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Screening is caring: Community-based non-invasive diagnosis and treatment strategies for hepatitis C to reduce liver disease burden

  • Isabel Graupera
    Correspondence
    Corresponding author. Address: Liver Unit, Hospital Clinic of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
    Affiliations
    Liver Unit, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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  • Frank Lammert
    Affiliations
    Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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      Linked Article

      For several chronic liver diseases, effective treatment is available. This includes hereditary hemochromatosis and other inborn errors of metabolism, primary biliary cholangitis and autoimmune hepatitis as well as chronic viral hepatitis. However, many patients are not identified by current strategies for the prevention, screening and diagnosis of liver disease.
      • Ginès P.
      • Graupera I.
      • Lammert F.
      • Angeli P.
      • Caballeria L.
      • Krag A.
      • et al.
      Screening for liver fibrosis in the general population: a call for action.
      • Williams R.
      • Alexander G.
      • Armstrong I.
      • Baker A.
      • Bhala N.
      • Camps-Walsh G.
      • et al.
      Disease burden and costs from excess alcohol consumption, obesity, and viral hepatitis: fourth report of the Lancet Standing Commission on Liver Disease in the UK.
      Since the implementation of the highly successful therapy with direct acting antivirals (DAA) against the hepatitis C virus (HCV), the eradication of HCV infection as a major public health threat has come into reach. In fact, one of the goals of Global Health Sector Strategy for Viral Hepatitis released by the World Health Organization (WHO) is to eliminate HCV infection as a major public health threat by 2030.
      European Union HCV Collaborator
      Hepatitis C virus prevalence and level of intervention required to achieve the WHO targets for elimination in the European Union by 2030: a modelling study.

      WHO. Draft global health sector strategy on viral hepatitis 2016–2021. http://www.who.int/hepatitis/strategy2016–2021/Draft_global_health_sector_strategy_viral_hepatitis_13nov.pdf?ua=1

