Natural history of chronic hepatitis B virus infection: New light on an old story

Chronic hepatitis B virus (HBV) infection is one of the most common persistent virus infection in man. It causes significant morbidity and mortality, and therefore is important. Extensive studies on clinicopathologic studies and long-term follow up on hepatitis B surface antigen (HBsAg) carriers have largely disclosed the natural history of chronic HBV infection. The infection easily becomes chronic when contracted in early infancy. As high as 90% of babies born to HBV carrier mothers will also become HBsAg carriers. Once chronic infection is established, it is refractory, and HBsAg carriage usually persists for life. However, the chronic infection is not monotonous, it actually evolves from an HBV replicative phase to a non-replicative phase. The host responds differently and with more complexity in different phases. The virus-host interactions, divided into three phases, virus tolerance, virus clearance and residual HBV integrated phases, result in a heterogeneous variety of hepatic lesions. The first two phases occur when HBV is actively replicating, and the last corresponds to the non-replicative phase. The high HBV level (and hence HBV gene products) renders the host's immune system tolerant to the virus, and the infected host does not exert an effort to get rid of the virus. At this stage, the liver is nearly normal, and the host is asymptomatic. However, later in the replicative phase, the HBV replication begins to wane, and the immune tolerance is no longer maintained. Hepatitis B core antigen/hepatitis B e antigen (HBcAg/HBeAg)-specific cellular immune responses result in lysis of the infected liver cells; the liver then begins to have active disease as revealed by the presence of lobular hepatitis. The asymptomatic carrier may then start to have symptoms of hepatitis. After a variable period, usually in years, the host eventually gets rid of active viral replication and only residual incomplete HBV genome integrated to host chromosomes is found. The carrier is now HBeAg negative/anti-HBe positive, serum HBV DNA decreases to very low levels, and the disease becomes qulescent at this stage. The outcome of the host is determined by the hepatic lesions caused by HBV-host interactions mentioned above, with cirrhosis and hepatocellular carcinoma (HCC) as the major sequelae of chronic HBV infection. Although HCC is usually preceded by HBV-induced cirrhosis, this is not always the case. Cirrhosis and HCC may develop independently, with cirrhosis as the most important precipitating factor or cofactor of HCC. A significant proportion of HBsAg carriers, particularly the males, will eventually die of these sequelae.     

Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion

In high endemic areas of hepatitis B virus (HBV) infection, the vast majority of infection is acquired perinatally or during early childhood. The age of the patient is, therefore, almost equivalent to the duration of HBV infection. The natural history of chronic HBV infection consists of three chronological phases: immune tolerance, immune clearance and low replicative phases. The prevalence of hepatitis B e antigen (HBeAg) in asymptomatic HBV carriers is around 90% before 15 years of age, and decreases remarkably to less than 10% after 40 years of age. The immune clearance phase is characterized by a series of hepatitis flares and remissions. These will be followed eventually by HBeAg seroconversion, which is usually accompanied by remission of liver disease and confers favourable outcome. However, patients with persistent HBeAg seropositivity over 40 years of age are associated with a significantly higher risk for progression to cirrhosis than those with HBeAg seroconversion before 40 years of age, and thus should be considered as patients with 'delayed' HBeAg seroconversion. Antiviral or immunomodulatory therapy should be considered seriously for these patients.     

Hepatitis B virus vaccination and antenatal transmission of HBV markers to neonates

The high prevalence of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) in pregnant women is considered to be the most important factor contributing to the high carrier rate of HBsAg in some populations. Several factors, including the age at which infection occurs, predispose to the acquisition and frequency of the carrier state. The proportion of infected people who become chronic carriers ranges from about 80 to 95% for babies born to HBsAg/HBeAg-positive mothers. In this study of Indonesian infants receiving only active immunization against HBV, we measured the HBV markers passively acquired from their HBsAg-positive mothers. The relationship of these markers with vaccination response and with HBV infection status was studied longitudinally in the infants. In the exposed neonates from the HBsAg-positive mothers (n=61), the seroconversion rate to hepatitis B surface antibody (HBsAb) positivity was 95% after the first booster vaccination, with a geometric mean titre (GMT) of 2017 IUl-1. After 60 months, the GMT in this group decreased to 50 IUl-1. Four newborns in this group became HBsAg carriers. Of the four vaccination failures, three newborns were HBsAg/HBeAg positive at birth, suggesting that they had been infected in utero. No vaccination strategy (active alone, or passive/active) can prevent this transmission from occurring. One carrier was HBsAg negative at birth and up to month 4 but was HBsAg positive at month 12 and subsequently, suggesting a postnatal infection. Vaccination early in life can, to a large extent, prevent perinatal transmission and hepatitis B virus (HBV) infection later in infancy and childhood. In this study, the protective efficacy of the vaccination was 85% in the subcohort of neonates from HBeAg-positive mothers and 100% in the subcohort of neonates from HBeAg-negative mothers. Lack of maternal antibodies to hepatitis B core antigen (HBcAb) correlated strongly with transmission of HBV infection.     

