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Natural history of hepatitis B

  • Giovanna Fattovich
    Correspondence
    Tel./fax: +39-45-807-4205
    Affiliations
    Servizio Autonomo Clinicizzato di Gastroenterologia, Dipartimento di Scienze Chirurgiche e Gastroenterologiche, University of Verona, Piazzale L.A. Scuro n. 10, 37134 Verona, Italy
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      1. Introduction

      Hepatitis B virus (HBV) infection is an important global health problem and may cause both acute and chronic infection in man [
      • Maddrey W.C.
      Hepatitis B: an important public health issue.
      ]. It is estimated that 400 million people worldwide are chronic HBV carriers [
      • Lee W.M.
      Hepatitis B virus infection.
      ]. The clinical spectrum of HBV infection ranges from subclinical to acute symptomatic hepatitis or, rarely, fulminant hepatitis during the acute phase and from the inactive hepatitis B surface antigen (HBsAg) carrier state, chronic hepatitis of various degree of histologic severity to cirrhosis and its complications during the chronic phase [
      • Lok A.S.
      • Heathcote E.J.
      • Hoofnagle J.H.
      Management of hepatitis B: 2000-Summary of a workshop.
      ,
      • Lok A.S.F.
      • McMahon B.J.
      Chronic hepatitis B.
      ]. Approx. 15–40% of patients with chronic hepatitis B progress to cirrhosis and end-stage liver disease [
      • Maddrey W.C.
      Hepatitis B: an important public health issue.
      ]. Understanding the natural history and prognosis of hepatitis B is of major importance for patient management and for the assessment of treatment strategies.

      2. Natural history of HBV infection

      Perinatal infection or horizontal infection early in childhood are the main routes of HBV transmission in high endemic area, such as South-East Asia, most Africa, Pacific Islands and the Arctic, whereas in low endemic regions, such as Western countries, hepatitis B is primarily a disease of adolescents and adults as a result of high risk sexual activity and injection drug use.
      HBV infection is a dynamic process characterized by replicative and non-replicative phases based on virus-host interaction, which are present in some form in all infected patients (Fig. 1) .
      Figure thumbnail gr1
      Fig. 1Natural course of HBV infection. The initial immunotolerant phase with HBeAg positivity and high levels of serum HBV-DNA is followed by the immunoactive phase with a decrease in serum HBV-DNA and increase in ALT levels and finally by the non-replicative or minimally replicative phase with seroconversion to antibody to HBeAg (anti-HBe) and remission of liver disease. Reactivation of HBV and of liver disease activity may occur after seroconversion from HBeAg to anti-HBe. Resolved hepatitis B involves loss of HBsAg and seroconversion to HBsAg (anti-HBs).
      HBsAg, hepatitis B e antigen (HBeAg), high levels of serum HBV DNA characterize the first immunotolerant phase. In adult acquired infection this phase marks the incubation period of acute HBV infection and lasts about 2–4 weeks. By contrast, in perinatal infection this phase often lasts for decades. During this phase patients have no symptoms, normal or slightly increased serum alanine aminotransferase (ALT) levels and minimal histological activity, which implies that there is a lack or very weak immune response against the infected hepatocytes. During the course of HBV infection, for unknown reasons, patients may enter the second immunoactive phase which is associated with a decrease of HBV DNA and an increase of ALT and histologic activity, reflecting the host immune mediated lysis of infected hepatocytes. In acute HBV infection this phase is the period of clinical symptoms and jaundice and usually lasts for 3–4 weeks, whereas in patients with chronic HBV infection it lasts from months to years.
      The third low or non-replicative phase involves seroconversion from HBeAg to anti-HBe usually preceded by a marked reduction of serum HBV DNA levels below 105 copies per ml, not detectable by hybridization techniques, and followed by ALT normalization and resolution of necroinflammation. Serum HBV DNA remains detectable only by ultrasensitive polymerase chain reaction (PCR) technique in many patients. In chronic HBV infection this phase is also referred to as inactive HBsAg carrier state [
      • Lok A.S.
      • Heathcote E.J.
      • Hoofnagle J.H.
      Management of hepatitis B: 2000-Summary of a workshop.
      ,
      • Lok A.S.F.
      • McMahon B.J.
      Chronic hepatitis B.
      ]. The inactive carrier state may last for lifetime, but a proportion of patients may undergo subsequent spontaneous or immunosuppression induced reactivation of HBV replication with reappearance of high levels of HBV DNA with or without HBeAg seroreversion and rise of ALT levels [
      • Lok A.S.
      • Heathcote E.J.
      • Hoofnagle J.H.
      Management of hepatitis B: 2000-Summary of a workshop.
      ]. For reasons that are not yet known during HBeAg clearance or later on after HBeAg seroconversion replication-competent HBV variants with mutations in the precore or core promoter regions preventing HBeAg production may be selected [
      • Hadziyannis S.J.
      • Vassilopoulos D.
      Hepatitis B e antigen-negative chronic hepatitis B.
      ].
      Patients who become HBsAg negative and develop anti-HBs have resolved their hepatitis B [
      • Lok A.S.
      • Heathcote E.J.
      • Hoofnagle J.H.
      Management of hepatitis B: 2000-Summary of a workshop.
      ,
      • Lok A.S.F.
      • McMahon B.J.
      Chronic hepatitis B.
      ]. This is an uncommon phenomenon in chronic HBV infection. During this stage HBV-DNA may still be detectable by PCR assay both in serum and liver [
      • Chemin I.
      • Zoulim F.
      • Merle P.
      • Arkhis A.
      • Chevallier M.
      • Kay A.
      • et al.
      High incidence of hepatitis B infections among chronic hepatitis cases of unknown aetiology.
      ]. In rare cases of severe immune suppression, such as cancer chemotherapy or after organ transplantation resolved hepatitis B can be reactivated [
      • Kawatani T.
      • Suou T.
      • Tajima F.
      • Ishiga K.
      • Omura H.
      • Endo A.
      • et al.
      Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for hematologic malignancies.
      ].

      3. Acute hepatitis B

      Acute HBV infection is generally subclinical and anicteric in neonates and children. By contrast, in adults approx. 30–50% develop icteric hepatitis [
      • McMahon B.J.
      • Alward W.L.M.
      • Hall D.B.
      • Heyward W.L.
      • Bender T.R.
      • Francis D.P.
      • et al.
      Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state.
      ]. Patients who recover from acute hepatitis B acquire protective levels of anti-HBs with lifelong immunity. However, a proportion of patients will be chronically infected and approx. 0.1–0.5% develop fulminant hepatitis. Acute HBV and hepatitis delta virus (HDV) coinfection is associated with a high rate of fulminant hepatitis [
      • Smedile A.
      • Farci P.
      • Verme G.
      • Caredda F.
      • Cargnel A.
      • Caporaso N.
      • et al.
      Influence of delta infection on severity of hepatitis B.
      ]. Acute HBV and hepatitis C virus (HCV) coinfection has also been reported to increase the risk of fulminant hepatitis [
      • Feray C.
      • Gigou M.
      • Samuel D.
      • Reyes G.
      • Bernuau J.
      • Reynes M.
      • et al.
      Hepatitis C virus RNA and hepatitis B virus DNA in serum and liver of patients with fulminant hepatitis.
      ]. It is generally believed that fulminant hepatitis is due to an enhanced immune response of the host resulting in inhibition of viral replication and massive lysis of infected hepatocytes, thus explaining the absence of serological markers of HBV infection in many patients [
      • Wright T.L.
      • Mamish D.
      • Combs C.
      • Kim M.
      • Donegan E.
      • Ferrel L.
      • et al.
      Hepatitis B virus and apparent fulminant non-A, non-B hepatitis.
      ].
      Persistence of HBsAg, HBeAg and high titer HBV DNA for more than 6 months implies progression to chronic HBV infection [
      • Fong T.L.
      • Di Bisceglie A.M.
      • Biswas R.
      • Biswas R.
      • Waggoner J.G.
      • Wilson L.
      • et al.
      High levels of viral replication during acute hepatitis B infection predict progression to chronicity.
      ]. Age at the time of infection is the best determinant of chronicity. Up to 90% of infants of highly infectious HBsAg and HBeAg positive mothers become chronic HBV carriers as compared with approx. 30% of children infected after the neonatal period but before the age of 5 years [
      • McMahon B.J.
      • Alward W.L.M.
      • Hall D.B.
      • Heyward W.L.
      • Bender T.R.
      • Francis D.P.
      • et al.
      Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state.
      ,
      • Chang M.H.
      Natural history of hepatitis B infection in children.
      ]. By contrast, only 1–5% of adults become chronically infected after clinically overt acute hepatitis [
      • Tassopoulos N.C.
      • Papaevangelou G.J.
      • Sjogren M.H.
      • Karayannis A.R.
      • Gerin J.L.
      • Purcell R.H.
      Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults.
      ]. In addition to age at infection, the maternal HBeAg/anti-HBe status is an important determinant of the outcome of HBV infection. Indeed, <10% of babies born to HBeAg negative/anti-HBe positive mothers become chronically infected, although approx. 5% develop acute symptomatic or fulminant hepatitis within the first 3–4 months of life [
      • Chang M.H.
      Natural history of hepatitis B infection in children.
      ]. High maternal viral load appears to increase the risk of persistent infection of the infant. HBV variants not producing HBeAg were detected both in babies with benign and fulminant hepatitis and their mothers, indicating that HBV genomic heterogeneity does not play a major role in the clinical outcome of perinatal HBV infection [
      • Burk R.D.
      • Hwang L.Y.
      • Ho G.Y.F.
      • Shafritz D.A.
      • Beasley R.P.
      Outcome of perinatal hepatitis B virus exposure is dependent on maternal virus load.
      ,
      • Cacciola I.
      • Cerenzia G.
      • Pollicino T.
      • Squadrito G.
      • Castellaneta S.
      • Zanetti A.R.
      • et al.
      Genomic heterogeneity of hepatitis B virus (HBV) and outcome of perinatal HBV infection.
      ].

