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EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection

Open AccessPublished:March 20, 2012DOI:https://doi.org/10.1016/j.jhep.2012.02.010

      Keywords

      Linked Article

      Introduction

      Our understanding of the natural history of hepatitis B virus (HBV) infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous EASL Clinical Practice Guidelines (CPGs) prepared in 2008 and published in early 2009 [
      • European Association for the Study of the Liver
      EASL clinical practice guidelines: management of chronic hepatitis B.
      ]. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The CPGs do not fully address prevention including vaccination. In addition, despite the increasing knowledge, areas of uncertainty still exist and therefore clinicians, patients, and public health authorities must continue to make choices on the basis of the evolving evidence.

      Context

      Epidemiology and public health burden

      Approximately one third of the world’s population has serological evidence of past or present infection with HBV and 350–400 million people are chronic HBV surface antigen (HBsAg) carriers. The spectrum of disease and natural history of chronic HBV infection are diverse and variable, ranging from an inactive carrier state to progressive chronic hepatitis B (CHB), which may evolve to cirrhosis and hepatocellular carcinoma (HCC) [
      • Fattovich G.
      Natural history and prognosis of hepatitis B.
      ,
      • McMahon B.J.
      The natural history of chronic hepatitis B virus infection.
      ,
      • Hadziyannis S.J.
      • Papatheodoridis G.V.
      Hepatitis Be antigen negative chronic hepatitis B – natural history and treatment.
      ]. HBV-related end stage liver disease or HCC are responsible for over 0.5–1 million deaths per year and currently represent 5–10% of cases of liver transplantation [
      • Ganem D.
      • Prince A.M.
      Hepatitis B virus infection – natural history and clinical consequences.
      ,
      • Hoofnagle J.H.
      • Doo E.
      • Liang T.J.
      • Fleischer R.
      • Lok A.S.
      Management of hepatitis B: summary of a clinical research workshop.
      ,
      • Liaw Y.F.
      Prevention and surveillance of hepatitis B virus-related hepatocellular carcinoma.
      ,
      • Lok A.S.
      • McMahon B.J.
      Chronic hepatitis B.
      ]. Host and viral factors, as well as coinfection with other viruses, in particular hepatitis C virus (HCV), hepatitis D virus (HDV), or human immunodeficiency virus (HIV) together with other co-morbidities including alcohol abuse and obesity, can affect the natural course of HBV infection as well as efficacy of antiviral strategies [
      • Fattovich G.
      Natural history and prognosis of hepatitis B.
      ,
      • McMahon B.J.
      The natural history of chronic hepatitis B virus infection.
      ,
      • Hadziyannis S.J.
      • Papatheodoridis G.V.
      Hepatitis Be antigen negative chronic hepatitis B – natural history and treatment.
      ,
      • Ganem D.
      • Prince A.M.
      Hepatitis B virus infection – natural history and clinical consequences.
      ,
      • Hoofnagle J.H.
      • Doo E.
      • Liang T.J.
      • Fleischer R.
      • Lok A.S.
      Management of hepatitis B: summary of a clinical research workshop.
      ,
      • Liaw Y.F.
      Prevention and surveillance of hepatitis B virus-related hepatocellular carcinoma.
      ,
      • Lok A.S.
      • McMahon B.J.
      Chronic hepatitis B.
      ]. CHB may present either as hepatitis B e antigen (HBeAg)-positive or HBeAg-negative CHB. The prevalence of the HBeAg-negative form of the disease has been increasing over the last decade as a result of aging of the HBV-infected population and predominance of specific HBV genotypes and represents the majority of cases in many areas, including Europe [
      • Hadziyannis S.J.
      • Papatheodoridis G.V.
      Hepatitis Be antigen negative chronic hepatitis B – natural history and treatment.
      ,
      • Zarski J.P.
      • Marcellin P.
      • Leroy V.
      • Trepo C.
      • Samuel D.
      • Ganne-Carrie N.
      • et al.
      Characteristics of patients with chronic hepatitis B in France: predominant frequency of HBe antigen negative cases.
      ,
      • Funk M.L.
      • Rosenberg D.M.
      • Lok A.S.F.
      World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promoter variants.
      ]. Morbidity and mortality in CHB are linked to persistence of viral replication and evolution to cirrhosis and/or hepatocellular carcinoma (HCC). Longitudinal studies of untreated patients with CHB indicate that, after diagnosis, the 5-year cumulative incidence of developing cirrhosis ranges from 8% to 20%. The 5-year cumulative incidence of hepatic decompensation is approximately 20% for untreated patients with compensated cirrhosis [
      • Fattovich G.
      Natural history and prognosis of hepatitis B.
      ,
      • McMahon B.J.
      The natural history of chronic hepatitis B virus infection.
      ,
      • Hadziyannis S.J.
      • Papatheodoridis G.V.
      Hepatitis Be antigen negative chronic hepatitis B – natural history and treatment.
      ,
      • Fattovich G.
      • Bortolotti F.
      • Donato F.
      Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.
      ,
      • Fattovich G.
      • Olivari N.
      • Pasino M.
      • D’Onofrio M.
      • Martone E.
      • Donato F.
      Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years.
      ,
      • Fattovich G.
      • Stroffolini T.
      • Zagni I.
      • Donato F.
      Hepatocellular carcinoma in cirrhosis: incidence and risk factors.
      ]. Untreated patients with decompensated cirrhosis have a poor prognosis with a 14–35% probability of survival at 5 years [
      • Fattovich G.
      Natural history and prognosis of hepatitis B.
      ,
      • McMahon B.J.
      The natural history of chronic hepatitis B virus infection.
      ,
      • Hadziyannis S.J.
      • Papatheodoridis G.V.
      Hepatitis Be antigen negative chronic hepatitis B – natural history and treatment.
      ,
      • Fattovich G.
      • Olivari N.
      • Pasino M.
      • D’Onofrio M.
      • Martone E.
      • Donato F.
      Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years.
      ]. The worldwide incidence of HCC has increased, mostly due to persistent HBV and/or HCV infections; presently it constitutes the fifth most common cancer, representing around 5% of all cancers. The annual incidence of HBV-related HCC in patients with CHB is high, ranging from 2% to 5% when cirrhosis is established [
      • Fattovich G.
      • Stroffolini T.
      • Zagni I.
      • Donato F.
      Hepatocellular carcinoma in cirrhosis: incidence and risk factors.
      ]. However, the incidence of HBV related HCC appears to vary geographically and correlates with the underlying stage of liver disease and possibly exposure to environmental carcinogens such as aflatoxin. Population movements and migration are currently changing the prevalence and incidence of the disease in several low endemic countries in Europe and elsewhere. Substantial healthcare resources will be required for control of the worldwide burden of disease.

      Natural history

      Chronic HBV infection is a dynamic process. The natural history of chronic HBV infection can be schematically divided into five phases, which are not necessarily sequential.
      • (1)
        The “immune tolerant” phase is characterised by HBeAg positivity, high levels of HBV replication (reflected by high levels of serum HBV DNA), normal or low levels of aminotransferases, mild or no liver necroinflammation and no or slow progression of fibrosis [
        • Fattovich G.
        Natural history and prognosis of hepatitis B.
        ,
        • McMahon B.J.
        The natural history of chronic hepatitis B virus infection.
        ,
        • Hoofnagle J.H.
        • Doo E.
        • Liang T.J.
        • Fleischer R.
        • Lok A.S.
        Management of hepatitis B: summary of a clinical research workshop.
        ,
        • Lok A.S.
        • McMahon B.J.
        Chronic hepatitis B.
        ]. During this phase, the rate of spontaneous HBeAg loss is very low. This first phase is more frequent and more prolonged in subjects infected perinatally or in the first years of life. Because of high levels of viremia, these patients are highly contagious.
      • (2)
        The “immune reactive HBeAg-positive phase” is characterised by HBeAg positivity, relatively lower level of replication compared to the immune tolerant phase (as reflected by lower serum HBV DNA levels), increased or fluctuating levels of aminotransferases, moderate or severe liver necroinflammation and more rapid progression of fibrosis compared to the previous phase [
        • Fattovich G.
        Natural history and prognosis of hepatitis B.
        ,
        • McMahon B.J.
        The natural history of chronic hepatitis B virus infection.
        ,
        • Hadziyannis S.J.
        • Papatheodoridis G.V.
        Hepatitis Be antigen negative chronic hepatitis B – natural history and treatment.
        ,
        • Hoofnagle J.H.
        • Doo E.
        • Liang T.J.
        • Fleischer R.
        • Lok A.S.
        Management of hepatitis B: summary of a clinical research workshop.
        ,
        • Lok A.S.
        • McMahon B.J.
        Chronic hepatitis B.
        ]. This phase may occur after several years of immune tolerance (partial breakdown of tolerance) and is more frequently and/or more rapidly reached in subjects infected during adulthood, paralleling maturation of specific anti-HBV immunity. It may last for several weeks to several years. The rate of spontaneous HBeAg loss is enhanced. This phase ends with seroconversion to anti-HBe.
      • (3)
        The “inactive HBV carrier state” may follow seroconversion from HBeAg to anti-HBe antibody. It is characterised by very low or undetectable serum HBV DNA levels and normal serum aminotransferases. A minimum follow-up of 1 year with alanine aminotransferase (ALT) levels at least every 3–4 months and serum HBV DNA levels is required before classifying a patient as inactive HBV carrier. ALT levels should remain persistently within the normal range according to traditional cut-off values (approximately 40 IU/ml) [

        Papatheodoridis GV, Manolakopoulos S, Liaw Y-F, Lok A. Follow-up and indications for liver biopsy in HBeAg-negative chronic hepatitis B virus infection with persistently normal ALT: a systematic review. J Hepatol 2012, in press.

        ] and HBV DNA should be below 2000 IU/ml. Some inactive carriers, however, may have HBV DNA levels greater than 2000 IU/ml (usually below 20,000 IU/ml) accompanied by persistently normal ALT levels [

        Papatheodoridis GV, Manolakopoulos S, Liaw Y-F, Lok A. Follow-up and indications for liver biopsy in HBeAg-negative chronic hepatitis B virus infection with persistently normal ALT: a systematic review. J Hepatol 2012, in press.

        ,
        • Martinot-Peignoux M.
        • Boyer N.
        • Colombat M.
        • Akremi R.
        • Pham B.-N.
        • Ollivier S.
        • et al.
        Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers.
        ,
        • Manesis E.
        • Papatheodoridis G.V.
        • Sevastianos V.
        • Cholongitas E.
        • Papaioannou C.
        • Hadziyannis S.J.
        Significance of hepatitis B viremia levels determined by a quantitative polymerase chain reaction assay in patients with HBeAg-negative chronic hepatitis B virus infection.
        ,
        • Papatheodoridis G.V.
        • Manesis E.K.
        • Manolakopoulos S.
        • Elefsiniotis I.S.
        • Goulis J.
        • Giannousis J.
        • et al.
        Is there a meaningful serum HBV DNA cut-off level for therapeutic decisions in HBeAg-negative chronic hepatitis B virus infection?.
        ]. Patients with HBV DNA <2000 IU/ml and elevated ALT values should be usually advised to undergo liver biopsy for the evaluation of the cause of liver injury. As a result of immunological control of the infection, the inactive HBV carrier state confers a favourable long-term outcome with a very low risk of cirrhosis or HCC in the majority of patients [
        • de Franchis R.
        • Meucci G.
        • Vecchi M.
        • Tatarella M.
        • Colombo M.
        • Del Ninno E.
        • et al.
        The natural history of asymptomatic hepatitis B surface antigen carriers.
        ,
        • Tai D.I.
        • Lin S.M.
        • Sheen I.S.
        • Chu C.M.
        • Lin D.Y.
        • Liaw Y.F.
        Long-term outcome of hepatitis B e antigen-negative hepatitis B surface antigen carriers in relation to changes of alanine aminotransferase levels over time.
        ,
        • Chen Y.-C.
        • Huang S.-F.
        • Chu C.-M.
        • Liaw Y.-F.
        Serial HBV DNA levels in patients with persistently normal transaminase over 10 years following spontaneous HBeAg seroconversion.
        ]. HBsAg loss and seroconversion to anti-HBs antibody may occur spontaneously in 1–3% of cases per year, usually after several years with persistently undetectable HBV DNA [
        • Martinot-Peignoux M.
        • Boyer N.
        • Colombat M.
        • Akremi R.
        • Pham B.-N.
        • Ollivier S.
        • et al.
        Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers.
        ]. On the other hand, progression to CHB, usually HBeAg-negative, may also occur [
        • Papatheodoridis G.V.
        • Chrysanthos N.
        • Hadziyannis E.
        • Cholongitas E.
        • Manesis E.K.
        Longitudinal changes in serum HBV DNA levels and predictors of progression during the natural course of HBeAg-negative chronic hepatitis B virus infection.
        ]. Therefore, inactive HBV carriers should be followed up for life with ALT determinations at least every 6 months after the first year and periodical measurement of HBV DNA levels [

        Papatheodoridis GV, Manolakopoulos S, Liaw Y-F, Lok A. Follow-up and indications for liver biopsy in HBeAg-negative chronic hepatitis B virus infection with persistently normal ALT: a systematic review. J Hepatol 2012, in press.

        ]. The follow-up should be closer in cases with baseline serum HBV DNA levels above 2000 IU/ml, in whom non-invasive evaluation of liver fibrosis may be useful and even liver biopsy might be considered [

        Papatheodoridis GV, Manolakopoulos S, Liaw Y-F, Lok A. Follow-up and indications for liver biopsy in HBeAg-negative chronic hepatitis B virus infection with persistently normal ALT: a systematic review. J Hepatol 2012, in press.

