Background
It has been more than 50 years since the discovery of the Australia antigen which led to the identification of the Hepatitis B virus (HBV) [1, 2], and although there are effective treatments, no cure for this viral infection has yet been found. The HBV infects the liver causing acute and chronic inflammation, fibrosis, cirrhosis of the liver, hepatocellular carcinoma (HCC), and eventually death. Despite the fact that HBV can be effectively prevented through vaccination, an estimated 240 – 350 million people worldwide are chronically infected with HBV [3, 4], with 2.2 million living in the United States [5]. Current standard of care requires life-long treatment, not optimally accessible in many regions, making the search for a cure to this epidemic an urgent public health priority.
With the breakthroughs in Hepatitis C treatment (HCV) and cure [6, 7], industry, academia and patient communities shifted attention to find similarly effective therapeutic and curative alternatives for HBV [8]. However, the elimination of HBV in people who are chronically infected is challenging. The ultimate goal of HBV cure would be the eradication of cccDNA, also described as “absolute cure” [2]. Although in practice this is yet impossible [9], a functional cure, in which the patient returns to a state of health equivalent to that of a person who has recovered from HBV infection [1], may be achievable through other approaches [1, 9, 10], and may represent the first step towards the longer term goal of absolute cure.
The interest of pharmaceutical companies in developing new treatments and curative strategies is high, but the field remains challenged by the complexity of the approaches needed to achieve functional and/or absolute cures and the resulting implications for regulatory strategies. Stakeholders need a mechanism to advance the regulatory science for this field and increase the efficiency of drug development through evolving consensus and increasing clarity. Networking and opportunities for collaboration among all interested parties are key to reducing inefficiencies in processes such as biomarker identification, validation and acceptance.
The interest of pharmaceutical companies in developing new treatments and curative strategies is high, but the field remains challenged by the complexity of the approaches needed to achieve functional and/or absolute cures and the resulting implications for regulatory strategies. Stakeholders need a mechanism to advance the regulatory science for this field and increase the efficiency of drug development through evolving consensus and increasing clarity. Networking and opportunities for collaboration among all interested parties are key to reducing inefficiencies in processes such as biomarker identification, validation and acceptance.
The HBV Forum aims to advance the regulatory science for novel HBV therapeutic interventions and its associated morbidities in real time by providing an independent and neutral environment for ongoing multi-stakeholder dialogue. The goals of the HBV Forum are to:
- provide scientific guidance to facilitate discussion between the industry, regulatory bodies, the academic and patients’ communities and community advocates in the areas of HBV drug and diagnostic development, and
- facilitate evolving consensus, based on real-time scientific development in the areas of appropriate methodologies for novel therapeutic approaches, clinical trial design and standardization of definitions.
The Objectives of the HBV Forum are to:
- Provide a platform for ongoing and systematic dialogue to address the most relevant issues on innovative therapeutic and curative interventions.
- Produce recommendations, based on ongoing scientific review, to inform the regulatory path decision-making process; and
- Participate and collaborate with other initiatives to contribute to the advancement of the regulatory science of novel HBV therapeutic approaches.
Action Plan
The HBV Forum is led by a Steering Committee and managed by Forum staff. The HBV Forum meets regularly with topic-specific working group conference calls and email/web-based communication and in-person meetings, as appropriate, in the intervening time.
| EVENT | LOCATION | DATE | MATERIALS |
| HBV Forum 1 |
Boston, MA |
November 15, 2016 |
https://bit.ly/3lcDF3b |
| HBV Forum 2 |
Amsterdam, the Netherlands |
April 18, 2017 |
https://bit.ly/3AbGu8P |
| HBV Forum 3 |
Washington, DC |
October 24, 2017 |
https://bit.ly/3iz3qcm |
| HBV Forum 4 |
Paris, France |
April 2018 |
|
| HBV Forum 5 | Vienna, Austria | April 10, 2019 | https://bit.ly/2Yqj9U5 |
| HBV Forum 6 |
Boston, MA |
November 7, 2019 |
https://bit.ly/3BsEfzD |
| HBV Forum 7: Safety Panel | Virtual webinar | July 22, 2020 | https://bit.ly/3DfaRNK |
| HBV Forum 7: Intrahepatic Webinar | Virtual webinar | September 24, 2020 | https://bit.ly/2WHi5u4 |
| HBV Forum Stopping NUCs in Drug Development | Virtual webinar | July 14, 2021 | https://bit.ly/2YwgBng |
| HBV Forum Therapuetic Vaccines Webinar | Virtual webinar | January 18, 2022 | https://bit.ly/3N8N7QR |
| HBV Forum 8 | London, UK | June 21, 2022 |
HBV Forum members are recruited from regulatory and federal agencies, academia, professional societies, patient organizations, advocacy communities, and industry. The HBV Forum is open to all pharmaceutical, biotech and diagnostic companies involved in relevant clinical research, with industry members asked to contribute to the Forum's financial needs.
