Global hepatitis C elimination: an investment framework

Campbell Aitkin for his role in review & editing of this manuscript. Authors’ contributions: AP, MH, JH, SS, NS, JVC and DW jointly conceived of the study and were involved in critical review and interpretation and the writing of the manuscript. AP, JH and SS reviewed the literature and AP drafted the manuscript. NS and CK devised, programmed, and ran the model. All authors were involved in revising the manuscript and messaging of results.

1 Summary 1 The World Health Organization (WHO) has set global targets for the elimination of hepatitis B and 2 hepatitis C as a public health threat by 2030. However, investment in elimination programs remains 3 low. To drive political commitment and catalyse domestic and international financing, we developed 4 the first global investment framework for the elimination of hepatitis B and hepatitis C. This 5 manuscript focuses on the hepatitis C investment framework. The work was accompanied by 6 modelling demonstrating the cost of scaling up hepatitis C-specific elimination activities to meet 7 WHO's targets, considering both direct and indirect economic benefits. The investment framework 8 outlines national and international activities that will enable reductions in hepatitis C incidence and 9 mortality and identifies potential sources of funding and tools to help countries build the economic 10 case for investing in national elimination activities. The modelling demonstrated how strengthening 11 health systems, through improving workforce capacity and surveillance systems and integrating 12 activities into universal health programs, can improve coordination and optimize resource allocation, 13 making hepatitis C elimination cost-saving by 2027, with a net economic benefit of US$22.7 ($17.1-14 27.9) billion by 2030. This is the first global investment framework for hepatitis C elimination; it 15 demonstrates a way forward for countries, particularly those with limited resources, to gain the 16 substantial economic benefit and cost savings that come from investing in hepatitis C elimination. MEDLINE; EMBASE and grey literature, using the search terms "viral hepatitis", "hepatitis C", 26 "prevention", "testing", "treatment", "elimination", "financing", "economic modelling" and "cost-27 effectiveness". In addition, we reviewed published case studies, reports and interviewed global 28 experts including epidemiologists, clinicians, community advocates, public health experts and 29 policymakers, to inform the framework and identify countries that have achieved viral elimination 30 targets. Only papers published in English were reviewed. The final reference list was generated on 31 the basis of originality and relevance to the broad scope of this review.

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The Commission outlined innovative financing models to support country-level elimination 47 programmes, and called for the development of an investment case for viral hepatitis to 48 demonstrate the feasibility of elimination and quantify its health, social, and economic benefits.

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With an estimated 71 million people living with the hepatitis C infection, at current rates hepatitis C 51 will account for 0·84 million deaths annually by 2040 due to cirrhosis and liver cancer.(4) However, 52 new treatments known as direct-acting antivirals (DAAs) have revolutionised hepatitis C care, with 53 cure rates of over 95% following 8-12 weeks of once-daily well-tolerated tablets, providing a unique 54 opportunity to eliminate hepatitis C as a global public health threat. Since DAAs became available in 55 2013,(5) they have been shown to reduce the risk of liver failure and liver cancer (6, 7) and improve 56 patients' quality of life. (8,9) A full course of generic DAAs can now be purchased for less than 57 US$100 in multiple countries,(10) but are cost-effective even at a much higher cost across a range of 58 5 low, middle, and high-income country settings. (11,12,13) Nonetheless, globally, treatment 59 coverage remains low, with an estimated 1·5 million people initiating DAA-based treatment by 2016, 60 leaving the majority of people living with hepatitis C infection untreated. (14) Emerging data on the 61 productivity losses associated with hepatitis C, and conversely the improvements in productivity 62 post-cure (15-17), will help quantify the broader economic losses attributable to hepatitis C (18, 19

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While these diseases have different epidemic characteristics, they share many similarities in health 81 system requirements and approaches for effective disease control,(3) including interventions to 82 prevent infections (safety of blood supply, safety of health care-associated injections) and testing 83 6 and treatment programmes that are delivered through common platforms (population-based, 84 community-level, heath centre, primary, secondary, tertiary-level hospitals) and workforces 85 (specialists, doctors and nurses). (22) The framework adopts a public health and health systems 86 strengthening approach to identify national and international activities that would support country-87 level implementation of viral hepatitis elimination strategies across diverse settings. For the 88 purposes of this paper, we focus on hepatitis C elimination to demonstrate how policymakers and 89 others can use this framework to support and justify investment in hepatitis C activities.

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An investment framework for hepatitis C elimination 92 Firstly, the framework identifies the importance of using multiple financing mechanisms to 93 encourage investment from domestic, private sector and international sources and enable 94 policymakers and financiers to galvanise support for action. Secondly, the framework identifies 95 activities that countries and international agencies can implement, along with critical enablers to 96 allow the effective implementation of hepatitis C programmes at scale. Finally, the framework 97 outlines the economic benefits of achieving hepatitis C elimination, including direct, indirect and 98 cross-sectoral economic benefits, and the broader benefits that investment can provide through 99 health systems strengthening. To demonstrate the impact of the investment framework, we 100 modelled two investment scenarios for hepatitis C: eliminationwhere investments in activities 101 were scaled up to meet the WHO 2030 diagnosis and treatment elimination targets, and progress -102 where more modest investments in activities were made to implement current WHO screening 103 guidelines. The models estimate the impact, cost, cost-effectiveness and economic benefits over 104 time of both scenarios at a global and WHO regional level. Uniquely, the models estimate the 105 economic productivity losses associated with hepatitis C infection due to absenteeism and 106 presenteeism. A detailed model description and additional findings are explored in the 107 accompanying modelling paper. (23) 7

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Hepatitis C elimination will require considerable leadership, political will, and financial investment.

