Natural history of chronic hepatitis B virus infection in adults with emphasis on the occurrence of cirrhosis and hepatocellular carcinoma

The natural course of perinatally acquired hepatitis B virus (HBV) infection has three phases. In the first ‘immune tolerance phase’, patients are HBeAg positive and have high serum levels of HBV DNA, but have no symptoms, normal ALT levels and minimal histological activity. The second ‘immune clearance phase’ usually occurs between 15 and 35 years of age, during which HBV replication declines, accompanied by increased serum ALT levels and inflammatory activity in the liver; HBeAg to anti‐HBe seroconversion is then observed, frequently preceded by a flare of the ALT level. The average rate of spontaneous HBeAg seroconversion is 10% per year. In the third ‘low‐replicative phase’, serum HBsAg persists, but HBeAg is no longer detectable and HBV DNA can only be detected by PCR assay. During this phase, patients are usually asymptomatic and liver disease is inactive; some patients, however, may progress to cirrhosis and hepatocellular carcinoma (HCC). The ultimate outcome of chronic HBV infection appears to depend on the duration and severity of liver injury during the immune clearance phase. About 2.1% of patients with chronic type B hepatitis develop cirrhosis each year. Patients who have a severe acute exacerbation complicated by subacute hepatic failure or who have recurrent episodes of acute exacerbations with bridging hepatic necrosis are more likely to develop cirrhosis. A significant proportion of those with HBsAg eventually develop HCC; they have a 100‐fold increased risk of HCC relative to those without. The development of HCC, however, is closely related to the severity of the underlying liver disease. The annual incidence of HCC is only 0.1% in asymptomatic HBsAg individual, 1% in patients with chronic hepatitis B, but increases to 3–10% in patients with cirrhosis. Some anti‐HBe‐positive patients continue to have active liver disease and they should be tested for HBV DNA by hybridization assay to determine whether the disease results from replicative precore mutant HBV infection or other causes of liver disease, such as superinfection with HCV and HDV. A substantial number of apparently healthy HBV‐infected individuals are first recognized when they present with episodes of acute hepatitis. About 30% of these cases could be attributed to other hepatotropic virus superinfection. Acute viral hepatitis in patients with concurrent HBV infection is associated with an increased risk of fulminant hepatic failure. Finally, HBsAg disappears from serum in about 1% of patients each year. HCV superinfection can enhance the termination of HBsAg positivity. HCV, however, replaces HBV as the dominant cause of chronic viral hepatitis. The outcome of HBV‐infected persons with ‘spontaneous’ seroclearance of HBsAg is usually favourable, though progress to cirrhosis and HCC is still possible.     

Role of viral factors in the natural course and therapy of chronic hepatitis B

Hepatitis B virus (HBV) infection is a global health problem that causes a wide spectrum of liver disease, including acute or fulminant hepatitis, inactive carrier state, chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The pathogenesis of hepatocyte damage associated with HBV is mainly through immune-mediated mechanisms. On the basis of the virus and host interactions, the natural history of HBV carriers who are infected in early life can be divided into four dynamic phases. The frequency, extent, and severity of hepatitis flares or acute exacerbation in the second immune clearance and/or fourth reactivation phase predict liver disease progression in HBV carriers. In the past decade, hepatitis B viral factors including serum HBV DNA level, genotype, and naturally occurring mutants predictive of clinical outcomes have been identified. The higher the serum HBV DNA level after the immune clearance phase, the higher the incidence of adverse outcomes over time. In addition, high viral load, genotype C, basal core promoter mutation, and pre-S deletion correlate with increased risk of cirrhosis and HCC development. As to the treatment of chronic hepatitis B, patients with high HBV DNA level and genotype C or D infection are shown to have a worse response to interferon therapy. In conclusion, serum HBV DNA level, genotype, and naturally occurring mutants are identified to influence liver disease progression and therapy of chronic hepatitis B. More investigations are needed to clarify the molecular mechanisms of the viral factors involved in the pathogenesis of each stage of liver disease and the response to antiviral treatments.     