Hepatitis B problem in Thailand

HBV infection is hyperendemic in Thailand. Approximately 5 million Thais are chronic HBV carriers. The prevalence of HBV markers in general population varies from 40-60%. Approximately 10-20% of children between the ages 1-5 years have serologic evidence of HBV infection and this prevalence increases with age reaching a plateau of 40-60% by age 20. High risk groups are household contacts of HBsAg carriers and babies born to HBsAg positive mothers. Approximately 75% of the babies born to HBsAg & HBeAg positive mothers become HBsAg positive at 3 months after birth. A few studies showed that the HBV prevalence of hospital personnel and other high risk groups is similar to that of the general population. The prevalence of chronic HBsAg carrier varies from 5-10% and is highest among age groups 10-30 years. Primary hepatocellular carcinoma (PHC) is the first and third most common cancer among Thai males and females, respectively. Approximately 35%-75% of PHC in adults are HBsAg positive. Histological studies showed that 47.3% of cryptogenic cirrhosis, 58%-66% of PHC and 35%-85% of cryptogenic cirrhosis with PHC were HBsAg positive. Studies on Hepatitis B immune globulin and Hepatitis B vaccine revealed a 70% and 56%, respectively, reduction in the HBsAg prevalence of infants born to HBsAg and HBeAg positive mothers. More epidemiologic, clinical and laboratory studies on HBV infection are being carried out by groups of scientists and investigators in the Ministry of Public Health and many medical schools. A national committee has been appointed to plan strategy for controlling HBV.     

HBV感染垂直传播阻断研究的现状与问题

乙型肝炎病毒(HBV)感染是严重的公共卫生问题.随着献血管理的加强和乙肝疫苗的逐步推广,HBV感染水平传播的流行势头已经得到遏制,而垂直传播成为导致HBV慢性感染的主要途径之一.HBV感染垂直传播包括母婴传播和父婴传播,以前者为主.传播的途径包括:宫前感染、宫内感染、产程感染、出生后感染.对新生儿联合使用乙肝免疫球蛋白和乙肝疫苗已成为阻断母婴传播的重要措施,但仍有部分病例未能获得有效保护.其中,HBV宫内感染的存在是导致阻断措施失败的重要原因之一.     

Epidemiology and immunopathogenesis of chronic hepatitis B virus infection

Hepatitis B virus (HBV) infection has global health implications. Approximately 5% of the world population consists of chronic HBV carriers, of which one-quarter to one-third will develop progressive liver disease. The prevalence of HBV varies widely, with high endemic regions in Asia and sub-Saharan Africa to low endemic regions in Western Europe and the United States. The main method of transmission of HBV varies with perinatal and sexual transmission as the predominant routes in high- and low-prevalence regions, respectively. The transition from acute infection to the chronic carrier state appears to be immunologically mediated. A strong humoral and cellular immune response are characteristic of resolved infections, whereas a weak antiviral immune response is observed in chronic HBV infection. The immunologic processes by which chronic HBV infection develops remain to be elucidated. Animal models of HBV infection, however, may help to define immunologic mechanisms that underlie chronic infection.     

Hepatitis B virus genotype D infection among antenatal patients attending a maternity hospital in Calcutta, India: assessment of infectivity status

A seroepidemiological study was conducted to determine the hepatitis B virus carrier rate and infectivity status among antenatal patients in Calcutta. Fifteen of 400 antenatal mothers (3.74%) were carriers of HBV genotype D. Four (1.0%) of them were positive for HBeAg with a high risk of transmitting infection to their babies. The presence of precore mutant HBV, which has been associated with transmission events from HBeAg mothers to their babies, was not detected in any of the HBeAg negative mothers.     

