Optimal management of hepatitis B virus infection – EASL Special Conference

doi:10.1016/j.jhep.2015.06.026

Journal of Hepatology

Volume 63, Issue 5, November 2015, Pages 1238-1253

https://doi.org/10.1016/j.jhep.2015.06.026 Get rights and content

Summary

There have been great strides in the management of chronic hepatitis B virus (HBV) infection, but considerable challenges remain. The European Association for the Study of the Liver (EASL) convened a special conference focusing on all clinical aspects of the management of this disease.

Immigration patterns are having a huge effect on the incidence, prevalence and genotype predominance of HBV in many European countries. In recent years there has been significant progress in our understanding of the virology and immunopathology of HBV, particularly the identification of the entry receptor for HBV conferring its hepatotropism, sodium taurocholate co-transporting polypeptide, and a better understanding of the regulation of the covalently closed circular DNA form of HBV – the major barrier to cure. However, more fundamental scientific research is needed.

Serum biomarkers and transient elastography offer equivalent performance in the grading of disease stage and progression and monitoring of treatment. Occult HBV infection is often overlooked, but has many important implications for e.g., immuno-suppression, liver transplantation and the progression and severity of liver diseases from other causes.

Hepatitis B e antigen positive immunotolerant patients, who are a significant source of horizontal and vertical transmission, are at risk for developing active chronic hepatitis B, but current treatment options are ineffective. Pegylated interferon therapy, given for a finite duration, offers sustained off-treatment responses in a minority of patients. Nucleos(t)ide analogues suppress the virus, improve liver histological lesions, reverse cirrhosis in the majority of cases, and improve survival, but ‘cure’ cannot be achieved. There is also a pressing need for novel HBV/hepatitis D virus co-infection therapies. Novel therapeutic strategies, e.g. immunomodulation, RNA interference and viral entry inhibition have demonstrated promising early results.

Introduction

The European Association for the Study of the Liver (EASL) Special Conference on hepatitis B virus (HBV) held in Athens in September 2014 brought together internationally-leading scientists and clinicians for a comprehensive overview of the current state-of-the-art management of chronic HBV (CHB) infection. Galvanised by recent advances in hepatitis C cure, the focus was on how to further optimise the treatment of HBV. How could a better understanding of the epidemiology, natural history, virology and immunology be applied to the development of new approaches to screening, monitoring, prevention and therapy? What are the public health and cost implications of more widespread screening, prophylaxis of groups at risk of de novo infection or reactivation, and treatment? Which biomarkers are most informative to monitor disease progression and therapy response? What are the major barriers to cure and can novel combinations of existing drugs or new virological or immunological tactics be developed to overcome these? Here we briefly summarise each of the presentations addressing these topical controversies as a further step towards the optimal management of HBV.

Section snippets

Epidemiology, public health, and burden of disease

In this initial session, there were four presentations: on the changing HBV epidemiology by Alfredo Alberti, the barriers to diagnosis and treatment in Europe and Asia by Emmanuel Tsochatzis and Sang-Hoon Ahn, respectively, and the possibility of global HBV eradication by Mark Thursz.

Alfredo Alberti from Italy stressed that HBV, as with any infectious disease, is dynamic, making it very difficult to obtain a robust understanding of epidemiology. Several factors are thought to contribute to the

Virology and immunopathogenesis

There were five presentations in this session: on new insights into HBV entry and replication by Maura Dandri, the HBV genotypes and mutations by Stephen Locarnini, immune responses in HBV infection by Carlo Ferrari, interactions between HBV, host immunity and the liver by Percy Knolle and the possible need for reclassification of the CHB phases based on immunopathology by Antonio Bertoletti.

According to Maura Dandri from Germany, the entry of HBV into the host cell is a complex, multi-stage

Natural history

There were six presentations on the natural history and particularly on the natural course of HBV infection and predictors of disease progression and HCC in Western and Eastern countries by Giovanna Fattovich and Yun-Fan Liaw, respectively, the role of host genomics on the natural course by Jia-Horng Kao, the role of non-invasive markers in CHB infection by Laurent Castera, the indications and cost/effectiveness of HCC surveillance by Massimo Colombo and the clinical significance of occult HBV

Treatment indications, endpoints, and options

There were five presentations on this session: on the international guidelines on the optimal follow-up for untreated patients, treatment indications and therapeutic endpoints by Spilios Manolakopoulos, the pros and cons of treating HBeAg positive with normal ALT immunotolerant patients by Thomas Berg and Teerha Piratvisuth, respectively, the mechanisms of actions of IFN-α and NAs by Georgios Germanidis and the possibility of HBsAg and cccDNA clearance by Massimo Levrero.

Spilios Manolakopoulos

Optimal treatment for chronic hepatitis B

Six presentations focused on the optimal treatment of CHB and particularly on the optimal use of pegylated interferon (PegIFN) for HBeAg positve and HBeAg negative CHB by Harry Janssen and Mauricia Brunetto, NAs as first-line therapy for CHB by Seng Gee Lim, management of NAs failures by Fabien Zoulim, safety and monitoring during long-term NAs therapy by Maria Buti and cost-effectiveness of current therapeutic options by Kostas Athanasakis.

