Hepatitis B virus infection

doi:10.1016/S0140-6736(09)60207-5

The Lancet

Volume 373, Issue 9663, 14–20 February 2009, Pages 582-592

https://doi.org/10.1016/S0140-6736(09)60207-5 Get rights and content

Summary

Since the introduction of the hepatitis B vaccine and other preventive measures, the worldwide prevalence of hepatitis B infection has fallen. However, chronic infection remains a challenging global health problem, with more than 350 million people chronically infected and at risk of hepatic decompensation, cirrhosis, and hepatocellular carcinoma. An improved understanding of hepatitis B virology, immunology, and the natural course of chronic infection, has identified hepatitis B virus replication as the key driver of immune-mediated liver injury and disease progression. The approval of potent oral antiviral agents has revolutionised hepatitis B treatment since 1998. Conventional and pegylated interferon alfa and nucleoside and nucleotide analogues are widely authorised treatments, and monotherapy with these drugs greatly suppresses virus replication, reduces hepatitis activity, and halts disease progression. However, hepatitis B virus is rarely eliminated, and drug resistance is a major drawback during long term therapy. The development of new drugs and strategies is needed to improve treatment outcomes.

Introduction

Hepatitis B virus is one of the most serious and prevalent health problems, affecting more than 2 billion people worldwide. Although highly effective vaccines against hepatitis B virus have been available since 1982, there are still more than 350 million chronic carriers, 75% of whom reside in the Asia Pacific region. People with hepatitis B are at increased risk of developing hepatic decompensation, cirrhosis, and hepatocellular carcinoma. The estimated worldwide mortality is 0·5 to 1·2 million deaths a year.¹

Substantial improvement in the understanding of hepatitis B virology and immunology during past decades, combined with the advent of highly sensitive assays, has led to new insights into the natural history of such infection. Furthermore, the approval of oral antiviral agents has revolutionised hepatitis B treatment since 1998, and enabled effective clinical management of the disease.

Section snippets

Viral epidemiology

Hepatitis B virus is a double-stranded DNA virus of the hepadnaviridae family. The virus is enveloped, and contains a viral DNA genome of about 3200 bps within its core. After the virus enters a hepatocyte, the viral genome is delivered to the nucleus, and the relaxed circular DNA is converted to covalently-closed-circular DNA (cccDNA). The cccDNA serves as a template for the transcription of the viral RNA. The hepatitis B virus replication cycle includes reverse transcription of RNA

Prevention

Through understanding the routes and modes of hepatitis B transmission, infection can be prevented by avoidance or interruption of transmission. Since the 1970s, serological screening of donor blood has become progressively routine, resulting in substantial reduction of transfusion-associated hepatitis B.¹ Syringe-exchange programmes are run in the USA and other high-income countries, and provide free sterile syringes in exchange for used syringes, reducing transmission of blood-borne

Pathophysiology

Hepatitis B virus is not cytopathogenic. In acute infection, clinical hepatitis B becomes apparent after an incubation period of 45–180 days. The elimination of hepatitis B virus by non-cytopathic mechanisms begins several weeks before the disease onset. Hepatitis B virus DNA clearance is mediated largely (up to 90%) by antiviral cytokines that are produced by cells of the innate and adaptive immune responses—including tumour necrosis factor α, interferon alfa, or interferon beta.15, 16, 17

Natural history

The spectrum of acute hepatitis B infection ranges from asymptomatic infection to self-limited hepatitis, to fulminant hepatitis and it depends on various viral and host factors. Symptomatic hepatitis is rare in neonates (less than 1%) and occurs in about 10% of children 1–5 years old.1, 22 Fulminant hepatitis is very rare in paediatric patients, with most reported cases being in infants born to HBeAg-negative, HBsAg-carrier mothers.²⁸ One proposed explanation is that the absence of HBeAg in

