Innovative strategies for the elimination of viral hepatitis at a national level: A country case series

Abstract Viral hepatitis is a leading cause of morbidity and mortality worldwide, but has long been neglected by national and international policymakers. Recent modelling studies suggest that investing in the global elimination of viral hepatitis is feasible and cost‐effective. In 2016, all 194 member states of the World Health Organization endorsed the goal to eliminate viral hepatitis as a public health threat by 2030, but complex systemic and social realities hamper implementation efforts. This paper presents eight case studies from a diverse range of countries that have invested in responses to viral hepatitis and adopted innovative approaches to tackle their respective epidemics. Based on an investment framework developed to build a global investment case for the elimination of viral hepatitis by 2030, national activities and key enablers are highlighted that showcase the feasibility and impact of concerted hepatitis responses across a range of settings, with different levels of available resources and infrastructural development. These case studies demonstrate the utility of taking a multipronged, public health approach to: (a) evidence‐gathering and planning; (b) implementation; and (c) integration of viral hepatitis services into the Agenda for Sustainable Development. They provide models for planning, investment and implementation strategies for other countries facing similar challenges and resource constraints.


| INTRODUC TI ON
Viral hepatitis contributes substantially to the global burden of disease, with 248 million people infected with hepatitis B and 71 million infected with hepatitis C worldwide. 1 If left untreated, chronic viral hepatitis can cause life-threatening complications, such as cirrhosis and hepatocellular carcinoma. 2 Despite this, the public health consequences of viral hepatitis have long been neglected. 1 In contrast to the progress in combating many other communicable diseases in recent years, viral hepatitis-related morbidity and mortality continue to rise. 1,3 In 2010 viral hepatitis was the 10th leading cause of death, but by 2015, with 1.2 million deaths, it had overtaken HIV, malaria and tuberculosis to rise to sixth. 4 Most viral hepatitis deaths are avertable through increased access to prevention, diagnosis and treatment.
In areas of high hepatitis B endemicity (eg Southeast Asia and sub-Saharan Africa), perinatal mother-to-child transmission • Planning, implementation and integration of national responses to viral hepatitis is ongoing, and many countries have adopted innovative approaches to address the diverse challenges of this endeavour in their local contexts • Existing approaches demonstrate that investing in viral hepatitis is affordable and cost-effective, provides multisectoral cost-benefits, and alleviates the human burden of the epidemic drive transmission elsewhere. [5][6][7] Risk of developing chronic hepatitis B infection is inversely related to age at infection: around 90% of infants infected perinatally develop chronic infection, unless vaccinated at birth. This risk decreases to around 30% among children infected before the age of six years and to less than 5% of persons infected as adults. [8][9][10] The hepatitis C epidemic is similarly geographically diverse and mode of transmission differs substantially between regions. [11][12][13][14] Globally, an estimated 52% of people who inject drugs (PWID) are hepatitis C antibody positive. 15 Lack of access to needle and syringe programmes (NSPs) and opioid antagonist treatment (OAT) result in unsafe injecting practices, which are the major route of transmission in high-income countries. 15,16 In low-and middle-income countries, additional transmission occurs in healthcare settings through substandard infection control practices. 17 In 2016, the 69th World Health Assembly adopted the Global Health Sector Strategy on Viral Hepatitis (GHSSH) 2016-2021. The strategy outlines five synergistic prevention and treatment service coverage targets to achieve the elimination of viral hepatitis as a public health threat by 2030 (defined as 90% reduction in incidence and 65% in mortality, see Table 1). 18 Implementation of the strategy is expected to strengthen health systems while enabling progress toward the United Nations' Sustainable Development Goal (SDG) 3 target of universal health coverage. 19,20 Modelling studies suggest that rapid investment in diagnostic, prevention, and treatment services could achieve the World Health Organization (WHO) targets by 2030. 21,22

