Kidney transplantation in adults: Hepatitis B virus infection in kidney transplant recipients

INTRODUCTION — Hepatitis B virus (HBV) infection is a major risk factor for liver injury after kidney transplantation because of the requirement for immunosuppressive therapies [1,2]. Although the incidence of HBV infection has declined among dialysis patients, the prevalence is still high in endemic areas.

This topic reviews the prognosis and management of HBV in patients with end-stage kidney disease (ESKD) who are undergoing kidney transplantation. The serologic diagnosis of HBV infection and a general overview of HBV management are provided elsewhere:

●(See "Hepatitis B virus: Screening and diagnosis in adults".)

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

GOALS OF MANAGEMENT

●Preventing de novo HBV infection – In patients without prior hepatitis B virus (HBV) infection who receive a kidney transplant from a donor with chronic or prior HBV infection, the primary goal of management is prevention of de novo HBV infection. The risk of de novo infection through kidney transplantation is generally low with careful selection of donors according to their HBV status. HBV does not reside in the transplanted kidney, except when the donor is hepatitis B surface antigen (HBsAg) positive, the donor has high HBV DNA levels, and there is residual donor blood (and HBV) in the kidney.

●Preventing reactivation of HBV infection – In kidney transplant recipients with chronic or prior HBV, the primary goal of management is prevention of HBV reactivation and worsening of liver disease.

HBV reactivation and/or a flare of HBV can occur among those with serologic evidence of chronic HBV infection (ie, HBsAg positive and hepatitis B core antibody [anti-HBc] positive) as well as those with prior HBV infection (ie, HBsAg negative and anti-HBc positive) because HBV is present in the liver even after clearance of HBsAg.

●HBV reactivation – Among HBsAg-positive patients, reactivation of HBV replication is generally defined by the appearance of HBV DNA in a patient who has had undetectable HBV DNA previously or by a >1 to 2 logarithmic (10- to 100-fold) increase in HBV DNA. Among HBsAg-negative patients, reactivation is defined by the appearance of HBV DNA or the reappearance of HBsAg.

●HBV flare – Some patients who experience HBV reactivation will develop a hepatitis flare characterized by elevated levels of liver-associated enzymes. A flare of HBV infection is typically defined as a rise in alanine aminotransferase (ALT) that is at least three to five times the baseline value and above the reference range. Patients experiencing a flare may or may not experience clinical signs and symptoms of hepatitis.

Hepatitis associated with HBV reactivation can lead to severe, symptomatic disease and may even lead to liver failure. Although the risk of liver failure is higher in patients with cirrhosis due to the reduced liver reserve, it can occur as a result of severe reactivation even in patients without cirrhosis. However, with administration of prophylactic or preemptive antiviral therapy, the incidence of liver failure is very low. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

PRETRANSPLANTATION ASSESSMENT OF HBV STATUS — The hepatitis B virus (HBV) status of both the recipient and the donor (living or deceased) should be assessed prior to transplantation to determine if the recipient is at risk for de novo HBV infection or HBV reactivation.

Other aspects of pretransplant screening, including evaluation for other viral infections (eg, HIV and hepatitis C virus [HCV]), are discussed separately:

●(See "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient".)

●(See "Kidney transplantation in adults: Evaluation of the living kidney donor candidate".)

●(See "Evaluation of the potential deceased organ donor (adult)".)

Recipients — The following serologic testing should be performed: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc; total or immunoglobulin G [IgG]) (table 1) [3]. Anti-HBc immunoglobulin M (IgM) does not play a role in assessing for the risk of de novo infection or HBV reactivation, and should only be obtained in cases where acute infection is suspected.

The need for additional testing, evaluation, or vaccination depends upon the results. As examples:

●Anti-HBs positive (immunity) – Recipients who have an anti-HBs titer ≥10 milli-international units (mIU)/mL have immunity to HBV infection either through vaccination (anti-HBc negative) or through prior infection (anti-HBc positive).

If a recipient was vaccinated and had protective levels of anti-HBs in the past and now has an undetectable anti-HBs titer (<10 mIU/mL), a booster dose of hepatitis B vaccine is recommended, and a repeat level should be checked after one month. If the anti-HBs titer is increased to ≥10 mIU/mL after the booster dose, the recipient is protected. Studies have shown that most vaccinated patients whose anti-HBs level has decreased to below 10 mIU/mL develop an anamnestic response after one dose of vaccine booster, though this may not be true for immunosuppressed patients [4].

Vaccinated patients who are on dialysis should have annual testing to ensure that the anti-HBs titer remains ≥10 mIU/mL. (See "Immunizations in patients with end-stage kidney disease", section on 'Hepatitis B virus vaccine'.)

