Sage Journals: Discover world-class research

Abstract

Hepatitis B virus (HBV) is a small nonenveloped DNA virus that is a member of the Hepadnaviridae family. Chronic HBV infection is estimated to effect more than 350 million people worldwide with over 2 billion people being exposed to the virus. Risk factors for chronic infection include age of exposure to the virus, concurrent immunosuppression and HIV infection. Individuals chronically infected are 200 times more likely to develop hepatocellular carcinoma (HCC) than uninfected individuals and are at risk of developing cirrhosis and the risks of decompensated liver disease. This article focuses on the recent therapeutic advances that reduce the risk of developing these complications, those that prevent the spread of HBV and strategies for the prevention of post-liver-transplantation recurrence of HBV.

Keywords

chronic infection hepatitis B treatment

Natural history and molecular structure of the hepatitis B virus

The outcome following exposure to hepatitis B virus (HBV) is either clearance or persistence of HBV surface antigen. The latter state is referred to as chronic infection and is clinically defined as the presence of HBV surface antigen in the serum 6 months from the time of exposure.

Acute exposure may be asymptomatic (in up to 70%), but may also present as either an acute hepatitis or rarely as fulminant hepatic failure. The subsequent risk of chronic infection is determined by a number of factors of which the most important is the age of acquisition. Neonates born to mothers have a risk of developing chronic infection themselves of between 20% and 90% depending on the mother’s hepatitis B secreted e antigen (HBeAg) status and her level of HBV DNA viraemia [Del Canho et al. 1994]. Adult exposure usually leads to chronic infection in less than 5% of exposed individuals. It is ultimately the strength and breadth of both the innate and the subsequent adaptive immune response that will determine the host’s outcome. This in turn may be ultimately determined by host and viral genetic determinants [Chen et al. 2005].

The HBV virus is a member of the Hepadnaviridae family and is a 42–44 nm spherical structure that is encapsulated by hepatitis B surface antigen (HBsAg) embedded in a host-derived envelope membrane. This complex surrounds the nucleocapsid formed from hepatitis B core antigen (HBcAg). Within the nucleocapsid is the relaxed circular partially double stranded DNA viral genome (3.2 Kb) which is covalently linked to the viral polymerase (HBV polymerase) [Blum et al. 1989].

The HBV genome has four open reading frames (ORFs); preS1/pres2/S which encodes the surface proteins (L, M, S); precore/core which encodes the core and (nonstructural) secreted HBeAg; pol encoding the viral polymerase (with reverse transcriptase, DNA polymerase and RNAase activity); and X encoding the regulatory X protein. Sequencing of the HBV genome has divided the virus into eight different genotypes [Dandri and Locarnini, 2012].

The lifecycle of HBV involves the HBV virion binding to an as-yet unelucidated, hepatocyte-specific receptor. The nucleocapsid is then released into the cytoplasm and the HBV genome is transferred to the host cell nucleus where it is converted into covalently closed circular DNA (cccDNA). Replication of the HBV genome is an error-prone mechanism. Owing to an overlapping of the ORFs of the viral products, mutations in one opening frame can cause an amino acid substitution in a different viral protein product [Cheng et al. 2012].

Utilization of the host cellular transcription/translation machinery leads to production of the viral particle as well as noninfectious spherical and filamentous subviral particles (SVPs) that only contain the small HBV S protein.

HBV immunity and HBV viral escape

Hepatocellular injury in HBV is immune-mediated, with human leukocyte antigen (HLA) class I restricted CD8 cells recognizing HBV peptide fragments processed and presented on hepatocytes. Direct cell killing by CD8 cytotoxic T lymphocytes then occurs, in association with noncytolytic inhibition of virus replication. However, the activation of the CD8+ T-cell adaptive immune response only occurs once the innate immune system has recognized HBV along with assistance from activated CD4+ T cells. Several studies have highlighted the role of type 1 interferon (IFN) in the production of the antiviral state in acute HBV [Fletcher et al. 2012], with Toll-like receptors (TLRs) [Tjwa et al. 2012] mediating the production of IFN. HBeAg has been shown to induce a tolerogenic effect by acting as an immune decoy for the core antigen and also by downregulating cell signalling suppressing TLR-induced IFN beta activation [Visvanathan et al. 2007]. By mechanisms that are as-yet unclear, HBV-infected cells have been shown to have downregulation of signal transducer and activator of transcription-1, thereby reducing the antiviral state further [Lutgehetmann et al. 2011]. HBeAg is not alone in its immunomodulatory effects: Protein X downregulates mitochondrial antiviral signalling [Bouchard et al. 2003] by suppressing the retinoic acid inducible gene I (RIG-I) [Civril et al. 2011; Luo et al. 2011] and SVPs have been shown in vitro to inhibit TLR-9 mediated IFN alpha production by dendritic cells [Xie et al. 2009].