Management

Acute hepatitis B in adults is selflimiting in more than 95% of cases, therefore, antiviral therapy is indicated only for patients with protracted severe acute hepatitis or fulminant hepatitis B.²⁵ Management of patients with chronic hepatitis B infection should include thorough patient assessment and counselling. Although patients are usually asymptomatic, they can be anxious and attribute a wide range of negative psychological, social, and physical symptoms to their condition.⁹¹ Counselling

References (131)

J Summers et al.
Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate
Cell
(1982)
JF Botha et al.
Hepatitis B virus carrier state in black children in Ovamboland: role of perinatal and horizontal infection
Lancet
(1984)
CJ Chu et al.
Prevalence of HBV precore/core promoter variants in the United States
Hepatology
(2003)
EK Manesis
HBeAg-negative chronic hepatitis B: from obscurity to prominence
J Hepatol
(2006)
J Zuckerman et al.
Should hepatitis B vaccination be introduced into childhood immunisation programmes in northern Europe?
Lancet Infect Dis
(2007)
YH Ni et al.
Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies
Gastroenterology
(2007)
A Bertoletti et al.
Role of hepatitis B virus specific cytotoxic T cells in liver damage and viral control
Antiviral Res
(2003)
RG Gish et al.
Chronic hepatitis B: current testing strategies
Clin Gastroenterol Hepatol
(2006)
G Raimondo et al.
Occult hepatitis B virus infection
J Hepatol
(2007)
D Milich et al.
Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection
Hepatology
(2003)

YS Hsu et al.

Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B

Hepatology

(2002)

CL Lai et al.

Viral hepatitis B

Lancet

(2003)

CM Chu et al.

Subcellular localization of hepatitis B core antigen in relation to hepatocyte regeneration in chronic hepatitis B

Gastroenterology

(1995)

CM Chu et al.

Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels

Am J Med

(2004)

CM Chu et al.

Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline

J Hepatol

(2005)

CJ Chu et al.

Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C

Gastroenterology

(2002)

YH Ni et al.

Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma

Gastroenterology

(2004)

MF Yuen et al.

Epidemiological study of hepatitis B virus genotypes, core promoter and precore mutations of chronic hepatitis B infection in Hong Kong

J Hepatol

(2004)

SE Livingston et al.

Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F

Gastroenterology

(2007)

M Manno et al.

Natural history of chronic HBV carriers in northern Italy: morbidity and mortality after 30 years

Gastroenterology

(2004)

YH Ni et al.

Viremia profiles in children with chronic hepatitis B virus infection and spontaneous e antigen seroconversion

Gastroenterology

(2007)

JM Sánchez-Tapias et al.

Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients

Gastroenterology

(2002)

YC Chen et al.

Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection

Gastroenterology

(2002)

F Bonino et al.

Chronic hepatitis B e antigen (HBeAg) negative, anti-HBe positive hepatitis B: an overview

J Hepatol

(2003)

CM Chu et al.

Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B

Gastroenterology

(2007)

UH Iloeje et al.

The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (the REVEAL-HBV) Study Group Predicting cirrhosis risk based on the level of circulating hepatitis B viral load

Gastroenterology

(2006)

UH Iloeje et al.

Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-hepatitis B Virus Study Group. Risk and predictors of mortality associated with chronic hepatitis B infection

Clin Gastroenterol Hepatol

(2007)

JH Kao et al.

Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B

Gastroenterology

(2000)

H Sumi et al.

Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease

Hepatology

(2003)

MF Yuen et al.

Significance of hepatitis B genotype in acute exacerbation, HBeAg seroconversion, cirrhosis-related complications, and hepatocellular carcinoma

Hepatology

(2003)

SM Lin et al.

Interferon therapy in HBeAg positive chronic hepatitis reduces cirrhosis and hepatocellular carcinoma

J Hepatol

(2007)

MR Brunetto et al.

Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study

J Hepatol

(2002)

YF Liaw et al.

Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection

Gastroenterology

(2004)

G Fattovich et al.

Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients

Am J Gastroenterol

(2002)

JH Kao et al.

Core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers

Gastroenterology

(2003)

CH Chen et al.

Pre-S deletion and complex mutations of hepatitis B virus related to advanced liver disease in HBeAg-negative patients

Gastroenterology

(2007)

M Lai et al.