HBV pathogenesis in animal models: recent advances on the role of platelets

Hepatitis B virus (HBV) causes acute and chronic necroinflammatory liver diseases and hepatocellular carcinoma (HCC). HBV replicates noncytopathically in the hepatocyte, and most of the liver injury associated with this infection reflects the immune response. While the innate immune response may not contribute significantly to the pathogenesis of liver disease or viral clearance, the adaptive immune response, particularly the cytotoxic T lymphocyte (CTL) response, contributes to both. Recent observations also reveal that antigen-nonspecific inflammatory cells enhance CTL-induced liver pathology and, more surprisingly, that platelets facilitate the intrahepatic accumulation of CTLs, suggesting that the host response to HBV infection is a highly complex but coordinated process. The notion that platelets contribute to liver disease and viral clearance by promoting the recruitment of virus-specific CTLs into the liver is a new concept in viral pathogenesis, which may prove useful to implement treatments of chronic HBV infection in man.     

New insight in the pathobiology of hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection remains a major health burden and the main risk factor for the development of hepatocellular carcinoma worldwide. However, HBV is not directly cytopathic and liver injury appears to be mostly caused by repeated attempts of the host's immune responses to control the infection. Recent studies have shown that the unique replication strategy adopted by HBV enables it to survive within the infected hepatocyte while complex virus-host interplays ensure the virus is able to fulfil its replication requirements yet is still able to evade important host antiviral innate immune responses. Clearer understanding of the host and viral mechanisms affecting HBV replication and persistence is necessary to design more effective therapeutic strategies aimed at improving the management of patients with chronic HBV infection to eventually achieve viral eradication. This article focuses on summarising the current knowledge of factors influencing the course of HBV infection, giving emphasis on the use of novel assays and quantitative serological and intrahepatic biomarkers as tools for predicting treatment response and disease progression.     

DNA-mediated immunization in a transgenic mouse model of the hepatitis B surface antigen chronic carrier state.

Transgenic mice expressing the sequences coding for the envelope proteins of the hepatitis B virus (HBV) in the liver have been used as a model of the HBV chronic carrier state. We evaluated the possibility of inducing a specific immune response to the viral envelope antigens and thus potentially controlling chronic HBV infection. Using HBV-specific DNA-mediated immunization in this transgenic model, we show that the immune response induced after a single intramuscular injection of DNA resulted in the complete clearance of circulating hepatitis B surface antigen and in the long-term control of transgene expression in hepatocytes. This response does not involve a detectable cytopathic effect in the liver. Adoptive transfer of fractionated primed spleen cells from DNA-immunized mice shows that T cells are responsible for the down-regulation of HBV mRNA in the liver of transgenic mice. To our knowledge, this is the first demonstration of a potential immunotherapeutic application of DNA-mediated immunization against an infectious disease and raises the possibility of designing more effective ways of treating HBV chronic carriers.     

Revisiting the Natural History of Chronic HBV Infection

Although effective vaccines have been available for more than three decades, hepatitis B virus (HBV) infection remains a global public health issue. It is estimated around 248 million people are chronically infected by HBV, and most of them are residing in the Asia-Pacific region. In HBV-endemic regions, the virus is primarily transmitted during the perinatal period or early childhood with an immature immune system, so it has a high rate of chronicity. Based on the virological and clinical manifestations, the natural course of chronic hepatitis B can be divided into four classical phases: immune tolerance, immune clearance, inactive carrier, and reactivation phases. The majority of patients will undergo spontaneous HBeAg seroconversion and enter an inactive carrier state. However, a small portion of patients may encounter intermittent or persistent hepatitis and eventually lead to severe adverse outcomes, such as liver cirrhosis, hepatic failure, or hepatocellular carcinoma. With recent advances in molecular and immunological technologies, several viral and host factors that may affect the clinical outcomes of chronic HBV infection have been identified. By integration of these emerging serological and viral biomarkers, the natural history of chronic HBV infection should be revisited. In conclusion, accurate definition of the natural history of chronic HBV infection not only sheds light on the pathogenesis of chronic hepatitis B but also helps determine the optimal timing for antiviral therapy to cure HBV.     