In kidney transplant recipients with resolved hepatitis B infection, a decrease in anti-HBs to <10 mIU/mL and exposure to high-dose glucocorticoids or other potent immunosuppressive medications (eg, for treatment of transplant rejection) are independent risk factors associated with HBV reactivation [5].

●HBsAg negative, anti-HBc negative, anti-HBs negative (no prior exposure) – Individuals without prior exposure to HBV should receive vaccination as early as possible since the efficacy of vaccination decreases as chronic kidney disease (CKD) becomes more severe. Seroconversion rates below 50 percent have been reported in patients with end-stage kidney disease (ESKD). Approaches to enhance the HBV vaccination response in CKD patients are discussed in more detail elsewhere. (See "Immunizations in patients with end-stage kidney disease", section on 'Hepatitis B virus vaccine'.)

If vaccination was not performed prior to the availability of a kidney allograft, or if the patient did not respond (ie, anti-HBs <10 mIU/mL), the patient may be at risk for de novo infection. Preventing de novo infection is discussed below. (See 'Antiviral therapy to prevent de novo infection' below.)

●HBsAg positive (chronic HBV) – Patients who are HBsAg positive should receive further testing to assess the hepatitis B e antigen (HBeAg) status, the HBV DNA level, and the presence or absence of cirrhosis. (See "Hepatitis B virus: Overview of management", section on 'Initial evaluation'.)

The presence of chronic HBV infection, including in patients with compensated cirrhosis (ie, without complications (table 2) and no evidence of portal hypertension), is not a contraindication to kidney transplantation. Antiviral therapy has been shown to reduce the risk of HBV reactivation associated with the use of immunosuppressive therapy, with improvements in survival approaching that of HBsAg-negative kidney transplant recipients [6-8]. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'Who should receive antiviral therapy' and 'Antiviral therapy to prevent reactivation' below.)

By contrast, those with decompensated cirrhosis (ascites, variceal bleeding, or hepatic encephalopathy) and portal hypertension may be considered for combined liver and kidney transplantation. The prognosis of patients with cirrhosis undergoing kidney transplantation is discussed below. (See 'Patients with cirrhosis' below.)

●Isolated anti-HBc positive – Patients who are negative for both HBsAg and anti-HBs and positive for anti-HBc are considered to be isolated anti-HBc positive. In such patients, we measure a circulating HBV DNA level to better assess HBV status. In general, most patients are HBV DNA negative in serum or have viremia levels below the limit for quantitation, although HBV DNA may be present in the liver, and in these patients, it is reasonable to give a booster dose of the hepatitis B vaccine with follow-up anti-HBs titer measurement. If the recipient develops an anti-HBs titer ≥10 mIU/mL, then they most likely had prior resolved infection. If there is no response to the booster dose, the patient likely has chronic HBV with loss of HBsAg or occult HBV. Alternatively, it is possible that the patient may have failed to mount an antibody response to the booster vaccine due to the impaired immune responsiveness in CKD. Regardless, these patients had prior infection with HBV and are at risk of HBV reactivation [9]. (See "Hepatitis B virus: Screening and diagnosis in adults", section on 'Diagnostic algorithms'.)

If HBV DNA is detected, vaccination is not warranted. Evaluation for liver cirrhosis should be guided by clinical or biochemical features since it is unlikely that patients who are isolated anti-HBc positive would have significant liver disease, even if HBV DNA is detected, unless other causes of liver disease such as hepatitis C are present.

Donors — Potential kidney donors (living and deceased) should be tested for HBsAg, anti-HBc, and HBV DNA nucleic acid testing (NAT); this approach is consistent with guidelines from the United States Centers for Disease Control and Prevention [3].

For living donors, testing should be done within the 28 days before organ procurement; for deceased donors, testing should be performed within 96 hours before organ procurement. Frequently in deceased donors, only qualitative HBV DNA testing is performed since quantitative testing might delay donor decision-making. In countries where there are barriers to access to the HBV DNA assay, testing for HBV DNA can be reserved for donors who are positive for HBsAg or anti-HBc.

It should be noted that HBV does not reside or replicate in the kidney, so the risk of HBV transmission is via residual blood and peripheral blood mononuclear cells in these organs despite flushing.

RECIPIENTS WITHOUT PRIOR HBV INFECTION (INCLUDING THOSE VACCINATED) — Recipients without prior hepatitis B virus (HBV) infection include (see 'Recipients' above):

●Patients with HBV immunity due to vaccination (hepatitis B core antibody [anti-HBc] negative, hepatitis B surface antibody [anti-HBs] positive, anti-HBs >10 milli-international units [mIU]/mL)

●Patients with no evidence of prior infection or immunity (ie, hepatitis B surface antigen [HBsAg] negative, anti-HBc negative, and anti-HBs negative)

Suitable donors — The suitability of a donor-recipient pair for kidney transplantation depends upon the HBV status of both the donor and recipient (table 3).

