Sage Journals: Discover world-class research

Abstract

Rates of transmission of hepatitis B virus (HBV) infection from organ donors with HBV markers to recipients along with reactivation of HBV during immunosuppression following transplantation have fallen significantly with the advent of hepatitis B immune globulin (HBIg) and effective antiviral therapy. Although the availability of potent antiviral agents and HBIg has highly impacted the survival rate of HBV-infected patients after transplantation, the high cost associated with this practice represents a major financial burden. The availability of potent antivirals with high genetic barrier to resistance and minimal side effects have made it possible to recommend an HBIg-free prophylactic regimen in selected patients with low viral burden prior to transplant. Significant developments over the last two decades in the understanding and treatment of HBV infection necessitate a re-appraisal of the guidelines for prophylaxis of HBV infection in solid organ transplant recipients.

Keywords

HBV prophylaxis HBV recurrence HBV reinfection solid organ transplant

Introduction

Liver transplantation for end-stage liver disease due to hepatitis B was associated with a substantially diminished graft survival until the mid-1990s because of the increased incidence of hepatitis B reactivation and graft loss in recipients. With the advent of antiviral agents such as nucleos(t)ide analogs and hepatitis B immune globulin (HBIg), however, the risk of reactivation of hepatitis B and graft reinfection has been substantially reduced. The overall current survival after liver transplantation for hepatitis B related cirrhosis exceeds 85% in the first year and 75% at year 5 [Kim et al. 2004; Steinmüller et al. 2002; Vargas et al. 2002], in contrast to a 2-year graft survival of 50% in the past [Starzl et al. 1989]. A combination regimen of lamivudine (LAM) and HBIg has been shown to reduce the hepatitis B virus (HBV) recurrence rate after transplant to <5% at 5 years [Markowitz et al. 1998]. Thus, with appropriate prophylactic therapy, liver transplantation in patients with chronic hepatitis B is now associated with excellent long-term outcomes. Although the availability of potent antiviral agents and HBIg has highly impacted the survival rate of HBV-infected patients after transplantation, the high cost associated with this practice represents a major financial burden in developed countries, as well as in HBV endemic countries with limited financial resources. This has led to the consideration of prophylaxis without HBIg for selected patients undergoing liver transplantation. Significant developments over the last two decades in the understanding and treatment of HBV infection necessitate a reappraisal of the guidelines for prophylaxis of HBV infection in solid organ transplant recipients.

HBV reinfection following liver transplantation in prior hepatitis B surface antigen positive recipients

Enhanced viral replication occurs due to the use of immunosuppressive medications in the post-transplant period [McMillan et al. 1995; Tur-Kaspa et al. 1988]. Extrahepatic reservoirs of HBV, predominantly the peripheral mononuclear cells and spleen [Omata, 1990], are the most likely sources of HBV reinfection after transplantation. The reappearance of hepatitis B surface antigen (HBsAg) and HBV DNA in the serum of an HBV-infected patient after liver transplantation is called reinfection (and not reactivation) because the HBV-infected liver is removed at transplantation and the new graft is reinfected by HBV virions present in the circulation or released from extrahepatic sites. Most cases of HBV reinfection occur in those who are hepatitis B extracellular antigen (HBeAg) positive with elevated HBV DNA levels in the serum at the time of transplantation. Reinfection occurs almost universally after orthotopic liver transplantation (OLT) in patients who are HBsAg positive but is uncommon in those recipients with anti hepatitis B core antigen (anti-HBc) without HBsAg [Markowitz et al. 1998]. The presence of HBV DNA in serum, as detected by sensitive polymerase chain reaction (PCR) assays, precedes the elevation of serum aminotransferases or reappearance of HBsAg. As untreated reinfection can lead to fibrosing cholestatic hepatitis, progressive liver disease or cirrhosis, it is important to monitor patients who are not receiving prophylactic therapy in the post OLT period, so that antiviral therapy can be initiated as soon as serum HBV DNA is detectable. Alternatively, some patients with detectable HBV DNA in the liver or peripheral mononuclear cells remain HBsAg negative with no clinical or histological evidence of recurrent HBV [Feray et al. 1990; Roche et al. 2003]. Owing to the enhanced sensitivity of the current HBV DNA assays, detection of low-level transient viremia without clinical evidence of reinfection has been noted. Patients with detectable HBsAg and persistent HBV DNA levels are at risk for clinical disease and graft loss [Fox and Terrault, 2012].

Strategies to prevent HBV allograft reinfection include HBIg monotherapy, a combination of HBIg and antiviral therapy, and antiviral monotherapy. These are discussed below.

HBIg monotherapy and combination therapy with antiviral agents

HBIg is a polyclonal purified preparation of human anti-HBs (hepatitis B surface antibody) derived from pooled plasma. In addition to neutralizing circulating virions, anti-HBs decreases HBsAg secretion by interacting with HBsAg within the cells after endocytosis by hepatocytes [Schilling et al. 2003]. Prophylaxis with HBIg has been shown to decrease reinfection, and improve patient and graft survival [Konig et al. 1994; McGory et al. 1996; Müller et al. 1991; Samuel et al. 1991, 1993; Sawyer et al. 1998]. The maximum benefit from HBIg is conferred when the total viral burden is lowest (the anhepatic phase) and also during the time of intense immunosuppression in the early post-transplant period, i.e. during the first 6–12 months after transplant.