| How can viral hepatitis be eliminated by 2030?
Eliminating viral hepatitis requires substantial investments in health systems strengthening and the full continuum of hepatitis services. 18 Investing in the prevention and treatment of viral hepatitis provides many direct, indirect and cross-sectoral economic benefits through saving lives and alleviating the cost burden of disease to the individual, their families and the state. [23][24][25][26] To achieve elimination at a national level, the country-specific context and its unique challenges must be considered. A multipronged approach comprising three main pillars is most effective in addressing the local context; comprising (a) evidence-gathering and planning the response; (b) implementation of disease-specific activities, including investments in the delivery of care; and (c) integration of the viral hepatitis response into SDG 3 by adopting a public health approach and embedding services into universal health coverage. 27 The necessary tools for viral hepatitis elimination are already available, but worldwide implementation of a concerted viral hepatitis response is slow and faces many challenges. These include low levels of investments in health overall; inadequate data and weak surveillance systems; poor infrastructure; low awareness among policymakers, at-risk populations and primary care practitioners; high prices of some diagnostics and treatments; and a lack of prioritisation of viral hepatitis. 28,29 While most countries are on track to meet the WHO's 2030 target of < 0.1% Hepatitis B surface antigen (HBsAg) prevalence among 5-year-olds, without substantial further investments this target is currently unachievable for 20 countries, mainly in Africa and the Western Pacific. Moreover, only 12 countries are currently on track to achieve the hepatitis C elimination goal that all WHO member states adopted in 2016. 30 We have developed a Viral Hepatitis Investment Framework outlining the resourcing required to achieve elimination, the cost of the elimination of viral hepatitis globally, and methods for countries to address existing challenges. 31 The Viral Hepatitis Investment Framework highlights key enablers to support a comprehensive viral hepatitis response and outlines priority national and international activities to maximise return on investment (Figure 1). Using the structure of the Investment Framework, this paper presents case studies from diverse countries ( Table 2) that are successfully implementing innovative strategies to eliminate viral hepatitis (see Table 3). Additional case studies listed in Table 3 are summarised in the Appendix S1 (Figures 2-4).

| Evidence-gathering and planning
Low-quality surveillance systems and a lack of reliable cause-specific mortality data limit countries' capacity to guide, implement and monitor effective viral hepatitis responses. 32,33 To advocate for an adequate allocation of domestic resources and to mobilise external funding support, countries should develop a national plan that sets ambitious but achievable targets, informed by a robust local investment case for viral hepatitis. Gathering accurate data to inform a targeted approach can improve the cost-effectiveness of specific interventions. [34][35][36] Since the launch of the GHSSH 2016-2021, more countries have developed national hepatitis plans 1 and both local and global investment cases for the elimination of viral hepatitis have been built. 31,35,37 Many countries have begun collecting epidemiological data through national seroprevalence surveys or by adding key hepatitis indicators into existing surveillance systems. Below, we give examples of countries that have gathered evidence and are developing a national plan (Georgia), produced an investment case for elimination (South Africa) and obtained accurate data to inform the response (Scotland).

