Journal of Hepatology 50 (2009) 227–242 www.elsevier.com/locate/jhep EASL Clinical Practice Guidelines: Management of chronic hepatitis B European Association for the Study of the Liver*Keywords: Hepatitis B virus; EASL guidelines; Treatment; Interferon alpha; Nucleoside/nucleotide analogues1. Introduction ease or HCC are responsible for over 1 million deaths per year and currently represent 5–10% of cases of liver Our understanding of the natural history of hepatitis B transplantation [2–5]. Host and viral factors, as well asvirus (HBV) infection and the potential for therapy of the coinfection with other viruses, in particular hepatitis Cresultant disease has improved. Several new and eﬀective virus (HCV), hepatitis D virus (HDV), or human immu-antiviral agents have been evaluated and licensed since the nodeﬁciency viru s (HIV) together with other co-mor-EASL International Consensus Conference on hepatitis B bidities including alcohol abuse and overweight, canheld in 2002 . The objective of these EASL Clinical aﬀect the natural course of HBV infection as well asPractice Guidelines (CPGs) is to update recommenda- the eﬃcacy of antiviral strategies.tions for the optimal management of chronic hepatitis B CHB may present either as hepatitis B e antigen(CHB). The CPGs do not focus on prevention and vacci- (HBeAg)-positive or HBeAg-negative CHB. HBeAg-nation. Several diﬃculties remain in formulating treat- positive CHB is due to so-called ‘‘wild type” HBV. Itments for CHB; thus areas of uncertainty exist. At the typically represents the early phase of chronic HBVpresent time clinicians, patients and public health author- infection. HBeAg-negative CHB is due to replicationities must continue to make choices on the basis of evi- of naturally occurring HBV variants with nucleotidedence that is not fully matured. substitutions in the precore and/or basic core promoter regions of the genome and represents a later phase of2. Context chronic HBV infection. The prevalence of the HBeAg- negative form of the disease has been increasing over2.1. Epidemiology and public health burden the last decade as a result of HBV-infected population aging and represents the majority of cases in many Approximately one third of the world’s population areas, including Europe [6–8].has serological evidence of past or present infection with Morbidity and mortality in CHB are linked to persis-HBV and 350 million people are chronically infected. tence of viral replication and evolution to cirrhosis orThe spectrum of disease and natural history of chronic HCC. Longitudinal studies of patients with CHB indi-HBV infection is diverse and variable, ranging from a cate that, after diagnosis, the 5-year cumulative inci-low viremic inactive carrier state to progressive chronic dence of developing cirrhosis ranges from 8 to 20%.hepatitis, which may evolve to cirrhosis and hepatocellu- The 5-year cumulative incidence of hepatic decompensa-lar carcinoma (HCC). HBV-related end stage liver dis- tion is approximately 20% with the 5-year probability of Contributors: Clinical Practice Guidelines Panel: Patrick Marcellin, Geoﬀrey Dusheiko, Fabien Zoulim, Rafael Esteban, Stefanos Hadzi- * EASL oﬃce, 7 rue des Battoirs, CH 1205 Geneva, Switzerland. yannis, Pietro Lampertico, Michael Manns, Daniel Shouval, CihanTel.: +41 22 807 0360; fax: +41 22 328 0724. Yurdaydin; Reviewers: Antonio Craxi, Xavier Forns, Darius Morad- E-mail address: easloﬃce@easloﬃce.eu pour, Jean-Michel Pawlotsky, Joerg Petersen, Heiner Wedemeyer.0168-8278/$34.00 Ó 2009 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.doi:10.1016/j.jhep.2008.10.001
228 European Association for the Study of the Liver / Journal of Hepatology 50 (2009) 227–242survival being approximately 80–86% in patients with neously in 1–3% of cases per year, usually aftercompensated cirrhosis [4,9–13]. Patients with decompen- several years with persistently undetectable HBVsated cirrhosis have a poor prognosis with a 14–35% DNA .probability of survival at 5 years. The worldwide inci- (4) ‘‘HBeAg-negative CHB” may follow seroconver-dence of HCC has increased, mostly due to HBV and sion from HBeAg to anti-HBe antibodies duringHCV infections; presently it constitutes the ﬁfth most the immune reactive phase and represents a latercommon cancer, representing around 5% of all cancers. phase in the natural history of CHB. It is charac-The annual incidence of HBV-related HCC in patients terized by periodic reactivation with a pattern ofwith CHB is high, ranging from 2% to 5% when cirrho- ﬂuctuating levels of HBV DNA and aminotrans-sis is established . However, the incidence of HBV- ferases and active hepatitis. These patients arerelated HCC appears to vary geographically and corre- HBeAg-negative, and harbour HBV variants withlates with the underlying stage of liver disease. nucleotide substitutions in the precore and/or the Population movements and migration are currently basal core promoter regions unable to express orchanging the prevalence and incidence of the disease in expressing low levels of HBeAg. HBeAg-negativeseveral low endemicity countries in Europe and else- CHB is associated with low rates of prolongedwhere. Substantial healthcare resources will be required spontaneous disease remission. It is importantfor control of the worldwide burden of disease. and sometimes diﬃcult to distinguish true inactive HBV carriers from patients with active HBeAg-2.2. Natural history negative CHB in whom phases of spontaneous remission may occur. The former patients have a Chronic hepatitis B is a dynamic process. The natural good prognosis with a very low risk of complica-history of CHB can be schematically divided into ﬁve tions, while the latter patients have active liver dis-phases, which are not necessarily sequential. ease with a high risk of progression to advanced hepatic ﬁbrosis, cirrhosis and subsequent compli- (1) The ‘‘immune tolerant” phase is characterized by cations such as decompensated cirrhosis and HBeAg positivity, high levels of HBV replication HCC. A careful assessment of the patient is needed (reﬂected by high levels of serum HBV DNA), nor- and a minimal follow-up of one year with serum mal or low levels of aminotransferases, mild or no alanine aminotransferase (ALT) and HBV DNA liver necroinﬂammation and no or slow progres- levels every 3 months usually allows detection of sion of ﬁbrosis [3,5]. During this phase, the rate ﬂuctuations of activity in patients with active of spontaneous HBeAg loss is very low. This ﬁrst HBeAg-negative CHB . phase is more frequent and more prolonged in sub- (5) In the ‘‘HBsAg-negative phase” after HBsAg loss, jects infected perinatally or in the ﬁrst years of life. low-level HBV replication may persist with detect- Because of high levels of viremia, these patients are able HBV DNA in the liver . Generally, HBV highly contagious. DNA is not detectable in the serum while anti- (2) The ‘‘immune reactive phase” is characterized by HBc antibodies with or without anti-HBs are HBeAg positivity, a lower level of replication (as detectable. HBsAg loss is associated with improve- reﬂected by lower serum HBV DNA levels), ment of the outcome with reduced risk of cirrhosis, increased or ﬂuctuating levels of aminotransfer- decompensation and HCC. The clinical relevance ases, moderate or severe liver necroinﬂammation of occult HBV infection (detectable HBV DNA and more rapid progression of ﬁbrosis compared in the liver with low-level [<200 international units to the previous phase [3,5]. It may last for several (IU)/ml] HBV DNA in blood) is unclear . weeks to several years. In addition, the rate of Immunosuppression may lead to reactivation in spontaneous HBeAg loss is enhanced. This phase these patients [17,18]. may occur after several years of immune tolerance and is more frequently reached in subjects infected during adulthood. 3. Methodology (3) The ‘‘inactive HBV carrier state” may follow sero- conversion from HBeAg to anti-HBe antibodies. It These EASL CPGs have been developed by a CPG is characterized by very low or undetectable serum Panel of experts chosen by the EASL Governing Board; HBV DNA levels and normal aminotransferases. the recommendations were peer-reviewed by external As a result of immunological control of the infec- expert reviewers and approved by the EASL Governing tion, this state confers a favourable long-term out- Board. The CPGs have been based as far as possible on come with a very low risk of cirrhosis or HCC in evidence from existing publications, and, if evidence was the majority of patients. HBsAg loss and serocon- unavailable, the experts’ personal experience and opin- version to anti-HBs antibodies may occur sponta- ion. Manuscripts and abstracts of important meetings