The clinical significance of persistently normal ALT in chronic hepatitis B infection

J Hepatol

(2007)

A Craxì et al.

Interferon-alpha for HBeAg-positive chronic hepatitis B

J Hepatol

(2003)

HLA Janssen et al.

Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial

Lancet

(2005)

D Lavanchy

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

J Viral Hepatol

(2004)

JH Kao

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

Hepatol Int

(2007)

A Wasley et al.

Surveillance for acute viral hepatitis—United States, 2006

MMWR Morb Mortal Wkly Rep

(2008)

K Okada et al.

e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants

N Engl J Med

(1976)

HH Lin et al.

Secular trend of age-specific prevalence of hepatitis B surface and e antigenemia in pregnant women in Taiwan

J Med Virol

(2003)

CA McKnight et al.

Syringe exchange programs—United States, 2005

MMWR Morb Mortal Wkly Rep

(2007)

Hepatitis B vaccines

Wkly Epidemiol Rec

(2004)

YC Chien et al.

Nationwide hepatitis B vaccination program in Taiwan: effectiveness in the 20 years after it was launched

Epidemiol Rev

(2006)

JM Murray et al.

Dynamics of hepatitis B virus clearance in chimpanzees

Proc Natl Acad Sci USA

(2005)

LG Guidotti et al.

Viral clearance without destruction of infected cells during acute HBV infection

Science

(1999)

R Thimme et al.

CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection

J Virol

(2003)

Cited by (1095)