Recipients with HBV immunity due to vaccination and recipients without evidence of prior infection or immunity should ideally receive a kidney transplant from the following donors:

●Living or deceased donors who have no evidence of prior HBV infection with or without immunity to HBV through vaccination (HBsAg negative, anti-HBc negative, anti-HBs positive).

●Living or deceased donors with prior HBV infection (HBsAg negative, anti-HBc positive). The risk of HBV transmission is low unless the donor is HBV DNA positive, in which case prophylactic antiviral therapy is recommended [10]. (See 'Antiviral therapy to prevent de novo infection' below.)

A series from Japan reported that among 45 HBV-naïve recipients of kidneys from donors with resolved HBV infection and negative HBV DNA at the time of kidney donation, one patient (2.2 percent) seroconverted to anti-HBc positive and another patient (2.2 percent) showed transient positivity for HBV DNA without detection of HBsAg after kidney transplantation; both did not receive antiviral therapy [11].

Sometimes, the available donor may be an individual with chronic HBV infection (HBsAg positive). Recipients with HBV immunity due to vaccination may receive a kidney transplant from donors with chronic HBV infection (HBsAg positive). The risk of de novo infection is low but not zero [12-17], which may be due in part to a decrease in anti-HBs titer over time and with immunosuppression. As an example, in one report, 3 of 26 HBsAg-negative recipients developed acute HBV infection after kidney transplantation from HBsAg-positive donors, and all three had been anti-HBs positive through previous vaccination [13]. Thus, prophylactic antiviral therapy, and possibly a short course of hepatitis B immune globulin (HBIG), is recommended, as discussed below. (See 'Antiviral therapy to prevent de novo infection' below and 'Role of hepatitis B immune globulin' below.)

By contrast, recipients without prior HBV infection or immunity should generally avoid a kidney transplant from donors with chronic HBV infection given the risk of acquisition of de novo HBV infection by the recipient. However, in the era of antiviral medications, such transplantation may be performed when transplantation is urgently needed for life-saving reasons (such as exhaustion of dialysis access). In this setting, recipients should receive antiviral therapy and possibly HBIG to prevent de novo infection, although there are no data on the efficacy of HBIG in such circumstances. (See 'Indications' below and 'Role of hepatitis B immune globulin' below.)

Antiviral therapy to prevent de novo infection — Antiviral therapy should be administered to certain recipients who are at risk for de novo HBV infection (table 3). (See 'Suitable donors' above.)

Indications for administering HBIG are discussed below. (See 'Role of hepatitis B immune globulin' below.)

Indications — Indications for antiviral therapy in recipients without a history of prior HBV (regardless of vaccination status) are as follows:

●If they receive a kidney from a donor with chronic HBV (HBsAg positive), regardless of the donor's HBV DNA status.

●If they receive a kidney from a donor with prior HBV infection (HBsAg negative, anti-HBc positive) and the donor has detectable HBV DNA or the HBV DNA is unknown. Antiviral therapy is generally not necessary if the HBV DNA is negative, although some experts administer antiviral therapy for a year regardless of the donor HBV DNA status [18].

The choice of regimen and suggested duration of treatment is discussed below. (See 'Choice of regimen' below.)

Among recipients without a history of prior HBV (regardless of vaccination status) who receive a kidney transplant from donors with chronic HBV infection (HBsAg positive), the risk of de novo HBV infection is low because hepatitis B virus does not reside in the kidney [12-17]. However, it is common practice to give the recipient prophylactic antiviral therapy to further reduce this risk.

In a retrospective study of 83 HBsAg-positive donor to HBsAg-negative recipient kidney transplants, in which 65 recipients received antiviral prophylaxis, none of the 63 recipients who were anti-HBs positive before transplantation developed de novo HBV infection over a median of 36 months [19]. Two HBsAg-negative, anti-HBs-negative, and anti-HBc-negative patients became HBsAg positive after transplantation, despite prophylactic lamivudine treatment for 1.5 and 2 months, respectively, starting at the time of transplantation. Although these findings support the use of prophylactic antiviral therapy in recipients without a history of prior HBV who receive a kidney from a donor with chronic HBV, short treatment durations of two months may be inadequate.