Inhibition of viral replication using antiviral agents (LAM and adefovir ± LAM) in the pre- and immediate post-transplant period has been shown to protect grafts from HBV reinfection after transplant [Perrillo et al. 2001; Schiff et al. 2007; Yoshida et al. 2007]. These studies have also revealed the limitations of antiviral monotherapy, however. The emergence of drug resistance with LAM monotherapy limits its efficacy. Newer, more potent antivirals with higher genetic barriers to resistance such as tenofovir and entecavir have been shown to be safe in decompensated liver disease and effective in achieving HBV DNA suppression before transplant [Liaw et al. 2011], and hence are the recommended antivirals in patients with decompensated HBV cirrhosis.

Multiple studies have reported on the efficacy of combination therapy with HBIg and an antiviral agent in preventing HBV reinfection [Angus et al. 2000; Gane et al. 2007; Markowitz et al. 1998; Terrault et al. 2005]. Combination therapy has been associated with a significantly lower rate of both HBV-related and all-cause mortality compared with HBIg monotherapy, according to the results of a meta-analysis of two prospective and four retrospective studies [Loomba et al. 2008a]. A serum HBV DNA level greater than 100,000 copies/ml at the time of OLT is associated with a 50% risk for recurrent disease even with prophylactic therapy, whereas a pretransplant viral load less than 200 copies/ml carried no risk for recurrent disease [Marzano et al. 2005]. There was no difference in the observed HBV recurrence rate between patients treated with HBIg monotherapy versus combined HBIg and LAM prophylaxis in this study, probably due to comparably low viremic loads in both groups at the time of surgery. Antiviral therapy before transplant has been shown to reduce the risk of reinfection by reducing the circulating viral load at the time of transplant and prolonging the half-life of HBIg [Dickson et al. 2006]. Although a combination regimen of LAM and HBIg has been the standard of care for prevention of HBV reinfection in most transplant centers, a number of small studies have confirmed the efficacy and safety of entecavir [Xi et al. 2009] and entecavir plus tenofovir [Jimenez-Perez et al. 2010] when used in conjunction with HBIg after OLT.

The usual dose of HBIG is 10,000 intravenous units (IUs) as a bolus dose intravenously during the anhepatic phase, followed by daily doses during the first week and monthly thereafter or dosed according to anti-HBs titers. It has been suggested that, in addition to continuation of antiviral therapy, high-risk patients should receive intravenous (IV) HBIg during the first post OLT year and intramuscular (IM) HBIg in the second year, whereas low-risk patients receive IV HBIg for 1 week only [Degertekin et al. 2010; Nath et al. 2006; Wong et al. 2007]. A trough anti-HBs titer of >500 IU/l (or at least 100 IU/l) has been shown to reduce reinfection rates [McGory et al. 1996; Terrault et al. 1996].

Use of a lower dose of IM HBIg (400–800 IU daily for 7 days and monthly thereafter) along with LAM at 100 mg daily has been shown to cost less than 10% of the high-dose IV HBIg-based combination therapy, with an actuarial risk of HBV recurrence of only 1% at 1 year and 4% at 5 years [Gane et al. 2007]; however, more than half the patients in this study had undetectable HBV DNA at the time of transplant. Another study using 800 IU IM HBIg (daily for 6 days, weekly for 3 weeks and monthly thereafter) along with LAM resulted in a higher rate of prophylaxis failure (28% versus 8% p = 0.015) in those with HBV DNA ≥10⁵ copies/ml at transplantation compared with those with HBV DNA levels <10⁵ copies/ml [Zheng et al. 2006]. Thus, the risk of recurrence with the low-dose HBIg approach appears to be primarily determined by the level of HBV DNA at the time of transplantation.

Anti-HBs titers can vary within the same patient even with the administration of a fixed dose of HBIg. Hence, the strategy of dosing HBIg to achieve a specific anti-HBs titer in the serum requires more intensive monitoring of titers. A target trough anti-HBs titer of 50–100 IU/l is ideal, when antiviral agents are given in combination with HBIg for prophylaxis [Fox and Terrault, 2012]. The rate of virologic recurrence using IM HBIg and LAM was <8.2% over a 3–93 month follow-up period, when the anti-HBs titers were maintained between 50 and 100 IU/l [Karademir et al. 2006; Karasu et al. 2004]. Another approach that has been shown to be effective is to titrate the dose of IM HBIg from 400 to 1200 IU/l, where HBIg is administered every 2–4 weeks to achieve an anti-HBs level of ≥100 IU/l [Jiang et al. 2010]. Thus, low-dose IM HBIg along with antiviral therapy may be a cost-effective strategy for prophylaxis. A randomized study that examined continuation of HBIg plus LAM versus switching over to LAM plus adefovir after 1 year of combination therapy with HBIg and LAM post-transplant showed significant cost reduction in the adefovir plus LAM group with only one patient in this group becoming transiently positive for HBsAg [Angus et al. 2008]. Most patients in this study were at low risk of recurrence, however, and a quarter of the patients had undetectable viral DNA at the time of transplant. More importantly, HBIg therapy was stopped only after the first post-transplant year, which is the most vulnerable period for reinfection. Another randomized controlled study evaluated the feasibility of discontinuation of HBIg 1 month after transplant in those who received a combination of LAM and HBIg therapy with an 18-month follow up [Buti et al. 2003] and a subsequent longer-term follow up of the same cohort [Buti et al. 2007]. The cases of HBV DNA and HBsAg positivity occurred in association with poor adherence to antiviral therapy upon discontinuation of HBIg, providing support for the feasibility of this practice in adherent patients who are on effective antiviral therapy. Strategies employing active immunization using HBV vaccination after transplantation as a replacement for HBIg infusions have yielded inconsistent results with either lack of initial response or failure to maintain protective anti-HBs levels [Angelico et al. 2002; Rosenau et al. 2007], and are hence not recommended.

