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

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.

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.

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.