Understanding the host genetics of chronic hepatitis B and C

The outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are heterogeneous, ranging from an asymptomatic self-limiting infection to cirrhosis and hepatocellular carcinoma. Several viral environmental and demographic variables have been identified as determinants of disease outcome, but these fail to explain a large proportion of the variability. Evidence from twin studies suggests that the host genetic background is an important contributor to disease outcome. Identification of genes that influence the outcome of infection has been attempted using a wide spectrum of approaches including candidate gene disease association studies, genome-wide scanning in affected sibling pairs and most recently genome-wide association studies. We summarize the main findings from a large number of studies in this review. Many studies have focused on the MHC loci from which several reproducible disease associations have been identified. More recently, genome-wide association studies have identified an important locus within the IL-28 - Il-29 region on chromosome 29, which appears to be a major determinant of the treatment response in patients infected with HCV and also a determinant of spontaneous resolution of infection. Translation of the genetic architecture of chronic viral hepatitis into therapeutic opportunities has been slow to proceed. One clinical trial and one drug development program have been based on genetic discoveries. The use of IL-28B genotyping to predict the response to pegylated interferon and ribavirin may also find its way into clinical practice. Indeed, stratification of clinical trial populations based on IL-28B genotype is already considered mandatory.     

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.     

Impact of determination of hepatitis B virus subgenotype and pre-core/core-promoter mutation for the prediction of acute exacerbation of asymptomatic carriers

Aim:  A large cohort study in Japan revealed that the specific viral profile may influence the fulminant outcome in acute hepatitis B virus (HBV) infections, while the genetic influence on outcome has not been clarified in patients with acute exacerbation of chronic liver disease caused by HBV. We experienced a case of fatal liver failure that developed as the result of chronic HBV infection. To determine possible genetic factor involving acute exacerbation, genetic analysis of serum from the patient and his siblings was performed.
Methods:  HBV subgenotype as well as pre-core/core-promoter mutations of samples mentioned above were determined.
Results:  Patient had HBV-Bj with pre-core (1896/1899) and core-promoter (1762/1764) mutations, the genomic profile frequently seen in fulminant hepatitis caused by acute HBV infection.
Conclusion:  This result suggests that determination of the HBV subgenotype and pre-core/core promoter mutations could provide a rationale for development of a treatment strategy in asymptomatic HBV carriers.     

Pathogenesis of hepatitis B virus infection

Infection with hepatitis B virus (HBV) leads to a wide spectrum of clinical presentations ranging from an asymptomatic carrier state to self-limited acute or fulminant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma. Infection with HBV is one of the most common viral diseases affecting man. Both viral factors as well as the host immune response have been implicated in the pathogenesis and clinical outcome of HBV infection. In this review, we will discuss the impact of virus-host interactions for the pathogenesis of HBV infection and liver disease. These interactions include the relevance of naturally occurring viral variants for clinical disease, the role of virus-induced apoptosis for HBV-induced liver cell injury and the impact of antiviral immune responses for outcome of infection.     

Occult hepatitis B virus infection and its clinical implications

Occult hepatitis B virus (HBV) infection is characterized by presence of HBV infection with undetectable hepatitis B surface antigen (HBsAg). Serum HBV level is usually less than 10⁴ copies/mL in these patients. Diagnosis of occult HBV infection requires sensitive HBV-DNA PCR assay. Several possibilities have been hypothesized as the mechanisms of occult HBV infection. These include: (i) mutations of HBV-DNA sequence; (ii) integration of HBV-DNA into host's chromosomes; (iii) infection of peripheral blood mononuclear cells by HBV; (iv) formation of HBV-containing immune complex; (v) altered host immune response; and (vi) interference of HBV by other viruses. The precise prevalence of occult HBV infection remains to be defined. The clinical implications of occult HBV infection involve different clinical aspects. First of all, occult HBV infection harbours potential risk of HBV transmission through blood transfusion, haemodialysis, and organ transplantation. Second, it may serve as the cause of cryptogenic liver disease, contribute to acute exacerbation of chronic hepatitis B, or even fulminant hepatitis. Third, it is associated with development of hepatocellular carcinoma. Fourth, it may affect disease progression and treatment response of chronic hepatitis C. Most of the previous studies utilized retrospective observation without control groups, and lacked direct association of occult HBV infection with specific pathological changes and disease progression. Highly sensitive, quantitative, and functional molecular analyses of HBV, combined with a well-designed prospective clinical assessment will provide the best approach for the future study of occult HBV infection.     

