplant receive appropriate doses of nucleos(t)ide analog post-transplant after their renal function has recovered.

●Ideally, all pretransplant patients with chronic hepatitis B should be on therapy. However, if a recipient is not on a nucleos(t)ide analog at the time of transplantation, we initiate an antiviral agent as soon as possible. The preferred antivirals are the same as those initiated pretransplant. (See 'Pretransplant management' above.)

Antiviral prophylaxis with a drug that has a high barrier to resistance (eg, entecavir or tenofovir) should be continued indefinitely post-transplant to prevent HBV reinfection, even if the risk of reinfection is low (table 1). We do not use lamivudine monotherapy due to risk of drug resistance.

Antiviral prophylaxis with nucleos(t)ide analog(s) either alone or in combination with another nucleos(t)ide analog post-transplant has been associated with undetectable levels of serum HBV DNA in liver transplant recipients and low rates of HBsAg positivity [12-14,26-29]. In a study including 265 liver transplant recipients who were given entecavir alone with median follow-up of 59 months, rates of HBsAg positivity at 1, 3, 5, and 8 years were 15, 12, 13, and 8 percent, respectively [14]. All patients (including those who remained HBsAg positive) had undetectable levels of serum HBV DNA. In a prior study of 362 transplant recipients who received prophylaxis with nucleos(t)ide analog(s) only (entecavir, lamivudine, or combination of two nucleos[t]ide analogs), the rate of HBsAg positivity at eight years was 12 percent [13]. At one year after transplant, rates of achieving undetectable levels of HBV DNA for entecavir, lamivudine, or combination therapy were 95, 97, and 94 percent, respectively.

More detailed discussions of antiviral therapy for HBV infection, including the risk of adverse events, are found separately:

●(See "Hepatitis B virus: Overview of management".)

●(See "Entecavir in the treatment of chronic hepatitis B virus infection", section on 'Decompensated cirrhosis'.)

●(See "Tenofovir and adefovir for the treatment of chronic HBV infection", section on 'Tenofovir'.)

Immunoprophylaxis for high-risk patients — The decision to administer immunoprophylaxis in addition to antiviral therapy varies depending upon the transplant center since the incremental benefits of immunoprophylaxis are uncertain [30]. For those who administer immunoprophylaxis, the dose and duration of HBIG can vary.

We use HBIG only in high-risk patients (table 1). When used, we administer HBIG perioperatively. Our typical HBIG regimen includes [31]:

•At transplantation: HBIG 10,000 international units intravenously (IV) administered as a bolus dose.

•Week 1 postoperative: HBIG 10,000 international units IV daily for seven days.

•HBIG is usually stopped after the first week except for patients who remain HBsAg positive and have high HBV DNA levels post-transplant.

This fixed-dose schedule routinely results in hepatitis B surface antibody (anti-HBs) titers of >500 international unit/L for a few months post-transplant. For additional information on HBIG, please refer to the drug database included within UpToDate.

Before the widespread use of nucleos(t)ide analog therapy, HBIG alone was used for prophylaxis. The rationale for using HBIG is that administered antibody will bind to HBsAg (anti-HBs) and neutralize circulating virions, thereby preventing graft infection [26,32]. Anti-HBs also undergoes endocytosis by hepatocytes, and that leads to intracellular accumulation of HBsAg within the cells and decreased HBsAg secretion. A trough anti-HBs titer of at least 100 international units/L was generally regarded as protective when prophylaxis relied on HBIG monotherapy, and some studies have suggested that the rate of HBV recurrence can be reduced further in patients with anti-HBs titers consistently above 500 international unit/L [17,33-35].

Data evaluating HBIG in combination with antiviral therapy suggest that a short course of HBIG is effective for preventing HBV reinfection. In a study including 42 HBsAg-positive liver transplant recipients who were given long-term antiviral prophylaxis (tenofovir, entecavir, or tenofovir/emtricitabine) with a short course of HBIG (5000 international units IV in the anhepatic phase and then daily for five days), the one-, three-, and five-year reinfection rates (defined as HBsAg positivity) were 2.9 percent (95% CI 0.4 to 19.1 percent) for all time points [36].