Treatment
- Should people with immune tolerant disease or with HBeAg negative disease who are considered inactive be included in clinical trials with novel agents?
- Should they be included in current clinical trials and what is the long-term clinical benefit?
- What are the surrogate endpoints or long-term clinical outcomes?
- When to stop treatment (and potentially re-initiation of treatment)?
- What is an acceptable benefit-risk profile to support a development program?
- What are efficient models for monitoring long-term safety?
- When is it appropriate to start testing combination regimen and different therapeutic strategies?
- What is the goal of therapeutic vaccines moving forward?
Clinical Trials
- What are appropriate clinical trial designs for different interventions?
- What are appropriate populations to enroll?
- Inclusion and exclusion criteria for enrollment
- What are appropriate and acceptable control groups and comparator regimen?
- When is it appropriate to study combination regimens with different targets?
- What are the challenges for clinical trial design in the global setting, under different regulatory jurisdictions and standards of care?
- What are the regulatory expectations for post-marketing evaluations?
Endpoints
- Do current biomarkers accurately reflect disease progression and clearance?
- Is there room for improvement?
- Primary efficacy endpoints – HBV DNA suppression?
- Monitoring of HBsAg levels
- HBsAg clearance or seroconversion
- Durability of response
- What is needed for validating and accepting different endpoints for evaluating short and long-term treatment goals?
- What are the collaborative opportunities for improving the efficiency of regulatory acceptance of biomarkers and surrogate endpoints?
Working groups
Working groups have been developed to carry on the work of the HBV Forum by addressing priority areas identified by both the steering committee and HBV Forum members. Expected outcomes of the working groups include recommendations, position papers, reports, manuscripts for submission to peer-reviewed journals, and presentations at conferences. Throughout the year, working groups communicate and collaborate by conference calls, email, in-person meetings, and workshops as needed. There is no time requirement for participation; however, working group members are expected to be active participants and participate in as many calls and activities as possible.
In progress:
- Capsid Assembly Modulators- Aims: To create a joint statement on behalf of both the HBV Forum and ICE-HBV regarding how to standardize CAM nomenclature and promote consensus within the field.
- Stopping Treatment: This working group will examine stopping treatment (and potentially re-initiation of treatment) by highlighting key points of uncertainty, laying out the challenges and developing a framework, discussing important considerations for patient safety endpoints, considering different stopping rules for different modes or classes of drugs, exploring criteria for re-initiation of treatment, and/or discussing whether standardization and a strict consensus is possible.
- Evaluating Different Mechanisms of Action in the Right Populations: This group will aim to take a mechanisms approach in determining considerations for matching the “right” treatments for the “right” populations of Hepatitis B patients, in order to ensure that different therapies are being studied in appropriate ways.
- HDV Co-Infection: To further advance the HDV co-infection field through a focus on clinical and regulatory considerations, including a discussion on screening, diagnostics especially as it relates to HDV RNA assays, and endpoints.
Completed: The following working groups are no longer active as their goals have been met
- Immune Monitoring: Co-chairs Adam Gehring, PhD and Patricia Mendez, MD. Aims: i) identify a minimum set of basic assays, and the protocols to implement them to facilitate cross-trial and cross-study comparison; ii) consider to what extent assay standardization recommendations can be made to complement the work of ICE-HBV on standardization of reagents; iii) identify biomarkers for immune-based interventions that predict effective immunological control or, toxicity; and iv) identify biomarkers that stratify specific groups of patients more likely to respond to different immune-based interventions. This group is working to facilitate data acquisition from clinical trials for the use of developing models to aid in drug development for HBV
- Surrogate Endpoints: Co-chaired by Marion Peters, MD and Oliver Lenz, PhD. Aim: Strengthen the link of surrogate markers (endpoint in clinical studies) with long terms clinical outcomes; e.g. liver disease progression/HCC
- Diagnostics/Biomarkers sub Working Group: Co-chaired by Ed Marins, MD and Gavin Cloherty, MD. The working group aimed to develop clarity on what is needed for biomarker acceptance and validation for HBV drug/diagnostic development. The working group charge has been achieved and is in quiescent mode and to be reactivated once sufficient new science and data warrant this step.
- Treatment Combination: Co-chaired by Prof. Lim Seng Gee, MD and Bruce Given, MD. Aims: i) provide clarity on the requirements of novel agents in clinical development, and ii) identify mechanisms to speed up the development of combination of different promising agents across companies. The working group charge has been achieved and is in quiescent mode and will be reactivated once sufficient new science and data warrant this step.