Host genetic factors affecting hepatitis B infection outcomes:Insights from genome-wide association studies

The clinical outcome of hepatitis B virus(HBV) infection depends on the success or failure of the immune responses to HBV,and varies widely among individuals,ranging from asymptomatic self-limited infection,inactive carrier state,chronic hepatitis,cirrhosis,hepatocellular carcinoma,to liver failure,depending on the success or failure of immune response to HBV.Genome-wide association studies(GWAS) identified key genetic factors influencing the pathogenesis of HBV-related traits.In this review,we discuss GWAS for persistence of HBV infection,antibody response to hepatitis B vaccine,and HBV-related advanced liver diseases.HBV persistence is associated with multiple genes with diverse roles in immune mechanisms.The strongest associations are found within the classical human leukocyte antigen(HLA) genes,highlighting the central role of antigen presentation in the immune response to HBV.Associated variants affect both epitope binding specificities and expression levels of HLA molecules.Several other susceptibility genes regulate the magnitude of adaptive immune responses,determining immunity vs tolerance.HBV persistence and nonresponse to vaccine share the same risk variants,implying overlapping genetic bases.On the other hand,the risk variants for HBV-related advanced liver diseases are largely different,suggesting different host-virus dynamics in acute vs chronic HBV infections.The findings of these GWAS are likely to pave the way for developing more effective preventive and therapeutic interventions by personalizing the management of HBV infection.     

Chronic hepatitis B virus infection and rubella susceptibility in pregnant women

Summary. Increased rubella susceptibility has been shown in subjects from the Asian‐Pacific region where chronic hepatitis B virus (HBV) infection is endemic. This study was performed to explore the relationship between chronic HBV infection and rubella susceptibility in the obstetric population. We conducted a retrospective cohort study on 50556 pregnant women delivered in a university obstetric unit from January 1998 to June 2008. The incidence of rubella susceptibility according to maternal HBV carrier status was examined. HBV infection and rubella susceptibility were found in 5105 (10.1%) and 6102 (12.1%) women, respectively. Rubella susceptibility was more common in women with HBV (13.1%vs 12.0%, P = 0.017), even after adjusting for other confounding factors (odds ratio 1.11, 95% confidence interval 1.01–1.21). Advancing age was associated with progressively decreasing odds of rubella susceptibility, from 0.48 at age 20–24 years to 0.34 at age ≥40 years in women without HBV infection, but had no effect in women with hepatitis B. In conclusion, our study is the first to demonstrate an association between chronic HBV infection with rubella susceptibility. Further studies are warranted to confirm whether chronic HBV infection, especially that acquired by vertical transmission, may impair the immune response to rubella vaccine or natural infection throughout the reproductive age.     

Molecular Mechanisms during Hepatitis B Infection and the Effects of the Virus Variability

The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients’ responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance or persistence of the infection is complicated due to the difficulty to detect patients at the most adequate points of the disease, especially in the time lapse between the onset of the infection and the viral emergence. Despite this, there is valuable data obtained from animal and in vitro models, which have helped to clarify some aspects of the early immune response against HBV infection. The diversity of the HBV (genotypes and variants) has been proven to be associated not only with the development and outcome of the disease but also with the response to treatments. That is why factors involved in the virus evolution need to be considered while studying hepatitis B infection. This review brings together some of the published data to try to explain the immunological and molecular mechanisms involved in the different stages of the infection, clinical outcomes, viral persistence, and the impact of the variants of HBV in these processes.     

Regulatory T cells in viral hepatitis

The pathogenesis and outcome of viral infections are significantly influenced by the host immune response. The immune system is able to eliminate many viruses in the acute phase of infection. However, some viruses, like hepatitis C virus (HCV) and hepatitis B virus (HBV), can evade the host immune responses and establish a persistent infection. HCV and HBV persistence is caused by various mechanisms, like subversion of innate immune responses by viral factors, the emergence of T cell escape mutations, or T cell dysfunction and suppression. Recently, it has become evident that regulatory T cells may contribute to the pathogenesis and outcome of viral infections by suppressing antiviral immune responses. Indeed, the control of HCV and HBV specific immune responses mediated by regulatory T cells may be one mechanism that favors viral persistence, but it may also prevent the host from overwhelming T cell activity and liver damage. This review will focus on the role of regulatory T cells in viral hepatitis.     