      4. Chronic hepatitis B

      4.1 HBeAg positive chronic hepatitis

      Clinical data indicate that HBV infection acquired in the perinatal period is characterized by a prolonged immunotolerant phase and very low rate of spontaneous HBeAg clearance [
      • Chang M.H.
      Natural history of hepatitis B infection in children.
      ]. Most carriers infected at birth or in the first few years of life present with HBeAg positive chronic hepatitis with normal ALT and this clinical condition is likely to be maintained up to adulthood by a proportion of the patients [
      • Lok A.S.
      • Heathcote E.J.
      • Hoofnagle J.H.
      Management of hepatitis B: 2000-Summary of a workshop.
      ,
      • Lok A.S.F.
      • McMahon B.J.
      Chronic hepatitis B.
      ]. Many of these patients enter the immunoactive phase and develop HBeAg positive chronic hepatitis with elevated ALT levels only after 10–30 years of infection [
      • Lok A.S.F.
      • Lai C.L.
      • Wu P.C.
      • Leung E.K.Y.
      • Lam T.S.
      Spontaneous hepatitis B e antigen to antibody seroconversion and reversion in Chinese patients with chronic hepatitis B virus infection.
      ]. By contrast, patients who acquire HBV infection in the late childhood, during adolescence or adulthood and become chronic carriers usually present in the immunoactive phase with active liver disease.
      The age of adult patients at the time of initial presentation with HBeAg positive chronic hepatitis B is between 24 and 36 years (median 31); men usually outnumber women and the male to female ratio ranges from 1.5 to 4.9 (18–27). Liver damage ranges from mild (24–42%) to moderate or severe chronic hepatitis (44–63%) or active cirrhosis (10–24%) [
      • Hoofnagle J.H.
      • Dusheiko G.M.
      • Seef L.B.
      • Jones E.A.
      • Waggoner J.G.
      • Bales Z.B.
      Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis.
      ,
      • Fattovich G.
      • Rugge M.
      • Brollo L.
      • Pontisso P.
      • Noventa F.
      • Guido M.
      • et al.
      Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B.
      ,
      • Moreno-Otero R.
      • Garcia-Monzòn C.
      • Garcia-Sànchez A.
      • Buey L.G.
      • Pajares J.M.
      • Di Bisceglie A.M.
      Development of cirrhosis after chronic type B hepatitis: a clinicopathologic and follow-up study of 46 HBeAg-positive asymptomatic patients.
      ,
      • Zarski J.P.
      • Marcellin P.
      • Cohard M.
      • Lutz J.M.
      • Bouche C.
      • Rais A.
      Comparison of anti-HBe-positive and HBe-antigen-positive chronic hepatitis B in France.
      ,
      • Di Marco V.
      • Lo Iacono O.
      • Cammà C.
      • Vaccaro A.
      • Giunta M.
      • Martorana G.
      • et al.
      The long-term course of chronic hepatitis B.
      ,
      • Yuen M.F.
      • Hui C.K.
      • Cheng C.C.
      • Wu C.H.
      • Lai Y.P.
      • Lai C.L.
      Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: the effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications.
      ]. Chronic hepatitis B tends to be milder in children with histologically minimal to mild chronic hepatitis in 86–90% of children. Nevertheless, severe liver disease including cirrhosis may occur in a small proportion of patients during childhood [
      • Chang M.H.
      • Hsu H.Y.
      • Hsu H.C.
      • Ni Y.H.
      • Chen J.S.
      • Chen D.S.
      The significance of spontaneous hepatitis B e antigen seroconversion in childhood: with special emphasis on the clearance of hepatitis B e antigen before 3 years of age.
      ,
      • Bortolotti F.
      • Jara P.
      • Crivellaro C.
      • Hierro L.
      • Cadrobbi P.
      • Frauca E.
      • et al.
      Outcome of chronic hepatitis B in Caucasian children during a 20-year observation period.
      ].
      A key event in the natural history of HBeAg positive chronic hepatitis is HBeAg seroconversion. Several longitudinal studies conducted in cohorts of patients with HBeAg positive chronic hepatitis have shown that seroconversion from HBeAg to anti-HBe with marked reduction of HBV replication is associated with biochemical and histologic regression of inflammatory activity in the majority of patients [
      • Realdi G.
      • Alberti A.
      • Rugge M.
      • Bortolotti F.
      • Rigoli A.M.
      • Tremolada F.
      • et al.
      Seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection.
      ,
      • Hoofnagle J.H.
      • Dusheiko G.M.
      • Seef L.B.
      • Jones E.A.
      • Waggoner J.G.
      • Bales Z.B.
      Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis.
      ,
      • Sànchez-Tapias J.M.
      • Vilar J.H.
      • Costa J.
      • Bruguera M.
      • Ballesta A.M.
      • Ròdes J.
      Natural history of chronic persistent hepatitis B. Relationship between hepatitis B virus replication and the course of the disease.
      ,
      • Fattovich G.
      • Rugge M.
      • Brollo L.
      • Pontisso P.
      • Noventa F.
      • Guido M.
      • et al.
      Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B.
      ,
      • Bortolotti F.
      • Jara P.
      • Crivellaro C.
      • Hierro L.
      • Cadrobbi P.
      • Frauca E.
      • et al.
      Outcome of chronic hepatitis B in Caucasian children during a 20-year observation period.
      ,
      • Hsu Y.S.
      • Chien R.N.
      • Yeh C.T.
      • Sheen I.S.
      • Chiou H.Y.
      • Chu C.M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ]. Histologic improvement occurs gradually months to years after HBeAg seroconversion [
      • Fong T.L.
      • Di Bisceglie A.M.
      • Gerber M.A.
      • Waggoner J.G.
      • Hoofnagle J.H.
      Persistence of hepatitis B virus DNA in the liver after loss of HBsAg in chronic hepatitis B.
      ].
      In longitudinal studies the observed probability of clearing HBeAg was about 50 and 70% within 5 and 10 years of diagnosis, respectively [
      • Fattovich G.
      • Rugge M.
      • Brollo L.
      • Pontisso P.
      • Noventa F.
      • Guido M.
      • et al.
      Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B.
      ,
      • Yuen M.F.
      • Hui C.K.
      • Cheng C.C.
      • Wu C.H.
      • Lai Y.P.
      • Lai C.L.
      Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: the effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications.
      ,
      • McMahon B.J.
      • Holck P.
      • Bulkow L.
      • Snowball M.
      Serologic and clinical outcomes of 1536 Alaska natives chronically infected with hepatitis B virus.
      ,
      • Bortolotti F.
      • Cadrobbi P.
      • Crivellaro C.
      • Guido M.
      • Rugge M.
      • Noventa F.
      • et al.
      Long-term outcome of chronic type B hepatitis in patients who acquire hepatitis B virus infection in childhood.
      ]. Most studies have found that the mean annual rate of spontaneous HBeAg seroconversion is between 8 and 15% in children or adults showing biochemical signs of liver disease activity [
      • Lok A.S.
      • Heathcote E.J.
      • Hoofnagle J.H.
      Management of hepatitis B: 2000-Summary of a workshop.