- Liver Safety Monitoring sub Working Group: Co-chaired by Robert Fontana, MD and Maria Beumont-Mauviel. Aim: to facilitate HBV drug development by developing consensus terminology and definitions for industry, regulators, and investigators to use when testing the safety and efficacy of novel therapeutic agents for chronic HBV when used alone or in combination with other investigational or approved anti-HBV agents.
The HBV Forum has developed or is developing the following manuscripts for peer-reviewed publication:
| MANUSCRIPT DETAILS | WORKING GROUP | STATUS |
| Advancing the regulatory path on hepatitis B virus treatment and curative research: a stakeholders’ consultation (11) | HBV Forum |
Journal of Virus Eradication. 2017;3 |
| Inventory of diagnostics approval status by US-FDA and the EU | Diagnostics and Biomarkers |
|
| Association between HBsAg loss and long-term clinical outcome in chronic hepatitis B: a systematic review and meta-analysis. | Surrogate Endpoints |
Late-breaking abstract 5256. EASL 2019 |
| Association between HBsAg loss and risk of hepatocellular carcinoma in chronic hepatitis B: a systemic review and meta-analysis | Surrogate Endpoints | |
| Association Between Seroclearance of Hepatitis B Surface Antigen and Long-term Clinical Outcomes of Patients With Chronic HBV Infection: Systematic Review and Metaanalysis |
Surrogate Endpoints |
|
| Challenges, Considerations, and Principles to Guide Trials of Combination Therapies for Chronic Hepatitis B Virus | Treatment Combination Working Group |
https://www.gastrojournal.org/article/S0016-5085(18)35378-2/fulltext?referrer=https%3A%2F%2Fforumresearch.org%2F |
| Liver safety assessment in clinical trials of new agents for chronic hepatitis B | Liver Safety Monitoring Working Group |
https://onlinelibrary.wiley.com/doi/abs/10.1111/jvh.13223 |
| Immunological Biomarker Discovery in Cure Regimens for Chronic Hepatitis B Virus Infection | Immune Monitoring Working Group |
https://www.journal-of-hepatology.eu/article/S0168-8278(22)00127-1/fulltext |
Governance/Membership/Funding
The HBV Forum membership is by invitation only. Project members are recruited from academia, community, federal agencies, professional societies, and industry. Membership is open to scientific experts from pharmaceutical, biotech, and diagnostic industry organizations committed to and actively engaged in research and development in HBV.
Participation from industry is conditional on an annual sponsorship contribution. Industry members will be acknowledged as HBV Forum sponsors. Sponsorship includes participation in-person meetings, working groups, webinars, remote attendance, and project updates. Non-sponsoring industry will have access to information published on the HBV Forum’s website. Annual contributions from non-industry organizations are encouraged. Members from pharmaceutical, biotech, device, and diagnostic industry organizations must be scientific or regulatory experts actively engaged in research and development in the field of HBV. Industry members join as an organization. Commercial, marketing, and investment experts are not permitted to attend closed HBV Forum members meetings, but will be allowed to participate in any public meetings the Forum sponsors.
The Forum does not cover any honoraria or provides items of value (gifts) to any speakers or attendees. Membership cannot be combined/divided for participation in different disease specific projects at the Forum.
References
1. Gish, R.G., et al., Chronic hepatitis B: Virology, natural history, current management and a glimpse at future opportunities. Antiviral Res, 2015. 121: p. 47-58.
2. Block, T.M., et al., Chronic hepatitis B: what should be the goal for new therapies? Antiviral Res, 2013. 98(1): p. 27-34.
3. Ott, J.J., et al., Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine, 2012. 30(12): p. 2212-9.
4. CDC, Hepatitis B, in Epidemiology and Prevention of Vaccine-Preventable Diseases., J. Hamborsky, A. Kroger, and S. Wolfe, Editors. 2015, Public Health Foundation: Washington, DC. p. 149-174.
5. Kowdley, K.V., et al., Prevalence of chronic hepatitis B among foreign-born persons living in the United States by country of origin. Hepatology, 2012. 56(2): p. 422-33.
6. Pawlotsky, J.M., et al., From non-A, non-B hepatitis to hepatitis C virus cure. J Hepatol, 2015. 62(1 Suppl): p. S87-99.
7. Lucifora, J. and C. Trepo, Hepatitis: After HCV cure, HBV cure? Nat Rev Gastroenterol Hepatol, 2015. 12(7): p. 376-8.
8. Lok, A.S., Progress in Hepatitis B: A 30-Year Journey Through Three Continents. Hepatology, 2014. 60(1): p. 7.
9. Zeisel, M.B., et al., Towards an HBV cure: state-of-the-art and unresolved questions--report of the ANRS workshop on HBV cure. Gut, 2015. 64(8): p. 1314-26.
10. Locarnini, S., et al., Strategies to control hepatitis B: Public policy, epidemiology, vaccine and drugs. J Hepatol, 2015. 62(1 Suppl): p. S76-86.
Updated October 5th, 2021
