Natural History Of Hepatitis B Virus Infection Research Articles

Chronic hepatitis B in Asia—new insights from the past decade

Chronic hepatitis B virus (HBV) infection is a major health problem in the Asia-Pacific region. In the past decade, much progress has been made in the understanding and management of this disease. The introduction of universal vaccination has significantly reduced the incidence of perinatal infection in most Asia-Pacific countries. As the majority of the adult population have not been immunized at birth, we are still facing a large population of young HBV-infected patients in the coming two decades. The study of long-term longitudinal databases has provided deeper insight into the clinical significance of HBV DNA suppression, hepatitis B e antigen (HBeAg) seroconversion and hepatitis B surface antigen (HBsAg) seroclearance in chronic hepatitis B. With a better understanding on the natural history of HBV infection, one can now stratify the risk of chronic hepatitis B patients for adverse clinical outcomes and use this to individualize management. The introduction of non-invasive assessment of liver fibrosis can potentially reduce the necessity of liver biopsy. There have also been great advances in the development of antiviral therapy in the past decade. However, the high cost of HBV antiviral drugs poses major challenges to health authorities in many Asia-Pacific countries. Properly performed cost-effective analysis and understanding on the best timing of stopping antiviral drugs will be important to facilitate the most appropriate allocation of resources.

Management of hepatitis B: Consensus of the Japan Society of Hepatology 2009

Recently, much progress has been made in the field of hepatitis B, such as natural history of the disease in relation to the amount of hepatitis B virus (HBV) DNA, genotypes of HBV influencing the natural course and treatment effects, mutations of HBV influencing the severity of the disease and development of hepatocellular carcinoma, and antiviral treatment such as nucleos(t)ide analogues and pegylated interferon. To make the consensus for the diagnosis, management and treatment of hepatitis B, a meeting was held during 45th annual meeting of Japan Society of Hepatology (JSH) in June 2009. In the meeting, recommendations and informative statements were discussed on the following subjects: (i) natural history of HBV infection; (ii) clinical implication of HBV genotypes; (iii) HBV mutations and their potential impact on pathogenesis of HBV infection; (iv) indications for antiviral treatment of chronic hepatitis B; (v) nucleos(t)ide analogues for chronic hepatitis B; and (vi) interferon therapy for chronic hepatitis B. The presenters reviewed the data on these subjects and proposed the consensus statements and recommendations. These statements were discussed among the organizers and presenters, and were approved by the participants of the meeting. In the current report, the relevant data were reviewed and the 12 consensus statements and nine recommendations on chronic hepatitis B were described.

Therapy with Nucleos(t)ide Analogues: Current Role in Dialysis Patients

Hepatitis B virus (HBV) infection persists among patients undergoing maintenance dialysis in the industrialized world. Knowledge of the epidemiology and the natural history of HBV infection in dialysis patients has markedly improved but antiviral therapy for hepatitis B remains a significant challenge in this population. A variety of therapeutic options are now available for the treatment of chronic hepatitis B, including potent new nucleos(t)ide analogues, along with standard and pegylated interferon. The most extensive experience in the dialysis population has been with lamivudine. Although several questions about lamivudine use in dialysis patients remain unanswered, it has shown potent antiviral activity: the range of clearance of HBV viremia (HBV DNA) from serum is between 56% and 100% in dialysis patients with chronic hepatitis B. Its major limitation is emergence of resistance. Tolerance to conventional or pegylated interferon monotherapy is poor in the dialysis population. There is limited data regarding adefovir dipivoxil (ADV) therapy in the dialysis population, while very little information is available about the use of the newer agents, tenofovir and entecavir, in patients with renal failure. It is recommended that dialysis patients with persistent HBsAg seropositive status be evaluated for antiviral treatment and that the decision to treat be based on the potential benefits and risks of therapy including life expectancy, candidacy for kidney transplantation, and comorbidities. Hepatitis B is relatively uncommon among patients undergoing dialysis in developed countries and this clearly hampers prospective clinical trials aimed to evaluate the efficacy and safety of therapy with nucleos(t)ide analogues for chronic hepatitis B in this population.