        ]. Inactive carriers have been reported to have serum HBsAg levels <1000 IU/ml, but such HBsAg levels may occasionally be detected in CHB patients as well [
        • Brunetto M.R.
        • Oliveri F.
        • Colombatto P.
        • Moriconi F.
        • Ciccorossi P.
        • Coco B.
        • et al.
        Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers.
        ].
      • (4)
        “HBeAg-negative CHB” may follow seroconversion from HBeAg to anti-HBe antibodies during the immune reactive phase or may develop after years or decades of the inactive carrier state. It represents a later immune reactive phase in the natural history of chronic HBV infection. It is characterised by periodic reactivation with a pattern of fluctuating levels of HBV DNA and aminotransferases and active hepatitis [
        • Hadziyannis S.J.
        • Papatheodoridis G.V.
        Hepatitis Be antigen negative chronic hepatitis B – natural history and treatment.
        ,
        • Hadziyannis S.J.
        • Vassilopoulos D.
        Hepatitis B e antigen-negative chronic hepatitis B.
        ,
        • Brunetto M.R.
        • Giarin M.
        • Oliveri F.
        • Saracco G.
        • Barbera C.
        • Parella T.
        • et al.
        ‘e’ Antigen defective hepatitis B virus and course of chronic infection.
        ,
        • Brunetto M.R.
        • Oliveri F.
        • Coco B.
        • Leandro G.
        • Colombatto P.
        • Gorin J.M.
        • et al.
        Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long-term cohort study.
        ]. These patients are HBeAg-negative and harbour a predominance of HBV virions with nucleotide substitutions in the precore and/or the basal core promoter regions that are hence unable to express or express low levels of HBeAg. HBeAg-negative CHB is associated with low rates of prolonged spontaneous disease remission [
        • Hadziyannis S.J.
        • Papatheodoridis G.V.
        Hepatitis Be antigen negative chronic hepatitis B – natural history and treatment.
        ,
        • Hadziyannis S.J.
        • Vassilopoulos D.
        Hepatitis B e antigen-negative chronic hepatitis B.
        ]. It is important and sometimes difficult to distinguish true inactive HBV carriers from patients with active HBeAg negative CHB in whom phases of spontaneous remission may occur. The former patients have a good prognosis with a very low risk of complications, while the latter patients have active liver disease with a high risk of progression to advanced hepatic fibrosis, cirrhosis and subsequent complications such as decompensated cirrhosis and HCC. A careful assessment of the patients is needed and, as reported in the inactive carrier state, a minimal follow-up of 1 year with serum ALT levels every 3–4 months and HBV DNA levels usually allows detection of fluctuations of activity in patients with active HBeAg-negative CHB [
        • Hadziyannis S.J.
        • Vassilopoulos D.
        Hepatitis B e antigen-negative chronic hepatitis B.
        ].
      • (5)
        In the “HBsAg-negative phase” after HBsAg loss, low-level HBV replication may persist with detectable HBV DNA in the liver [
        • Raimondo G.
        • Allain J.P.
        • Brunetto M.R.
        • Buendia M.A.
        • Chen D.S.
        • Colombo M.
        • et al.
        Statements from the Taormina expert meeting on occult hepatitis B virus infection.
        ]. Generally, HBV DNA is not detectable in the serum, while anti-HBc antibodies with or without anti-HBs are detectable. HBsAg loss before the onset of cirrhosis is associated with improvement of the outcome with reduced risk of cirrhosis, decompensation and HCC. The clinical relevance of occult HBV infection [detectable HBV DNA in the liver with low level (<200 IU/ml) or undetectable HBV DNA in blood] is unclear [
        • Raimondo G.
        • Allain J.P.
        • Brunetto M.R.
        • Buendia M.A.
        • Chen D.S.
        • Colombo M.
        • et al.
        Statements from the Taormina expert meeting on occult hepatitis B virus infection.
        ]. Immunosuppression may lead to HBV reactivation in these patients [
        • Knoll A.
        • Pietrzyk M.
        • Loss M.
        • Goetz W.A.
        • Jilg W.
        Solid-organ transplantation in HBsAg-negative patients with antibodies to HBV core antigen: low risk of HBV reactivation.
        ,
        • Marcellin P.
        • Giostra E.
        • Martinotpeignoux M.
        • Loriot M.A.
        • Jaegle M.L.
        • Wolf P.
        • et al.
        Redevelopment of hepatitis-B surface-antigen after renal-transplantation.
        ]. If cirrhosis has developed before spontaneous or treatment-induced HBsAg loss, patients remain at risk of HCC [
        • Huo T.I.
        • Wu J.C.
        • Lee P.C.
        • Chau G.Y.
        • Lui W.Y.
        • Tsay S.H.
        • et al.
        Sero-clearance of hepatitis B surface antigen in chronic carriers does not necessarily imply a good prognosis.
        ,
        • Chen Y.C.
        • Sheen I.S.
        • Chu C.M.
        • Liaw Y.F.
        Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection.
        ,
        • Simonetti J.
        • Bulkow L.
        • McMahon B.J.
        • Homan C.
        • Snowball M.
        • Negus S.
        • et al.
        Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus.
        ] and therefore HCC surveillance should continue (C2), although the cost-effectiveness of surveillance has not been determined in this setting.

      Methodology

      Figure thumbnail fx6
      Table 1Grading of evidence and recommendations (adapted from the GRADE system)
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • Falck-Ytter Y.
      • Vist G.E.
      • Liberati A.
      • et al.
      Going from evidence to recommendations.
      ,
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • Vist G.E.
      • Falck-Ytter Y.
      • Schunemann H.J.
      What is “quality of evidence” and why is it important to clinicians?.
      ,
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • Kunz R.
      • Falck-Ytter Y.
      • Alonso-Coello P.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      ,
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • Jaeschke R.
      • Helfand M.
      • Liberati A.
      • et al.
      Incorporating considerations of resources use into grading recommendations.
      ,
      • Jaeschke R.
      • Guyatt G.H.
      • Dellinger P.
      • Schunemann H.
      • Levy M.M.
      • Kunz R.
      • et al.
      Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive.
      ,
      • Schunemann H.J.
      • Oxman A.D.
      • Brozek J.
      • Glasziou P.
      • Jaeschke R.
      • Vist G.E.
      • et al.
      Grading quality of evidence and strength of recommendations for diagnostic tests and strategies.
      .

      Guidelines

      Pre-therapeutic assessment of liver disease

      As a first step, the causal relationship between chronic HBV infection and liver disease has to be established and an assessment of the severity of liver disease needs to be performed. In addition, all first degree relatives and sexual partners of patients with chronic HBV infection should be advised to be tested for HBV serological markers (HBsAg, anti-HBc, anti-HBs) and to be vaccinated if they are negative for these markers (A1).
      Not all patients with chronic HBV infection have persistently elevated aminotransferases. Patients in the immune tolerant phase and inactive carriers have persistently normal ALT levels, while a proportion of patients with HBeAg-negative CHB may have intermittently normal ALT levels. Therefore, appropriate longitudinal long-term follow-up is crucial.
      • (1)
        The assessment of the severity of the liver disease should include: biochemical markers, including aspartate aminotransferase (AST) and ALT, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase, bilirubin, and serum albumin and globulins, blood counts and prothrombin time, and hepatic ultrasound (A1). Usually, ALT levels are higher than those of AST. However, when the disease progresses to cirrhosis, the ratio may be reversed. A progressive decline in serum albumin concentrations and/or increase of (gamma-)globulins and prolongation of the prothrombin time, often accompanied by declining platelet counts, are characteristically observed after cirrhosis has developed.
      • (2)
        HBV DNA detection and HBV DNA level measurement are essential for the diagnosis, decision to treat and subsequent monitoring of patients (A1). Follow-up using real-time PCR quantification assays is strongly recommended because of their sensitivity, specificity, accuracy and broad dynamic range [
        • Stelzl E.
        • Muller Z.
        • Marth E.
        • Kessler H.H.
        Rapid quantification of hepatitis B virus DNA by automated sample preparation and real-time PCR.
        ,
        • Thibault V.
        • Pichoud C.
        • Mullen C.
        • Rhoads J.
        • Smith J.B.
        • Bitbol A.
        • et al.
        Characterization of a new sensitive PCR assay for quantification of viral DNA isolated from patients with hepatitis B virus infections.
        ,
        • Chevaliez S.
        • Bouvier-Alias M.
        • Laperche S.
        • Pawlotsky J.M.
        Performance of the Cobas AmpliPrep/Cobas TaqMan real-time PCR assay for hepatitis B virus DNA quantification.
        ,
        • Pawlotsky J.M.
        • Dusheiko G.
        • Hatzakis A.
        • Lau D.
        • Lau G.
        • Liang T.J.
        • et al.
        Virologic monitoring of hepatitis B virus therapy in clinical trials and practice: recommendations for a standardized approach.
        ] (A1). The World Health Organization (WHO) has defined an international standard for normalisation of expression of HBV DNA concentrations [
        • Saldanha J.
        • Gerlich W.
        • Lelie N.
        • Dawson P.
        • Heermann K.
        • Heath A.
        An international collaborative study to establish a World Health Organization international standard for hepatitis B virus DNA nucleic acid amplification techniques.
        ]. Serum HBV DNA levels should be expressed in IU/ml to ensure comparability; the same assay should be used in the same patient to evaluate antiviral efficacy. All HBV DNA values in this manuscript are reported in IU/ml; values given as copies/ml were converted to IU/ml by dividing by a factor of 5.
      • (3)
        Other causes of chronic liver disease should be systematically looked for including co-infections with HDV, HCV and/or HIV (A1). Patients with chronic HBV infection should be also tested for antibody against hepatitis A virus (anti-HAV) and should be advised to be vaccinated against HAV if they are anti-HAV negative. Co-morbidities, including alcoholic, autoimmune, metabolic liver disease with steatosis or steatohepatitis should be assessed (A1).
      • (4)
        A liver biopsy is often recommended for determining the degree of necroinflammation and fibrosis since hepatic histology can assist the decision to start treatment (A1).
      The indications for liver biopsy are reported within the indications for treatment. The biopsy is also useful for evaluating other possible causes of liver disease such as fatty liver disease. Although liver biopsy is an invasive procedure, the risk of severe complications is very low (1/4000–10,000). It is important that the size of the needle biopsy specimen is large enough to accurately assess the degree of liver injury, in particular fibrosis [
      • Bedossa P.
      • Dargere D.
      • Paradis V.
      Sampling variability of liver fibrosis in chronic hepatitis C.
      ] (A1). A liver biopsy is usually not required in patients with clinical evidence of cirrhosis or in those in whom treatment is indicated irrespective of the grade of activity or the stage of fibrosis (A1). There is growing interest in the use of non-invasive methods, including serum markers and transient elastography, to assess hepatic fibrosis to complement or avoid a liver biopsy [
      • Myers R.P.
      • Tainturier M.H.
      • Ratziu V.
      • Piton A.
      • Thibault V.
      • Imbert-Bismut F.
      • et al.
      Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B.
      ,
      • Poynard T.
      • Morra R.
      • Halfon P.
      • Castera L.
      • Ratziu V.
      • Imbert-Bismut F.
      • et al.
      Meta-analyses of FibroTest diagnostic value in chronic liver disease.
      ,
      • Marcellin P.
      • Ziol M.
      • Bedossa P.
      • Douvin C.
      • Poupon R.
      • De L.V.
      • et al.
      Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B.
      ,
      • Castera L.
      Transient elastography and other non-invasive tests to assess hepatic fibrosis in patients with viral hepatitis.
      ,
      • Castera L.
      • Bernard P.H.
      • Le B.B.
      • Foucher J.
      • Trimoulet P.
      • Merrouche W.
      • et al.
      Transient elastography and biomarkers for liver fibrosis assessment and follow-up of inactive hepatitis B carriers.
      ,
      • Fraquelli M.
      • Branchi F.
      The role of transient elastography in patients with hepatitis B viral disease.
      ,
      • Cardoso A.C.
      • Carvalho-Filho R.J.
      • Marcellin P.
      Transient elastography in chronic viral hepatitis: a critical appraisal.
      ,
      • Cardoso A.C.
      • Carvalho-Filho R.J.
      • Stern C.
      • Dipumpo A.
      • Giuily N.
      • Ripault M.P.
      • et al.
      Direct comparison of diagnostic performance of transient elastography in patients with chronic hepatitis B and chronic hepatitis C.
      ]. Transient elastography, which is a non-invasive method widely used in Europe, offers high diagnostic accuracy for the detection of cirrhosis, although the results may be confounded by severe inflammation associated with high ALT levels and the optimal cut-off of liver stiffness measurements vary among studies [
      • Arena U.
      • Vizzutti F.
      • Corti G.
      • Ambu S.
      • Stasi C.
      • Bresci S.
      • et al.
      Acute viral hepatitis increases liver stiffness values measured by transient elastography.
      ,
      • Tsochatzis E.A.
      • Gurusamy K.S.
      • Ntaoula S.
      • Cholongitas E.
      • Davidson B.R.
      • Burroughs A.K.
      Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy.
      ].

      Goal of therapy

      The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensated cirrhosis, end-stage liver disease, HCC and death. This goal can be achieved if HBV replication can be suppressed in a sustained manner. Then, the accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and decreases the risk of HCC, particularly in non-cirrhotic patients [
      • Liaw Y.F.
      • Sung J.J.
      • Chow W.C.
      • Farrell G.
      • Lee C.Z.
      • Yuen H.
      • et al.
      Lamivudine for patients with chronic hepatitis B and advanced liver disease.
      ] (B1). However, chronic HBV infection cannot be completely eradicated due to the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes, which may explain HBV reactivation [
      • Raimondo G.
      • Allain J.P.
      • Brunetto M.R.
      • Buendia M.A.
      • Chen D.S.
      • Colombo M.
      • et al.
      Statements from the Taormina expert meeting on occult hepatitis B virus infection.
      ,
      • Brechot C.
      • Hadchouel M.
      • Scotto J.
      • Fonck M.
      • Potet F.
      • Vyas G.N.
      • et al.
      State of hepatitis B virus DNA in hepatocytes of patients with hepatitis B surface antigen-positive and -negative liver diseases.
      ,
      • Brechot C.
      • Thiers V.
      • Kremsdorf D.
      • Nalpas B.
      • Pol S.
      • Paterlini-Brechot P.
      Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: clinically significant or purely “occult”?.
      ]. Moreover, the HBV genome integrates into the host genome and might favour oncogenesis and the development of HCC [
      • Brechot C.
      Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new paradigms.
      ,
      • Bonilla G.R.
      • Roberts L.R.
      The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma.
      ,
      • Pollicino T.
      • Saitta C.
      • Raimondo G.
      Hepatocellular carcinoma: the point of view of the hepatitis B virus.
      ].