Prophylactic antiviral medication should be administered to HBV-naïve patients who receive kidneys from HBV DNA viremic donors, even if they were previously immunized. Therapy should be administered irrespective of the level of anti-HBs in the kidney recipient at the time of transplantation. A series from the United States reported the outcome of eight kidney recipients who were anti-HBc negative and anti-HBs positive with antibody titer >10 mIU/mL at the time of kidney transplantation who received kidneys from donors who were HBV DNA positive (four HBsAg positive and four HBsAg negative) [20]. Four patients were started on entecavir at the time of transplant operation. Of these, two became anti-HBc positive within one month after transplantation, both had anti-HBs titer <100 mIU/mL, and both received kidneys from HBsAg-positive donors. The other two patients had anti-HBs titer >100 mIU/mL and remained anti-HBc negative after receiving kidneys from HBsAg-negative donors. Of the other four patients not given preventive antiviral medication, three became anti-HBc positive including two with anti-HBs titer 79 and 752 mIU/mL who received kidneys from HBsAg-positive donors and one with anti-HBs 1000 mIU/mL who received kidney from an HBsAg-negative HBV DNA-positive donor. None of the patients became HBsAg positive during follow-up. These data suggest that transmission of infection can occur, but patients do not progress to chronic infection.

Choice of regimen — For most kidney transplant recipients who require antiviral therapy to prevent de novo HBV infection, preferred antiviral regimens include entecavir and tenofovir. Antiviral therapy should be started at the time of transplantation. The optimal duration of therapy is unknown. We typically administer treatment for one year, based upon anecdotal observations and reports that suggest that shorter durations of therapy may be inadequate [19], as described above. (See 'Indications' above.)

We typically administer entecavir since it is not associated with kidney toxicity; dose adjustments are required for those with reduced kidney function (table 4). If tenofovir is used, we generally prefer tenofovir alafenamide to tenofovir disoproxil fumarate because it is associated with a lower risk of kidney toxicity. However, there may be certain drug interactions with tenofovir alafenamide that are not seen with tenofovir disoproxil fumarate (eg, rifamycins, certain anticonvulsants). In addition, some centers may not use tenofovir alafenamide, because it is not yet approved in the posttransplantation setting due to lack of data.

Entecavir and tenofovir are preferred over lamivudine, which had previously been the mainstay of treatment, because lamivudine has been associated with a high rate of drug resistance with long-term use [6,7,21-33]. As an example, in one report of 29 HBsAg-positive kidney transplant patients who received almost 60 months of therapy with lamivudine, 14 (48 percent) developed lamivudine resistance [28]. Lamivudine resistance may result in hepatitis flares as well as liver failure. Telbivudine, though more potent than lamivudine in viral suppression, is also associated with a significant rate of resistance after prolonged treatment and is therefore not recommended. Telbivudine is no longer available in the United States.

Pegylated interferon alfa should not be used in kidney transplant recipients, because it may precipitate acute allograft rejection [34-36]. Adefovir should also be avoided due to its nephrotoxicity and its weak antiviral activity [37-39].

Monitoring — HBsAg, anti-HBc, and HBV DNA should be checked every three months during therapy to monitor for acquisition of de novo HBV infection. If these parameters remain negative after one year, antiviral therapy can be discontinued. After treatment discontinuation, the frequency of HBsAg and HBV DNA monitoring is reduced progressively from once every three months to annually.

Recipients should be vaccinated if they have no prior immunity, although the efficacy in eliciting an anti-HBs response is reduced due to the effect of immunosuppressive medications. In patients with immunity from prior infection or vaccination, we check the anti-HBs titer prior to discontinuing antiviral therapy and administer a booster dose of vaccine if the titer is <10 mIU/mL. Maintaining a high anti-HBs titer (ie, >100 mIU/mL) has been associated with favorable transplantation outcomes and the prevention of de novo HBV infection among transplant recipients of kidneys from HBsAg-positive donors [40]. In addition, maintaining a protective anti-HBs titer (>10 mIU/mL) in kidney transplant patients in HBV-endemic regions would reduce their chance of contracting HBV in the community.

Role of hepatitis B immune globulin — HBIG may be used in addition to antiviral therapy to prevent do novo HBV infection in select patients (table 3). We administer HBIG to recipients without prior HBV immunity or infection who receive a kidney from a donor with chronic HBV (HBsAg positive). The rationale for administering HBIG in this setting is to provide passive immunity to cover an at-risk period, similar to its use in postexposure prevention of acute hepatitis B and in the prevention of perinatal transmission. The role of perioperative HBIG to prevent HBV transmission in kidney recipients with prior HBV immunity through vaccination is uncertain but may be considered perioperatively if the anti-HBs level is below 100 mIU/mL.