Genetic epidemiological study on single nucleotide polymorphisms associated with hepatocellular carcinoma in patients with chronic HBV infection

Hepatocellular carcinoma (HCC) is associated with hepatitis B virus (HBV) as an etiologic agent in 80% of cases, and is the major cause of death among HBV carriers. Family history of HCC is a known risk factor for the development of HCC among chronically HBV infected patients; therefore, genetic factors are likely to modify the risk of HCC. However, the genetic factors that determine progression to HCC remain mostly to be recovered. It is estimated that there are millions of single nucleotide polymorphisms (SNPs) within human genome and they are likely to explain much of the genetic diversity of individuals. In this review, the natural history of HBV infection and host genetic factors related to HCC, study design and target gene selection for the detection of SNPs related to the occurrence of HCC were discussed. Also, several SNPs or haplotypes, which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection, were reviewed. Especially, recent studies in Korea, one of the HBV endemic areas, were discussed. Screening of these polymorphisms might be useful in clinical practice to stratify the lower or higher risk group for HCC and might modify the design of HCC surveillance programs in patients with chronic HBV infection, if further genetic susceptibilities are identified. The ongoing studies of the distributions and functions of the implicated allele polymorphisms will not only provide insight into the pathogenesis of HCC, but may also provide a novel rationale for new methods of diagnosis and therapeutic strategies.

Hepatitis B virus infection: Understanding its epidemiology, course, and diagnosis

Although hepatitis B virus (HBV) infection is not as common in the United States as in some countries, 5000 Americans die from it every year. This number can be significantly decreased with proper screening and by vaccinating people at risk. Internists should be aware of the natural history of HBV infection, a vital prerequisite to correctly assessing disease severity and subsequently determining the need for antiviral therapy.

Natural history of chronic hepatitis B virus infection: What determines prognosis after cirrhotic decompensation?

Natural history of chronic hepatitis B virus infection: What determines prognosis after cirrhotic decompensation?

Entecavir (Baraclude) in patients with chronic hepatitis B virus (HPV) infection

Hepatitis B is the most common serious liver infection in the world, with about 350 million people who are infected with the hepatitis B virus (HBV) and about 1 million deaths annually.Hepatitis B is characterized by an acute and a chronic phase, if the subject fails to produce adequate immune response. About 5-10% of adults infected with HBV go on to develop chronic infection and become chronic carriers (CHB); moreover, the liver damage, if not stopped, continues until cirrhosis or hepatocellular carcinoma. In the natural history of HBV infection, the most important event is HBeAg seroconversion, characterized by loss of HBeAg (a specific antigen of the virus) and development of Anti-HBe antibodies (HBeAg-positive patients). If the seroconversion has occurred early (when liver damage is not yet significant) and is maintained,long-term prognosis is excellent. The disease can follow a more aggressive course if active viral replication persists despite anti-HBe positivity. This state, characterized by continuing viral replication, has been termed as HBeAg-negative CHB, and is the most prevalent form in Italy. At the moment, there are 4 approved antiviral drug classes, with different antiviral efficacy, for the treatment of chronic hepatitis B: interferons, nucleoside analogues, nucleotide analogues, and cyclopents. The primary target of the treatment is a prolonged suppression of viral replication, in order to avoid long term complications and increase survival.

Natural history and clinical management of chronic hepatitis B virus infection in children