In our opinion, antiviral therapy should be considered prior to OLT in all patients with positive serum HBV DNA and continued indefinitely after transplant, regardless of the magnitude of the viral load. The loss of HBs Ag after OLT is postulated to be attributable to the sudden decrease in viral load upon removal of the infected native liver and the effect of antiviral suppression. In spite of effective prophylaxis with HBIg and antivirals and the absence of detectable HBV DNA/HBsAg in serum, HBV can still be detected in the allograft and peripheral mononuclear cells, and may be the source of HBsAg [Coffin et al. 2011]. There have been reports of reinfection in patients who are maintained on HBIg prophylactic therapy [Carman et al. 1996; Ghany et al. 1998; Hawkins et al. 1996; Protzer-Knolle et al. 1998]. These cases may be due to inadequate dosing of HBIg or, more importantly, due to the emergence of HBIg-induced mutant virus that can escape neutralization. These findings underscore the importance of continuation of prophylactic antiviral therapy after OLT. It is also likely that the HBsAg positivity in recipients in this setting may not lead to an adverse outcome.

HBIg-free prophylaxis

Given the availability of more potent drugs such as entecavir with high genetic barrier to resistance and lack of nephrotoxicity, the role of HBIg therapy is diminishing. A recent study of 80 consecutive patients with chronic HBV undergoing liver transplantation on an HBIg-free regimen of entecavir monotherapy found a 91% loss of HBsAg and 98.8% achievement of serum HBV DNA clearance over a median follow-up time of 26 months post OLT [Fung et al. 2011]. In this study, low pretransplant HBV DNA level in itself was not significantly associated with HBsAg loss, but a combination of low HBV DNA level (<5 log₁₀copies/ml) with low HBsAg level (<3 log₁₀IU/ml was associated with a 100% HBsAg loss at 18 months. It should be noted that no resistance mutations were identified on entecavir monotherapy after a median follow up of 26 months. The results of this study suggest that antiviral therapy alone (with potent agents such as entecavir) without HBIg effectively prevents reinfection in at least low-risk recipients with undetectable viral load at the time of transplant. The recipients at low risk for HBV reinfection include those with negative HBeAg and low viral load (<20,000 IU/ml), fulminant HBV or coinfection with HDV (Vargas et al., 2002). Thus, patients achieving viral suppression pretransplant are the best candidates for an HBIg-free prophylaxis strategy.

However, potential liver transplant recipients with known antiviral drug resistance and those who have positive or negative HBeAg with high viral load (>20,000 IU/ml) are considered to be at high risk for HBV reinfection [Marzano et al. 2005; McGory et al. 1996; Omata, 1990]. Despite the lower reinfection rates in patients with HDV coinfection, this may represent a group in whom an HBIg-free strategy is not suitable because of the need to rapidly remove all circulating HBsAg in order to halt HDV reinfection of the graft in the immediate postoperative period. Thus patients with detectable HBV DNA, known antiviral resistance, higher risk for recurrence of hepatocellular carcinoma (HCC) and limited options if prophylactic antiviral therapy fails are not ideal candidates for an HBIg-free strategy and will need long-term HBIg in conjunction with antiviral agents [Fox and Terrault, 2012] (Table 1).

Table 1.

Candidates for antiviral monotherapy versus combination therapy for HBV prophylaxis.

Antiviral monotherapy	Combination (HBIg + antiviral) therapy
Those with positive HBV markers, but undetectable or very low HBV DNA pretransplant (particularly if levels <40 IU/ml)	Those with detectable pretransplant HBV DNA (particularly if levels >20,000 IU/ml or HBeAg positive) Prior drug resistant HBV Those at higher risk for HCC recurrence Those with HDV/HIV coinfection

HBeAg, hepatitis B extracellular antigen; HBIg, hepatitis B immune globulin; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HDV, hepatitis D virus; HIV, human immunodeficiency virus; IU, intravenous unit.

HBV infection following OLT in prior HBsAg negative recipients

HBV infection after OLT is discussed below in the following categories: liver transplantation from donors with isolated hepatitis B core immunoglobulin G (anti-HBc IgG), transplant recipients with isolated anti-HBc IgG, and transplantation from donors with no positive HBV markers.

Liver transplantation from isolated anti-HBc IgG positive donors

Prior studies have shown a substantial risk of acquiring HBV infection in recipients who receive livers from donors who are anti-HBc positive [Dickson et al. 1997; Prieto et al. 2001; Wachs et al. 1995]. Although recipients who have positive anti-HBs and/or anti-HBc at the time of OLT are considered less likely to acquire HBV infection from an anti-HBc positive donor [Prieto et al. 2001], HBV infection has been noted to occur in recipients who have protective surface antibody from vaccination or prior infection [Dickson et al. 1997]. Thus, the risk of acquiring HBV infection cannot be prevented solely by directing anti-HBc positive livers to those recipients with anti-HBs and administration of prophylactic antiviral therapy is essential in such settings.

