Management of chronic hepatitis B in Africa: is a one-stop assessment of liver disease enough? The MATCH-B study

Lead Research Organisation: Imperial College London
Department Name: Dept of Surgery and Cancer

Abstract

Infection with hepatitis B virus (HBV) is a major public health issue worldwide with about 250 million people chronically infected. HBV is an important cause of severe liver disease including liver cancer, which has a poor prognostic. Although an effective vaccine is available to prevent HBV transmission, many people are not vaccinated in particular in Africa and get infected with a risk of serious hepatic complications. The World Health Organization (WHO) has recently recognized HBV infection as an important health threat and has called for scaling up screening and treatment interventions for hepatitis B globally in order to control HBV-related mortality by 2030 and eventually eliminate the infection. Significant progress has been made in the management of HBV-infected patients. A highly effective treatment is now available at low cost in many countries and is recommended to the most severe patients with active hepatitis. However in developing countries, which account for 80% of the HBV epidemic, interventions to fight against hepatitis B are very limited. In Africa about 80 million people are estimated to be chronically infected with HBV. Yet screening and treatment interventions and research activities to fight against hepatitis B are almost inexistent in Africa. The complexity and high cost of the current international recommendations for the management of hepatitis B represent one of the barriers to scale up HBV screening and treatment interventions in Africa. The first screen-and-treat programme for hepatitis B in Africa called PROLIFICA (Prevention of Liver Fibrosis and Cancer in Africa) has been set up in 2011 in Gambia and Senegal. With the support of the Gambian and Senegalese Ministries of Health and the local communities, the programme has been very successful: almost 20,000 persons have been screened for HBV and about 2,000 infected persons have been offered clinical assessment, and 283 given antiviral treatment. PROLIFICA has also generated unique data on chronic hepatitis B in Africa, which have informed the WHO and the local Ministries of Health on the burden of hepatitis B in West Africa. The study demonstrated that the vast majority of HBV-infected adults in West Africa have inactive or mild hepatitis and do not require immediate treatment. However, whether these patients remain so without liver disease progression in mid- to long-term or do they require regular follow-up as they may develop liver complications is unknown in Africa. In addition whether HBV antiviral therapy is effective and safe to control liver complications has never been demonstrated. Within the following study, we propose to re-assess the liver disease of the 2,108 patients (untreated or treated) previously enrolled in the PROLIFICA programme. We will re-invite each patient previously enrolled in the programme in Gambia and Senegal for a comprehensive liver assessment. Infected subjects with liver disease progression will be given treatment. This study will therefore address two key unknown questions for Africa: 1/ What is the rate of liver disease progression in African patients with inactive or mild hepatitis B exposed to the African environment and can they be offered a limited monitoring? 2/ Is HBV antiviral therapy effective and safe to reduce hepatic liver complications in patients with active chronic hepatitis B in Africa? If we demonstrate that patients diagnosed to have inactive or mild hepatitis B at one single time point have no significant liver disease progression over time, it may be unnecessary to do the conventional frequent follow-up for the millions of patients with mild hepatitis B in Africa. This will save considerable amount of resources since healthcare resources are seriously limited in Africa. We believe that our study will also promote awareness on hepatitis B and its findings will eventually contribute to the development of simplified guidelines for the management of HBV infection in Africa.