Cytotoxic T cell responses against hepatitis B virus polymerase induced by genetic immunization

BACKGROUND/AIMS: Individuals with chronic hepatitis B may benefit from genetic (DNA-based) immunization through induction of viral clearance by enhancement of suboptimal cellular immune responses. While marked cellular immune responses to hepatitis B virus (HBV) nucleocapsid and envelope proteins occur after genetic immunization in mice, it is unknown whether genetic immunization is capable of eliciting such responses to HBV polymerase. We wished to develop assays for the determination of HBV polymerase specific immune responses in mice and investigate whether genetic immunization may elicit humoral and cellular immune responses to HBV polymerase. METHODS: BALB/c (H-2d) mice were injected with a DNA expression construct for HBV polymerase. Humoral immune responses to HBV polymerase were analyzed with a newly established ELISA. Cellular immune responses were determined using recombinant vaccinia virus infected target cells expressing HBV polymerase at high levels. RESULTS: Assays for the detection of HBV polymerase-specific immune responses were developed. Immunized animals exhibited substantial polymerase-specific cytotoxic T lymphocyte responses. However, no humoral immune responses to HBV polymerase were detectable. CONCLUSIONS: Our study demonstrates that DNA-based immunization will generate substantial CTL responses to HBV polymerase and may be an important component of an immunotherapeutic strategy to combat chronic HBV infection.     

Current therapy for hepatitis C or D or immunodeficiency virus concurrent infection with chronic hepatitis B

Concurrent hepatitis C virus (HCV), hepatitis delta virus (HDV), or human immunodeficiency virus (HIV) infection with chronic hepatitis B virus (HBV) appears to increase the risk of progressive liver disease including liver cirrhosis and hepatocellular carcinoma. There is a 10% prevalence of HCV infection in chronic HBV or HDV infection. Serological evidence of previous exposure to HBV is found in more than 80% of HIV-positive patients in the high risk group. Notably, the most recently acquired virus tends to suppress the pre-existing virus. In chronic HBV infection acquired perinatally or in early childhood, usually HCV is dominant and may suppress or even displace HBV and HDV. Less frequently, HBV or HDV suppresses HCV. It is generally agreed that the dominant virus should be identified in order to make appropriate treatment decisions. Studies with standard interferon (IFN) to treat patients with HCV dominantly dual HBV/HCV infection have showed only limited virological response. But high dose of IFN has been demonstrated with better response rate. Combined ribavirin with standard or pegylated IFN therapy could achieve a sustained HCV clearance rate comparable with those infected with HCV alone. On the contrary, patients with HBV dominantly dual viral infection might indicate more appropriate addition of lamivudine to IFN than ribavirin. Additionally, patients with concurrent infection of HBV and HDV, IFN seems to be the only effective agent. However, the efficacy of IFN is related to the dose. High dose of IFN [9 MU tiw (thrice per week)] and longer treatment duration (at least 2 years) have been shown to achieve adequate virological response. In patients with concurrently infected HBV and HIV, anti-HBV therapy should be considered for all patients with evidence of liver disease, irrespective of the CD4 cell count. In patients not requiring antiretroviral therapy, HBV therapy should be preferentially based on IFN, adefovir, or telbivudine. In contrast, in patients with CD4 cell counts <350 cells/μl or those already on antiretroviral therapy, agents with double anti-HBV and anti-HIV activity are preferred. At present, the evidence of therapeutic efficacy is not sufficient to make a recommendation in treating patients with dual HBV/HCV or HBV/HDV or HBV/HIV infection. Further studies of the well-designed, larger scale are needed to elucidate the role of different regimens or combination in the treatment of dual viral infection.     

Virus-host interaction in chronic hepatitis B virus infection

The clearance of HBV-infected cells from the liver is probably dependent on an interplay between the interferon system and the cellular limb of the host immune response. Although the importance of the nucleocapsid proteins as targets for sensitized cytotoxic T cells is established in chronic HBV infection, further studies are needed during the early phase of acute HBV infection. The relative importance of pre S sequences as inducers and targets of the virus neutralizing humoral immune response is becoming established, but their precise place will await the development of in vitro models of hepadnavirus infection and precise definition of the mechanism of viral uptake. Our understanding of the mechanisms underlying the development of chronic HBV infection is still incomplete. When this occurs in adult life, deficient production of alpha interferon and suppression of the ability of the host to respond to interferon are probably important factors, and the role of suppression of the humoral response remains to be determined. In the neonate, specific suppression of the cell-mediated immune response, perhaps because of exposure to soluble HBe antigen or to modulating quantities of maternally derived antinucleocapsid antibodies at a time when the immune system is "immature," may be involved. In each of these postulated mechanisms the virus has neutralized one important host defense. Increasing the response rate to therapy with interferon or synthetic antiviral compounds will depend on identifying the cause in each patient and devising specific therapies to reverse the host-virus balance in favor of the host defenses.     

