Reducing liver disease-related deaths in the Asia-Pacific: the important role of decentralised and non-specialist led hepatitis C treatment for cirrhotic patients

Finding new ways to increase access to hepatitis C (HCV) treatment is integral to reducing liver disease-related deaths and achieving HCV elimination in the Asia-Pacific. Decentralised, non-specialist led care is essential to expand access to HCV treatment, both by increasing the number of providers and the geographical coverage. The vast majority of direct-acting antiviral (DAA) treatments for HCV do not need to be provided by a specialist. While all patients should have appropriate liver disease assessment prior to treatment to determine the degree of liver fibrosis or cirrhosis and the severity of liver function impairment, most patients - including those with compensated cirrhosis - can be treated with DAAs by non-specialist practitioners (e.g. general practitioners (GPs)) in primary care settings.1World Health Organization (WHO). Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. 2018. Available from: https://apps.who.int/iris/bitstream/handle/10665/273174/9789241550345-eng.pdf?ua=1Google Scholar GPs treating HCV patients with compensated cirrhosis will be critical to ensuring adequate access to specialists for those who require specialist care for decompensated cirrhosis. For the first time there has been a reduction in HCV-related deaths globally, clearly demonstrating the impact and benefits of striving for HCV elimination. Despite this, treatment coverage remains low in the Asia-Pacific region, ranging from 5% in South East Asia to 10% in the Western Pacific.2World Health Organization (WHO). Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021. 2021. Available from: https://www.who.int/publications/i/item/9789240027077Google Scholar Only four countries in the Asia-Pacific (Australia, Japan, Mongolia, and Georgia) are on track to reach the World Health Organisation (WHO) elimination goals by 2030.3CDA Foundation. Just 12 countries worldwide on track to eliminate hepatitis C infection by 2030, with United Kingdom, Italy and Spain among those joining the list – CDA Foundation. Available from: http://cdafound.org/just-12-countries-worldwide-on-track-to-eliminate-hepatitis-c-infection-by-2030-with-united-kingdom-italy-and-spain-among-those-joining-the-list/Google Scholar Approaches adopted by these countries may be valuable for other countries pursuing elimination goals; common to all four is strong political commitment to achieving national targets through low-cost or subsidised testing and treatment programs.4World Health Organization (WHO). Progress report on access to hepatitis C treatment: focus on overcoming barriers in low- and middle-income countries. 2018. Available from: https://apps.who.int/iris/handle/10665/260445Google Scholar,5World Health Organization (WHO). Japan's hepatitis programme frees people from disease and financial hardship. Available from: https://www.who.int/australia/news/feature-stories/detail/japan's-hepatitis-programme-frees-people-from-disease-and-financial-hardshipGoogle Scholar For example, Mongolia undertook epidemiological work to inform the national targets, pursued options for generic DAAs, included these low cost DAAs into the national health insurance scheme, launched a nation-wide screening program, and delivered HCV treatment through integrated services within the primary healthcare system.4World Health Organization (WHO). Progress report on access to hepatitis C treatment: focus on overcoming barriers in low- and middle-income countries. 2018. Available from: https://apps.who.int/iris/handle/10665/260445Google Scholar,6Dore GJ Martinello M. Global elimination of hepatitis C virus by 2030: the optimistic view.Clin Dilemmas Viral Liver Dis. 2020; (Available from:): 238-243https://onlinelibrary.wiley.com/doi/full/10.1002/9781119533481.ch40Google Scholar,7Chan P-L Le L-V Ishikawa N Easterbrook P. Regional progress towards hepatitis C elimination in the Western Pacific Region, 2015-2020.Glob Heal Med. 2021; 3: 253-261Google Scholar More than half of the countries within the Asia-Pacific region are classified as low- or middle-income countries (LMICs).8World Bank. The World Bank Country and Lending Groups. 2020. Available from: https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groupsGoogle Scholar Many LMICs face multi-faceted barriers to scaling up access to HCV care: low public awareness of HCV, inadequate specialist workforce, limited implementation of decentralised care within existing health systems, and the unaffordable price of diagnostics and DAAs.4World Health Organization (WHO). Progress report on access to hepatitis C treatment: focus on overcoming barriers in low- and middle-income countries. 