European Association for the Study of the Liver / Journal of Hepatology 50 (2009) 227–242 229published prior to August 2008 have been evaluated. erant phase have persistently normal ALT levels and aThe evidence and recommendations in these guidelines proportion of patients with HBeAg-negative CHB mayhave been graded according to the Grading of Recom- have intermittently normal ALT levels. Thereforemendations Assessment Development and Evaluation appropriate, longitudinal long-term follow-up is crucial.(GRADE) system. The strength of recommendationsthus reﬂects the quality of underlying evidence. The (1) The assessment of the severity of the liver diseaseprinciples of the GRADE system have been enunciated. should include: biochemical markers, includingThe quality of the evidence in these CPGs has been clas- aspartate aminotransferase (AST) and ALT,siﬁed in one of three levels: high (A), moderate (B) or gamma-glutamyl transpeptidase (GGT), alkalinelow (C). The GRADE system oﬀers two grades of rec- phosphatase, prothrombin time and serum albu-ommendation: strong (1) or weak (2) (Table 1). The min; blood counts; and hepatic ultrasound (A1).CPGs thus consider the quality of evidence: the higher Usually, ALT levels are higher than those of AST.the quality of evidence, the more likely a strong recom- However, when the disease progresses to cirrhosis,mendation is warranted; the greater the variability in the ratio may be reversed. A progressive decline invalues and preferences, or the greater the uncertainty, serum albumin concentrations and prolongationthe more likely a weaker recommendation is warranted of the prothrombin time, often accompanied by a[19–25]. drop in platelet counts, are characteristically The CPG Panel members considered the following observed after cirrhosis has developed.questions: (2) HBV DNA detection and HBV DNA level mea- surement is essential for the diagnosis, decision How should liver disease be assessed before therapy? to treat and subsequent monitoring of patients What are the goals and end-points of treatment? (A1). Follow-up using real-time PCR quantiﬁca- What are the deﬁnitions of response? tion assays is strongly recommended because of What is the optimal approach to ﬁrst-line treatment? their sensitivity, speciﬁcity, accuracy and broad What are the predictors of response? dynamic range [26–29] (A1). The World Health What deﬁnitions of resistance should be applied and Organization (WHO) has deﬁned an international how should resistance be managed? standard for normalisation of expression of HBV How should treatment be monitored? DNA concentrations . Serum HBV DNA lev- When can treatment be stopped? els should be expressed in IU/ml to ensure compa- How should special groups be treated? rability; the same assay should be used in the same What are the current unresolved issues? patient to evaluate antiviral eﬃcacy (A1). (3) Other causes of chronic liver disease should be sys-4. Guidelines tematically looked for including coinfection with HDV, HCV and/or HIV. Co-morbidities, includ-4.1. Pretherapeutic assessment of liver disease ing alcoholic, autoimmune, metabolic liver disease with steatosis or steato-hepatitis should be As a ﬁrst step, the causal relationship between HBV assessed (A1).infection and liver disease has to be established and an (4) A liver biopsy is recommended for determining theassessment of the severity of liver disease needs to be degree of necroinﬂammation and ﬁbrosis in patientsperformed. Not all patients with CHB have persistently with either increased ALT or HBV DNA levelselevated aminotransferases. Patients in the immune tol- 2000 IU/ml (or both) since hepatic morphologyTable 1Grading of evidence and recommendations (adapted from the GRADE system) [19–25] Notes SymbolGrading of evidenceHigh-quality evidence Further research is very unlikely to change our conﬁdence in the estimate of eﬀect AModerate-quality evidence Further research is likely to have an important impact on our conﬁdence in the estimate B of eﬀect and may change the estimateLow- or very low-quality evidence Further research is very likely to have an important impact on our conﬁdence in the C estimate of eﬀect and is likely to change the estimate. Any estimate of eﬀect is uncertainGrading of recommendationStrong recommendation warranted Factors inﬂuencing the strength of the recommendation included the quality of the 1 evidence, presumed patient-important outcomes, and costWeaker recommendation Variability in preferences and values, or more uncertainty: more likely a weak 2 recommendation is warranted. Recommendation is made with less certainty; higher cost or resource consumption
230 European Association for the Study of the Liver / Journal of Hepatology 50 (2009) 227–242 can assist the decision to start treatment (A1). This is associated with a complete and deﬁnitive Biopsy is also useful for evaluating other possible remission of the activity of chronic hepatitis B causes of liver disease such as steatosis or steato- and an improved long-term outcome (A1). hepatitis. Although liver biopsy is an invasive proce- (2) In HBeAg-positive patients, durable HBe serocon- dure, the risk of severe complications is very low (1/ version is a satisfactory end-point because it has 4,000–10,000). It is important that the size of the been shown to be associated with improved prog- needle biopsy specimen be large enough to precisely nosis (A1). analyse the degree of liver injury and ﬁbrosis  (3) In HBeAg-positive patients who do not achieve (A1). A liver biopsy is usually not required in HBe seroconversion, and in HBeAg-negative patients with clinical evidence of cirrhosis or in patients, a maintained undetectable HBV DNA those in whom treatment is indicated irrespective level on treatment with NUCs or a sustained unde- of the grade of activity or the stage of ﬁbrosis tectable HBV DNA level after interferon therapy (A1). There is growing interest in the use of non- is the next most desirable end-point (A1). invasive methods, including serum markers and transient elastography, to assess hepatic ﬁbrosis to complement or avoid a liver biopsy [32–36]. 4.4. Deﬁnitions of response4.2. Goal of therapy Two diﬀerent types of drugs can be used in the treatment of CHB: interferon alpha and nucleoside/ The goal of therapy for hepatitis B is to improve nucleotide analogues referred to collectively as NUCsquality of life and survival by preventing progression in this document. The deﬁnition of response toof the disease to cirrhosis, decompensated cirrhosis, antiviral therapy varies according to the type ofend-stage liver disease, HCC and death. This goal can therapy.be achieved if HBV replication can be suppressed in asustained manner, the accompanying reduction in histo- (1) On interferon alpha therapy:logical activity of chronic hepatitis lessening the risk of Primary non-response is deﬁned as less than 1cirrhosis and decreasing the risk of HCC in non-cir- log10 IU/ml decrease in HBV DNA level fromrhotic patients and probably also, but to a lesser extent, baseline at 3 months of therapy.in cirrhotic patients  (B1). However, HBV infection Virological response is deﬁned as an HBV DNAcannot be completely eradicated due to the persistence concentration of less than 2000 IU/ml at 24 weeksof covalently closed circular DNA (cccDNA) in the of therapy.nucleus of infected hepatocytes. Serological response is deﬁned by HBe serocon- version in patients with HBeAg-positive CHB.4.3. End-points of therapy (2) On NUC therapy: Primary non-response is deﬁned as less than 1 Therapy must reduce HBV DNA to as low a level as log10 IU/ml decrease in HBV DNA level frompossible, ideally below the lower limit of detection of baseline at 3 months of therapy.real-time PCR assays (10–15 IU/ml), to ensure a degree Virological response is deﬁned as undetectableof virological suppression that will then lead to HBV DNA by real-time PCR assay within 48biochemical remission, histological improvement and weeks of therapy.prevention of complications. Interferon alpha or nucle- Partial virological response is deﬁned as a decre-oside/nucleotide analogue (NUC) therapy-induced ase in HBV DNA of more than 1 log10 IU/ml butHBV DNA reduction to low levels is associated with dis- detectable HBV DNA by real-time PCR assay.ease remission. Sustained HBV DNA reduction to unde- A partial virological response should be assessedtectable levels is necessary to reduce the risk of to modify therapy at 24 weeks of treatment forresistance to NUCs. It also increases the chance of moderately potent drugs or drugs with a lowHBe seroconversion in HBeAg-positive patients and genetic barrier to resistance (lamivudine andthe possibility of HBsAg loss on the mid to long term telbivudine) and at 48 weeks of treatment forin HBeAg-positive and HBeAg-negative patients. If highly potent drugs, drugs with a higher geneticreal-time PCR is unavailable, HBV DNA should be barrier to resistance or drugs with a latemeasured by the most sensitive assay possible. emergence of resistance (entecavir, adefovir and tenofovir). (1) In HBeAg-positive and HBeAg-negative patients, Virological breakthrough is deﬁned as a the ideal end-point of therapy is sustained HBsAg conﬁrmed increase in HBV DNA level of more loss with or without seroconversion to anti-HBs. than 1 log10 IU/ml compared to the nadir (low-