      ,
      • Lok A.S.F.
      • McMahon B.J.
      Chronic hepatitis B.
      ,
      • Realdi G.
      • Alberti A.
      • Rugge M.
      • Bortolotti F.
      • Rigoli A.M.
      • Tremolada F.
      • et al.
      Seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection.
      ,
      • Hoofnagle J.H.
      • Dusheiko G.M.
      • Seef L.B.
      • Jones E.A.
      • Waggoner J.G.
      • Bales Z.B.
      Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis.
      ,
      • Fattovich G.
      • Rugge M.
      • Brollo L.
      • Pontisso P.
      • Noventa F.
      • Guido M.
      • et al.
      Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B.
      ,
      • Yuen M.F.
      • Hui C.K.
      • Cheng C.C.
      • Wu C.H.
      • Lai Y.P.
      • Lai C.L.
      Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: the effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications.
      ,
      • Bortolotti F.
      • Cadrobbi P.
      • Crivellaro C.
      • Guido M.
      • Rugge M.
      • Noventa F.
      • et al.
      Long-term outcome of chronic type B hepatitis in patients who acquire hepatitis B virus infection in childhood.
      ,
      • Wong D.K.H.
      • Cheung A.M.
      • O'Rourke K.
      • Naylor C.D.
      • Detsky A.S.
      • Heathcote J.
      Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis.
      ,
      • Vajro P.
      • Migliaro F.
      • Fontanella A.
      • Orso G.
      Interferon: a meta-analysis of published studies in pediatric chronic hepatitis B.
      ]. On the other hand, in Asian children, most with normal ALT, the annual spontaneous HBeAg seroconversion occurs at a very low rate: <2% during the first 3 years of age and 4–5% in children older than 3 years [
      • Chang M.H.
      • Sung J.L.
      • Lee C.Y.
      • Chen C.J.
      • Chen J.S.
      • Hsu H.Y.
      • et al.
      Factors affecting clearance of hepatitis B e antigen in hepatitis B surface antigen carrier children.
      ].
      Some determinants for HBeAg seroconversion have been reported, including sex, age, biochemical activity and more recently HBV genotypes. Older carriers and female are more likely to clear HBeAg [
      • Lok A.S.F.
      • Lai C.L.
      • Wu P.C.
      • Leung E.K.Y.
      • Lam T.S.
      Spontaneous hepatitis B e antigen to antibody seroconversion and reversion in Chinese patients with chronic hepatitis B virus infection.
      ,
      • McMahon B.J.
      • Holck P.
      • Bulkow L.
      • Snowball M.
      Serologic and clinical outcomes of 1536 Alaska natives chronically infected with hepatitis B virus.
      ,
      • Alward W.L.M.
      • McMahon B.J.
      • Hall D.B.
      • Heyward W.L.
      • Francis D.P.
      • Bender T.R.
      The long-term serological course of asymptomatic hepatitis B virus carriers and the development of primary hepatocellular carcinoma.
      ]; in a study of 532 Alaska natives with HBeAg positive chronic hepatitis, a multivariate Cox proportional hazards model predicted clearance of HBeAg within 5 years in 33, 52 and 76% for persons 0–18, 19–30 and 31–78 years old, respectively [
      • McMahon B.J.
      • Holck P.
      • Bulkow L.
      • Snowball M.
      Serologic and clinical outcomes of 1536 Alaska natives chronically infected with hepatitis B virus.
      ].
      Spontaneous HBeAg seroconversion within 1 year occurs in over 50% of patients with serum ALT levels greater than five times the upper limit of normal (ULN) as compared to <10% of those with ALT levels less than five times the ULN [
      • Liaw Y.F.
      Current trends in therapy for chronic viral hepatitis.
      ]. Frequently, acute exacerbation of hepatitis, reflecting immune mediated lysis of HBV infected hepatocytes, with ALT elevations greater than ten times the ULN and more than twice the baseline value and with HBV DNA levels rising before and falling during the flare, precede HBeAg to anti-HBe seroconversion and usually lasts for 2–4 months [
      • Perillo R.P.
      Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.
      ]. The probability of HBeAg seroconversion correlates with the degree of histologic activity during the acute flare of hepatitis. A prospective study in Asian patients has indicated that approx. 70% of ALT flares with histological changes compatible with bridging hepatic necrosis sometimes associated with elevated serum alpha-fetoprotein are followed by HBeAg seroconversion compared to only 20% of acute exacerbations without [
      • Liaw Y.F.
      • Tsai S.L.
      Pathogenesis and clinical significance of spontaneous exacerbations and remissions in chronic HBV infection.
      ]. Indeed in some cases these spontaneous flares of hepatitis are not followed by subsequent HBeAg seroconversion and these episodes can be viewed as an abortive attempt at seroconversion. These temporary flares of hepatitis are usually asymptomatic and frequently unrecognized, but some are accompanied by symptoms of acute hepatitis and very rarely, primarily in patients with slightly compensated chronic liver disease, may lead to hepatic decompensation and even death due to massive necrosis [
      • Sheen I.S.
      • Liaw Y.F.
      • Tai D.I.
      • Chu C.M.
      Hepatic decompensation associated with hepatitis B e antigen clearance in chronic type B hepatitis.
      ].
      HBV can be classified into seven genotypes A–G and recent studies, all from Asia, suggest that HBV genotype B is associated with earlier HBeAg seroconversion than genotype C, thus most likely explaining the less progressive disease in patients with genotype B [
      • Orito E.
      • Mizokami M.
      • Sakugawa H.
      • Michitaka K.
      • Ishikawa K.
      • Ichida T.
      • et al.
      A case-control study for clinical and molecular biological differences between hepatitis B viruses of genotype B and C. Japan HBV Genotype Research Group.
      ,
      • Chu C.J.
      • Hussain M.
      • Lok A.S.F.
      Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared to hepatitis B virus genotype C.
      ].
      HBeAg seroconversion associated with liver disease remission marks the transition from chronic hepatitis B to the inactive HBsAg carrier state, however a small percentage of patients (approx. 5%) may continue to show biochemical activity and high levels of serum HBV-DNA at the time of HBeAg seroconversion [
      • Fattovich G.
      • Rugge M.
      • Brollo L.
      • Pontisso P.
      • Noventa F.
      • Guido M.
      • et al.
      Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B.
      ,
      • Bortolotti F.
      • Jara P.
      • Crivellaro C.
      • Hierro L.
      • Cadrobbi P.
      • Frauca E.
      • et al.
      Outcome of chronic hepatitis B in Caucasian children during a 20-year observation period.
      ,
      • Hsu Y.S.
      • Chien R.N.
      • Yeh C.T.
      • Sheen I.S.
      • Chiou H.Y.
      • Chu C.M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ]. These patients as well as those undergoing reactivation of hepatitis B after HBeAg seroconversion constitute the group of patients with HBeAg negative chronic hepatitis B.

