Is There a Role for Hepatitis B Immunoglobulin? Is Antiviral Monotherapy Sufficient?
The risk of hepatitis B virus (HBV) recurrence following liver transplantation (LT) has progressively decreased from 75% in the late 1980s, when no prophylaxis was available, to <5% at the present time1–3 (Fig. 1). Combination therapy with a nucleos(t)ide analogue (NUC) plus low-dose intramuscular hepatitis B immunoglobulin (HBIg) has become the standard of care worldwide. Most likely, entecavir (ETV) or tenofovir (TDF) will be increasingly used in combination with HBIg instead of lamivudine (LAM) or adefovir. Although experience is limited, recent studies showed complete absence of HBV recurrence when using low-dose HBIg + ETV. HBIg requires parenteral administration, has limited availability, and is expensive. However, when used in combination therapy, high doses and indefinite administration are no longer required.
Pre- and post-LT monotherapy with LAM resulted in high rates of recurrence (∼40%), mostly due to the emergence of YMDD mutations. Fung et al.4 recently showed that among 80 patients who received ETV monoprophylaxis the cumulative rate of hepatitis B surface antigen (HBsAg) loss was 91% with 98.8% of patients achieving undetectable HBV DNA. However, 18 patients (22.5%) were HBsAg-positive at the time of their last follow-up (persistence in eight and reappearance in 10). Are these results “good enough” to recommend HBIg-free prophylaxis to all patients transplanted for hepatitis B? The answer to this important question mostly relies on the definition of HBV recurrence. For many years, recurrent infection has been defined as persistence or reappearance of HBsAg in serum after its initial disappearance following LT. Based on this definition, results of the study by Fung et al. are inferior to those obtained with combination therapy in which >95% of patients remain HBsAg-negative after LT. In contrast, if HBV recurrence is defined as detectable serum HBV DNA, then persistence or reappearance of HBsAg after LT in the absence of viral replication should not be regarded as an inferior outcome. In any case, longer follow-up is required to establish whether patients with an inactive post-LT HBV carrier state induced by ETV will eventually clear HBsAg or go on to develop breakthrough and elevated ALT, as described with LAM.
Clearance of HBsAg from serum is the most desired endpoint of antiviral therapy in patients with chronic hepatitis B. It is now considered that levels of HBsAg in serum reflect the transcriptional activity of covalently closed circular DNA (ccc DNA) in the liver. Although the HBsAg secretory pathway is partially independent of HBV replication, it can provide an indirect measure of the number of infected hepatocytes. Therefore, HBsAg negativity after LT appears to be a desirable goal in addition to the absence of replication.
Although the mechanisms by which HBIg prevents graft reinfection are not completely understood, it is known that it binds circulating virions and may also decrease the horizontal spread of HBV infection within the liver. Recent studies suggest that after surgical removal of the diseased liver, 1 week of HBIg prophylaxis may be sufficient to clear HBsAg from serum and thus improve the efficacy of maintenance therapy with NUCs. Because combination therapy may offer synergistic protection against graft reinfection, it is potentially more effective than single-agent prophylaxis. Although avoiding HBIg will decrease cost, this strategy will not be cost-effective if savings are at the expense of higher recurrence rates.
Importantly, new prophylactic strategies should be individualized according to the status of HBV replication at the time of LT and to the presence of other predictors of recurrence (Table 1).5 Prophylaxis of HBV recurrence has not been standardized, and therefore studies comparing head-to-head HBIg-free regimens versus combination therapy with short-term, low-dose HBIg are urgently needed. Until then, the wide adoption of monoprophylaxis with NUCs, especially for HBV DNA-positive patients, cannot be universally recommended.
Table 1. Predictors of HBV Recurrence at the Time of Liver Transplantation Influencing the Choice of Prophylactic Regimen
Abbreviations: HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HDV, hepatitis delta virus; HIV, human immunodeficiency virus; HCC, hepatocellular carcinoma.
Modified from Fox AN and Terrault NA.
HBV DNA levels
Quantitative HBsAg levels
Drug resistant HBV
High risk of HCC recurrence
Liver Transplantation from an Anti-HBc–Positive Donor: What Antiviral Prophylaxis?
