HEPATITIS B: THERAPEUTICS (P MARTIN, SECTION EDITOR)

Management of Patients with Chronic Hepatitis BBefore and After Liver Transplantation: An Update

Andres F. Carrion & Paul Martin & Christopher O’Brien

Published online: 10 March 2012# Springer Science+Business Media, LLC 2012

Abstract The use of newer and more potent antiviral agentsagainst hepatitis B virus (HBV) results in greater viralsuppression; however, liver transplantation is still requiredfor complications of HBV infection. Post-transplant out-comes for HBV-related disorders are currently comparableto or slightly better than for other indications for livertransplantation in adults in the United States. In the absenceof prophylactic antiviral therapy, recurrent HBV infectionoccurs invariably in patients with detectable serum HBV-deoxyribonucleic acid (DNA) at the time of transplantation,leading to poorer outcomes with severe graft injury, reducedpatient and allograft survival. Therefore, anti-HBV therapyis indicated in all patients with detectable serum HBV-DNApre-transplantation and prophylactic therapy to prevent re-current HBV infection is standard-of-care. This review sum-marizes available evidence for the use of different antiviralagents before liver transplantation, the effectiveness of pro-phylactic agents in preventing recurrent HBV infection post-liver transplantation, and the efficacy of several regimens fortreating recurrent HBV infection post-liver transplantation.

Keywords Hepatitis B . Cirrhosis . Liver transplantation

Introduction

Hepatitis B virus (HBV) infection remains a global chal-lenge. Approximately 400 million people worldwide havechronic hepatitis B, defined as persistence of serum hepatitisB surface antigen (HBsAg) for greater than 6 months [1].There are important geographic variations in the incidenceand prevalence of the disease with China, Southeast Asia,Western Pacific and sub-Saharan Africa being considered“hyperendemic” areas for HBV infection [1, 2]. Data fromthe Centers for Disease Control and Prevention (CDC)indicate that 800,000–1.4 million people in the UnitedStates have chronic HBV infection; nevertheless, these esti-mates often exclude incarcerated populations and do nottake into account recent immigration of individuals fromendemic areas [3]. Therefore, the actual prevalence ofchronic HBV infection in the United States may be as highas 2 million people when these populations are included [4].The incidence of acute HBV infection in the United Stateshowever, continues to steadily decline as a result of HBVvaccination [5]. In 2009, the CDC recorded the lowestincidence ever of acute HBV infection: 1.1 per 100,000people. Importantly, these data do not include asymptomaticpatients and cases not reported to infection control authori-ties, thus the actual incidence of acute HBV infection maystill be ten-fold higher than recorded [6].

Over the past 20 years, seven agents have been licensedfor treatment of chronic HBV infection: interferon alfa-2b,lamivudine, adefovir, entecavir, peginterferon alfa-2a, telbi-vudine, and tenofovir. The use of newer, more potent anti-viral agents with lower rates of drug resistance has resultedin greater viral suppression, less frequent and more tolerable

A. F. Carrion (*)University of Miami Miller School of Medicine,Miami Veterans Affairs Medical Center,1201 NW 16th Street, Office B-1039,Miami, FL 33125, USAe-mail: acarrionmonsalve@med.miami.edu

P. Martin :C. O’BrienUniversity of Miami Miller School of Medicine,1500 NW 12th Avenue, Suite 1101-E,Miami, FL 33136, USA