      4.2 HBeAg negative chronic hepatitis

      The diagnosis of HBeAg negative chronic hepatitis B is based on chronic HBsAg carriership, HBeAg negativity with anti-HBe positivity, detectable serum HBV DNA by molecular hybridization techniques or by quantitative PCR assays, with HBV DNA usually exceeding 105–106 copies per ml, ALT elevation, liver necroinflammation at histology and exclusion of other concomitant or superimposed causes of liver disease, such as superinfection with other hepatitis viruses, alcohol abuse, hepatotoxic drug use, autoimmune or metabolic liver diseases [
      • Lok A.S.
      • Heathcote E.J.
      • Hoofnagle J.H.
      Management of hepatitis B: 2000-Summary of a workshop.
      ,
      • Lok A.S.F.
      • McMahon B.J.
      Chronic hepatitis B.
      ,
      • Hadziyannis S.J.
      • Vassilopoulos D.
      Hepatitis B e antigen-negative chronic hepatitis B.
      ]. The atypical serological profile is sustained by HBV variants which are unable to express HBeAg. The most frequent precore mutation is a G–A change at nucleotide 1896 (G1896A), which creates a stop codon in the precore region of the HBV genome with loss of HBeAg synthesis [
      • Hadziyannis S.J.
      • Vassilopoulos D.
      Hepatitis B e antigen-negative chronic hepatitis B.
      ]. Other patients may harbor other changes in the precore region or mutations in the core promoter region, which reduces pre-core mRNA synthesis and HBeAg production; the most common core promoter mutation involve a two nucleotide substitution, A–T at nucleotide 1762 and G–A at nucleotide 1764 (TA) [
      • Chan H.L.Y.
      • Leung N.W.Y.
      • Hussain M.
      • Wong M.L.
      • Lok A.S.F.
      Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong.
      ].
      HBeAg negative chronic hepatitis has been reported to prevail in certain part of the world such as in the Mediterranean basin, the middle East and Asia [
      • Lok A.S.
      • Heathcote E.J.
      • Hoofnagle J.H.
      Management of hepatitis B: 2000-Summary of a workshop.
      ,
      • Hadziyannis S.J.
      • Vassilopoulos D.
      Hepatitis B e antigen-negative chronic hepatitis B.
      ]. Recent data suggest that HBeAg negative chronic hepatitis is more common than previously suspected and that is present worldwide [
      • 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.
      ]. The geographical variations in the prevalence of HBeAg negative chronic hepatitis and associated precore and core promoter variants is related to the predominant HBV genotype in each area. Indeed the most common precore mutant (G1896A) can accumulate only in patients infected with HBV genotypes B,C,D,E with a thymidine (T) at precore position 1858. On the other hand, in HBV genotype A the nucleotide 1858 is a cytosine (C), precluding a G1896A mutation. This explains why HBeAg negative chronic hepatitis associated with precore stop codon variant is prevalent in the Mediterranean area where non-A genotypes, particularly D, predominate and is infrequent in North America, Northern Europe and parts of Africa where genotype A predominates [
      • Hadziyannis S.J.
      • Vassilopoulos D.
      Hepatitis B e antigen-negative chronic hepatitis B.
      ]. In Asian countries, where both A and non-A genotypes exist, HBeAg negative chronic hepatitis is associated with mutation in the core promoter region in addition to precore mutants [
      • Chan H.L.Y.
      • Leung N.W.Y.
      • Hussain M.
      • Wong M.L.
      • Lok A.S.F.
      Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong.
      ]. Clinical experience suggests that the prevalence of HBeAg negative chronic hepatitis is increasing during the last decade particularly in the Mediterranean area and in Asia, but this issue is supported only by few studies [
      • Chan H.L.Y.
      • Leung N.W.Y.
      • Hussain M.
      • Wong M.L.
      • Lok A.S.F.
      Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong.
      ,
      • Rizzetto M.
      • Volpes R.
      • Smedile A.
      Response of pre-core mutant chronic hepatitis B infection to lamivudine.
      ].
      Patients with HBeAg negative chronic hepatitis are usually older than patients with HBeAg positive chronic hepatitis (36–45 years; median 40); male predominate and the male/female ratio ranges from 3.9 to 17 [
      • Di Marco V.
      • Lo Iacono O.
      • Cammà C.
      • Vaccaro A.
      • Giunta M.
      • Martorana G.
      • et al.
      The long-term course of chronic hepatitis B.
      ,
      • Fattovich G.
      • Farci P.
      • Rugge M.
      • Brollo L.
      • Mandas A.
      • Pontisso P.
      • et al.
      Randomized controlled trial of lymphoblastoid interferon alfa in patients with chronic hepatitis B who lacked hepatitis B e antigen.
      ,
      • Lampertico P.
      • Del Ninno E.
      • Manzin A.
      • Donato M.F.
      • Rumi M.G.
      • Lunghi G.
      • et al.
      A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum.
      ,
      • 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. Lamivudine Precore Mutant Group.
      ,
      • 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.
      ]. Current data indicate that the clinical profile of HBeAg negative chronic hepatitis differs from that seen in patients with HBeAg positive chronic hepatitis. Indeed histologically minimal or mild chronic hepatitis is infrequent and severe necroinflammation is seen in >50% of HBeAg negative patients at diagnosis [
      • Di Marco V.
      • Lo Iacono O.
      • Cammà C.
      • Vaccaro A.
      • Giunta M.
      • Martorana G.
      • et al.
      The long-term course of chronic hepatitis B.
      ,
      • Fattovich G.
      • Farci P.
      • Rugge M.
      • Brollo L.
      • Mandas A.
      • Pontisso P.
      • et al.
      Randomized controlled trial of lymphoblastoid interferon alfa in patients with chronic hepatitis B who lacked hepatitis B e antigen.
      ,
      • 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.
      ,
      • Papatheodoridis G.V.
      • Manesis E.
      • Hadziyannis S.J.
      The long-term outcome of interferon-α treated and untreated patients with HBeAg-negative chronic hepatitis B.
      ]. In large series from the Mediterranean area 29–38% of patients had cirrhosis at the time of their first presentation [
      • Zarski J.P.
      • Marcellin P.
      • Cohard M.
      • Lutz J.M.
      • Bouche C.
      • Rais A.
      Comparison of anti-HBe-positive and HBe-antigen-positive chronic hepatitis B in France.
      ,
      • Di Marco V.
      • Lo Iacono O.
      • Cammà C.
      • Vaccaro A.
      • Giunta M.
      • Martorana G.
      • et al.
      The long-term course of chronic hepatitis B.
      ,
      • 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.
      ,
      • Papatheodoridis G.V.
      • Manesis E.
      • Hadziyannis S.J.
      The long-term outcome of interferon-α treated and untreated patients with HBeAg-negative chronic hepatitis B.
      ]. The older age and the high rate of advanced liver disease at presentation of HBeAg negative as compared to HBeAg positive patients suggest that HBeAg negative chronic hepatitis represents a late phase in the natural history of chronic HBV infection. In support of this concept a recent long term study showed that HBeAg negative chronic hepatitis accumulated over time after HBeAg seroconversion with a cumulative incidence of approx. 25% at 16 years of follow-up [
      • Hsu Y.S.
      • Chien R.N.
      • Yeh C.T.
      • Sheen I.S.
      • Chiou H.Y.
      • Chu C.M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ]. Thus the increasing prevalence of HBeAg negative chronic hepatitis may only reflect the increased duration of infection in chronic HBV carriers and long term monitoring of patients.
      Moreover, the clinical course of HBeAg negative chronic hepatitis differs from the HBeAg positive forms with respect to fluctuations of ALT and viremia, with relapses of hepatitis alternating with periods of biochemical remission in most patients and a lower rate of sustained spontaneous remission. During follow-up three main biochemical profiles are observed, namely recurrent ALT flares with (pattern 1) or without (pattern 2) spontaneous ALT normalization between flares, and persistently increased ALT without tendency for spontaneous remission (pattern 3). In a recent longitudinal study approx. two-thirds of patients showed recurrent ALT flares and the frequency of patterns 1, 2 and 3 was reported to be 45, 20 and 35%, respectively [
      • 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.
      ]. Flares of hepatitis may be severe and disease exacerbations correlate with progression to end stage complications of cirrhosis [
      • 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.
      ]. Periods of remission with normal ALT and low serum HBV DNA (<105 copies per ml) may be long lasting, but usually the disease recurs and sustained spontaneous remission of disease activity is uncommon [
      • Hadziyannis S.J.
      • Vassilopoulos D.
      Hepatitis B e antigen-negative chronic hepatitis B.
      ]. Delayed spontaneous HBsAg clearance occurs at a low rate of 0.5% per year [
      • Hsu Y.S.
      • Chien R.N.
      • Yeh C.T.
      • Sheen I.S.
      • Chiou H.Y.
      • Chu C.M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ,
      • Papatheodoridis G.V.
      • Manesis E.
      • Hadziyannis S.J.
      The long-term outcome of interferon-α treated and untreated patients with HBeAg-negative chronic hepatitis B.
      ].