Phases of HBV infection

Chronic hepatitis B (CHB) natural history is regarded as consisting of four phases: immune tolerant (high DNA, HBeAg+, normal alanine transaminase [ALT]), immune clearance (HBeAg+, abnormal ALT, high DNA), inactive (low DNA, HBeAg–, normal ALT) and immune escape (HBeAg–, high DNA, abnormal ALT). Finally, HBsAg may be lost with or without the development of anti-HBs (1% of patients per year). The four phases are not sequential and any patient can move in any direction along the phases. Patients in immune clearance and immune escape phases are candidates for antiviral therapy, the aim being to prevent cirrhosis and development of hepatocellular carcinoma (HCC).

HBeAg seroconversion is predictive of a substantial reduction in HBV DNA levels, a decrease in intrahepatic inflammation and improved prognosis [Chen et al. 2002; Neiderau et al. 1996]. The level of HBV DNA is also thought to have prognostic value, as a chronically high level of HBV DNA is associated with an increased risk of progression to cirrhosis and HCC [Chen et al. 2011]. Whilst no threshold of HBV viraemia has been determined for predictive value of outcome at an individual level, a titre of 2000–20,000 IU/ml of HBV DNA is often recommended as a cut off [Chevaliez et al. 2012]. Hence, HBeAg seroconversion, a reduction in HBV DNA and HBsAg loss are important clinical treatment endpoints.

In the immune clearance/immune escape phases, therapy is often considered if the HBV DNA is >2000 IU/ml along with either an ALT > 2× the reference range or either moderate inflammation or moderate liver fibrosis on liver biopsy.

Prevention of hepatitis B

There are two important preventative measures that reduce the spread of HBV: prevention of transmission and immunization. In endemic areas these are in effect the same goal as the main mode of transmission is vertical. In nonendemic areas, such as the UK, education regarding high-risk behaviour avoidance is relatively more important.

Vaccination

HBV vaccines are currently derived from yeast using DNA recombinant technology (Engerix B®, Fendrix®, HBvaxPRO®). Around 10% of patients are hyporesponders (defined as not producing >100 Miu/ml anti-HBsAg titre). Hy-poresponse is associated with increasing age, the presence of renal failure [Fabrizi et al. 2012], certain HLA types and the method of vaccination (intramuscular < intradermal).

In terms of the burden of hepatitis B and the consequences of infection in childhood, the World Health Organization (WHO) has strongly recommended that all countries integrate HBV vaccination into their national immunization programmes [World Health Organization, 2010]. As of 2007 more than 88% of the WHO Health Assembly States had introduced an HBV vaccine and several countries have national goals for the elimination of HBV.

In the UK, whilst the Joint Committee on Vaccination and Immunisation (JCVI) recommends universal HBV vaccination [Lancet et al. 2012] it is only currently offered to children of HBsAg positive mothers (see see http://www.patient.co.uk/doctor/Hepatitis-B-Vaccination-and-Hepatitis-B-Prevention.htm and http://www.patient.co.uk/doctors/immunisation-schedule-(UK).htm) and those at high risk of HBV acquisition (Box 1).

Box 1.

Recommendations for hepatitis B vaccination (see http://www.patient.co.uk/doctor/Hepatitis-B-Vaccination-and-Hepatitis-B-Prevention.htm and http://www.patient.co.uk/doctors/immunisation-schedule-(UK).htm)

Healthcare workers

Carers of high-risk or known patients

Travellers to high-prevalence areas

High risk due to planned activities

Multiple changes in sexual partners

Travellers with comorbidities that may require medical procedures abroad

Injecting drug users

Partners and children of injecting drug users

Noninjecting drug users who live with injecting drug users

Individuals in residential accommodation for those with learning difficulties

Haemophiliacs requiring treatment

Patients who are receiving blood or blood products regularly

Prisoners and prison officers

Family contacts of those with chronic hepatitis b INFECTION

Patients with chronic kidney disease and chronic liver disease.

Prevention of vertical transmission

Up to 40% of those infected with hepatitis B worldwide have incurred transmission vertically (from mother to infant intrauterine, intrapartum or postpartum) [Shahnaz et al. 2005]. Children perinatally infected have also been shown to be a source of horizontal transmission to their siblings, especially when there are overcrowded living conditions [Agbede et al. 2007].