P. Martine-mail: pmartin2@med.miami.edu

C. O’Briene-mail: cobrien@med.miami.edu

Curr Hepatitis Rep (2012) 11:102–110DOI 10.1007/s11901-012-0128-4

side effects [7–9]. Liver transplantation is however, stillrequired for complications of HBV infection, notablydecompensated cirrhosis, acute liver failure, and hepatocel-lular carcinoma. Data from the United Network for OrganSharing (UNOS) show that 4.2 % of 113,927 patients listedfor liver transplantation in the United States between 1985and 2006 had chronic HBV infection [10••]. These data alsoshow a steady decline in the number of patients with chronicHBV infection listed for liver transplantation due to acuteliver failure and end-stage liver disease; in contrast, thenumber of patients with hepatitis B listed for liver transplan-tation with hepatocellular carcinoma continues to rise [10••,11•]. Post-liver transplant outcomes for HBV-related disor-ders are currently comparable to or slightly better than forother indications for liver transplantation in adults in theUnited States, which contrasts to an earlier era when recur-rent HBV post-liver transplant was typical [12]. In theabsence of prophylactic therapy, recurrent HBV infectionoccurred almost invariably in patients with detectable serumHBV-deoxyribonucleic acid (DNA) at the time of transplan-tation, leading to poorer outcomes with severe graft injury,reduced patient and allograft survival [13–15]. Therefore,anti-HBV therapy is indicated in all patients with detectableserum HBV-DNA pre-transplantation [16].

Recurrent HBV infection after liver transplantation hastypically been defined as reappearance of HBsAg in theserum, although polymerase chain reaction (PCR) assayscan detect HBV-DNA even before HBsAg is identified[17]. Some investigators have suggested that presence oflow levels of serum HBV-DNA after liver transplantationmay in fact not reflect recurrent infection of the allograft andinstead, only denote a transient phenomenon not associatedwith HBV recurrence on follow up [17, 18]. Although theclinical significance of this serologic profile (detectableHBV-DNA and negative HBsAg) is yet to be elucidated,indefinite antiviral prophylaxis after liver transplantationremains the strategy of choice to prevent HBV recurrence.

Management of Hepatitis B Before LiverTransplantation

Current guidelines endorse the use of anti-HBV therapy inpatients with cirrhosis and detectable HBV-DNA but there isa minor discrepancy between the European and AmericanAssociations for the Study of Liver Disease (EASL andAASLD, respectively) with respect to the threshold levelsof HBV-DNA and alanine aminotransferase (ALT) to starttreatment [19, 20]. EASL recommends treating patients withchronic HBV infection and compensated cirrhosis with anylevel of circulating serum HBV-DNA, even if ALT levelsare normal, whereas the AASLD recommends initiatingantiviral therapy in this population when HBV-DNA levels

are greater than 2,000 IU/mL or the ALT is elevated [19,20]. Both societies endorse initiation of oral anti-HBVtherapy in all patients with decompensated cirrhosis, assignificant clinical improvement may be associated withsuppression of viral replication. Patients with decompen-sated cirrhosis should also be referred for evaluation forliver transplantation because some patients with advanceddisease will not improve despite potent antiviral therapy [19,20]. Antiviral therapy for patients awaiting liver transplan-tation is intended to suppress HBV replication and to reducethe risk of recurrent HBV infection of the allograft. The useof anti-HBV therapy in this population may also result inclinical stabilization of the liver disease and even delay orprevent liver transplantation in some patients, although thisis not invariable [21]. Effective suppression of viral replica-tion is associated with improved hepatocellular functionwith normalization of serum markers of necroinflammationsuch as ALT as well as indices of synthetic function such asalbumin, bilirubin, and prothrombin time [21]. Additionally,rapid and prolonged suppression of HBV-DNA pre-transplant improves survival rates up to 87 % at 3 yearspost-liver transplantation (compared to historical data show-ing 44 % survival at 3 years in patients with untreated HBVinfection) [13, 21]. Nevertheless, there is no consensusabout the optimal antiviral regimen for HBV prior to livertransplantation.

Experience with lamivudine in patients with decompen-sated cirrhosis awaiting liver transplantation is extensiveand the safety profile of this agent has been well character-ized. Nevertheless, development of lamivudine resistance isa major concern, as a significant proportion of virologicbreakthrough (91 %) during therapy with this agent is dueto mutations in the tyrosine-methionine-aspartate-aspartate(YMDD) motif of the HBV-DNA polymerase gene [22, 23].Importantly, development of YMDD mutants has beenassociated with progression of liver disease and pooreroutcomes [24].