Hepatitis B viral genotypes: clinical relevance and molecular characteristics

Hepatitis B virus (HBV) infection is a global health problem and the clinical outcome of chronic HBV infection depends on the frequency and severity of hepatitis flares in the immune clearance phase. Currently, four subtypes and seven genotypes of HBV are identified and most have specific geographic distributions. The impact of HBV genotypes on the clinical outcome of chronic HBV infection has been partially clarified. In Taiwan, genotype C is associated with more severe liver disease and genotype B is associated with the development of hepatocellular carcinoma (HCC) in young non-cirrhotic patients. In contrast, genotype B has a relatively good prognosis in Japan and China and is rarely associated with the development of HCC. Similarly, genotype D is associated with more severe liver disease than genotype A in India and may predict occurrence of HCC in young patients. Although superinfection of HBV on top of hepatitis B carriers occurs in Taiwan, it is rarely associated with acute exacerbations. As to the response to antiviral treatment, genotypes C and D are associated with a lower response rate to interferon therapy compared with genotypes B and A. In addition, the subtype adw is reported to be associated with a higher risk of lamivudine resistance than ayw. In HBV subtype adw-infected HCC patients, genotype B responds better to embolization therapy and has a lower rate of HCC recurrence than genotype C. In summary, pathogenic and therapeutic differences do exist among HBV genotypes and determining the genotype in patients with chronic HBV infection would help gain further information for etiologic, clinical, virologic and anthropologic investigations. Further studies to clarify the molecular virological factors that contribute to these differences are awaited.     

Current status and prospects of studies on human genetic alleles associated with hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection can cause a broad spectrum diseases, including from asymptomatic HBV carriers or cryptic hepatitis, to acute hepatitis, chronic hepatitis, Liver cirrhosis and primary hepatocellular carcinoma. The variable pattern and clinical outcome of the infection were mainly determined by virological itself factors, host immunological factors and genetic factors as well as the experimental factors. Among the human genetic factors, major candidate or identified genes involved in the process of HBV infection fall into the following categories: (1) genes that mediate the processes of viral entry into hepatocytes, including genes involved in viral binding, fusion with cellular membrane and transportation in target cells; (2) genes that modulate or control the immune response to HBV infection; (3) genes that participate in the pathological alterations in liver tissue;(4) genes involved in the development of liver cirrhosis and hepatocellular carcinoma associated with chronic HBV infection, including genes related to mother-to-infant transmission of HBV infection; and (5) those that contribute to resistance to antiviral therapies. Most of the reports of human genes associated with HBV infection have currently focused on HLA associations. For example, some investigators reported the association of the HLA class Ⅱ alleles such as DRB1^*1302 or HLA-DR13 or DQA1^*0501-DQB1^*0301-DQB1^*1102 haplotypes with acute and/or chronic hepatitis B virus infection, respectively. Several pro-inflammatory cytokines such as Th1 cytokines (including IL-2 and IFN-γ)and TNF-α have been identified to participate the process of viral clearance and host immune response to HBV. In contrast, the Th2 cytokine IL-10 serves as a potent inhibitor of Th1 effector cells in HBV diseases. The MBP polymorphisms in its encoding region were found to be involved in chronic infection. Thus, reports from various laboratories have shown some inconsistencies with regard to the effects of host genetic factors on HBV clearance and persistence. Since genetic interactions are complex, it is unlikely that a single allelic variant is responsible for HBV resistance or susceptibility. However, the collective influence of several single nucleotide polymorphisms (SNPs) or haplotype (s)may underlie the natural combinational or synergistic protection against HBV. The future study including the multicohort collaboration will be needed to clarify these preliminary associations and identify other potential candidate genes.The ongoing study of the distributions and functions of the implicated allele polymorphisms will not only provide insight into the pathogenesis of HBV infection, but may also providea novel rationale for new methods of diagnosis and therapeutic strategies.     