      End points of therapy

      Therapy must ensure a degree of virological suppression that will then lead to biochemical remission, histological improvement and prevention of complications. The ideal end point is HBsAg loss, which however is infrequently achievable with the currently available anti-HBV agents. A more realistic end point is the induction of sustained or maintained virological remission.
      • (1)
        In HBeAg-positive and HBeAg-negative patients, the ideal end point is sustained off-therapy HBsAg loss, with or even without seroconversion to anti-HBs. This is associated with a complete and definitive remission of the activity of CHB and an improved long-term outcome (A1).
      • (2)
        Induction of sustained off-therapy virological and biochemical response in HBeAg-negative patients (either HBeAg-positive cases at baseline with durable anti-HBe seroconversion or HBeAg-negative cases from baseline) is a satisfactory end point, because it has been shown to be associated with improved prognosis (A1).
      • (3)
        A maintained virological remission (undetectable HBV DNA by a sensitive PCR assay) under long-term antiviral therapy in HBeAg-positive patients who do not achieve anti-HBe seroconversion and in HBeAg-negative patients is the next most desirable end point (A1).

      Definitions of response

      Responses can be divided into biochemical, serological, virological and histological. All responses can be estimated at several time points during and after therapy. The definitions of virological responses vary according to the timing (on or after therapy) and type of therapy. Two different types of drugs can be used in the treatment of CHB: conventional or pegylated interferon alpha (IFN or PEG-IFN) and nucleoside/nucleotide analogues referred to collectively as NAs in this document.
      Biochemical response is defined as normalisation of ALT levels. It can be evaluated at several time points on-therapy, at the end and after the end of therapy. Since ALT activity often fluctuates over time, a minimum follow-up of at least 1 year post-treatment with ALT determinations at least every 3 months is required to confirm sustained off-treatment biochemical response (B1). It should be noted that the rates of sustained off-treatment biochemical responses may sometimes be difficult to evaluate, as transient (usually ⩽3 months duration) ALT elevations before long-term biochemical remission may occur in some CHB patients within the first year after treatment discontinuation. In such cases, additional close ALT follow-up of at least 2 years after ALT elevation seems to be reasonable in order to confirm sustained off-therapy biochemical remission (C2).
      Serological response for HBeAg applies only to patients with HBeAg-positive CHB and is defined as HBeAg loss and seroconversion to anti-HBe.
      Serological response for HBsAg applies to all CHB patients and is defined as HBsAg loss and development of anti-HBs.
      Virological responses on IFN/PEG-IFN therapy:
      • Primary non-response has not been well established.
      • Virological response is defined as an HBV DNA concentration of less than 2000 IU/ml. It is usually evaluated at 6 months and at the end of therapy as well as at 6 and 12 months after the end of therapy.
      • Sustained off-treatment virological response is defined as HBV DNA levels below 2000 IU/ml for at least 12 months after the end of therapy.
      Virological responses on NA therapy:
      • Primary non-response is defined as less than 1 log10 IU/ml decrease in HBV DNA level from baseline at 3 months of therapy.
      • Virological response is defined as undetectable HBV DNA by a sensitive PCR assay. It is usually evaluated every 3–6 months during therapy depending on the severity of liver disease and the type of NA.
      • Partial virological response is defined as a decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA after at least 6 months of therapy in compliant patients.
      • Virological breakthrough is defined as a confirmed increase in HBV DNA level of more than 1 log10 IU/ml compared to the nadir (lowest value) HBV DNA level on therapy; it may precede a biochemical breakthrough, characterised by an increase in ALT levels. The main causes of virological breakthrough on NA therapy are poor adherence to therapy and/or selection of drug-resistant HBV variants (resistance) (A1).
      • HBV resistance to NA(s) is characterised by selection of HBV variants with aminoacid substitutions that confer reduced susceptibility to the administered NA(s). Resistance may result in primary non-response or virological breakthrough on therapy (A1).
      • NA(s) discontinuation is not common practice to date. However, NA(s) may be discontinued in some patients. Sustained off-treatment virological response may be defined similarly to the definition used for IFN therapy, which requires HBV DNA values below 2000 IU/ml for at least 12 months after treatment discontinuation.
      Histological response is defined as decrease in necroinflammatory activity (by ⩾2 points in HAI or Ishak’s system) without worsening in fibrosis compared to pre-treatment histological findings.
      Complete response is defined as sustained off-treatment virological response together with loss of HBsAg.

      Indications for treatment

      The indications for treatment are generally the same for both HBeAg-positive and HBeAg-negative CHB. This is based mainly on the combination of three criteria:
      • Serum HBV DNA levels.
      • Serum ALT levels.
      • Severity of liver disease.
      Patients should be considered for treatment when they have HBV DNA levels above 2000 IU/ml, serum ALT levels above the upper limit of normal (ULN) and severity of liver disease assessed by liver biopsy (or non-invasive markers once validated in HBV-infected patients) showing moderate to severe active necroinflammation and/or at least moderate fibrosis using a standardised scoring system (A1). In patients who fulfil the above criteria for HBV DNA and histological severity of liver disease, treatment may be initiated even if ALT levels are normal (A1). Indications for treatment may also take into account age, health status, family history of HCC or cirrhosis and extrahepatic manifestations.
      The need for liver biopsy and treatment should be considered separately in the following subgroups of patients:
      • Immunotolerant patients: HBeAg-positive patients under 30 years of age with persistently normal ALT levels and a high HBV DNA level, without any evidence of liver disease and without a family history of HCC or cirrhosis, do not require immediate liver biopsy or therapy. Follow-up at least every 3–6 months is mandatory (B1). Consider liver biopsy or even therapy in such patients over 30 years of age and/or with a family history of HCC or cirrhosis.
      • HBeAg-negative patients with persistently normal ALT levels (ALT determinations at least every 3 months for at least 1 year) and HBV DNA levels above 2000 but below 20,000 IU/ml, without any evidence of liver disease, do not require immediate liver biopsy or therapy (B1). Close follow-up with ALT determinations every 3 months and HBV DNA every 6–12 months for at least 3 years is mandatory (C1). After 3 years, they should be followed for life like all inactive chronic HBV carriers. Evaluation of the severity of fibrosis by a non-invasive method, such as Fibroscan, might be useful in such cases (C2).
      • Patients with obviously active CHB: HBeAg-positive and HBeAg-negative patients with ALT above 2 times ULN and serum HBV DNA above 20,000 IU/ml may start treatment even without a liver biopsy (B1). In such patients, liver biopsy may provide additional useful information, but it does not usually change the decision for treatment. A non-invasive method for the estimation of the extent of fibrosis and most importantly to confirm or rule out cirrhosis is extremely useful in patients who start treatment without liver biopsy (B1).
      • Patients with compensated cirrhosis and detectable HBV DNA must be considered for treatment even if ALT levels are normal (B1).
      • Patients with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Significant clinical improvement can be associated with control of viral replication [
        • Shim J.H.
        • Lee H.C.
        • Kim K.M.
        • Lim Y.S.
        • Chung Y.H.
        • Lee Y.S.
        • et al.
        Efficacy of entecavir in treatment-naive patients with hepatitis B virus-related decompensated cirrhosis.
        ,
        • Liaw Y.F.
        • Sheen I.S.
        • Lee C.M.
        • Akarca U.S.
        • Papatheodoridis G.V.
        • Suet-Hing W.F.
        • et al.
        Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease.
        ,
        • Liaw Y.F.
        • Raptopoulou-Gigi M.
        • Cheinquer H.
        • Sarin S.K.
        • Tanwandee T.
        • Leung N.
        • et al.
        Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation: a randomized, open-label study.
        ]. However, antiviral therapy may not be sufficient to rescue some patients with very advanced liver disease who should be considered for liver transplantation at the same time (A1).