Passive–active immunoprophylaxis with HBV immunoglobulin and vaccination has been 70–90% effective in endemic areas [Eke et al. 2010; Zou et al. 2012; Chen, 2009]. Failure of this approach is directly related to the level of maternal viraemia [Wiseman et al. 2009]. HBV DNA concentrations >1×10⁸ copies/ml confer a 10% higher risk of transmission despite vaccination or immunoglobulin [Burk, 2004].

Telbivudine and tenofovir (category B drugs in pregnancy) have been examined with the aim of reducing vertical transmission. An open-label, prospective study of 88 HBeAg positive pregnant women with HBV DNA >1×10⁶ copies/ml were given either telbivudine or no treatment, starting from the second or third trimester and continuing until 28 weeks post partum. Of the telbivudine arm, none of the infants had immunoprophylaxis failure, compared with 8.6% of infants in the control arm. During the trial period there was no pregnancy or foetus-related adverse events [Pan et al. 2013]. A small case series of 11 women who received tenofovir in the third trimester of pregnancy showed similar findings [Pan et al. 2013]. Further larger, multicentre trials are required to confirm efficacy and safety.

Post liver transplantation

Another very important area of prevention is HBV prophylaxis after liver transplant. A systemic review in 2011 highlighted that the use of adefovir and hepatitis B immunoglobulin (HBIG) were more effective than lamivudine and HBIG use (alone or in combination) [Cholongitas et al. 2011]. However, a recent small single-centre study highlighted the effectiveness of tenofovir or entecavir monotherapy in 47 liver transplant recipients after HBIG withdrawal. Further larger trials are required [Cholongitas et al. 2012] to delineate the best treatment post orthotopic liver transplantation (OLT).

Current management of chronic HBV infection

The goal of treatment of CHB is to prevent cirrhosis, hepatic decompensation and HCC leading to an improved quality of life and survival. The ideal endpoint of therapy is HBsAg loss. However, this is an infrequent occurrence with current therapies. Other clinically important end points are biochemical remission, HBeAg seroconversion and induction of sustained virological remission (undetectable HBV viraemia). These secondary endpoints should lead to histological improvement and a reduction in risk of HCC. Drugs available for the treatment of CHB currently include IFN, pegylated IFN and six nucleos(t)ide analogues (NAs). Either drug class can be used in the different phases of infection.

Pegylated IFN

The goals with pegylated IFN therapy are either HBeAg seroconversion or an HBV DNA 12 months post treatment of <2000 IU/ml (if treating HBeAg-negative patients).

In a multicentre, randomized, partially double-blind study (67 sites, 16 countries), 814 patients with HBeAg-positive CHB were randomized to either pegylated IFN alpha 2a (PIFN) plus oral placebo, PIFN plus lamivudine, or lamivudine alone [Lau et al. 2005]. This study showed that PIFN or combination therapy at 72 weeks had a higher rate of HBV DNA suppression (32% and 34%, respectively) compared with lamivudine monotherapy (22%). In terms of HBsAg response, the rates of seroconversion were very low in all three arms and the rate of histologic response was similar.

Resistance to lamivudine occurred in 27% of the lamivudine monotherapy cohort compared with 4% of the combined cohort. A total of 41% of patients on PIFN alone had normalization of ALT by 72 weeks, as compared with 28% of patients on lamivudine monotherapy. This study observed greater HBeAg seroconversion by PIFN in genotype A disease.

The benefits therefore of PIFN include a defined period of therapy, a lower rate of viral resistance and the theoretical potential for immune-mediated virological control. In addition, there is a higher loss of HBsAg at 3–7%. It is however contraindicated in decompensated liver disease, autoimmune disease, uncontrolled severe depression/psychosis and pregnancy.

A 48-week course is mainly recommended for patients. Pretreatment factors for predicting HBeAg seroconversion include an HBV DNA <2×10⁸ copies/ml, high serum ALT (2–5× upper limit of normal [ULN]), HBV genotype (A/B > C/D) and moderate inflammation on liver biopsy. On-treatment predictors of seroconversion have also been identified. These include a fall in HBV DNA to <20,000 IU/ml at week 12, ALT flares with a fall in DNA, an HBsAg titre <1500 IU/ml at week 12 and possibly interleukin (IL)-28B polymorphisms (akin to HCV genotype one treatment).

Nucleos(t)ide analogues

Prolonged oral therapy with these agents has been proven to induce a reduction in HBV DNA resulting in an improvement in histology and liver biochemistry. For some patients this may lead to HBeAg seroconversion and possibly even HBsAg loss. The rates of these are shown in Tables 1 and 2, respectively, at 12 months into therapy. Nomenclature with regards to usage of these drugs is outlined in Box 2.

Table 1.