      To achieve this ambitious aim, three different pillars have been proposed by the WHO, including “90% reduction of new cases of chronic hepatitis C (CHC), 65% reduction in CHC associated deaths and treatment of 80% of eligible people with CHC”. Data from the global prevalence of HCV modeling study
      Polaris Observatory HCV Collaborators
      Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study.
      have shown that global prevalence of viraemic HCV is estimated to be 1% (95% CI 0.8–1.1), corresponding to 71 million viraemic infections (95% CI 63–79). Less than 40% of these patients have been diagnosed today. Therefore, it is essential to develop and implement new supranational, national or regional strategies to reach these targets and to assess their cost-effectiveness. Data from Europe has shown that since the introduction of DAAs, the number of patients treated doubled from 2013 to 2015, but to achieve the targets of WHO a further increase of up to 25% is required by 2025.
      Polaris Observatory HCV Collaborators
      Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study.
      This will reduce the number of patients with decompensated cirrhosis, hepatocellular carcinoma and liver-related deaths.
      • Lens S.
      • Alvarado-Tapias E.
      • Mariño Z.
      • Londoño M.C.
      • LLop E.
      • Martinez J.
      • et al.
      Effects of all-oral anti-viral therapy on HVPG and systemic hemodynamics in patients with hepatitis c virus-associated cirrhosis.
      Public health programs oriented to population-based screening for all 60% of silent HCV infections can be envisioned, but new strategies to provide access to treatment for all these patients should be addressed.
      Across Europe, the treatment for HCV infected patients is mainly administrated by specialists, but the short duration regimens and the low rates of adverse events make DAA-therapy suitable for administration in the community setting. In fact, there is increasing evidence of the efficacy of community-based programs for CHC diagnosis and treatment.
      • Scott N.
      • Hainsworth S.W.
      • Sacks-Davis R.
      • Pedrana A.
      • Doyle J.
      • Wade A.
      • et al.
      Heterogeneity in hepatitis C treatment prescribing and uptake in Australia: a geospatial analysis of a year of unrestricted treatment access.
      • Morris L.
      • Smirnov A.
      • Kvassay A.
      • Leslie E.
      • Kavanagh R.
      • Alexander N.
      • et al.
      Initial outcomes of integrated community-based hepatitis C treatment for people who inject drugs: Findings from the Queensland Injectors’ Health Network.
      • Radley A.
      • Tait J.
      • Dillon J.F.
      DOT-C: a cluster randomised feasibility trial evaluating directly observed anti-HCV therapy in a population receiving opioid substitute therapy from community pharmacy.
      • Capileno Y.A.
      • Van den Bergh R.
      • Donchunk D.
      • Hinderaker S.G.
      • Hamid S.
      • Auat R.
      • et al.
      Management of chronic hepatitis C at a primary health clinic in the high-burden context of Karachi, Pakistan.
      However, in patients with advanced liver disease antiviral treatment regimens should be prescribed cautiously to avoid potential toxicity. Current European Association for the Study of the Liver guidelines recommend assessing liver disease severity prior to therapy by non-invasive serum surrogate markers or liver stiffness measurement (LSM) to identify patients with advanced fibrosis or cirrhosis.
      European Association for the Study of the Liver
      EASL recommendations on treatment of hepatitis C 2018.
      Accordingly, patients without advanced liver fibrosis might qualify for management by primary care centres. Hence, the identification of patients with chronic liver diseases and advanced fibrosis should be integrated into screening programs for liver patients in the community. Until now, LSM is mainly used in tertiary care settings, and data on the utility of LSM in primary care is scarce.
      • Caballería L.
      • Pera G.
      • Arteaga I.
      • Rodríguez L.
      • Alumà A.
      • Morillas R.M.
      • et al.
      High prevalence of liver fibrosis among European adults with unknown liver disease: a population-based study.
      In this issue of Journal of Hepatology, Bloom and co-authors confirm the role of LSM for fibrosis assessment in patients with CHC in the community setting and suggest that LSM may predict liver-related events in this scenario.
      • Bloom S.
      • Kemp W.
      • Nicoll A.
      • Roberts S.K.
      • Gow P.
      • Dev A.
      Liver stiffness measurement in the primary care setting detects high rates of advanced fibrosis and predicts liver-related events in hepatitis C.
      Bloom et al. included 780 patients from 21 primary care centres in Australia with CHC infection and compared the fibrosis prevalence of this community cohort with that of a cohort of hospital-referred patients with CHC. The individuals were identified by their primary care providers either by disclosure, universal testing in high-risk populations (for example, people who inject drugs) and in the setting of abnormal liver function tests, as outlined in Australian guidelines, but there is the potential for ascertainment bias given the method of identification of assessment sites. Median LSM was 6.9 kPa in the community with 16.5% at risk of advanced fibrosis (LSM ≥12.5 kPa) and 24.6% with LSM between 8.0 and 12.5 kPa, which was surprisingly not different to the hospital-referred cohort, which displayed a median LSM of 6.8 kPa and 20.2% of patients at risk of advanced fibrosis and 18% with LSM ranging from 8.0 to 12.5 kPa (p = 0.2 and p = 0.051, respectively). Interestingly, in the community cohort, 17.3% of patients at risk of advanced fibrosis had no signals of advanced disease, as assessed by clinical signs, biochemical scores or ultrasound, therefore LSM was able to detect patients at risk who otherwise could have been missed or misclassified. Out of the 780 patients, 231 were referred for further evaluation to a tertiary centre, 89 with LSM between 8 and 12.5 kPa and 129 with LSM ≥12.5 kPa; 15 patients suffered from dual infection (CHC plus chronic hepatitis B). The best LSM thresholds in screening studies have yet to be defined, but the recent population-based study in the Barcelona metropolitan area reported that LSM <9.2 kPa had the highest accuracy to rule out significant liver fibrosis, but here only 9 out of 3,076 patients (0.3%) were anti-HCV positive.
      • Caballería L.
      • Pera G.
      • Arteaga I.
      • Rodríguez L.
      • Alumà A.
      • Morillas R.M.
      • et al.
      High prevalence of liver fibrosis among European adults with unknown liver disease: a population-based study.
      During a median follow-up of 12.4 months only, 9.3% of patients with LSM ≥12.5 kPa developed liver-related events, which is a 56-fold increased rate of liver-related events. In this study, the best LSM cut-off for prediction of liver-related events in the community setting was 24.0 kPa (hazard ratio 152). Based on their data the authors propose that a community-based program for CHC cirrhosis detection with LSM is feasible and could identify those patients who need to be referred for treatment in tertiary centres, whereas the others could be managed in a primary care setting. The uptake of LSM screening was particularly high (75.7%), taking into consideration the rates of participation in other screening programs, but data on the clinical differences between those who did and did not accept screening in the study is limited. Although the authors also suggest that LSM could also be helpful for the prediction of liver-related events in the community setting, the number of clinical events is low and the potential clinical value should be evaluated further. More studies with patient numbers and more clinical events are needed to confirm these results.
      In Australia, non-specialists have been able to prescribe DAAs since 2016, and during the first 14 months of the program, 46% of all therapies (20,323/44,382) have been indicated by non-specialists.
      • Scott N.
      • Hainsworth S.W.
      • Sacks-Davis R.
      • Pedrana A.
      • Doyle J.
      • Wade A.
      • et al.
      Heterogeneity in hepatitis C treatment prescribing and uptake in Australia: a geospatial analysis of a year of unrestricted treatment access.
      In the era of DAAs and with the WHO eradication goal on the horizon, the Australian example points to new public health strategies that could be implemented, including non-specialists as prescribers and “liver nurses” for follow-up and compliance.
      In summary, Bloom et al. provide novel evidence that a screening program with LSM measurement could be useful to detect patients at risk of advanced cirrhosis and decompensation in the population. This data may be useful to design new programs for screening and subsequent treatment of patients with chronic liver disease, involving community-based resources to maximize the delivery of state-of-the-art diagnostic tools and treatment options to reduce the burden and costs from chronic liver disease.

      Financial support

      Isabel Graupera has received grant support from: EIT Health 2018, project number 18258. Frank Lammert has received grant support from BMBF (LiSyM 031L0051).

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

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