      Results of current therapies

      Drugs available for the treatment of CHB include IFN, PEG-IFN and six NAs. NAs for HBV therapy can be classified into nucleosides (lamivudine, telbivudine, emtricitabine, entecavir) and nucleotides (adefovir and tenofovir). PEG-IFN-2b and emtricitabine are not licensed for HBV treatment in most European countries. Lamivudine, adefovir, entecavir, telbivudine and tenofovir have been approved in Europe for HBV treatment, and the combination of tenofovir and emtricitabine in one tablet has been licensed for the treatment of human HIV infection. The efficacy of these drugs has been assessed in randomized controlled trials at 1 year (2 years with telbivudine). Longer-term results are now available from extension of the randomized trials sometimes in patient subgroups and several cohort studies. Table 2, Table 3 show the response rates with these drugs from different trials. These trials used different HBV DNA assays and there are not head-to-head comparisons for all the drugs.
      Table 2Results of main studies for the treatment of HBeAg-positive chronic hepatitis B at 6 months following 12 months (48 or 52 weeks) of pegylated interferon alpha (PEG-IFN) and at 12 months (48 or 52 weeks) of nucleos(t)ide analogue therapy.
      PEG-IFN were given as percutaneous injections once weekly and nucleos(t)ide analogues as oral tablets once daily.
      #The definition of ALT normalisation varied among different trials (i.e. decrease of ALT to ⩽1.25-times the upper limit of normal (ULN) in the entecavir or ⩽1.3-times the ULN in the telbivudine trial).
      Table 3Results of main studies for the treatment of HBeAg-negative chronic hepatitis B at 6 months following 12 months (48 weeks) of pegylated interferon alpha (PEG-IFN) and at 12 months (48 or 52 weeks) of nucleos(t)ide analogue therapy.
      PEG-IFN-2a was given as percutaneous injections once weekly and nucleos(t)ide analogues as oral tablets once daily.
      #The definition of ALT normalisation varied among different trials (i.e. decrease of ALT to ⩽1.25-times the upper limit of normal (ULN) in the entecavir or ⩽1.3-times the ULN in the telbivudine trial).
      (1) HBeAg-positive patients
      Response rates at 6 months following 12 months of PEG-IFN and at 12 months of NA therapy are given in Table 2 [
      • Lau G.K.
      • Piratvisuth T.
      • Luo K.X.
      • Marcellin P.
      • Thongsawat S.
      • Cooksley G.
      • et al.
      Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.
      ,
      • Janssen H.L.
      • van Z.M.
      • Senturk H.
      • Zeuzem S.
      • Akarca U.S.
      • Cakaloglu Y.
      • et al.
      Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.
      ,
      • Lai C.L.
      • Chien R.N.
      • Leung N.W.
      • Chang T.T.
      • Guan R.
      • Tai D.I.
      • et al.
      A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group.
      ,
      • Dienstag J.L.
      • Schiff E.R.
      • Wright T.L.
      • Perrillo R.P.
      • Hann H.W.
      • Goodman Z.
      • et al.
      Lamivudine as initial treatment for chronic hepatitis B in the United States.
      ,
      • Chang T.T.
      • Gish R.G.
      • de Man R.
      • Gadano A.
      • Sollano J.
      • Chao Y.C.
      • et al.
      A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.
      ,
      • Lai C.L.
      • Gane E.
      • Liaw Y.F.
      • Hsu C.W.
      • Thongsawat S.
      • Wang Y.
      • et al.
      Telbivudine versus lamivudine in patients with chronic hepatitis B.
      ,
      • Marcellin P.
      • Chang T.T.
      • Lim S.G.
      • Tong M.J.
      • Sievert W.
      • Shiffman M.L.
      • et al.
      Adefovir dipivoxil for the treatment of hepatitis B antigen-positive chronic hepatitis B.
      ,
      • Marcellin P.
      • Heathcote E.J.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
      ]. Anti-HBe seroconversion rates were of the order of 30% with PEG-IFN and approximately 20% with NAs. A 6-month course of PEG-IFN-2a and/or a lower dose are inferior to the recommended 12-month course [
      • Liaw Y.F.
      • Jia J.D.
      • Chan H.L.
      • Han K.H.
      • Tanwandee T.
      • Chuang W.L.
      • et al.
      Shorter durations and lower doses of peginterferon alfa-2a are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B virus genotypes B or C.
      ]. Anti-HBe seroconversion rates are enhanced during the first 6 months following PEG-IFN therapy [
      • Lau G.K.
      • Piratvisuth T.
      • Luo K.X.
      • Marcellin P.
      • Thongsawat S.
      • Cooksley G.
      • et al.
      Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.
      ,
      • Van Zonneveld M.
      • Honkoop P.
      • Hansen B.E.
      • Niesters H.G.
      • Murad S.D.
      • de Man R.A.
      • et al.
      Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B.
      ]. Anti-HBe seroconversion rates increase with continued NA therapy [
      • Liaw Y.-F.
      • Leung N.W.Y.
      • Chang T.-T.
      • Guan R.
      • Tai D.-I.
      • Ng K.-Y.
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      Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B.
      ,
      • Lok A.S.
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      ,
      • Leung N.W.
      • Lai C.L.
      • Chang T.T.
      • Guan R.
      • Lee C.M.
      • Ni Y.H.
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      Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy.
      ,
      • Marcellin P.
      • Chang T.T.
      • Lim S.G.
      • Sievert W.
      • Tong M.
      • Arterburn S.
      • et al.
      Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.
      ,
      • Liaw Y.F.
      • Gane E.
      • Leung N.
      • Zeuzem S.
      • Wang Y.
      • Lai C.L.
      • et al.
      2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B.
      ,
      • Chang T.T.
      • Lai C.L.
      • Kew Y.S.
      • Lee S.S.
      • Coelho H.S.
      • Carrilho F.J.
      • et al.
      Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B.
      ], but are affected if resistance occurs [
      • Reijnders J.G.
      • Perquin M.J.
      • Zhang N.
      • Hansen B.E.
      • Janssen H.L.
      Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B.
      ]. Anti-HBe seroconversion is less durable after discontinuation of NA compared to PEG-IFN therapy [
      • Reijnders J.G.
      • Perquin M.J.
      • Zhang N.
      • Hansen B.E.
      • Janssen H.L.
      Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B.
      ,
      • van Nunen A.B.
      • Hansen B.E.
      • Suh D.J.
      • Lohr H.F.
      • Chemello L.
      • Fontaine H.
      • et al.
      Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pre-treatment serum hepatitis B virus DNA and alanine aminotransferase.
      ,
      • Buster E.H.
      • Flink H.J.
      • Cakaloglu Y.
      • Simon K.
      • Trojan J.
      • Tabak F.
      • et al.
      Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b.
      ,
      • Wong V.W.
      • Wong G.L.
      • Yan K.K.
      • Chim A.M.
      • Chan H.Y.
      • Tse C.H.
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      Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B.
      ] (B1). Durability after anti-HBe seroconversion following treatment with more potent agents, i.e. entecavir and tenofovir, requires further evaluation. In patients adherent to treatment, virological remission rates of >90% can be maintained with ongoing entecavir or tenofovir after ⩾3 years [
      • Chang T.T.
      • Lai C.L.
      • Kew Y.S.
      • Lee S.S.
      • Coelho H.S.
      • Carrilho F.J.
      • et al.
      Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B.
      ,
      • Yuen M.F.
      • Seto W.K.
      • Fung J.
      • Wong D.K.
      • Yuen J.C.
      • Lai C.L.
      Three years of continuous entecavir therapy in treatment-naive chronic hepatitis B patients: viral suppression, viral resistance, and clinical safety.
      ,
      • Marcellin P.
      • Buti M.
      • Gane E.J.
      • Krastev Z.
      • Flisiak R.
      • Germanidis G.
      • et al.
      Five years of treatment with tenofovir DF (TDF) for chronic hepatitis B (CHB) infection is associated with sustained viral suppression and significant regression of histological fibrosis and cirrhosis.
      ,
      • Heathcote E.J.
      • Marcellin P.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B.
      ].
      Rates of HBsAg loss following 12 months of treatment were 3–7% with PEG-IFN, 1% with lamivudine, 0% with adefovir, 2% with entecavir, 0.5% with telbivudine, and 3% with tenofovir [
      • Lau G.K.
      • Piratvisuth T.
      • Luo K.X.
      • Marcellin P.
      • Thongsawat S.
      • Cooksley G.
      • et al.
      Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.
      ,
      • Janssen H.L.
      • van Z.M.
      • Senturk H.
      • Zeuzem S.
      • Akarca U.S.
      • Cakaloglu Y.
      • et al.
      Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.
      ,
      • Lai C.L.
      • Chien R.N.
      • Leung N.W.
      • Chang T.T.
      • Guan R.
      • Tai D.I.
      • et al.
      A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group.
      ,
      • Dienstag J.L.
      • Schiff E.R.
      • Wright T.L.
      • Perrillo R.P.
      • Hann H.W.
      • Goodman Z.
      • et al.
      Lamivudine as initial treatment for chronic hepatitis B in the United States.
      ,
      • Chang T.T.
      • Gish R.G.
      • de Man R.
      • Gadano A.
      • Sollano J.
      • Chao Y.C.
      • et al.
      A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.
      ,
      • Lai C.L.
      • Gane E.
      • Liaw Y.F.
      • Hsu C.W.
      • Thongsawat S.
      • Wang Y.
      • et al.
      Telbivudine versus lamivudine in patients with chronic hepatitis B.
      ,
      • Marcellin P.
      • Chang T.T.
      • Lim S.G.
      • Tong M.J.
      • Sievert W.
      • Shiffman M.L.
      • et al.
      Adefovir dipivoxil for the treatment of hepatitis B antigen-positive chronic hepatitis B.
      ,
      • Marcellin P.
      • Heathcote E.J.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
      ]. HBsAg loss rates increase after the end of (PEG-)IFN therapy in patients with sustained off-treatment virological response [
      • Van Zonneveld M.
      • Honkoop P.
      • Hansen B.E.
      • Niesters H.G.
      • Murad S.D.
      • de Man R.A.
      • et al.
      Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B.
      ,
      • Buster E.H.
      • Flink H.J.
      • Simsek H.
      • Heathcote E.J.
      • Sharmila S.
      • Kitis G.E.
      • et al.
      Early HBeAg loss during peginterferon alpha-2b therapy predicts HBsAg loss: results of a long-term follow-up study in chronic hepatitis B patients.
      ,
      • Moucari R.
      • Korevaar A.
      • Lada O.
      • Martinot-Peignoux M.
      • Boyer N.
      • Mackiewicz V.
      • et al.
      High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: a long-term follow-up study.
      ,
      • Piratvisuth T.
      • Lau G.
      • Chao Y.C.
      • Jin R.
      • Chutaputti A.
      • Zhang Q.B.
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      Sustained response to peginterferon alfa-2a (40 kD) with or without lamivudine in Asian patients with HBeAg-positive and HBeAg-negative chronic hepatitis B.
      ] and with prolongation of NA(s) therapy [
      • Liaw Y.F.
      • Gane E.
      • Leung N.
      • Zeuzem S.
      • Wang Y.
      • Lai C.L.
      • et al.
      2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B.
      ,
      • Chang T.T.
      • Lai C.L.
      • Kew Y.S.
      • Lee S.S.
      • Coelho H.S.
      • Carrilho F.J.
      • et al.
      Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B.
      ,
      • Marcellin P.
      • Buti M.
      • Gane E.J.
      • Krastev Z.
      • Flisiak R.
      • Germanidis G.
      • et al.
      Five years of treatment with tenofovir DF (TDF) for chronic hepatitis B (CHB) infection is associated with sustained viral suppression and significant regression of histological fibrosis and cirrhosis.
      ,
      • Heathcote E.J.
      • Marcellin P.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B.
      ,
      • Gish R.G.
      • Chang T.T.
      • Lai C.L.
      • de M.R.
      • Gadano A.
      • Poordad F.
      • et al.
      Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naive HBeAg-positive patients with chronic hepatitis B.
      ].
      (2) HBeAg-negative patients
      Response rates at 6 months following 12 months of PEG-IFN and at 12 months of NA therapy are given in Table 3 [
      • Lai C.L.
      • Gane E.
      • Liaw Y.F.
      • Hsu C.W.
      • Thongsawat S.
      • Wang Y.
      • et al.
      Telbivudine versus lamivudine in patients with chronic hepatitis B.
      ,
      • Marcellin P.
      • Heathcote E.J.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
      ,
      • Tassopoulos N.C.
      • Volpes R.
      • Pastore G.
      • Heathcote J.
      • Buti M.
      • Goldin R.D.
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      Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B.
      ,
      • Marcellin P.
      • Lau G.K.
      • Bonino F.
      • Farci P.
      • Hadziyannis S.
      • Jin R.
      • et al.
      Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.
      ,
      • Lai C.L.
      • Shouval D.
      • Lok A.S.
      • Chang T.T.
      • Cheinquer H.
      • Goodman Z.
      • et al.
      Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.
      ,
      • Hadziyannis S.J.
      • Tassopoulos N.C.
      • Heathcote E.J.
      • Chang T.T.
      • Kitis G.
      • Rizzetto M.
      • et al.
      Adefovir dipivoxil for the treatment of hepatitis B antigen-negative chronic hepatitis B.
      ]. Rates of sustained off-treatment virological response were of the order of 20% at 6 months following 12 months of PEG-IFN therapy and <5% following discontinuation of 12 months of NA(s) therapy [
      • Tassopoulos N.C.
      • Volpes R.
      • Pastore G.
      • Heathcote J.
      • Buti M.
      • Goldin R.D.
      • et al.
      Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B.
      ,
      • Marcellin P.
      • Lau G.K.
      • Bonino F.
      • Farci P.
      • Hadziyannis S.
      • Jin R.
      • et al.
      Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.
      ,
      • Lai C.L.
      • Shouval D.
      • Lok A.S.
      • Chang T.T.
      • Cheinquer H.
      • Goodman Z.
      • et al.
      Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.
      ,
      • Hadziyannis S.J.
      • Tassopoulos N.C.
      • Heathcote E.J.
      • Chang T.T.
      • Kitis G.
      • Rizzetto M.
      • et al.
      Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B.
      ,
      • Shouval D.
      • Lai C.L.
      • Chang T.T.
      • Cheinquer H.
      • Martin P.
      • Carosi G.
      • et al.
      Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy.
      ]. In patients adherent to treatment, virological remission rates of >95% can be maintained with entecavir or tenofovir at ⩾3–5 years [
      • Marcellin P.
      • Buti M.
      • Gane E.J.
      • Krastev Z.
      • Flisiak R.
      • Germanidis G.
      • et al.
      Five years of treatment with tenofovir DF (TDF) for chronic hepatitis B (CHB) infection is associated with sustained viral suppression and significant regression of histological fibrosis and cirrhosis.
      ,
      • Shouval D.
      • Lai C.-L.
      • Chang T.-T.
      • Gadano A.
      • Wu S.-S.
      • Halota W.
      • et al.
      Three years of entecavir (ETV) re-treatment of HBeAg(−) ETV patients who previously discontinued ETV treatment: results from study ETV-901.
      ].
      Rates of HBsAg loss following 12 months of treatment were 3% with PEG-IFN-2a (at 6 months after the end of therapy) and 0% with lamivudine, adefovir, entecavir, telbivudine or tenofovir [
      • Lai C.L.
      • Gane E.
      • Liaw Y.F.
      • Hsu C.W.
      • Thongsawat S.
      • Wang Y.
      • et al.
      Telbivudine versus lamivudine in patients with chronic hepatitis B.
      ,
      • Marcellin P.
      • Heathcote E.J.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
      ,
      • Tassopoulos N.C.
      • Volpes R.
      • Pastore G.
      • Heathcote J.
      • Buti M.
      • Goldin R.D.
      • et al.
      Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B.
      ,
      • Marcellin P.
      • Lau G.K.
      • Bonino F.
      • Farci P.
      • Hadziyannis S.
      • Jin R.
      • et al.
      Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.
      ,
      • Lai C.L.
      • Shouval D.
      • Lok A.S.
      • Chang T.T.
      • Cheinquer H.
      • Goodman Z.
      • et al.
      Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.
      ,
      • Hadziyannis S.J.
      • Tassopoulos N.C.
      • Heathcote E.J.
      • Chang T.T.
      • Kitis G.
      • Rizzetto M.
      • et al.
      Adefovir dipivoxil for the treatment of hepatitis B antigen-negative chronic hepatitis B.
      ]. HBsAg loss rates increase to 9% at 3 years and 12% at 5 years following PEG-IFN-2a therapy [
      • Marcellin P.
      • Bonino F.
      • Lau G.K.
      • Farci P.
      • Yurdaydin C.
      • Piratvisuth T.
      • et al.
      Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2a.
      ,
      • Marcellin P.
      • Piratvisuth T.
      • Brunetto M.
      • Bonino F.
      • Lau G.K.K.
      • Farci P.
      • et al.
      Increasing rates of HBsAg clearance and seroconversion in patients with HBeAg-negative disease treated with peginterferon alfa-2a ± lamivudine: results of 5-year post-treatment follow up.
      ]. In contrast, HBsAg loss is exceptionally observed during the first 4–5 years of NA(s) therapy in HBeAg-negative CHB patients [
      • Liaw Y.F.
      • Gane E.
      • Leung N.
      • Zeuzem S.
      • Wang Y.
      • Lai C.L.
      • et al.
      2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B.
      ,
      • Marcellin P.
      • Buti M.
      • Gane E.J.
      • Krastev Z.
      • Flisiak R.
      • Germanidis G.
      • et al.
      Five years of treatment with tenofovir DF (TDF) for chronic hepatitis B (CHB) infection is associated with sustained viral suppression and significant regression of histological fibrosis and cirrhosis.
      ,
      • Papatheodoridis G.V.
      • Dimou E.
      • Dimakopoulos K.
      • Manolakopoulos S.
      • Rapti I.
      • Kitis G.
      • et al.
      Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine.
      ,
      • Hadziyannis S.J.
      • Tassopoulos N.C.
      • Heathcote E.J.
      • Chang T.T.
      • Kitis G.
      • Rizzetto M.
      • et al.
      Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years.
      ].

      Predictors of response

      Certain general baseline and on-treatment predictors of subsequent response have been identified. Predictors of response for the existing antiviral therapies at various time points vary for different agents. Predictors may be useful to guide initiation and continuation of antiviral therapy.
      (1) For IFN/PEG-IFN based treatment
      • Pre-treatment factors
        In HBeAg-positive CHB, predictors of anti-HBe seroconversion are low viral load (HBV DNA below 2 × 108 IU/ml), high serum ALT levels (above 2–5 times ULN), HBV genotype and high activity scores on liver biopsy (at least A2) [
        • Lau G.K.
        • Piratvisuth T.
        • Luo K.X.
        • Marcellin P.
        • Thongsawat S.
        • Cooksley G.
        • et al.
        Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.
        ,
        • Janssen H.L.
        • van Z.M.
        • Senturk H.
        • Zeuzem S.
        • Akarca U.S.
        • Cakaloglu Y.
        • et al.
        Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.
        ,
        • Perrillo R.P.
        • Schiff E.R.
        • Davis G.L.
        • Bodenheimer H.C.
        • Lindsay K.
        • Payne J.
        • et al.
        A randomized, controlled trial of interferon alfa-2B alone and after prednisone withdrawal for the treatment of chronic hepatitis-B.
        ,
        • Wong D.K.H.
        • Cheung A.M.
        • O’Rourke K.
        • Naylor C.D.
        • Detsky A.S.
        • Heathcote J.
        Effect of alpha-interferon in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis.
        ] (B2). HBV genotypes A and B have been shown to be associated with higher rates of anti-HBe seroconversion and HBsAg loss than genotypes D and C, respectively, after treatment with PEG-IFN [
        • Lau G.K.
        • Piratvisuth T.
        • Luo K.X.
        • Marcellin P.
        • Thongsawat S.
        • Cooksley G.
        • et al.
        Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.
        ,
        • Janssen H.L.
        • van Z.M.
        • Senturk H.
        • Zeuzem S.
        • Akarca U.S.
        • Cakaloglu Y.
        • et al.
        Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.
        ,
        • Flink H.J.
        • van Z.M.
        • Hansen B.E.
        • de Man R.A.
        • Schalm S.W.
        • Janssen H.L.
        Treatment with peg-interferon alpha-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype.
        ,
        • Buster E.H.
        • Hansen B.E.
        • Lau G.K.
        • Piratvisuth T.
        • Zeuzem S.
        • Steyerberg E.W.
        • et al.
        Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa.
        ].
        In HBeAg-negative CHB, there are no strong pre-treatment predictors of virological response.
      • During treatment
        In HBeAg-positive CHB, a HBV DNA decrease to <20,000 IU/ml at 12 weeks is associated with a 50% chance of anti-HBe seroconversion [
        • Fried M.W.
        • Piratvisuth T.
        • Lau G.K.
        • Marcellin P.
        • Chow W.C.
        • Cooksley G.
        • et al.
        HBeAg and hepatitis B virus DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic hepatitis B.
        ] and immunologically induced ALT flares followed by a HBV DNA decrease are associated with more frequent anti-HBe seroconversion [
        • Flink H.J.
        • Sprengers D.
        • Hansen B.E.
        • van Z.M.
        • de Man R.A.
        • Schalm S.W.
        • et al.
        Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during peg-interferon {alpha}-2b therapy.
        ] (B2). Recent data showed that decline of HBsAg levels below 1500 IU/ml at 12 weeks is a strong predictor of anti-HBe seroconversion [

        Piratvisuth T, Marcellin P, Popescu M, Kapprell HP, Rothe V, Lu ZM. Hepatitis B surface antigen: association with sustained response to peginterferon alfa-2a in hepatitis B e antigen-positive patients. Hepatol Int 2011. PMID: 21701902 [Epub ahead of print].