2018. Available from: https://apps.who.int/iris/handle/10665/260445Google Scholar In most LMICs, there are not enough specialists to provide care to those requiring their services. Furthermore, the specialist workforce is often concentrated in major urban health centres. In the case of HCV, the high workloads of specialists lead to long waiting times for patients, hampering timely treatment and leading to many becoming disengaged from care.9Palmer AY Wade AJ Draper B Howell J Doyle JS Petrie D et al.A cost-effectiveness analysis of primary versus hospital-based specialist care for direct acting antiviral hepatitis C treatment.Int J Drug Policy. 2020; 76102633Google Scholar,10Wade AJ Doyle JS Gane E Stedman C Draper B Iser D et al.Outcomes of Treatment for Hepatitis C in Primary Care, Compared to Hospital-based Care: A Randomized, Controlled Trial in People Who Inject Drugs.Clin Infect Dis. 2019; Google Scholar While the cost of diagnostics and DAAs remains a barrier to scaling up access to HCV care, the price of DAAs is continually declining, and some promising patent-free options are in the pipeline.4World Health Organization (WHO). Progress report on access to hepatitis C treatment: focus on overcoming barriers in low- and middle-income countries. 2018. Available from: https://apps.who.int/iris/handle/10665/260445Google Scholar,11Andrieux-Meyer I Tan S-S Thanprasertsuk S Salvadori N Menetrey C Simon F et al.Efficacy and safety of ravidasvir plus sofosbuvir in patients with chronic hepatitis C infection without cirrhosis or with compensated cirrhosis (STORM-C-1): interim analysis of a two-stage, open-label, multicentre, single arm, phase 2/3 trial.Lancet Gastroenterol Hepatol. 2021; Google Scholar However, achieving global HCV elimination requires more than merely access to affordable DAAs. Increasing access to treatment is integral to reducing liver disease-related deaths and achieving HCV elimination. One way to achieve this is to train non-specialist practitioners (e.g., GPs, nurse practitioners, pharmacists) to treat HCV with DAAs. We call for a renewed focus on treating people with compensated cirrhosis in primary care. This will allow for increased access to treatment for all and give priority access to specialists for those who require specialist management. General practitioners and other non-specialist providers in primary care settings can easily treat HCV in those with compensated cirrhosis, without the need of a specialist.12Tran TT. Hepatitis C: Who should treat hepatitis C virus? The role of the primary care provider.Clin Liver Dis. 2018 Mar 1; 11: 66-68Google Scholar Referral to the specialist for further evaluation of ongoing liver disease can be done after the completion of DAA treatment. This approach will ensure that people with HCV cirrhosis are treated early, preserving liver function and reducing the risk of liver cancer.1World Health Organization (WHO). Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. 2018. Available from: https://apps.who.int/iris/bitstream/handle/10665/273174/9789241550345-eng.pdf?ua=1Google Scholar,13Ginès P Krag A Abraldes JG Solà E Fabrellas N Kamath PS. Liver cirrhosis.Lancet. 2021 Oct 9; 398: 1359-1376Google Scholar Evidence from one cohort of patients with confirmed liver cirrhosis through liver biopsy found that sustained virological response (SVR) was associated with reduced incidence of hepatic decompensation and liver cancer.14Nahon P Bourcier V Layese R Audureau E Cagnot C Marcellin P et al.Eradication of Hepatitis C Virus Infection in Patients With Cirrhosis Reduces Risk of Liver and Non-Liver Complications.Gastroenterology. 2017; 152 (e2): 142-156Google Scholar Evidence from a study using transient elastography to measure liver stiffness found that approximately one third of cirrhotic patients were reclassified as non-cirrhotic post-SVR.15Fernandes FF Piedade J Guimaraes L Nunes EP Chaves U Goldenzon RV et al.Effectiveness of direct-acting agents for hepatitis C and liver stiffness changing after sustained virological response.J Gastroenterol Hepatol. 2019; 34: 2187-2195Google Scholar Another study found that those with Child-Pugh A cirrhosis had significantly reduced likelihood of clinical disease progression if they achieved SVR, compared to those who did not achieve a cure.16Krassenburg LAP Maan R Ramji A Manns MP Cornberg M Wedemeyer H et al.Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity.J Hepatol. 