Technical Summary

Infection with hepatitis B virus (HBV) is highly endemic in Africa and is a leading cause of death mainly from cirrhosis and hepatocellular carcinoma. The World Health Organization has recently called for HBV elimination and scaling up screen-and-treat interventions in particular in sub-Saharan Africa.
Between 2011-2014 the PROLIFICA project-the first "screen-and-treat" intervention for HBV in Africa-has demonstrated that the vast majority (90%) of HBV-infected adults in west Africa are inactive carriers (IC) and do not require antiviral therapy. Whether these subjects are at risk of liver disease progression and need regular follow-up is unknown in the African settings. The aim of this study is 1) to determine the rate of HBV reactivation and liver disease progression in HBV inactive carriers in Africa and 2) the efficacy of antiviral therapy to reduce HBV-related complications in the African context.
We will re-assess the untreated (n=1,825) and treated patients (n=283) previously enrolled in the PROLIFICA project. Using reference tests (e.g HBV DNA and Fibroscan) patients will be re-assessed after a minimum of 4 years following the first liver assessment. In the untreated cohort (mainly IC) the primary objective will be to determine whether patients who did not meet treatment eligibility criteria at baseline remain so without progression of liver disease. In the treatment cohort the primary objective will be to assess the clinical effectiveness of tenofovir in West African patients. If untreated patients do not exhibit significant liver progression it may be possible to limit the number of follow-up of the millions of patients with inactive hepatitis B in Africa where healthcare resources are seriously limited.
This study will provide unique longitudinal data on chronic hepatitis B in Africa and will therefore contribute to the development of national and regional strategies for the control of HBV infection in Africa adapted to the local environment.

Planned Impact

In 2011 was set up the first screen-and-treat programme for hepatits B in Africa (in Gambia and Senegal), called PROLIFICA (Prevention of Liver Fibrosis and Cancer in Africa). With the support of the Gambian and Senegalese ministry of health and the local communities, the programme has been very successful. By screening more than 16,000 subjects and assessing the liver disease of about 2,000 HBV-infected patients PROLIFICA has generated unique data on chronic hepatitis B in Africa, which have informed the World Health organization (WHO) and the local ministry of health on the burden of hepatitis B in West Africa.
HBV treatment has been given to the most severe patients (n=257) according to the international guidelines.
The programme activities have now ended. However, care and treatment are still provided to the treated patients thanks to the support of the local partners. However the untreated HBV-infected subjects (mainly inactive carriers) who did not require treatment at diagnosis do not benefit from regular clinical and virological follow-up. As a result whether these untreated patients have progressed to significant liver disease and now require treatment is unknown.
Within the following study, we propose to reinvite each patient previously enrolled in the PROLIFICA programme in Gambia and Senegal for a comprehensive liver assessment in order to determine 1) the rate of liver disease progression in untreated HBV-infected patients in Africa and 2) the efficacy and safety of antiviral therapy in treated patients.
The following study will direclty impact:
1) the patients who will receive care, treatment and support.
2) the local healthcare workers and team members who will benefit from education and training on the management of liver disease.
3) the Senegalese and Gambian ministry of health and national programme on viral hepatitis who will get stronger data and simplified algorithms for the management of hepatitis B;these data will be used to develop strategic plans against hepatitis B adapted to the local setting.
5) the WHO viral hepatitis unit that will use our results to update the guidelines on the management of hepatitis B in Africa
6) the African and international community of researchers and clinicians working on HBV infection (e.g see letter of support from ICE-HBV).
7) The study will also indirectly impact the patient associations in Gambia, Senegal and more broadly in Africa and non-governmental organizations fighting against HBV in Africa since our study will raise awareness and promote advocacy.

Our study will therefore have a triple impact: 1) societal & political, 2) academic and 3) economic.
Partners and Impacts are summarized in the figure attached to the "Pathway to impact" document in annex. Please see this document in annex.

Publications

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Sonderup MW (2019) Hepatitis B in sub-Saharan Africa-How many patients need therapy? in Journal of viral hepatitis

 
Description ANRS Scientific Advisory Board
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description Gilead Advisory Board
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact Collaboration with Gilead as a member of their advisory board. The focus of the advisory board is how to achieve the HBV elimination targets in Africa, established by WHO.
 
Description The Gambian National Hepatitis Programme, Viral Hepatitis Unit WHO
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact The research has informed WHO policy in viral hepatitis as well as the Gambian National Hepatitis Programme.
 