        ,
        • Gane E.
        • Jia J.
        • Han K.
        • Tanwandee T.
        • Chuang W.L.
        • Chuang W.L.
        • et al.
        Neptune study: on-treatment HBsAg level analysis confirms prediction of response observed in phase 3 study of peginterferon alfa-2a in HBeAg-positive patients.
        ] (C2), while HBsAg levels >20,000 IU/ml or no decline of HBsAg levels at 12 weeks are associated with a very low probability of subsequent anti-HBe seroconversion [

        Piratvisuth T, Marcellin P, Popescu M, Kapprell HP, Rothe V, Lu ZM. Hepatitis B surface antigen: association with sustained response to peginterferon alfa-2a in hepatitis B e antigen-positive patients. Hepatol Int 2011. PMID: 21701902 [Epub ahead of print].

        ,
        • Gane E.
        • Jia J.
        • Han K.
        • Tanwandee T.
        • Chuang W.L.
        • Chuang W.L.
        • et al.
        Neptune study: on-treatment HBsAg level analysis confirms prediction of response observed in phase 3 study of peginterferon alfa-2a in HBeAg-positive patients.
        ,
        • Sonneveld M.J.
        • Rijckborst V.
        • Boucher C.A.
        • Hansen B.E.
        • Janssen H.L.
        Prediction of sustained response to peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline.
        ] (C2). HBeAg levels at week 24 may also predict anti-HBe seroconversion [
        • Fried M.W.
        • Piratvisuth T.
        • Lau G.K.
        • Marcellin P.
        • Chow W.C.
        • Cooksley G.
        • et al.
        HBeAg and hepatitis B virus DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic hepatitis B.
        ] (B2).
        In HBeAg-negative CHB, HBV DNA decrease to <20,000 IU/ml at 12 weeks has been reported to be associated with a 50% chance of sustained off-treatment response [
        • Bonino F.
        • Marcellin P.
        • Lau G.K.
        • Hadziyannis S.
        • Jin R.
        • Piratvisuth T.
        • et al.
        Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B.
        ]. A combination of no HBsAg decline and <2 log10 IU/ml decline of HBV DNA seems to be a predictor of non-response in European HBeAg-negative patients with genotype D [
        • Rijckborst V.
        • Hansen B.E.
        • Cakaloglu Y.
        • Ferenci P.
        • Tabak F.
        • Akdogan M.
        • et al.
        Early on-treatment prediction of response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA levels.
        ,
        • Rijckborst V.
        • Hansen B.E.
        • Ferenci P.
        • Brunetto M.R.
        • Tabak F.
        • Cakaloglu Y.
        • et al.
        Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alfa-2a.
        ] (B2). Several recent reports showed that HBsAg decline is predictive of sustained off-treatment virological response and HBsAg loss [
        • Brunetto M.R.
        • Moriconi F.
        • Bonino F.
        • Lau G.K.
        • Farci P.
        • Yurdaydin C.
        • et al.
        Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B.
        ,
        • Moucari R.
        • Mackiewicz V.
        • Lada O.
        • Ripault M.P.
        • Castelnau C.
        • Martinot-Peignoux M.
        • et al.
        Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients.
        ,
        • Moucari R.
        • Martinot-Peignoux M.
        • Mackiewicz V.
        • Boyer N.
        • Ripault M.P.
        • Castelnau C.
        • et al.
        Influence of genotype on hepatitis B surface antigen kinetics in hepatitis B e antigen-negative patients treated with pegylated interferon-alpha2a.
        ]. However, further studies are needed to clarify how to optimise the use of HBsAg levels in the management of patients in clinical practice.
      (2) For NAs treatment
      • Pre-treatment factors
        In HBeAg-positive CHB, pre-treatment factors predictive of anti-HBe seroconversion are low viral load (HBV DNA below 2 × 108 IU/ml), high serum ALT levels, high activity scores on liver biopsy [
        • Marcellin P.
        • Chang T.T.
        • Lim S.G.
        • Tong M.J.
        • Sievert W.
        • Shiffman M.L.
        • et al.
        Adefovir dipivoxil for the treatment of hepatitis B antigen-positive chronic hepatitis B.
        ,
        • Marcellin P.
        • Heathcote E.J.
        • Buti M.
        • Gane E.
        • de Man R.A.
        • Krastev Z.
        • et al.
        Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
        ,
        • Liaw Y.F.
        • Gane E.
        • Leung N.
        • Zeuzem S.
        • Wang Y.
        • Lai C.L.
        • et al.
        2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B.
        ,
        • Perrillo R.P.
        • Lai C.L.
        • Liaw Y.F.
        • Dienstag J.L.
        • Schiff E.R.
        • Schalm S.W.
        • et al.
        Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B.
        ] (A1).
        HBV genotype does not influence the virological response to any NA [
        • Wiegand J.
        • Hasenclever D.
        • Tillmann H.L.
        Should treatment of hepatitis B depend on hepatitis B virus genotypes? A hypothesis generated from an explorative analysis of published evidence.
        ] (A1).
      • During treatment
        Virological response (undetectable HBV DNA) at 24 weeks during treatment with lamivudine or telbivudine and at 48 weeks during treatment with adefovir is associated with a lower incidence of resistance, i.e. an improved chance of maintained virological response, in both HBeAg-positive and HBeAg-negative patients and with a higher chance of anti-HBe seroconversion in HBeAg-positive patients [
        • Liaw Y.F.
        • Gane E.
        • Leung N.
        • Zeuzem S.
        • Wang Y.
        • Lai C.L.
        • et al.
        2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B.
        ,
        • Hadziyannis S.J.
        • Tassopoulos N.C.
        • Heathcote E.J.
        • Chang T.T.
        • Kitis G.
        • Rizzetto M.
        • et al.
        Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years.
        ,
        • Yuen M.F.
        • Sablon E.
        • Hui C.K.
        • Yuan H.J.
        • Decraemer H.
        • Lai C.L.
        Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy.
        ,
        • Zeuzem S.
        • Gane E.
        • Liaw Y.F.
        • Lim S.G.
        • DiBisceglie A.
        • Buti M.
        • et al.
        Baseline characteristics and early on-treatment response predict the outcomes of 2 years of telbivudine treatment of chronic hepatitis B.
        ] (B1).
        A decline of HBsAg during NA treatment in HBeAg-positive patients may identify cases with subsequent HBeAg or HBsAg loss [
        • Wursthorn K.
        • Jung M.
        • Riva A.
        • Goodman Z.D.
        • Lopez P.
        • Bao W.
        • et al.
        Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients.
        ,
        • Lee J.M.
        • Ahn S.H.
        • Kim H.S.
        • Park H.
        • Chang H.Y.
        • Kim D.Y.
        • et al.
        Quantitative hepatitis B surface antigen and hepatitis B e antigen titers in prediction of treatment response to entecavir.
        ,
        • Marcellin P.
        • Heathcote E.J.
        • Buti M.
        • Krastev Z.
        • Jacobson I.
        • de Man R.A.
        • et al.
        HBsAg kinetics in patients with chronic hepatitis B (CHB) treated with tenofovir disoproxil fumarate (TDF) for up to 4 years.
        ] (C2).

