Hepatitis B virus infection

doi:10.1016/S0140-6736(14)60220-8

The Lancet

Volume 384, Issue 9959, 6–12 December 2014, Pages 2053-2063

https://doi.org/10.1016/S0140-6736(14)60220-8 Get rights and content

Summary

Hepatitis B virus infection is a major public health problem worldwide; roughly 30% of the world's population show serological evidence of current or past infection. Hepatitis B virus is a partly double-stranded DNA virus with several serological markers: HBsAg and anti-HBs, HBeAg and anti-HBe, and anti-HBc IgM and IgG. It is transmitted through contact with infected blood and semen. A safe and effective vaccine has been available since 1981, and, although variable, the implementation of universal vaccination in infants has resulted in a sharp decline in prevalence. Hepatitis B virus is not cytopathic; both liver damage and viral control—and therefore clinical outcome—depend on the complex interplay between virus replication and host immune response. Overall, as much as 40% of men and 15% of women with perinatally acquired hepatitis B virus infection will die of liver cirrhosis or hepatocellular carcinoma. In addition to decreasing hepatic inflammation, long-term antiviral treatment can reverse cirrhosis and reduce hepatocellular carcinoma. Development of new therapies that can improve HBsAg clearance and virological cure is warranted.

Introduction

Hepatitis B virus (HBV) infection is the most common chronic viral infection in the world. An estimated 2 billion people have been infected, and more than 350 million are chronic carriers of the virus.¹ In the 2010 Global Burden of Disease study,² HBV infection ranked in the top health priorities in the world, and was the tenth leading cause of death (786 000 deaths per year). These data have led WHO to include viral hepatitis in its major public health priorities.

Safe and effective prophylactic vaccines and effective antiviral drugs are available to prevent and treat HBV infection, but the global burden will remain high without concerted efforts from governments, health-care providers, and communities to raise awareness and improve access to care.

Section snippets

Epidemiology

Roughly 30% of the world's population shows serological evidence of current or past HBV infection.3, 4 About half the total liver cancer mortality in 2010 was attributed to HBV infection, and from 1990 to 2010, the worldwide mortality associated with liver cancer increased by 62% and that associated with cirrhosis increased by 29%.²

HBV is transmitted through contact with infected blood or semen. Three major modes of transmission prevail. In areas of high endemicity, HBV is transmitted mostly

Prevention

HBV infection can be prevented by avoiding transmission from infected people and by inducing immunity in unexposed people. Screening of blood donors for HBsAg and implementation of universal precautions resulted in a substantial reduction in transmission in health-care settings. The addition of HBV DNA testing to screening processes further decreases the incidence of transfusion-associated disease, but implementation is hampered by incremental cost.¹⁰ Counselling infected people to prevent

Diagnosis

Serological markers for HBV infection include HBsAg, anti-HBs, HBeAg, anti-HBe, and anti-HBc IgM and IgG (figure 2; table 1). HBsAg is the hallmark of infection. During acute infection, anti-HBc (initially both IgM and IgG) appears 1–2 weeks after the appearance of HBsAg at the same time as raised aminotransferase concentrations and symptoms, while IgG persists during chronic infection. IgM anti-HBc can be present in some patients with severe exacerbations of chronic HBV infection but the titre

Immunopathogenesis

HBV is not cytopathic: both liver damage and viral control are immunomediated. The clinical outcome of infection is dependent on the complex interplay between HBV replication and host immune response.29, 30, 31 HBV is a weak inducer of the innate immune response.³² Resolution of acute infection is mainly mediated through the adaptive immune response. People with serological recovery from acute HBV infection have strong T-cell responses to several epitopes in different regions of the HBV genome.

Virology

HBV belongs to the Hepadnaviridae family. It is a partly doublestranded DNA virus with approximately 3200 base pairs. The transcriptional template of HBV is the cccDNA, which resides inside the hepatocyte nucleus as a mini-chromosome.⁴² The maintenance of cccDNA is essential for the persistence of the virus. The replication of HBV implicates reverse transcription of the pregenomic RNA intermediate into HBV DNA. Reverse transcriptase is error prone and the mutation rate is high (appendix). The

Natural history

The occurrence of symptoms during acute HBV infection and the outcome depend on age at infection. Infants and children are mostly asymptomatic, whereas roughly 70% of adults have subclinical or anicteric hepatitis and 30% have icteric hepatitis. Less than 1% of acute HBV infection in adults progresses to fulminant hepatitis, which has a mortality of around 80% without liver transplantation.

