Title: Natural History of Hepatitis B Virus Infection: An Update for Clinicians
Abstract: Hepatitis B virus (HBV) is a common viral pathogen that causes a substantial health burden worldwide. Significant progress has been made in the past few decades in understanding the natural history of HBV infection. A dynamic balance between viral replication and host immune response is pivotal to the pathogenesis of liver disease. In immunocompetent adults, most HBV infections spontaneously resolve, whereas in most neonates and infants they become chronic. Those with chronic HBV may present in 1 of 4 phases of infection: (1) in a state of immune tolerance, (2) with hepatitis B e antigen (HBeAg)-positive chronic hepatitis, (3) as an inactive hepatitis B surface antigen carrier, or (4) with HBeAg-negative chronic hepatitis. Of these, HBeAg-positive and HBeAg-negative chronic hepatitis may progress to cirrhosis and its long-term sequelae including hepatic decompensation and hepatocellular carcinoma. Several prognostic factors, such as serum HBV DNA concentrations, HBeAg status, serum aminotransferases, and certain HBV genotypes, have been identified to predict long-term outcome. These data emphasize the importance of monitoring all patients with chronic HBV infection to identify candidates for and select optimal timing of antiviral treatment, to recognize those at risk of complications, and to implement surveillance for early detection of hepatocellular carcinoma. Hepatitis B virus (HBV) is a common viral pathogen that causes a substantial health burden worldwide. Significant progress has been made in the past few decades in understanding the natural history of HBV infection. A dynamic balance between viral replication and host immune response is pivotal to the pathogenesis of liver disease. In immunocompetent adults, most HBV infections spontaneously resolve, whereas in most neonates and infants they become chronic. Those with chronic HBV may present in 1 of 4 phases of infection: (1) in a state of immune tolerance, (2) with hepatitis B e antigen (HBeAg)-positive chronic hepatitis, (3) as an inactive hepatitis B surface antigen carrier, or (4) with HBeAg-negative chronic hepatitis. Of these, HBeAg-positive and HBeAg-negative chronic hepatitis may progress to cirrhosis and its long-term sequelae including hepatic decompensation and hepatocellular carcinoma. Several prognostic factors, such as serum HBV DNA concentrations, HBeAg status, serum aminotransferases, and certain HBV genotypes, have been identified to predict long-term outcome. These data emphasize the importance of monitoring all patients with chronic HBV infection to identify candidates for and select optimal timing of antiviral treatment, to recognize those at risk of complications, and to implement surveillance for early detection of hepatocellular carcinoma. Hepatitis B virus (HBV) infection is a challenging global health problem, affecting an estimated 2 billion persons worldwide. Of those infected with HBV, 400 million remain chronically infected, and an estimated 1 million die of HBV-related liver diseases annually.1Ocama P Opio CK Lee WM Hepatitis B virus infection: current status.Am J Med. 2005; 118: 1413.e15-1413.e22Abstract Full Text Full Text PDF Scopus (68) Google Scholar According to the Centers for Disease Control and Prevention, the incidence of newly acquired HBV infection in the United States has declined steadily since the mid-1980s,2Mast EE Mahoney FJ Alter MJ Margolis HS Progress toward elimination of hepatitis B virus transmission in the United States.Vaccine. 1998; 16: S48-S51Crossref PubMed Scopus (47) Google Scholar, 3Alter MJ Community acquired viral hepatitis B and C in the United States.Gut. 1993; 34: S17-S19Crossref PubMed Google Scholar, 4Goldstein ST Alter MJ Williams IT et al.Incidence and risk factors for acute hepatitis B in the United States, 1982-1998: implications for vaccination programs.J Infect Dis. 2002 Mar 15; 185 (Epub 2002 Feb 28.): 713-719Crossref PubMed Scopus (170) Google Scholar a decrease attributed to several public health interventions such as screening of pregnant women, vaccination of infants and adolescents, and safe injection practices in general.5Mast EE Williams IT Alter MJ Margolis HS Hepatitis B vaccination of adolescent and adult high-risk groups in the United States.Vaccine. 