Seroepidemiological study of hepatitis B virus (HBV) infection in the rural community in Kenya--changing pattern of transmission model of HBV in Kenya

The seroepidemiological study of HBV infection has been done against 9044 inhabitants in order to define a predominant transmission mode and a target population of HBV infection in Kenya. Results are as follows: 1) A total of 379 HBV carriers were identified. The prevalence of HBV carrier ranged from 4 to 9% in adults and 1 to 2% in children under 5 years of age. 2) The prevalences of HBs antigen and anti-HBc antibody in family members of carriers were 2 or 3 times higher than the other population. 3) 60 to 90% of the carrier children under 10 years old was positive for anti-HBe and 10 to 15% of the adult carrier and the pregnant carrier were found to be positive for e antigen. 4) Yearly infection ratio by horizontal route of transmission in the carrier family (1.4%) was 4 times higher than the control groups (0.3%). 5) 49% of the 96 carrier children was born to the carrier mother and in 40% the parent was negative for HBs antigen. 6) E antigen positive carrier mothers were highly infectious against their children than anti-HBe positive carrier mothers and fathers. These results suggest that HBV infection will happen more frequently within the family members of carriers either by horizontal and vertical infection. Marked reduction of carrier rate and infectivity observed in the children under 5 years of age infers that the improved way of mass immunization using disposable needles during infancy will deplete the incidence of horizontal mode of infection and that in the future mother to baby transmission appears to be the main route of HBV infection as in other developed countries.     

Combined passive and active immunization for interruption of perinatal transmission of hepatitis B virus in Taiwan

We attempted a clinical trial to interrupt transmission of hepatitis B virus (HBV) infection from hepatitis B surface antigen (HBsAg) positive and hepatitis Be antigen (HBsAg) positive mothers to their infants in Taiwan. Screening of 5,595 pregnant women revealed that 856 (15.3%) were HBsAg positive. Three hundred and sixty-one (42.2%) of the HBsAg positive pregnant women were HBeAg positive. Infants born to HBsAg and HBeAg positive mothers were randomized into 3 groups to receive the HBV vaccine alone or combined with hepatitis B immune globulin (HBIG). HGV vaccine was given at 2, 6, and 10 weeks after birth. Group I received HBV vaccine alone while Group II received HBV vaccine in combination with HBIG at birth and group III received HBV vaccine plus HBIG at birth and again at one month old. Group IV constituted the control group when their parents refused vaccination. At 6 months of age, the HBV carrier rate was 23.7% (9/38) in Group I, 11.1% (4/36) in Group II, and 5.3% (2/38) in Group III infants. Compared with 90% of infants who became HBV carriers in the control group (Group IV), the efficacy of HBV vaccination in preventing HBV infection among these high risk infants at the 6th month was 73.7% in Group I, 87.7% in Group II, and 94.1% in Group III. The antibody to HBsAg (anti-HBs) positivity rate in sera of Group I, II, III infants at 6 months of age was 79.0%, 88.9% and 94.7%, respectively. These initial results indicate that combined passive and active immunization is efficacious in interrupting perinatal transmission of HBV infection.     

Hepatitis B and pregnancy

Chronic hepatitis B virus (HBV) infection remains an important cause of chronic liver disease worldwide and affects a disproportionate number of individuals from areas of high endemicity, where perinatal transmission is the predominant mode of infection. Introduction of a safe and effective hepatitis B vaccine has led to universal infant vaccination and resulted in a reduced rate of perinatal HBV transmission from infected mothers. With appropriate hepatitis B vaccination and passive immunoprophylaxis using hepatitis B immune globulin (HBIG), infants born to mothers with HBV infection have perinatal transmission rates between 5% and 10%. Management of pregnant women with chronic HBV infection is aimed primarily at counseling regarding maternal risk of infection, rates of vertical transmission, and preparation for neonatal vaccination. Limited data suggest that intrauterine infection may occur at higher rates in mothers with high serum HBV DNA levels, leading to failure of standard passive-active immunoprophylaxis with HBIG and vaccine. Thus, treatment with an oral HBV antiviral agent in the third trimester may be considered after discussing the risks and benefits of therapy with the mother.     