Adefovir is a nucleotide reverse transcriptase as well asDNA polymerase inhibitor with activity against wild typeand lamivudine resistant HBV strains [25]. Data from anopen-label multicenter study of 226 wait-listed patients withlamivudine-resistant HBV treated with adefovir indicatedcomplete viral suppression (undetectable HBV-DNA) at 48and 96 weeks in 59 % and 65 % of patients, respectively[21]. HBV viremia at baseline is an important determinantof successful suppression of viral replication. For instance,82 % of wait-listed patients with baseline serum HBV-DNAgreater than or equal to 5 log10 copies/mL treated withadefovir who had lamivudine resistance had reductions ofmore than 3 log10 copies/mL by week 48 compared topatients with less than 5 log10 copies/mL at baseline whohad 100 % undetectable HBV-DNA during the same followup period [21]. Some data support the efficacy of combination

Curr Hepatitis Rep (2012) 11:102–110 103

therapy with adefovir and lamivudine, which may increaseviral suppression and reduce adefovir resistance compared toadefovir monotherapy [26, 27]. Antiviral therapy with adefo-vir not only suppresses viral replication but also results innormalization of ALT, bilirubin, prothrombin time, and albu-min level in 60 % to 84 % of wait-listed patients after48 weeks. [21]. Importantly, viral suppression is also reflectedin a median reduction of −2 points in the Child-Turcotte-Pugh(CTP) and Model for End-stage Liver Disease (MELD)scores. The median survival for wait-listed patients (38 %patients were CTP class B, and 22 % were CTP class C)treated with adefovir was 86 % and 78 % at 48 and 96 weeks,respectively [21]. Adefovir therapy before liver transplanta-tion was associated with side effects in 19 % of patientsincluding increased serum creatinine (≥0.5 mg/dL) in approx-imately 6 % of patients [21]. Impaired renal function inpatients taking adefovir is of particular concern as this agentis nephrotoxic and dose reductions are required when thecreatinine clearance is less than 50 mL/minute [25]. Thestandard dose of adefovir in patients with normal renal func-tion (10 mg orally, daily) confers relatively weak antiviralactivity and reductions below this dose due to renal impair-ment may further decrease its antiviral activity [28]. There-fore, potent antiviral agents such as entecavir and tenofovir arepreferred for treating chronic HBV infection before livertransplantation [20].

Entecavir and tenofovir are currently the appropriate firstline agents for treating HBV infection in both non-cirrhoticas well as cirrhotic patients due to their enhanced antiviralactivity, excellent side effect profile, and high barriers toresistance [20, 29]. Entecavir is the most potent nucleosideanalog licensed for the treatment of HBV infection [30].Resistance to this agent was not observed in nucleoside-naïve non-transplant patients treated for 48 weeks in twolarge multicenter studies and no nephrotoxicity was reported[7, 8]. Entecavir is effective in suppressing HBV-DNA incompensated and decompensated cirrhotic patients naïve totreatment after 12 months of therapy (baseline MELD scores7 and 11.5, respectively; baseline CTP scores 5.3 and 8.1,respectively) [31••]. Entecavir (0.5 mg orally, daily) therapyfor 12 months results in viral suppression in 81.3 % and92.7 % of patients with compensated and decompensatedcirrhosis, respectively [31••]. Although entecavir is generallywell tolerated in decompensated cirrhosis, lactic acidosis hasbeen reported as a rare complication [32–35]. Lactic acido-sis reflects mitochondrial toxicity and all nucleos(t)ideanalogues licensed for treating HBV and human immuno-deficiency virus (HIV) infection have a “Black Box” warn-ing. Although the warning was initially based on lacticacidosis occurring in HIV-infected patients treated withnucleos(t)ide analogues, subsequent reports also describedthis complication in patients with HBV infection treatedwith these agents [36, 37]. A report of five cases of lactic

acidosis in patients with HBV infection treated with enteca-vir suggests a correlation between the MELD score and thiscomplication as it occurred only in patients with MELDscores >20 [34••]. Importantly, lactic acidosis may occuras late as 1 year after initiation of treatment and impairedliver and/or renal function may increase the risk of thiscomplication (despite dose-adjustments based on creatinineclearance) as the liver and kidneys are the main organsresponsible for clearance of lactate [34••]. The risk of lacticacidosis may also be increased with concomitant use ofdrugs that inhibit mitochondrial oxidation such as metfor-min, some anti-HIV agents (zidovudine, stavudine, didano-sine, zalcitabine), tetracyclines, valproic acid, amiodarone,salicylic acid, buprenorphine, tamoxifen, and ethanol [38].Other cofactors associated with an increased risk of mito-chondrial toxicity and development of lactic acidosis areolder age, female gender, pregnancy, malnutrition, andgenetic differences in phosphorylation of nucleos(t)ideanalogues [38–41].