In one retrospective study of 83 HBsAg-positive donor to HBsAg-negative recipient kidney transplants, 51 percent of recipients received HBIG, while 78 percent received antiviral therapy; only two patients developed HBV infection [19]. The number of patients who received HBIG or antiviral therapy alone versus combination prophylaxis was not reported. For the two recipients who became HBsAg positive after transplantation, one (whose kidney donor was HBsAg positive, hepatitis B e antigen [HBeAg] negative, hepatitis B e antibody [anti-HBe] positive, and HBV DNA negative) was treated with only lamivudine for 1.5 months, and the other recipient (whose donor was HBsAg positive, HBeAg negative, anti-HBe positive, and HBV DNA positive) received HBIG 2000 IU and lamivudine for two months. The relative importance of HBIG and antiviral therapy for the prevention of de novo HBV infection in the kidney transplantation setting remains to be determined, especially in anti-HBs-positive kidney recipients. Whether HBIG may play a more significant preventive role in recipients who do not have protective levels of anti-HBs remains to be investigated.

RECIPIENTS WITH PRIOR OR CHRONIC HBV INFECTION

Considerations for donor selection — In general, kidney transplant recipients with prior (ie, hepatitis B surface antigen [HBsAg] negative, hepatitis B core antibody [anti-HBc] positive) or chronic (HBsAg positive) hepatitis B virus (HBV) infection may receive a kidney transplant from any donor regardless of the HBV status of the donor (table 3).

Antiviral therapy to prevent reactivation — Antiviral therapy should be administered to all recipients with chronic or prior HBV infection, including patients infected with both HBV and hepatitis C virus (HCV) (table 3). (See 'Monitoring/management of reactivation' below.)

The risk of HBV reactivation following transplantation is related to the HBV status of the recipient at the time of kidney transplantation (ie, HBsAg positive or negative) and the type of immunosuppressive therapy that is being used [12,41-44]. As an example, although all transplant recipients who are anti-HBc positive are at risk for HBV reactivation, those who are HBsAg positive (ie, chronic HBV infection) have a much higher risk of reactivation than patients who are HBsAg negative (ie, prior HBV infection). In a retrospective study of 147 HBsAg-negative anti-HBc-positive kidney transplant recipients in the United States who had not received antiviral prophylaxis, the reactivation rate was 3.4 percent [45].

All patients with chronic or prior HBV infection (ie, anti-HBc positive) who receive rituximab (even a single dose) should initiate preventive antiviral therapy, regardless of their HBsAg or hepatitis B surface antibody (anti-HBs) status. Several case series have described HBV reactivation in kidney transplant recipients who received rituximab and were HBsAg negative, anti-HBc positive at baseline, although different definitions of reactivation were used [46-48]. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'Who should receive antiviral therapy'.)

A detailed discussion of the risk of HBV reactivation in patients receiving immunosuppressive therapy (including solid organ recipients) is found elsewhere. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'How to assess risk'.)

Patients with prior HBV infection — Antiviral therapy is indicated in patients with prior hepatitis B virus (HBV) infection (HBsAg negative and anti-HBc positive), even when anti-HBs is detected (ie, resolved HBV infection). Although very few patients (<5 percent) with prior HBV have detectable HBV DNA in serum, most have detectable HBV DNA in the liver. Thus, an undetectable serum HBV DNA does not exclude the possibility of HBV reactivation.

●For recipients with prior HBV infection, we suggest either entecavir or tenofovir alafenamide to prevent HBV reactivation. Antiviral therapy should be initiated at the time of transplantation. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'Which agents to use'.)

●The duration of antiviral therapy in patients with prior HBV can vary, and there is no high-quality evidence to support one approach over another [49]. Some experts administer lifelong antiviral therapy to all recipients with prior HBV infection, whereas other experts may administer prophylaxis only when patients receive high-dose triple immunosuppressive therapy (eg, in the first 6 to 12 months posttransplantation and after treatment for rejection) or agents that are associated with a high risk of HBV reactivation (eg, B cell-depleting agents, such as rituximab, or other similarly potent immunosuppressive agents, such as belatacept) [50].

Antiviral therapy may need to be resumed if the dose of immunosuppression is increased to treat immune-mediated kidney allograft injury. Clinical decisions are informed by the perceived risk of reactivation based upon the potency of immunosuppression.

The approach to monitoring is discussed below. (See 'Monitoring/management of reactivation' below.)

Patients with chronic HBV infection — Recipients with chronic hepatitis B virus (HBV) infection need to receive antiviral therapy indefinitely after transplantation [49]. Although some patients with chronic HBV do not require antiviral therapy prior to transplantation, HBV reactivation occurs in a high proportion of patients who are treated with potent immunosuppression, and hepatitis B e antigen (HBeAg) status and HBV DNA level prior to transplantation do not reliably predict the occurrence or timing of subsequent HBV reactivation. The choice of agent depends upon their prior antiviral history.