Early application of IFNγ mediated the persistence of HBV in an HBV mouse model
2024, Antiviral Research
The antiviral activity of interferon gamma (IFNγ) against hepatitis B virus (HBV) was demonstrated both in vivo and in vitro in a previous study. IFNγ can suppress HBV replication by accelerating the decay of replication-competent nucleocapsids of HBV. However, in this study, we found that the direct application of the mouse IFNγ (mIFNγ) expression plasmid to the liver of an HBV hydrodynamic injection (HI) mouse model led to the persistence of HBV, as indicated by sustained HBsAg and HBeAg levels in the serum as well as an increased percentage of the HBsAg positive mice, whereas the level of HBV DNA in the serum and the expression of HBcAg in the liver were inhibited at the early stage after HI. Meanwhile, we found that the productions of both HBcAb and HBsAb were suppressed after the application of mIFNγ. In addition, we found that HBV could be effectively inhibited in mice immunized with HBsAg expression plasmid before the application of mIFNγ. Furthermore, mIFNγ showed antiviral effect and promoted the production of HBsAb when the mice subjected to the core-null HBV plasmid. These results indicate that the application of mIFNγ in the HBV HI mouse model, the mice showed defective HBcAg-specific immunity that impeded the production of HBcAb and HBsAb, finally allowing the persistence of the virus. Moreover, IFNγ-induced negative immune regulatory factors also play an important role in virus persistence.
HIV coinfection exacerbates HBV-induced liver fibrogenesis through a HIF-1α- and TGF-β1-dependent pathway
2024, Journal of Hepatology
Persons with chronic HBV infection coinfected with HIV experience accelerated progression of liver fibrosis compared to those with HBV monoinfection. We aimed to determine whether HIV and its proteins promote HBV-induced liver fibrosis in HIV/HBV-coinfected cell culture models through HIF-1α and TGF-β1 signaling.
The HBV-positive supernatant, purified HBV viral particles, HIV-positive supernatant, or HIV viral particles were directly incubated with cell lines or primary hepatocytes, hepatic stellate cells, and macrophages in mono or 3D spheroid coculture models. Cells were incubated with recombinant cytokines and HIV proteins including gp120. HBV sub-genomic constructs were transfected into NTCP-HepG2 cells. We also evaluated the effects of inhibitor of HIF-1α and HIV gp120 in a HBV carrier mouse model that was generated via hydrodynamic injection of the pAAV/HBV1.2 plasmid into the tail vein of wild-type C57BL/6 mice.
We found that HIV and HIV gp120, through engagement with CCR5 and CXCR4 coreceptors, activate AKT and ERK signaling and subsequently upregulate hypoxia-inducible factor-1α (HIF-1α) to increase HBV-induced transforming growth factor-β1 (TGF-β1) and profibrogenic gene expression in hepatocytes and hepatic stellate cells. HIV gp120 exacerbates HBV X protein-mediated HIF-1α expression and liver fibrogenesis, which can be alleviated by inhibiting HIF-1α. Conversely, TGF-β1 upregulates HIF-1α expression and HBV-induced liver fibrogenesis through the SMAD signaling pathway. HIF-1α small-interfering RNA transfection or the HIF-1α inhibitor (acriflavine) blocked HIV-, HBV-, and TGF-β1-induced fibrogenesis.
Our findings suggest that HIV coinfection exacerbates HBV-induced liver fibrogenesis through enhancement of the positive feedback between HIF-1α and TGF-β1 via CCR5/CXCR4. HIF-1α represents a novel target for antifibrotic therapeutic development in HBV/HIV coinfection.
HIV coinfection accelerates the progression of liver fibrosis compared to HBV monoinfection, even among patients with successful suppression of viral load, and there is no sufficient treatment for this disease process. In this study, we found that HIV viral particles and specifically HIV gp120 promote HBV-induced hepatic fibrogenesis via enhancement of the positive feedback between HIF-1α and TGF-β1, which can be ameliorated by inhibition of HIF-1α. These findings suggest that targeting the HIF-1α pathway can reduce liver fibrogenesis in patients with HIV and HBV coinfection.
Perspectives on Outcome Prediction in Patients With Chronic Hepatitis B Virus Infection
2024, Gastro Hep Advances
Identification of novel tetrahydroquinoxaline derived phenyl ureas as modulators of the hepatitis B virus nucleocapsid assembly
2023, European Journal of Medicinal Chemistry
A key step of hepatitis B virus (HBV) replication is the selective packaging of pregenomic RNA (pgRNA) by core protein (Cp) dimers, forming a nucleocapsid where the reverse transcriptional viral DNA replication takes place. One approach in the development of new anti-HBV drugs is to disrupt the assembly of HBV nucleocapsids by misdirecting Cp dimers to assemble morphologically normal capsids devoid of pgRNA. In this study, we built upon our previous discovery of benzamide-derived HBV capsid assembly modulators by exploring fused bicyclic scaffolds with an exocyclic amide that is β, γ to the fused ring, and identified 1,2,3,4-tetrahydroquinoxaline derived phenyl ureas as a novel scaffold. Structure-activity relationship studies showed that a favorable hydrophobic substitution can be tolerated at the 2-position of the 1,2,3,4-tetrahydroquinoxaline core, and the resulting compound 88 demonstrated comparable or improved antiviral potencies in mouse and human hepatocyte-derived HBV-replicating cell lines compared to our previously reported benzamide compound, 38017 (8). In addition, a novel bis-urea series based on 1,2,3,4-tetrahydroquinoxaline was also found to inhibit HBV DNA replication with sub-micromolar EC₅₀ values. The mode of action of these compounds is consistent with specific inhibition of pgRNA encapsidation into nucleocapsids in hepatocytes.
Long-term comparisons of the durability of 6 months versus 12 months antiviral therapy for hepatitis B after chemotherapy cessation
2023, Journal of Infection and Public Health
Prophylaxis antiviral therapy is recommended for patients with hepatitis B receiving chemotherapy but the ideal treatment duration after chemotherapy cessation needs more evidence for clarification.
This study aimed to compare the relapse rate of short finite intervals of 6 months and 12 months of -nucleos(t)ide analogue (NA) therapy in patients stratified by low hepatitis B virus (HBV)-DNA of < 2000 IU/ml or high HBV DNA of ≥ 2000 IU/ml.
Patients started tenofovir or entecavir treatment 1 week before chemotherapy and were assigned to different treatment duration groups randomly after stratified by HBV DNA pretreatment: (1) HBV DNA of < 2000 IU/ml at 6-month or 12-month duration; (2)HBV DNA of ≥ 2000 IU/ml at 6-month or 12-month duration. Virological relapse (VR) was defined as HBV DNA of > 2000 IU/ml, and clinical relapse (CR) was defined as HBV DNA of > 2000 IU/ml and alanine aminotransferase of > 80 IU/L during the follow-up period. The primary endpoint was to compare the durability between groups 1 year after antiviral therapy cessation. The secondary endpoint was VR and CR rate at long-term follow-up after antiviral therapy cessation.
This study enrolled 61 patients, and 5 patients were lost to follow-up or tumor recurrence. VR and CR rates were 46.4% and 14.3% at 1-year and 55.3% and 16.1%, at long-term follow-up, respectively. VR and CR rates demonstrated no difference between the groups. Pretreatment HBV DNA at ≥ 2000 IU/ml and end-of-treatment hepatitis B surface antigen (HBsAg) at ≥ 500 IU/ml were the predictor of VR (hazard ratio [HR]: 2.98; p = 0.010 and HR: 2.38; p = 0.037).
Prolongation from 6 months to 12 months of NA consolidation after chemotherapy cessation did not affect the VR or CR of HBV. High pretreatment HBV DNA and end-of-treatment HBsAg levels could predict VR after antiviral therapy cessation for chemotherapy.
PreS1- targeting chimeric antigen receptor T cells diminish HBV infection in liver humanized FRG mice
2023, Virology
Current therapies control but rarely achieve a cure for hepatitis B virus (HBV) infection. Restoration of the HBV-specific immunity by cell-based therapy represents a potential approach for a cure. In this study, we generated HBV specific CAR T cells based on an antibody 2H5-A14 targeting a preS1 region of the HBV large envelope protein. We show that the A14 CAR T cell is capable of killing hepatocytes infected by HBV with high specificity; adoptive transfer of A14 CAR T cells to HBV infected humanized FRG mice resulted in reductions of all serum and intrahepatic virological markers to levels below the detection limit. A14 CAR T cells treatment increased the levels of human IFN-γ, GM-CSF, and IL-8/CXCL-8 in the mice. These results show that A14 CAR T cells may be further developed for curative therapy against HBV infection by eliminating HBV-infected hepatocytes and inducing production of pro-inflammatory and antiviral cytokines.