HBsAg appears in the serum 2–10 weeks after exposure to HBV, before onset of symptoms and increases in

General

Acute HBV infection is self-limiting in more than 95% of immunocompetent adults. Therefore management is supportive, and so far antiviral therapy is indicated only for patients with protracted or severe acute disease. Management of chronic infection should include assessment of HBV replication status; screening for HIV, hepatitis C virus, and hepatitis D virus co-infection; and assessment of severity of liver disease. Clinical assessment, blood counts, analysis of liver enzymes, and liver

Search strategy and selection criteria

We focused on advances in the management of hepatitis B in the past 5 years. We searched the Cochrane Library, PubMed, and Embase with the terms “hepatitis B”, “chronic hepatitis B”, and “hepatitis B virus”, together with “epidemiology”, “burden of disease”, “immunopathogenesis”, “prevention”, “vaccination”, “natural history”, “treatment”, “antiviral therapy”, and “hepatocellular carcinoma” for articles published in English between Jan 1, 2008, and Dec 31, 2013. Landmark studies published

References (101)

YF Liaw et al.
Hepatitis B virus infection
Lancet
(2009)
R Lozano et al.
Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010
Lancet
(2012)
RP Beasley
Rocks along the road to the control of HBV and HCC
Ann Epidemiol
(2009)
HS Te et al.
Epidemiology of hepatitis B and C viruses: a global overview
Clin Liver Dis
(2010)
MP Busch
Should HBV DNA NAT replace HBsAg and/or anti-HBc screening of blood donors?
Transfus Clin Biol
(2004)
WH Wen et al.
Mother-to-infant transmission of hepatitis B virus infection: significance of maternal viral load and strategies for intervention
J Hepatol
(2013)
D FitzSimons et al.
Hepatitis B vaccination: a completed schedule enough to control HBV lifelong? Milan, Italy, 17–18 November 2011
Vaccine
(2013)
YH Ni et al.
Minimization of hepatitis B infection by a 25-year universal vaccination program
J Hepatol
(2012)
G Raimondo et al.
Occult hepatitis B virus infection
J Hepatol
(2007)
HL Chan et al.
Hepatitis B surface antigen quantification: why and how to use it in 2011—a core group report
J Hepatol
(2011)

M Martinot-Peignoux et al.

Hepatitis B surface antigen serum level is associated with fibrosis severity in treatment-naive, e antigen-positive patients

J Hepatol

(2013)

ML Michel et al.

Therapeutic vaccines and immune-based therapies for the treatment of chronic hepatitis B: perspectives and challenges

J Hepatol

(2011)

F Zoulim et al.

Targeting innate immunity: a new step in the development of combination therapy for chronic hepatitis B

Gastroenterology

(2013)

YF Liaw et al.

Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis

Gastroenterology

(1983)

AS Lok et al.

Acute exacerbations in Chinese patients with chronic hepatitis B virus (HBV) infection. Incidence, predisposing factors and etiology

J Hepatol

(1990)

T Maruyama et al.

Serology of acute exacerbation in chronic hepatitis B virus infection

Gastroenterology

(1993)

AS Lok et al.

Spontaneous hepatitis B e antigen to antibody seroconversion and reversion in Chinese patients with chronic hepatitis B virus infection

Gastroenterology

(1987)

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)

J Liu et al.

A predictive scoring system for the seroclearance of HBsAg in HBeAg-seronegative chronic hepatitis B patients with genotype B or C infection

J Hepatol

(2013)

MF Yuen et al.

HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma

Gastroenterology

(2008)

YC Chen et al.

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

Gastroenterology

(2002)

CM Chu et al.

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

Gastroenterology

(2007)

RP Beasley et al.

Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan

Lancet

(1981)

G Fattovich et al.

Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors

J Hepatol

(2008)

UH Iloeje et al.

Predicting cirrhosis risk based on the level of circulating hepatitis B viral load

Gastroenterology

(2006)

F Degos et al.

Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study)

J Hepatol

(2010)

S Yapali et al.

Management of hepatitis B: our practice and how it relates to the guidelines

Clin Gastroenterol Hepatol

(2014)

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)

EH Buster et al.

Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b

Gastroenterology

(2008)

EH Buster et al.

Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa

Gastroenterology

(2009)

P Marcellin et al.

Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study

Lancet

(2013)

YF Liaw et al.

2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B

Gastroenterology

(2009)

RP Perrillo et al.

Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B

Hepatology

(2002)

JL Dienstag et al.

Histological outcome during long-term lamivudine therapy

Gastroenterology

(2003)

M Lai et al.

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

J Hepatol

(2007)

Hepatitis B. Fact Sheet N°204

A Hatzakis et al.