HBIg monotherapy for the prevention of infection is considered inferior to antiviral therapy due to the inability of the HBIg to inhibit HBV replication [Roche et al. 2010]. A systematic review analyzing the incidence of de novo hepatitis B infection in liver transplant recipients from donors who were HBsAg negative and anti-HBc positive showed an incidence of 2.7% in patients receiving LAM only prophylaxis versus 3.6% in patients receiving HBIg plus LAM combination therapy [Saab et al. 2010]. The median follow-up time for the monotherapy group was 25.4 months, whereas the median follow-up time for the LAM + HBIG group was 31.1 months. The investigators concluded HBIg + LAM combination therapy was no more effective than LAM only treatment. Owing to the high rate of drug resistance with LAM, entecavir is now the preferred first line antiviral agent in the nucleoside naïve patient. Although many experts have recommended combination therapy, the lack of data to support this recommendation together with the high genetic barrier to resistance with entecavir likely obviate the need for combination therapy in this setting. There is a cost difference of US$79,395 during the first year with the use of LAM monotherapy at a dose of 100 mg per day compared with LAM + HBIg therapy at a dose of 10,000 IU of HBIg daily for 7 days and then monthly (excluding the costs of office visits and HBIG administration) [Saab et al. 2009, 2010]. A newer generation antiviral such as entecavir, at a dose of 0.5 mg/day given as monotherapy, is associated with a cost reduction of US$73,772 compared with LAM + HBIg combination therapy. Hence, indefinite antiviral monotherapy (without HBIg) is recommended for prophylaxis in this setting.

Isolated anti-HBc IgG positive recipients

Although reactivation of HBV replication (positive HBV DNA on liver biopsy) has been reported in recipients who are HBsAg negative but anti-HBc positive pretransplant, none of the recipients became HBsAg-positive or developed clinical hepatitis B after transplantation. Thus, prophylactic antiviral therapy is not warranted routinely after liver transplantation in HBsAg-negative, anti-HBc-positive recipients [Abdelmalek et al. 2003]. It is reasonable to monitor HBV DNA and alanine transaminase (ALT) periodically in the post OLT setting in those who are not receiving prophylactic therapy, particularly if they do not have or lose the protective surface antibodies over time. Such patients should be considered for antiviral therapy as soon as serum HBV DNA is detectable.

Liver transplantation from donors with no positive HBV markers

Although this scenario is associated with the lowest risk of HBV transmission, there have been reports of de novo HBV infection occurring in OLT recipients who received livers from donors with no positive serologic markers of HBV infection [Chazouilleres et al. 1994; Ghisetti et al. 2004]. This may be explained by the presence of occult HBV infection in these donors, as evidenced by the presence of HBV DNA in their serum or liver tissue. Prophylactic treatment of the recipient is not recommended. HBV transmission in this setting can be largely prevented by routinely vaccinating all potential OLT recipients.

Tables 2, 3, and 4 summarize risk stratification, suggested prophylactic regimens and monitoring algorithms for patients following liver transplantation. As shown in Table 2, the antiviral agent of choice for HBV prophylaxis in solid organ transplant recipients is entecavir due to its relative lack of nephrotoxicity, unless the patients were on LAM, tenofovir or emtricitabine/tenofovir pretransplant, in which case the same antiviral agent is continued post-transplantation.

Table 2.

Choice of antiviral agent and dosage.*

❖ First line agent is entecavir 0.5 mg po daily unless:

the patient is lamivudine experienced in which case tenofovir is first line

the patient was on tenofovir or emtricitabine/tenofovir pretransplant, in which case continue the same medication after transplant

❖ Tenofovir 300 mg po daily

❖ Emtricitabine/tenofovir (200/300 mg) one tablet po daily (not licensed for use)

Dose to be adjusted according to renal function.

po, orally.

Table 3.

Suggested HBV prophylaxis in liver transplant recipients.

Recipient status	Donor status	Prescription pretransplant	Prescription post-transplant
Those at high risk for recurrence or HBsAg (+) and HBV DNA(+)	HBV marker (+) or (−)	Nucleos(t)ide analogue	Entecavir or tenofovir or emtricitabine/tenofovir + HBIG 10,000 IU IV at anhepatic phase; then 10, 000 IU IV daily for 5–7 days;^ then 400–1200 IU IM* monthly indefinitely^#
Those at low risk for recurrence or HBsAg (+) but HBV DNA (−)	HBV marker (+) or (−)	Nucleos(t)ide analogue	Entecavir or tenofovir or emtricitabine/tenofovir + HBIG 10,000 IU at anhepatic phase
Anti-HBs (+) or (−) and HBsAg(−)	Anti-HBc (+) HBV DNA (−) Anti-HBs (+) or (−)	None	Entecavir or tenofovir or emtricitabine/tenofovir
Anti-HBs (+) or (−) and HBsAg (−)	Anti-HBc (−) HBsAg (−) AntiHBs (+) or (−)	None	None
Anti-HBc (+) and HBs Ag (−)	HBV marker (−)	None	HBV DNA surveillance every 3 months and antiviral therapy if HBV DNA is detectable

If HBV DNA level at OLT is not known or details of drug resistance are not known or if the patient is on two anti-HBV medications at the time of OLT, patient is considered high risk and treated accordingly.

If HBsAg is positive on day 3, then the dose of HBIg is continued to day 7.

IM HBIg only if INR <1.5 and platelets >50K; if not, give IV; the dose of IM HBIg is adjusted between 400 and 1200 IU IM (at 400 IU increments) to achieve a trough anti-HBs titer of ≥100 units/l.

Discontinuation of HBIg prophylaxis in adherent patients who are on effective antiviral agents with high genetic barrier to resistance therapy may be considered on an individual basis, once persistent viral suppression has been achieved. These patients should be monitored indefinitely for emergence of drug resistance with periodic HBV DNA testing while on treatment.

anti-HBc, anti-hepatitis B core antigen; anti-HBs, human anti-HBs; HBIg, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IM, intramuscular; IU, intravenous unit; IV, intravenous; OLT, orthotopic liver transplantation.