Tenofovir is a nucleotide reverse transcriptase inhibitorthat was originally licensed for the treatment of HIVand wassubsequently licensed for the treatment of both nucleos(t)ide-naïve and lamivudine-resistant chronic HBV infection[9]. This agent is structurally similar to and has comparableantiviral activity to adefovir (on a molar basis), thus thehigher efficacy of tenofovir 300 mg compared to adefovir10 mg [42, 43]. Tenofovir is an effective and relatively safenucleotide reverse transcriptase inhibitor for treating HBVinfection in patients with decompensated cirrhosis. Recentdata from a phase II randomized clinical trial evaluating thesafety of tenofovir in this population showed equivalenttolerability of this agent compared to entecavir [32]. Teno-fovir (300 mg orally, daily) monotherapy and in combina-tion with emtricitabine (200 mg orally, daily) effectivelysuppressed viral replication in 70 % and 88 % of patientswith decompensated cirrhosis during 48 weeks of treatment,respectively. Additionally, 26 % of patients treated withtenofovir monotherapy and 48 % of patients treated withtenofovir/emtricitabine experienced a reduction of ≥2 pointsin the CTP score [32]. Initial concerns about nephrotoxicityin patients taking tenofovir were supported by structuralsimilarities of tenofovir to adefovir and cidofovir, twoagents known to cause acute kidney injury due to mitochon-drial tubular dysfunction, acute tubular necrosis, and Fanconi’ssyndrome [44]. Although pre- and post-marketing data sup-ported the safety of tenofovir in the treatment of HIV, includ-ing the absence of nephrotoxicity, subsequent reportsdescribed several cases of acute tubular necrosis and Fanconi’ssyndrome (both largely reversible after discontinuation oftenofovir) associated with this agent [45]. Concerns aboutbone demineralization as a metabolic side effect of tenofovirhave also emerged from retrospective data of patients withHIV treated with this agent [46]. However, evidence

104 Curr Hepatitis Rep (2012) 11:102–110

confirming an association between tenofovir and clinicallyimportant outcomes such as bone fractures in patients withHBV infection treated with this agent is absent. Data from arecent prospective study with extended follow up show thatbone fractures occurred infrequently (0.8 % to 1.7 % per year)during anti-HBV treatment with tenofovir and none wereactually considered related to this agent [47].

Prevention and Treatment of Recurrent Hepatitis BAfter Liver Transplantation

Prevention of Hepatitis B Recurrence After LiverTransplantation

In the absence of suppressive antiviral therapy, patients withactive hepatitis B undergoing liver transplantation almostinvariably develop recurrence in the graft post-transplant.Recurrent HBV infection after liver transplantation resultsfrom reinfection of the allograft by circulating virions fromextrahepatic sites and was previously associated with highrates of graft loss and poor patient survival [48]. ActiveHBV replication and a direct cytotoxic effect of the virusdue to post-transplant immunosuppression account for theaggressive clinical course of the disease in this setting [49].

Initial prophylactic regimens against recurrent HBV in-fection consisted of monotherapy with hepatitis B immuneglobulin (HBIG), a polyclonal preparation of human anti-HBs purified from pooled donor plasma. Data from a mul-ticenter retrospective study of 334 patients with detectableHBsAg who underwent liver transplantation show that long-term prophylaxis (>6 months) with parenteral HBIG signif-icantly reduced HBV recurrence to 33 % compared to 75 %in patients not receiving prophylaxis during a mean followup period of 24 months post-transplant [50]. Long-termprophylaxis with parenteral HBIG however, is associatedwith major cost. Furthermore, development of resistantmutants has also been reported [51]. Additionally the effi-cacy of HBIG in preventing HBV recurrence after livertransplantation is dependent on the level of HBV replicationpre-transplant, the dose of HBIG, and duration of therapy[52]. The efficacy of short-term (<2 months) prophylaxiswith HBIG for prevention of HBV recurrence post-transplant was also evaluated; however, recurrence rateswere comparable to those of patients that did not receiveprophylaxis [50]. The standard HBIG dose is 10,000 IUadministered intravenously during the anhepatic phase fol-lowed by daily doses throughout the first week post-transplantation. The frequency of subsequent doses can beadjusted according to anti-HBs serum titers (>100 IU/L isthought to be an adequate protective level) [53].