1998; 16: S27-S29Crossref PubMed Scopus (42) Google Scholar If the incidence of new infections continues to decrease in the United States, depleting the pool of infected persons, it is hoped that endogenous transmission will eventually be eliminated. However, the prevalence of chronic HBV infection has yet to show a decrease.6Kim WR Benson JT Therneau TM Torgerson HA Yawn BP Melton III, LJ Changing epidemiology of hepatitis B in a US community.Hepatology. 2004; 39: 811-816Crossref PubMed Scopus (44) Google Scholar Moreover, the rate of HBV-related hospitalizations, cancers, and deaths has more than doubled during the past decade, largely because of an influx of immigrants to the United States from endemic areas.7Kim WR Ishitani MB Dickson ER Rising burden of hepatitis B in the United States: should the other virus be forgotten? [abstract].Hepatology. 2002; 36: 222AGoogle Scholar Understanding the natural history of HBV infection has become increasingly relevant for clinicians for several reasons. First, in the past 10 years, antiviral agents specific for the treatment of HBV have proliferated, providing opportunities to fundamentally alter the natural history of HBV infection. However, limitations of the currently available therapies, including their inability to eradicate the infection completely or to prevent emergence of resistant mutations, necessitate optimal timing of the therapies in selected patients. Second, epidemiologic studies have yielded important information about the effects of the genetic diversity of HBV on its natural history. For example, hepatitis B e antigen (HBeAg)-negative chronic hepatitis B, which is associated with the so-called precore mutant, was once thought rare but now is seen commonly in practice. As more information about the HBV genotype becomes available, it may play a greater role in clinical decision making. Third, the availability of highly sensitive HBV DNA assays, combined with a better understanding of HBV virology and of the host immune response to HBV infection, has led to new insights into the natural history of HBV infection. Thus, understanding the dynamic nature of chronic HBV infection is essential for management of HBV carriers, not only in selecting optimal treatment candidates but also in instituting appropriate monitoring for the prevention and early detection of complications from chronic HBV infection. The observation that many HBV carriers are asymptomatic with minimal liver injury, despite extensive and continuing intrahepatic replication of the virus, supports the concept that HBV is not directly cytotoxic to hepatocytes.8de Franchis R Meucci G Vecchi M et al.The natural history of asymptomatic hepatitis B surface antigen carriers.Ann Intern Med. 1993; 118: 191-194Crossref PubMed Google Scholar, 9Ganem D Prince AM Hepatitis B virus infection—natural history and clinical consequences [published correction appears in N Engl J Med. 2004; 351:351].N Engl J Med. 2004; 350: 1118-1129Crossref PubMed Scopus (905) Google Scholar The severity of hepatocellular injury is modulated by the strength of host immune responses.10Villeneuve JP The natural history of chronic hepatitis B virus infection.J Clin Virol. 2005; 34: S139-S142Abstract Full Text PDF PubMed Scopus (43) Google Scholar, 11Eddleston AL Mondelli M Immunopathological mechanisms of liver cell injury in chronic hepatitis B virus infection.J Hepatol. 1986; 3: S17-S23Abstract Full Text PDF PubMed Google Scholar, 12Rapicetta M Ferrari C Levrero M Viral determinants and host immune responses in the pathogenesis of HBV infection.J Med Virol. 2002; 67: 454-457Crossref PubMed Scopus (39) Google Scholar In patients with fulminant HBV infection, rapid viral clearance is achieved after severe liver injury as a result of a vigorous host immune response.10Villeneuve JP The natural history of chronic hepatitis B virus infection.J Clin Virol. 