Hepatitis B virus (HBV) infection may cause acute, fulminant, or chronic hepatitis, leading to liver cirrhosis or hepatocellular carcinoma. Despite the availability of effective vaccine, HBV infection during infancy or early childhood is common in areas of high endemicity. In these regions, mother-to-infant transmission accounts for approximately 50% of chronic infections. Although the natural history of HBV infection in adults is well characterized, little information is available in the literature regarding the natural history of HBV infection in children. Similar to infection in adults, chronic HBV infection in children can be divided into distinct phases: immune tolerant, immune clearance, and inactive carrier state. However, acute exacerbation, with reactivation of HBV replication and re-elevation of alanine aminotransferase levels after hepatitis B e antigen seroconversion, is relatively rare in children, in comparison to adults. Although several potent antiviral agents are now available for the treatment of chronic hepatitis B, experience with these agents in the pediatric setting is limited. To date, conventional interferon alpha and lamivudine are the only two antiviral agents approved to treat chronic hepatitis B in children. The rapid emergence of resistant HBV associated with long-term lamivudine therapy, as well as poor tolerability associated with conventional interferon alpha, are factors that should be considered before initiating antiviral therapy. This article reviews current knowledge regarding the natural history and treatment of chronic hepatitis B in children. Factors that affect the natural history of HBV infection in children are also reviewed.

New concepts in the immunopathogenesis of chronic hepatitis B: the importance of the innate immune response

Acute and chronic infection with hepatitis B virus (HBV) is associated with an increased risk of developing liver disease including cirrhosis, decompensated liver disease, and hepatocellular carcinoma. The clinical presentation and natural history of HBV infection is mediated through complex interactions between the virus and the host immune response. HBV is not directly cytopathic to heptocytes; however, the interaction between the virus and the host immune response plays a central role in the pathogenesis of necroinflammation and liver fibrosis. Emerging data from immunopathogenesis studies in animal models and in vitro studies of liver biopsies from patients with chronic hepatitis B demonstrate a potentially important interaction between hepatitis B e antigen, HBV, and components of the innate immune response including Toll-like receptors, Kupffer cells, natural killer T-cells, and dendritic cells. These findings suggest that the innate immune response has an important role in influencing the outcome of acute and chronic HBV infection. The current knowledge regarding the interaction between HBV and components of the innate immune response during acute and chronic HBV infection is reviewed.

Telbivudine (Sebivo) in patients with hepatitis B virus (HBV) chronic infection

Hepatitis B is the most common serious liver infection in the world, with about 350 million people who are infected with the hepatitis B virus (HBV) and about 1 million deaths annually.Hepatitis B is characterized by an acute and a chronic phase, if the subject fails to produce adequate immune response.About 5-10% of adults infected with HBV go on to develop chronic infection and become chronic carriers (CHB); moreover, the liver damage, if not stopped, continues until cirrhosis or hepatocellular carcinoma. In the natural history of HBV infection, the most important event is HBeAg seroconversion, characterized by loss of HBeAg (a specific antigen of the virus) and development of anti-HBe antibodies (HBeAg-positive patients). If the seroconversion has occurred early (when liver damage is not already significant) and is maintained, long-term prognosis is excellent. The disease can follow a more aggressive course if active viral replication persists despite anti-HBe positivity. This state, characterized by continuing viral replication, has been termed as HBeAg-negative CHB, and is the most prevalent form in Italy. At the moment, there are 4 approved antiviral drug classes, with different antiviral efficacy, for the treatment of chronic hepatitis B: interferons, nucleoside analogues, nucleotide analogues, and cyclopents.The primary target of the treatment is a prolonged suppression of viral replication, in order to avoid long term complications and increase survival.

Hepatitis B virus and human immunodeficiency virus co-infection: impact on transmission and natural history of disease

There is overwhelming evidence of a strong association between human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections in areas of low endemicity for both viruses, due to shared risk factors. There is also much evidence that HIV modifies the natural history of HBV infection in these areas: co-infected individuals are more likely to be HBV chronic carriers, with higher levels of HBV infectivity, than HIV-negative individuals. Also, immunosuppression brought about by HIV infection reduces persistence of anti-HBs in previously immune and vaccinated individuals, and can cause HBV reactivation or re-infection in those previously exposed to HBV. Furthermore, HIV infection increases the risk of death from liver disease in HBV co-infected individuals, and this risk increases when these patients are treated with highly active anti-retroviral therapy. However, extensive research has found no convincing evidence that HBV impacts on the transmission and natural history of HIV infection. However, the...