The 12-month treatment responses for clinical variables for patients treated with lamivudine, entecavir and telbivudine. Numbers in brackets are for patients who are hepatitis B virus (HBV) e antigen negative (HBeAg) who receive treatment.

Response parameter	Lamivudine	Entecavir	Telbivudine
Log reduction in HBV DNA, copies/ml	5.5	6.9	6.5
% Undetectable HBV DNA	36–44 (60–73)	67 (90)	60 (88)
% ALT Normalisation	41–55	68	77
% Loss of HBeAg	17–32	22	26
% HBeAg seroconversion	16–21	12–18	22
% Hepatitis B surface antigen (HBsAg) loss	< 1 (< 1)	2 (< 1)	< 1 (< 1)
% Histological improvement*	49–56 (60–66)	72 (70)	22
% Genotype resistance	27 (23)	0 (0.2)	< 1 (2.7)

Greater than 2-point decrease in necroinflammatory score and no worsening of fibrosis score.

Table 2.

The 12-month treatment responses for clinical variables for patients treated with adefovir and tenofovir. Numbers in parentheses are for patients who are hepatitis B virus (HBV) e antigen (HBeAg) negative who receive treatment.

Response parameter	Adefovir	Tenofovir
Log reduction in HBV DNA, copies/ml	3.5	6.2
% Undetectable HBV DNA	13–21 (51)	76 (93)
% Alanine transaminase (ALT) normalization	48–61	77
% Loss of HBeAg	24	21
% HBeAg seroconversion	12–18	21
% Hepatitis B surface antigen (HBsAg) loss	0 (< 1)	3 (0)
% Histological improvement	53 (64–69)	74 (72)
% Genotype resistance	0 (0)	0 (0)

Greater than z2-point decrease in necroinflammatory score and no worsening of fibrosis score.

Box 2.

Definitions of treatment response for use during treatment with either pegylated interferon or nucleos(t)ide analogues.

Biochemical response: the normalisation of alanine transaminase (ALT). As ALT fluctuates over time, EASL (European Association for the Study of the Liver) recommends 3-monthly ALT checks for a minimum of a year. Transient ALT elevations should prompt follow up of the ALT for 2 years to ensure sustained biochemical response.

Serological response for HBeAg (for HBeAg-positive chronic hepatitis B): seroconversion to anti-HBe and loss of HBeAg.

Serological response for hepatitis B surface antigen (HBsAg): HBsAg loss and development of anti-HBs.

Virological response:

Pegylated interferon therapy:

Primary nonresponse is not well established

Response is defined as hepatitis B virus (HBV) DNA concentration of less than 2000 IU/ml. DNA levels should be checked at 6 months and at the end of treatment, plus 6 months and 12 months thereafter.

Off-treatment virological response is defined at HBV DNA levels <2000 IU/ml 12 months after end of treatment.

Nucleos(t)ide analogues

Primary nonresponse: <1 log₁₀ reduction in HBV DNA from baseline at 3 months of therapy

Virological response: undetectable HBV DNA, usually tested every 3–6 months during therapy.

Partial virological response: >1 log₁₀ reduction in HBV DNA from baseline but still detectable after 6 months (in compliant patients)

Virologic breakthrough: increase in HBV DNA >1 log₁₀ higher than the nadir on therapy.

HBV resistance: selection of HBV variants with amino acid substitutions that confer resistance to nucleos(t)ide analogues. May result in primary nonresponse or virologic breakthrough.

Histological response: decrease in necroinflammatory activity (by >2 points in hepatic activity index (HAI) or Ischak’s system without worsening fibrosis compared with pretreatment histology.

Complete response: sustained off-treatment virological response plus loss of HBsAg.

As all of these drugs target the HBV polymerase, their prolonged may lead to viral resistance with a resultant rise in HBV DNA titres. For each class of drugs the cumulative incidence and respective mutations across the seven domains of the HBV polymerase are outlined in Figures 1 and 2, respectively.

Figure 1.

Cumulative incidences of hepatitis B virus (HBV) resistance to lamivudine (LAM), adefovir (ADV), entecavir (ETV), telbivudine (LdT) and tenofovir (TDF) in nucleos(t)ide-naïve patients.

Figure 2.

Hepatitis B virus (HBV) DNA polymerase gene mutations associated with resistance to nucleos(t)ide analogues [Yuen et al. 2007].

Lamivudine monotherapy has a high percentage of genotype resistance [Lok et al. 2000] over time and is therefore not recommended as first-line monotherapy. Telbivudine also has a low barrier to resistance, and despite the table results, high incidences of resistance have been seen in patients with a high baseline HBV DNA [Lai et al. 2007]. In one study virologic breakthrough and incidence of resistance in HBeAg positive patients1o be used as a single therapy on a long-term basis.