●Patients already on antiviral therapy – For recipients who are virologically suppressed on entecavir or tenofovir, we generally continue their therapy unless they are receiving tenofovir disoproxil fumarate, in which case, we prefer to switch them to tenofovir alafenamide. However, if entecavir is used, the dose may need to be adjusted as kidney function returns to normal. (See 'Choice of regimen' above.)

●Patients not on antiviral therapy at the time of transplantation – For treatment-naïve patients with chronic HBV who are not on therapy at the time of transplantation, we administer either entecavir or tenofovir (see 'Choice of regimen' above). By contrast, for those who have received lamivudine in the past, we prefer tenofovir alafenamide over entecavir. Tenofovir is more likely to provide sustained viral suppression in this setting compared with entecavir. (See "Entecavir in the treatment of chronic hepatitis B virus infection", section on 'Resistance'.)

Patients with chronic HBV should initiate antiviral therapy around the time of surgery. For deceased-donor kidney transplantation, we initiate antiviral treatment for HBV at the time of transplantation concurrently with immunosuppressive therapy. In the case of living-donor kidney transplantation and for kidney recipients with a high baseline serum HBV DNA level (eg, >4 log₁₀ IU/mL), we prefer to initiate antiviral therapy prior to transplantation so that the HBV DNA level is suppressed to <3 log₁₀ IU/mL (preferably undetectable) prior to administration of immunosuppressive therapy.

The approach to monitoring is discussed below. (See 'Monitoring/management of reactivation' below.)

Monitoring/management of reactivation

●What to monitor – The approach to monitoring for HBV reactivation or flare depends upon whether the recipient is receiving preventive antiviral therapy and/or the type of immunosuppressive regimen that is used:

•Recipients on antiviral therapy – Recipients receiving antiviral therapy to prevent reactivation or flare should have serum aminotransferases and HBV DNA monitored every six months or more frequently as indicated.

Among patients who develop elevated HBV DNA or alanine aminotransferase (ALT) while on antiviral therapy, clinicians should investigate whether reactivation or flare is related to one or more of the following:

-HBV reactivation related to poor adherence to antiviral therapy or inadequate dosing (if dosing was adjusted due to impaired kidney function)

-The development of drug resistance, although this is rare with entecavir or tenofovir (see "Hepatitis B virus: Overview of management", section on 'Persistent viremia/breakthrough infection')

-An etiology other than HBV infection (see "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'Differential diagnosis')

•Recipients with prior HBV infection who discontinue treatment – Some centers may discontinue therapy in recipients with prior HBV infection when immunosuppression is reduced (see 'Patients with prior HBV infection' above). If antiviral therapy is discontinued, we monitor liver chemistries, HBV DNA, and HBsAg every three months for at least one year.

-For those with normal liver enzymes, every-six-months monitoring after the first year is reasonable. However, every-three-months or more frequent monitoring should be resumed if the immunosuppressive regimen is intensified (eg, treatment of rejection). In addition, if an agent such as rituximab is added, preventive antiviral therapy should be resumed.

-If liver chemistries are measured for other purposes (eg, monitoring for drug toxicity), HBsAg and HBV DNA testing should be performed if the ALT is elevated.

If reactivation occurs, patients should resume antiviral therapy. The same agent may be used. Antiviral therapy has been found to be effective in treating reactivation of HBV infection among transplant recipients who discontinued prophylactic antiviral therapy [6,23,25,26,51,52]. As an example, in a study that included 10 kidney transplant recipients who had reactivation of HBV replication with hepatic failure, mortality was lower in patients who received lamivudine compared with those who did not (40 versus 100 percent, respectively) [25]. However, antiviral therapy should be initiated early since salvage therapy was associated with inferior clinical outcomes. Although lamivudine was used in earlier studies, it is no longer the preferred antiviral agent because of the high risk of drug resistance.

Additional monitoring — In addition to monitoring for reactivation or flare, those who are HBsAg positive also need surveillance for hepatocellular carcinoma. Indications for hepatocellular carcinoma screening are presented separately. (See "Surveillance for hepatocellular carcinoma in adults".)

PROGNOSIS — Safe and effective antiviral treatment has improved the long-term clinical outcomes of transplant recipients with hepatitis B virus (HBV) infection.