Occult Hepatitis B Virus Infection in HIV-Infected Patients with Isolated Hepatitis B Core Antibody

Objective: Detection of hepatitis B virus (HBV) DNA without detectable hepatitis B surfaceantigen (HBsAg) is defined as occult HBV infection. In patients co-infected with human immunodeficiency virus (HIV) and HBV, HIV interferes with the natural history of HBV infection by enhancing HBV replication, leading to more severe liver disease. The aim of this study was to assess occult HBV infection in Iranian HIV-positive patients with isolated hepatitis B core antibody (anti-HBc). Methods: The presence of HBV-DNA was determined quantitatively in plasma samples of HIV-infected patients with isolated anti-HBc by real-time PCR using the artus HBV RG PCR kit on the Rotor-Gene 3000 real-time thermal cycler. Hepatitis C antibody (anti-HCV), alanine aminotransferase (ALT), aspartate aminotransferase (AST), HIV viral load and CD4+ count were also tested in all subjects. Results: Of 106 patients enrolled in this study, 22 subjects (20.75%, 95% CI 13–28) had isolated anti-HBc. HBV-DNA was detectable in 3 of the 22 patients (13.6%, 95% CI 0.0–28) who had isolated anti-HBc. Conclusion: A serological profile of isolated anti-HBc could be associated with occult HBV infection in Iranian HIV-infected patients. Therefore the risk of transmission of HBV is probable in these patients.

A Customized Approach to the Management of Hepatitis B Viral Infection

Chronic hepatitis B virus (HBV) infection affects at least 1.25 million people in the United States. Current treatment guidelines for this incurable infection, which are based on alanine aminotransferase activity and serum HBV DNA concentration, are aimed at reducing the viral load to undetectable concentrations and preventing or delaying the progression to severe liver disease, including cirrhosis and hepatocellular carcinoma. These goals require a customized approach to long-term therapy for patients infected with HBV. Recent clinical findings suggest that hepatitis B viral load is the strongest predictor of disease progression and that this progression can be delayed by administering nucleoside and nucleotide analogues. However, long-term management of HBV infection with nucleoside and nucleotide analogues is associated with the emergence of drug-resistant mutants. These inherent challenges in the treatment of HBV were addressed by a satellite symposium held during the 57th Annual Meeting of the American Association for the Study of Liver Diseases in Boston, Massachusetts. In response to presentations of hypothetical patient scenarios, expert panelists discussed practical considerations for halting the natural history of HBV infection, tailoring HBV therapy, and treating pregnant or immunosuppressed patients infected with HBV. The challenging case studies presented during the satellite symposium serve as the foundation for the articles contained in this supplement. After successfully completing these articles, participants should be able to apply emerging evidence-based and consensus findings to the management of HBV infection in diverse subpopulations of patients. I hope this information will arm you with the knowledge and skills needed to customize your approach to the management of HBV infection.

Influences of MxA gene –88 G/T and IFN‐gamma +874 A/T on the natural history of hepatitis B virus infection in an endemic area

The influence of human genetics on the natural history of hepatitis B virus (HBV) infection may be diminished in endemic areas because infection at a young age predisposes to chronic HBV infection. The present study aimed to address this issue through the determination of the influences of single nucleotide polymorphisms (SNPs) of myxovirus resistence-1 (MxA) -88 G/T and interferon (IFN)-gamma +874 A/T on the natural history of HBV infection in endemic regions. One hundred adult patients with self-limiting HBV infection (positive for both anti-HBs and anti-HBc) and 340 adult patients with persistent HBV infection were recruited from southern China, an endemic area with an HBsAg carrier rate of 17.8%. SNPs of MxA -88 G/T and interferon (IFN)-gamma +874 A/T were typed using a protocol based on competitively differentiated polymerase chain reaction. A highly significant difference in the distribution of MxA -88 G/T was observed between those with persistent and self-limiting HBV infections. The latter displayed a lower frequency of the GG genotype (41.0% vs. 52.9%, P = 0.036) and a higher frequency of the TT genotype (16.0% vs. 2.4%, P = 0.000), compared to patients with persistent infection. These differences were not gender- or age-specific. However, a significant distribution difference of IFN-gamma +874 A/T was not observed. Between two groups of patients, respectively, the distribution frequencies of the AA genotype (65.0% vs. 72.8%, P = 0.139) and the TT genotype (2.0% vs. 1.2%, P = 0.894) were found. These results suggest that MxA gene -88 G/T and IFN-gamma +874 A/T behave differently in endemic HBV infections. Further study is necessary to clarify the influences of human genetics on endemic HBV infections.