European Association for the Study of the Liver / Journal of Hepatology 50 (2009) 227–242 231 est value) HBV DNA level on therapy; it usu- (1) In HBeAg-positive patients, virological response ally precedes a biochemical breakthrough, rates at one year (undetectable HBV DNA, deﬁned characterized by an increase in ALT levels. variously in the diﬀerent trials and diﬀerently from The main causes of virological breakthrough the present guidelines) were 25%, 36–40%, 21%, on NUC therapy are poor adherence to therapy 67%, 60% and 74% with pegylated interferon and selection of drug-resistant HBV variants alpha-2a/2b, lamivudine, adefovir, entecavir, (resistance) (A1). telbivudine and tenofovir, respectively (Fig. 1) HBV resistance to NUCs is characterized by [38–44]. HBe seroconversion rates were of the order selection of HBV variants with amino acid sub- of 30% with conventional and pegylated interferon stitutions that confer reduced susceptibility to alpha and approximately 20% for NUCs. HBe sero- the administered NUC(s). Resistance may result conversion rates increase with continued NUCs in primary treatment failure or virological treatment, but are aﬀected if resistance occurs breakthrough on therapy (A1). (B1). Loss of HBsAg rates after one year were 3– 4% with pegylated interferon alpha, 1% with lamivudine, 0% with adefovir, 2% with entecavir,4.5. Results of current therapies 0% with telbivudine, and 3% with tenofovir. (2) In HBeAg-negative patients, virological response Seven drugs are now available for the treatment of rates at one year (undetectable HBV DNA, deﬁnedchronic hepatitis B: they include conventional interferon variously in the diﬀerent trials and diﬀerently fromalpha, pegylated interferon alpha and NUCs. NUCs for the present guidelines) were 63%, 72%, 51%, 90%,HBV therapy belong to three classes: L-nucleosides 88% and 91% with pegylated interferon alpha-2a,(lamivudine, telbivudine, and emtricitabine), deoxygua- lamivudine, adefovir, entecavir, telbivudine andnosine analogues (entecavir) and acyclic nucleoside tenofovir, respectively (Fig. 2) [41,45–49]. Loss ofphosphonates (adefovir and tenofovir). Lamivudine, HBsAg rates after one year were 3% with pegylatedadefovir, entecavir, telbivudine and tenofovir have been interferon alpha and 0% with lamivudine, adefovir,approved in Europe for HBV treatment, and the combi- entecavir, telbivudine or tenofovir.nation of tenofovir and emtricitabine in one tablet hasbeen licensed for the treatment of HIV infection. The eﬃcacy of these drugs has been assessed in ran- 4.6. Indications for treatmentdomized controlled trials at one year (two years withtelbivudine). Longer-term results (up to 5 years) are The indications for treatment are generally the sameavailable for lamivudine, adefovir, entecavir, telbivu- for both HBeAg-positive and HBeAg-negative CHB.dine and tenofovir in patient subgroups. Figs. 1 and This is based mainly on the combination of three2 show response rates with these drugs from diﬀerent criteria:trials. These trials used diﬀerent HBV DNA assays Serum HBV DNA levels.and they were not head-to-head comparisons for all Serum aminotransferase levels.the drugs. Histological grade and stage. 100% HBe seroconversion Undetectable HBV DNA Normal ALT 90% 80% 77% 74% 68% 69% 70% 67% 66% 60% 60% 50% 48% 39% 39% 40% 30% 30% 25% 22% 21% 23% 21% 21% 20% 12% 10% 0% V V T F V V T F V V T F IFN LA M AD ET Ld TD IFN LA M AD ET Ld TD IFN LA M AD ET Ld TD G- G- G- PE PE PEFig. 1. Rates of HBe seroconversion, undetectable HBV DNA and normal ALT at one year of therapy with pegylated interferon alpha-2a (PEG-IFN),lamivudine (LAM), adefovir (ADV), entecavir (ETV), telbivudine (LdT) and tenofovir (TDF) in HBeAg-positive patients with CHB in randomizedclinical trials. These trials used diﬀerent HBV DNA assays and they were not head-to-head comparisons for all the drugs; thus, these numbers are onlyindicative and should be considered with caution.
232 European Association for the Study of the Liver / Journal of Hepatology 50 (2009) 227–242 Undetectable HBV DNA Normal ALT 100% 90% 91% 90% 88% 80% 78% 77% 72% 74% 72% 74% 70% 63% 60% 51% 50% 38% 40% 30% 20% 10% 0%Fig. 2. Rates of undetectable HBV DNA and normal ALT at one year of therapy with pegylated interferon alpha-2a (PEG-IFN), lamivudine (LAM),adefovir (ADV), entecavir (ETV), telbivudine (LdT) and tenofovir (TDF) in HBeAg-negative patients with CHB in randomized clinical trials. These trialsused diﬀerent HBV DNA assays and they were not head-to-head comparisons for all the drugs; thus, these numbers are only indicative and should beconsidered with caution. Patients should be considered for treatment when improvement can be associated with control of viralHBV DNA levels are above 2000 IU/ml (i.e. approxi- replication, but patients with very advanced liver dis-mately 10,000 copies/ml) and/or the serum ALT levels ease may not always beneﬁt if treated at this lateare above the upper limit of normal (ULN) for the lab- stage and should be considered for liver transplanta-oratory, and liver biopsy (or non-invasive markers when tion (A1).validated in HBV-infected patients) shows moderate tosevere active necroinﬂammation and/or ﬁbrosis using astandardised scoring system (for example at least grade 4.7. Predictors of responseA2 or stage F2 by METAVIR scoring) (A1). Indicationsfor treatment must also take into account age, health Certain general baseline and on-treatment predictorsstatus, and availability of anti-viral agents in individual of subsequent response have been identiﬁed. Predictorscountries. of response for the existing antiviral therapies at various The following special groups of patients should be time points vary for diﬀerent agents.considered: (1) For interferon alpha-based treatment: Immunotolerant patients: most patients under 30 Pre-treatment factors predictive of HBe serocon- years of age with persistently normal ALT levels version are low viral load (HBV DNA below 107 and a high HBV DNA level (usually above 107 IU/ IU/ml or 7 log10 IU/ml), high serum ALT levels ml), without any suspicion of liver disease and with- (above 3 times ULN), and high activity scores on out a family history of HCC or cirrhosis do not liver biopsy (at least A2) [50–52] (B2). require immediate liver biopsy or therapy. Follow- During treatment, an HBV DNA decrease to less up is mandatory (B1). than 20,000 IU/ml at 12 weeks is associated with a Patients with mild CHB: patients with slightly ele- 50% chance of HBe seroconversion in HBeAg-posi- vated ALT (less than 2 times ULN) and mild histo- tive patients and with a 50% chance of sustained logical lesions (less than A2F2 with METAVIR response in HBeAg-negative patients [53,54]. scoring) may not require therapy. Follow-up is man- During treatment, HBeAg decrease at week 24 datory (B1). may predict HBe seroconversion [54,55] (B2). Patients with compensated cirrhosis and detectable Further studies are needed to determine the role HBV DNA may be considered for treatment even of HBsAg quantitation to predict sustained vir- if ALT levels are normal and/or HBV DNA levels ological response and HBsAg loss. are below 2000 IU/ml (i.e. approximately 10,000 HBV genotype A and B have been shown to be copies/ml) (B1). associated with a better response to interferon Patients with decompensated cirrhosis require urgent alpha than genotypes C and D . However, the antiviral treatment. Rapid and profound viral sup- HBV genotype has a poor individual predictive pression and eﬃcacious prevention of resistance are value and currently, genotype alone should not particularly needed in this group. Signiﬁcant clinical override the choice of treatment (B2).