Immunopathogenesis: role of innate and adaptive immune responses

Hepatitis B virus (HBV) infection in immunocompetent adults usually results in a self-limited, transient liver disease and viral clearance, with only a small percentage (5 to 10%) developing chronic hepatitis associated with viral persistence. In contrast, when neonates are infected, more than 90% become persistently infected, suffering differing degrees of chronic liver disease. Activation of immunity plays a central role in host-virus interactions, greatly influencing viral replication and the clinical outcome of infection. Although all of the specific mechanisms and consequences of this interaction have not been elucidated, the purpose of this article is to describe the basic arms of the immune system as they interact with the HBV and describe the present state of knowledge in this area. These arms may be divided broadly into innate and specific immune responses, and they have different roles and responses in acute and chronic infection.     

Occult Hepatitis B Infection and its Possible Impact on Chronic Hepatitis C Virus Infection

As a well-recognized clinical phenomenon, persistent detectable viral genome in liver or sera in the absence of other serological markers for active hepatitis B virus (HBV) replication is called occult HBV infection. The main mechanism through which occult infection occurs is not completely understood and several possible explanations, such as integration into human genome and maintenance in peripheral mononuclear cells, exist. Occult HBV infection has been reported in different populations, especially among patients with Hepatitis C (HCV) related liver disease. The probable impact of occult HBV in patients with chronic HCV infection has been previously investigated and the evidence suggests a possible correlation with lower response to anti-viral treatment, higher grades of liver histological changes, and also developing hepatocellular carcinoma. However, in the absence of conclusive results, further studies should be conducted to absolutely assess the impact of occult HBV contamination on the HCV related liver disease.     

Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures

Hepatitis B virus (HBV) infection is a serious global health problem, with 2 billion people infected worldwide, and 350 million suffering from chronic HBV infection. The 10th leading cause of death worldwide, HBV infections result in 500 000 to 1.2 million deaths per year caused by chronic hepatitis, cirrhosis, and hepatocellular carcinoma; the last accounts for 320 000 deaths per year. In Western countries, the disease is relatively rare and acquired primarily in adulthood, whereas in Asia and most of Africa, chronic HBV infection is common and usually acquired perinatally or in childhood. More efficacious treatments, mass immunization programs, and safe injection techniques are essential for eliminating HBV infection and reducing global HBV-related morbidity and mortality. Safe and effective vaccines against HBV infection have been available since 1982. The implementation of mass immunization programs, which have been recommended by the World Health Organization since 1991, have dramatically decreased the incidence of HBV infection among infants, children, and adolescents in many countries. However, not all countries have adopted these recommendations and there remains a large number of persons that were infected with HBV prior to the implementation of immunization programs. Antiviral treatment is the only way to reduce morbidity and mortality from chronic HBV infection. Conventional interferon alfa and lamivudine have been the primary treatments to date. Conventional interferon alfa produces a durable response in a moderate proportion of patients but has undesirable side-effects and must be administered subcutaneously three times per week. Lamivudine also produces a response in a modest proportion of patients and causes few side-effects. However, prolonged treatment is often necessary to prevent relapse on cessation of therapy, and continuous treatment can lead to the development of lamivudine resistance. Promising emerging new treatments include adefovir, entecavir and peginterferon alfa-2a (40 kDa).     