Monoprophylaxis with either HBIG or lamivudine resultsin diminished HBV recurrence rates and HBV-related

mortality after liver transplantation [54]. Recurrence inpatients taking lamivudine monotherapy may be as low as10 % [55, 56]. Unfortunately lamivudine does not eradicateHBV and patients require indefinite suppressive therapywith this agent, which is associated with development ofviral resistance in up to 70 % of patients during the initial5 years of therapy [28]. Importantly, lamivudine resistancemay accelerate progression of the disease and/or increasethe frequency of hepatitis flares, which are risk factors forhepatic decompensation [57]. The combination of HBIGand lamivudine prophylaxis has independent but synergisticeffects and reduces HBV recurrence to less than 5 % at 1 yearof follow up [54, 58, 59]. Combination prophylactic therapy isalso associated with significant improvements in clinicallyimportant outcomes such as graft survival, all-cause andHBV-related mortality [60, 61]. Therefore, post-liver trans-plantation prophylaxis with HBIG and lamivudine became thestandard of care for prevention of HBV recurrence [62].

The economic burden and inconvenience associated withintravenous HBIG motivated investigators to study differentregimens and routes of administration of this agent. Datafrom a retrospective study show that low-dose intramuscularHBIG (400–800 IU daily for 1 week and monthly thereafter)plus lamivudine provides effective prophylaxis againstHBV recurrence (1 % and 4 % recurrence at 1 and 5 yearspost-liver transplant, respectively) at a small fraction(<10 %) of the cost of high-dose HBIG [62]. The efficacyand safety of subcutaneous administration of a novel formu-lation of HBIG was recently evaluated in Europe in a phase IIIstudy. Post-liver transplant patients self-injected this agentweekly at home for 18 weeks (500 IU for patients <75 kgand 1,000 IU for patients ≥75 kg) and all of them had thera-peutic anti-HBs levels (>100 IU/L) during a follow up periodof 4 months [63•]. These data suggest that subcutaneousself-injection of HBIG may be an effective alternative toreducing costs associated with intravenous or intramuscularadministration of this agent.

A systematic review suggested that HBIG plus adefovirmay be more effective than HBIG plus lamivudine in reduc-ing HBV recurrence [64•]. The addition of adefovir toprophylactic therapy with HBIG plus lamivudine furtherdecreases the risk of HBV recurrence after liver transplan-tation to 2 % compared to 6.1 % with HBIG plus lamivu-dine. When lamivudine was excluded from this tripleregimen, the combination of HBIG plus adefovir remainedeffective [64•]. Adefovir was also studied in combinationwith lamivudine in a randomized, open-label, multicentertrial showing equivalent prophylactic efficacy against recur-rent HBV infection when compared to HBIG plus lamivu-dine but at a significantly lower economic cost [65]. Out of15 patients in each arm of the study, none had HBV recur-rence (defined as detectable HBsAg and HBV-DNA); nev-ertheless, one patient in the adefovir/lamivudine arm had a

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low HBsAg titer (0.05 IU/mL) at 5 months of follow up butHBV-DNA remained undetectable over 20 months of followup [65].