View all citing articles on Scopus

View full text

SeminarHepatitis B virus infection

Summary

Introduction

Section snippets

Viral epidemiology

Prevention

Pathophysiology

Natural history

Management

Cell

Lancet

Hepatology

J Hepatol

Lancet Infect Dis

Gastroenterology

Antiviral Res

Clin Gastroenterol Hepatol

J Hepatol

Hepatology

Hepatology

Lancet

Gastroenterology

Am J Med

J Hepatol

Gastroenterology

Gastroenterology

J Hepatol

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

J Hepatol

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Gastroenterology

Hepatology

Hepatology

J Hepatol

J Hepatol

Gastroenterology

Am J Gastroenterol

Gastroenterology

Gastroenterology

J Hepatol

J Hepatol

Lancet

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

J Viral Hepatol

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

Hepatol Int

Surveillance for acute viral hepatitis—United States, 2006

MMWR Morb Mortal Wkly Rep

e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants

N Engl J Med

Secular trend of age-specific prevalence of hepatitis B surface and e antigenemia in pregnant women in Taiwan

J Med Virol

Syringe exchange programs—United States, 2005

MMWR Morb Mortal Wkly Rep

Hepatitis B vaccines

Wkly Epidemiol Rec

Nationwide hepatitis B vaccination program in Taiwan: effectiveness in the 20 years after it was launched

Epidemiol Rev

Dynamics of hepatitis B virus clearance in chimpanzees

Proc Natl Acad Sci USA

Viral clearance without destruction of infected cells during acute HBV infection

Science

CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection

J Virol

Seminar
Hepatitis B virus infection