2005; 34: S139-S142Abstract Full Text PDF PubMed Scopus (43) Google Scholar, 11Eddleston AL Mondelli M Immunopathological mechanisms of liver cell injury in chronic hepatitis B virus infection.J Hepatol. 1986; 3: S17-S23Abstract Full Text PDF PubMed Google Scholar, 12Rapicetta M Ferrari C Levrero M Viral determinants and host immune responses in the pathogenesis of HBV infection.J Med Virol. 2002; 67: 454-457Crossref PubMed Scopus (39) Google Scholar However, in neonates with an immature immune system, exposure to HBV often results in minimal acute liver injury but high rates of chronic infection (up to 90%). Conversely, HBV carriers with mild or no liver disease may have a severe flare of hepatitis when they undergo cancer chemotherapy or immunosuppressive therapy for organ transplantation.13Vassiliadis T Garipidou V Tziomalos K Perifanis V Giouleme O Vakalopoulou S Prevention of hepatitis B reactivation with lamivudine in hepatitis B virus carriers with hematologic malignancies treated with chemotherapy—a prospective case series.Am J Hematol. 2005; 80: 197-203Crossref PubMed Scopus (38) Google Scholar, 14Idilman R Lamivudine prophylaxis in HBV carriers with haematooncological malignancies who receive chemotherapy.J Antimicrob Chemother. 2005 Jun; 55 (Epub 2005 Apr 22.): 828-831Crossref PubMed Scopus (20) Google Scholar, 15Lin PC Poh SB Lee MY Hsiao LT Chen PM Chiou TJ Fatal fulminant hepatitis B after withdrawal of prophylactic lamivudine in hematopoietic stem cell transplantation patients.Int J Hematol. 2005; 81: 349-351Crossref PubMed Scopus (16) Google Scholar Limited data suggest that in this setting an overwhelming degree of viral replication usurps the cellular functions necessary for viability and makes HBV essentially cytopathic.16Meuleman P Libbrecht L Wieland S et al.Immune suppression uncovers endogenous cytopathic effects of the hepatitis B virus.J Virol. 2006; 80: 2797-2807Crossref PubMed Scopus (30) Google Scholar Hepatitis B virus was thought to be cleared completely in those who recover from acute HBV infection. However, with the development of sensitive assays for HBV DNA detection, traces of the HBV genome have been frequently identified in the liver or serum up to 10 years after clinical recovery from acute HBV infection, despite the disappearance of viral antigens and the appearance of antiviral antibodies and specific cytotoxic T lymphocytes.17Yuki N Nagaoka T Yamashiro M et al.Long-term histologic and virologic outcomes of acute self-limited hepatitis B.Hepatology. 2003; 37: 1172-1179Crossref PubMed Scopus (89) Google Scholar, 18Rehermann B Ferrari C Pasquinelli C Chisari FV The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response.Nat Med. 1996; 2: 1104-1108Crossref PubMed Scopus (458) Google Scholar, 19Yotsuyanagi H Yasuda K Iino S et al.Persistent viremia after recovery from self-limited acute hepatitis B.Hepatology. 1998; 27: 1377-1382Crossref PubMed Scopus (125) Google Scholar, 20Marusawa H Uemoto S Hijikata M et al.Latent hepatitis B virus infection in healthy individuals with antibodies to hepatitis B core antigen.Hepatology. 2000; 31: 488-495Crossref PubMed Google Scholar These observations suggest that HBV is rarely completely eradicated after recovery from acute infection, which may account for several reports of reactivation of HBV replication in persons with serologic markers of recovery from HBV who receive chemotherapy or immunosuppression after organ transplantation.21Blanpain C Knoop C Delforge ML et al.Reactivation of hepatitis B after transplantation in patients with pre-existing anti-hepatitis B surface antigen antibodies: report on three cases and review of the literature.Transplantation. 1998; 66: 883-886Crossref PubMed Scopus (85) Google Scholar, 22Coiffier B Hepatitis B virus reactivation in patients receiving chemotherapy for cancer treatment: role of Lamivudine prophylaxis.Cancer Invest. 