Overall survival — Although earlier studies showed that kidney transplant patients with HBV infection had inferior survival compared with patients who were not infected [53], subsequent studies in the era of antiviral therapy have found comparable patient and graft survival rates [7,8,54-56]. As examples:

●One study found no difference in the five-year patient or graft survival between 1346 HBsAg-positive and 74,335 HBsAg-negative recipients in the United States who were transplanted between 2001 and 2007 (85.3 versus 85.6 percent, respectively, for patient survival, and 74.9 versus 75.1 percent, respectively, for graft survival) [54]. However, the five-year incidence of hepatic failure was still higher among HBsAg-positive compared with HBsAg-negative recipients (1.3 versus 0.2 percent, respectively), despite the use of lamivudine. This may in part be related to the high rate of lamivudine resistance and the lack of salvage antiviral therapy in the early years.

●In a report based on the French national database that included 31,433 kidney transplant recipients from 1993 to 2010, of whom 575 had chronic HBV infection, chronic HBV infection had no impact on 10-year patient and kidney allograft survival [55].

●A retrospective analysis of data from the Organ Procurement and Transplantation Network (OPTN) in the United States from 2000 to 2019 showed that HBsAg status of kidney donor or recipient did not impact patient or graft survival after kidney transplantation [56].

The benefit of antiviral therapy was demonstrated in a retrospective study of 63 HBsAg-positive patients in an endemic area who underwent kidney transplantation between 1985 and 2008 and received lamivudine [7]. The 10-year survival rate among patients transplanted in the era of oral antiviral agents was 81 percent. Patients treated with lamivudine had better 10- and 20-year survival rates compared with historical control patients who were not treated (90 and 83 percent compared with 55 and 34 percent, respectively).

One study of 10 treatment-naïve, HBsAg-positive kidney transplant recipients who received entecavir as preventive antiviral therapy showed effective virologic suppression in all subjects, no virologic breakthrough after a mean follow-up of 24.9 months, and a patient survival rate of 90 percent at 24 months [57].

Fibrosing cholestatic hepatitis — There are reports of fibrosing cholestatic hepatitis due to HBV following kidney transplantation [58]. Fibrosing cholestatic hepatitis is a histologic diagnosis first reported in patients with hepatitis B after liver transplantation. Affected patients are markedly jaundiced, have very high serum HBV DNA levels, and progress rapidly to liver failure. Liver biopsy reveals severe cholestasis and intense staining for HBV but mild-to-moderate necroinflammation. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients".)

Fibrosing cholestatic hepatitis has not been reported in patients receiving prophylactic antiviral agents. In addition, case reports have demonstrated that some patients not given antiviral prophylaxis who developed this condition responded to salvage treatment with antiviral therapy [26].

Patients with cirrhosis — Patients with cirrhosis had been considered to be at high risk for hepatic failure following transplantation because of the immunosuppressive therapy that is used to prevent rejection [59,60]. However, reports that described a high risk of mortality were published prior to the widespread use of antiviral therapies. Antiviral agents such as tenofovir and entecavir, which are the mainstay of treatment for HBV, are safe, can reduce the risk of HBV reactivation in the setting of immunosuppressive therapy, and may also reverse cirrhosis after three to five years of maintained viral suppression:

●(See 'Choice of regimen' above.)

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

●(See "Entecavir in the treatment of chronic hepatitis B virus infection", section on 'The efficacy of entecavir in different patient populations'.)

There are no studies that have specifically examined the survival of patients with HBV-related cirrhosis who were treated with antiviral agents before and after kidney transplantation. One retrospective study compared the outcome of kidney transplantation in patients with and without HBV-associated liver cirrhosis prior to kidney transplantation (12 and 90 patients, respectively) [61]. After kidney transplantation, the majority received antiviral therapy (83 versus 89 percent in the patients with and without cirrhosis, respectively). One patient with prior liver cirrhosis showed deterioration in both the model for end-stage liver disease (MELD) score (from 22.3 to 44.1 points) and the Child-Pugh score (from 5 to 10 points), while the liver status in the other 11 patients remained stable. Patient survival rate at five years was similar in patients with or without prior cirrhosis (100 and 94 percent, respectively). Studies of antiviral therapy in non-transplant patients have shown a decrease in hepatic decompensation, hepatocellular carcinoma, and liver-related mortality. (See "Tenofovir and adefovir for the treatment of chronic HBV infection", section on 'Effect on clinical outcomes' and "Entecavir in the treatment of chronic hepatitis B virus infection", section on 'Effect on long-term outcomes'.)

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: Hepatitis B infection in solid organ transplant candidates and recipients".)

SUMMARY AND RECOMMENDATIONS

●General principles – Hepatitis B virus (HBV) infection in the donor is a risk factor for HBV infection in the recipient. HBV infection in the recipient is a risk factor for HBV reactivation after kidney transplantation. De novo infection and HBV reactivation can be minimized by careful attention to the HBV status of the donor and recipient and preventive therapeutic measures. (See 'Goals of management' above.)