Hepatitis B Virus Infection in 6,130 Unvaccinated Korean-Americans Surveyed Between 1988 and 1990

During the past decades, the influx of immigrants from hepatitis B virus (HBV) endemic regions has brought significant changes in the prevalence of HBV-associated liver diseases and hepatocellular carcinoma (HCC) in the United States. Our program, which was intended to identify those in need of hepatitis B vaccination, helped us to learn of the natural history of HBV infection in Korean Americans. Between November of 1988 and May 1990, we screened 6,130 Korean Americans in the eastern United States for HBV infection. The overall hepatitis B surface antigen (HBsAg) (+) rate was 6.1%, with 8.0% for males and 4.4% for females. The carrier rate peaked in subjects between the ages of 21 and 40 yr. The HBsAg (+) rate for 452 U.S.-born children was lower (2.7%) than that of 623 Korean-born (5.5%). None received hepatitis B immune-globulin or HBV vaccination. The vertical transmission rate was 30.3% in children born to HBsAg (+) mothers and 100% in those born to hepatitis B e antigen (HBeAg) positive mothers. In contrast, the paternal transmission rate was low; 10.3% in children with HBsAg (+) fathers and 19.2% in those with HBeAg (+) fathers. Another significant observation was the unexpected finding of ongoing liver diseases in incidentally identified carriers. Evaluation of 139 asymptomatic adult carriers revealed that 42% had elevated liver enzymes and 11% had already developed liver cirrhosis. These findings strongly suggest the need for active HBV screening of immigrants from endemic regions and, most importantly, the need for careful monitoring of the carriers.

Gene Expression Analysis in HBV Transgenic Mouse Liver: A Model to Study Early Events Related to Hepatocarcinogenesis

Hepatitis B virus (HBV) is one of the major etiological factors responsible for the development of hepatocellular carcinoma (HCC). We used a transgenic mouse, containing HBV sequences, as a model system to unravel the molecular mechanisms of hepatocarcinogenesis induced by HBV. We chose this animal model because it consistently develops liver cancer after intermediate steps that mimic the natural history of HBV infection in humans. In this study, we focus our attention on the early events leading to liver cancer. We compared the gene expression profile of 3-month-old transgenic mice with that of 3-month-old wild-type (wt) animals. In the transgenic mouse, microarray data analysis showed a total of 45 significantly differentially expressed genes, 25 highly expressed (fold change > or =2; P = 0.0025), and 20 downregulated (fold change < or =0.5; P = 0.0025). These genes belong to several different functional categories such as the regulation of immunological response, transcription, intracellular calcium ion mobilization, regulation of cell cycle and proliferation, NF-kappab signal transduction cascades, and apoptosis. In particular, the upregulation of the antiapoptotic gene NuprI and the downregulation of the proapoptotic gene Bnip3 were found. This observation was supported by an in vitro apoptosis assay that showed downregulation of apoptosis in hepatocytes of HBV transgenic mouse compared with wt mice treated with staurosporine. In conclusion, our experimental approach allowed identification of new genes modulated by HBV and showed that the apoptotic process was deregulated in transgenic mouse hepatocytes. These data shed light on one possible mechanism by which HBV induces hepatocarcinogenesis.