Prevention of vertical transmission of hepatitis B virus infection

Hepatitis B virus (HBV) is the leading cause of chronic viral hepatitis. Annually, almost two million children younger than 5 years acquire the infection, mostly through vertical or horizontal transmission in early life. Vertical transmission of HBV is a high efficacy phenomenon ranging, in the absence of any preventive interventions, from 70% to 90% for hepatitis e antigen positive mothers and from 10% to 40% for hepatitis e antigen-negative mothers. Maternal viraemia is a preeminent risk factor for vertical transmission of HBV. Maternal screening is the first step to prevent vertical transmission of HBV. Hepatitis B passive and active immunoprophylaxis at birth together with antiviral treatment of highly viraemic mothers are the key strategies for global elimination of HBV infection. Strategies are needed to promote implementation of birth-dose vaccination and hepatitis B immunoglobulins in low- and middle-income countries where the prevalence of the infection is at the highest.     

Hepatitis B vaccination with or without hepatitis B immunoglobulin at birth to babies born of HBsAg‐positive mothers prevents overt HBV transmission but may not prevent occult HBV infection in babies: a randomized controlled trial

Vertical transmission of Hepatitis B virus HBV can result in a state of chronic HBV infection and its complications. HBV vaccination with or without hepatitis B immunoglobulin (HBIG) prevents transmission of overt infection to the babies. However, whether it also prevents occult HBV infection in babies is not known. Consecutive pregnant women of any gestation found to be HBsAg positive were followed till delivery, and their babies were included in the study. Immediately after delivery, babies were randomized to receive either HBIG or placebo in addition to recombinant HBV vaccine (at 0, 6, 10 and 14 weeks). The primary end‐point of the study, assessed at 18 weeks of age, was remaining free of any HBV infection (either overt or occult) plus the development of adequate immune response to vaccine. The babies were further followed up for a median of 2 years of age to determine their eventual outcome. Risk factors for HBV transmission and for poor immune response in babies were studied. Of the 283 eligible babies, 259 were included in the trial and randomized to receive either HBIG (n = 128) or placebo (n = 131) in addition to recombinant HBV vaccine. Of the 222 of 259 (86%) babies who completed 18 weeks of follow‐up, only 62/222 (28%) reached primary end‐point. Of the remaining, 6/222 (3%) developed overt HBV infection, 142/222 (64%) developed occult HBV infection, and 12/222 (5%) had no HBV infection but had poor immune response. All 6 overt infections occurred in the placebo group (P = 0.030), while occult HBV infections were more common in the HBIG group (76/106 [72%] vs. 66/116 [57%]; P = 0.025). This may be due to the immune pressure of HBIG. There was no significant difference between the two groups in frequency of babies developing poor immune response or those achieving primary end‐point. The final outcome of these babies at 24 months of age was as follows: overt HBV infection 4%, occult HBV infection 42%, no HBV infection but poor immune response 8% and no HBV infection with good immune response 28%. Women who were anti‐HBe positive were a low‐risk group, and their babies were most likely to remain free of HBV infection (occult or overt) and had good immune response to the vaccine. Maternal HBeAg‐positive status and negativity for anti‐HBe predicted not only overt but also any infection (both overt and occult) in babies. In addition, high maternal HBV DNA and treatment with vaccine alone were significant factors for overt HBV infection in babies. The current practice of administration of vaccine with HBIG at birth to babies born of HBsAg‐positive mothers is not effective in preventing occult HBV infection in babies, which may be up to 40%. Because the most important risk factors for mother‐to‐baby transmission of HBV infection are the replicative status and high HBV DNA level in mothers; it will be worthwhile investigating the role of antivirals and HBIG administration during pregnancy to prevent mother‐to‐child transmission of HBV infection.     

Management of the pregnant hepatitis B patient

Chronic hepatitis B virus (HBV) infection is an important cause of chronic liver disease worldwide. It affects a disproportionate number of individuals from areas of high endemicity, where perinatal transmission is the predominant mode of infection. Introduction of a safe, effective hepatitis B vaccine has led to universal infant vaccination, resulting in a reduced rate of perinatal HBV infection from infected mothers. Because of appropriate hepatitis B vaccination and passive immunoprophylaxis with hepatitis B immune globulin (HBIG) in infants of mothers with HBV infection, perinatal transmission has been reduced to less than 5% to 10%. Management of pregnant women with chronic HBV infection should be aimed at counseling on maternal risk of infection, rates of vertical transmission, and preparation for neonatal vaccination. Limited data suggest that intrauterine infection may occur at higher rates in mothers with high serum HBV DNA levels, leading to failure of standard passive-active immunoprophylaxis with HBIG and vaccine. Thus, treatment of these individuals with an oral HBV antiviral agent in the third trimester may be considered after discussion with the mother regarding the risks and benefits of therapy.     