      4.3 Inactive HBsAg carrier state

      The inactive HBsAg carrier state is diagnosed by HBeAg negativity with anti-HBe positivity, no or low HBV DNA detectable by PCR based assays, repeatedly normal ALT levels, and histologically minimal or no necroinflammation, slight fibrosis or even normal liver, although inactive cirrhosis may be present [
      • Lok A.S.
      • Heathcote E.J.
      • Hoofnagle J.H.
      Management of hepatitis B: 2000-Summary of a workshop.
      ,
      • Lok A.S.F.
      • McMahon B.J.
      Chronic hepatitis B.
      ]. The prognosis of the inactive HBsAg carrier state is usually benign. Follow-up up to 18 years of these carriers both referred to clinical centers or from population-based studies have indicated that the vast majority show sustained biochemical remission and very low risk of cirrhosis or hepatocellular carcinoma (HCC) [
      • Hsu Y.S.
      • Chien R.N.
      • Yeh C.T.
      • Sheen I.S.
      • Chiou H.Y.
      • Chu C.M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ,
      • 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.
      ,
      • Bellentani S.
      • Dal Molin G.
      • Miglioli L.
      • Crocè L.
      • Masutti F.
      • Castiglione A.
      • et al.
      Natural history of HBV infection: a 9 years follow-up of the Dionysos cohort.
      ]. Some patients, even non-cirrhotics, may develop a HCC during the inactive HBsAg carrier state [
      • Hsu Y.S.
      • Chien R.N.
      • Yeh C.T.
      • Sheen I.S.
      • Chiou H.Y.
      • Chu C.M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ,
      • Fattovich G.
      • Giustina G.
      • Realdi G.
      • Corrocher R.
      • Schalm S.W.
      Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa.
      ]. In addition, approx. 20–30% of inactive HBsAg carriers may undergo spontaneous reactivation of hepatitis B with reappearance of biochemical and necroinflammatory activity, high serum HBV DNA with or without seroreversion to HBeAg [
      • Lok A.S.F.
      • Lai C.L.
      • Wu P.C.
      • Leung E.K.Y.
      • Lam T.S.
      Spontaneous hepatitis B e antigen to antibody seroconversion and reversion in Chinese patients with chronic hepatitis B virus infection.
      ,
      • Bortolotti F.
      • Jara P.
      • Crivellaro C.
      • Hierro L.
      • Cadrobbi P.
      • Frauca E.
      • et al.
      Outcome of chronic hepatitis B in Caucasian children during a 20-year observation period.
      ,
      • Hsu Y.S.
      • Chien R.N.
      • Yeh C.T.
      • Sheen I.S.
      • Chiou H.Y.
      • Chu C.M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ,
      • Davis G.L.
      • Hoofnagle J.H.
      • Waggoner J.G.
      Spontaneous reactivation of chronic hepatitis B virus infection.
      ,
      • Fattovich G.
      • Brollo L.
      • Alberti A.
      • Realdi G.
      • Pontisso P.
      • Giustina G.
      • et al.
      Spontaneous reactivation of hepatitis B virus infection in patients with chronic type B hepatitis.
      ]. Multiple episodes of reactivation or sustained reactivation may be observed and can cause progressive liver disease and even decompensation [
      • Davis G.L.
      • Hoofnagle J.H.
      • Waggoner J.G.
      Spontaneous reactivation of chronic hepatitis B virus infection.
      ,
      • Fattovich G.
      • Brollo L.
      • Alberti A.
      • Realdi G.
      • Pontisso P.
      • Giustina G.
      • et al.
      Spontaneous reactivation of hepatitis B virus infection in patients with chronic type B hepatitis.
      ]. HBV reactivation is usually asymptomatic, but may mimic acute viral hepatitis [
      • Tassopoulos N.C.
      • Papaevangelou G.J.
      • Sjogren M.H.
      • Karayannis A.R.
      • Gerin J.L.
      • Purcell R.H.
      Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults.
      ].
      Acute flares of hepatitis occurring during the inactive HBsAg carrier state or in patients who are in the replicative stage of chronic HBV infection (both HBeAg positive or HBeAg negative) should be distinguished from superinfection with other hepatotropic viruses. As many as 20–30% of these acute exacerbations may be caused by superinfection with HDV, HCV or hepatitis A virus and can be associated with an increased risk of fulminant hepatic failure [
      • Perillo R.P.
      Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.
      ,
      • Chu C.M.
      • Yeh C.T.
      • Liaw Y.F.
      Fulminant hepatic failure in acute hepatitis C: increased risk in chronic carriers of hepatitis B virus.
      ].
      Some carriers eventually become HBsAg negative and develop anti-HBs. The incidence of delayed HBsAg clearance has been estimated to be 1–2% per year in Western countries, where HBV infection is usually acquired in adulthood [
      • Alward W.L.M.
      • McMahon B.J.
      • Hall D.B.
      • Heyward W.L.
      • Francis D.P.
      • Bender T.R.
      The long-term serological course of asymptomatic hepatitis B virus carriers and the development of primary hepatocellular carcinoma.
      ,
      • Fattovich G.
      • Giustina G.
      • Sanchez-Tapias J.
      • Quero C.
      • Mas A.
      • Olivotto P.G.
      • et al.
      Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis.
      ], but only 0.05–0.8% per year in endemic areas where HBV infection is mostly acquired perinatally or in the early childhood [
      • Yuen M.F.
      • Hui C.K.
      • Cheng C.C.
      • Wu C.H.
      • Lai Y.P.
      • Lai C.L.
      Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: the effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications.
      ,
      • McMahon B.J.
      • Holck P.
      • Bulkow L.
      • Snowball M.
      Serologic and clinical outcomes of 1536 Alaska natives chronically infected with hepatitis B virus.
      ,
      • Liaw Y.F.
      • Sheen I.S.
      • Chen T.J.
      • Chu C.M.
      • Pao C.C.
      Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study.
      ]. Clearance of HBsAg has been reported to be higher in women and in older carriers [
      • Alward W.L.M.
      • McMahon B.J.
      • Hall D.B.
      • Heyward W.L.
      • Francis D.P.
      • Bender T.R.
      The long-term serological course of asymptomatic hepatitis B virus carriers and the development of primary hepatocellular carcinoma.
      ,
      • McMahon B.J.
      • Alberts S.R.
      • Wainwright R.B.
      • Bulkow L.
      • Lanier A.P.
      Hepatitis B-related sequelae. Prospective study in 1400 hepatitis B surface antigen-positive Alaska Native carriers.
      ]. Prognosis is improved by loss of HBsAg as there is no evidence of active or progressive liver disease, but HBsAg clearance does not prevent occurrence of decompensation or HCC development both in Caucasian and Asian patients with cirrhosis [
      • Fattovich G.
      • Giustina G.
      • Sanchez-Tapias J.
      • Quero C.
      • Mas A.
      • Olivotto P.G.
      • et al.
      Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis.
      ,
      • 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 not necessarily implies a good prognosis.
      ].

