key: cord-0686741-qzg1a59m authors: Howell, Jessica; Pedrana, Alisa; Schroeder, Sophia E.; Scott, Nick; Aufegger, Lisa; Atun, Rifat; Baptista-Leite, Ricardo; Hirnschal, Gottfried; Hoen, Ellen ‘t; Hutchinson, Sharon J.; Lazarus, Jeffrey V.; Olufunmilayo, Lesi; Peck, Raquel; Sharma, Manik; Sohn, Annette H.; Thompson, Alexander; Thursz, Mark; Wilson, David; Hellard, Margaret title: A global investment framework for the elimination of hepatitis B date: 2020-09-22 journal: J Hepatol DOI: 10.1016/j.jhep.2020.09.013 sha: 81e04bf38173cdd1ed0a1a2bc0dc5e33e7db3727 doc_id: 686741 cord_uid: qzg1a59m BACKGROUND AND AIMS: More than 292 million people are living with hepatitis B worldwide and are at risk of death from liver cirrhosis and liver cancer. The World Health Organization (WHO) has set global targets for the elimination of viral hepatitis as a public health threat by 2030. However, current levels of global investment in viral hepatitis elimination programmes are insufficient to achieve these goals. METHODS: To catalyse political commitment and to encourage domestic- and international-financing, we used published modelling data and key stakeholder interviews to develop an investment framework to demonstrate the return on investment for viral hepatitis elimination. RESULTS: The framework utilizes a public health approach to identify evidence-based national activities that reduce viral hepatitis-related morbidity and mortality, as well as international activities and critical enablers that allow countries to achieve maximum impact on health outcomes from investment to achieve WHO 2030 elimination targets. CONCLUSION: Focusing on hepatitis B, this health policy paper employs the investment framework to estimate the substantial economic benefits of investing in the elimination of hepatitis B and demonstrates how such investments could be cost-saving by 2030. • Community education and awareness raising • Strengthen surveillance systems and reporting • Health system strengthening • Strengthen maternal child health and birth dose vaccine delivery • Integration hepatitis B into existing chronic disease services • Investment in community-based models of care, task shifting, training nonspecialist workforce • Re-prioritise budgets for rapid scale-up • Innovative funding models to safeguard sustainability • Investment in research and diagnostics, including cure Hepatitis B is transmitted most commonly at birth from mother to baby, in early childhood, or sexually through blood and body fluid contact (4, 5) . Without treatment, the cumulative incidence of liver cirrhosis over five years is around 10-20% in people with chronic active hepatitis B infection, and 2-5% of those with cirrhosis develop liver cancer each year (6) . Those infected at birth are at greater risk of disease progression to cirrhosis and liver cancer (7) . The rising global prevalence of the metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) coupled with hazardous alcohol consumption will likely increase liver-related mortality rates in people living with hepatitis B through accelerated progression of hepatitis B-related liver disease and liver cancer (8) . Hepatitis B also has an adverse impact on the quality of life, employment and personal finances of those living with the virus. In 2016, the estimated global impact of hepatitis B on human health and wellbeing was 5,160,000 ageadjusted disability-adjusted life years (DALYs) lost (9, 10) . The broader societal and economic impact of hepatitis B is often overlooked in fiscal decision-making J o u r n a l P r e -p r o o f by governments and funders of health programmes due to the long duration of the disease that precedes the development of end-stage complications (11, 12) . In response to the substantial public health threat of hepatitis B, in 2016, the World Health Assembly adopted the WHO Global Health Sector Strategy (GHSS) on Viral Hepatitis 2016-2021 (13). This strategy broadly outlines the key activities to achieve viral hepatitis elimination and sets clear hepatitis B elimination targets to be achieved by 2030: a 90% reduction in new chronic infections and a 65% reduction in mortality compared to 2015 levels(13). Though currently there is no cure for hepatitis B infection, elimination targets are made possible by the availability of a highly-effective low-cost vaccine and safe, effective suppressive treatment that halts viral transmission and liver disease progression, reduces the risk of liver cancer and prolongs life of those affected by hepatitis B (4) . Despite the availability of vaccines and treatments to achieve elimination and a high global mortality burden from hepatitis B infection comparable to other high-impact diseases such as tuberculosis, HIV and malaria, there has not been an equivalent political commitment to community mobilization and investment in a strong hepatitis B response (2, 14 and only between 5 to 17% of those eligible for treatment in accordance with international guidelines were receiving treatment(1, 2), despite nucleos(t)ide analogue therapy being proven to markedly reduce the risk of death from liver cirrhosis and liver cancer. To achieve the elimination targets, major investments and resourcing are required