HBV genotypes: Epidemiology and implications regarding natural history

Hepatitis B virus (HBV) infection is a global health problem and eight different genotypes (A to H) have been identified. The epidemiology of HBV genotypes and their implications for the natural history of HBV infection have become increasingly recognized. Genotypes A and D are common in Europe, whereas genotypes B and C are prevalent in Asia. In Asian countries, genotype B is shown to be associated with spontaneous hepatitis B e antigen (HBeAg) seroconversion at a younger age, less active liver disease, slower progression to cirrhosis, and less frequent development of hepatocellular carcinoma than genotype C. In Western countries, genotype D is shown to have a lower positivity of HBeAg, less chance of sustained remission after seroconversion, and a less favorable prognosis than genotype A. Thus, clinical differences do exist among HBV genotypes, and further research is needed on the molecular mechanisms underlying the clinical phenotypes of different HBV genotypes.

The expression of hepatitis B spliced protein (HBSP) encoded by a spliced hepatitis B virus RNA is associated with viral replication and liver fibrosis

Background/Aims : We have previously demonstrated the in vivo expression of a new spliced hepatitis B virus (HBV) protein (HBSP) encoded by a singly spliced pregenomic RNA. The present study was designed to evaluate the impact of HBSP expression on the clinical status and liver pathology of HBV infection. Methods : Sera from 125 chronic HBV carriers were tested for the presence of HBSP antibodies by an indirect enzyme-linked immunosorbent assay test. The severity of liver damage was evaluated using the Knodell score. Results : Anti-HBSP antibody prevalence in HBV chronic carriers was 46%. We highlighted the concomitant expression of HBSP protein and anti-HBSP antibody. An association between anti-HBSP antibody detection and serum markers of HBV replication was demonstrated. With respect to HBV-related liver disease, an association was only observed with the severity of fibrosis. Furthermore, an elevation of secreted tumor necrosis factor α (TNF α), but not of soluble TNF α receptor 75, was observed in anti-HBSP-antibody-positive patients. Multivariate analysis showed that anti-HBSP antibody detection was independently associated with viral replication, severity of fibrosis and elevated TNF α secretion. Conclusions : Our data suggest the hypothesis that HBSP might play a role in the natural history of HBV infection and may be involved in the pathogenesis and/or persistence of HBV infection.

Clinical and virological aspects of hepatitis B co-infection in individuals infected with human immunodeficiency virus type-1.

The improved prognosis of HIV-infection that has occurred since the introduction of highly active antiretroviral therapy (HAART) has resulted in renewed emphasis being placed on co-morbidities associated with HIV-infection, and chronic viral hepatitis in particular. Hepatitis B virus (HBV) infection is an important infection in HIV-1 infected individuals because of the influence of HIV-1 co-infection on the natural history of HBV infection. Antiviral therapies with activity against both viruses have enabled targeted therapy in co-infected individuals, however, optimism regarding improved prognosis has been tempered by the development of antiviral resistant HBV. Emerging new classes of HBV therapies herald the possibility of combination HBV therapy.

An economic evaluation of universal infant vaccination against hepatitis B virus using a combination vaccine (Hib-HepB): a decision analytic approach to cost effectiveness.

To evaluate the health impact and cost effectiveness of two infant vaccination strategies for protection against hepatitis B virus (HBV) infection in the Australian population. Vaccinating only high-risk infants, assuming 65% compliance, was compared with universal vaccination of infants using a combination Hib-HepB vaccine, with 87.4% compliance. A Markov model simulated the natural history of HBV infection and disease in an Australian birth cohort. The cohort was divided into those at high risk of infection (infants born into high-risk families) and low-risk infants. Clinical and epidemiological data used were obtained from published reports and a survey of clinical experts. The model included the health costs associated with acute and chronic HBV infection, and the sequelae of chronic HBV infection. The model predicted that universal hepatitis B vaccination of an Australian birth cohort (260,000 births) would result in a 77% reduction in cases of HBV infection. The incremental cost per life year gained was $11,862, which is low compared with many other health care interventions. With no discounting of costs or consequences, universal vaccination with the combination vaccine was predicted to save lives and reduce costs. There is no socially accepted threshold value for cost per life year gained to guide decisions about funding Australian health care interventions. Nevertheless, based on these results, universal hepatitis B vaccination of Australian infants using a combination Hib-HepB vaccine would almost certainly be regarded as a worthwhile investment of public funds.