Entecavir has a high barrier to resistance. There have been several trials assessing the efficacy of entecavir. In one study [Ono et al. 2012] 474 CHB nucleos(t)ide-naïve patients were given entecavir with a follow up period to 4 years. The trial highlighted 96% undetectable HBV DNA, 42% HBeAg loss, 38% seroconversion and 93% ALT normalization by the fourth year. There was only a 0.4% resistance rate seen. No histological data were, however, available in this trial.

Entecavir is therefore recommended as monotherapy. Resistance is rare, but is more likely to occur if there is preceding lamivudine resistance. In addition, a higher dose of drug is needed if there is preceding lamivudine resistance.

As can be seen from Table 2, adefovir is less efficacious than tenofovir, with well-described resistance patterns (Box 2) and, hence, tenofovir is approved for single usage. Indeed in a large phase III study of nucleoside-naïve patients (both HBeAg positive and negative) randomly assigned to receive either tenofovir or adefovir on a 2:1 basis, 76% of the patients on tenofovir achieved undetectable HBV DNA, 68% had ALT normalization, 3% had HBsAg loss, 74% reduction >2 in their necroinflammatory score without worsening of their fibrosis and a 21% HBeAg seroconversion. It also highlighted a 3% virologic breakthrough at 144 weeks (associated with poor compliance) but not viral resistance [Snow-Lampart et al. 2011].

Special groups

Cirrhosis

The mortality from HBV cirrhosis is dependent on the degree of liver compensation and the presence of HCC. It is estimated that 5% of patients with cirrhosis decompensate each year. HBeAg positivity and HBV DNA replication are common in patients with liver cirrhosis, and increase the risk of decompensation, death and HCC. It is therefore proposed that HBV viral suppression would reduce the risks of these complications.

Indeed, a large case-control study assessed long-term outcomes and prognostic factors in HBV-related compensated cirrhosis [Kim et al. 2012]. There were 240 patients who were given NAs. Of these 78% had sustained viral suppression by 5 years, and the 5-year cumulative incidences of death, decompensation and HCC were 19.4%, 15.4% and 13.8%, respectively. These were all statistically significant values when compared with historical case controls.

The use of PIFN in advanced fibrosis and cirrhosis has been studied as a part of a randomised, multicentre trial looking at the safety and efficacy of PIFN [Buster et al. 2007]. This trial had 70 patients with advanced fibrosis (Ischak fibrosis score 4–6) and found a higher rate of HBeAg seroconversion than nonfibrotic patients (36% compared with 29%). However, PIFN is contraindicated in decompensated cirrhosis.

In summary, all patients with cirrhosis and detectable HBV DNA (at any level) should receive treatment.

Co-infections

Co-infection with human immunodeficiency virus (HIV) provides a unique challenge as the treatment of one has an impact on the other. The EPIB [Piroth et al. 2010] study provided good evidence that the early dual treatment of HBV and HIV regardless of immunological, virological or histological considerations gives a better outcome; therefore, the use of tenofovir and emtricitibine or lamivudine is recommended by the European Association for the Study of the Liver (EASL) [European Association for the Study of the Liver, 2012]. If HBV monotreatment is undergone in a dually infected patient, there is a significant risk of the development of HIV mutants and the above regimes that have a high barrier to resistance should be employed.

The management of co-infection with human delta virus (HDV) is difficult as there is a paucity of evidence for treatment paradigms. PIFN appears to work against it [Farci et al. 2004], however the duration of therapy to have a sustained off-treatment virological response is unclear. EASL guidelines state that more than 1 year of treatment may be necessary. NAs do not work against HDV. The diagnosis is often difficult with nonstandardized HDV RNA assays, and HDV antigen and IgM anti-HDV assays are not widely available.

Future developments

Clevudine is licensed in South Korea. In a 48-week follow up head-to-head comparison with entecavir, the reduction in viral load was similar for both drugs in HBeAg-positive and -negative patients, with a similar number reaching undetectable viral DNA levels. Clevudine however was associated with a higher virologic breakthrough rate and clinical myopathy [Shin et al. 2011]. This was further correlated in a 2-year follow up [Yoon et al. 2011].

MIV-210 a prodrug of 3′-fluoro-2′,3′-dideoxy-guanosine has been shown with woodchuck hepatitis virus to produce a rapid virological response and is currently undergoing further phase II trials [Michalak et al. 2009].

LB80380 is a nucleoside analogue that has been tested in 65 HBeAg-positive patients with lamivudine resistance. It was shown to be safe over 12 weeks [Yuen et al. 2010].