at both national and global levels. In 2020, though there are encouraging signs of national-level investment and achievements, it is clear that investment globally is substantially below target to achieve hepatitis B elimination by 2030 (16) . Domestic funding mobilisation through innovative financing sources will be critical to implement the GHSS, as the large-scale global investments by donors for HIV, tuberculosis and malaria are unlikely to J o u r n a l P r e -p r o o f occur for viral hepatitis in part due to a flattening of overseas development assistance for health (17) . As the global community battles the health, social and economic effects of the COVID-19 pandemic, competing priorities and opportunity costs of investment in other infectious and chronic disease management programmes is being weighed against immediate needs and careful justification of investment is essential. We have therefore developed a strategic investment framework for viral hepatitis (B and C) (12) which provides a map of the required elimination activities and funding mechanisms to achieve WHO viral hepatitis targets by 2030. In this paper, we focus on hepatitis B elimination and present how policymakers and others can use the investment framework and published cost modelling data to justify funding hepatitis B prevention, treatment, and care activities. We outline the key barriers to achievement of hepatitis B elimination, how to finance elimination activities, the financial return on investment and the key activities required to achieve hepatitis B elimination. Finally, we discuss ways in which investment in national COVID-19 responses can be leveraged to support hepatitis B elimination activities. J o u r n a l P r e -p r o o f Hepatitis B poses unique challenges to elimination. It is a chronic disease whose mode of transmission, health impact and management change across the lifespan and therefore requires ongoing monitoring throughout its course (6) . Current international hepatitis B management guidelines are complex, as not all patients are currently recommended to have treatment (7, 18) . Moreover, unlike hepatitis C there is currently no cure, and even when the disease is wellcontrolled by treatment there remains a residual risk of liver cancer (19) . Key programmatic challenges to elimination are outlined in Panel 1 (12) . Building on the work of the WHO GHSS on viral hepatitis (2016) (13), we developed a strategic investment framework (Figure 1) for the global elimination of hepatitis B and hepatitis C by 2030 (20) . The framework adopts a public health and health systems strengthening approach and identifies national (14, 16, 20) . Moreover, channeling funding and resources available for chronic non communicable diseases such as diabetes and hypertension may be appropriate in countries with moderate-high general population hepatitis B endemicity, as has been shown effectively in Egypt and Pakistan with hepatitis C (16) . The Global Fund has also allowed remaining funds from other projects to be spent on hepatitis B and C-related activities for HIV coinfected patients. There are several components to consider when evaluating the return on investment for hepatitis B elimination: the epidemiological impact, the amount of investment required, the cross-sectoral benefits of investment and affordability. Several published global and country-specific cost-effectiveness models outline the clear impact of investment in hepatitis B elimination on morbidity and mortality (11, 15, (33) (34) (35) . Although hepatitis B intervention cost-effectiveness depends on the economic, health systems and epidemiologic contexts in each country, published models have universally demonstrated the cost-effectiveness of investment in hepatitis B elimination (11, 15, 33, 34, (36) (37) (38) . However, for many low-income countries, affordability, rather than cost-effectiveness, is a major barrier (34) . In these settings, highlighting the indirect returns on investment such as socioeconomic development, improved education, strengthening of health systems and economic returns support the argument for investment in hepatitis B elimination. Examples of cost-effectiveness models developed for hepatitis B are outlined in Table 2 . A global model was developed in 2016 by Nayagam and colleagues (15) million hepatitis B-related liver cancer cases (37) . Nayagam and colleagues (15) The challenge to achieve hepatitis B elimination is affordability, particularly in low and middle-income countries. With the world in the midst of a global pandemic with unpredictable far-reaching health, social, geopolitical and economic impacts, how we sustain chronic disease programmes, revitalize economies and replenish devastated health infrastructure is a critical concern. In all countries, to varying extents, the focus for health services and governments has shifted to pandemic responses. Countries with moderate to high hepatitis B endemicity are also disproportionately represented among the most vulnerable national health systems and economies, which will bear the greatest impact from COVID-19. Beyond the impact on domestic resources and funding, external funding is likely to be massively curtailed due to diversion