      4.4 Progression to cirrhosis and risk factors

      In untreated patients with predominantly HBeAg positive chronic hepatitis B the incidence of cirrhosis ranges from 2 to 5.4 per 100 person years with a 5 year cumulative incidence of cirrhosis of 8–20% [
      • Liaw Y.F.
      • Tai D.I.
      • Chu C.M.
      • Chen T.J.
      The development of cirrhosis in patients with chronic type B hepatitis: a prospective study.
      ,
      • Moreno-Otero R.
      • Garcia-Monzòn C.
      • Garcia-Sànchez A.
      • Buey L.G.
      • Pajares J.M.
      • Di Bisceglie A.M.
      Development of cirrhosis after chronic type B hepatitis: a clinicopathologic and follow-up study of 46 HBeAg-positive asymptomatic patients.
      ,
      • Lin S.M.
      • Sheen I.S.
      • Chien R.N.
      • Chu C.M.
      • Liaw Y.F.
      Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.
      ,
      • Fattovich G.
      • Brollo L.
      • Giustina G.
      • Noventa F.
      • Pontisso P.
      • Alberti A.
      • et al.
      Natural history and prognostic factors of chronic hepatitis type B.
      ,
      • Ikeda K.
      • Saitoh S.
      • Suzuki Y.
      • Kobayashi M.
      • Tsubota A.
      • Koida I.
      • et al.
      Disease progression and hepatocellular carcinogenensis in patients with chronic viral hepatitis: a prospective observation in 2215 patients.
      ,
      • Mazzella G.
      • Saracco G.
      • Festi D.
      • Rosina F.
      • Marchetto S.
      • Jaboli F.
      • et al.
      Long-term results with interferon therapy in chronic type B hepatitis: a prospective randomized trial.
      ]. A higher rate of cirrhosis has been reported in HBeAg negative as compared to HBeAg positive patients [
      • Fattovich G.
      • Brollo L.
      • Alberti A.
      • Pontisso P.
      • Giustina G.
      • Realdi G.
      Long term follow-up of anti-HBe positive chronic active hepatitis B.
      ,
      • Brunetto M.R.
      • Oliveri F.
      • Rocca G.
      • Criscuolo D.
      • Chiaberge E.
      • Capalbo M.
      • et al.
      Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen.
      ].
      The variability in the rate of progression to cirrhosis may be related to differences in the clinical and serological features of HBV infected patients. Indeed various risk factors for cirrhosis development have been identified (Table 1) . In one study the severity of the fibrosis stage at presentation did correlate with the probability of developing cirrhosis, which was 0, 6 and 17% after 5 years for stages F1, F2 and F3, respectively [
      • Ikeda K.
      • Saitoh S.
      • Suzuki Y.
      • Kobayashi M.
      • Tsubota A.
      • Koida I.
      • et al.
      Disease progression and hepatocellular carcinogenensis in patients with chronic viral hepatitis: a prospective observation in 2215 patients.
      ]. In addition the severity of necroinflammation at diagnosis and recurrent episodes of severe acute exacerbation with bridging hepatic necrosis during follow-up are important factors that predict an unfavorable natural course [
      • Liaw Y.F.
      • Tai D.I.
      • Chu C.M.
      • Chen T.J.
      The development of cirrhosis in patients with chronic type B hepatitis: a prospective study.
      ,
      • Moreno-Otero R.
      • Garcia-Monzòn C.
      • Garcia-Sànchez A.
      • Buey L.G.
      • Pajares J.M.
      • Di Bisceglie A.M.
      Development of cirrhosis after chronic type B hepatitis: a clinicopathologic and follow-up study of 46 HBeAg-positive asymptomatic patients.
      ,
      • Perillo R.P.
      Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.
      ,
      • Fattovich G.
      • Brollo L.
      • Giustina G.
      • Noventa F.
      • Pontisso P.
      • Alberti A.
      • et al.
      Natural history and prognostic factors of chronic hepatitis type B.
      ].
      Table 1Factors affecting prognosis of chronic hepatitis B and compensated cirrhosis
      Viral
       Replication
       Variants
       Genotype
       Coinfection
      Clinical
       Age at diagnosis
       Gender
       Stage of liver disease at presentation
       Recurrent flares of hepatitis
       Sustained ALT normalization
       Alcohol intake
      Older age and ongoing HBV replication detected by sustained or intermittent HBV DNA positivity by non-PCR assays are also well established predictors for cirrhosis development [
      • Liaw Y.F.
      • Tai D.I.
      • Chu C.M.
      • Chen T.J.
      The development of cirrhosis in patients with chronic type B hepatitis: a prospective study.
      ,
      • Moreno-Otero R.
      • Garcia-Monzòn C.
      • Garcia-Sànchez A.
      • Buey L.G.
      • Pajares J.M.
      • Di Bisceglie A.M.
      Development of cirrhosis after chronic type B hepatitis: a clinicopathologic and follow-up study of 46 HBeAg-positive asymptomatic patients.
      ,
      • 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.
      ,
      • Fattovich G.
      • Brollo L.
      • Giustina G.
      • Noventa F.
      • Pontisso P.
      • Alberti A.
      • et al.
      Natural history and prognostic factors of chronic hepatitis type B.
      ]. Taken together, these studies emphasize the prognostic importance of biochemical and virologic follow-up.
      Studies in Asian patients suggest that HBV genotype C is associated with a higher risk of cirrhosis than genotype B and preliminary data suggest that genotype C, but not core promoter or precore stop mutations, correlates with more severe liver disease in HBeAg negative chronic hepatitis [
      • Kao J.H.
      • Chen P.J.
      • Lai M.Y.
      • Chen D.S.
      Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.
      ,
      • Chan H.L.
      • Tsang S.W.
      • Liew C.T.
      • Tse C.H.
      • Wong M.L.
      • Ching J.Y.
      • et al.
      Viral genotype and hepatitis B virus DNA levels are correlated with histological liver damage in HBeAg-negative chronic hepatitis B virus infection.
      ].
      Other clinical aspects contribute to the progression of chronic hepatitis B: concurrent HDV, HCV or human immunodeficiency virus (HIV) infection or concomitant alcohol abuse. Heavy drinking carries a 6 fold higher risk for progression to cirrhosis [
      • Ikeda K.
      • Saitoh S.
      • Suzuki Y.
      • Kobayashi M.
      • Tsubota A.
      • Koida I.
      • et al.
      Disease progression and hepatocellular carcinogenensis in patients with chronic viral hepatitis: a prospective observation in 2215 patients.
      ].
      Concurrent HBV/HCV infection has been reported in approx. 10–25% of patients, particularly among drug abusers [
      • Fattovich G.
      • Tagger A.
      • Brollo L.
      • Giustina G.
      • Pontisso P.
      • Realdi G.
      • et al.
      Hepatitis C virus infection in chronic hepatitis B virus carriers.
      ,
      • Fong T.L.
      • Di Bisceglie A.M.
      • Waggoner J.G.
      • Banks S.M.
      • Hoofnagle J.H.
      The significance of antibody to hepatitis C virus in patients with chronic hepatitis B.
      ] and is characterized by a reciprocal inhibition of the respective genome [
      • Sagnelli E.
      • Coppola N.
      • Scolastico C.
      • Filippini P.
      • Santantonio T.
      • Stroffolini T.
      • et al.
      Virologic and clinical expression of reciprocal inhibitory effect of hepatitis B, C and delta viruses in patients with chronic hepatitis.
      ]. The clinical presentation and prognosis are generally more severe in patients with HBV/HCV coinfection than in those with single infection [
      • Fattovich G.
      • Tagger A.
      • Brollo L.
      • Giustina G.
      • Pontisso P.
      • Realdi G.
      • et al.
      Hepatitis C virus infection in chronic hepatitis B virus carriers.
      ,
      • Fong T.L.
      • Di Bisceglie A.M.
      • Waggoner J.G.
      • Banks S.M.
      • Hoofnagle J.H.
      The significance of antibody to hepatitis C virus in patients with chronic hepatitis B.
      ,
      • Sagnelli E.
      • Coppola N.
      • Scolastico C.
      • Filippini P.
      • Santantonio T.
      • Stroffolini T.
      • et al.
      Virologic and clinical expression of reciprocal inhibitory effect of hepatitis B, C and delta viruses in patients with chronic hepatitis.
      ]. In a longitudinal study of patients with HBV/HCV coinfection the incidence of progression to cirrhosis was 4.3 per 100 person years during 1–11 years of follow-up [
      • Fattovich G.
      • Tagger A.
      • Brollo L.
      • Giustina G.
      • Pontisso P.
      • Realdi G.
      • et al.
      Hepatitis C virus infection in chronic hepatitis B virus carriers.
      ].
      Recent data indicate a decline in HDV infection throughout the industrialized world as a consequence of the control of HBV infection [
      • Gaeta G.B.
      • Stroffolini T.
      • Chiaramonte M.
      • Ascione T.
      • Stornaiuolo G.
      • Lobello S.
      • et al.
      Chronic hepatitis D: a vanishing disease? An Italian multicenter study.
      ]. HDV superinfection in chronic HBV carriers has been extensively investigated and found to be associated with more severe chronic liver disease and rapid progression to cirrhosis [
      • Gaeta G.B.
      • Stroffolini T.
      • Chiaramonte M.
      • Ascione T.
      • Stornaiuolo G.
      • Lobello S.
      • et al.
      Chronic hepatitis D: a vanishing disease? An Italian multicenter study.
      ,
      • Fattovich G.
      • Boscaro S.
      • Noventa F.
      • Pornaro E.
      • Stenico D.
      • Alberti A.
      • et al.
      Influence of hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis type B.
      ,
      • Rosina F.
      • Conoscitore P.
      • Cuppone R.
      • Rocca G.
      • Giuliani A.
      • Cozzolongo R.
      • et al.
      Changing pattern of chronic hepatitis D in Southern Europe.
      ]. In a large series of HDV infected patients the median time from acute hepatitis to cirrhosis was 9 years and in only a minority of patients the disease was non-progressive [
      • Rosina F.
      • Conoscitore P.
      • Cuppone R.
      • Rocca G.
      • Giuliani A.
      • Cozzolongo R.
      • et al.
      Changing pattern of chronic hepatitis D in Southern Europe.
      ]. In another study patients with chronic delta hepatitis showed a significantly higher incidence of cirrhosis (approx. 50% at 5 years) than HBsAg carriers with chronic hepatitis and no evidence of HDV infection [
      • Fattovich G.
      • Boscaro S.
      • Noventa F.
      • Pornaro E.
      • Stenico D.
      • Alberti A.
      • et al.
      Influence of hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis type B.
      ].
      In homosexual men with chronic hepatitis B, HIV infection is associated with high level of HBV replication, low rate of spontaneous HBeAg seroconversion and a 4.2 fold increased risk for cirrhosis as compared to HIV negative patients (95% confidence interval (CI) 1.3–13.8) [
      • 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.
      ].

      5. Morbidity

      In chronic hepatitis B, the average age of patients at the time of diagnosis of cirrhosis was 41–52 years (median 46) with a male to female ratio between 2.2 and 18 [
      • 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.
      ,
      • Liaw Y.F.
      • Lin D.Y.
      • Chen T.J.
      • Chu C.M.
      Natural course after the development of cirrhosis in patients with chronic type B hepatitis: a prospective study.
      ,
      • Kato Y.
      • Nakata K.
      • Omagari K.
      • Furukawa R.
      • Kusumoto Y.
      • Mori I.
      • et al.
      Risk of hepatocellular carcinoma in patients with cirrhosis in Japan. Analysis of infectious hepatitis viruses.
      ,
      • Mazzella G.
      • Accogli E.
      • Sottili S.
      • Festi D.
      • Orsini M.
      • Salzetta A.
      • et al.
      Alpha interferon treatment may prevent hepatocellular carcinoma in HCV-related liver cirrhosis.
      ,
      • Ikeda K.
      • Saitoh S.
      • Suzuki Y.
      • Kobayashi M.
      • Tsubota A.
      • Fukuda M.
      • et al.
      Interferon decreases hepatocellular carcinogenesis in patients with cirrhosis caused by the hepatitis B virus.
      ,
      • Fattovich G.
      • Giustina G.
      • Christensen E.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • et al.
      Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B.
      ]. In a European study of 366 patients with compensated cirrhosis due to hepatitis B, only 24% were referred to the enrolling center for non-specific symptoms of fatigue, dyspepsia and upper abdominal discomfort, indicating that cirrhosis development is insidious and mostly asymptomatic [
      • Realdi G.
      • Fattovich G.
      • Hadziyannis S.
      • Schalm S.W.
      • Almasio P.
      • Sanchez-Tapias J.
      • et al.
      Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study.
      ].