2021 May 1; 74: 1053-1063Google Scholar Evidence from these studies demonstrate how treatment induced cure reduces the risk of liver disease progression and the risk of developing liver cancer. In addition, reducing the number of patients referred to specialists for DAA treatment will allow specialists more time to provide appropriate treatment to patients with advanced liver disease. Even in LMICs, strategies to reduce progression of cirrhosis among those with decompensated cirrhosis are available, for example: use of beta-blockers to reduce portal hypertension, banding of oesophageal varices in bleeders and those at high risk of bleeding (requiring access to endoscopy), and the use of lactulose to prevent hepatic encephalopathy.13Ginès P Krag A Abraldes JG Solà E Fabrellas N Kamath PS. Liver cirrhosis.Lancet. 2021 Oct 9; 398: 1359-1376Google Scholar,17EASL EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.J Hepatol. 2018 Aug 1; 69: 406-460Google Scholar Key to expanding safe and effective HCV treatment by GPs is the development of clear HCV testing and treatment guidelines, and the simplified tools to assess the degree of fibrosis or cirrhosis and whether the cirrhosis is compensated or decompensated, prior to initiating treatment. Identifying whether a patient has decompensated cirrhosis and requires referral is a pillar of differentiated care, where specific groups receive different levels of care depending on need. Liver disease assessment can be performed by trained non-specialist practitioners in primary care settings. Transient elastography of the liver (e.g., FibroScan®) is currently used as best practice, as it provides a clear clinical picture of the liver fibrosis and aids with planning post-DAA therapy care. However, FibroScan® technology has accessibility and affordability issues for most people in the Asia-Pacific. Further, FibroScan® is a specialised technology for liver fibrosis assessment which requires frequent maintenance, and intensive training for operators to perform the scan and interpret the results.18Londeix P. Diagnosis and monitoring of hepatitis C (HCV) in Morocco: Current status and strategies for universal access. Benchmarking HCV diagnostics, fibrosis evaluation, and treatment monitoring. 2018. Available from: https://www.alcs.ma/wp-content/uploads/2018/05/BenchmarkVA.pdfGoogle Scholar,19FibroScan for assessing liver fibrosis and cirrhosis in primary care Medtech innovation briefing. 2020. Available from: www.nice.org.uk/guidance/mib216Google Scholar Recognising this, the WHO Guidelines for HCV treatment (2018) recommend aspartate aminotransferase (AST) /platelet ratio index (APRI) score or FIB-4 test to assess liver fibrosis in resource limited settings.1World Health Organization (WHO). Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. 2018. Available from: https://apps.who.int/iris/bitstream/handle/10665/273174/9789241550345-eng.pdf?ua=1Google Scholar In many settings, APRI score is used to triage patients for FibroScan®. In others, it is used in conjunction with assessment for physical signs of liver decompensation. For example, the Myanmar National Guidelines require GPs to calculate the APRI score to decide treatment duration and to refer those with physical signs of hepatic decompensation to a specialist.20Ministry of Health and Sports Myanmar. Myanmar National Simplified Treatment Guidelines for Hepatitis C Infection - Second Edition, July 2019. Available from: https://mohs.gov.mm/page/3212Google Scholar The Pakistan HCV Testing and Treatment Guidelines also allow GPs to decide the duration of treatment based on APRI score, and only refer those with APRI >1·5 to a specialist.21Pakistan HCV Treatment Guidelines, 2020. Available from: http://phrc.org.pk/assets/pakistan-national-hcv-treatment-guidelines-sample-2.pdfGoogle Scholar The simple blood tests (AST, platelets) required for APRI score are widely available in most settings. Furthermore, it is worth noting that the presence of compensated cirrhosis does not change treatment duration recommendations for some treatment regimens.1World Health Organization (WHO). Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. 