| Georgia: the development of a national plan
Georgia was the first country in the WHO European region to set a hepatitis C elimination goal and develop a national plan for viral hepatitis tailored to the local context. Georgia's significant experience with HIV prevention and control programmes and the existing human and technical capacities to implement large-scale health programmes facilitated the implementation of their national hepatitis C elimination programme. 38 An international Technical Advisory Group assisted with describing the local hepatitis C epidemiology and proposing strategies, objectives and actions to address gaps in advocacy and awareness, surveillance, harm reduction, blood safety, infection control, and evidence-based screening and linkage to care.
Gilead Science provided direct-acting antiviral (DAA) w to Georgia at no cost after the elimination programme commenced; reportedly, a key reason for their decision was the Georgian Government's commitment to an elimination response.
The programme initially focused on increasing access to affordable diagnostics; providing free DAA treatment to persons with severe liver disease at highest-risk of hepatitis C-related mortality; and building capacity to achieve programme goals of preventing transmission and eliminating the disease. 39 Initial obstacles included suboptimal alignment of programme development and implementation, leading to bottlenecks in patient flow and wait lists. 40 Training for healthcare workers was only provided after the programme launched; however, doctors have subsequently received continuous technical support.
The programme has now expanded its scope to treat every person chronically infected with hepatitis C, as outlined in the "Strategic plan for the Elimination of Hepatitis C Virus in Georgia, 2016-2020".
Hepatitis C treatment services are provided at treatment centres located throughout the country and treatment decentralisation in harm reduction centres and primary care is ongoing. Patient out-ofpocket fees for diagnostics and clinical monitoring are based on ability to pay. Georgia is working to integrate its hepatitis C elimination programme into the overall health system, because this will benefit the management of other health problems such as HIV and tuberculosis. 41 This is primarily being achieved via treatment decentralisation into primary care and harm reduction services.
The implementation of the national action plan increased access to hepatitis C testing and linkage to care while driving improvements in monitoring and surveillance, infection control and prevention. 38,41 The evaluation of harm reduction-based peer-supported hepatitis C treatment demonstrated excellent treatment uptake and retention in care among PWID based in Tbilisi. 42    for the full implementation. The five-year Action Plan was estimated to cost US$270 million, with the "testing, care, and treatment" component being the most costly. Whilst this is a significant amount of money, seen against 5-year HIV expenditure, the cost of the Hepatitis Action Plan is estimated to be less than 4% of the projected HIV spend in South Africa. 43 Integrating the action plan into the existing health system, particularly maternal and child health and HIV/AIDS services, was estimated to improve implementation feasibility.
The modelling data suggest the initial five-year investment could avert an estimated 13 000 hepatitis B-related deaths and 7000 hepatitis C-related deaths. Moreover, a continued expansion of the treatment programme beyond 2021 has the potential to avert 672 000 hepatitis B-infections and 60 000 deaths averted from hepatitis C-related liver disease, which would put South Africa firmly on the path to achieve elimination by 2030 ( Figure 5B). 35 The multi-stakeholder approach used to develop an investment case for the cost-effectiveness and affordability of hepatitis control and elimination for South Africa provides a template for other countries. 44  DAAs are yet to be registered in South Africa due to administrative delays at the South African Health Products Regulatory Authority, preventing broader hepatitis C treatment scale-up.
In order to address these obstacles, the South African Viral Hepatitis Working Group has established three subcommittees to oversee implementation of the hepatitis B birth dose vaccine, training of healthcare workers in conjunction with training on new HIV treatment regimens, and hepatitis C micro-elimination programmes.

| Scotland: accurate data to inform the response
In Scotland, advocates used political pressure and scientific evidence to raise awareness of the human impact of hepatitis C and its links to inequalities, which generated political consensus to support significant funding and evidence-based policy initiatives. 45  700 000 (0.71%) 104 9.8 million (0.7%) 105 3.81 million (7%) 76 175 000 (3.1%) 11 230 000 (1%) of dried blood spot (DBS) sampling in community drug services made the model of viral hepatitis care more acceptable to affected communities and helped overcome barriers to testing. 46 Adopting a project management approach ensured achievable goal-setting and controlled ongoing cost. Substantial investment in a robust monitoring and surveillance system -combined with ambitious treatment targets -facilitated progress and demonstrated immediate impact, which helped to sustain momentum. 47 Scotland's response -the National Hepatitis C Action Plan -has been a phased one. Borne Viruses, which adopts a multi-agency outcomes-based approach with a strong focus on challenging inequalities. 48,49 The national strategy to improve prevention, diagnosis and treatment services led to a significant decline in hepatitis C incidence, more new diagnoses, more people undergoing hepatitis C treatment and achieving cure, reductions in liver-related morbidity and mortality, and a decreased population prevalence of chronic hepatitis C. 47 The recent scale-up of DAA therapy to PWID is hoped to bring a treatment-as-prevention benefit. 54 While the roll-out of DBS testing was effective at diagnosing infection, a substantial minority of the infected population remains undiagnosed. It has proven difficult to fully engage general practitioners in case-finding initiatives, with awareness-raising campaigns having limited success. 55,56 However, it is hoped that the availability of DAAs within primary care and other community settings will increase treatment uptake as the utility of the new therapies is recognised.