The use of a high genetic barrier nucleos(t)ide analog plus HBIG has been associated with lower rates of HBV recurrence after liver transplantation than agents with a low barrier to resistance. In a study including 2214 liver transplant recipients with median follow-up of 30 months, prophylaxis with HBIG resulted in lower rates of HBV recurrence when used in combination with a nucleos(t)ide analog that has a high genetic barrier to resistance (entecavir or tenofovir) compared with an antiviral agent with a low barrier to resistance (lamivudine; 1 versus 6 percent) [37].

Available data suggest that HBIG can be safely withdrawn after liver transplantation as long as nucleos(t)ide analog is continued indefinitely [14,38,39]. In an observational study that included 69 liver transplant recipients who received HBIG in combination with nucleos(t)ide analog, HBIG was withdrawn after a minimum of six months, and patients were followed for a median of 69 months [38]. 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.

Managing immunosuppression — For patients transplanted for chronic HBV infection, we generally use the lowest level of immunosuppression that is necessary to prevent rejection of the liver graft. In general, glucocorticoids are tapered by three to six months, and most patients are on a single drug, usually a calcineurin inhibitor, after six months. (See "Liver transplantation in adults: Initial and maintenance immunosuppression".)

Role of HBV immunization — The role of HBV immunization in preventing HBV reinfection after liver transplant is unclear. Although it is reasonable to administer HBV vaccination to patients on low-dose immunosuppression, nucleos(t)ide analogs should not be discontinued, regardless of the anti-HBs response.

Active immunization using hepatitis B vaccine was studied as a way to reduce the need for lifelong prophylaxis with HBIG, which had been the standard of care prior to the introduction of antiviral agents with a high barrier to resistance. Most studies have focused on lower-risk patients who are more than one to two years post-transplant. The results of the initial study were encouraging, but subsequent studies found that response rates were variable and sometimes low (ranging from 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 [32-35,40]. (See "Hepatitis B virus immunization in adults".)

HBV reinfection

Surveillance post-transplant — Liver transplant recipients with chronic HBV infection should be monitored during the first year after transplant for reinfection as follows (see 'HBV reinfection' above):

●HBV tests (HBsAg, HBV DNA level) are obtained every month.

●Liver biochemical tests should be tested monthly after graft function is stable and liver tests are normal or near normal.

After the first year, patients with undetectable HBV DNA and normal liver biochemical tests can reduce the frequency of laboratory testing to every two to six months depending on post-transplantation institutional protocol. However, more frequent monitoring should be resumed if the immunosuppressive regimen is intensified (eg, treatment of rejection). (See "Liver transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection of the liver allograft".)

Surveillance can allow for detection of reinfection before liver damage develops (see 'Diagnosis' below). Studies have demonstrated that some patients have detectable serum HBV DNA prior to the reappearance of HBsAg or elevation of aminotransferases [41].

Clinical manifestations — The clinical features of HBV reinfection can vary. Patients with HBV reinfection may have normal or mildly elevated liver enzyme levels, while others may experience a hepatitis flare, characterized by marked increase in alanine aminotransferase (ALT) levels, although this occurs less commonly in the era of antiviral prophylaxis [42]. Patients experiencing a flare may or may not experience clinical signs and symptoms of acute hepatitis. (See "Hepatitis B virus: Clinical manifestations and natural history", section on 'Acute hepatitis'.)

Diagnosis — The diagnosis of HBV reinfection is based on the type of prophylaxis that was used (see 'General principles' above):

●For patients receiving prophylactic nucleos(t)ide analog only, HBV reinfection is diagnosed by the reappearance of HBV DNA in plasma because HBsAg may remain detectable for varying periods of time post-transplant.

●For patients receiving HBIG as part of the prophylactic regimen, reinfection is associated with the reappearance of HBsAg and/or HBV DNA in the serum.

Diagnosis of reinfection based on redetection of low-level HBV DNA or detectable but not quantifiable HBV DNA should be confirmed by repeating the HBV DNA test within a month and reinforcement of adherence to nucleos(t)ide analog.

Histologic findings that support a diagnosis of recurrent hepatitis due to HBV include positive staining on immunohistochemical evaluation for HBsAg and hepatitis B core antigen (HBcAg) in the liver graft, along with histologic evidence of acute or chronic hepatitis or fibrosing cholestatic hepatitis [43].

