Survey of programmatic experiences and challenges in delivery of hepatitis B and C testing in low- and middle-income countries

Hepatitis B virus (HBV) and C (HCV) infections are major causes of chronic liver disease and associated morbidity due to cirrhosis and hepatocellular carcinoma (HCC) globally and together accounted for an estimated 1.34 million deaths in 2015 [1]. The disease burden of chronic HCV and HBV infection is disproportionately high in low- and middle-income countries (LMICs), especially in East and South East Asia and in Sub-Saharan Africa for HBV infection [2]. However, despite the high prevalence of disease, and the availability of effective curative treatment for HCV infection using the new direct acting anti-viral (DAA) drugs, as well as long-term suppressive antiviral treatment for HBV, most people infected with HBV or HCV globally have never been tested and so remain unaware of their infection. Key reasons for this current very low rate of hepatitis testing in LMICs include: limited laboratory capacity and access to reliable, low-cost, HCV diagnostics, and lack of testing guidance specifically for LMICs [3].

WHO has recently developed guidelines on testing for hepatitis B and C infection that are intended as the basis for development of national guidelines for hepatitis testing in resource-limited settings [4]. Formulation of the recommendations was based on the GRADE approach (Grading of Recommendations, Assessment, Development and Evaluation) that include an assessment of the quality of evidence, but also considerations of patient and healthcare worker acceptability and preferences, resource use and feasibility [5, 6]. At present, although there are more than 40 published reports of different viral hepatitis testing programmes [7‐55], the majority of these (88%) were from high-income countries, mainly the United States and Western Europe. In LMICs, there have been only two reports from Sub-Saharan Africa [27, 31], three from Asia [44, 49, 52] and one from Latin America [46]. We therefore undertook a survey of programmatic experience with testing for hepatitis B and C across a range of settings in LMICs, where access to laboratory infrastructure and specialised tests is limited. Our objective was to inform feasibility of potential recommendations on testing approaches (who and where to test) and how to test (selection of assays) in the WHO viral hepatitis testing guidelines, and also to assess key perceived barriers/challenges and strategies to address these and so guide implementation of hepatitis testing and treatment services.

There is still limited published experience of viral hepatitis testing and treatment in low- and middle-income countries to inform development of future programmes. This survey of 22 different hepatitis testing programmes in 19 predominantly low- and middle-income countries in Africa, Asia and Eastern Europe (of which 4 were from upper-middle income countries) representing a wide range of different HBV and HCV prevalence and epidemic patterns provides several valuable insights into current practices and future priorities in the delivery of hepatitis testing.

Overall, half of the programmes were being implemented by NGOs or IOs, and about half of them were only being implemented at a few sites, and so are not representative of national testing policies and approaches. The majority of testing programmes involved targeted testing of high-risk populations such as PWID, men who have sex with men (MSM), sex workers and prisoners, but also pregnant women and health care workers, alone or in combination with some general population testing approaches. NGO/IO supported programmes had a greater emphasis on testing of key and marginalised populations with the few government programmes supporting a general population testing approach. The majority of testing was undertaken in hospital-based settings, and in HIV, Tuberculosis (TB) and sexually transmitted infection (STI) clinics, and antenatal clinics. There was limited community-based or outreach testing. Of note, around half of the countries included in the survey have existing national policies on routine HBV screening for all pregnant women, and were Fiji, Georgia, Hong Kong SAR/China, India, Kenya, Myanmar, Philippine, Thailand and Ukraine [71‐88].

There were several other common features to these testing programmes: First, two-thirds of the programmes were using a single RDT serological test for HBV and HCV. Second, 70% of the testing programmes were integrating viral hepatitis testing with existing clinics and services in HIV, TB and STI clinics as well as harm reduction services – alongside testing for HIV, TB and syphilis, as viral hepatitis is also prevalent in these populations. Third, in the programmes surveyed viral hepatitis testing was still provider-initiated by a physician in the majority of testing programmes, although this largely reflects practices in the predominantly facility-based programmes included in the survey. Fourth, staging of liver disease to assess eligibility for treatment was being undertaken by 73% of programmes, about a half of them with use of Fibroscan rather than the lower cost and more available APRI score. NAT testing to confirm the presence of viraemia and treatment eligibility was only performed by 6 of the HCV programmes and 4 of the HBV programmes. Fifth, it was of concern that 18% of programmes were not able to offer treatment for HBV mono-infection despite the wide availability of low cost generic tenofovir, and around a quarter were not providing HCV treatment. In addition, around a third of programmes were not routinely providing HBV vaccination, a low cost and highly effective preventative measure. Finally, although the testing costs were wholly or partly supported by the programme in more than 80% of the programmes, funding was covered by additional patient self-payment or private insurance in around a third. Treatment cost were covered by programmes in a third of cases.