| Brazil: raising awareness and stigma reduction
Brazil, a middle-income country, has been providing universal access to antiretroviral therapy for HIV since 1996, driven by strong politi- The remarkable process applied in Brazil was based on epidemiological data and scientific evidence, and motivated by its engagement with the SDGs, which may inspire other countries to identify ways to achieve these goals by 2030. 57 Brazil has pledged to provide free hepatitis C treatment to everyone infected and is one of 12 countries on track to achieve hepatitis C elimination by 2030 ( Figure 6A). 30 Despite this progress, geographical, social and economic disparities in Brazil challenge the provision of equitable service access across varied geographical regions. Brazil is working to improve diagnosis rates and mitigate losses to follow-up, resulting from the long delays between diagnosis and treatment initiation arising from small numbers of specialists who can provide DAA treatment. 68

| China: investment in prevention
China is home to nearly one third of all people living with hepatitis B infection globally. HBsAg prevalence is estimated at 5.5% 2 and hepatitis B causes over 300 000 deaths annually due to liver diseases. 69 The implementation of a universal hepatitis B vaccination programme for infants has reduced chronic hepatitis B incidence dramatically dur- By 2019, over 2.4 million Egyptians had been treated, and the country is on track to achieve WHO elimination targets in spite of its high hepatitis C prevalence ( Figure 6C). 78

| Integration
The cost burden of viral hepatitis diagnostic tests and treatmentin particular the new DAA treatment for hepatitis C -challenges the feasibility and sustainability of effective viral hepatitis elimination activities. Unlike for other major communicable diseases such as HIV, tuberculosis and malaria, there is little funding available for viral hepatitis at an international level and most countries lack dedicated hepatitis budgets or programmes. 18 Although the private sector (such as pharmaceutical companies) and international funders and organisations are important actors in global elimination efforts, most funding will have to be mobilised from public, domestic sources to ensure the sustainability of viral hepatitis services as part of a broader effort to increase overall investments in health. 29,81,82 Increasing investment in infrastructure and health service delivery (ie health systems strengthening) is not only a key enabler for viral hepatitis elimination but a requirement to reach the overarching SDG 3 for health and its target of universal health coverage. 19 Ensuring that hepatitis services are integrated within these systems can reduce costs, compared to an isolated, non-strategic approach, 31 exemplified here in the case of Rwanda.
Integrating the viral response into the health system by utilising existing structures and trained workforces can save costs and generate efficiencies, as well as maximising access to services for key risk populations. 83 For example conducting viral hepatitis testing at HIV services is likely to yield high diagnosis rates because people living with HIV have a higher risk of hepatitis B or hepatitis C co-infection, and may improve their engagement in care. 84 However, it is important to look beyond integrating the response into HIV programmes, because further opportunities exist to broaden the viral hepatitis response by integrating it within tuberculosis, maternal and child health, and diabetes programmes. Also such an approach may not be useful in countries with generalised epidemics (such as China and Egypt) that require population-based approaches to testing and treatment.
Even when the response is integrated within the broader health system, there will be extra costs due to the need to expand services and to increase staffing levels to accommodate the increased activity. For example, additional time is needed to administer a hepatitis B vaccine or to provide post-test counselling for positive test results. 82 Due to concerns about extra costs and workload, efforts to integrate viral hepatitis responses into existing systems and platforms may receive substantial pushback, particularly initially. However, there is no evidence to support the notion that introducing viral hepatitis care into these systems causes existing structures to collapse. 85 Moreover, multiple countries have been able to make treatment accessible to the broader population by successfully negotiating with patent holders (eg Australia), making use of patent licenses either available directly from the patent owner or those held by the Medicines Patent Pool (eg Rwanda), 86 or using TRIPS flexibilities to circumvent patent barriers to accessing lower priced generic DAAs (eg Malaysia, see Table 4 and Appendix S1). 87 Below are examples of integration: health systems strengthening (Rwanda) and investment and financing for sustainability (Australia).
Importantly, the health systems in both countries have coped with this considerable scale-up of treatment and care.