AGX-1009 is a prodrug of tenofovir that is currently completing preclinical trials in China, with an aim to start phase I trials in 2013.

Nonnucleos(t)ide antivirals that are in current phase II trials include Myrcludex B, which is an entry inhibitor shown to prevent viral spread among human hepatocytes in UPA mice [Barek et al. 2011]. Other interesting compounds in phase I trials include Bay 41-4109, which is a heteroaryldihydropyrimidine (HAP) antiviral compound that accelerates and misdirects viral capsid production, leading to unstable viral capsid production [Stray and Zlotnick, 2006]. Rep 9AC which is an HBsAg release inhibitor is undergoing a proof-of-concept trial to show it can elicit a sustain virological response [Al-Mahtab et al. 2011] and nitazoxanide has been shown to modulate host antiviral pathways via activation of a protein kinase involved in cellular antiviral response.

Finally, immune modulators such as IL-7, GS9260 (a TLR7 agonist) are still in phase I trials, but there is more evidence for their use in T-cell reconstitution in the treatment of HIV [Levy et al. 2012].

Summary

These are exciting times with regard to the pathobiology of hepatitis B and the new virologic tools becoming available to allow for more exacting standards of care. The greater understanding of this virus, with the technology and drugs with better resistance profiles, should allow for a reduction in cirrhosis and the development of HCC in patients with CHB infection.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare no conflict of interest in preparing this article.

References

Agbede

O.O.

Iseniyi

J.O.

Kolawole

M.O.

Ojuwo

(2007) Risk factors and seroprevalence of hepatitis B surface antigenaemia in mothers and their pre-school age children in Ilorian, Nigeria. Future Medicine 4: 67–72.

Al-Mahtab

Bazinet

Vaillant

(2011) Rep 9AC is a potent HBsAg release inhibitor which clears serum HBsAG and elicits SVRs in patients with Chronic Hepatitis B. EASL Oral presentation.

Barek

Volt

Lutgehetmann

Allweiss

Warlich

Lohse

A.W.

(2011) Administration of the entry inhibitor myrcludex-B after establishment of hepatitis B virus infection prevents viral spreading among human hepatocytes in UPA mice. EASL Oral presentation.

Blum

H.E.

Gerok

Vyas

G.N.

(1989) The molecular biology of Hepatitis B Virus. Trends Genet 5: 154–8.

Bouchard

M.J.

Puro

R.J.

Wang

(2003) Activation and inhibition of cellular calcium and tyrosine kinase signalling pathways identify targets of the HBx protein involved in hepatitis B virus replication. J Virol 77: 7713–9.

Burk

R.D.

Hwang

L.Y.

G.Y.

Shafritz

D.A.

Beasley

R.P.

(1994) Outcome of perinatal hepatitis B virus exposure is dependant on maternal virus load. J Infect Dis 170: 1418–1423.

Buster

E.H.

Hansen

B.E.

Buti

Delwaide

Niederau

Michielsen

P.P.

. (2007) Peglyated interferon alpha 2b is safe and effective in HBeAg positive chronic hepatitis B patients with advanced fibrosis. Hepatology 46: 388–394.

Chen

C.F.

Lee

W.C.

Yang

H.I.

Chang

H.C.

Jen

C.L.

Iloeje

U.H.

. (2011) Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma. Gastroenterology 141: 1240–1248.

Chen

D.S.

(2009) Hepatitis B vaccination: the key towards elimination and eradication of hepatitis B. J Hepatology 50: 805–16.

10.

Chen

Sallberg

Hughes

Jones

Guidotti

L.G.

Chisari

F.V.

. (2005) Immune tolerance split between hepatitis B virus precore and core proteins. J Virol 79: 3016–27.

11.

Chen

Y.C.

Sheen

I.S.

Chu

C.M.

Liaw

Y.F.

(2002) Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology 123: 1084–9.

12.

Cheng

C.P.

Lee

P.F.

Liu

W.C.

(2012) Analysis of precore/core covariances associated with viral kinetics and genotypes in hepatitis B e antigen-positive chronic hepatitis B patients. PLoS One 7: e32553 (epub ahead of print Feb 27 2012).

13.

Chevaliez

Rodriguez

Pawlotsky

J.M.

(2012) New virologic tools for management of hepatitis B and C. Gastroenterology 142: 1303–13.

14.

Cholongitas

Goulis

Akriviadis

Papatheodoridis

G.V.

(2011) Hepatitis B immunoglobulin and/or nucleos(t)ide analogues for prophylaxis against hepatitis B virus recurrence after liver transplantation: a systematic review. Liver Transpl 17: 1176–1190.

15.