Table 4.

Monitoring of HBV patients post liver transplant and approximate cost of prophylactic therapy.

Antivirals alone	Antivirals + HBIg	Not on therapy	Approximate monthly cost of prophylactic therapy*
HBV DNA monthly for the first 3 months and every 3 months thereafter Those on tenofovir: serum phosphate and creatinine at baseline and routinely if at risk for renal impairment; bone density if at risk for osteopenia or history of pathologic bone fracture Those on entecavir or nucleoside analogs with decompensated liver disease are at risk for mitochondrial toxicity and lactic acidosis	HBV DNA monthly for the first 3 months and every three months thereafter Anti-HBs titer prior to each IM HBIG dose	HBsAg and HBV DNA as part of any ALT elevation work-up or periodically (every 3 months) if HBV markers are present, but deemed not to require prophylactic therapy	Entecavir: $682–920 Tenofovir: $614–772 Emtricitabine/tenofovir: $1,085 Lamivudine: $340–386 Adefovir: $772–1,014 IM HBIg (2,000 units, 2.5 cc vial): $805–985 IV HBIg (10,000 units): $4,179–4,925

Based on data available from (Saab et al., 2009; Abdelmalek et al., 2003) and Epocrates® Online (https://online.epocrates.com); excludes expenses for medication administration, office/nurse visits and laboratory monitoring.

anti-HBs, human anti-HBs; HBIg, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IM, intramuscular; IV, intravenous.

Prophylaxis in other solid organ transplant recipients

Before the advent of effective antiviral agents for treatment of HBV infection, the presence of hepatitis B infection was considered a contraindication for organ transplantation. HBsAg positivity has been shown to be associated with an increased risk of renal allograft loss and death [Fabrizi et al. 2005]. The risk of re-activation of HBV is higher in the HBsAg positive recipient with detectable HBV DNA or HBeAg positivity compared with a HBV carrier with no detectable DNA or HBeAg [Fairley et al. 1991]. The risk of HBV infection is highest when an HBV negative recipient receives an organ from an HBsAg positive donor; it is lower if the HBV negative recipient receives the organ from an HBsAg negative but anti-HBc positive donor, and the lowest if the recipient has protective anti-HBs antibodies [Wachs et al. 1995].

The two primary approaches to prevent HBV reactivation after renal transplantation are prophylactic and preemptive strategies, in addition to routine vaccination of all prospective recipients who are not immune. The prophylactic strategy involves administration of antiviral agents prior to transplantation in patients who are at risk for reactivation. The preemptive strategy involves using sensitive PCR assays to detect HBV DNA in the post-transplant period (ideally every 3 months in the first year and 6-monthly thereafter), with prompt treatment in the event of persistent or progressive rise of HBV DNA. There have been no studies that have compared the two approaches in the renal transplant setting. Although preemptive LAM therapy based on serial HBV DNA levels and clinical monitoring has been shown to improve the survival of HBsAg-positive renal allograft recipients [Chan et al. 2002], many studies have shown the efficacy of prophylactic approach in both kidney transplant [Lewandowska et al. 2000; Park et al. 2001] as well as in nonkidney transplant setting where patients undergo chemotherapy for malignancy [Loomba et al. 2008b; Perrillo, 2001]. Observational studies have also suggested that treatment of HBV reactivation after detection of aminotransferase elevation is less effective in terms of preventing hepatic flares or hepatic decompensation than either a prophylactic or preemptive strategy [Fabrizi et al. 2005; Filik et al. 2006].

Hence, it appears reasonable to consider a prophylactic approach in situations where HBV DNA is detectable either in the donor or recipient and the preferred antiviral agent is entecavir (dosed according to renal function) due to its relative lack of nephrotoxicity. In all other cases, where HBV markers may be present either in the donor or recipient but with undetectable HBV DNA, a preemptive approach may be considered. The approach described here for prophylaxis of HBV infection in renal transplant recipients can be extrapolated to other solid organ transplant recipients but there are less data in these settings. The suggested regimen for prophylaxis of HBV infection in other solid organ transplant recipients is presented in Table 5.

Table 5.

Summary of prophylaxis for kidney/heart/lung/pancreas transplant recipients.

Recipient status	Donor status	Prescription pretransplant	Prescription post-transplant
Vaccinated and immune	No positive HBV markers	None	None
Vaccinated and immune	IgG anti-HBc (+) and HBV DNA (+/-)	None	HBV DNA surveillance every 3months and antiviral therapy if HBV DNA is detectable
Nonimmune with HBsAg (+) or HBV DNA (+)	HBV DNA (+/-)	As clinically indicated	Entecavir or tenofovir or emtricitabine/tenofovir
Nonimmune with isolated anti-HBc (+) and HBV DNA (−)	HBV DNA (+)	None	Entecavir or tenofovir or emtricitabine/tenofovir
Nonimmune with isolated anti-HBc (+) and HBV DNA (−)	HBV DNA (−)	None	HBV DNA surveillance every 3 months (or sooner if there is evidence of liver dysfunction) and antiviral therapy if HBV DNA is detectable
Nonimmune with HBV DNA (−) and no HBV markers	HBV DNA (−)	None	None

In cases where HBV DNA status is not known, assume HBV DNA (+) and provide prophylaxis accordingly. The use of donor HBV DNA testing is suggested given the potential risk of transmission with detectable HBV DNA (McMillan et al., 1995).

anti-HBc, anti-hepatitis B core antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IgG, immunoglobulin G.