Natural history and prognosis of hepatitis B

The natural history of hepatitis B virus (HBV) infection is complex and variable and is greatly influenced by the age at infection, the level of HBV replication, and host immune status. Chronic HBV infection generally consists of an early replicative phase with active liver disease (hepatitis B e antigen [HBeAg]-positive chronic hepatitis) and a late low or nonreplicative phase with HBeAg seroconversion and remission of liver disease (inactive carrier state). After HBeAg seroconversion, some patients may have active hepatitis due to HBV variants not expressing HBeAg (HBeAg-negative chronic hepatitis). Morbidity and mortality are linked to development of cirrhosis and hepatocellular carcinoma. Survival is reasonably good (about 85% probability at 5 years) in compensated cirrhosis but very poor in decompensated cirrhosis. Both cirrhotic and noncirrhotic patients with sustained reduction of HBV replication and normalization of aminotransferase after interferon alfa therapy have a reduced risk for liver-related complications.     

Source of transmission in children with chronic hepatitis B infection after the implementation of a strategy for prevention in those at high risk

Aim: In order to clarify the sources of chronic HBV (hepatitis B virus) infection in children after the implementation of an “at‐risk” strategy in Japan, chronically infected children were assessed. In addition, chronically infected children born to HBsAg‐negative mothers and their family members were assessed to identify the sources of HBV transmission. Methods: Fifty‐seven children who tested HBsAg‐positive after the initiation of a mother‐to‐child transmission prevention program were enrolled in this study. The full‐genome HBV DNA sequence was analyzed to confirm the transmission sources. Results: Of the 57 patients, 37 (65%) were born to HBV carrier mothers. The remaining 20 (35%) patients were born to HBsAg‐negative mothers. Fourteen of these patients had HBV carrier fathers, and 2 patients, who were siblings, did not have an HBV carrier father. The remaining 4 patients had no family members with HBV infection. Phylogenetic tree analysis confirmed that father‐to‐child transmission and sibling‐to‐sibling transmission occurred in 3 families and 1 family, respectively. Conclusion: Although vaccine failure of mother‐to‐child transmission was the major cause of chronic HBV infection in children, father‐to‐child transmission was the second most common mode of transmission. In addition, sibling‐to‐sibling transmission was found. Unless at‐risk individuals and groups can be accurately identified to prevent horizontal transmission, the introduction of universal vaccination is essential for achieving the elimination of HBV infection in Japan.     

Advances in the diagnosis and treatment of the infection by the hepatitis B virus

Infection by the hepatitis B virus (HBV) is a significant cause of morbidity and mortality, mainly due to evolvement to cirrhosis and hepatocellular carcinoma. The prevalence and genotypic distribution of HBV infection has marked geographic differences. HBV infection is a very dynamic process, with a phase of immune tolerance and high viral replication, followed by HBeAg clearance, not always accompanied by complete suppression of HBV replication. The latter situation corresponds to negative HBeAg hepatitis, which represents a group relatively resistant to therapy. The three approved drugs for the treatment of HBV infection (interferon alpha, lamivudine and adefovir) have limited efficacy. Relapses are more common with lamivudine and adefovir, requiring often long-term treatment. While the selection of lamivudine resistance mutations is frequent, adefovir has a high genetic barrier. HIV infection negatively impacts on HBV disease, requiring these coinfected patients strategies aimed to manage both viruses.     

Critical analysis of the immune tolerance phase of chronic HBV infection: Natural history and diagnosis

Hepatitis B virus (HBV) infection is the major cause of cirrhosis and hepatocellular carcinoma worldwide. Based on virus-host interactions, the natural history of HBV carriers can be divided into four phases. In the prolonged immune tolerance phase, HBV carriers are positive for hepatitis B e antigen (HBeAg) and have high HBV replication but minimal liver disease. Early termination of immune tolerance and subsequent HBeAg seroconversion usually confer a favorable outcome, whereas delayed HBeAg seroconversion may accelerate the progression of liver disease. In recent years, viral and host factors such as the rapid decline of serum HBV DNA level, HBV genotype, possible naturally occurring mutants, and specific HLA haplotypes have been shown to affect the loss of immune tolerance in chronic hepatitis B. HBV carriers with an immune tolerant phenotype may be defined as having HBeAg positivity, persistently low-normal serum alanine aminotransferase, and serum HBV DNA greater than 2 × 10⁷ IU/mL. These patients should be monitored; many have a rapid transition to an inactive carrier state with favorable outcomes.     