There are not extensive data to date supporting prophy-lactic use of entecavir or tenofovir post-liver transplantationfor preventing HBV recurrence. Data from two small case–control studies showed no recurrences of HBV in a total of93 post-liver transplant patients treated with HBIG plusentecavir (0.5 mg orally, daily) compared to 9.5 % – 11 %in patients treated with HBIG plus lamivudine [66, 67••]. Arecent cohort study evaluating entecavir monoprophylaxisafter liver transplantation in patients with chronic hepatitis Bdemonstrated clearance of HBsAg in 86 % and 91 % ofpatients after 1 and 2 years of follow up, respectively [68].None of the patients treated with entecavir received HBIG atthe time of transplantation or during the post-transplantperiod. The cumulative rate of recurrence of HBsAg afterinitial clearance was 11.6 % at 1 year and 13.7 % at 2 years.Importantly, however, 17 out of the 18 (94 %) patients withHBsAg recurrence remained HBV-DNA negative on con-tinued entecavir therapy. Patients without HBV recurrencepost-transplant had significantly lower HBsAg levels butsimilar HBV-DNA levels at the time of transplantation. Noside effects attributable to entecavir were reported during amedian follow up of 26 months [68]. Although entecavir isassociated with low rates of resistance in nucleoside-naïvepatients, this agent should be avoided in lamivudine-experienced patients, in whom tenofovir is a better optionby extrapolating data from the non-transplant setting wherelamivudine resistance is associated with high probabilitiesof entecavir resistance [68–70]. Results from a single-center,retrospective study show a recurrence rate of 4.8 % in 41patients treated with lamivudine plus tenofovir during amean follow up of 15 months after discontinuation of HBIG[71••].

Data from a small study of 37 patients evaluating theefficacy of the combination of emtricitabine/tenofovir withand without HBIG (after 24 weeks of initial therapy with

HBIG) showed no HBV recurrence post-liver transplanta-tion in both groups after 48 weeks of follow up. Importantly,all patients that completed the study had some degree ofrenal impairment (73 % had creatinine clearance 50–80 mL/min and 27 % had creatinine clearance 30–49 mL/min) butnone experienced progressive deterioration of renal functionand treatment was, in general, well tolerated [72••].

Telbivudine is another nucleoside analog. Although theresistance profile of telbivudine is better than lamivudine,monotherapy with this agent is associated with moderateresistance and thus it should not be used as a single agent forHBV prophylaxis post-liver transplantation [73, 74].

The efficacy of different prophylactic regimens againstrecurrent HBV infection post-liver transplantation is sum-marized in Table 1.

Treatment of Recurrent Hepatitis B Infection After LiverTransplantation

Lamivudine was evaluated in a multicenter study of 52patients with established recurrent HBV infection post-liver transplantation. After 48 weeks of treatment with thisagent, 60 % of patients had undetectable serum HBV-DNAlevels [75]. Subsequent smaller studies have also replicatedthis outcome in post-liver transplant patients treated withlamivudine [76, 77]. Importantly, antiviral therapy withlamivudine is associated with regression of histologicchanges in patients with recurrent HBV infection post-livertransplantation. Patients treated with lamivudine for24 weeks had significant improvement in total Knodellhistological activity index score and each of its componentsexcept fibrosis [75]. Virologic breakthrough due to YMDDmutants occurred in 27 % of post-liver transplant patientswith recurrent HBV infection treated with lamivudine with amedian time to development of resistance of 32 weeks [75].This proportion of patients with YMDD mutations is onlyslightly higher than in non-transplant patients after 1 year oflamivudine therapy (24 %), perhaps reflecting a higher risk

Table 1 Efficacy of different prophylactic regimens for the prevention of recurrent hepatitis B post-liver transplantation

Prophylactic agent(s) Recurrence rate Mean/median follow up Type of study Reference

None >75 % 2 years Retrospective cohort Samuel D, et al. [50]

HBIG 33 % 2 years Retrospective cohort Samuel D, et al. [50]

Lamivudine 10 % 14 months Randomized trial Katz LH, et al. [55]

HBIG/Lamivudine 0 % 1 year Prospective cohort Markowitz JS, et al. [58]; Han SH, et al. [59]

HBIG/Adefovir 2 % 21 months Systematic review Cholongitas E, et al. [64•]

HBIG/Entecavir 0 % 41 months Case control Xi ZF, et al. [66];

Cai CJ, et al. [67••]

Entecavir 1.2 % 2 years Prospective cohort Fung J, et al. [68]

Tenofovir/Lamivudine 4.8 % 15 months Retrospective cohort Saab S, et al. [71••]

Tenofovir/Emtricitabine 0 % 1 year Randomized trial Taperman L, et al. [72••]

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of mutation due to enhanced viral replication in immunosup-pressed patients [78, 79]. Higher rates of lamivudine resistantmutants are anticipated with longer treatment. Implications ofdevelopment of YMDD mutants are increased viral replica-tion and clinical exacerbation of liver disease; [80] neverthe-less, histologic improvement may be comparable in patientswith and without lamivudine resistant mutants based ondata from non-liver transplant patients [81].