The survey identified key barriers to testing services across different aspects of the health system but also some key strategies to address these challenges. Key strategies to facilitate access to testing identified from the survey were: awareness raising about viral hepatitis among the general population; decentralization of hepatitis testing with quality assurance on laboratory tests, and expanding access to technologies such as point of care NAT such as GeneXpert, dried blood spots sampling, use of oral RDT and self-testing; improving the training and capacity of staff in management of hepatitis; and incorporation of hepatitis testing and treatment into national health reimbursement programmes. Other diagnostic innovations to promote testing include multi-analyte testing, multiplex analysis or multi platforms for testing combined with syphilis [3, 89, 90]. Dried blood spot sampling may enhance access to both serological (using laboratory based EIA assays) and virological (using nucleic acid tests) testing [91]. However, at present, none of the manufacturers of commercial assays have validated their use with DBS samples or developed standard operating procedures, and nor is there any regulatory approval for their use from stringent regulatory authorities, such as WHO. The limited availability of low cost generic DAA treatments for HCV infection and tenofovir therapy for HBV mono-infected persons in many programmes was also identified as a key impediment to testing. Of note, 11 programmes highlighted the other benefits of testing in the absence of current access to treatment. These include opportunities to introduce measures and counselling to reduce transmission to family members and other close contacts including hepatitis B vaccination, and to counsel infected persons about measures to reduce disease progression of liver disease.

How well do our findings relate to existing reports on programmatic experience in viral hepatitis testing? We identified 49 published reports from different viral hepatitis testing programmes based on a PubMED search of existing relevant literatures on hepatitis B or C testing practices published since 2007 [7‐55]. The majority of these (88%) were from high-income countries, mainly the United States and Western Europe, with only 6 from LMICs. These reports described testing programmes in a range of populations including: 13 of HCV birth-cohort testing in the context of the United States national recommendation to screen all adults living in the United States born between 1945 and 1965 at least once [8, 16, 19, 22‐25, 38, 42, 45, 47, 51, 53]; 10 of HCV and one of both HBV and HCV in people who use drugs or harm reduction settings [10, 12, 20, 21, 32, 34, 35, 39‐41, 51]; 4 of HCV in prisons [7, 15, 17, 54]; 3 of HBV testing in pregnant women [29, 46, 52]; and one of HBV and one of HCV in migrants [14, 43]. Of note, most of the programmes described were also community based or implemented in primary health care or prevention services. Although, descriptions of testing models and an evaluation of impact on cascade of care were provided in most of the reports, there was limited critical evaluation of programmatic lessons learnt.

In contrast, our survey was based on a broad range of facility and community based testing programmes from mainly LMICs with a focus on experiences with current testing practices, and common barriers. There were several key limitations to this survey. First, it was based on an opportunistic sample of 22 testing programmes that did not include any from Latin America or the Caribbean. Second, included programmes are not representative of national testing policies and approaches, as half of the programmes were being implemented by NGOs or IOs, and about half of them were only being implemented at a few sites. Third, the majority of programmes were also based in health facilities and there were few community based or outreach initiatives, which are likely to have different lab and service delivery approaches and unique challenges. There was also considerable variability in the way programmes were organised, especially between NGO/IO and governmental programmes, and so it was difficult to standardise reporting and data collection of their experiences, and to draw any inferences about programmatic effectiveness.

What were the implications of our findings for both the formulation of recommendations in the WHO testing guidelines [4] and for future strategies to promote scale-up of viral hepatitis testing globally? The survey demonstrates that progress has been made in scale-up of hepatitis testing under the auspices of government and non-governmental initiatives, building on existing opportunities for testing through other services and on laboratory infrastructure. In spite of the many barriers highlighted, it also shows the feasibility of implementing HBV and HCV testing programmes across a wide range of LMICs. In particular, targeted testing is being effectively implemented among various higher risk groups, and RDTs have been widely adopted. However, there remains limited access to NAT for assessment of viraemia, and requirement for patient co-payment for testing and treatment remains a significant barrier.

These issues of feasibility and challenges encountered were considered in the formulation of recommendations on who to test and how to test in the 2017 WHO guidelines on testing for hepatitis B and C [4], with a promotion of the use of quality assured RDTs to promote access, strategies to promote linkage to care and treatment, use of simple low-cost non-invasive tests (NITs) such as APRI score for staging of liver disease, and universal adoption of targeted or focussed testing of specific populations most affected by HBV or HCV infection (i.e. who are either part of a population with higher seroprevalence or who have a history of exposure to or high-risk behaviours for HBV or HCV infection). These include HIV infected persons, PWID, prisoners, sexual partners and family members, including children of those affected by hepatitis B, pregnant women and health care workers. General population testing was recommended in high prevalence countries (above 5%) using existing testing infrastructure and approaches.

In terms of future policy, there is scope for increasing community-based testing and involving non-health workers with task-shifting to promote testing as achieved with HIV [92], and in access to point of care NAT technologies as well as dried blood spots sampling to improve access to virological testing. As countries progressively embrace universal health coverage, the current barrier to testing of costly self-payment of diagnostics can also be addressed. Finally, there is a need for more systematic reporting of experience with hepatitis testing and treatment programmes in LMICs. This will be further informed by a portfolio of important implementation science and demonstration projects supported by UNITAID and other organisations examining the impact of simplified and decentralised hepatitis C testing and treatment programmes.