Molecular characteristics and stages of chronic hepatitis B virus infection

Hepatitis B virus （HBV） is a common viral pathogen that causes a substantial health burden worldwide. Remarkable progress has been made in our under- standing of the natural stages of chronic HBV infection. A dynamic balance between viral replication and host immune response is pivotal to the pathogenesis of liver disease. Knowledge of the HBV genome organization and replication cycle can unravel HBV genotypes and molecular variants, which contribute to the heterogeneity in outcome of chronic HBV infection. Most HBV infections are spontaneously resolved in immunocompetent adults, whereas they become chronic in most neonates and infants at a great risk of developing complications such as cirrhosis and hepatocellular carcinoma （HCC）. Those with chronic HBV infection may present in one of the four phases of infection： immune tolerance, immune clearance [hepatitis B e antigen （HBeAg）-positive chronic hepatitis B （CHB）], inactive carrier state, and reactivation （HBeAg-negative CHB）. Understanding the dynamic nature of chronic HBV infection is crucial in the management of HBV carriers. Long-term monitoring and optimal timing of antiviral therapy for chronic HBV infection help to prevent progression of HBV-related liver disease to its later stage, particularly in patients with higher risk markers of HCC, such as serum DNA concentration, HBeAg status, serum aminotransferase, HBV genotypes, and pre-core or core mutants.     

6 Immunopathogenesis of viral hepatitis

More than 500 million people world-wide suffer from viral hepatitis which can be caused by a variety of distinct infectious agents. The spectrum of disease, which ranges from acute self-limited hepatitis to liver cirrhosis, not only reflects the different biological properties and pathogenicity of the hepatitis viruses, but is also the result of the specific interaction between each virus and the immune system of the infected host. The immune response plays a crucial role in the elimination of the infecting virus as well as in disease pathogenesis and is described in detail for acute and chronic hepatitis B and C virus infection. Acute hepatitis B virus infection is characterized by a vigorous, polyclonal cytotoxic T lymphocyte response against HBV that is not readily detectable in patients with chronic hepatitis B, suggesting that resolution of disease is mediated by the HBV-specific CTL response in these patients. Because traces of virus as well as HBVspecific CTL can perist for decades after clinical recovery, continuous priming of new CTL by minute traces of virus is thought to protect from reactivation of disease. In contrast, the hepatitis C virus causes chronic liver disease despite a polyclonal and multispecific immune response, suggesting that distinct immunological and viral mechanisms determine the different clinical outcome of HBV and HCV infection. Their implications for the development of immunomodulatory vaccines to cure patients with chronic viral hepatitis are discussed.     

The role of the virus specific T-cell response in acute and chronic HBV and HCV infection

Infections with hepatitis B (HBV) and hepatitis C virus (HCV) are worldwide one of the most frequent causes for chronic liver disease, liver cirrhosis and hepatocellular carcinoma. The mechanisms responsible for the elimination or the persistence of the virus are not well understood. The immunopathogenesis of HBV and HCV infection is primarily mediated by virus specific CD4+- and CD8+-T-cells. During acute infection a strong and multispecific T-cell response against different viral epitopes can be detected and is associated with the clearance of the virus. In case of viral persistence virus specific T-cells contribute to liver inflammation. In this article we summarize the current concepts about the role of the virus specific T-cell response in acute and chronic HBV and HCV infection.     

Viral cross talk: intracellular inactivation of the hepatitis B virus during an unrelated viral infection of the liver.

Hepatitis B virus (HBV) infection is thought to be controlled by virus-specific cytotoxic T lymphocytes (CTL). We have recently shown that HBV-specific CTL can abolish HBV replication noncytopathically in the liver of transgenic mice by secreting tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) after antigen recognition. We now demonstrate that hepatocellular HBV replication is also abolished noncytopathically during lymphocytic choriomeningitis virus (LCMV) infection, and we show that this process is mediated by TNF-alpha and IFN-alpha/beta produced by LCMV-infected hepatic macrophages. These results confirm the ability of these inflammatory cytokines to abolish HBV replication; they elucidate the mechanism likely to be responsible for clearance of HBV in chronically infected patients who become superinfected by other hepatotropic viruses; they suggest that pharmacological activation of intrahepatic macrophages may have therapeutic value in chronic HBV infection; and they raise the possibility that conceptually similar events may be operative in other viral infections as well.     