Data from a prospective, open-label, compassionate-usestudy of post-liver transplant patients with lamivudine-resistant recurrent HBV infection treated with adefovir(10 mg orally, daily) show undetectable HBV-DNA levelsin 40 % of patients after 48 weeks of therapy (mean changeof HBV-DNA level from baseline −4.0 log10 copies/mL)[21]. Longer therapy with adefovir seems to increase theproportion of patients with undetectable HBV-DNA. Thiswas observed in 65 % and 78 % of patients at 96 and144 weeks of follow up, respectively [21]. Importantly,serologic markers of liver function also improved over timeduring adefovir therapy with normalization of albumin andprothrombin time in 81 % and 56 % of patients, respectively.Improvements were also evidenced in the CTP score andpatients with baseline classes B and C had a median changein their CTP scores of −3 points at week 48 [21]. Adefovirtherapy may also benefit liver transplant recipients withlamivudine-resistant HBV recurrence after liver transplanta-tion as shown by survival rates of 91 % by week 48, 88 %by week 96, and 87 % by week 144 [21]. Although dataabout emergence of adefovir-resistant mutants post-livertransplantation are scarce, concerns persist [82]. The largeststudy to date evaluating adefovir therapy in post-liver trans-plant patients with recurrent HBV infection indicated cumu-lative probabilities of developing adefovir resistance (inpatients with known lamivudine resistance treated with ade-fovir monotherapy) of 0 % by week 48, 2 % by week 96,and 2 % by week 144 [21].

The efficacy and safety of tenofovir for treatment of HBVinfection in non-transplant patients (including patients withlamivudine-resistant HBV) is clear [30, 47]. There are how-ever, limited data about the efficacy of this agent in thetreatment of recurrent HBV infection post-liver transplanta-tion. Nevertheless, data from a retrospective review of8 patients with lamivudine-resistant HBV infection treatedwith tenofovir (300 mg orally, daily) plus lamivudine isencouraging. Seven out of 8 (88 %) patients had undetect-able HBV-DNA after a median treatment time of 5 monthsand renal function remained unchanged in all patients after amedian treatment period of 19 months [83]. Similar resultssupporting the efficacy of tenofovir in combination withentecavir were described in a report of four cases of HBVrecurrence post-liver transplantation successfully treatedwith this regimen [84]. These results, although encouraging,need to be confirmed by larger prospective studies.

Conclusions

Prevention of graft reinfection following liver transplanta-tion has been a major advance in the management ofHBV. Antiviral therapy against HBV before liver trans-plantation has demonstrated efficacy in improving hepaticfunction and may obviate the need for transplantation insome patients. Newer antiviral agents offer significantbenefits by overcoming HBV resistance to lamivudineand by having better side effect profiles. As data support-ing favorable safety profiles of potent antiviral agentssuch as entecavir and tenofovir in patients with decom-pensated liver disease continues to emerge, these agentsare expected to be used more frequently in patients await-ing liver transplantation.

Combination therapy with HBIG and antiviral agentssignificantly reduces the risk of recurrent HBV infectionafter liver transplantation. Although the optimal combina-tion is yet to be established, emerging data support the useof newer agents. The economic burden created by HBIGalong with the efficacy of entecavir monotherapy make thelatter agent an attractive therapeutic option in patients with-out lamivudine resistance. In patients with lamivudine re-sistance however, tenofovir may be the agent of choice.Emerging data support the efficacy of HBIG-free prophy-lactic regimens after liver transplantation; nevertheless, it ispremature to change clinical practice and the efficacy ofthese therapies must be corroborated by well-designed ran-domized clinical trials.

Disclosure Dr. Carrion and Dr. O’Brien have no conflict of interest;Dr. Martin is a consultant for Bristol-Myers Squibb and Gilead, hasreceived grants from Gilead.

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