European Association for the Study of the Liver / Journal of Hepatology 50 (2009) 227–242 233 (2) For NUCs treatment: to achieve a sustained virological response oﬀ- Pre-treatment factors predictive of HBe serocon- treatment (A1). version are low viral load (HBV DNA below 107 Finite-duration treatment with pegylated IU/ml or 7 log10 IU/ml), high serum ALT levels interferon alpha: a 48-week course of pegylated (above 3 times ULN), high activity scores on interferon alpha is mainly recommended for liver biopsy (at least A2) . HBeAg-positive patients with the best chance During treatment with lamivudine, adefovir or of HBe seroconversion. It can also be used for telbivudine, a virological response at 24 or 48 HBeAg-negative patients who have the best weeks (undetectable HBV DNA in a real-time chance of a sustained response oﬀ-treatment. In PCR assay) is associated with a lower incidence both groups, these are patients with high base- of resistance, i.e. an improved chance of main- line ALT (3 times ULN) and HBV DNA less tained virological response, and HBe serocon- than 2 Â 106 IU/ml (approximately 107 copies/ version in HBeAg-positive patients [41,46,57] ml) or 6.3 log10 IU/ml at baseline. Full informa- (B1). tion about the advantages, adverse events and HBV genotype does not inﬂuence the response to inconveniences of pegylated interferon alpha any NUC. versus NUCs (Table 2) should be provided so the patient can participate in the decision (B2).4.8. Treatment strategies: how-to-treat The combination of pegylated interferon alpha with lamivudine showed a higher on-treatment The main theoretical advantages of interferon alpha response but did not show a higher rate of sus-(conventional or pegylated) are the absence of resistance tained response. There is limited information o-and the potential for immune-mediated containment of n the eﬃcacy and safety of combination ofHBV infection with an opportunity to obtain a sus- pegylated interferon alpha with other NUCs a-tained virological response oﬀ-treatment and a chance nd presently this type of combination is notof HBsAg loss in patients who achieve and maintain recommended.undetectable HBV DNA. Frequent side eﬀects and Finite-duration treatment with NUCs is achiev-subcutaneous injection are the main disadvantages of able for HBeAg-positive patients who developinterferon alpha treatment. Interferon alpha is contrain- HBe seroconversion on treatment. However,dicated in patients with decompensated HBV-related duration is unpredictable prior to therapy as itcirrhosis or autoimmune disease and in those with depends on when HBe seroconversion occurs.uncontrolled severe depression or psychosis (A1). HBe seroconversion is more frequent in patients Entecavir and tenofovir are potent HBV inhibitors with high baseline ALT (3 times ULN) and H-and they have a high barrier to resistance [38,58,59]. BV DNA less than 2 Â 106 IU/ml (approximatelyThus they can be conﬁdently used as ﬁrst-line monother- 107 copies/ml) or 6.3 log10 IU/ml at baseline (A1).apies (A1). The role of monotherapy with entecavir or An attempt at ﬁnite treatment should use the mosttenofovir could be modiﬁed if higher rates of resistance potent agents with the highest barrier to resistancebecome apparent with longer treatment duration. (entecavir or tenofovir) to rapidly reduce levels of Adefovir is more expensive than tenofovir, is less eﬃ- viremia to undetectable levels and avoid reboundscacious, and engenders higher rates of resistance (A1). due to HBV resistance (A1). Telbivudine might beTelbivudine is a potent inhibitor of HBV but, due to a used in patients with good predictors of responselow genetic barrier to resistance, a high incidence of (HBV DNA 2 Â 106 IU/ml, i.e. approximatelyresistance has been observed in patients with high base- 107 copies/ml, or 6.3 log10 IU/ml at baseline) withline levels of replication and in those with detectable veriﬁcation of HBV DNA suppression below de-HBV DNA after 24 weeks of therapy  (A1). Lamivu- tection in real-time PCR assay at 24 weeks. Oncedine is an inexpensive agent, but engenders very high HBe seroconversion occurs on NUC, treatmentrates of resistance with monotherapy [60,61] (A1). should be prolonged for an additional 6 to Several treatment options exist for individual (preferentially) 12 months; a durable responsepatients, making rational choices for ﬁrst- and second- (persistence of anti-HBe antibodies oﬀ-treat-line treatment sometimes diﬃcult. Two diﬀerent treat- ment) can be expected in 80% of these patientsment strategies are applicable in both HBeAg-positive (B1).and HBeAg-negative CHB patients: treatment of ﬁnite (2) Long-term treatment with NUCs. This strategy isduration with pegylated interferon alpha or NUCs and necessary for patients who cannot achieve a sus-long-term treatment with NUCs. tained virological response oﬀ-treatment and require extended therapy, i.e. for HBeAg-positive (1) Treatment of ﬁnite duration with pegylated inter- patients who do not develop HBe seroconversion feron alpha or NUCs. This strategy is intended and in HBeAg-negative patients. This strategy is
234 European Association for the Study of the Liver / Journal of Hepatology 50 (2009) 227–242Table 2 entecavir is recommended (B1). Primary non-Main respective advantages and disadvantages of pegylated interferon response is rarely observed with lamivudine, tel-alpha and NUCs in the treatment of CHB bivudine, entecavir or tenofovir. In patients with Pegylated interferon alpha NUCs primary non-response, it is important to check for compliance. In a compliant patient with a pri-Advantages Finite duration Potent antiviral eﬀect mary non-response, identiﬁcation of possible HBV Absence of resistance Good tolerance Higher rates of HBe and Oral administration resistance mutations can formulate a rescue HBs seroconversion strategy that must reasonably be based on an early change to a more potent drug that is active againstDisadvantages Moderate antiviral eﬀect Indeﬁnite duration Poor tolerance Risk of resistance the resistant HBV variant (B1). Subcutaneous injections Lower rates of HBe (2) Partial virological response. Partial virological and HBs seroconversion response may be encountered with all available NUCs. It is important to check for compliance. In patients receiving lamivudine, adefovir or tel- bivudine with a partial virological response at also recommended in patients with cirrhosis irre- week 24, two strategies can be used: change to a spective of HBeAg status or HBe seroconversion more potent drug (entecavir or tenofovir) or addi- on treatment (A1). tion of a more potent drug that does not share cross-resistance (add tenofovir to lamivudine or The most potent drugs with the optimal resistance telbivudine, or add entecavir to adefovir) (A1).proﬁle, i.e. tenofovir or entecavir, should be used as In patients receiving entecavir or tenofovir with aﬁrst-line monotherapies (A1). It is optimal to maintain partial virological response at week 48, someHBV DNA suppression to undetectable HBV DNA in experts would suggest adding the other drug inreal-time PCR, whatever the drug used (B1). The long- order to prevent resistance in the long term (C1).term eﬀects, safety and tolerability of entecavir and ten- The long-term safety of tenofovir and entecavirofovir (i.e. after ﬁve to ten years) are still unknown. in combination is however unknown. There are as yet no data to indicate an advantage (3) Virological breakthrough. Virological break-of de novo combination treatment with NUCs in naive through in compliant patients is related to viralpatients receiving either entecavir or tenofovir (C1). resistance. Rates of resistance at up to 5 years ofTherapeutic trials are in progress. Some experts rec- administration are shown for the diﬀerent NUCsommend a de novo combination therapy approach to in Fig. 3. Resistance is associated with prior treat-prevent potential resistance in patients with a high ment with NUCs (i.e., lamuvidine, adefovir, tel-likelihood of developing resistance (high baseline bivudine, emtricitabine) or, in treatment-naiveHBV DNA levels) or in whom the occurrence of viral patients, with high baseline HBV DNA levels, aresistance would be life-threatening due to the under- slow decline in HBV DNA and partial virologicallying condition (cirrhosis). However, the long-term response during treatment. Resistance should besafety of the combination of NUCs, and in particular identiﬁed as early as possible before clinical break-of the combination of entecavir and tenofovir is through (increased ALT) by means of HBV DNAunknown and this approach is costly (B2). Tenofovir monitoring, and if possible identiﬁcation of theplus lamivudine, or tenofovir plus emtricitabine in pattern of resistance mutations should be used toone tablet, may be considered de novo for these adapt therapeutic strategies. Indeed, clinical andpatients (C1). virological studies have demonstrated the beneﬁt of an early treatment adaptation, as soon as viral4.9. Treatment failure load increases [52,63] (A1). It is important to distinguish between primary non- In case of resistance, an appropriate rescue therapyresponse (less than 1 log10 drop of HBV DNA at 12 should be initiated with the most eﬀective antiviral eﬀectweeks), partial virological response (detectable HBV and the minimal risk to induce multiple drug-resistantDNA on real-time PCR assay during continuous ther- strains. Therefore, adding-on a second drug withoutapy) and virological breakthrough due to antiviral drug cross-resistance is the only eﬃcient strategy. Table 3resistance [29,62]. shows cross-resistance data for the most frequent resis- tant HBV variants . The safety of some combina- (1) Primary non-response. Primary non-response tions in the long term is unknown. seems to be more frequent with adefovir (approx- imately 10–20%) than with other NUCs because of Lamivudine resistance: add tenofovir (add adefovir if suboptimal dosing. A rapid switch to tenofovir or tenofovir not yet available) (B1).