Maternal transmission of hepatitis B surface antigen in patients with hepatocellular carcinoma in Taiwan

To determine the source of the highly prevalent hepatitis B virus (HBV) infection in our patients with hepatocellular carcinoma (HCC), we examined hepatitis B surface antigen (HBsAg) and its subtypes and antibody in 11 patients with HCC and their parents. All the patients were positive for HBsAg. Eight (73%) of the mothers were also HBsAg-positive, whereas only one of the seven fathers was an HBsAg carrier (P = 0.025). The observation is compatible with maternal transmission as a source of HBV infection in most of our patients with HCC. The subtype was identifiable in 10 patients, 9 with HBsAg/adw and one with adr. The subtype was identical in the patient--mother carrier pairs, suggesting that HBV infection in the patient and the mother is intimately related. This is further evidenced by the observation of a relatively uncommon adr subtype in one patient--mother pair. These observations suggest that the HBV infection in our patients results from vertical transmission from their carrier mothers probably long before the development of HCC.     

Vertical transmission of hepatitis B virus during pregnancy and delivery in Denmark

Objective: In Denmark, pregnant women have been screened for hepatitis B virus (HBV) since 2005, and children born to HBV-infected mothers offered hepatitis B immunoglobulin at birth, vaccination against HBV at birth and after 1, 2 and 12 months. The purpose of this study was to determine the risk of vertical HBV transmission in children born to mothers with chronic HBV infection, to investigate the antibody response in the children and to investigate possible maternal predictive risk factors for HBV transmission.

Materials and methods: Through the Danish Database for Hepatitis B and C, we identified 589 HBV-infected women who had given birth to 686 children, of whom 370 children were born to 322 women referred to hospital. 132 (36%) children, born to 109 mothers, were included in the study; 128 children had blood samples tested for HBsAg, anti-HBc (total), anti-HBs and HBV-DNA and four children had saliva samples tested for anti-HBc.

Results: We found vertical HBV transmission in Denmark to be 2.3% [95% CI: 0.5, 6.5], a high proportion of HBsAg-negative children with low levels of anti-HBs (18.4%) and a high proportion (15.2%) with resolved HBV infection. No maternal risk factor was statistically significantly associated with HBV vertical transmission.

Conclusion: In a HBV low prevalence setting as Denmark, despite a national vaccination program, vertical HBV transmission occurred in 2.3% of children born to HBV-infected mothers. In addition, a high proportion of the children had insufficient anti-HBs levels and a high proportion had serological signs of resolved HBV infection.     

Immune control of hepatitis B virus

Human hepatitis B virus (HBV) infects the liver of humans or humanoid primates. In humans, HBV infection often causes an inflammatory liver disease - hepatitis B. The virus is transmitted by perinatal, percutaneous and sexual exposure, as well as by close person-to-person contact. The latter occurs especially among young children, presumably by open cuts or sores. Vertical transmission from mothers to their neonates, or infection during the first year of life, results in persistent often lifelong infection in >90% of cases. In contrast, infection during adulthood is cleared in >95% of cases, and results in lifelong protective immunity. While a correlation between the strength of HBV-specific T cell responses and virus clearance has been established, factors determining the strength of a T cell response as well as factors shifting the balance from immune tolerance to immune clearance are hardly understood. The innate immune response, early adaptive B and T cell responses, regulatory T cells, the liver microenvironment, and the peculiar properties of hepatocytes and nonparenchymal liver cells to present antigen seem to play a role. Understanding this complex interplay requires systematic immune monitoring of well characterized human cohorts, but also experimental approaches using primary human cells and genetically modified mouse models. Using these models, we begin to understand the immune recognition of HBV and how it influences the outcome of HBV infection. In this paper we review the current knowledge about virus-host interactions and how it influences the outcome of HBV infection and describe the immune signatures associated with clinical recovery and/or persistent infection.