Management — For most patients with confirmed HBV reinfection, the primary intervention is adjusting the antiviral regimen and reinforcement of adherence. HBIG should be stopped in patients who had been receiving prophylactic regimens including HBIG. Adjustments to antiviral regimen are primarily informed by prior nucleos(t)ide analog exposure. If possible, antiviral resistance mutation testing should also be performed to help guide regimen selection. Patients with HBV reinfection should be managed in conjunction with a hepatologist.

When resistance testing is not available (or pending the results), our approach is as follows:

●For patients on a nucleos(t)ide analog with a high barrier to resistance (entecavir or tenofovir), we switch to another nucleos(t)ide analog (eg, from entecavir to tenofovir) or use entecavir and tenofovir in combination.

●For patients receiving lamivudine prophylaxis, we switch from lamivudine to TAF or TDF, which is effective against lamivudine-resistant HBV. Factors influencing the decision to use TDF versus TAF are discussed above. (See 'Use of antivirals' above.)

We do not use entecavir monotherapy in patients with lamivudine-resistant HBV infection. Entecavir-resistant mutations are more likely to be selected in the presence of lamivudine-resistant mutations. (See "Entecavir in the treatment of chronic hepatitis B virus infection", section on 'The efficacy of entecavir in different patient populations'.)

For liver transplant recipients with HBV reinfection, we do not use interferon-alpha, lamivudine monotherapy, adefovir, or telbivudine monotherapy because of lack of efficacy, risk of adverse effects, and/or risk of drug resistance [44-47].

Prior to the availability of effective antiviral agents, retransplantation for HBV-related graft failure was performed for patients with HBV reinfection, but this approach was associated with poor outcomes [48-51]. With use of nucleos(t)ide analogs with low rates of resistance, the need for retransplantation for HBV recurrence has markedly diminished.

RECIPIENTS OF ANTI-HEPATITIS B CORE-POSITIVE LIVERS — Efforts to expand the donor pool have included using hepatitis B core antibody (anti-HBc)-positive donor livers. In most cases, these donors had past HBV infection (anti-HBc positive, hepatitis B surface antigen [HBsAg] negative).

Anti-HBc-positive livers should ideally be reserved for recipients who are HBsAg positive pretransplant, because such patients will routinely receive post-transplant prophylaxis to prevent HBV reinfection.

However, anti-HBc-positive donor livers have also been used for patients without chronic HBV infection because of the scarcity of suitable liver grafts, particularly in countries where HBV infection is endemic. (See "Epidemiology, transmission, and prevention of hepatitis B virus infection", section on 'Epidemiology of chronic HBV'.)

This section will focus on preventing graft-related infection in patients without chronic HBV.

Risk of graft-related HBV infection — For recipients without a history of chronic HBV infection, the goal of prophylaxis is to prevent graft-related (also referred to as de novo) HBV infection of the recipient. Graft-related infection is defined as new-onset HBsAg positivity and detectable HBV DNA in the recipient [52,53]. HBV infection may be acquired from the anti-HBc-positive donor liver due to the persistence of HBV covalently closed circular DNA (cccDNA) in the donor liver which can be reactivated secondary to immunosuppression of the recipient [54,55].

The risk of graft-related HBV infection from an anti-HBc-positive donor liver varies by the HBV status in the recipient [53,56]:

●Recipients who are HBV naïve (ie, HBsAg negative, anti-HBc negative, hepatitis B surface antibody [anti-HBs] negative): In a systematic review of 39 studies including 222 recipients who were HBV naïve, post-transplant prophylaxis was associated with lower rates of HBV infection compared with no prophylaxis (12 versus 48 percent) [57].

●Recipients with immunity due to vaccination (ie, anti-HBc negative, anti-HBs positive): In a systematic review of 26 studies including 78 recipients who were anti-HBc negative/anti-HBs positive, post-transplant prophylaxis was associated with lower rates of HBV infection compared with no prophylaxis (2 versus 18 percent) [58].

●Recipients with prior HBV infection (anti-HBc positive, HBsAg negative): In a systematic review of 39 studies including 257 recipients who were anti-HBc positive, post-transplant prophylaxis was associated with lower rates of HBV infection compared with no prophylaxis (3 versus 15 percent) [57].