European Association for the Study of the Liver / Journal of Hepatology 50 (2009) 227–242 235 100% Year 1 90% Year 2 Year 3 80% Year 4 70% 70% 67% Year 5 60% 50% 49% 40% 38% 29% 30% 24% 20% 18% 17% 11% 10% 3% 0.5% 1.2% 4% 0% 0.2% 1.2% 1.2% 0% 0% LAM ADV ETV LdT TDFFig. 3. Cumulative incidence of HBV resistance to lamivudine (LAM), adefovir (ADV), entecavir (ETV), telbivudine (LdT) and tenofovir (TDF) inpublished pivotal trials in NUC-naive patients. For method of calculation, see ref. . These trials included diﬀerent populations, used diﬀerent exclusioncriteria and diﬀerent follow-up endpoints. Adefovir resistance: it is recommended to switch to ten- DNA below 2000 IU/ml (approximately 10,000 ofovir if available and add a second drug without cross- copies/ml), i.e. 3.3 log10 IU/ml, is the desired out- resistance. If an N236T substitution is present, add come (A1). Undetectable serum HBV DNA by lamivudine, entecavir or telbivudine or switch to ten- real-time PCR during follow-up is the optimal out- ofovir plus emtricitabine (in one tablet) (C1). If an come since it is associated with a high chance of A181T/V substitution is present, add entecavir (the HBsAg loss. HBeAg-positive patients who develop safety of the tenofovir–entecavir combination is unknown) HBe seroconversion with pegylated interferon or or switch to tenofovir plus emtricitabine (B1). NUCs require long follow-up because of the possi- Telbivudine resistance: add tenofovir (add adefovir if bility of HBe seroreversion or HBeAg-negative tenofovir not yet available). The long-term safety of chronic hepatitis B. HBsAg should be checked at these combinations is unknown (C1). 6-month intervals after HBe seroconversion if Entecavir resistance: Add tenofovir (the safety of this HBV DNA is undetectable. Quantitative HBsAg combination is unknown) (C1). assay is still a research tool. In case of a primary Tenofovir resistance: resistance to tenofovir has not non-response, i.e. failure to achieve a 1 log10 reduc- been described so far. It is recommended that genotyp- tion from baseline at 12 weeks, interferon treat- ing and phenotyping be done by an expert laboratory ment should be stopped and replaced by a NUC to determine the cross-resistance proﬁle. Entecavir, (B1). telbivudine, lamivudine or emtricitabine could be HBeAg-negative patients should be similarly moni- added (the safety of these combinations is unknown) (B1). tored for eﬃcacy and safety through 48 weeks of treatment. A virological response with HBV DNA4.10. How to monitor treatment and stopping points 2000 IU/ml (approximately 10,000 copies/ml), i.e. 3.3 log10 IU/ml, is generally associated with4.10.1. Finite therapy with pegylated interferon alpha remission of the liver disease. Undetectable HBV In patients treated with pegylated interferon alpha, DNA in real-time PCR is the ideal desired oﬀ-full blood counts and serum ALT levels should be mon- treatment sustained response with a high probabil-itored monthly. Serum HBV DNA level should be ity of HBsAg loss in the longer term. HBsAgassessed at weeks 12 and 24 to verify primary response. should be checked at 6-month intervals if HBV DNA is undetectable (B1). In HBeAg-positive patients, HBeAg and anti-HBe antibodies should be checked at weeks 24 and 48 All patients treated with pegylated interferon alpha and 24 weeks post-treatment. HBe seroconversion should be monitored for the known adverse eﬀects of together with ALT normalisation and serum HBV interferon.
236 European Association for the Study of the Liver / Journal of Hepatology 50 (2009) 227–242Table 3Cross-resistance data for the most frequent resistant HBV variants. The amino-acid substitution proﬁles are shown in the left column and the level ofsusceptibility is given for each drug: S (sensitive), I (intermediate/reduced susceptibility), R (resistant) HBV variant Level of susceptibility Lamivudine Telbivudine Entecavir Adefovir TenofovirWild-type S S S S SM204I R R I S SL180M + M204V R R I S SA181T/V I S S R SN236T S S S R IL180M + M204V/I ± I169T ± V173L ± M250V R R R S SL180M + M204V/I ± T184G ± S202I/G R R R S S4.10.2. Finite treatment with NUCs in HBeAg-positive has rarely been reported in CHB patients treated withpatients telbivudine. Peripheral neuropathy has been observed The objective of ﬁnite treatment with NUCs is HBe in patients treated with pegylated interferon and telbivu-seroconversion. HBV DNA should be measured every dine; this combination should be avoided (B1).12 weeks. HBV DNA suppression to undetectable levelsin real-time PCR and subsequent HBe seroconversion is 4.11. Treatment of patients with severe liver diseaseassociated with biochemical and histological responses.Studies have suggested that NUC therapy can be 4.11.1. Treatment of patients with cirrhosisstopped 24 to 48 weeks after HBe seroconversion (B1). Treatment of patients with cirrhosis should not beHBsAg should be checked at 6-month intervals after based on ALT levels, as these may be normal inHBe seroconversion. HBsAg loss is however rarely advanced disease. Interferon alpha increases the risk ofobserved after NUC therapy. sepsis and decompensation in patients with advanced cirrhosis. However, interferon can be used for the treat-4.10.3. Long-term therapy with NUCs ment of well compensated cirrhosis  (A1). The use of HBV DNA levels should be monitored at week 12 to potent NUCs with very low risk of resistance, i.e. ten-ascertain virological response and then every 12 to 24 ofovir or entecavir, is particularly relevant in this groupweeks. HBV DNA reduction to undetectable levels by of patients (B1). Close monitoring of HBV DNA levelsreal-time PCR (i.e. below 10–15 IU/ml) should ideally is important and resistance must be prevented by addingbe achieved to avoid resistance. HBV DNA monitoring a second drug without cross-resistance if HBV DNA isis thus critical to detect treatment failure (A1). In not undetectable at week 48 of therapy. If lamivudineHBeAg-positive patients, HBeAg and subsequently has to be prescribed (because of local policy), it shouldanti-HBe antibodies once HBeAg is negative should be be used in combination with adefovir or preferably ten-measured at intervals of 6 to 12 months. ofovir (B1). NUCs are cleared by the kidneys, and appropriate Hepatic decompensation may occur with exacerba-dosing adjustments are recommended for patients with tions of disease that must be distinguished fromreduced creatinine clearance (A1). Drug concentrations non-compliance and resistance . Thus patients withare comparable in patients with varying degrees of cirrhosis require long-term therapy, with careful moni-hepatic impairment but this has not been fully studied. toring for resistance and ﬂares. Clinical studies indicateExacerbations of hepatitis B may occur and require that prolonged and adequate suppression of HBV DNAmore intensive monitoring (monthly in the ﬁrst three may stabilize patients and delay or even obviate need formonths) in patients with cirrhosis. The onset of compli- transplantation [37,66] (B1). Partial regression of ﬁbro-cations in these patients requires urgent management sis has been reported.(B1). Renal impairment has rarely been reported inpatients with HIV infection receiving anti-HBV drugs, 4.11.2. Treatment of patients with decompensatedor in patients receiving nephrotoxic drugs and treated cirrhosiswith tenofovir or adefovir 10 mg/day and appropriate Patients with decompensated cirrhosis should be trea-monitoring for nephrotoxicity and dose adjustments is ted in specialized liver units, as the application of antivi-necessary. ral therapy is complex, and these patients may be Decreases in bone mineral density have rarely been candidates for liver transplantation. End-stage liver dis-reported in HIV-positive patients treated with tenofovir ease should be treated as a matter of urgency. Treatment(B2). Long-term study is needed. Long-term monitoring is indicated even if HBV DNA level is low in order tofor carcinogenesis with entecavir is ongoing. Myopathy prevent recurrent reactivation. Potent NUCs with good