2018. Available from: https://apps.who.int/iris/bitstream/handle/10665/273174/9789241550345-eng.pdf?ua=1Google Scholar DAAs are safe and effective in people with compensated cirrhosis, and HCV eradication through DAA therapy is itself associated with reduced risk of developing cirrhosis and liver cancer. As such, HCV treatment should not be unduly delayed by requirements for special tests for cirrhosis (e.g. FibroScan®, ultrasound); especially in settings where the specialist management for portal hypertension or liver cancer screening is not widely available or utilised. Task-shifting to GPs and decentralisation of care into primary care settings is supported by growing evidence globally.22Oru E Trickey A Shirali R Kanters S Easterbrook P. Decentralisation, integration, and task-shifting in hepatitis C virus infection testing and treatment: a global systematic review and meta-analysis.Lancet Glob Heal. 2021; Google Scholar,23Radley A Robinson E Aspinall EJ Angus K Tan L Dillon JF A systematic review and meta-analysis of community and primary-care-based hepatitis C testing and treatment services that employ direct acting antiviral drug treatments.BMC Health Serv Res. 2019 Dec 28; 19: 765Google Scholar Systematic reviews have shown GPs can safely and effectively perform liver disease assessment and initiate DAA therapy for compensated cirrhotic patients in community settings, resulting in few adverse outcomes and high sustained virological response (SVR12) rates.22Oru E Trickey A Shirali R Kanters S Easterbrook P. Decentralisation, integration, and task-shifting in hepatitis C virus infection testing and treatment: a global systematic review and meta-analysis.Lancet Glob Heal. 2021; Google Scholar,23Radley A Robinson E Aspinall EJ Angus K Tan L Dillon JF A systematic review and meta-analysis of community and primary-care-based hepatitis C testing and treatment services that employ direct acting antiviral drug treatments.BMC Health Serv Res. 2019 Dec 28; 19: 765Google Scholar Ensuring patient safety is paramount, and this can be facilitated through use of quality-assured diagnostics and laboratories, and through adequate training and support for GPs. Clear clinical decision-making tools, including APRI score calculator, drug-drug interaction checkers, and summary tables of key pre-treatment assessments and treatment options, are available in many settings to support GPs to prescribe DAAs. For example, the EC toolkit in Australia was developed to collate available tools and develop extra tools to address unmet needs within primary care in Australia (see: https://ecpartnership.org.au/toolkit). Task-shifting care to GPs and decentralisation into primary care settings will allow for increased access to HCV treatment outside of urban centres, ensuring more equitable access to care. Country-specific assessments on where to focus efforts, considering the epidemiology of disease burden, will be required to inform distribution of resources needed to serve the general population, or various key population groups including people who inject drugs, people in prison, or people living with HIV. Implementation of robust national data systems would improve the data available to inform strategies and to monitor progress. Such country-specific assessments can also help inform the testing strategy and assist practitioners to target testing, either through regular testing of key population groups and/or to general population one-time screening; the approach will be country-specific based on estimated HCV prevalence among general population and key population groups, considering resource availability.24Easterbrook PJ. Who to test and how to test for chronic hepatitis C infection –2016 WHO testing guidance for low- and middle-income countries.J Hepatol. 2016 Oct; 65: S46-S66Google Scholar With low-cost rapid diagnostics available for screening, it is unlikely that excessive screening of HCV will occur; however, it is important to ensure all those who screen positive have access to confirmatory nucleic acid testing to diagnose active infection. Successful implementation of simplified clinical pathways in secondary and tertiary based hospitals, and some at decentralised HIV treatment sites, through national programs has been demonstrated in Myanmar, Cambodia, India, and Indonesia.25Boeke CE Adesigbin C Agwuocha C Anartati A Aung HT Aung KS et al.Initial from a public health approach to hepatitis C testing, treatment and cure in The to Global 2020; Scholar work in Myanmar and work from and effective of care for treatment, using simplified clinical B H A Howell J et al.Outcomes of the A for hepatitis C testing and treatment in Liver 2021; M D J K V P et hepatitis C testing and treatment in evaluation of a simplified integrated in existing public health Gastroenterol Hepatol. 