It should be noted that many of the early studies used lamivudine, an antiviral agent with a low barrier to resistance, for antiviral prophylaxis rather than an agent with a high barrier to resistance (ie, entecavir or tenofovir), and graft-related HBV infection rates are negligible when the latter antiviral agents are used.

Preventive strategies — Antiviral prophylaxis with a nucleos(t)ide analog is associated with low rates of graft-related HBV infection. In most patients, hepatitis B immune globulin (HBIG) does not provide additional benefit.

Antiviral therapy — All recipients of anti-HBc-positive liver grafts should receive lifelong antiviral prophylaxis. We administer entecavir or tenofovir alafenamide (TAF) for prophylaxis because of its efficacy, tolerability, and high barrier to resistance. The antiviral agent should be initiated at the time of transplant. For most patients, either agent can be used. (See "Hepatitis B virus: Overview of management", section on 'Choice of initial agent'.)

The use of antiviral therapy alone for preventing graft-related infection was supported in a study of 108 HBsAg-negative patients who received an anti-HBc-positive liver and were treated with lamivudine or entecavir post-transplant. Three patients (3 percent) on lamivudine developed de novo HBV infection after a median follow-up of eight years, whereas none of the patients who received entecavir prophylaxis developed de novo infection [59]. (See 'Risk of graft-related HBV infection' above.)

Additional considerations for regimen selection in recipients with chronic HBV are discussed above. (See 'Chronic hepatitis B infection' above.)

Role of immunoprophylaxis — In general, there is no role for immunoprophylaxis with HBIG in recipients of anti-HBc-positive liver grafts. Observational data have suggested that antiviral prophylaxis with a nucleos(t)ide analog was associated with low rates of graft-related HBV infection [57-62] and that HBIG did not provide additional benefit. In a systematic review of 13 studies including 183 patients who were HBsAg negative and who received an anti-HBc-positive liver, the rate of HBV infection for patients on lamivudine prophylaxis alone was 3 percent after median follow-up of 25 months versus 4 percent after a median follow-up of 31 months in those who received lamivudine plus HBIG [62].

However, on the rare occasion that a patient receives a liver from a HBsAg-positive donor, some transplant centers administer HBIG in addition to nucleos(t)ide therapy. (See 'Recipients of HBsAg-positive livers' below.)

Surveillance post-transplant — For HBsAg-negative recipients of an anti-HBc-positive graft, post-transplant monitoring includes monthly laboratory testing for HBsAg and HBV DNA for one year then every six months. The presence of HBsAg or HBV DNA is indicative of de novo infection.

SPECIAL POPULATIONS

Recipients with prior HBV infection — Most patients with prior HBV infection (hepatitis B surface antigen [HBsAg] negative, hepatitis B core antibody [anti-HBc] positive) who require liver transplantation are not at risk for HBV reactivation because their liver is discarded, provided that levels of HBV DNA at the time of transplant are undetectable. Thus, such patients do not routinely require antiviral therapy. The one exception is if the recipient receives a liver from an anti-HBc-positive donor. (See 'Recipients of anti-hepatitis B core-positive livers' above.)

Patients with acute HBV — Most patients with acute HBV infection do not progress to acute liver failure and do not require antivirals because acute HBV infections are usually cleared without treatment in immunocompetent adults [63]. (See "Hepatitis B virus: Overview of management", section on 'Acute liver failure or decompensated cirrhosis'.)

However, if a patient with acute HBV infection develops acute liver failure and undergoes liver transplantation, the risk of HBV reinfection is regarded as low. Thus, such patients are typically given long-term prophylaxis with an antiviral agent alone [4,64,65]. (See 'Use of antivirals' above.)

Patients with HIV coinfection — Outcomes after liver transplantation for patients with HIV and HBV coinfection have been overall favorable [66]. However, patients with HIV coinfection who receive liver transplantation are at higher risk for HBV reinfection. Antiviral prophylaxis with a nucleos(t)ide analog indefinitely plus HBIG perioperatively is warranted [67].

Patients who are coinfected with HBV and HIV should be on an HIV regimen that contains tenofovir with lamivudine or emtricitabine. Patients with a contraindication to tenofovir should be managed in conjunction with a specialist in HIV and HBV infection. (See "Treatment of chronic hepatitis B in patients with HIV".)