European Association for the Study of the Liver / Journal of Hepatology 50 (2009) 227–242 237resistance proﬁles (entecavir or tenofovir) should be cated as single agents for hepatitis B in coinfectedused. However, there are little data for the safety of patients (A1). However, if these drugs with a low barrierthese agents in decompensated cirrhosis (B1). Patients to resistance do not reach the goal of undetectable HBVmay show slow clinical improvement over a period of DNA, treatment of HIV infection should be envisaged.3–6 months. However some patients with advancedhepatic disease with a high Child–Pugh or MELD score 4.13.2. HDV co-infected patientsmay have progressed beyond the point of no return, and Active co-infection with HDV is conﬁrmed by themay not beneﬁt, thus requiring transplantation if possi- presence of detectable HDV RNA, immuno-histochem-ble . In that situation, treatment with NUCs will ical staining for HDV antigen, or IgM anti-HDV. Inter-decrease the risk of HBV recurrence in the graft. feron alpha (conventional or pegylated) is the only drug eﬀective on HDV replication [80–85]. The eﬃcacy of4.12. Prevention of recurrent hepatitis B after liver interferon alpha therapy should be assessed at 24 weekstransplantation by measuring HDV RNA levels. More than one year of therapy may be necessary, but is of unproven eﬃcacy Recurrent HBV infection in the transplanted liver  (B2). A proportion of patients become HDVhas previously been a major problem. Pre-transplant RNA-negative or even HBsAg-negative, with accompa-therapy with a potent NUC with a high barrier to nying improvement in histology. NUC monotherapyresistance is recommended for all HBsAg-positive does not appear to impact HDV replication and relatedpatients undergoing liver transplantation for HBV- disease.related end-stage liver disease or HCC, to achievethe lowest possible level of HBV DNA before trans- 4.13.3. HCV co-infected patientsplantation [68–70] (A1). To date, lamivudine and/or HBV DNA level is often low or is undetectable andadefovir have been given post-transplant in combina- HCV is responsible for the activity of chronic hepatitistion with hepatitis B immunoglobulin (HBIg). This in most patients, although this is variable. Thusregimen has reduced the risk of graft infection to less patients should receive pegylated interferon alpha withthan 10%. Adefovir has been successfully added for ribavirin as for HCV  (B1). Sustained virologicallamivudine resistance. Shorter courses and lower doses response (SVR) rates for HCV are broadly comparableof HBIg and other forms of prophylaxis, including with HCV monoinfected patients [88–91]. There is aadefovir in combination with lamivudine and enteca- potential risk of HBV reactivation during or after clear-vir, are being studied. Eﬃcacy and safety data with ance of HCV that must then be treated with NUCsnewer, more potent NUCs with lower rates of resis- (B1).tance, i.e. entecavir and tenofovir, have not been pub-lished but these agents should be considered, as 4.13.4. Acute severe hepatitisprofound suppression and low rates of resistance are More than 95–99% of adults with acute HBV infec-advantageous (B1). Antiviral therapy for prophylaxis tion will recover spontaneously and seroconvert to anti-of recurrent hepatitis B probably requires life-long HBs without anti-viral therapy. However, somecontinuation of treatment (B1). patients with fulminant hepatitis or severe protracted subacute hepatic necrosis may beneﬁt from NUC treat-4.13. Treatment in special patient groups ment. Support for such a strategy may be found in a small number of reports with lamivudine but the eﬃ-4.13.1. HIV co-infected patients cacy is unproven (B1). As for chronic hepatitis, more HIV-positive patients with CHB are at increased risk potent drugs with a high barrier to resistance, i.e. ente-of cirrhosis [71–76]. Treatment of HIV may lead to ﬂares cavir or tenofovir, should be used. The duration ofof hepatitis B due to immune restitution. The indications treatment is not established. However, continuation offor therapy are the same as in HIV-negative patients, anti-viral therapy for at least 3 months after serocon-based on HBV DNA levels, serum ALT levels and histo- version to anti-HBs or at least 6 months after HBelogical lesions . In agreement with recent HIV guide- seroconversion without HBsAg loss is recommendedlines, it is recommended that most coinfected patients be (B2). Sometimes, the distinction between true acutesimultaneously treated for both HIV and HBV de novo hepatitis B and reactivation of chronic hepatitis B. Tenofovir and emtricitabine (FTC) together, plus may be diﬃcult and may require liver biopsy. However,a third agent active against HIV, are indicated  in both cases NUC treatment is the treatment of choice(A1). In a small number of patients, HBV may have to [92–94].be treated before HIV; adefovir and telbivudine, whichare not proven to be active against HIV, should be 4.13.5. Childrenpreferred. Lamivudine, entecavir and tenofovir have Chronic hepatitis B causes benign disease in mostactivity against both HIV and HBV and are contraindi- children. Only conventional interferon alpha, lamivu-
238 European Association for the Study of the Liver / Journal of Hepatology 50 (2009) 227–242dine and adefovir have been evaluated for safety and ommended that patients, especially those with a higheﬃcacy comparable to adults [95–98]. There are ongoing HBV DNA level, be protected with a NUC with highstudies of other NUCs in children to better deﬁne treat- antiviral potency and a high barrier to resistance, i.e.ment strategies for children. entecavir or tenofovir (A1). HBsAg-negative patients with positive anti-HBc anti-4.13.6. Healthcare workers bodies and undetectable HBV DNA in the serum who Healthcare workers, especially surgeons, involved in receive chemotherapy and/or immunosuppressionexposure-prone procedures who are HBsAg-positive should be followed carefully by means of ALT andwith HBV DNA P2000 IU/ml or 3.3 log10 IU/ml HBV DNA testing and treated with NUC therapy uponshould be treated with a potent antiviral agent with a conﬁrmation of HBV reactivation before ALT eleva-high barrier to resistance (i.e. entecavir or tenofovir), tion. NUC prophylaxis is also recommended in patientsto reduce levels of HBV DNA ideally to undetectable receiving bone marrow transplantation from a non-and at least to 2000 IU/ml before resuming expo- immune donor.sure-prone procedures (B1). The long-term safety, eﬃ- Recipients of anti-HBc-positive liver grafts shouldcacy, complications and economic implications of such receive NUC prophylaxis combined with HBIg (A1).a policy in diﬀerent countries are unknown . The optimal duration of combined prophylaxis is not known.4.13.7. Pregnant women Lamivudine, adefovir and entecavir are listed by the 4.13.9. Dialysis and renal transplant patientsFDA as pregnancy category C drugs, and telbivudine Most data in this group are available for lamivudine;and tenofovir as category B drugs. These classiﬁcations the dose of lamivudine should be adapted for renal fail-are based on the risk of teratogenicity in preclinical eval- ure  (A1). There are reports of worsening of renaluation. There is a considerable body of safety data in graft function in patients treated with adefovir. Enteca-pregnant HIV-positive women who have received