The state of hepatitis B and C in the Mediterranean and Balkan countries: report from a summit conference

J Viral Hepat

(2013)

Global immunization data

C Rossi et al.

Seroprevalence of chronic hepatitis B virus infection and prior immunity in immigrants and refugees: a systematic review and meta-analysis

PLoS One

(2012)

T Mitchell et al.

The increasing burden of imported chronic hepatitis B—United States, 1974–2008

PLoS One

(2011)

CE Stevens et al.

Vertical transmission of hepatitis B antigen in Taiwan

N Engl J Med

(1975)

CQ Pan et al.

Antiviral therapy for chronic hepatitis B in pregnancy

Semin Liver Dis

(2013)

BJ McMahon et al.

Antibody levels and protection after hepatitis B vaccine: results of a 22-year follow-up study and response to a booster dose

J Infect Dis

(2009)

M Mendy et al.

Observational study of vaccine efficacy 24 years after the start of hepatitis B vaccination in two Gambian villages: no need for a booster dose

PLoS One

(2013)

TW Wu et al.

Chronic hepatitis B infection in adolescents who received primary infantile vaccination

Hepatology

(2013)

MH Chang et al.

Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study

J Natl Cancer Inst

(2009)

A Wasley et al.

Surveillance for acute viral hepatitis–United States, 2006

MMWR Surveill Summ

(2008)

A Wasley et al.

The prevalence of hepatitis B virus infection in the United States in the era of vaccination

J Infect Dis

(2010)

SJ Hahné et al.

Prevalence of hepatitis B virus infection in The Netherlands in 1996 and 2007

Epidemiol Infect

(2012)

P Van Damme et al.

Should Europe have a universal hepatitis B vaccination programme?

BMJ

(2013)

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Hepatitis B virus (HBV) virus-like particles (VLPs) are promising therapeutic agents derived from HBV core proteins (Cp). This study investigates the assembly dynamics of HBV VLPs, which is crucial for their potential as drug carriers or gene delivery systems. Coarse-grained molecular dynamics simulations explore the impact of C-terminal domain length (in the Cp ranging from Cp149 to wild-type Cp183) on Cp assembly and stability, particularly in the presence of DNA. Our findings reveal that the C-terminal nucleic acid binding region significantly influences Cp assembly and stability of trimers comprising Cp dimers. Shorter C-terminal domains (Cp164, Cp167) enhance stability and protein-protein interactions, while interactions between naturally occurring Cp183 are destabilized in the absence of DNA. Interestingly, DNA addition further stabilizes Cp assemblies, and this effect is influenced by the length of the nucleic acid binding region. Shorter C-terminal domains show less dependency on DNA content. This stabilization is attributed to electrostatic forces between positively charged C-terminal chains and negatively charged nucleic acids. Our study sheds light on the molecular mechanisms governing protein-protein and protein-DNA interactions in HBV VLP assembly, providing insights into Cp processability and informing the development of efficient gene therapy carriers using VLP technology.
A Randomized Controlled Study of Efficacy and Safety of Accelerated Versus Standard Hepatitis B Vaccination in Patients With Advanced CKD
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Hepatitis B virus (HBV) vaccination is crucial for seronegative patients with advanced chronic kidney disease (CKD) for protection during dialysis while preparing for transplantation. A standard regimen for HBV vaccination requires 24 weeks to be completed. An accelerated HBV vaccination regimen completed within 8 weeks has shown early effective seroconversion in healthcare workers. However, data for patients with advanced CKD are limited.
A randomized controlled trial was conducted in patients with advanced CKD (estimated glomerular filtration rate [GFR] <30 ml/min per 1.73 m²) and patients on dialysis. The patients were randomly assigned to either a standard HBV vaccination regimen (Engerix B; 40 μg at 0, 4, 8, and 24 weeks) or an accelerated regimen (40 μg at 0, 1, 4, and 8 weeks). The hepatitis B surface antibodies (anti-HBs) were measured at 12, 28, and 52 weeks. Seroconversion were defined as anti-HBs ≥10 IU/l.
At 12 weeks, among the intention-to-treat (ITT) population of 133 participants (65 in the accelerated and 68 in the standard groups), the accelerated group demonstrated significantly higher rates of seroconversion (83.08% vs. 63.24%, P = 0.01). In the per-protocol (PP) analysis of 125 patients (62 in the standard and 63 in the accelerated groups), the accelerated group exhibited higher seroconversion rate compared with the standard group (85.71% vs. 69.35%, P = 0.03). At 28 and 52 weeks, the seroconversion rates were similar between the 2 groups.
In patients with advanced CKD, the accelerated HBV vaccination regimen demonstrated a significantly higher seroconversion rate at 12 weeks of vaccination. This finding suggests that the accelerated regimen is an effective option to achieve rapid seroconversion before initiating hemodialysis or before undergoing kidney transplantation.
Identification of dihydroquinolizinone derivatives with nitrogen heterocycle moieties as new anti-HBV agents
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The sustained loss of HBsAg is considered a pivotal indicator for achieving functional cure of HBV. Dihydroquinolizinone derivatives (DHQs) have demonstrated remarkable inhibitory activity against HBsAg both in vitro and in vivo. However, the reported neurotoxicity associated with RG7834 has raised concerns regarding the development of DHQs. In this study, we designed and synthesized a series of DHQs incorporating nitrogen heterocycle moieties. Almost all of these compounds exhibited potent inhibition activity against HBsAg, with IC₅₀ values at the nanomolar level. Impressively, the compound (S)-2a (10 μM) demonstrated a comparatively reduced impact on the neurite outgrowth of HT22 cells and isolated mouse DRG neurons in comparison to RG7834, thereby indicating a decrease in neurotoxicity. Furthermore, (S)-2a exhibited higher drug exposures than RG7834. The potent anti-HBV activity, reduced neurotoxicity, and favorable pharmacokinetic profiles underscore its promising potential as a lead compound for future anti-HBV drug discovery.
Seroprevalence of hepatitis B virus infection (HBsAg) and associated factors among antenatal clinic attendees in a secondary-level facility in southern Ghana
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Vertical transmission of Hepatitis B Virus (HBV) infection is the predominant mode of HBV transmission in highly endemic settings worldwide where the HBV seroprevalence is above 8%. Newborns who contract HBV at birth have a higher risk of chronic infections that can result in liver cancer and liver cirrhosis. Preventing mother-to-child transmission of HBV through screening of pregnant women during the antenatal period and universal vaccination of newborns are important strategies for eliminating new childhood HBV infections. This study sought to estimate the prevalence of HBV infection among pregnant women in the study area and to determine the factors associated with a positive HBV disease status. The findings from this study will help in obtaining a baseline for comparing future trends and identifying risk factors for HBV that need to be eliminated in southern Ghana.
This was a cross-sectional hospital-based analytic study in which 225 pregnant women were surveyed using a semi structured questionnaire. Blood samples were taken and analysed qualitatively for HBsAg. The data were entered into Epi-data version 3.1 and exported into STATA version 17 for analysis, with a significance level set at <0.05.
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SeminarHepatitis B virus infection