| Rwanda: expanding on universal health coverage
Rwanda is a low-income country that is using a public health framework for hepatitis control and care to progress on its aim to achieve universal health coverage.
The country has made tremendous gains in maternal and child health, malaria, tuberculosis and HIV outcomes. The Rwandan Government now invests major resources in viral hepatitis, using programmatic steps that form a blueprint for other low-income countries in the region. 88 Key elements of Rwanda's programme for viral hepatitis prevention and treatment include: To ascertain feasibility and ensure financing for sustainability, a national operational plan was developed to demonstrate priority-setting of key activities and provide costing estimates for different levels of coverage of screening, diagnosis, and treatment of both hepatitis B and C. 88 Several initiatives were used to secure funding, including support from international donors, in particular the Clinton Health Access Initiative. Rwanda has a voluntary licensing agreement for DAAs and is therefore able to produce medication at reduced cost (approx. US$ 560 in 2017). 66,88 Rwanda's Essential Medicines List includes generic hepatitis B medicines treatment; this is subsidised by government for people with HIV coinfection. All major private health insurance companies (as well as military medical insurance) reimburse for the cost of DAAs, and the Rwanda social security board covers 85% of the cost. Ultimately, the aim is to provide reimbursement for hepatitis C diagnostics and treatment by the community-based health insurance scheme. 88 As of June 2017, 2500 patients had been treated with DAAs and treatment for 9000 additional patients had been procured ( Figure 7A). Rwanda aims to establish treatment capacity at all 48 district hospitals countrywide by 2020. Estimates of hepatitis B vaccination coverage were produced only for countries with universal birth dose policy. 75 laboratory testing and availability of medications) or the skills and experience required of clinicians. These guidelines thus lacked local contextualisation and recommended unavailable or unaffordable management; consequently, they were impractical and did not influence daily clinical practice greatly.

| Australia: a multipronged approach to elimination
In 1999, Australia was one of the first countries to implement and subsequently refine their national hepatitis C strategies and has since then become a best practice model for hepatitis C elimination.
Key to Australia's response, including achieving universal treatment access (described below), has been strong community advocacy,  92 there is an incentive to diagnose and treat as many people as possible to maximise Australia's investment and its public health benefits. This provides an enabling environment to prioritise high-prevalence groups with ongoing risks for treatment, such as PWID and prisoners, necessary to achieve hepatitis C elimination.
In addition, all registered medical practitioners are able to prescribe DAA therapy, enabling more convenient, patient-centred care. In Australia, close collaboration between people living with hepatitis C, community organisations, clinicians and policymakers facilitated improved access to diagnosis and treatment scale-up ( Figure 7B).  93 With the successful implementation of its hepatitis C strategy -a global benchmark for best practice 94 -Australia is on track to achieve elimination by 2030. 95 Of concern in Australia is the continuing drop off in the num- put the elimination effort at risk. The decline in treatment numbers demonstrates that universal availability of DAA treatment alone is not enough to improve access to diagnosis and retention in care.
Continued political commitment and policy and health system interventions are needed to facilitate treatment access for key populations to sustain momentum and overcome ongoing programme challenges to treatment scale-up.

| D ISCUSS I ON
The broader benefits of investing in the elimination of viral hepatitis -including progressing on the SDGs -are increasingly being recognised. Countries with different income levels, public health infrastructures and policy environments are effectively responding to their respective epidemics.
Attaining the viral hepatitis elimination targets set by the global community in 2016 is achievable but also highly ambitious and comes with considerable challenges (see Appendix S1). These should not be  96 it is yet to be broadly adopted.
Even in countries such as Australia, where there is close collaboration between community, government and health practitioners to guide implementation, elimination cannot be guaranteed because many patients remain undiagnosed and/or do not access treatment. 93 84 and in many countries legal protections remain insufficient. 68 The impact of regressive policies and laws on the elimination response cannot be underestimated.
The country case studies presented here demonstrate that major gains are possible in spite of these challenges -across various epidemic profiles, within a diverse range of resource constraints and within relatively short-time frames. The case studies illustrate that political will and commitment, civil society advocacy, donor support and community acceptance are crucial and can make a difference.
From concerted screening efforts in Egypt and using innovative approaches to increase hepatitis C testing in Scotland, to building local investment cases in South Africa, to integrating viral hepatitis ser-

AHS reports grants and travel funding to her institution from ViiV
Healthcare. ETH is the former director of the Medicines Patent