Antibody to hepatitis B core antigen (anti-HBc)–positive donors have been used increasingly in recent years in an effort to address the scarcity of liver grafts. The major limitation of this strategy is that donor occult HBV infection can reactivate after LT due to the effects of immunosuppression. The risk of de novo hepatitis B post-LT is influenced both by the pre-LT serologic status of the recipient (Fig. 2) and by the use of post-LT prophylaxis.6 Anti-HBc–positive donors with or without detectable antibody to HBsAg (anti-HBs) carry the same risk of HBV transmission. There are no randomized studies comparing different prophylactic strategies. However, recently reported systematic reviews have clearly established that both long-term monoprophylaxis with LAM or combination of LAM with HBIg are equally effective to prevent de novo HBV infection in >95% of recipients of anti-HBc–positive donors.6, 7 Although cost saving, the major concern with lifelong use of LAM is the emergence of drug resistance. Following LT with anti-HBc–positive donors, serum HBV DNA is usually undetectable, and in this scenario the risk of LAM resistance appears to be much lower than in patients with chronic hepatitis B. Therefore, it remains to be determined whether use of drugs with a better resistance profile such as ETV or TDV instead of LAM will be cost-effective.
When possible, anti-HBc–positive donors should be preferentially allocated to patients transplanted for hepatitis B, which will require indefinite prophylaxis or alternatively to those with serologically resolved HBV infection (anti-HBc–positive, anti-HBs–positive) who carry a very low risk of recurrence (Fig. 2). All patients grafted with anti-HBc–positive donors should receive long-term treatment with NUCs. In this scenario, there is no need for HBIg prophylaxis. Additional studies are required to assess whether low-risk patients may receive short-term prophylaxis and to further establish the efficacy and safety of the new and more potent oral antivirals.
Kidney Transplant in HBsAg-Positive Patients: Prophylactic Antiviral for All?
Many studies performed before the availability of safe and effective therapies against HBV showed decreased survival in HBsAg-positive kidney transplant recipients. Mortality was related to enhanced viral replication due to immunosuppresion which in turn resulted in accelerated liver failure. However, a recent analysis of the UNOS database showed similar 5-year patient and kidney graft survival in HBV-infected (n = 1,346) and noninfected patients (n = 74,335).8 Without any doubt, this significant improvement in outcome during the last decade was due to the increasing efficacy of antiviral agents to prevent HBV-related liver failure. There is now universal consensus that all HBsAg-positive candidates for kidney transplantation should receive antiviral therapy with NUCs shortly before or at the time of grafting in order to maintain undetectable serum HBV DNA levels.9 Pre-emptive therapy is indicated regardless of HBV DNA levels or fibrosis stage and should be maintained for life or as long as immunosuppression is required. ETV and TDF are now preferable to LAM or adefovir. The dosage of all NUCs has to be adjusted based on renal function. Recently, Knoll et al.10 showed that among 23 kidney transplant recipients with isolated anti-HBc positivity who were grafted with HBV-negative donors, 10 (43%) developed subclinical HBV reactivation (detectable HBV DNA), which cannot be easily distinguished from de novo hepatitis B. In this patient population, it is recommended to obtain HBV DNA levels every 3 to 6 months after kidney transplantation and to administer NUCs upon confirmation of viral reactivation but before elevation of ALT or clinical hepatitis.
What About Kidney Transplants from Anti-HBc–Positive Donors?
The risk of transmitting HBV infection when using anti-HBc+ donors for kidney transplantation is very low. Analyzing the UNOS database, Fong et al showed that anti-HBc seroconversion occurred in only 17/763 (2.2%) patients grafted with anti-HBc–positive donors, although this rate was significantly higher when compared with recipients of anti-HBc–negative donors (287/24,662 (1.1%), P = 0.02).11 However, no significant difference was found between groups for HBsAg seroconversion (0.6 versus 0.2%, respectively). Most likely, the low infectivity of anti-HBc–positive donors in this scenario is due to the absence of HBV replication and the low concentration of lymphoid cells in kidney tissue. In most centers, anti-HBc–positive kidneys are preferably allocated to successfully immunized recipients, although around 4% of vaccinated patients may lose protective antibodies and develop anti-HBc seroconversion (without clinical or biochemical hepatitis).12 Serum anti-HBs concentration should be periodically monitored during the waitlist time in order to administer booster vaccination. Although LAM or HBIg have been used in recipients of anti-HBc–positive donors, universal prophylaxis is not indicated. However, because HBV naïve and nonimmune patients are not completely free of viral transmission, posttransplantation serologic and virologic testing is recommended to allow early diagnosis and treatment of de novo HBV infection. Use of anti-HBc–positive donors for kidney transplantation has no impact on patient and graft survival.