2006; 24: 548-552Crossref PubMed Scopus (31) Google Scholar In acute HBV infection, hepatitis B surface antigen (HBsAg) becomes detectable in the serum after an incubation period of 4 to 10 weeks, followed shortly by the appearance of antibody against the hepatitis B core antigen, which is predominantly of the IgM isotope in the early phase.23Hoofnagle JH Serologic markers of hepatitis B virus infection.Annu Rev Med. 1981; 32: 1-11Crossref PubMed Google Scholar Levels of HBV DNA are generally very high, frequently in the range of 200 million IU/mL to 200 billion IU/mL (109–1012 copies/mL).24Ribeiro RM Lo A Perelson AS Dynamics of hepatitis B virus infection.Microbes Infect. 2002; 4: 829-835Crossref PubMed Scopus (42) Google Scholar Circulating HBeAg can be detected in most patients with acute HBV infection, and these patients can readily transmit the infection.25Koff RS Slavin MM Connelly JD Rosen DR Contagiousness of acute hepatitis B: secondary attack rates in household contacts.Gastroenterology. 1977; 72: 297-300Abstract Full Text PDF PubMed Google Scholar, 26Kajino K Jilbert AR Saputelli J Aldrich CE Cullen J Mason WS Woodchuck hepatitis virus infections: very rapid recovery after a prolonged viremia and infection of virtually every hepatocyte.J Virol. 1994; 68: 5792-5803PubMed Google Scholar Aminotransferase levels do not increase until after viral infection is well established because time is required for specific cytotoxic T lymphocyte responses to develop against virally infected hepatocytes. Approximately 30% to 50% of infected adults present with an icteric illness after an incubation period of 6 weeks to 6 months.27McMahon BJ Alward WL Hall DB et al.Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state.J Infect Dis. 1985; 151: 599-603Crossref PubMed Google Scholar The outcome of acute HBV infection depends on age and immune competence at the time of infection.27McMahon BJ Alward WL Hall DB et al.Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state.J Infect Dis. 1985; 151: 599-603Crossref PubMed Google Scholar, 28Beasley RP Trepo C Stevens CE Szmuness W The e antigen and vertical transmission of hepatitis B surface antigen.Am J Epidemiol. 1977; 105: 94-98Crossref PubMed Scopus (0) Google Scholar, 29Tassopoulos NC Papaevangelou GJ Sjogren MH Roumeliotou-Karayannis A Gerin JL Purcell RH Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults.Gastroenterology. 1987; 92: 1844-1850Abstract PubMed Google Scholar, 30Beasley RP Hwang LY Lin CC et al.Incidence of hepatitis B virus infections in preschool children in Taiwan.J Infect Dis. 1982; 146: 198-204Crossref PubMed Google Scholar For example, chronic HBV infection will develop in as many as 90% of infected neonates and infants but only in 1% to 5% of immunocompetent adults (excluding those with acute exacerbations of chronic HBV infection). Children aged 1 to 5 years have an intermediate risk (approximately 30%).27McMahon BJ Alward WL Hall DB et al.Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state.J Infect Dis. 1985; 151: 599-603Crossref PubMed Google Scholar, 28Beasley RP Trepo C Stevens CE Szmuness W The e antigen and vertical transmission of hepatitis B surface antigen.Am J Epidemiol. 1977; 105: 94-98Crossref PubMed Scopus (0) Google Scholar, 29Tassopoulos NC Papaevangelou GJ Sjogren MH Roumeliotou-Karayannis A Gerin JL Purcell RH Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults.Gastroenterology. 1987; 92: 1844-1850Abstract PubMed Google Scholar, 30Beasley RP Hwang LY Lin CC et al.Incidence of hepatitis B virus infections in preschool children in Taiwan.J Infect Dis. 1982; 146: 198-204Crossref PubMed Google Scholar In the United States, most persons with acute HBV infection are adults. As a rule, acute HBV infection resolves without the need for intervention or antiviral treatment. Fulminant hepatitis occurs in 0.1% to 0.5% of those with acute HBV infection and often demonstrates no evidence of HBV replication because of the massive immune-mediated lysis of infected hepatocytes.31Wright TL Mamish D Combs C et al.Hepatitis B virus and apparent fulminant non-A, non-B hepatitis.Lancet. 