      5.1 Development of hepatocellular carcinoma

      Chronic HBV infection and cirrhosis of the liver are well recognized HCC risk factors [
      • Beasley R.P.
      Hepatitis B virus. The major etiology of hepatocellular carcinoma.
      ]. The major risk factor is significant liver disease. In high endemic areas HCC incidence per 100 person years is about 0.1 for chronic asymptomatic HBsAg carriers [
      • Yu M.W.
      • Hsu F.C.
      • Sheen I.S.
      • Chu C.M.
      • Lin D.Y.
      • Chen C.J.
      • et al.
      Prospective study of hepatocellular carcinoma and liver cirrhosis in asymptomatic chronic hepatitis B virus carriers.
      ,
      • McMahon B.J.
      • Bulkow L.
      • Harpster A.
      • Snowball M.
      • Lanier A.
      • Sacco F.
      • et al.
      Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population based study.
      ] and approx. 1.0 for patients with chronic hepatitis B without preexisting cirrhosis at diagnosis [
      • Lin S.M.
      • Sheen I.S.
      • Chien R.N.
      • Chu C.M.
      • Liaw Y.F.
      Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.
      ,
      • Liaw Y.F.
      • Tai D.I.
      • Chu C.M.
      • Lin D.Y.
      • Sheen I.S.
      • Chen T.J.
      • et al.
      Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis. A prospective study.
      ]. In longitudinal studies of patients with compensated cirrhosis type B from Asia HCC incidence was 3 per 100 person years, but even higher incidences of 6–8 have been reported from Singapore and Japan [
      • Liaw Y.F.
      • Lin D.Y.
      • Chen T.J.
      • Chu C.M.
      Natural course after the development of cirrhosis in patients with chronic type B hepatitis: a prospective study.
      ,
      • Kato Y.
      • Nakata K.
      • Omagari K.
      • Furukawa R.
      • Kusumoto Y.
      • Mori I.
      • et al.
      Risk of hepatocellular carcinoma in patients with cirrhosis in Japan. Analysis of infectious hepatitis viruses.
      ,
      • Ikeda K.
      • Saitoh S.
      • Suzuki Y.
      • Kobayashi M.
      • Tsubota A.
      • Fukuda M.
      • et al.
      Interferon decreases hepatocellular carcinogenesis in patients with cirrhosis caused by the hepatitis B virus.
      ,
      • Oon C.J.
      Long-term survival following treatment of hepatocellular carcinoma in Singapore: evaluation of Wellferon in the prophylaxis of high-risk pre-cancerous conditions.
      ].
      The natural history of compensated cirrhosis caused by hepatitis B was analyzed in a subgroup of 161 out of 366 patients enrolled in the above referred European study [
      • Realdi G.
      • Fattovich G.
      • Hadziyannis S.
      • Schalm S.W.
      • Almasio P.
      • Sanchez-Tapias J.
      • et al.
      Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study.
      ], who were delta negative at diagnosis and remained untreated during a mean follow-up of 6.4 years [
      • Fattovich G.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • Schalm S.W.
      • Christensen E.
      Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients.
      ]. In this study population the 5-year cumulative incidence of HCC was 9%, the incidence per 100 person years was 2.2 and the mean interval between the time of diagnosis of cirrhosis and the occurrence of HCC was 44 months (range 6–180) (Fig. 2A) [
      • Fattovich G.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • Schalm S.W.
      • Christensen E.
      Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients.
      ]. The majority of patients with HCC did not experience hepatic decompensation before or by the time of diagnosis, indicating that HCC usually arises in the clinical setting of compensated cirrhosis which may be clinically silent [
      • Fattovich G.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • Schalm S.W.
      • Christensen E.
      Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients.
      ].
      Figure thumbnail gr2
      Fig. 2Cumulative incidence of HCC and decompensation (A); and cumulative probability of survival and survival after the appearance of the first episode of decompensation (B) in 161 untreated Caucasian patients with compensated cirrhosis due to hepatitis B . The 5-year rate of HCC and decompensation was 9 and 16%, respectively. The 5-year probability of survival and survival after decompensation was 86 and 28%, respectively. The number of patients under observation refers to the survival probability.
      Host, viral and other factors may contribute to the progression of hepatitis to HCC. HCC incidence is three to six times higher in males than in females, suggesting a tumorigenic effect of androgens [
      • McMahon B.J.
      • Alberts S.R.
      • Wainwright R.B.
      • Bulkow L.
      • Lanier A.P.
      Hepatitis B-related sequelae. Prospective study in 1400 hepatitis B surface antigen-positive Alaska Native carriers.
      ,
      • Beasley R.P.
      Hepatitis B virus. The major etiology of hepatocellular carcinoma.
      ].
      Several studies have indicated that older age, which may be a determinant in itself or simply reflect a longer duration of infection and liver disease, is an important determinant of HCC [
      • McMahon B.J.
      • Alberts S.R.
      • Wainwright R.B.
      • Bulkow L.
      • Lanier A.P.
      Hepatitis B-related sequelae. Prospective study in 1400 hepatitis B surface antigen-positive Alaska Native carriers.
      ,
      • Beasley R.P.
      Hepatitis B virus. The major etiology of hepatocellular carcinoma.
      ,
      • Fattovich G.
      • Giustina G.
      • Schalm S.W.
      • Hadziyannis S.
      • Sanchez-Tapias J.
      • Almasio P.
      • et al.
      Occurrence of hepatocellular carcinoma and decompensation in Western European patients with cirrhosis type B.
      ,
      • Benvegnù L.
      • Fattovich G.
      • Noventa F.
      • Tremolada F.
      • Chemello L.
      • Cecchetto A.
      • et al.
      Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis.
      ].
      The relationship between ongoing HBV replication and HCC risk has been evaluated in the European cohort of patients with compensated cirrhosis B. The HCC risk did not differ among patients who were HBeAg positive or HBeAg negative/HBV DNA positive or HBeAg negative/HBV DNA negative at entry (5-year cumulative HCC incidence: 9, 14 and 8%, respectively (P=0.4 by log rank test)) and the relative risk (95% CI) for HCC was 0.89 (0.30–2.63) in HBV DNA positive relative to HBV DNA negative patients [
      • Fattovich G.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • Schalm S.W.
      • Christensen E.
      Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients.
      ]. These data suggest that the HBeAg and HBV DNA status at the time of diagnosis of cirrhosis has no predictive value for HCC development and that, in addition to chronic HBV infection, cirrhosis per se is a HCC risk factor.
      Alcohol and infection with HCV or HDV increases the HCC risk [
      • Fattovich G.
      • Giustina G.
      • Christensen E.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • et al.
      Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B.
      ,
      • Benvegnù L.
      • Fattovich G.
      • Noventa F.
      • Tremolada F.
      • Chemello L.
      • Cecchetto A.
      • et al.
      Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis.
      ,
      • Tsai J.F.
      • Jeng J.E.
      • Ho M.S.
      • Chang W.Y.
      • Hsieh M.Y.
      • Lin Z.Y.
      • et al.
      Effect of hepatitis C and B virus infection on risk of hepatocellular carcinoma: a prospective study.
      ]. In a longitudinal study conducted in a cohort of 290 Italian patients with cirrhosis, age, male sex, previous alcohol abuse and HCV coinfection were independent HCC risk factors by multivariate analysis [
      • Benvegnù L.
      • Fattovich G.
      • Noventa F.
      • Tremolada F.
      • Chemello L.
      • Cecchetto A.
      • et al.
      Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis.
      ]. The effect of HDV infection as a HCC risk factor has been evaluated in a EUROHEP longitudinal cohort study of 200 patients (20% coinfected by HDV) followed for a mean period of 6.6 years; in this study HDV infection was associated with 3-fold (95% CI 1.0–10) increased HCC risk [
      • Fattovich G.
      • Giustina G.
      • Christensen E.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • et al.
      Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B.
      ].

      5.2 Hepatic decompensation

      In the EUROHEP cohort study the 5-year cumulative incidence of hepatic decompensation was 16%, the incidence per 100 person years was 3.3 and the mean interval between the time of diagnosis of cirrhosis and the appearance of the first episode of decompensation was 31 months (range 6–109) (Fig. 2A) [
      • Fattovich G.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • Schalm S.W.
      • Christensen E.
      Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients.
      ]. The first episode of decompensation was caused by ascites in 49% of patients and by variceal bleeding, jaundice or more than one complication in 9, 12 and 30% of patients, respectively. Longitudinal studies conducted in Asia including patients with recent development of cirrhosis (Child class A) have indicated similar rates of decompensation with a 5-year cumulative incidence of approximately 20% (4 per 100 person years) [
      • Liaw Y.F.
      • Lin D.Y.
      • Chen T.J.
      • Chu C.M.
      Natural course after the development of cirrhosis in patients with chronic type B hepatitis: a prospective study.
      ]. These findings indicate that a significant proportion of patients presenting with compensated cirrhosis B are stable for several years and that hepatic decompensation usually occurs at a relatively late stage of the disease.