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Global financing mechanisms, such as the Global Fund,(24) Gavi,(25) and Unitaid,(26) have 111 successfully brought together elements of the financing value chain to mobilise, pool and invest in or 112 "replenish" health programmes. (27)    Our investment framework identifies national and international activities that would support the 9 implemented effectively at scale ( Table 2). These were framed to address existing challenges that 159 underpin the lack of investment and action in many countries, which are often interlinked and have 160 cascading impacts that perpetuate each other in a negatively reinforced cycle (Figure 2). For 161 example, many LMICs with a growing hepatitis C disease burden lack a formally costed hepatitis C 162 elimination programme. This can arise from a lack of awareness among policymakers about the 163 burden of hepatitis C-related disease and potential benefits of prioritization of hepatitis C 164 elimination. This lack of awareness of the disease burden is often driven by inadequate data and 165 weak surveillance systems. These in turn reduce governments' capacity to prioritize resource 166 allocation for national viral hepatitis elimination action plans and limited public sector-optimized 167 procurement of medicines or diagnostics. Countries then have fragmented procurement, rather than 168 national pooled procurement; this can lead to a high mark-up in drug prices from pharmaceutical 169 companies, and the perception that DAAs are expensive. This in turn prevents national programme 170 managers from investing and consequently they miss valuable opportunities to appropriately invest 171 in hepatitis C elimination and maximise the return on investment.
172 Table 2 details the national and international activities and key enablers of hepatitis C elimination, 173 tools to support the implementation of these activities, and countries that are successfully 174 implementing activities. National activities include purchased commodities and programmes that 175 have a direct effect on reducing hepatitis C transmission, morbidity, and mortality. These should be 176 informed by surveillance data and local epidemiology and scaled up according to the size of the 177 affected population. Supporting governments to develop national plans and local investment case 178 will help to raise the profile of hepatitis C elimination and build political commitment through global,  Debt2Health initiative (67)-initiative of the Global Fund that helps channel the resources of developing countries away from debt repayment and toward lifesaving investments in health.

Innovations and efficiencies over time
Dried blood sampling to reduce diagnostics costs Non-specialist care, including task sharing and task-shifting

Financial Transaction Tax
Australia (57), Scotland (58) UNITAID (27) has raised US$2 billion from a €1 levy on air tickets leaving France. This 'air levy' now been applied in 15 countries globally.

Private-Public Partnerships (PPP)
Formal risk management mechanism -where public authorities partner with the private sector to provide services. PPP's aims to share the risks and costs of investment, while enhancing the development of innovation through partnerships.
The Gavi Matching Fund (25) is a publicprivate funding mechanism designed to incentivise private sector investments in immunisation.

Dedicated hepatitis fund
Create a global viral hepatitis fund to leverage resources and cultivate synergies through innovative public-private partnerships, and catalyse action on viral hepatitis.
The proposed fund would primarily support the mostaffected countries and communities where, despite national commitment, national health systems cannot adequately or effectively address hepatitis epidemics.
EndHEP2030 Fund (31)-is the only grantmaking organization dedicated exclusively to the mission of ending viral hepatitis

Pooled financing
Bringing together development and commercial actors to pool financing and offer opportunities to scale up blended finance models Global Procurement Fund (GPRO) (31)works with participating countries to pool orders from member countries and uses international competitive bidding to purchase products at negotiated prices. GPRO only works with manufacturers that have freedom to operate -either with a license from the originator-companies or those with a license from the Medicines Patent Pool.

Results-based financing
Seeks to create 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.
Since 2014, the Global Fund has implemented a Results Based Financing model in Rwanda (36), called 'National Strategy Financing' to incentivize results and efficiency.

Social Impact Bonds (SIB) and Development Impact Bonds (DIBs)
SIBs and DIBs draw on elements of impact investing and public-private partnerships and allow outcome funders to pay directly for the achievement of outcomes rather than for inputs. Investors provide the upfront risk capital and play a critical role in helping improve service delivery by bringing private sector discipline into practice.
Global Fund (25) supports a social impact bond to address HIV in adolescent girls and young women in South Africa. The International Finance Facility for Immunization uses donor pledges to issue vaccine bonds to raise money for Gavi Alliance.

Table 2. Challenges and activities to support investment in hepatitis C elimination, including tools and example countries
Challenges to hepatitis C elimination Activities to support investment in hepatitis C elimination Non-evidence-based restrictive and discriminatory policies and legislation, such as liver-disease stage restrictions and restrictions based on recent drug and/or alcohol use,(74) perpetuate stigmatisation of key risk populations and prevent people from accessing treatment.
National -Raise awareness of hepatitis C to reduce stigma and increase community demand for testing and treatment: • Encourage community sector advocacy and civil society engagement to highlight inadequate hepatitis C funding • Ensure local epidemiology and surveillance data to inform national hepatitis plans; promote community-focused activities • Enable community-led reform of restrictive/stigmatising laws, policies and guidelines (e.g. criminalisation of syringe possession and drug use (75)) •

World Hepatitis Day events and awareness campaigns
Brazil (61) Scotland (58) Portugal (76) France (77) International -Raise the profile of hepatitis C, support awareness-raising activities and advocate on behalf of affected communities: • Advocate for community sector support and funding, including civil society, hepatitis C councils and affected populations • Ensure international testing and treatment guidelines (78-81-) support simplified clinical pathways and community-focused responses