Cholongitas

Vasiliadis

Antoniadis

Goulis

Papanikolaou

Akriviadis

(2012) Hepatitis B prophylaxis post liver transplantation with newer nucleos(t)ide analogues after hepatitis B immunoglobulin discontinuation. Transpl Infect Dis 14: 479–87.

16.

Civril

Bennett

Moldt

Deimling

Witte

Schiesser

. (2011) The RIG-1 ATPase domain structure reveals insights into ATP-dependent antiviral signalling. EMBO Rep. 12: 1127–34.

17.

Dandri

Locarnini

(2012) New insight in the pathobiology of hepatitis B virus infection. Gut 61 (suppl 1): i6–17.

18.

Del Canho

Grosheide

P.M.

Schalm

S.W.

de Vries

R.R.

Heijtink

R.A.

(1994) Failure of neonatal hepatitis B vaccination: the role of HBV-DNA levels in hepatitis B carrier mothers and HLA antigens in neonates. J Hepatol 20: 483–486.

19.

Eke

A.C.

Eke

U.A.

Uchenna

(2010) Hepatitis B immunoglobulin during pregnancy for the prevention of mother to child transmission of hepatitis B virus. (Protocol) Cochrane collaboration.

20.

European Association for the Study of the Liver (2012) EASL Clinical Practice Guidelines: Management of chronic Hepatitis B virus infection. J Hepatology 57: 167–85.

21.

Fabrizi

Dixit

Martin

Messa

(2012) Erythropoeitin use and immunogenicity of Hepatitis B vaccine in chronic kidney disease patients: a meta analysis. Kidney Blood Press 14: 504–510.

22.

Farci

Roskams

Chessa

Peddis

Mazzoleni

A.P.

Scioscia

. (2004) Long term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology 126: 1740–9.

23.

Fletcher

S.P.

Chin

D.J.

Cheng

D.T.

Ravindran

Bitter

Gruenbaum

. (2013) Identification of an intrahepatic transcriptional signature associated with self-limiting infection in the woodchuck model of hepatitis B. Hepatology doi: 10.1002/hep.25954 (epub ahead of print).

24.

Joint Committee on Vaccination and Immunisation. (2012) JCVI response on Hepatitis B vaccination. Lancet 379: 803.

25.

Kim

Seo

Jung

JY.

Kim

J.D.

Yim

H.J.

. (2012) The prognosis of hepatitis B-related liver cirrhosis in the era of oral nucleos(t)ide analog antiviral agents. J Gastroenterol Hepat 27: 1589–95.

26.

Lai

C.L.

Gane

Liaw

Y.F.

Hsu

C.W.

Thongsawat

Wang

. (2007) Telbivudine vs lamivudine in patients with chronic hepatitis B. NEJM 357: 2576–88.

27.

Lau

Piratvisuth

Luo

Marcellin

Thongsawat

Cooksley

. (2005) Peginterferon Alfa 2a, Lamivudine and the combination for HBeAg-positive chronic hepatitis B. NEJM 352: 2682–95.

28.

Levy

Sereti

Tambussi

Routy

J.P.

Lelievre

J.D.

Delfraissy

J.F.

. (2012) Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV- infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo controlled, multicenter study. Clin Infect Dis 15: 291–300.

29.

Lok

A.S.

Hussain

Cursano

Margotti

Gramenzi

Grazi

GL.

. (2000) Evolution of hepatitis B polymerase gene mutations in hepatitis B e antigen-negative patients receiving lamivudine therapy. Hepatology 32: 1145–53.

30.

Luo

Ding

S.C.

Vela

Kohlway

Lindenbach

B.D.

Pyle

A.M.

(2011) Structural insights into RNA recognition by RIG-1. Cell 147: 409–22.

31.

Lutgehetmann

Bornscheuer

Volz

Allweiss

Bockmann

J.H.

Pollok

J.M.

. (2011) Hepatitis B virus limits response of human hepatocytes to interferon-alpha in chimeric mice. Gastroenterology 140: 2074–83.

32.

Michalak

Zhang

Churchill

N.D.

Larsson

Johansson

N.G.

Oberg

(2009) Profound antiviral effect of oral administration of MIV-210 on chronic hepadnaviral infection in a woodchuck model of hepatitis B. Antimicrobial Agents Chemother. 53: 3803–14.

33.

Neiderau

Heintges

Lange

Goldmann

Niederau

C.M.

Mohr

. (1996) Long term follow up of HBeAg-positive patients treated with interferon alpha for chronic hepatitis B. NEJM 334: 1422–7.

34.