      Treatment strategies: how-to-treat

      Currently, there are two different treatment strategies for both HBeAg-positive and HBeAg-negative CHB patients: treatment of finite duration with (PEG-)IFN or a NA and long-term treatment with NA(s).
      The main theoretical advantages of (PEG-)IFN are the absence of resistance and the potential for immune-mediated control of HBV infection with an opportunity to obtain a sustained virological response off-treatment and a chance of HBsAg loss in patients who achieve and maintain undetectable HBV DNA. Frequent side effects and subcutaneous injection are the main disadvantages of (PEG-)IFN treatment. (PEG-)IFN is contraindicated in patients with decompensated HBV-related cirrhosis or autoimmune disease, in patients with uncontrolled severe depression or psychosis, and in female patients during pregnancy (A1).
      Entecavir and tenofovir are potent HBV inhibitors with a high barrier to resistance [
      • Chang T.T.
      • Gish R.G.
      • de Man R.
      • Gadano A.
      • Sollano J.
      • Chao Y.C.
      • et al.
      A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.
      ,
      • Marcellin P.
      • Heathcote E.J.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
      ,
      • Chang T.T.
      • Lai C.L.
      • Kew Y.S.
      • Lee S.S.
      • Coelho H.S.
      • Carrilho F.J.
      • et al.
      Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B.
      ,
      • Heathcote E.J.
      • Marcellin P.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B.
      ,
      • Lai C.L.
      • Shouval D.
      • Lok A.S.
      • Chang T.T.
      • Cheinquer H.
      • Goodman Z.
      • et al.
      Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.
      ,
      • Marcellin P.
      • Heathcote E.J.
      • Corsa A.
      • Liu Y.
      • Miller M.D.
      • Kitrinos K.M.
      No detectable resistance to tenofovir disoproxil fumarate (TDF) following up to 240 weeks of treatment in patients with HBeAg+ and HBeAg− chronic hepatitis B virus infection.
      ] (Fig. 1). Thus, they can be confidently used as first-line monotherapies [
      • European Association for the Study of the Liver
      EASL clinical practice guidelines: management of chronic hepatitis B.
      ] (A1).
      Figure thumbnail gr1
      Fig. 1Cumulative incidence of HBV resistance to lamivudine (LAM), adefovir (ADV), entecavir (ETV), telbivudine (LdT) and tenofovir (TDF) in pivotal trials in nucleos(t)ide-naive patients with chronic hepatitis B. For method of calculation, see Ref.
      [
      • Pawlotsky J.M.
      • Dusheiko G.
      • Hatzakis A.
      • Lau D.
      • Lau G.
      • Liang T.J.
      • et al.
      Virologic monitoring of hepatitis B virus therapy in clinical trials and practice: recommendations for a standardized approach.
      ]
      . These trials included different populations, used different inclusion and exclusion criteria and different follow-up end points.
      The other three NAs may only be used in the treatment of CHB if more potent drugs with high barrier to resistance are not available or appropriate (A1). Lamivudine is an inexpensive agent, but engenders very high rates of resistance with long-term monotherapy [
      • Lok A.S.
      • Hussain M.
      • Cursano C.
      • Margotti M.
      • Gramenzi A.
      • Grazi G.L.
      • et al.
      Evolution of hepatitis B virus polymerase gene mutations in hepatitis B e antigen-negative patients receiving lamivudine therapy.
      ,
      • Hadziyannis S.J.
      • Papatheodoridis G.V.
      • Dimou E.
      • Laras A.
      • Papaioannou C.
      Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B.
      ,
      • Papatheodoridis G.V.
      • Dimou E.
      • Laras A.
      • Papadimitropoulos V.
      • Hadziyannis S.J.
      Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease.
      ,
      • Di Marco V.
      • Marzano A.
      • Lampertico P.
      • Andreone P.
      • Santantonio T.
      • Almasio P.L.
      • et al.
      Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine.
      ]. Adefovir is less efficacious and more expensive than tenofovir, engendering higher rates of resistance [
      • Marcellin P.
      • Heathcote E.J.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
      ,
      • Heathcote E.J.
      • Marcellin P.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B.
      ,
      • Hadziyannis S.J.
      • Tassopoulos N.C.
      • Heathcote E.J.
      • Chang T.T.
      • Kitis G.
      • Rizzetto M.
      • et al.
      Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years.
      ]. Telbivudine is a potent inhibitor of HBV replication, but, due to a lower barrier to resistance, a high incidence of resistance has been observed in patients with high baseline HBV DNA levels and in those with detectable HBV DNA after 6 months of therapy [
      • Lai C.L.
      • Gane E.
      • Liaw Y.F.
      • Hsu C.W.
      • Thongsawat S.
      • Wang Y.
      • et al.
      Telbivudine versus lamivudine in patients with chronic hepatitis B.
      ,
      • Liaw Y.F.
      • Gane E.
      • Leung N.
      • Zeuzem S.
      • Wang Y.
      • Lai C.L.
      • et al.
      2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B.
      ]; resistance rates to telbivudine are relatively low in patients with low baseline viremia (<2 × 108 IU/ml for HBeAg-positive and <2 × 106 IU/ml for HBeAg-negative patients) who achieve undetectable HBV DNA at 6 months of therapy [
      • Liaw Y.F.
      • Gane E.
      • Leung N.
      • Zeuzem S.
      • Wang Y.
      • Lai C.L.
      • et al.
      2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B.
      ,
      • Gane E.J.
      • Wang Y.
      • Liaw Y.F.
      • Hou J.
      • Thongsawat S.
      • Wan M.
      • et al.
      Efficacy and safety of prolonged 3-year telbivudine treatment in patients with chronic hepatitis B.
      ].
      (1) Treatment of finite duration with (PEG-)IFN or a NA. This strategy is intended to achieve a sustained off-treatment virological response (A1).
      • Finite-duration treatment with (PEG-)IFN. PEG-IFN, if available, has replaced standard IFN in the treatment of CHB mostly due to its easier applicability (once weekly administration). A 48-week course of PEG-IFN is mainly recommended for HBeAg-positive patients with the best chance of anti-HBe seroconversion. It can also be used for HBeAg-negative patients, as it is practically the only option that may offer a chance for sustained off-treatment response after a finite duration of therapy. Full information about the advantages, adverse events and inconveniences of (PEG-)IFN versus NAs (Table 4) should be provided so the patient can participate in the decision (A1).
        Table 4Main respective advantages and disadvantages of (pegylated) interferon alpha [(PEG-)IFN] and nucleos(t)ide analogues (NAs) in the treatment of chronic hepatitis B.
        The combination of PEG-IFN with lamivudine showed a higher on-treatment virological response but did not show a higher rate of sustained off-treatment virological or serological response [
        • Lau G.K.
        • Piratvisuth T.
        • Luo K.X.
        • Marcellin P.
        • Thongsawat S.
        • Cooksley G.
        • et al.
        Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.
        ,
        • Janssen H.L.
        • van Z.M.
        • Senturk H.
        • Zeuzem S.
        • Akarca U.S.
        • Cakaloglu Y.
        • et al.
        Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.
        ,
        • Marcellin P.
        • Lau G.K.
        • Bonino F.
        • Farci P.
        • Hadziyannis S.
        • Jin R.
        • et al.
        Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.
        ]. The combination of PEG-IFN with telbivudine showed a potent antiviral effect, but it is prohibited because of a high risk of severe polyneuropathy [
        • Marcellin P.
        • Avila C.
        • Wursthorn K.
        • Chuang W.L.
        • Lau G.K.
        • Peng C.Y.
        • et al.
        Telbivudine (LDT) plus peg-interferon (PEGIFN) in HBeAg-positive chronic hepatitis B – very potent antiviral efficacy but risk of peripheral neuropathy (PN).
        ]. Thus, presently the combinations of PEG-IFN with lamivudine or telbivudine are not recommended (A1). There is limited information on the efficacy and safety of combination of PEG-IFN with other NAs and presently this type of combination is not recommended.
      • Finite-duration treatment with a NA is achievable for HBeAg-positive patients who seroconvert to anti-HBe on treatment. However, treatment duration is unpredictable prior to therapy as it depends on the timing of anti-HBe seroconversion and the treatment continuation post anti-HBe seroconversion. Anti-HBe seroconversion may not be durable after NAs discontinuation, at least with less potent agents, in a substantial proportion of these patients requiring close virologic monitoring after treatment cessation. An attempt for finite NA treatment should use the most potent agents with the highest barrier to resistance to rapidly reduce levels of viremia to undetectable levels and avoid breakthroughs due to HBV resistance (A1). Once anti-HBe seroconversion occurs during NA administration, treatment should be prolonged for an additional 12 months [
        • Lee H.W.
        • Lee H.J.
        • Hwang J.S.
        • Sohn J.H.
        • Jang J.Y.
        • Han K.J.
        • et al.
        Lamivudine maintenance beyond one year after HBeAg seroconversion is a major factor for sustained virologic response in HBeAg-positive chronic hepatitis B.
        ]; a durable off-treatment response (persistence of anti-HBe seroconversion) can be expected in 40–80% of these patients [
        • Reijnders J.G.
        • Perquin M.J.
        • Zhang N.
        • Hansen B.E.
        • Janssen H.L.
        Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B.
        ,
        • van Nunen A.B.
        • Hansen B.E.
        • Suh D.J.
        • Lohr H.F.
        • Chemello L.
        • Fontaine H.
        • et al.
        Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pre-treatment serum hepatitis B virus DNA and alanine aminotransferase.
        ,
        • Lee H.W.
        • Lee H.J.
        • Hwang J.S.
        • Sohn J.H.
        • Jang J.Y.
        • Han K.J.
        • et al.
        Lamivudine maintenance beyond one year after HBeAg seroconversion is a major factor for sustained virologic response in HBeAg-positive chronic hepatitis B.
        ,
        • Song B.-C.
        • Suh D.J.
        • Lee H.C.
        • Chung Y.-H.
        • Lee Y.S.
        Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea.
        ,
        • Dienstag J.L.
        • Cianciara J.
        • Karayalcin S.
        • Kowdley K.V.
        • Willems B.
        • Plisek S.
        • et al.
        Durability of serologic response after lamivudine treatment of chronic hepatitis B.
        ,
        • Yoon S.K.
        • Jang J.W.
        • Kim C.W.
        • Bae S.H.
        • Choi J.Y.
        • Choi S.W.
        • et al.
        Long-term results of lamivudine monotherapy in Korean patients with HBeAg-positive chronic hepatitis B: response and relapse rates, and factors related to durability of HBeAg seroconversion.
        ,
        • Wu I.C.
        • Shiffman M.L.
        • Tong M.J.
        • Marcellin P.
        • Mondou E.
        • Frederick D.
        • et al.
        Sustained hepatitis B e antigen seroconversion in patients with chronic hepatitis B after adefovir dipivoxil treatment: analysis of precore and basal core promoter mutants.
        ] (B1).
      (2) Long-term treatment with NA(s). This strategy is necessary for patients who are not expected or fail to achieve a sustained off-treatment virological response and require extended therapy, i.e. for HBeAg-positive patients who do not develop anti-HBe seroconversion and HBeAg-negative patients. This strategy is also recommended in patients with cirrhosis irrespective of HBeAg status or anti-HBe seroconversion on treatment (C1).
      The most potent drugs with the optimal resistance profile, i.e. tenofovir or entecavir, should be used as first-line monotherapies (A1). It is optimal to achieve and maintain undetectable HBV DNA level tested by real-time PCR, whatever the drug used (B1). The long-term effects, safety and tolerability of entecavir and tenofovir are still unknown. Treatment with either tenofovir or entecavir monotherapy for ⩾3 years achieves maintained virological remission in the vast majority of patients [
      • Chang T.T.
      • Lai C.L.
      • Kew Y.S.
      • Lee S.S.
      • Coelho H.S.
      • Carrilho F.J.
      • et al.
      Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B.
      ,
      • Marcellin P.
      • Buti M.
      • Gane E.J.
      • Krastev Z.
      • Flisiak R.
      • Germanidis G.
      • et al.
      Five years of treatment with tenofovir DF (TDF) for chronic hepatitis B (CHB) infection is associated with sustained viral suppression and significant regression of histological fibrosis and cirrhosis.
      ,
      • Heathcote E.J.
      • Marcellin P.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B.
      ] (A1).
      There are as yet no data to indicate an advantage of de novo combination treatment with NAs in NA naive patients receiving either entecavir or tenofovir [
      • Lok A.S.
      • Trihn H.N.
      • Carosi G.
      • Akarca U.S.
      • Gadano A.
      • Habersetzer F.
      • et al.
      Entecavir (ETV) monotherapy for 96 weeks is comparable to combination therapy with ETV plus tenofovir (TDF) in nucleos(t)ide naive patients with chronic hepatitis B: the BELOW study.
      ] (C1).

      Treatment failure

      It is important to distinguish between primary non-response, partial virological response and virological breakthrough [
      • Pawlotsky J.M.
      • Dusheiko G.
      • Hatzakis A.
      • Lau D.
      • Lau G.
      • Liang T.J.
      • et al.
      Virologic monitoring of hepatitis B virus therapy in clinical trials and practice: recommendations for a standardized approach.
      ,
      • Lok A.S.
      • Zoulim F.
      • Locarnini S.
      • Bartholomeusz A.
      • Ghany M.G.
      • Pawlotsky J.M.
      • et al.
      Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management.
      ].
      (1) Primary non-response. Primary non-response is rarely observed with entecavir or tenofovir, telbivudine or lamivudine. In patients with primary non-response to any NA, it is important to check for compliance. In a compliant patient with a primary non-response, genotyping of HBV strains for identification of possible resistance mutations may help in formulating a rescue strategy that must reasonably be based on an early change to a more potent drug that is active against the resistant HBV variant (B1).
      Primary non-response seems to be more frequent with adefovir (approximately 10–20%) than with other NAs because of suboptimal antiviral efficacy. In NA(s) naive patients with primary non-response to adefovir, a rapid switch to tenofovir or entecavir is recommended (B1).
      (2) Partial virological response. Partial virological response may be encountered with all available NAs. It is always important to check for compliance.
      In patients receiving lamivudine or telbivudine (drugs with a low genetic barrier to resistance) with a partial virological response at week 24 or in patients receiving adefovir (moderately potent drug that engenders relatively late emergence of resistance) with a partial response at week 48, change to a more potent drug (entecavir or tenofovir), preferentially without cross-resistance, is recommended (A1).
      The optimal management of patients with partial virological response under entecavir or tenofovir (highly potent drugs with a high genetic barrier to resistance) is currently debatable. In such patients with a partial virological response at week 48, the HBV DNA levels at week 48 and their kinetics must be taken into account. Patients with declining serum HBV DNA levels may continue treatment with the same agent (entecavir or tenofovir) given the rise in rates of virological response over time and the very low risk of resistance with long-term monotherapy with both these agents [
      • Zoutendijk R.
      • Reijnders J.G.
      • Brown A.
      • Zoulim F.
      • Mutimer D.
      • Deterding K.
      • et al.
      Entecavir treatment for chronic hepatitis B: adaptation is not needed for the majority of naive patients with a partial virological response.
      ] (B1). Some experts would suggest adding the other drug in order to prevent resistance in the long term, particularly in the rare patients without further HBV DNA decline despite drug compliance (C2).
      (3) Virological breakthrough. Virological breakthrough in compliant patients is related to the development of HBV drug resistance. Testing for genotypic resistance may be performed in compliant patients with confirmed virological breakthroughs, although it is not absolutely necessary for NA naive patients with confirmed virological breakthroughs under monotherapy with lamivudine or telbivudine (B1). Rates of resistance after up to 5 years of administration of the different NAs are shown in Fig. 1. The rates of resistance at 5 years in NA naive patients are <1.5% and 0% for entecavir and tenofovir, respectively [
      • Chang T.T.
      • Lai C.L.
      • Kew Y.S.
      • Lee S.S.
      • Coelho H.S.
      • Carrilho F.J.
      • et al.
      Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B.
      ,
      • Marcellin P.
      • Heathcote E.J.
      • Corsa A.
      • Liu Y.
      • Miller M.D.
      • Kitrinos K.M.
      No detectable resistance to tenofovir disoproxil fumarate (TDF) following up to 240 weeks of treatment in patients with HBeAg+ and HBeAg− chronic hepatitis B virus infection.
      ]; thus, virological breakthroughs in NA naive patients receiving entecavir or tenofovir are usually due to poor drug compliance.
      The risk of resistance is associated with high baseline HBV DNA levels, a slow decline in HBV DNA and suboptimal previous NA treatment. Resistance should be identified by HBV DNA monitoring as early as possible before biochemical breakthrough (increased ALT), and ideally identification of the pattern of resistance mutations should be used to adapt therapeutic strategies. Indeed, clinical and virological studies have demonstrated the benefit of an early treatment adaptation, as soon as viral load increases [
      • Papatheodoridis G.V.
      • Dimou E.
      • Dimakopoulos K.
      • Manolakopoulos S.
      • Rapti I.
      • Kitis G.
      • et al.
      Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine.
      ,
      • Lampertico P.
      • Vigano P.
      • Manenti E.
      • Iavarone M.
      • Lunghi G.
      • Colombo M.
      Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine.
      ] (B1).
      In case of resistance, an appropriate rescue therapy should be initiated with the most effective antiviral agent that does not share cross resistance to minimise the risk of inducing multiple drug-resistant strains (A1). It should be noted that sequential monotherapies with agents with low barriers and hence high or intermediate risk of resistance (lamivudine, adefovir, telbivudine) should be strictly avoided because of the high risk for emergence of multi-drug resistance strains (C1). Table 5 shows cross-resistance data for the most frequent resistant HBV variants [
      • Zoulim F.
      • Locarnini S.
      Hepatitis B virus resistance to nucleos(t)ide analogues.
      ].
      Table 5Cross-resistance data for the most frequent resistant HBV variants. The amino-acid substitution profiles are shown in the left column and the level of susceptibility is given for each drug: S (sensitive), I (intermediate/reduced susceptibility), R (resistant)
      • Zoulim F.
      • Locarnini S.
      Hepatitis B virus resistance to nucleos(t)ide analogues.
      .
      In case of resistance to lamivudine, most experts based on the current evidence suggest that switching to tenofovir is as effective as adding tenofovir to lamivudine [
      • Van Bommel F.
      • de Man R.A.
      • Wedemeyer H.
      • Deterding K.
      • Petersen J.
      • Buggisch P.
      • et al.
      Long-term efficacy of tenofovir monotherapy for hepatitis B virus-monoinfected patients after failure of nucleoside/nucleotide analogues.
      ]. In case of adefovir resistance, a switch to entecavir or tenofovir or tenofovir plus emtricitabine (in a single tablet) is an option [
      • Reijnders J.G.
      • Deterding K.
      • Petersen J.
      • Zoulim F.
      • Santantonio T.
      • Buti M.
      • et al.
      Antiviral effect of entecavir in chronic hepatitis B: influence of prior exposure to nucleos(t)ide analogues.
      ,
      • Berg T.
      • Marcellin P.
      • Zoulim F.
      • Moller B.
      • Trinh H.
      • Chan S.
      • et al.
      Tenofovir is effective alone or with emtricitabine in adefovir-treated patients with chronic-hepatitis B virus infection.
      ]. The efficacy of tenofovir monotherapy has been reported to be suboptimal in patients with high serum HBV DNA levels due to virological breakthroughs associated with adefovir resistance [
      • Van Bommel F.
      • de Man R.A.
      • Wedemeyer H.
      • Deterding K.
      • Petersen J.
      • Buggisch P.
      • et al.
      Long-term efficacy of tenofovir monotherapy for hepatitis B virus-monoinfected patients after failure of nucleoside/nucleotide analogues.
      ]. In case of telbivudine resistance, a switch to or adding-on tenofovir are the preferred options [
      • Lok A.S.
      • Zoulim F.
      • Locarnini S.
      • Bartholomeusz A.
      • Ghany M.G.
      • Pawlotsky J.M.
      • et al.
      Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management.
      ]. There are few data for the treatment of the rare patients with entecavir resistance, and therefore a switch to or adding-on tenofovir may be preferred in such cases [
      • Lok A.S.
      • Zoulim F.
      • Locarnini S.
      • Bartholomeusz A.
      • Ghany M.G.
      • Pawlotsky J.M.
      • et al.
      Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management.
      ]. To date, resistance to tenofovir has not been described. It is recommended that genotyping and phenotyping should be done in such cases by an expert laboratory to determine the cross-resistance profile. In case of confirmed tenofovir resistance, an add-on combination with a nucleoside analogue should be preferred, while a switch to entecavir may be sufficient if the patient had no prior lamivudine resistance. In patients with multidrug resistance, genotypic resistance testing is very useful and a combination of a nucleoside and a nucleotide (preferably tenofovir) should be used.
      • Lamivudine resistance: switch to tenofovir (add adefovir if tenofovir is not available) (B1).
      • Adefovir resistance: if the patient was NA naive before adefovir, switch to entecavir or tenofovir (B1); entecavir may be preferred in such patients with high viraemia (C2). If the patient had prior lamivudine resistance, switch to tenofovir and add a nucleoside analogue (C1).
      • Telbivudine resistance: switch to or add tenofovir (add adefovir if tenofovir is not available) (C1).
      • Entecavir resistance: switch to or add tenofovir (add adefovir if tenofovir is not available) (C1).
      • Tenofovir resistance: tenofovir resistance has not been detected to date and therefore there is no experience, but it seems reasonable to add entecavir, telbivudine, lamivudine or emtricitabine if tenofovir resistance is confirmed (C2). A switch to entecavir may be sufficient if the patient has not been treated with lamivudine in the past, while adding entecavir may be the preferred option for patients with prior lamivudine resistance (C2).