of the funds to the pandemic and also vaccine coverage will be essential to deliver high coverage of a future SARS-CoV2 vaccine (44) . At this stage, data to support the success of these approaches are lacking and the future remains uncertain. It is vital that all opportunities are taken to minimize the substantial additional economic and health system burden from hepatitis B for countries with high endemicity. Strong advocacy will be essential to ensure CHB is a public health priority postpandemic. The framework identifies key national and international elimination activities and enabling conditions for scaling up hepatitis B testing and treatment to achieve WHO 2030 elimination targets (outlined in Supplementary Table 1 and Panel 2). The framework also highlights enabling contextual factors that facilitate viral hepatitis elimination and how these may be financed. context-specific scale-up of hepatitis B diagnosis, linkage to care and treatment pathways tailored to local epidemiology, budgets and health system constraints. Creating a local investment case, using available tools and a national hepatitis strategy supported by regional and international expertise are essential first steps to place hepatitis B on national health and cross-sectoral government agendas, mobilise funds and plan realistic and sustainable elimination responses (14) . Table 1 ) (51) (52) (53) . Community advocacy has successfully pressured governments to invest in hepatitis B and C elimination activities in countries such as Australia, Brazil, Georgia and Rwanda (26) . There is also a clear association between level of engagement between WHO member states and civil society organizations and the development of national hepatitis B strategies and dedicated investment in hepatitis B activities (24) . Eighty-four percent of WHO member states who had formal engagement with civil society had national action plans and 52% had dedicated hepatitis B funding compared to 44% with national strategies and 23% dedicated investment among WHO members states with no civil society engagement (24) . Strategies to overcome financial and logistical barriers to birth dose delivery include utilization of skilled birth attendants outside of health facilities, use of vaccine outside of cold chain and use of auto-disposable syringes (54, 55) . Modelling work by Scott and colleagues(56) demonstrated that adopting a controlled temperature chain strategy for birth dose vaccination was costeffective in most world regions with high hepatitis B prevalence; this is now supported by Strategic Advisory Group of Experts on Immunisation (WHO) (57) . Integrating hepatitis B birth dose vaccination with Millennium Development Goal 4 (reducing infant and child mortality) and 5 (reducing maternal mortality) activities promotes mutual health system strengthening and efficiency gains (35, 42, 58) . GAVI has committed to support birth dose vaccination from 2021(59). Among adults, integration of targeted catch-up immunization programmes with J o u r n a l P r e -p r o o f other vaccines such as pertussis reduces costs (26, 60). Regional pooled procurement could improve hepatitis B immunoglobulin access in LMICs (2) and tenofovir (TDF) for pregnant women with high viral loads should be incorporated into the essential medicines list. Provision of TDF in third trimester for pregnant women with hepatitis B who are HBeAg positive with a high viral load reduces transmission risk to <1% (61) and is supported by WHO as a cost-effective strategy for achieving the WHO elimination target of <0.1% prevalence among children by 2030 (15, 35, 62, 63) . This strategy may reduce transmission risk in settings where timely birth dose delivery is difficult to achieve (14) . New twodose hepatitis B vaccines are now available that have high efficacy, which may improve full schedule completion rates due to easier adherence and warrant inclusion in future modelling work. Access to affordable diagnostics is a key barrier for many countries, with diagnostics often costing more than treatment (14, 64 There is increasing interest in novel approaches to treatment that simplify current guidelines, as was the case with hepatitis C (74) , and obviate the need for complex and expensive testing to determine treatment eligibility, such as a "test and treat-all" approach (75) . Whilst such an approach has not yet been explored in a clinical trial, a novel pilot study evaluating the cost-effectiveness and affordability of such an approach is currently underway in Uzbekistan (75). Over-reliance on centralized specialist services to deliver hepatitis services, J o u r n a l P r e -p r o o f International agencies, multilateral organisations, NGOs and donors can support advocacy to address funding gaps to strengthen the community sector and civil society (72, 80) , leverage funding from donors, provide technical expertise including guidelines and training modules, support investment case development, and support regional approaches to drug and diagnostics procurement, particularly price negotiations (60) . Tools are available to support connectivity to support quality assurance and supply chain management (64) . Greater advocacy by civil society including