Patients with hepatitis D virus coinfection — Hepatitis D virus (HDV, hepatitis delta virus) infection can only occur in patients with HBV infection. Liver transplant recipients with history of HBV/HDV coinfection typically receive prophylaxis with a nucleos(t)ide analog plus HBIG, although risk of HBV reinfection in these patients is low. In the rare case of HBV reinfection, HDV reinfection may also occur, and rescue therapies in this setting have been limited. Prevention and management of HBV reinfection for patients with HDV coinfection are discussed separately. (See "Liver transplantation in adults: Hepatitis D virus reinfection in liver transplant recipients".)

Recipients of HBsAg-positive livers — Transplantation of livers from HBsAg-positive donors is generally avoided because of the high risk of graft-related HBV 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 [68,69].

For recipients of HBsAg-positive liver grafts, a nucleos(t)ide analog is given indefinitely to prevent HBV infection, and in some centers, HBIG is also administered. (See 'Role of immunoprophylaxis' above.)

In some reports, biopsy of the donor liver was performed to exclude moderate/severe inflammation or fibrosis prior to transplantation. Although the reported results were generally favorable, data on outcomes for HBsAg-negative recipients of a HBsAg-positive liver graft are very limited, and publication bias cannot be ruled out.

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" and "Society guideline links: Management of hepatitis B".)

SUMMARY AND RECOMMENDATIONS

●Background – Hepatitis B virus (HBV) infection in the liver transplant recipient has been described as follows (see 'General principles' above):

•HBV reinfection – For liver transplant recipients who were hepatitis B surface antigen (HBsAg) positive pretransplant and whose prophylaxis consists of a nucleos(t)ide analog alone, HBV reinfection is defined as the appearance of HBV DNA in plasma (for those who had undetectable HBV DNA pretransplant) or by a >1 to 2 logarithmic (10- to 100-fold) increase in HBV DNA.

•HBV recurrence – HBV recurrence refers to patients with HBV reinfection and clinical manifestations of liver disease (eg, active hepatitis, jaundice).

•Graft-related HBV infection – For liver transplant recipients who were HBsAg negative pretransplant, graft-related HBV infection (ie, de novo infection) is defined as new-onset HBsAg positivity and/or detectable HBV DNA from an immunoglobulin G (IgG) hepatitis B core antibody (anti-HBc)-positive donor liver. (See 'Recipients of anti-hepatitis B core-positive livers' above.)

●Liver transplant recipients with chronic HBV infection

•Determining risk of HBV reinfection – For patients with chronic HBV infection who undergo liver transplantation, the estimated risk of HBV reinfection is based on patient characteristics and virologic factors as outlined in the table (table 1). (See 'Determining risk of HBV reinfection post-transplant' above.)

•Preventive strategies – We recommend that all patients who are HBsAg positive and who undergo liver transplantation receive lifelong antiviral prophylaxis rather than no prophylaxis (Grade 1B). Antiviral prophylaxis with nucleos(t)ide analog(s) has been associated with low rates of HBV reinfection and with successfully achieving undetectable levels of serum HBV DNA. (See 'Strategies to prevent HBV reinfection' above.)

Entecavir or tenofovir is preferred for liver transplant recipients given their efficacy, low rates of resistance with long-term use, and safety profiles.

For patients who are at higher risk for HBV reinfection, we suggest immunoprophylaxis with hepatitis B immune globulin (HBIG) in addition to antiviral prophylaxis with a nucleos(t)ide analog rather than antiviral prophylaxis alone (Grade 2C). (See 'Immunoprophylaxis for high-risk patients' above.)

•Managing HBV recurrence – For most patients with HBV recurrence despite antiviral prophylaxis, the primary intervention is adjusting the antiviral regimen. For transplant recipients with HBV recurrence, adjustments to antiviral agents are primarily informed by prior nucleos(t)ide analog exposure. If possible, antiviral resistance mutation testing should also be performed to help guide regimen selection. (See 'HBV reinfection' above.)

●Recipients of anti-HBc-positive donor livers – For recipients without chronic HBV infection (ie, HBsAg negative) who received an anti-HBc-positive donor liver, we recommend lifelong antiviral prophylaxis rather than no prophylaxis to prevent graft-related HBV infection (Grade 1B). We administer a nucleos(t)ide analog with a high barrier to resistance (eg, entecavir or tenofovir alafenamide [TAF]) because of its efficacy and tolerability.