      6. Mortality from liver disease and risk factors

      HCC and liver failure are the main causes of death and currently over 500,000 people die each year from the consequence of HBV infection.
      The mortality rate depends on the initial clinical features at which patients are studied. Among inactive HBsAg positive carriers both referred to clinical centers and in population-based studies none died from liver related causes when followed up to 16 years [
      • Hsu Y.S.
      • Chien R.N.
      • Yeh C.T.
      • Sheen I.S.
      • Chiou H.Y.
      • Chu C.M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ,
      • 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.
      ,
      • Bellentani S.
      • Dal Molin G.
      • Miglioli L.
      • Crocè L.
      • Masutti F.
      • Castiglione A.
      • et al.
      Natural history of HBV infection: a 9 years follow-up of the Dionysos cohort.
      ].
      In patients with chronic hepatitis B the survival rate was 99–100% at 5 years following the diagnosis of chronic hepatitis [
      • Fattovich G.
      • Brollo L.
      • Giustina G.
      • Noventa F.
      • Pontisso P.
      • Alberti A.
      • et al.
      Natural history and prognostic factors of chronic hepatitis type B.
      ,
      • Ikeda K.
      • Saitoh S.
      • Suzuki Y.
      • Kobayashi M.
      • Tsubota A.
      • Koida I.
      • et al.
      Disease progression and hepatocellular carcinogenensis in patients with chronic viral hepatitis: a prospective observation in 2215 patients.
      ]. In long-term studies of untreated patients with chronic hepatitis B, both HBeAg positive and HBeAg negative, without preexisting cirrhosis at baseline and without HDV infection, the incidence of liver related death was low and ranged from 0 to 1.06 per 100 person years (personal communication of the authors of refs. [
      • Di Marco V.
      • Lo Iacono O.
      • Cammà C.
      • Vaccaro A.
      • Giunta M.
      • Martorana G.
      • et al.
      The long-term course of chronic hepatitis B.
      ,
      • Lin S.M.
      • Sheen I.S.
      • Chien R.N.
      • Chu C.M.
      • Liaw Y.F.
      Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.
      ,
      • Papatheodoridis G.V.
      • Manesis E.
      • Hadziyannis S.J.
      The long-term outcome of interferon-α treated and untreated patients with HBeAg-negative chronic hepatitis B.
      ,
      • Mazzella G.
      • Saracco G.
      • Festi D.
      • Rosina F.
      • Marchetto S.
      • Jaboli F.
      • et al.
      Long-term results with interferon therapy in chronic type B hepatitis: a prospective randomized trial.
      ]).
      The probability of survival is approx. 80–86% at 5 years in patients with compensated cirrhosis [
      • Liaw Y.F.
      • Lin D.Y.
      • Chen T.J.
      • Chu C.M.
      Natural course after the development of cirrhosis in patients with chronic type B hepatitis: a prospective study.
      ,
      • Realdi G.
      • Fattovich G.
      • Hadziyannis S.
      • Schalm S.W.
      • Almasio P.
      • Sanchez-Tapias J.
      • et al.
      Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study.
      ,
      • De Jongh F.E.
      • Janssen H.L.A.
      • De Man R.A.
      • Hop W.C.J.
      • Schalm S.W.
      • Van Blankestein M.
      Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver.
      ]. In the EUROHEP cohort of 161 untreated patients with HBsAg positive, HDV negative compensated cirrhosis the 5-year probability of survival was 86% and the incidence per 100 person years of liver related death was 3.5; there was a linear, although slow rate of HCC development, hepatic decompensation and liver related death in this cohort of patients (Fig. 2B) [
      • Fattovich G.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • Schalm S.W.
      • Christensen E.
      Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients.
      ]. The causes of death or liver transplantation included complications of HCC in 35%, liver failure in 53% and causes unrelated to liver disease in 12% [
      • Fattovich G.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • Schalm S.W.
      • Christensen E.
      Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients.
      ].
      Strong predictors for survival are age and parameters that relate to hepatocellular function (albumin, bilirubin) and the presence of portal hypertension (platelets, splenomegaly); these are similar to the risk factors for HCC and decompensation and reflect the stage and severity of the underlying cirrhosis (Table 1) [
      • Realdi G.
      • Fattovich G.
      • Hadziyannis S.
      • Schalm S.W.
      • Almasio P.
      • Sanchez-Tapias J.
      • et al.
      Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study.
      ,
      • Fattovich G.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • Schalm S.W.
      • Christensen E.
      Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients.
      ,
      • De Jongh F.E.
      • Janssen H.L.A.
      • De Man R.A.
      • Hop W.C.J.
      • Schalm S.W.
      • Van Blankestein M.
      Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver.
      ].
      HBV replication has been reported as a negative prognostic factor, whereas viral clearance and ALT normalization correlated with increased survival [
      • Fattovich G.
      • Giustina G.
      • Realdi G.
      • Corrocher R.
      • Schalm S.W.
      Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa.
      ,
      • De Jongh F.E.
      • Janssen H.L.A.
      • De Man R.A.
      • Hop W.C.J.
      • Schalm S.W.
      • Van Blankestein M.
      Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver.
      ]. In the EUROHEP cohort of patients with compensated cirrhosis B survival was significantly lower in HBeAg positive or HBeAg negative/HBV DNA positive patients as compared to HBeAg negative/HBV DNA negative patients (5-year survival probability: 79, 86 and 97%, respectively, P=0.01); the risk of decompensation and mortality was 4.0 fold (95% CI 1.09–15.1) and 5.9 fold (95% CI 1.64–21.3), respectively, in HBV DNA positive as compared to HBV DNA negative patients [
      • Fattovich G.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • Schalm S.W.
      • Christensen E.
      Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients.
      ].
      Moreover, HBeAg loss during follow-up of cirrhotic patients was associated with a 2.2 fold decrease in death rate [
      • De Jongh F.E.
      • Janssen H.L.A.
      • De Man R.A.
      • Hop W.C.J.
      • Schalm S.W.
      • Van Blankestein M.
      Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver.
      ]. In another study of HBeAg positive cirrhotic patients multivariate analysis demonstrated that ALT normalization during follow-up was a better predictor of survival than HBeAg clearance [
      • Fattovich G.
      • Giustina G.
      • Realdi G.
      • Corrocher R.
      • Schalm S.W.
      Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa.
      ]. This data is in agreement with the observation that in the natural course of chronic hepatitis B a proportion of patients do not benefit from HBeAg seroconversion, as shown by persistence of HBV viremia and disease activity or by HBV reactivation.
      In a study of chronic delta hepatitis the 5 year probability of survival was 100% for patients with mild hepatitis, 90% for severe hepatitis and 81% for asymptomatic cirrhosis [
      • Rosina F.
      • Conoscitore P.
      • Cuppone R.
      • Rocca G.
      • Giuliani A.
      • Cozzolongo R.
      • et al.
      Changing pattern of chronic hepatitis D in Southern Europe.
      ]. Chronic hepatitis D rapidly advances to cirrhosis, but available data indicate that thereafter the disease remains stable and asymptomatic in a high proportion of patients for more than one decade similarly to that observed in compensated cirrhosis B. On the other hand the prognosis of patients with hepatitis D and with clinical cirrhosis at presentation is poor with a 5 year survival of 49% [
      • Rosina F.
      • Conoscitore P.
      • Cuppone R.
      • Rocca G.
      • Giuliani A.
      • Cozzolongo R.
      • et al.
      Changing pattern of chronic hepatitis D in Southern Europe.
      ].

      6.1 Survival after decompensation

      Once decompensation occurs the prognosis is poor. The probability of survival ranges from 55 to 70% at 1 year and from 14 to 28% at 5 years, considerably lower than the survival for compensated cirrhosis B (Fig. 2B) [
      • Fattovich G.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • Schalm S.W.
      • Christensen E.
      Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients.
      ,
      • De Jongh F.E.
      • Janssen H.L.A.
      • De Man R.A.
      • Hop W.C.J.
      • Schalm S.W.
      • Van Blankestein M.
      Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver.
      ]. Moreover, the type of decompensation may affect survival. The lowest survival rate was observed in patients with more than one complication (35% at 3 years and 23% at 5 years) and the highest survival rate for decompensated patients who presented with ascites (50% at 3 years and 38% at 5 years) [
      • Fattovich G.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • Schalm S.W.
      • Christensen E.
      Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients.
      ]. A recent study demonstrated that encephalopathy and hypoalbuminemia indicate a poor prognosis after onset of hepatic decompensation [
      • Hui A.Y.
      • Chan H.L.
      • Leung N.W.
      • Hung L.C.
      • Chan F.K.
      • Sung J.J.
      Survival and prognostic indicators in patients with hepatitis B virus-related cirrhosis after onset of hepatic decompensation.
      ]. In decompensated patients with cirrhosis HBV clearance and delayed HBsAg loss can be associated with improvement of liver disease [
      • Chung H.T.
      • Lai C.L.
      • Lok A.S.
      Pathogenic role of hepatitis B virus in hepatitis B surface antigen-negative decompensated cirrhosis.
      ]. These information's are helpful for patient management, including referral for liver transplantation.

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