ten- vir may be the optimal choice of drug for patients under-ofovir and/or lamivudine or emtricitabine . Recent going renal transplantation. Tenofovir should be usedreports suggest that lamivudine therapy during the last with caution in renal impairment (B1).trimester of pregnancy in pregnant HBsAg-positivewomen with high levels of viremia reduces the risk ofintra-uterine and perinatal transmission of HBV if given 4.13.10. Extrahepatic diseasein addition to passive and active vaccination by HBIg HBsAg-positive patients with extra-hepatic manifes-and HBV vaccination . Tenofovir or tenofovir with tations and active HBV replication may respond toemtricitabine or entecavir could be considered. antiviral therapy. Lamivudine has been most widelyAlthough apparently safe, these protocols require fur- used to date. Entecavir and tenofovir are expectedther conﬁrmation (B2). HBV-infected women should to have enhanced eﬃcacy in this group and the indi-be monitored closely after delivery as exacerbations of cations and management do not diﬀer from patientschronic hepatitis B may occur . without extra-hepatic manifestations. Plasmapheresis can be useful in addition to NUC therapy in special4.13.8. Pre-emptive therapy before immunosuppressive cases (C2).therapy or chemotherapy In HBV carriers receiving chemotherapy or immu-nosuppressive therapy, the risk of reactivation is high,particularly if rituximab is given alone or in combina- 5. Unresolved issues and unmet needstion with steroids . All candidates for chemother-apy and immunosuppressive therapy should be (1) Improve knowledge of the natural history, in par-screened for HBsAg and anti-HBc antibodies prior ticular of immunotolerant patients, with long-termto initiation of treatment [104,105]. Vaccination follow-up of cohorts: experimental studies to pro-against HBV in seronegative patients is highly vide more deﬁnite prognostic information, andrecommended. biomarkers to determine prognosis and indications HBsAg-positive candidates for chemo- and immuno- for treatment.suppressive therapy should be tested for HBV DNA lev- (2) Develop and assess new therapeutic approaches,els and receive pre-emptive NUC administration during particularly immunomodulatory therapies totherapy (regardless of HBV DNA levels) and for 12 enhance loss of HBeAg and HBsAg and subse-months after cessation of therapy. Most experience with quent seroconversion.pre-emptive treatment has been with lamivudine, which (3) Assess the role of indirect markers (serum and bio-may suﬃce for patients with low HBV DNA levels and a physical) to assess the severity of liver disease andlow risk of resistance [103,106–108]. It is however rec- for the follow-up of treated and untreated patients.
European Association for the Study of the Liver / Journal of Hepatology 50 (2009) 227–242 239 (4) Assess the role of HBV genotype to determine – Michael Manns has received grant support, hono- prognosis and response to therapy and the risk raria and/or has served as an advisor for Hofmann- of resistance. La Roche, Gilead Sciences, GlaxoSmithKline, Bris- (5) Assess the eﬃcacy of diﬀerent durations (24 weeks tol-Myers Squibb and Novartis/Idenix. to 2 years) and lower doses of pegylated interferon – Daniel Shouval has received research support from alpha. Hofmann-La Roche, GlaxoSmithKline and Bristol- (6) Assess long-term eﬃcacy and safety and resistance Myers Squibb and has been a lecturer for Gilead to new analogues (entecavir, telbivudine and Sciences. tenofovir). – Cihan Yurdaydin has acted as an advisor and lecturer (7) Better deﬁne monitoring algorithms: timing of HBV for Gilead Sciences, Novartis/Idenix, Bristol-Myers DNA measurement with the new generation of Squibb and Hofmann-La Roche. NUCs with a high genetic barrier to resistance; role – Antonio Craxi has received research support and has of genotypic resistance assays in adapting therapy. acted as an advisor and a lecturer for Hofmann-La (8) Assess the role of combination therapy with two Roche, Gilead Sciences, Novartis/Idenix and Bris- NUCs to reduce resistance. tol-Myers Squibb. (9) Assess the eﬃcacy of the combination of pegylated – Xavier Forns has received research support from interferon alpha with potent NUCs (entecavir or Hofmann-La Roche and has served as an advisor to tenofovir) to increase HBe and HBs seroconver- Hofmann-La Roche and Novartis/Idenix. sion rates. – Darius Moradpour has received research support and(10) Develop new drugs to manage multidrug resistant has acted as an advisor for Hofmann-La Roche and HBV resistant to both lineages of current NUCs. Novartis/Idenix.(11) Assess long-term impact of therapy on the preven- – Jean-Michel Pawlotsky has received research support tion of cirrhosis and its complications and HCC. from Gilead Sciences and has acted as an advisor for(12) Develop eﬀective and optimum treatment for Hofmann-La Roche, Gilead Sciences, Novartis/Ide- HDV coinfection. nix, Bristol-Myers Squibb, Siemens Medical Solu- tions Diagnostics and Abbott Molecular.Conﬂicts of interest disclosure – Joerg Petersen has received research support and has acted as an advisor and a lecturer for Hofmann-La– Patrick Marcellin has received research support from Roche, Gilead Sciences, Novartis/Idenix and Bris- Hofmann-La Roche, Schering-Plough and Gilead tol-Myers Squibb. Sciences and has acted as an advisor and lecturer – Heiner Wedemeyer has received research support and for Hofmann-La Roche, Schering-Plough, Gilead has acted as an advisor and a lecturer for Hofmann- Sciences, Novartis/Idenix and Bristol-Myers Squibb. La Roche, Gilead Sciences, Novartis/Idenix and Bris-– Geoﬀrey Dusheiko has received research support and tol-Myers Squibb. has acted as an advisor to Hofmann-La Roche, Gilead Sciences, Novartis/Idenix, GlaxoSmithKline and Bristol-Myers Squibb. References– Fabien Zoulim has received research support from ´ Gilead Sciences and BioMerieux and has acted as  EASL International Consensus Conference on Hepatitis B. 13– an advisor and/or lecturer for Gilead Sciences, Nov- 14 September, 2002: Geneva, Switzerland. Consensus statement artis/Idenix, Bristol-Myers Squibb, Transgene, Sie- (short version). J Hepatol 2003;38:533–540. mens Medical Solutions Diagnostics and Abbott  Ganem D, Prince AM. Hepatitis B virus infection – natural Molecular. history and clinical consequences. N Engl J Med 2004;350: 1118–1129.– Rafael Esteban has acted as an advisor and lecturer  Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. for Schering-Plough, Gilead Sciences, Novartis/ Management of hepatitis B: summary of a clinical research Idenix, Bristol-Myers Squibb and GlaxoSmith workshop. Hepatology 2007;45:1056–1075. Kline.  Liaw YF. Prevention and surveillance of hepatitis B virus-related– Stefanos Hadziyannis has received research support hepatocellular carcinoma. Semin Liver Dis 2005;25:40–47.  Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology from Hofmann-La Roche and Gilead Sciences, and 2007;45:507–539. has acted as an advisor or a lecturer to  Rizzetto M. Viral hepatitis in the third millennium. Res Virol Hofmann-La Roche, Gilead Sciences, Novartis/Ide- 1998;149:251–256. nix, Bristol-Myers Squibb and GlaxoSmithKline.  Rizzetto M, Ciancio A. Chronic HBV-related liver disease. Mol– Pietro Lampertico has acted as an advisor to Hof- Aspects Med 2008;29:72–84.  Zarski JP, Marcellin P, Leroy V, Trepo C, Samuel D, Ganne- mann-La Roche, Gilead Sciences, and is a lecturer Carrie N, et al. Characteristics of patients with chronic hepatitis for Hofmann-La Roche, GlaxoSmithKline, Gilead B in France: predominant frequency of HBe antigen negative Sciences, Novartis/Idenix and Bristol-Myers Squibb. cases. J Hepatol 2006;45:355–360.