Primary hepatocellular carcinoma following nonspecific non-B hepatitis with tumor DNA negative for HBV DNA

Summary An association between non-A, non-B hepatitis and hepatocellular carcinoma has been made on the basis of negative serological markers for hepatitis B virus (HBV); however, hepatocellular carcinomas have been found to contain hepatitis B virus deoxyribonucleic acid (HBV DNA) in individuals who lack serological markers of HBV infection. Therefore, reports which ascribed a hepatocellular carcinoma to non-A, non-B hepatitis but did not examine the tumor for HBV DNA are open to question. We describe a case of chronic active hepatitis with primary hepatocellular carcinoma that lacked HBV DNA in the tumor, the nontumorous liver tissue, and serum. The individual lacked all serological markers for HBV infection. This report more fairly supports the association between hepatocellular carcinoma, and chronic hepatitis not due to hepatitis B. Whether this is related specifically to a non-A, non-B hepatitis agent requires identification of the viral agents that cause non-A, non-B hepatitis.     

Factors influencing liver disease progression in chronic hepatitis B

Abstract: Chronic hepatitis B virus (HBV) infection is a serious health issue in the Asia‐Pacific region, where most infections are acquired perinatally or during early childhood and may lead to the development of chronic sequelae such as liver cirrhosis and hepatocellular carcinoma (HCC). Studies have identified several host factors (age, gender, immune status) and viral factors (HBV viral load, genotype, basal core promoter and other naturally occurring HBV mutations) associated with disease progression. Other factors, including lifestyle (habitual alcohol consumption, cigarette smoking), exposure to aflatoxin, and viral superinfection may also influence liver disease progression in patients with chronic HBV. This review highlights pertinent data on the factors associated with progressive HBV‐related liver disease in patients with chronic hepatitis B. An enhanced understanding of factors associated with HBV disease progression may lead to improvements in the selection of candidates for intervention and overall disease management. Interventions such as lifestyle changes and antiviral therapy may thus prevent or reduce disease progression.     

Natural history of chronic hepatitis B virus infection

In chronic hepatitis B virus (HBV) infection acquired during adulthood, which is the type mostly seen in the Caucasian population, there is biochemical and histologic regression after HBeAg seroconversion, and the risk of death from hepatitis B‐related causes is low. In chronic HBV infection acquired during birth or early childhood, which is the type most commonly seen in the Asian population, there is a prolonged phase of immunotolerance. The immune clearance phase is characterized by multiple acute exacerbations preceeded by elevations in serum HBV DNA levels, HBeAg concentration and HBeAg/anti‐HBe immune complexes. Of these patients, 2.4% may develop hepatic decompensation during the stage of HBeAg seroconversion. The development of cirrhosis occurs more frequently in patients with episodes of decompensation and with repeated severe acute exacerbations. However progression to cirrhosis can be relatively silent and can occur even in children. After HBeAg seroconversion, precore and core promotor mutations occur frequently in the Asian population. However, there is little correlation between the occurrence of these mutations and alanine aminotransferase elevation in patients who are positive for anti‐HBe. Although cirrhosis develops during the process of HBeAg seroconversion, 68% of the complications of cirrhosis and of hepatocellular carcinoma occur after HBeAg seroconversion. These complications may still occur even after HBsAg seroclearance.     

A virological perspective on the need for vaccination

Superinfecton of chronic carriers of hepatitis B virus (HBV) or hepatitis C virus (HCV) with hepatitis A virus (HAV) is often associated with more severe liver disease than infection with HAV alone. Superinfection commonly causes markers of HBV and HCV replication to fall to significantly lower levels. The pathogenesis of acute liver damage characteristic of viral hepatitis is thought to be mediated by host cytotoxic T-lymphocytes (CTLs) directed against virus-infected hepatocytes. It has been proposed that the more aggressive liver disease observed in individuals infected with HAV in addition to chronic HBV/HCV is a result of the induction of interferon (IFN)-alpha during acute HAV infection. This accounts for the antiviral effect on the active markers of HBV/HCV replication, and the enhanced CTL response against HBV/HCV-infected hepatocytes. Alternatively, HAV may indirectly stimulate the T helper 1 (Th1)-type cytokine responses, such as interleukin (IL)-2, IFN-gamma and tumour necrosis factor (TNF)-alpha, which directly promote the antiviral CTL response. Clearance of HBV infection, and possible HAV and HCV, is associated with a specific CTL response, while viral persistence in chronic HBV and HCV infection has been attributed to an imbalance in the Th1-Th2 arms of the immune response. Vaccination against hepatitis A should be considered for patients with chronic HBV/HCV infection, to minimize the risk of exacerbating underlying liver disease.