According to Harry Janssen from Canada, approximately

Challenges for the current treatment options

Five presentations discussed the current challenges in the treatment of CHB. In particular, the possibilities of NAs discontinuation was discussed by Anna Lok, whether cirrhosis can be really reversed by Pierre Bedossa, the remaining challenges in the management of decompensated cirrhosis by Cihan Yurdaydin and whether treatment reduces the HCC risk in Western and Eastern countries by Ray Kim and Henry Chan, respectively.

Anna Lok from the USA proposed that the best and safest stopping rule for

Special groups

The optimal management of six HBV special groups was discussed, with presentations on reactivation of HBV in immunosuppressed patients by Evangelos Cholongitas, post-transplant patients by Didier Samuel, pregnant women by Ulus Akarca, severe acute hepatitis B by Bulent Degertekin, hepatitis B and D co-infection by Markus Cornberg (on behalf of Heiner Wedemeyer) and hepatitis B and C co-infection by Stanislas Pol.

Evangelos Cholongitas from Greece gave a presentation on optimal HBV prophylaxis in

Future treatment options

Finally, four presentations focused on future treatment options and particularly on the role of PegIFN and NA combinations by Jörg Petersen, the role of dual NA combinations by Markus Cornberg, novel virological approaches by Stephen Urban and novel immunological approaches by Michael Roggendorf Jörg Petersen from Germany discussed studies in mice with humanised livers (uPA mice) infected with HBV, and in patients suggesting that NAs and PegIFN may have additive or even synergistic effects

Conflicts of interest

P. Lampertico: speaking bureau/advisor for Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Roche.

M. Maini: advisory boards, educational committees and consultancy/contract work for Bristol-Myers Squibb, Gilead, Roche, MedImmune, Transgene, ITS.

G.V. Papatheodoridis: advisor/lecturer for Abbott/Abbvie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, Roche; research grants from Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Roche;

Financial support

MKM is funded by a Wellcome Trust Investigator Award and MRC grants.

Authors’ contributions

P. Lampertico: Conception and design of the manuscript; Drafting and revision of the manuscript; Approval of the final version of the manuscript.

M. Maini: Conception and design of the manuscript; Drafting and revision of the manuscript; Approval of the final version of the manuscript.

GV Papatheodoridis: conception and design of the manuscript; Drafting and revision of the manuscript; Approval of the final version of the manuscript.

Acknowledgements

The authors would like to thank the EASL office for organising this meeting and Ross Piper PhD for medical writing of the initial draft of this manuscript.

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ReviewOptimal management of hepatitis B virus infection – EASL Special Conference

Summary

Introduction

Section snippets

Epidemiology, public health, and burden of disease

Virology and immunopathogenesis

Natural history

Treatment indications, endpoints, and options

Optimal treatment for chronic hepatitis B

Challenges for the current treatment options

Special groups

Future treatment options

Conflicts of interest

Financial support

Authors’ contributions

Acknowledgements

Vaccine

Lancet

Lancet

J Hepatol

Gastroenterology

Mol Ther Nucleic Acids

Cell Rep

Gastroenterology

J Hepatol

J Hepatol

J Hepatol

Lancet

J Hepatol

Gastroenterology

Gastroenterology

Gastroenterology

J Hepatol

J Hepatol

Dig Liver Dis

J Hepatol

J Hepatol

Hepatology

J Hepatol

J Hepatol

J Hepatol

Gastroenterology

J Hepatol

Lancet

Gastroenterology

J Hepatol

J Hepatol

Dig Liver Dis

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

PLoS One

Changing epidemiology of hepatitis B and migration—a comparison of six Northern and North-Western European countries

Eur J Public Health

Barriers to care and treatment for patients with chronic viral hepatitis in Europe: a systematic review

Liver Int

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

J Viral Hepat

Molecular and clinical characteristics of hepatitis B virus in Korea

J Med Virol

HBV genotypes: relevance to natural history, pathogenesis and treatment of chronic hepatitis B

Antivir Ther

Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma

Gut

Efficacy and effectiveness of infant vaccination against chronic hepatitis B in the Gambia Hepatitis Intervention Study (1986–90) and in the nationwide immunisation program

BMC Infect Dis

Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans

Hepatology

Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus

Elife

Hepatitis B virus requires intact caveolin-1 function for productive infection in HepaRG cells

J Virol

Regulation of hepatitis B virus infection by Rab5, Rab7, and the endolysosomal compartment

J Virol

Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA

Science

IFN-alpha inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome

J Clin Invest

Genotypes and genetic variability of hepatitis B virus

Intervirology

The host-pathogen interaction during HBV infection: immunological controversies

Antivir Ther

Review
Optimal management of hepatitis B virus infection – EASL Special Conference