Hepatitis B virus: Prevention of recurrent infection

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Once regarded as a contraindication, hepatitis B virus (HBV) infection is today one of the best indications for liver transplantation (LT). During the last 2 decades, the risk of graft reinfection has progressively decreased from approximately 75%‐85% (when prophylaxis was not available) to <5% at the present time.

The first major advance was the use of high and fixed intravenous (IV) doses of hepatitis B immunoglobulin (HBIG) in the early 1990s. Overall, long‐term or indefinite high‐dose HBIG monotherapy prevented HBV recurrence in approximately 70% of cases, but it was ineffective in most patients with active viral replication at the time of LT.1 In addition, HBIG is not available everywhere and is very expensive.

The second major advance in the field was the advent of lamivudine (LAM), an orally administered antiviral agent that was found to be safe and well tolerated in patients with decompensated HBV cirrhosis. Suppression of HBV replication with LAM results in significant clinical improvement to the point that in many patients, LT is no longer required.2 However, antiviral therapy may have limited or no efficacy in patients with severely decompensated HBV cirrhosis.3 Therefore, patients with advanced liver failure and high Model for End‐Stage Liver Disease scores should be prioritized for urgent LT, regardless of the antiviral response.

The major drawback of LAM therapy was the emergence of mutations in the YMDD locus of the polymerase gene. The risk of virological breakthrough increased in parallel with the length of therapy, and on occasion, it was followed by flares of hepatitis and rapidly progressive liver failure. A large, multicenter trial showed that adefovir dipivoxil (ADV) was effective at inhibiting HBV replication of wild‐type and YMDD mutant strains of HBV both before and after LT.4 However, ADV monotherapy is no longer considered a first‐line therapy because of its weak antiviral activity, drug resistance, and nephrotoxicity. New‐generation nucleos(t)ide analogues (NUCs) with potent antiviral activity and high genetic barriers, such as entecavir (ETV) and tenofovir disoproxil fumarate (TDF), have largely replaced LAM and ADV as first‐line therapies for HBV infections in the non‐LT setting.

Although the reported experience with wait‐listed patients with decompensated HBV cirrhosis is still limited, both drugs have shown excellent antiviral activity and good safety profiles and tolerability.5, 6 Therefore, either agent can be used as a first‐line therapy in the LT setting as well (ETV may be preferable for patients with renal dysfunction, and TDF may be preferable for those with LAM‐resistant HBV). An additional benefit of pre‐LT antiviral therapy is that the clearance of serum HBV DNA while a patient is on the wait list significantly decreases the risk of HBV recurrence. Active HBV replication at the time of LT is the strongest predictor of HBV recurrence, regardless of the type of prophylaxis used. Therefore, antiviral therapy should be indicated for all patients with detectable serum HBV DNA at the time of listing. When ETV or TDF, alone or in combination with emtricitabine (Truvada), or even LAM plus ADV are used for prolonged periods before LT, the risk of developing drug resistance is negligible.

Post‐LT combination prophylaxis with NUCs and HBIG is currently the most effective strategy for preventing graft reinfection. A recently reported review7 showed that HBV recurrence occurred in 6% of 1889 patients receiving HBIG plus LAM and in only 2% of 152 patients treated with HBIG plus ADV. Systematic reviews and a meta‐analysis have shown that combination therapy with HBIG and LAM is more effective than single‐agent therapy with either HBIG or LAM.7, 8, 9 This is not surprising when we consider that both drugs can have synergistic effects, with HBIG neutralizing circulating virions and LAM inhibiting HBV replication in the liver and extrahepatic sites.

Limited information is available regarding the use of combination prophylaxis with HBIG plus ETV or TDF. However, a recently reported systematic review10 showed that the risk of HBV recurrence was negligible (1%) and significantly lower for patients treated with the combination of HBIG and NUCs with a high genetic barrier (ETV/TDF) in comparison with patients on HBIG and LAM (Table 1).

Table 1.

Risk of HBV Recurrence According to the Type of Prophylaxis Used After LT

Definition of HBV Recurrence	HBV Recurrence [n/N (%)]
	HBIG + LAMa	HBIG + ETV/TDFa	ETV/TDF After HBIG Withdrawal	ETV/TDF Monotherapy
HBsAg or HBV DNA	115/1889 (6.1)b	3/303 (1)	4/102 (3.9)	29/112 (26)
HBsAg	109/1834 (5.9)c, d	3/303 (1)	NA	29/112 (26)
HBV DNA	42/1111 (3.8)e	1/303 (0.3)	NA	1/112 (0.9)

The data for this table were taken from American Journal of Transplantation 10 (with permission).

^aFor patients who remained on combination therapy.

^b P = 0.0004 versus HBIG + ETV/TDF.

^c P < 0.001 versus HBIG + ETV/TDF.

^d P < 0.0001 versus ETV/TDF monotherapy.

^e P = 0.003 versus HBIG + ETV/TDF.