Conclusion

Rates of transmission of HBV infection from organ donors with HBV markers to recipients along with reactivation of HBV during immunosuppression following transplantation have fallen significantly with the advent of HBIg and effective antiviral therapy. The availability of potent antivirals with high genetic barrier to resistance and minimal side effects have made it possible to recommend an HBIg-free prophylactic regimen in selected patients with low viral burden prior to transplant. While this approach has not yet been proven sufficient for all organ recipients, it is likely that we can recommend a universal HBIg-free prophylactic strategy in the near future pending results of more definitive studies. This strategy could lead to a significant curtailment of health care cost without compromising long-term graft and recipient outcomes. Surveillance of HBV DNA is critical for early detection of new or recurrent infection because the appearance and rise of HBV DNA can precede development of necroinflammatory disease by weeks. Early implementation of antiviral therapy can effectively forestall graft or life threatening HBV infection.

Footnotes

Funding

R.C. has received research grants from Gilead and Roche/Genentech.

Conflict of interest statement

The authors declare no conflicts of interest in preparing this article.

References

Abdelmalek

Pasha

Zein

Persing

Wiesner

Douglas

(2003) Subclinical reactivation of hepatitis B virus in liver transplant recipients with past exposure. Liver Transplant 9: 1253–1257.

Angelico

Di Paolo

Trinito

Petrolati

Araco

Zazza

. (2002) Failure of a reinforced triple course of hepatitis B vaccination in patients transplanted for HBV-related cirrhosis. Hepatology 35: 176–181.

Angus

McCaughan

Gane

Crawford

Harley

(2000) Combination low-dose hepatitis B immune globulin and lamivudine therapy provides effective prophylaxis against posttransplantation hepatitis B. Liver Transplant 6: 429–433.

Angus

Patterson

Strasser

McCaughan

Gane

(2008) A randomized study of adefovir dipivoxil in place of HBIG in combination with lamivudine as post-liver transplantation hepatitis B prophylaxis. Hepatology 48: 1460–1466.

Buti

Mas

Prieto

Casafont

Gonzalez

Miras

. (2003) A randomized study comparing lamivudine monotherapy after a short course of hepatitis B immune globulin (HBIg) and lamivudine with long-term lamivudine plus HBIg in the prevention of hepatitis B virus recurrence after liver transplantation. J Hepatol 38: 811–817.

Buti

Mas

Prieto

Casafont

Gonzalez

Miras

. (2007) Adherence to Lamivudine after an early withdrawal of hepatitis B immune globulin plays an important role in the long-term prevention of hepatitis B virus recurrence. Transplantation 84: 650–654.

Carman

Trautwein

van Deursen

Colman

Dornan

McIntyre

. (1996) Hepatitis B virus envelope variation after transplantation with and without hepatitis B immune globulin prophylaxis. Hepatology 24: 489–493.

Chan

Fang

Tang

Cheng

Lai

(2002) Preemptive lamivudine therapy based on HBV DNA level in HBsAg-positive kidney allograft recipients. Hepatology 36: 1246–1252.

Chazouilleres

Mamish

Kim

Carey

Ferrell

Roberts

. (1994) ‘Occult’ hepatitis B virus as source of infection in liver transplant recipients. Lancet 343: 142–146.

10.

Coffin

Mulrooney-Cousins

van Marle

Roberts

Michalak

Terrault

(2011) Hepatitis B virus quasispecies in hepatic and extrahepatic viral reservoirs in liver transplant recipients on prophylactic therapy. Liver Transplant 17: 955–962.

11.

Degertekin

Han

Keeffe

Schiff

Luketic

Brown

Jr. . (2010) Impact of virologic breakthrough and HBIG regimen on hepatitis B recurrence after liver transplantation. Am J Transplant 10: 1823–1833.

12.

Dickson

Everhart

Lake

Wei

Seaberg

Wiesner

. (1997) Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. The National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Gastroenterology 113: 1668–1674.

13.

Dickson

Terrault

Ishitani

Reddy

Sheiner

Luketic

. (2006) Protective antibody levels and dose requirements for IV 5% Nabi Hepatitis B immune globulin combined with lamivudine in liver transplantation for hepatitis B-induced end stage liver disease. Liver Transplant 12: 124–133.

14.

Fabrizi

Martin

Dixit

Kanwal

Dulai

(2005) HBsAg seropositive status and survival after renal transplantation: meta-analysis of observational studies. Am Jf Transplant 5: 2913–2921.

15.

Fairley

Mijch

Gust

Nichilson

Dimitrakakis

Lucas

(1991) The increased risk of fatal liver disease in renal transplant patients who are hepatitis Be antigen and/or HBV DNA positive. Transplantation 52: 497–500.

16.

Feray

Zignego

Samuel

Bismuth

Reynes

Tiollais

. (1990) Persistent hepatitis B virus infection of mononuclear blood cells without concomitant liver infection. The liver transplantation model. Transplantation 49: 1155–1158.

17.

Filik

Karakayali

Moray

Dalgic

Emiroglu

Ozdemir

. (2006) Lamivudine therapy in kidney allograft recipients who are seropositive for hepatitis B surface antigen. Transplant Proc 38: 496–498.

18.

Fox

Terrault

(2012) The option of HBIG-free prophylaxis against recurrent HBV. J Hepatol.56: 1189–1197.

19.