Human genomics of acute liver failure due to hepatitis B virus infection: An exome sequencing study in liver transplant recipients

Acute liver failure (ALF) or fulminant hepatitis is a rare, yet severe outcome of infection with hepatitis B virus (HBV) that carries a high mortality rate. The occurrence of a life‐threatening condition upon infection with a prevalent virus in individuals without known risk factors is suggestive of pathogen‐specific immune dysregulation. In the absence of established differences in HBV virulence, we hypothesized that ALF upon primary infection with HBV could be due to rare deleterious variants in the human genome. To search for such variants, we performed exome sequencing in 21 previously healthy adults who required liver transplantation upon fulminant HBV infection and 172 controls that were positive for anti‐HBc and anti‐HBs but had no clinical history of jaundice or liver disease. After a series of hypothesis‐driven filtering steps, we searched for putatively pathogenic variants that were significantly associated with case‐control status. We did not find any causal variant or gene, a result that does not support the hypothesis of a shared monogenic basis for human susceptibility to HBV‐related ALF in adults. This study represents a first attempt at deciphering the human genetic contribution to the most severe clinical presentation of acute HBV infection in previously healthy individuals.     

The influence of the human genome on chronic viral hepatitis outcome

The mechanisms that determine viral clearance or viral persistence in chronic viral hepatitis have yet to be identified. Recent advances in molecular genetics have permitted the detection of variations in immune response, often associated with polymorphism in the human genome. Differences in host susceptibility to infectious disease and disease severity cannot be attributed solely to the virulence of microbial agents. Several recent advances concerning the influence of human genes in chronic viral hepatitis B and C are discussed in this article: a) the associations between human leukocyte antigen polymorphism and viral hepatic disease susceptibility or resistance; b) protective alleles influencing hepatitis B virus (HBV) and hepatitis C virus (HCV) evolution; c) prejudicial alleles influencing HBV and HCV; d) candidate genes associated with HBV and HCV evolution; d) other genetic factors that may contribute to chronic hepatitis C evolution (genes influencing hepatic stellate cells, TGF-beta 1 and TNF-alpha production, hepatic iron deposits and angiotensin II production, among others). Recent discoveries regarding genetic associations with chronic viral hepatitis may provide clues to understanding the development of end-stage complications such as cirrhosis or hepatocellular carcinoma. In the near future, analysis of the human genome will allow the elucidation of both the natural course of viral hepatitis and its response to therapy.     

Association of single nucleotide polymorphisms in microRNAs with susceptibility to hepatitis B virus infection and HBV‐related liver complications: A study in a Saudi Arabian population

The aim of this study was to evaluate the association of 10 SNPs in different microRNAs (miRNAs) with susceptibility to hepatitis B virus (HBV) infection, HBV clearance, persistence of chronic HBV infection, and progression to liver cirrhosis and hepatocellular carcinoma (HCC). Patients were categorized into the following groups: inactive HBV carrier, active HBV carrier, HBV‐cleared subject and cirrhosis+HCC. Samples were analysed for 10 SNPs in microRNAs using either PCR‐based genotyping or the TaqMan assay. We found that rs1358379 was associated with susceptibility to HBV infection, HBV clearance, persistent chronic HBV infection and liver cirrhosis+HCC. In addition, we found that rs2292832 and rs11614913 were associated with risk of HBV infection, viral clearance and cirrhosis+HCC, whereas rs2910164 was associated with proneness to HBV infection, and ability to clear the virus. There was evidence of associations between rs6505162 and HBV clearance and the development of liver disease, whereas a single association was found between rs2289030 and HBV clearance. Similarly, rs7372209 and rs4919510 were specifically associated with the development of HBV‐induced liver complications. SNPs in miRNAs affect the susceptibility, clearance and progression of HBV infection in Saudi Arabian patients. We found, using Gene Ontology or pathway analyses, that these genes may contribute to the pathophysiology of HBV infection and related liver complications. However, differences in the association of examined SNPs with various clinical stages indicate variations in the respective functional roles of these polymorphisms and their miRNAs, and thus, further investigation to fully explore their therapeutic potential is warranted.     

The woodchuck as an animal model for pathogenesis and therapy of chronic hepatitis B virus infection

INTRODUCTION Infection of adult humans with the hepatitis B virus (HBV) results characteristically in self-limited hepatic disease with recovery based on serological and clinical parameters. Progression to chronic HBV infection occurs infrequently in infe…     