      How to monitor treatment and stopping points

      Finite therapy with PEG-IFN

      In patients treated with PEG-IFN, full blood counts and serum ALT levels should be monitored monthly and TSH should be monitored every 3 months. All patients should be monitored for safety through 12 months of treatment.
      • In HBeAg-positive patients, HBeAg and anti-HBe antibodies and serum HBV DNA levels should be checked at 6 and 12 months of treatment and at 6 and 12 months post-treatment. Sustained off-treatment anti-HBe seroconversion together with ALT normalisation and serum HBV DNA below 2000 IU/ml is the desired outcome (A1). Undetectable serum HBV DNA by real-time PCR during follow-up is the optimal outcome, since it is associated with a significant chance of HBsAg loss (B1). HBeAg-positive patients who develop anti-HBe seroconversion with PEG-IFN require long-term follow-up because of the possibility of HBeAg seroreversion or progression to HBeAg-negative CHB [
        • Buster E.H.
        • Flink H.J.
        • Cakaloglu Y.
        • Simon K.
        • Trojan J.
        • Tabak F.
        • et al.
        Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b.
        ,
        • Wong V.W.
        • Wong G.L.
        • Yan K.K.
        • Chim A.M.
        • Chan H.Y.
        • Tse C.H.
        • et al.
        Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B.
        ] (A1). HBsAg should be checked at 12-month intervals after anti-HBe seroconversion if HBV DNA is undetectable, as the rate of HBsAg loss increases over time [
        • Moucari R.
        • Korevaar A.
        • Lada O.
        • Martinot-Peignoux M.
        • Boyer N.
        • Mackiewicz V.
        • et al.
        High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: a long-term follow-up study.
        ]. Patients who become HBsAg negative should be tested for anti-HBs. Patients treated with PEG-IFN who achieve quick reductions of HBV DNA and/or HBsAg levels through 3 or 6 months of therapy have an increased probability of response. In contrast, HBeAg-positive patients treated with PEG-IFN who fail to achieve serum HBsAg levels below 20,000 IU/ml or any decline in serum HBsAg levels by month 3 have a low probability of achieving anti-HBe seroconversion [

        Piratvisuth T, Marcellin P, Popescu M, Kapprell HP, Rothe V, Lu ZM. Hepatitis B surface antigen: association with sustained response to peginterferon alfa-2a in hepatitis B e antigen-positive patients. Hepatol Int 2011. PMID: 21701902 [Epub ahead of print].

        ,
        • Gane E.
        • Jia J.
        • Han K.
        • Tanwandee T.
        • Chuang W.L.
        • Chuang W.L.
        • et al.
        Neptune study: on-treatment HBsAg level analysis confirms prediction of response observed in phase 3 study of peginterferon alfa-2a in HBeAg-positive patients.
        ,
        • Sonneveld M.J.
        • Rijckborst V.
        • Boucher C.A.
        • Hansen B.E.
        • Janssen H.L.
        Prediction of sustained response to peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline.
        ]; therefore, stopping PEG-IFN therapy may be considered (C2).
      • In HBeAg-negative patients, serum HBV DNA levels should be measured at 6 and 12 months of treatment and at 6 and 12 months post-treatment. A sustained off-treatment virological response with HBV DNA <2000 IU/ml is generally associated with remission of the liver disease. Undetectable HBV DNA by real-time PCR is the ideal desired sustained off-treatment response with a higher probability of HBsAg loss in the longer term. HBsAg should be checked at 12-month intervals if HBV DNA remains undetectable (B1). Patients who become HBsAg negative should be tested for anti-HBs. HBeAg-negative patients who achieve sustained off-treatment response at 12 months after a PEG-IFN course require long-term follow-up, because there is still a risk of future disease reactivation that seems to diminish over time [
        • Manesis E.K.
        • Hadziyannis S.J.
        Interferon-alpha treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B.
        ] (A1). HBeAg-negative patients, in particular those with genotype D, treated with PEG-IFN who fail to achieve any decline in serum HBsAg levels and a ⩾2 log10 IU/ml decline in serum HBV DNA levels by month 3, have a very low probability of response; therefore, stopping PEG-IFN therapy should be considered [
        • Rijckborst V.
        • Hansen B.E.
        • Cakaloglu Y.
        • Ferenci P.
        • Tabak F.
        • Akdogan M.
        • et al.
        Early on-treatment prediction of response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA levels.
        ,
        • Rijckborst V.
        • Hansen B.E.
        • Ferenci P.
        • Brunetto M.R.
        • Tabak F.
        • Cakaloglu Y.
        • et al.
        Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alfa-2a.
        ] (B2).

      Finite treatment with NAs in HBeAg-positive patients

      The objective of finite treatment with a NA is sustained off-treatment anti-HBe seroconversion with HBV DNA <2000 IU/ml and normal ALT, or even HBsAg clearance (A1). HBeAg and anti-HBe should be checked every 6 months. HBV DNA should be measured by a sensitive PCR assay every 3–6 months during treatment. HBV DNA suppression to undetectable levels in real-time PCR and subsequent anti-HBe seroconversion is associated with biochemical and histological responses. Studies have suggested that NA therapy can be stopped 12 months after anti-HBe seroconversion (B1). A proportion of patients who discontinue NA therapy after anti-HBe seroconversion may require retreatment, since they fail to sustain their serological and/or virological response [
      • Reijnders J.G.
      • Perquin M.J.
      • Zhang N.
      • Hansen B.E.
      • Janssen H.L.
      Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B.
      ,
      • van Nunen A.B.
      • Hansen B.E.
      • Suh D.J.
      • Lohr H.F.
      • Chemello L.
      • Fontaine H.
      • et al.
      Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pre-treatment serum hepatitis B virus DNA and alanine aminotransferase.
      ,
      • Song B.-C.
      • Suh D.J.
      • Lee H.C.
      • Chung Y.-H.
      • Lee Y.S.
      Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea.
      ,
      • Dienstag J.L.
      • Cianciara J.
      • Karayalcin S.
      • Kowdley K.V.
      • Willems B.
      • Plisek S.
      • et al.
      Durability of serologic response after lamivudine treatment of chronic hepatitis B.
      ,
      • Yoon S.K.
      • Jang J.W.
      • Kim C.W.
      • Bae S.H.
      • Choi J.Y.
      • Choi S.W.
      • et al.
      Long-term results of lamivudine monotherapy in Korean patients with HBeAg-positive chronic hepatitis B: response and relapse rates, and factors related to durability of HBeAg seroconversion.
      ,
      • Wu I.C.
      • Shiffman M.L.
      • Tong M.J.
      • Marcellin P.
      • Mondou E.
      • Frederick D.
      • et al.
      Sustained hepatitis B e antigen seroconversion in patients with chronic hepatitis B after adefovir dipivoxil treatment: analysis of precore and basal core promoter mutants.
      ]. Therefore, NA treatment may be continued until HBsAg clearance with or without antibodies to HBsAg, particularly in patients with severe fibrosis or cirrhosis (C1). HBsAg should be checked at 12-month intervals after anti-HBe seroconversion. HBsAg loss, however, is not observed sufficiently frequently during or after NA therapy (Table 2).

      Long-term therapy with NAs

      HBV DNA reduction to undetectable levels by real-time PCR (i.e. below 10–15 IU/ml) should ideally be achieved to avoid resistance. HBV DNA monitoring is thus critical to detect treatment failure (A1). HBV DNA levels should be monitored at month 3 to ascertain virological response and then every 3–6 months. During therapy with entecavir or tenofovir, agents with high barrier to resistance, the frequency of follow-up measurement of HBV DNA might be decreased once patient compliance and treatment efficacy are confirmed (C1).
      NAs are cleared by the kidneys, and appropriate dosing adjustments are recommended for patients with creatinine clearance <50 ml/min (A1). Therefore, all patients starting NA therapy should be tested for serum creatinine levels and estimated creatinine clearance before treatment (A1). In addition, the baseline renal risk should be assessed for all patients. High renal risk includes one or more of the following factors: decompensated cirrhosis, creatinine clearance <60 ml/min, poorly controlled hypertension, proteinuria, uncontrolled diabetes, active glomerulonephritis, concomitant nephrotoxic drugs, solid organ transplantation. Minimal rates of renal function decline have been reported with all NAs, except perhaps for telbivudine which seems to improve the creatinine clearance [
      • Gane E.J.
      • Deary G.
      • Piratvisuth T.
      • Chan H.L.
      • Zeuzem S.
      • Jia J.
      • et al.
      Renal function is improved for chronic hepatitis B (CHB) patients treated with telbivudine.
      ] (C1). The nephrotoxic potential seems to be higher for nucleotide analogues, particularly adefovir [
      • Ha N.B.
      • Ha N.B.
      • Garcia R.T.
      • Trinh H.N.
      • Vu A.A.
      • Nguyen H.A.
      • et al.
      Renal dysfunction in chronic hepatitis B patients treated with adefovir dipivoxil.
      ] (B1). Therefore, it seems appropriate for now to monitor for adverse renal effects with serum creatinine (estimated creatinine clearance) and serum phosphate levels during adefovir or tenofovir therapy in all CHB patients and with serum creatinine levels (estimated creatinine clearance) during nucleoside analogue therapy in CHB patients at high renal risk (C1). The frequency of renal monitoring can be every 3 months during the first year and every 6 months thereafter, in case of no worsening, in patients at low renal risk as well as every month for the first 3 months, every 3 months until the end of the first year and every 6 months thereafter, in case of no worsening, in patients at high renal risk (C2). Closer renal monitoring is required in patients who develop creatinine clearance <60 ml/min or serum phosphate levels <2 mg/dl) (C1).
      Drug concentrations are comparable in patients with varying degrees of hepatic impairment, but this has not been fully studied. Decreases in bone mineral density have rarely been reported in HIV-positive patients treated with tenofovir. Studies to evaluate bone densitometry in CHB patients under tenofovir are ongoing. Long-term monitoring for carcinogenesis in CHB patients under entecavir is ongoing. Myopathy has rarely been reported in CHB patients treated with telbivudine. The long-term safety of several NAs combination including tenofovir and entecavir is currently unknown.

      Treatment of patients with severe liver disease

      Treatment of patients with cirrhosis

      PEG-IFN may increase the risk of bacteraemic infection and hepatic decompensation in patients with advanced cirrhosis [
      • Perrillo R.
      • Tamburro C.
      • Regenstein F.
      • Balart L.
      • Bodenheimer H.
      • Silva M.
      • et al.
      Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus.
      ]. However, PEG-IFN in regimens similar to those used in CHB can be used for the treatment of well compensated cirrhosis [
      • Buster E.H.
      • Hansen B.E.
      • Buti M.
      • Delwaide J.
      • Niederau C.
      • Michielsen P.P.
      • et al.
      Peginterferon alpha-2b is safe and effective in HBeAg-positive chronic hepatitis B patients with advanced fibrosis.
      ] (A1). Among NAs, monotherapies with tenofovir or entecavir are preferred because of their potency and minimal risk of resistance [
      • Schiff E.
      • Simsek H.
      • Lee W.M.
      • Chao Y.C.
      • Sette Jr., H.
      • Janssen H.L.
      • et al.
      Efficacy and safety of entecavir in patients with chronic hepatitis B and advanced hepatic fibrosis or cirrhosis.
      ,
      • Buti M.
      • Hadziyannis S.
      • Mathurin P.
      • Urbanek P.
      • Sherman M.
      • Strasser S.
      • et al.
      Tenofovir disoproxil fumarate is highly active for treatment of chronic hepatitis B in subjects with cirrhosis.
      ] (A1). Lamivudine should not be used in such patients. Close monitoring of HBV DNA levels every 3 months at least during the first year of therapy and until HBV DNA undetectability is important, as exacerbations of hepatitis B may occur in patients with cirrhosis requiring urgent management. Thus, patients with cirrhosis require long-term therapy, with careful monitoring for resistance and flares.
      Clinical studies indicate that prolonged and adequate suppression of HBV DNA can stabilize patients and prevent the progression to decompensated liver disease [
      • Liaw Y.F.
      • Sung J.J.
      • Chow W.C.
      • Farrell G.
      • Lee C.Z.
      • Yuen H.
      • et al.
      Lamivudine for patients with chronic hepatitis B and advanced liver disease.
      ,
      • Papatheodoridis G.V.
      • Dimou E.
      • Dimakopoulos K.
      • Manolakopoulos S.
      • Rapti I.
      • Kitis G.
      • et al.
      Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine.
      ] (A1). Regression of fibrosis and even reversal of cirrhosis have been reported in patients with prolonged suppression of viral replication [
      • Chang T.T.
      • Liaw Y.F.
      • Wu S.S.
      • Schiff E.
      • Han K.H.
      • Lai C.L.
      • et al.
      Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B.
      ]. Nonetheless, long-term monitoring for HCC is mandatory despite virological remission under NA(s), since there is still a risk of developing HCC [
      • Papatheodoridis G.V.
      • Lampertico P.
      • Manolakopoulos S.
      • Lok A.
      Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review.
      ,
      • Papatheodoridis G.V.
      • Manolakopoulos S.
      • Touloumi G.
      • Vourli G.
      • Raptopoulou-Gigi M.
      • Vafiadis-Zoumbouli I.
      • et al.
      Virological suppression does not prevent the development of hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients with cirrhosis receiving oral antiviral(s) starting with lamivudine monotherapy: results of the nationwide HEPNET. Greece cohort study.
      ] (B1).
      NA therapy should usually be continued indefinitely in cirrhotic patients. After at least 12 months of consolidation therapy, treatment might be stopped in HBeAg-positive patients if they achieve confirmed anti-HBe seroconversion or ideally HBsAg loss and anti-HBs seroconversion and in HBeAg-negative patients if they achieve confirmed HBsAg loss and anti-HBs seroconversion (B1).