Fung

Cheung

Chan

Yuen

Chok

Sharr

. (2011) Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation. Gastroenterology 141: 1212–1219.

20.

Gane

Angus

Strasser

Crawford

Ring

Jeffrey

. (2007) Lamivudine plus low-dose hepatitis B immunoglobulin to prevent recurrent hepatitis B following liver transplantation. Gastroenterology 132: 931–937.

21.

Ghany

Ayola

Villamil

Gish

Rojter

Vierling

. (1998) Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis. Hepatology 27: 213–222.

22.

Ghisetti

Marzano

Zamboni

Barbui

Franchello

Gaia

. (2004) Occult hepatitis B virus infection in HBsAg negative patients undergoing liver transplantation: clinical significance. Liver Transplant 10: 356–362.

23.

Hawkins

Gilson

Gilbert

Wreghitt

Gray

Ahlers-de Boer

. (1996) Hepatitis B virus surface mutations associated with infection after liver transplantation. J Hepatol 24: 8–14.

24.

Jiang

Yan

Wen

Zhao

Jiang

. (2010) Prophylaxis against hepatitis B recurrence posttransplantation using lamivudine and individualized low-dose hepatitis B immunoglobulin. Am J Transplant 10: 1861–1869.

25.

Jimenez-Perez

Saez-Gomez

Mongil Poce

Lozano-Rey

Cruz-Lombardo

Rodrigo-Lopez

(2010) Efficacy and safety of entecavir and/or tenofovir for prophylaxis and treatment of hepatitis B recurrence post-liver transplant. Transplant Proc 42: 3167–3168.

26.

Karademir

Astarcioglu

Akarsu

Ozkardesler

Ozzeybek

Sayiner

. (2006) Prophylactic use of low-dose, on-demand, intramuscular hepatitis B immunoglobulin and lamivudine after liver transplantation. Transplant Proc 38: 579–583.

27.

Karasu

Ozacar

Akyildiz

Demirbas

Arikan

Kobat

. (2004) Low-dose hepatitis B immune globulin and higher-dose lamivudine combination to prevent hepatitis B virus recurrence after liver transplantation. Antiviral Ther 9: 921–927.

28.

Kim

Poterucha

Kremers

Ishitani

Dickson

(2004) Outcome of liver transplantation for hepatitis B in the United States. Liver Transplant 10: 968–974.

29.

Konig

Hopf

Neuhaus

Bauditz

Schmidt

Blumhardt

. (1994) Long-term follow-up of hepatitis B virus-infected recipients after orthotopic liver transplantation. Transplantation 58: 553–559.

30.

Lewandowska

Durlik

Kukula

Cieciura

Ciecierski

Walewska-Zielecka

. (2000) Treatment of chronic hepatitis B with lamivudine in renal allograft recipients. Transplant Proc 32: 1369–1370.

31.

Liaw

Sheen

Lee

Akarca

Papatheodoridis

Suet-Hing Wong

. (2011) Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology 53: 62–72.

32.

Loomba

Rowley

Wesley

Liang

Hoofnagle

Pucino

. (2008a) Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med 148: 519–528.

33.

Loomba

Rowley

Wesley

Smith

Liang

Pucino

. (2008b) Hepatitis B immunoglobulin and Lamivudine improve hepatitis B-related outcomes after liver transplantation: meta-analysis. Clin Gastroenterol Hepatol 6: 696–700.

34.

Markowitz

Martin

Conrad

Markmann

Seu

Yersiz

. (1998) Prophylaxis against hepatitis B recurrence following liver transplantation using combination lamivudine and hepatitis B immune globulin. Hepatology 28: 585–589.

35.

Marzano

Gaia

Ghisetti

Carenzi

Premoli

Debernardi-Venon

. (2005) Viral load at the time of liver transplantation and risk of hepatitis B virus recurrence. Liver Transplant 11: 402–409.

36.

McGory

Ishitani

Oliveira

Stevenson

McCullough

Dickson

. (1996) Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization. Transplantation 61: 1358–1364.

37.

McMillan

Shaw

Angus

Locarnini

(1995) Effect of immunosuppressive and antiviral agents on hepatitis B virus replication in vitro. Hepatology 22: 36–43.

38.

Müller

Gubernatis

Farle

Niehoff

Klein

Wittekind

. (1991) Liver transplantation in HBs antigen (HBsAg) carriers. Prevention of hepatitis B virus (HBV) recurrence by passive immunization. J Hepatol 13: 90–96.

39.

Nath

Kalis

Nelson

Payne

Lake

Humar

(2006) Hepatitis B prophylaxis post-liver transplant without maintenance hepatitis B immunoglobulin therapy. Clin Transplant 20: 206–210.

40.

Omata

(1990) Significance of extrahepatic replication of hepatitis B virus. Hepatology 12: 364–366.

41.

Park

Yang

Lee

Jung

Chang

Choi

. (2001) Outcome of renal transplantation in hepatitis B surface antigen-positive patients after introduction of lamivudine. Nephrol Dial Transplant 16: 2222–2228.

42.

Perrillo

(2001) Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 120: 1009–1022.

43.

Perrillo

Wright

Rakela

Levy

Schiff

Gish

. (2001) A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 33: 424–432.

44.

Prieto

Gomez

Berenguer

Cordoba

Rayon

Pastor

. (2001) De novo hepatitis B after liver transplantation from hepatitis B core antibody-positive donors in an area with high prevalence of anti-HBc positivity in the donor population. Liver Transplant 7: 51–58.

45.