REVIEW: Hepatitis B and liver transplantation

Liver transplantation in hepatitis B virus (HBV)-infected patients is very commonly followed by recurrence of infection in the transplanted liver. Most recipients with HBV recurrence will develop chronic hepatitis that follows a more aggressive course than is seen in non-immuno-compromized subjects and this frequently results in graft failure. The presence of hepatitis B e antigen or significant levels of HBV-DNA in the serum is highly predictive of recurrence and this has led to the view that patients, whose serum is positive for these conventional markers of replication, should be excluded from transplantation. The key to improving the results of transplantation in patients with HBV infection lies in the development of effective strategies to prevent reinfection. High dose anti-HBs immunoglobulin is effective in patients who are coinfected with hepatitis D, those transplanted for fulminant hepatitis and cirrhotic patients who have very low levels of viral replication prior to transplantation. Unfortunately, immunoprophylaxis does not seem to influence the outcome in those patients with higher levels of replication. There are several new orally active nucleoside analogues that are potent inhibitors of hepatitis B replication that may be effective for both the prevention and treatment of recurrent disease. The most promising are lamivudine (2',3', dideoxy, 3', thiacytidine) and famciclovir (a guanosine analogue). Both agents have been extensively evaluated in animal models of HBV and have been shown to rapidly suppress viral replication. The initial experience with these agents in liver transplant recipients has been promising and a number of studies are currently underway to determine whether these drugs, used alone or in combination with immunoprophylaxis, are able to prevent recurrence in those patients at highest risk of post-transplant HBV recurrence.     

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.     

Hepatitis D virus: an update

Hepatitis D virus (HDV) infection involves a distinct subgroup of individuals simultaneously infected with the hepatitis B virus (HBV) and characterized by an often severe chronic liver disease. HDV is a defective RNA agent needing the presence of HBV for its life cycle. HDV is present worldwide, but the distribution pattern is not uniform. Different strains are classified into eight genotypes represented in specific regions and associated with peculiar disease outcome. Two major specific patterns of infection can occur, i.e. co‐infection with HDV and HBV or HDV superinfection of a chronic HBV carrier. Co‐infection often leads to eradication of both agents, whereas superinfection mostly evolves to HDV chronicity. HDV‐associated chronic liver disease (chronic hepatitis D) is characterized by necro‐inflammation and relentless deposition of fibrosis, which may, over decades, result in the development of cirrhosis. HDV has a single‐stranded, circular RNA genome. The virion is composed of an envelope, provided by the helper HBV and surrounding the RNA genome and the HDV antigen (HDAg). Replication occurs in the hepatocyte nucleus using cellular polymerases and via a rolling circle process, during which the RNA genome is copied into a full‐length, complementary RNA. HDV infection can be diagnosed by the presence of antibodies directed against HDAg (anti‐HD) and HDV RNA in serum. Treatment involves the administration of pegylated interferon‐α and is effective in only about 20% of patients. Liver transplantation is indicated in case of liver failure.     

Is There Any Value to Hepatitis B Virus Genotype Analysis?

Hepatitis B may cause a varying spectrum of diseases ranging from an asymptomatic or mild anicteric acute illness, to severe or fulminant hepatitis. Similarly, the outcome of chronic hepatitis B is variable. Viral factors associated with outcome of chronic hepatitis B virus (HBV) infection include hepatitis B e antigen status, HBV DNA, genotype, and HBV variants. HBV genotypes and subgenotypes have been associated with differences in clinical and virological characteristics, indicating that they may play a role in the virus-host relationship. A total of ten hepatitis B virus genotypes have been defined with a distinct geographical distribution. Hitherto, genotypes A, B, C and D have been studied most extensively. The HBV genotype appears to influence not only the natural history of HBV related liver disease but also the response to HBV treatment. HBV genotypes are also linked with both core promoter and BCP mutations. Progression to chronic infection appears to occur more frequently following acute infection with genotypes A and D than with the other studied genotypes. Genotypes A and B appear to have higher rates of spontaneous HBeAg seroconversion. More advanced liver disease and progression to HCC is more often seen in chronic infection with genotypes C and D in contrast to genotypes A and B. More specifically, genotypes A1, C, B2–B5 and H appear to be associated with more serious complications than genotypes A2, B1 and B6. These observations suggest important pathogenic differences between HBV genotypes. Genotypes A and B have higher response rates to interferon based therapy than genotypes C and D. Knowledge of HBV genotype enables clinicians to identify those patients at increased risk of disease progression whilst aiding the selection of appropriate antiviral therapy. Genotyping and monoclonal subtyping can provide useful information for epidemiological studies. In conclusion, genotyping of chronic HBV infections can help practicing physicians identify those at risk of disease progression and determine optimal anti-viral therapy.