Summary

Introduction

Section snippets

Epidemiology

Prevention

Diagnosis

Immunopathogenesis

Virology

Natural history

General

Search strategy and selection criteria

Lancet

Lancet

Ann Epidemiol

Clin Liver Dis

Transfus Clin Biol

J Hepatol

Vaccine

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

Gastroenterology

Gastroenterology

J Hepatol

Gastroenterology

Gastroenterology

Gastroenterology

J Hepatol

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

J Hepatol

Gastroenterology

J Hepatol

Clin Gastroenterol Hepatol

Lancet

Gastroenterology

Gastroenterology

Lancet

Gastroenterology

Hepatology

Gastroenterology

J Hepatol

Hepatitis B. Fact Sheet N°204

The state of hepatitis B and C in the Mediterranean and Balkan countries: report from a summit conference

J Viral Hepat

Global immunization data

Seroprevalence of chronic hepatitis B virus infection and prior immunity in immigrants and refugees: a systematic review and meta-analysis

PLoS One

The increasing burden of imported chronic hepatitis B—United States, 1974–2008

PLoS One

Vertical transmission of hepatitis B antigen in Taiwan

N Engl J Med

Antiviral therapy for chronic hepatitis B in pregnancy

Semin Liver Dis

Antibody levels and protection after hepatitis B vaccine: results of a 22-year follow-up study and response to a booster dose

J Infect Dis

Observational study of vaccine efficacy 24 years after the start of hepatitis B vaccination in two Gambian villages: no need for a booster dose

PLoS One

Chronic hepatitis B infection in adolescents who received primary infantile vaccination

Hepatology

Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study

J Natl Cancer Inst

Surveillance for acute viral hepatitis–United States, 2006

MMWR Surveill Summ

The prevalence of hepatitis B virus infection in the United States in the era of vaccination

J Infect Dis

Prevalence of hepatitis B virus infection in The Netherlands in 1996 and 2007

Epidemiol Infect

Should Europe have a universal hepatitis B vaccination programme?

BMJ

Seminar
Hepatitis B virus infection