1992; 339: 952-955Abstract PubMed Google Scholar In endemic areas, exposure to HBV at birth or in early childhood results in higher rates of chronic HBV infection. Persons infected as children may present in adulthood with clinical manifestations similar to those of acute hepatitis if they have acute exacerbation of chronic HBV infection. These exacerbations frequently may be associated with elevated levels of IgM antibody to hepatitis B core antigen, which may lead to misdiagnosis of acute HBV infection,32Liaw YF Chu CM Su IJ Huang MJ Lin DY Chang-Chien CS Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis.Gastroenterology. 1983; 84: 216-219Abstract Full Text PDF PubMed Google Scholar, 33Liaw YF Yang SS Chen TJ Chu CM Acute exacerbation in hepatitis B e antigen positive chronic type B hepatitis: a clinicopathological study.J Hepatol. 1985; 1: 227-233Abstract Full Text PDF PubMed Google Scholar, 34Liaw YF Chu CM Huang MJ Sheen IS Yang CY Lin DY Determinants for hepatitis B e antigen clearance in chronic type B hepatitis.Liver. 1984; 4: 301-306Crossref PubMed Google Scholar and an increase in the serum α-fetoprotein concentration, which may raise concerns for the presence of hepatocellular carcinoma (HCC).35Lok AS Lai CL alpha-Fetoprotein monitoring in Chinese patients with chronic hepatitis B virus infection: role in the early detection of hepatocellular carcinoma.Hepatology. 1989; 9: 110-115Crossref PubMed Google Scholar Thus, it is important to define and understand the phases of acute and chronic HBV infection. Those with chronic HBV infection may present: (1) in a state of immune tolerance, (2) with HBeAg-positive chronic hepatitis, (3) as an inactive HBsAg carrier, or (4) with HBeAg-negative chronic hepatitis (Figure 1). Persistent HBV infection has an initial immune tolerance phase that can be characterized by the presence of HBeAg and high levels of serum HBV DNA due to a high rate of viral replication. This phase is mostly seen in patients who acquire the infection at birth or during early childhood; rarely, it also can be seen briefly in those who acquire the infection in late childhood or adulthood and have subsequent development of chronic HBV infection.36Chu CM Karayiannis P Fowler MJ Monjardino J Liaw YF Thomas HC Natural history of chronic hepatitis B virus infection in Taiwan: studies of hepatitis B virus DNA in serum.Hepatology. 1985; 5: 431-434Crossref PubMed Scopus (123) Google Scholar, 37Yim HJ Lok AS Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005.Hepatology. 2006; 43: S173-S181Crossref PubMed Scopus (201) Google Scholar The absence of liver disease despite high levels of HBV replication is thought to be a consequence of immune tolerance to HBeAg.38Hsu HY Chang MH Hsieh KH et al.Cellular immune response to HBcAg in mother-to-infant transmission of hepatitis B virus.Hepatology. 1992; 15: 770-776Crossref PubMed Google Scholar However, the mechanisms underlying this tolerance are incompletely understood. Experiments in mice suggest that transplacental transfer of maternal HBeAg may induce specific unresponsiveness of T cells to HBeAg and to hepatitis B core antigen, resulting in ineffective cytotoxic T cell lysis of infected hepatocytes.39Milich DR Jones JE Hughes JL Price J Raney AK McLachlan A Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero?.Proc Natl Acad Sci U S A. 1990; 87: 6599-6603Crossref PubMed Google Scholar, 40Chen M Sallberg M Hughes J et al.Immune tolerance split between hepatitis B virus precore and core proteins.J Virol. 2005; 79: 3016-3027Crossref PubMed Scopus (85) Google Scholar This tolerization leads to minimal host immune activity, characterized by normal serum aminotransferase levels and liver histological findings of minimal or no inflammation.41Chang MH Hwang LY Hsu HC Lee CY Beasley RP Prospective study of asymptomatic HBsAg carrier children infected in the perinatal period: clinical and liver histologic studies.Hepatology. 1988; 8: 374-377Crossref PubMed Google Scholar, 42Lok AS Lai CL A longitudinal follow-up of asymptomatic hepatitis B surface antigen-positive Chinese children.Hepatology. 1988; 8: 1130-1133Crossref PubMed Google Scholar As the host immune system matures and begins to recognize HBV-related epitopes on hepatocytes, immune-mediated hepatocellular injury ensues.43Tsai SL Chen PJ Lai MY et al.Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens: implications for hepatitis B e antigen seroconversion.J Clin Invest. 1992; 89: 87-96Crossref PubMed Google Scholar, 44Chu CM Liaw YF Intrahepatic distribution of hepatitis B surface and core antigens in chronic hepatitis B virus infection: hepatocyte with cytoplasmic/membranous hepatitis B core antigen as a possible target for immune hepatocytolysis.Gastroenterology. 1987; 92: 220-225Abstract PubMed Scopus (0) Google Scholar Although HBV replication continues in the liver and viremia is continual, the viral level in the serum becomes lower than during theimmune tolerance phase when viral replication is completely unopposed.45Tedder RS Ijaz S Gilbert N et al.Evidence for a dynamic host-parasite relationship in e-negative hepatitis B carriers.J Med Virol. 2002; 68: 505-512Crossref PubMed Scopus (24) Google Scholar In patients with perinatally acquired HBV infection, transition from the immune tolerance to the HBeAg-positive chronic hepatitis phase occurs during the second or third decade of life.46Liaw YF Tai DI Chu CM Pao CC Chen TJ Acute exacerbation in chronic type B hepatitis: comparison between HBeAg and antibody-positive patients.Hepatology. 1987; 7: 20-23Crossref PubMed Scopus (67) Google Scholar This phase is characterized by the presence of HBeAg, high levels of serum HBV DNA, elevation of serum aminotransferase levels, and histological findings of active inflammation and often fibrosis in the liver.32Liaw YF Chu CM Su IJ Huang MJ Lin DY Chang-Chien CS Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis.Gastroenterology. 1983; 84: 216-219Abstract Full Text PDF PubMed Google Scholar, 47Liaw YF Pao CC Chu CM Sheen IS Huang MJ Changes of serum hepatitis B virus DNA in two types of clinical events preceding spontaneous hepatitis B e antigen seroconversion in chronic type B hepatitis.Hepatology. 1987; 7: 1-3Crossref PubMed Scopus (25) Google Scholar Most patients with HBeAg-positive chronic hepatitis remain asymptomatic, making it difficult to detect the transition from the immune tolerance phase based on clinical grounds alone. However, some patients present with a symptomatic flare of hepatitis that mimics acute hepatitis or even with fulminant hepatic failure.48Lok AS Liang RH Chiu EK Wong KL Chan TK Todd D Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy: report of a prospective study.Gastroenterology. 1991; 100: 182-188Abstract PubMed Google Scholar, 49Davis GL Hoofnagle JH Waggoner JG Spontaneous reactivation of chronic hepatitis B virus infection.Gastroenterology. 1984; 86: 230-235PubMed Google Scholar These flares may precede the disappearance of HBeAg and the development of antibody against it, culminating in remission of hepatitis activity.32Liaw YF Chu CM Su IJ Huang MJ Lin DY Chang-Chien CS Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis.Gastroenterology. 1983; 84: 216-219Abstract Full Text PDF PubMed Google Scholar However, some flares result in only transient decreases in serum HBV DNA levels without the clearance of HBeAg.32Liaw YF Chu CM Su IJ Huang MJ Lin DY Chang-Chien CS Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis.Gastroenterology. 1983; 84: 216-219Abstract Full Text PDF PubMed Google Scholar Occasionally, hepatic decompensation may occur after these flares.50Sheen IS Liaw YF Tai DI Chu CM Hepatic decompensation associated with hepatitis B e antigen clearance in chronic type B hepatitis.Gastroenterology. 1985; 89: 732-735Abstract PubMed Google Scholar Spontaneous HBeAg seroconversion, which occurs annually in as many as 10% to 20% of those with HBeAg-positive hepatitis, is an important landmark in the natural history of chronic HBV infection.37Yim HJ Lok AS Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005.Hepatology. 2006; 43: S173-S181Crossref PubMed Scopus (201) Google Scholar, 51Liaw YF Chu CM Lin DY Sheen IS Yang CY Huang MJ Age-specific prevalence and significance of hepatitis B e antigen and antibody in chronic hepatitis B virus infection in Taiwan: a comparison among asymptomatic carriers, chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma.J Med Virol. 1984; 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