Ono

Suzuki

Kamamura

Sezaki

Hosaka

Akuta

(2012) Long term continuous entecavir therapy in nucleos(t)ide naive chronic hepatitis B patients. J Hepatol 57: 508–14.

35.

Pan

C.Q.

Han

G.R.

Jiang

H.X.

Zhao

Cao

M.K.

Wang

C.M.

. (2012) Telbivudine prevents vertical transmission from HBeAg-positive women with chronic hepatitis B. Clinical Gastroenterol Hepatol 10: 520–26.

36.

Pan

C.Q.

Bunchorntavakul

Karsdon

Huang

W.M.

Singhvi

. (2012) Tenofovir disoproxil fumarate for prevention of vertical transmission of hepatitis B virus infection by highly viraemic pregnant women: a case series. Dig Dis Sci 57: 2423–9.

37.

Piroth

Pol

Lacombe

Miailhes

Rami

Rey

. (2010) Management and treatment of chronic hepatitis B virus infection in HIV positive and negative patients: the EPIB 2008 study. J Hepatology 53: 1006–12.

38.

Shahnaz

Reza

Seyed-Moayed

(2005). Risk factors in chronic hepatitis B infection: a case control study. Hepatitis Monthly 5: 109–15.

39.

Shin

S.R.

Yoo

B.C.

Choi

M.S.

Lee

D.H.

Song

S.M.

Lee

J.H.

. (2011) A comparison of 48-week treatment efficacy between clevudine and entecavir in treatment-naïve patients with chronic hepatitis B. Hepatol Int. 5: 664–70.

40.

Snow-Lampart

Chappell

Curtis

Zhu

Myrick

Schawalder

. (2011) No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of therapy in patients monoinfected with chronic hepatitis B virus. Hepatology 53: 763–73.

41.

Stray

Zlotnick

(2006) Bay 41-4109 has multiple effects on Hepatitis B virus capsid assembly. J Molec Recognit. 19: 542–8.

42.

Tjwa

E.T.

van Oord

G.W.

Biesta

P.J.

Boonstra

Janssen

H.L.

Woltman

A.M.

(2012) Restoration of TLR3-activated myeloid dendritic cell activity leads to improved natural killer cell function in chronic hepatitis B virus infection. J Virol 86: 4102–9.

43.

Visvanathan

Skinner

N.A.

Thompson

A.J.

Riordan

S.M.

Sozzi

Edwards

. (2007) Regulation of toll-like receptor2 expression in Chronic Hepatitis B by the precore protein. Hepatology 45: 102–10.

44.

World Health Organisation (2010) Sixty-third World Health Assembly. Viral Hepatitis. Report by the Secretariat.

45.

Wiseman

Fraser

M.A.

Holden

Glass

Kidson

B.L.

Heron

L.G.

. (2009) Perinatal transmission of hepatitis B virus: an Australian experience. Med J Aust 190: 489–92.

46.

47.

48.

Xie

Shen

H.C.

Jia

N.N.

Wang

Lin

L.Y.

B.Y.

. (2009) Patients with chronic hepatitis B infection display deficiency of plasmacytoid dendritic cells with reduced expression of TLR9. Microbes Infect 11: 515–23.

49.

Yoon

E.L.

Yim

H.J.

Lee

H.J.

Lee

Y.S.

Kim

J.H.

Jung

E.S.

. (2011) Comparison of clevudine and entecavir for treatment naïve patient with chronic hepatitis B virus infection: two year follow up data. J Clin Gastroenterol 45: 893–9.

50.

Yuen

Bartholomeusz

Ayres

Littlejohn

Locarnini

(2007) Multidrug resistance and cross resistance pathways in HBV as a consequence of treatment failure. Hepatology 46 (S1): Abstract #949.

51.

Yuen

Han

Yoon

S.K.

Kim

H.R.

Kim

. (2010) Antiviral activity and safety of LB80380 in Hepatitis B e antigen–positive chronic hepatitis B patients with lamivudine-resistant disease. Hepatology 51: 767–76.

52.

Zou

Chen

Duan

Zhang

Pan

(2012) Virological factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAg-positive mothers. J Viral Hepatitis 19: e18–25.

Therapeutic advances in the management of chronic hepatitis B infection

Abstract

Keywords

Natural history and molecular structure of the hepatitis B virus

HBV immunity and HBV viral escape

Phases of HBV infection

Prevention of hepatitis B

Vaccination

Box 1.

Prevention of vertical transmission

Post liver transplantation

Current management of chronic HBV infection

Pegylated IFN

Nucleos(t)ide analogues

Box 2.

Special groups

Cirrhosis

Co-infections

Future developments

Summary

Footnotes

Funding

Conflict of interest statement

References