●Pretransplantation assessment – The HBV status of both the recipient and the donor (living or deceased) should be assessed prior to transplantation. The following serologic testing should be performed in all potential recipients: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) (table 1); the need for additional testing or evaluation depends upon the results. Potential kidney donors (living and deceased) should be tested for HBsAg, anti-HBc, and HBV DNA. (See 'Pretransplantation assessment of HBV status' above.)

●Recipients without prior HBV infection – Recipients without prior HBV infection include patients with HBV immunity due to vaccination and patients with no evidence of prior infection or immunity. In these patients, the primary goal of management is prevention of de novo HBV infection.

•Suitable donors – Recipients without prior HBV infection should preferably receive a kidney transplant from living or deceased donors who have no evidence of prior HBV infection, including those who have immunity to HBV through vaccination. Living or deceased donors with prior HBV infection are also reasonable, although recipients of kidneys from such donors may require prophylactic antiviral therapy if the donor is HBV DNA positive. (See 'Suitable donors' above.)

•Antiviral therapy to prevent de novo infection – For all recipients without a history of prior HBV (regardless of vaccination) who receive a kidney from a donor with chronic HBV infection, we suggest antiviral therapy to prevent de novo infection (Grade 2C). In recipients who receive a kidney from a donor with prior HBV infection, antiviral therapy is generally not necessary unless the donor has detectable HBV DNA. (See 'Indications' above.)

-Preferred antiviral therapies include entecavir and tenofovir; if tenofovir is used, tenofovir alafenamide is preferred over tenofovir disoproxil fumarate. Antiviral therapy should be started at the time of transplantation and administered for one year. (See 'Choice of regimen' above.)

-HBsAg, anti-HBc, and HBV DNA should be checked every three months to monitor for acquisition of de novo HBV infection. If these parameters remain negative after one year, antiviral therapy can be discontinued. After treatment discontinuation, the frequency of HBsAg and HBV DNA monitoring is reduced progressively from once every three months to annually, unless clinically indicated. (See 'Monitoring' above.)

•Role of hepatitis B immune globulin (HBIG) – For all recipients without a history of prior HBV exposure who receive a kidney from a donor with chronic HBV, some experts administer HBIG at the time of kidney transplantation to further reduce the risk of de novo infection compared with antiviral therapy only. (See 'Role of hepatitis B immune globulin' above.)

●Recipients with prior or chronic HBV infection – In recipients with prior or chronic HBV infection, the primary goal of management is prevention of HBV reactivation and worsening of liver disease.

•Suitable donors – In general, kidney transplant recipients with prior or chronic HBV infection may receive a kidney transplant from any donor regardless of the HBV status of the donor (table 3). (See 'Considerations for donor selection' above.)

•Antiviral therapy to prevent reactivation

-Patients with prior HBV infection – For recipients with prior HBV infection, we suggest antiviral therapy to prevent HBV reactivation (Grade 2C). However, some experts may administer prophylaxis only when the patient receives agents that are associated with a high risk of HBV reactivation (eg, B cell-depleting agents) or when the patient receives high-dose triple immunosuppressive therapy or treatment for rejection.

Preferred antiviral therapies include entecavir and tenofovir; if tenofovir is used, tenofovir alafenamide is preferred over tenofovir disoproxil fumarate. Antiviral therapy should be initiated at the time of transplantation. The duration of antiviral therapy can vary. Some experts administer antiviral therapy indefinitely to all recipients with prior HBV, whereas others discontinue treatment when immunosuppression is reduced and monitor closely thereafter. (See 'Patients with prior HBV infection' above.)

-Patients with chronic HBV infection – Antiviral therapy to prevent reactivation must be administered to all recipients with chronic HBV infection. Recipients with chronic HBV infection need to receive antiviral therapy (typically entecavir or tenofovir alafenamide) indefinitely after transplantation. The choice of agent depends upon their prior antiviral history. (See 'Patients with chronic HBV infection' above.)

•Monitoring/management of reactivation – Recipients receiving antiviral therapy to prevent reactivation or flare should have serum aminotransferases and HBV DNA monitored every six months or more frequently as indicated. If antiviral therapy is discontinued in recipients with prior HBV infection after immunosuppression is decreased, we monitor liver chemistries, HBV DNA, and HBsAg at least once every three months for one year. If reactivation occurs, patients should resume antiviral therapy. In addition to monitoring for reactivation or flare, those who are HBsAg positive also need surveillance for hepatocellular carcinoma. (See 'Monitoring/management of reactivation' above and 'Additional monitoring' above.)