2021; Google Scholar studies found that treatment of compensated cirrhotic patients by GPs at was safe and with high cure and few adverse of treatment was high and there was limited to up from B H A Howell J et al.Outcomes of the A for hepatitis C testing and treatment in Liver 2021; M D J K V P et hepatitis C testing and treatment in evaluation of a simplified integrated in existing public health Gastroenterol Hepatol. 2021; Google Scholar Task-shifting to GPs required clear referral and pathways was important in the Myanmar for ensuring B H A Howell J et al.Outcomes of the A for hepatitis C testing and treatment in Liver 2021; Scholar and non-specialist led care has been in many countries in the Asia-Pacific In the Western Pacific region, a review of progress towards HCV elimination found that countries have their hepatitis services into primary P-L Le L-V Ishikawa N Easterbrook P. Regional progress towards hepatitis C elimination in the Western Pacific Region, 2015-2020.Glob Heal Med. 2021; 3: 253-261Google Scholar For example, in following of decentralised care in primary health care primary healthcare are treatment, with care provided by trained J H can from to achieve the of hepatitis C as a public health by – a Heal - 2021; Scholar In HCV treatment is half of patients treatment from 2016 to had their by a F GJ S Martinello M J et of direct-acting antiviral therapy by general practitioners for people with hepatitis C in treatment J 2021 Aug Scholar specialist and was required by GPs without DAAs. This was facilitated through and treatment of cirrhotic patients by GPs where access to a specialist was J A K M A et al.Outcomes of hepatitis C treatment by general practitioners and in Australia through specialist 2021 1; AJ A C K M N et for of a general practitioners to prescribe direct-acting antiviral therapy for hepatitis Viral 2018 1; Scholar A also for the treatment in Australia where provide treatment to those in for those without cirrhosis or with compensated L A M Iser D A et al.Outcomes of treatment for hepatitis C in using a of Hepatol. 2019; Scholar Simplified care with non-specialist practitioners DAAs be to reach the of coverage need to achieve elimination especially in LMICs where there are few is to ensure that national allow GPs and other non-specialist practitioners to treat patients with compensated cirrhosis, to provide frequent training for these practitioners, and to develop effective referral pathways for specialist review or and support to GPs can be provided through the for for the elimination of viral Gastroenterol Hepatol. 2019 1; Scholar is a where one provides support for a of primary care providers through use of frequent for specialists to best on HCV testing and treatment, and for community providers to case for and recommendations for a treatment for the elimination of viral Gastroenterol Hepatol. 2019 1; Scholar Evidence from hepatitis C and other has shown that a can be used for ongoing and of for the elimination of viral Gastroenterol Hepatol. 2019 1; L C N et and evaluation of a for the HIV 1; of in for in 2021 Aug Scholar Another for specialist support is through the use of with a in this is widely used by GPs in J A K M A et al.Outcomes of hepatitis C treatment by general practitioners and in Australia through specialist 2021 1; AJ A C K M N et for of a general practitioners to prescribe direct-acting antiviral therapy for hepatitis Viral 2018 1; Scholar for HCV care into primary care GPs to trained and provide HCV care, accessibility of for HCV testing and liver function and the workloads of GPs in primary these be within While all cirrhotic patients treated by GPs will receive ongoing post-DAA therapy liver care to monitor for liver disease in liver cancer through this is unlikely to be or widely in most settings and clinical are also For example, are available in and in Myanmar, access is limited in the public health and is Referral pathways for those with advanced disease or liver cancer should be where to ensure those who require specialist management can access on treating patients with cirrhosis can reduce the of liver disease in settings the Asia-Pacific care and non-specialist led HCV care will be key to expanding testing and treatment to all people by is time to in scaling up decentralised care, with training GPs, to ensure that all those living with HCV have access to a those with cirrhosis who are most to from timely treatment to reduce their risk of liver disease has from and for has from and and from for has for and from and for also on the of for of Australia has Health for has support from to for DAAs for Myanmar Liver and for liver for Myanmar Liver has support from and to has in for and has on the Liver Liver of specific for this The which this work was supported by through the