      Treatment of patients with decompensated cirrhosis

      Patients with decompensated cirrhosis should be treated in specialised liver units, as the application of antiviral therapy is complex, and these patients may be candidates for liver transplantation. Antiviral treatment is indicated irrespective of HBV DNA level in order to prevent reactivation.
      (PEG-)IFN is contraindicated in this setting. Entecavir or tenofovir should be used (A1). The licensed entecavir dose for patients with decompensated cirrhosis is 1 mg (instead of 0.5 mg for patients with compensated liver disease) once daily. Recent studies have shown that both drugs are not only effective but generally safe in these patients, at least in the first years of therapy [
      • Shim J.H.
      • Lee H.C.
      • Kim K.M.
      • Lim Y.S.
      • Chung Y.H.
      • Lee Y.S.
      • et al.
      Efficacy of entecavir in treatment-naive patients with hepatitis B virus-related decompensated cirrhosis.
      ,
      • Liaw Y.F.
      • Sheen I.S.
      • Lee C.M.
      • Akarca U.S.
      • Papatheodoridis G.V.
      • Suet-Hing W.F.
      • et al.
      Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease.
      ,
      • Liaw Y.F.
      • Raptopoulou-Gigi M.
      • Cheinquer H.
      • Sarin S.K.
      • Tanwandee T.
      • Leung N.
      • et al.
      Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation: a randomized, open-label study.
      ]. Lactic acidosis has been reported to develop in some NA, particularly entecavir, treated patients with advanced decompensated cirrhosis (MELD score >20) [
      • Lange C.M.
      • Bojunga J.
      • Hofmann W.P.
      • Wunder K.
      • Mihm U.
      • Zeuzem S.
      • et al.
      Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function.
      ]. Therefore, clinical and laboratory parameters should be closely monitored in this setting (A1). The dose of all NAs needs to be adjusted in patients with low creatinine clearance (<50 ml/min) (A1).
      Patients with decompensated cirrhosis may show slow clinical improvement over a period of 3–6 months under NA(s) and then transplantation may be avoided. In such cases, life-long treatment is recommended. The HCC risk is high in these patients even under effective NA therapy and therefore long-term HCC surveillance is mandatory [
      • Papatheodoridis G.V.
      • Manolakopoulos S.
      • Touloumi G.
      • Vourli G.
      • Raptopoulou-Gigi M.
      • Vafiadis-Zoumbouli I.
      • et al.
      Virological suppression does not prevent the development of hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients with cirrhosis receiving oral antiviral(s) starting with lamivudine monotherapy: results of the nationwide HEPNET. Greece cohort study.
      ] (A1). Some patients with advanced hepatic disease with a high Child–Pugh or MELD score may have progressed beyond the point of no return, and may not benefit, thus requiring liver transplantation [
      • Fontana R.J.
      • Hann H.W.
      • Perrillo R.P.
      • Vierling J.M.
      • Wright T.
      • Rakela J.
      • et al.
      Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy.
      ]. In that situation, treatment with NA(s) inducing HBV DNA undetectability at transplantation will decrease the risk of HBV recurrence in the graft [
      • Papatheodoridis G.V.
      • Cholongitas E.
      • Archimandritis A.J.
      • Burroughs A.K.
      Current management of hepatitis B virus infection before and after liver transplantation.
      ].

      Prevention of recurrent hepatitis B after liver transplantation

      Recurrent HBV infection in the transplanted liver has previously been a major problem. Pre-transplant therapy with a potent NA with a high barrier to resistance is recommended for all HBsAg-positive patients undergoing liver transplantation for HBV-related end-stage liver disease or HCC, to achieve the lowest possible level of HBV DNA before transplantation [
      • Papatheodoridis G.V.
      • Cholongitas E.
      • Archimandritis A.J.
      • Burroughs A.K.
      Current management of hepatitis B virus infection before and after liver transplantation.
      ,
      • Grellier L.
      • Mutimer D.
      • Ahmed M.
      • Brown D.
      • Burroughs A.K.
      • Rolles K.
      • et al.
      Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis.
      ,
      • Samuel D.
      Management of hepatitis B in liver transplantation patients.
      ,
      • Schiff E.
      • Lai C.L.
      • Hadziyannis S.
      • Neuhaus P.
      • Terrault N.
      • Colombo M.
      • et al.
      Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results.
      ] (A1). Lamivudine and/or adefovir in combination with hepatitis B immunoglobulin (HBIg) have reduced the risk of graft infection to less than 10% [
      • Papatheodoridis G.V.
      • Cholongitas E.
      • Archimandritis A.J.
      • Burroughs A.K.
      Current management of hepatitis B virus infection before and after liver transplantation.
      ,
      • Samuel D.
      Management of hepatitis B in liver transplantation patients.
      ,
      • Schiff E.
      • Lai C.L.
      • Hadziyannis S.
      • Neuhaus P.
      • Terrault N.
      • Colombo M.
      • et al.
      Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results.
      ]. Shorter courses and lower doses of HBIg and other forms of prophylaxis, including tenofovir with emtricitabine or entecavir monotherapy, are being studied. Recently, entecavir prophylaxis without HBIG was shown to be safe and effective in preventing HBV recurrence [
      • Fung J.
      • Cheung C.
      • Chan S.C.
      • Yuen M.F.
      • Chok K.S.
      • Sharr W.
      • et al.
      Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation.
      ]. Preliminary safety and efficacy data with tenofovir and emtricitabine with or without HBIG have also been reported [
      • Teperman L.
      • Spivey J.
      • Poordad F.
      • Schiano T.
      • Bzowej N.
      • Pungpapong S.
      • et al.
      Emtricitabine/tenofovir DF combination +/− HBIG post-orthotopic liver transplantation to prevent hepatitis B recurrence in patients with normal to moderate renal impairment: interim results.
      ]. In the setting of liver transplantation, nephrotoxicity should be always considered and renal function should be carefully monitored because of the concomitant use of calcineurin inhibitors (C1).

      Treatment in special patient groups

      HIV co-infected patients

      HIV-positive patients with CHB were at increased risk of cirrhosis before HAART and a higher risk of HCC is suggested [
      • Di Martino V.
      • Thevenot T.
      • Colin J.F.
      • Boyer N.
      • Martinot M.
      • Degos F.
      • et al.
      Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B.
      ,
      • Hoffmann C.J.
      • Thio C.L.
      Clinical implications of HIV and hepatitis B co-infection in Asia and Africa.
      ,
      • Puoti M.
      • Torti C.
      • Bruno R.
      • Filice G.
      • Carosi G.
      Natural history of chronic hepatitis B in co-infected patients.
      ,
      • Rockstroh J.K.
      Influence of viral hepatitis on HIV infection.
      ,
      • Soriano V.
      • Puoti M.
      • Bonacini M.
      • Brook G.
      • Cargnel A.
      • Rockstroh J.
      • et al.
      Care of patients with chronic hepatitis B and HIV co-infection: recommendations from an HIV–HBV International Panel.
      ,
      • Sulkowski M.S.
      Viral hepatitis and HIV coinfection.
      ,
      • Colin J.F.
      • Cazals-Hatem D.
      • Loriot M.A.
      • Martinot-Peignoux M.
      • Pham B.N.
      • Auperin A.
      • et al.
      Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men.
      ]. Treatment of HIV may lead to flares of hepatitis B due to immune reconstitution, but the risk of developing cirrhosis is negligible in HBV/HIV co-infected patients on long-term tenofovir combined with emtricitabine or lamivudine therapy [
      • Tuma P.
      • Medrano J.
      • Resino S.
      • Vispo E.
      • Madejon A.
      • Sanchez-Piedra C.
      • et al.
      Incidence of liver cirrhosis in HIV-infected patients with chronic hepatitis B or C in the era of highly active antiretroviral therapy.
      ]. The indications for therapy are the same as in HIV-negative patients, based on HBV DNA levels, serum ALT levels and histological lesions [
      • Alberti A.
      • Clumeck N.
      • Collins S.
      • Gerlich W.
      • Lundgren J.
      • Palu G.
      • et al.
      Short statement of the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV co-infected patients.
      ]. In agreement with recent HIV guidelines, it is recommended that most co-infected patients should be simultaneously treated for both HIV and HBV de novo [
      • Rockstroh J.K.
      • Bhagani S.
      • Benhamou Y.
      • Bruno R.
      • Mauss S.
      • Peters L.
      • et al.
      European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults.
      ]. Tenofovir combined with emtricitabine or lamivudine plus a third agent active against HIV are indicated [
      • Rockstroh J.K.
      • Bhagani S.
      • Benhamou Y.
      • Bruno R.
      • Mauss S.
      • Peters L.
      • et al.
      European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults.
      ,
      • de Vries-Sluijs T.E.
      • Reijnders J.G.
      • Hansen B.E.
      • Zaaijer H.L.
      • Prins J.M.
      • Pas S.D.
      • et al.
      Long-term therapy with tenofovir is effective for patients co-infected with human immunodeficiency virus and hepatitis B virus.
      ] (A1). The strong rationale for early dual anti-HIV and anti-HBV therapy have simplified the recommendations for widening the use of tenofovir and emtricitabine or lamivudine in HBV–HIV co-infected patients, irrespective of immunological, virological or histological considerations [
      • Piroth L.
      • Pol S.
      • Lacombe K.
      • Miailhes P.
      • Rami A.
      • Rey D.
      • et al.
      Management and treatment of chronic hepatitis B virus infection in HIV positive and negative patients: the EPIB 2008 study.
      ] (B1).
      In a small number of patients with CD4 count >500/ml, HBV can be treated before the institution of anti-HIV therapy; PEG-IFN, adefovir and telbivudine, which are not proven to be active against HIV, should be preferred [
      • Rockstroh J.K.
      • Bhagani S.
      • Benhamou Y.
      • Bruno R.
      • Mauss S.
      • Peters L.
      • et al.
      European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults.
      ]. However, if any of these two NAs with a low barrier to resistance does not reach the goal of undetectable HBV DNA after 12 months of therapy, treatment of HIV infection should be envisaged. Lamivudine, entecavir and tenofovir have activity against both HIV and HBV and are contraindicated as single agents for hepatitis B in co-infected patients because of the risk of HIV resistance (A1). Thus, all HBsAg-positive patients should be screened for HIV before these drugs are used in the treatment of HBV infection (A1).

      HDV co-infected patients

      Severe or fulminant hepatitis is more frequently observed in HBV-HDV co-infection compared to HBV mono-infection [
      • Yurdaydin C.
      • Idilman R.
      • Bozkaya H.
      • Bozdayi A.M.
      Natural history and treatment of chronic delta hepatitis.
      ]. Chronic infection after acute HBV-HDV hepatitis is less common, while chronic delta hepatitis develops in 70–90% of patients with HDV superinfection [
      • Yurdaydin C.
      • Idilman R.
      • Bozkaya H.
      • Bozdayi A.M.
      Natural history and treatment of chronic delta hepatitis.
      ,
      • Hughes S.A.
      • Wedemeyer H.
      • Harrison P.M.
      Hepatitis delta virus.
      ]. Active co-infection with HDV is confirmed by detectable HDV RNA, immuno-histochemical staining for HDV antigen, or IgM anti-HDV [
      • Hughes S.A.
      • Wedemeyer H.
      • Harrison P.M.
      Hepatitis delta virus.
      ]. However, diagnosis of active HDV infection may be difficult, as HDV RNA assays are not standardised and HDV antigen and IgM anti-HDV assays are not widely available [
      • Hughes S.A.
      • Wedemeyer H.
      • Harrison P.M.
      Hepatitis delta virus.
      ,
      • Mederacke I.
      • Bremer B.
      • Heidrich B.
      • Kirschner J.
      • Deterding K.
      • Bock T.
      • et al.
      Establishment of a novel quantitative hepatitis D virus (HDV) RNA assay using the Cobas TaqMan platform to study HDV RNA kinetics.
      ]. Persistent HDV replication leads to cirrhosis and HCC at annual rates of 4% and 2.8% and is the most important predictor of mortality evidencing the need of antiviral therapy [
      • Yurdaydin C.
      • Idilman R.
      • Bozkaya H.
      • Bozdayi A.M.
      Natural history and treatment of chronic delta hepatitis.
      ,
      • Romeo R.
      • Del N.E.
      • Rumi M.
      • Russo A.
      • Sangiovanni A.
      • De F.R.
      • et al.
      A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma.
      ,
      • Niro G.A.
      • Smedile A.
      • Ippolito A.M.
      • Ciancio A.
      • Fontana R.
      • Olivero A.
      • et al.
      Outcome of chronic delta hepatitis in Italy: a long-term cohort study.
      ].
      (PEG-)IFN is the only drug effective against HDV [
      • Farci P.
      Treatment of chronic hepatitis D: new advances, old challenges.
      ,
      • Farci P.
      • Mandas A.
      • Coiana A.
      • Lai M.E.
      • Desmet V.
      • Van E.P.
      • et al.
      Treatment of chronic hepatitis D with interferon alfa-2a.
      ,
      • Niro G.A.
      • Ciancio A.
      • Gaeta G.B.
      • Smedile A.
      • Marrone A.
      • Olivero A.
      • et al.
      Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta.
      ,
      • Yurdaydin C.
      • Bozkaya H.
      • Karaaslan H.
      • Onder F.O.
      • Erkan O.E.
      • Yalcin K.
      • et al.
      A pilot study of 2 years of interferon treatment in patients with chronic delta hepatitis.
      ,
      • Wedemeyer H.
      • Yurdaydin C.
      • Dalekos G.N.
      • Erhardt A.
      • Cakaloglu Y.
      • Degertekin H.
      • et al.
      Peginterferon plus adefovir versus either drug alone for hepatitis delta.
      ,