community-based organisations is paramount to encourage international funding bodies to invest in hepatitis B elimination as has been the case with other infectious diseases such as HIV. The final hurdle to achievement of hepatitis B elimination is the lack of a safe, well tolerated, easy-to-administer hepatitis B cure. Modelling has demonstrated that availability of hepatitis B cure would J o u r n a l P r e -p r o o f accelerate achievement of global hepatitis B elimination (15) . However, low and middle-income countries with the greatest hepatitis B burden may endure delays in accessing cure due to prohibitive costs, as has been seen with HIV and hepatitis C therapies. If hepatitis B cure becomes a reality, it will be important that low-cost and/or generic drug procurement is rapidly implemented. There should be some optimism this is possible given the price reduction and broad availability of generic drugs observed with hepatitis C therapies. By investing in hepatitis B elimination programmes now, the scene will be set for rapid introduction and scale-up of hepatitis B cure when such treatment becomes available (84) . Hepatitis B elimination is achievable but requires greater commitment from governments, international institutions, civil society and donors. Modelling shows that the required financial investment is likely to peak by 2025 but then rapidly fall in 2030 and beyond, with investment in hepatitis B activities likely to be cost-effective and cost-saving in many countries in the medium-to longterm. However, for countries currently not funding hepatitis B elimination activities, affordability of investment at the expense of competing priorities must be addressed. The investment framework presented in this study identifies key activities to achieve hepatitis B elimination targets and solutions to funding shortfalls to achieve maximal impact. Financial support by international agencies and donors for elimination activities are vital for many LMICs to successfully achieve elimination targets. Polaris Observatory CDA Foundation. 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Task shifting : rational redistribution of tasks among health workforce teams : global recommendations and guidelines We would like to acknowledge the contributions of Mary Ribeiro Pombo (Imperial J o u r n a l P r e -p r o o f Price negotiations with pharmaceutical manufacturers for hepatitis treatment and diagnostics Australia, Brazil, Thailand (16, 26) Local production of generic medicinesChina, India (26) Inclusion of diagnostics and medications under UHC, list on Essential medicines and Essential diagnostics list Rwanda, Pakistan, Brazil (26) Utilisation of TRIPs flexibilities to access affordable medicines and diagnosticsThailand (hepatitis C medications)(26) Integration of viral hepatitis into existing health services for HIV, maternal child health programmes, and non-communicable diseases Hepatitis B: South Africa (85) , Brazil (26) ; Hepatitis C: Egypt, Pakistan (16, 20) Adopting an investment case approach to guide investments South Africa (85) , China (26, 36) , Senegal(86), The Gambia ( China-utilization of public-private partnerships to roll-out universal infant hepatitis B vaccination and catch-up programs, supported by the GAVI Alliance (26) Rwanda-Use of novel blend of private and public insurance and pooled communitybased microfinancing to support treatment costs (16, 26) Global Procurement Fund (GPRO) (31)works with participating countries to pool medication orders from member countries and uses international competitive bidding to purchase products, working solely with manufacturers that operate either with a license from the originator-companies or those with a license from the Medicines Patent Pool.Civil society and regional public partnerships-Eastern Europe to fund STI prevention services(16) market incentives to achieve critical social outcomes by only paying when results are achieved. Two main types: Performance-based financing targets the supply side, whereas conditional cash transfers target the demand side of a given market. (HSS) and the Immunisation Services Support (ISS) of the GAVI Alliance (2) The Global Fund has implemented a Results Based Financing model in Rwanda called the 'National Strategy Financing' to incentivize results and efficiency. Bonds: Draw on elements of impact investing or blended finance as well as public-private partnerships and allow outcome funders to pay directly for the achievement of outputs or outcomes rather than for inputs or compliant behaviour. Investors provide upfront risk capital (opportunity for return), play a critical role in improving service delivery by bringing private sector discipline into practice. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f to guide domestic and international investment • This Health Policy paper outlines evidence to support the financial returns on investment in hepatitis B elimination, identifies national and international activities to achieve hepatitis B elimination targets and identifies potential funding sources • The goal of this investment framework is to pave the way for countries to build the economic case for investment in national hepatitis B elimination programmes.