240 European Association for the Study of the Liver / Journal of Hepatology 50 (2009) 227–242  Chu CM, Liaw YF. Hepatitis B virus-related cirrhosis: natural  Pawlotsky JM, Dusheiko G, Hatzakis A, Lau D, Lau G, Liang history and treatment. Semin Liver Dis 2006;26:142–152. TJ, et al. Virologic monitoring of hepatitis B virus therapy in  Fattovich G. Natural history and prognosis of hepatitis B. Semin clinical trials and practice: recommendations for a standardized Liver Dis 2003;23:47–58. approach. Gastroenterology 2008;134:405–415.  Fattovich G, Bortolotti F, Donato F. Natural history of chronic  Saldanha J, Gerlich W, Lelie N, Dawson P, Heermann K, Heath hepatitis B: special emphasis on disease progression and prog- A. An international collaborative study to establish a World nostic factors. J Hepatol 2008;48:335–352. Health Organization international standard for hepatitis B virus  Fattovich G, Olivari N, Pasino M, D’Onofrio M, Martone E, DNA nucleic acid ampliﬁcation techniques. Vox Sang Donato F. Long-term outcome of chronic hepatitis B in 2001;80:63–71. Caucasian patients: mortality after 25 years. Gut 2008;57:84–90.  Bedossa P, Dargere D, Paradis V. Sampling variability of liver  Fattovich G, Stroﬀolini T, Zagni I, Donato F. Hepatocellular ﬁbrosis in chronic hepatitis C. Hepatology 2003;38:1449–1457. carcinoma in cirrhosis: incidence and risk factors. Gastroenter-  Poynard T, Morra R, Halfon P, Castera L, Ratziu V, Imbert- ology 2004;127:S35–S50. Bismut F, et al. Meta-analyses of FibroTest diagnostic value in  Martinot-Peignoux M, Boyer N, Colombat M, Akremi R, Pham chronic liver disease. BMC Gastroenterol 2007;7:40. BN, Ollivier S, et al. Serum hepatitis B virus DNA levels and liver  Marcellin P, Ziol M, Bedossa P, Douvin C, Poupon R, de histology in inactive HBsAg carriers. J Hepatol 2002;36:543–546. ´ Ledinghen V, et al. Non-invasive assessment of liver ﬁbrosis by  Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative stiﬀness measurement in patients with chronic hepatitis B. Liver chronic hepatitis B. Hepatology 2001;34:617–624. Int; in press.  Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS,  Myers RP, Tainturier MH, Ratziu V, Piton A, Thibault V, Colombo M, et al. Statements from the Taormina expert meeting Imbert-Bismut F, et al. Prediction of liver histological lesions on occult hepatitis B virus infection. J Hepatol 2008;49:652– with biochemical markers in patients with chronic hepatitis B. J 657. Hepatol 2003;39:222–230.  Knoll A, Pietrzyk M, Loss M, Goetz WA, Jilg W. Solid-organ  Ogawa E, Furusyo N, Toyoda K, Takeoka H, Otaguro S, Hamada transplantation in HBsAg-negative patients with antibodies to M, et al. Transient elastography for patients with chronic hepatitis HBV core antigen: low risk of HBV reactivation. Transplanta- B and C virus infection: non-invasive, quantitative assessment of tion 2005;79:1631–1633. liver ﬁbrosis. Hepatol Res 2007;37:1002–1010.  Marcellin P, Giostra E, Martinot-Peignoux M, Loriot MA, Jaegle  Ngo Y, Benhamou Y, Thibault V, Ingiliz P, Munteanu M, ML, Wolf P, et al. Redevelopment of hepatitis-B surface antigen Lebray P, et al. An accurate deﬁnition of the status of inactive after renal transplantation. Gastroenterology 1991;100: hepatitis B virus carrier by a combination of biomarkers 1432–1434. (FibroTest–ActiTest) and viral load. PLoS ONE 2008;3:e2573.  Guyatt GH, Cook DJ, Jaeschke R, Pauker SG, Schunemann HJ.  Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Grades of recommendation for antithrombotic agents: American Lamivudine for patients with chronic hepatitis B and advanced College of Chest Physicians Evidence-Based Clinical Practice liver disease. N Engl J Med 2004;351:1521–1531. Guidelines (8th Edition). Chest 2008;133:123S–131S.  Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao  Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, YC, et al. A comparison of entecavir and lamivudine for HBeAg- Liberati A, et al. Going from evidence to recommendations. Br positive chronic hepatitis B. N Engl J Med 2006;354:1001–1010. Med J 2008;336:1049–1051.  Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca  Guyatt GH, Oxman AD, Kunz R, Jaeschke R, Helfand M, US, Cakaloglu Y, et al. Pegylated interferon alfa-2b alone or in Liberati A, et al. Incorporating considerations of resources combination with lamivudine for HBeAg-positive chronic hep- use into grading recommendations. Br Med J 2008; atitis B: a randomised trial. Lancet 2005;365:123–129. 336:1170–1173.  Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI,  Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, et al. A one-year trial of lamivudine for chronic hepatitis B. N Schunemann HJ. What is ‘‘quality of evidence” and why is it Engl J Med 1998;339:61–68. important to clinicians? Br Med J 2008;336:995–998.  Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y,  Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, et al. Telbivudine versus lamivudine in patients with chronic Alonso-Coello P, et al. GRADE: an emerging consensus on hepatitis B. N Engl J Med 2007;357:2576–2588. rating quality of evidence and strength of recommendations. Br  Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Med J 2008;336:924–926. Cooksley G, et al. Peginterferon alfa-2a, lamivudine, and the  Jaeschke R, Guyatt GH, Dellinger P, Schunemann H, Levy MM, combination for HBeAg-positive chronic hepatitis B. N Engl J Kunz R, et al. Use of GRADE grid to reach decisions on clinical Med 2005;352:2682–2695. practice guidelines when consensus is elusive. Br Med J  Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiﬀman 2008;337:744. ML, et al. Adefovir dipivoxil for the treatment of hepatitis B e  Schunemann HJ, Oxman AD, Brozek J, Glasziou P, Jaeschke R, antigen-positive chronic hepatitis B. N Engl J Med Vist GE, et al. Grading quality of evidence and strength of 2003;348:808–816. recommendations for diagnostic tests and strategies. Br Med J  Heathcote EJ, Gane E, Deman R, Lee S, Flisiak R, Manns MP, 2008;336:1106–1110. et al. A randomized, double-blind, comparison of tenofovir DF  Chevaliez S, Bouvier-Alias M, Laperche S, Pawlotsky JM. (TDF) versus adefovir dipivoxil (ADV) for the treatment of Performance of the Cobas AmpliPrep/Cobas TaqMan real-time HBeAG positive chronic hepatitis B (CHB): Study GS-US-174- PCR assay for hepatitis B virus DNA quantiﬁcation. J Clin 0103. Hepatology 2007;46:861A. Microbiol 2008;46:1716–1723.  Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R,  Thibault V, Pichoud C, Mullen C, Rhoads J, Smith JB, Bitbol A, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two et al. Characterization of a new sensitive PCR assay for in combination in patients with HBeAg-negative chronic hepa- quantiﬁcation of viral DNA isolated from patients with hepatitis titis B. N Engl J Med 2004;351:1206–1217. B virus infections. J Clin Microbiol 2007;45:3948–3953.  Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT,  Stelzl E, Muller Z, Marth E, Kessler HH. Rapid quantiﬁcation Kitis G, Rizzetto M, et al. Long-term therapy with adefovir of hepatitis B virus DNA by automated sample preparation and dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 real-time PCR. J Clin Microbiol 2004;42:2445–2449. years. Gastroenterology 2006;131:1743–1751.