Description Training of Clinical PhD Student
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Gibril's PhD research is nested within the PROLIFICA project and investigated: 1/ the prevalence and role of occult hepatitis B in liver disease progression in The Gambia; 2/ the rate and risk factors of liver disease progression among adults with chronic hepatitis B infection who did not meet the EASL criteria for antiviral therapy 3/ the safety and efficacy of antiviral therapy in Africans receiving Tenofovir 4/ the uptake of hepatitis B testing and treatment in HIV facilities in The Gambia He has reassessed approx. 800 patients with chronic HBV infection previously enrolled in the PROLIFICA study in The Gambia, and screened an addition 860 HIV patients in the largest HIV treatment centre in The Gambia. Gibril's PhD research at the HIV centre brought liver and viral hepatitis care and services to patients who otherwise do not have access to it. The follow-up reassessment of the PROLIFICA cohort, as part of the MATCH-B study, ensures continuity of care for the 1,180 patients with chronic hepatitis B in this cohort.
 
Description ANRS INFANT-B Study
Amount € 19,995 (EUR)
Organisation French National Agency for Research on AIDS and Viral Hepatitis (ANRS) 
Sector Public
Country France
Start 06/2020 
End 06/2021
 
Description Cepheid funding: validation of the clinical and virological performance of the new GeneXpert HBV DNA kits
Amount £5,000 (GBP)
Organisation Cepheid 
Sector Private
Country United States
Start  
 
Description Gilead - fellowship
Amount $100,000 (USD)
Organisation Gilead Sciences, Inc. 
Sector Private
Country United States
Start 04/2019 
End 05/2021
 
Description Gilead Sciences research funding
Amount $140,000 (USD)
Organisation Gilead Sciences, Inc. 
Sector Private
Country United States
Start 08/2018 
End 07/2019
 
Description Gilead - supply of drug 
Organisation Gilead Sciences, Inc.
Country United States 
Sector Private 
PI Contribution Clinical and scientific expertise
Collaborator Contribution Supply of drug used in the study
Impact Research still ongoing. Publications expected soon.
Start Year 2011
 
Description IRESSEF Senegal 
Organisation Institute for Health Research, Epidemiological Surveillance and Training
Country Senegal 
Sector Charity/Non Profit 
PI Contribution Financial support. Academic support Clinical and scientific expertise
Collaborator Contribution Recruitment of patients Clinical and lab assessment Training Link with ministry of health Provide staff and admin support Data management
Impact Publications in high impact journals Presentations in international conferences Collaboration with WHO and other health policy makers Clinical and academic training
Start Year 2011
 
Description MRC Gambia 
Organisation Medical Research Council (MRC)
Department MRC Unit, The Gambia
Country Gambia 
Sector Public 
PI Contribution Financial support Academic support Clinical and scientific expertise
Collaborator Contribution Recruitment of patients Clinical and lab assessment Training Link with ministry of health Provide staff and admin support Data management
Impact Publications in high impact journals (>25 publications) Presentations in international conferences Collaboration with WHO and other health policy makers Clinical and academic training (3 completed PhD, 2 ongoing PhD, 1 Postdoc, 2 Mph)
Start Year 2011
 
Title Tenofovir 
Description Provision of Tenofovir under international guidelines 
Type Therapeutic Intervention - Drug
Current Stage Of Development Market authorisation
Development Status Under active development/distribution
Impact No other impacts 
 
Description Contribution to a MOOC (massive open on line courses) on viral hepatitis organised by Pasteur Institue International 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The MOOC is an education programme aimed to general audience
Year(s) Of Engagement Activity 2020
 
Description Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Education about hepatitis in Africa B and associated with a publication press release, organised by Imperial
Year(s) Of Engagement Activity 2018
 
Description Patient Association in Gambia 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Education and support to patients for the screening, treatment and follow-up for hepatitis B.
Year(s) Of Engagement Activity 2018
 
Description Project website www.prolifica.africa 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The project website, which has been live since 2018, aims to engage the public by providing information on hepatitis research. The website acts as a repository for resources and provides links to updates, articles and further information such as key collaborators and funding bodies. The website also aims to educate the audience on hepatitis research, providing clear, accessible information to patients, the public and researchers.
We also have developed a twitter account @ProlificaA
Year(s) Of Engagement Activity 2018
URL https://www.prolifica.africa/