A major benefit of therapy with NUCs before and after orthotopic liver transplantation (OLT) is that it makes immunoprophylaxis much less expensive. The cost savings have resulted from a reduction in the amount of HBIG administered (either by lowering of the doses or shortening of the duration of therapy). After the advent of LAM, it became clear that in the presence of effective inhibition of viral replication, lower doses of intramuscular (IM) HBIG were required to prevent HBV recurrence. Both fixed‐dosing schedules and individualized regimens targeting predefined putatively protective levels of serum antibody to hepatitis B surface antigen (anti‐HBs) were found to be effective, even for high‐risk patients with active viral replication at the time of LT.11, 12, 13, 14 When combined with antiviral therapy, all HBIG regimens are associated with similar rates of HBV recurrence.15 The most impressive and cost‐effective results were reported by the Australian and New Zealand Multicenter Transplant Group.12 In that study, patients received LAM in combination with IM HBIG doses of only 400 to 800 IU (daily for the first postoperative week, weekly for 4 weeks, and monthly thereafter). The total amount of HBIG administered during the first year ranged from 7600 to 15,200 IU (in contrast to 200,000 IU in high‐dose IV regimens). Importantly, the 5‐year actuarial rate of HBV recurrence in this study was only 4% (5/141). The rationale for individualized regimens is to target predefined putatively protective levels of serum anti‐HBs as defined in pharmacokinetic studies reported in the late 1990s.13

When NUCs are used in combination therapy, it is also recognized that the indefinite administration of HBIG is no longer required for all patients. Many studies have shown that the discontinuation of immunoprophylaxis at variable time intervals after LT followed by NUC monotherapy, HBV vaccination, or both appears to be safe and effective, at least for low‐risk patients.16, 17, 18, 19, 20 A finite course of HBIG, for as short as 1 month or even 1 week, followed by indefinite maintenance therapy with NUCs has been shown to be enough to clear hepatitis B surface antigen (HBsAg) and HBV DNA from serum.16, 17, 18 In a recent report by Gane et al.,21 20 patients received LAM plus ADV from the time of listing and combination prophylaxis after LT with the same antiviral regimen and low‐dose IM HBIG for only 1 week (800 IU/day for a total of 6400 IU). After a median follow‐up of 57 months, all patients remained HBsAg‐ and HBV DNA‐negative.

Results of active immunization with currently licensed HBV vaccines after HBIG discontinuation have been discordant and controversial. Despite the use of reinforced schedules and repeated courses of vaccination, only approximately 20% of patients developed anti‐HBs titers ≥ 100 IU/L.19 Although standard vaccines formulated with immunomodulatory adjuvants and third‐generation vaccines showed improved immunogenicity,20 it has to be proven that the endogenous antibodies elicited will be effective and long‐lasting in order to discontinue HBIG prophylaxis safely.

Historically, the major challenge in LT for HBV has been to develop cost‐effective strategies to prevent graft reinfection. HBIG has been used for almost 25 years, and although its use has been optimized, there is still no established consensus regarding the doses, route of administration, and length of therapy when it is used in combination with NUCs22 (Fig. 1). The most important question at present is whether the use of potent antivirals with a high genetic barrier and no cross‐resistance will allow HBIG‐free prophylaxis. Previous experience with LAM monotherapy was disappointing because of the high rates of recurrence (up to 50%), which were mostly due to the emergence of resistant species.23, 24 Notably, the risk of recurrence was acceptably low (0%‐25%) for patients with nonreplicating HBV at the time of LT. A The only available large series of patients who received ETV after LT as single‐agent prophylaxis was recently reported by Fung et al.25 This study showed that almost all 80 patients remained nonviremic after LT. However, at the time of last follow‐up, 18 patients (22.5%) were HBsAg‐positive, and they included 10 patients in whom this marker reappeared after being initially undetectable after LT. Longer follow‐up is required to assess whether these patients will clear HBsAg from serum or, as happened with LAM, will develop virological breakthrough and histological hepatitis. More recently, Gane et al.21 showed an absence of HBV recurrence (HBsAg negativity and HBV DNA undetectability) among 18 patients with serum HBV DNA levels < 3 log₁₀ IU/mL at the time of LT who received combined LAM and ADV therapy from the time of listing without any HBIG administration. In agreement with the authors, the LAM/ADV regimen is most likely to be replaced by LAM/TDF or Truvada. Until then, HBIG‐free prophylaxis with antiviral agents cannot be recommended to all patients undergoing LT for HBV infection. The most awaited unfulfilled need would be a randomized comparison of pre‐ and post‐LT antiviral monotherapy with ETV or TDF with combination prophylaxis using these same agents and a short course (1‐4 weeks) of HBIG.

Figure 1.

Immunoprophylaxis regimens for preventing HBV recurrence. *Only for patients with HBV replication. **Proposed on the basis of data reported by McGory et al.13

Overall, prophylactic strategies should be individualized according to the risk of HBV recurrence. High‐risk groups are those with active HBV replication at the time of OLT (HBeAg positivity and elevated HBV DNA and HBsAg serum levels), infections with drug‐resistant variants, hepatitis delta virus or human immunodeficiency virus coinfections, and an elevated risk of recurrence of hepatocellular carcinoma. At present, combined therapy with NUCs and low‐dose HBIG appears to be the most effective strategy for preventing HBV recurrence. It is unclear whether there is a subset of high‐risk patients who may benefit from more intense prophylaxis. New alternative regimens should be investigated in low‐risk patients with nonreplicating HBV and an absence of other comorbidities that may affect the outcome of HBV recurrence.

Abbreviations.

ADV

adefovir dipivoxil

anti‐HBs

antibody to hepatitis B surface antigen

ETV

entecavir

HBIG

hepatitis B immunoglobulin

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

IM

intramuscular

IV

intravenous

LAM

lamivudine

LT

liver transplantation

NUC

nucleos(t)ide analogue

OLT

orthotopic liver transplantation