Protzer-Knolle

Naumann

Bartenschlager

Berg

Hopf

Meyer zum Buschenfelde

. (1998) Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high-dose hepatitis B immune globulin after liver transplantation. Hepatology 27: 254–263.

46.

Roche

Feray

Gigou

Roque-Afonso

Arulnaden

Delvart

. (2003) HBV DNA persistence 10 years after liver transplantation despite successful anti-HBS passive immunoprophylaxis. Hepatology 38: 86–95.

47.

Roche

Roque-Afonso

Sebagh

Delvart

Duclos-Vallee

Castaing

. (2010) Escape hepatitis B virus mutations in recipients of antibody to hepatitis B core antigen-positive liver grafts receiving hepatitis B immunoglobulins. Liver Transplant 16: 885–894.

48.

Rosenau

Hooman

Hadem

Rifai

Bahr

Philipp

. (2007) Failure of hepatitis B vaccination with conventional HBsAg vaccine in patients with continuous HBIG prophylaxis after liver transplantation. Liver Transplant 13: 367–373.

49.

Saab

Ham

Stone

Holt

Tong

(2009) Decision analysis model for hepatitis B prophylaxis one year after liver transplantation. Liver Transplant 15: 413–420.

50.

Saab

Waterman

Chi

Tong

(2010) Comparison of different immunoprophylaxis regimens after liver transplantation with hepatitis B core antibody-positive donors: a systematic review. Liver Transplant 16: 300–307.

51.

Samuel

Bismuth

Serres

Arulnaden

Reynes

Benhamou

. (1991) HBV infection after liver transplantation in HBsAg positive patients: experience with long-term immunoprophylaxis. Transplant Proc 23: 1492–1494.

52.

Samuel

Müller

Alexander

Fassati

Ducot

Benhamou

. (1993) Liver transplantation in European patients with the hepatitis B surface antigen. New Eng J Med 329: 1842–1847.

53.

Sawyer

McGory

Gaffey

McCullough

Shephard

Houlgrave

. (1998) Improved clinical outcomes with liver transplantation for hepatitis B-induced chronic liver failure using passive immunization. Ann Surg 227: 841–850.

54.

Schiff

Lai

Hadziyannis

Neuhaus

Terrault

Colombo

. (2007) Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transplant 13: 349–360.

55.

Schilling

Ijaz

Davidoff

Lee

Locarnini

Williams

. (2003) Endocytosis of hepatitis B immune globulin into hepatocytes inhibits the secretion of hepatitis B virus surface antigen and virions. J Virol 77: 8882–8892.

56.

Starzl

Demetris

Van Thiel

(1989) Liver transplantation (2). New Eng J Med 321: 1092–1099.

57.

Steinmüller

Seehofer

Rayes

Müller

Settmacher

Jonas

. (2002) Increasing applicability of liver transplantation for patients with hepatitis B-related liver disease. Hepatology 35: 1528–1535.

58.

Terrault

Roche

Samuel

(2005) Management of the hepatitis B virus in the liver transplantation setting: a European and an American perspective. Liver Transplant 11: 716–732.

59.

Terrault

Zhou

Combs

Hahn

Lake

Roberts

. (1996) Prophylaxis in liver transplant recipients using a fixed dosing schedule of hepatitis B immunoglobulin. Hepatology 24: 1327–1333.

60.

Tur-Kaspa

Shaul

Moore

Burk

Okret

Poellinger

. (1988) The glucocorticoid receptor recognizes a specific nucleotide sequence in hepatitis B virus DNA causing increased activity of the HBV enhancer. Virology 167: 630–633.

61.

Vargas

Dodson

Rakela

(2002) A concise update on the status of liver transplantation for hepatitis B virus: the challenges in 2002. Liver Transplant 8: 2–9.

62.

Wachs

Amend

Ascher

Bretan

Emond

Lake

. (1995) The risk of transmission of hepatitis B from HBsAg(−), HBcAb(+), HBIgM(−) organ donors. Transplantation 59: 230–234.

63.

Wong

Chu

Wai

Howell

Moore

Fontana

. (2007) Low risk of hepatitis B virus recurrence after withdrawal of long-term hepatitis B immunoglobulin in patients receiving maintenance nucleos(t)ide analogue therapy. Liver Transplant 13: 374–381.

64.

Xia

Zhang

Chen

Han

Wang

. (2009) The role of entecavir in preventing hepatitis B recurrence after liver transplantation. J Dig Dis 10: 321–327.

65.

Yoshida

Kato

Levi

Regev

Madariaga

Nishida

. (2007) Lamivudine monoprophylaxis for liver transplant recipients with non-replicating hepatitis B virus infection. Clin Transplant 21: 166–171.

66.

Zheng

Chen

Liang

Wang

Shen

. (2006) Prevention of hepatitis B recurrence after liver transplantation using lamivudine or lamivudine combined with hepatitis B Immunoglobulin prophylaxis. Liver Transplant 12: 253–258.

Prophylaxis of hepatitis B infection in solid organ transplant recipients

Abstract

Keywords

Introduction

HBV reinfection following liver transplantation in prior hepatitis B surface antigen positive recipients

HBIg monotherapy and combination therapy with antiviral agents

HBIg-free prophylaxis

HBV infection following OLT in prior HBsAg negative recipients

Liver transplantation from isolated anti-HBc IgG positive donors

Isolated anti-HBc IgG positive recipients

Liver transplantation from donors with no positive HBV markers

Prophylaxis in other solid organ transplant recipients

Conclusion

Footnotes

Funding

Conflict of interest statement

References