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EASL recommendations on treatment of hepatitis C: Final update of the series

Published:September 14, 2020DOI:https://doi.org/10.1016/j.jhep.2020.08.018

      Summary

      Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, with approximately 71 million chronically infected individuals worldwide. Clinical care for patients with HCV-related liver disease has advanced considerably thanks to an enhanced understanding of the pathophysiology of the disease, as well as developments in diagnostic procedures and improvements in therapy and prevention. These therapies make it possible to eliminate hepatitis C as a major public health threat, as per the World Health Organization target, although the timeline and feasibility vary from region to region. These European Association for the Study of the Liver recommendations on treatment of hepatitis C describe the optimal management of patients with recently acquired and chronic HCV infections in 2020 and onwards.

      Introduction

       Background

      In 2015 it was estimated that there were approximately 71 million individuals chronically infected with hepatitis C virus (HCV) worldwide,
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      HCV infection remains one of the main causes of chronic liver disease worldwide.
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      The long-term natural history of HCV infection is highly variable: the hepatic injury can range from minimal necro-inflammatory changes to extensive fibrosis and cirrhosis with or without hepatocellular carcinoma (HCC). Clinical care for patients with HCV-related liver disease has advanced considerably during the last couple of decades, thanks to an enhanced understanding of the pathophysiology of the disease, and because of developments in diagnostic procedures and radical improvements in therapy and prevention.
      The primary goal of HCV therapy is to cure the infection, i.e. to achieve a sustained virological response (SVR) defined as undetectable HCV RNA after treatment completion. An SVR corresponds to a cure of the HCV infection, as late relapse occurs in less than 0.2% of cases beyond 6 months of follow-up.
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      Late relapse versus hepatitis C virus reinfection in patients with sustained virologic response after sofosbuvir-based therapies.
      An SVR is generally associated with normalisation of liver enzymes and improvement or regression of liver necroinflammation and fibrosis, and improvement in liver function.
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      Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study.
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      Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy.
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      Portal pressure and liver stiffness measurements in the prediction of fibrosis regression after sustained virological response in recurrent hepatitis C.
      The risk of HCC and liver-related mortality is significantly reduced, but not eliminated, in patients with cirrhosis who clear HCV compared to untreated patients and non-sustained virological responders, especially in the presence of cofactors of liver morbidity, such as the metabolic syndrome, harmful alcohol consumption and/or concurrent hepatitis B virus (HBV) infection.
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      Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study.
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      Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis.
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      Survival of patients with HCV cirrhosis and sustained virologic response is similar to the general population.
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      Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications.
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      Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents.
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      Development of models estimating the risk of hepatocellular carcinoma after antiviral treatment for hepatitis C.
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      Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting antiviral agents.
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      The short-term incidence of hepatocellular carcinoma is not increased after hepatitis C treatment with direct-acting antivirals: an ERCHIVES study.
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      Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents.
      HCV is also associated with a number of extrahepatic manifestations, but viral elimination can reduce all-cause mortality.
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      Extrahepatic manifestations of chronic hepatitis C.
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      Chronic hepatitis C virus infection and lymphoproliferative disorders: mixed cryoglobulinemia syndrome, monoclonal gammopathy of undetermined significance, and B-cell non-Hodgkin lymphoma.
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      Reversion of disease manifestations after HCV eradication.
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      The effect of sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus infection.
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      Expanded benefits of curing the extrahepatic manifestations of HCV infection.
      This final update of the EASL Recommendations on Treatment of Hepatitis C series started in 2014 is intended to assist physicians and other healthcare providers, as well as patients and other interested individuals, in the clinical decision-making process, by describing the current optimal management of patients with acute and chronic HCV infections. These recommendations apply to therapies that have been approved by the European Medicines Agency and other national European agencies at the time of their publication. The panel recognises the heterogeneity of per capita incomes, health insurance systems and drug prices in different regions, and therefore the constraints that apply to access to branded and generic drugs.

       Methodology

      These EASL recommendations have been prepared by a panel of experts chosen by the EASL Governing Board. The recommendations are primarily based on evidence from existing publications and presentations at international meetings. In the absence of such evidence, the experts' personal experiences and opinions have been considered. The evidence and recommendations have been graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.
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      • et al.
      GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations.
      The strength of recommendations reflects the quality of underlying evidence. The quality of the evidence in the recommendations has been classified into 1 of 3 levels: high (A), moderate (B) or low (C). The GRADE system offers 2 grades of recommendation: strong (1) or weak (2) (Table 1). Thus, these recommendations consider the quality of evidence: the higher the quality of evidence, the more likely a strong recommendation is warranted; the greater the variability in values and preferences, or the greater the uncertainty, the more likely a weaker recommendation is warranted. The recommendations have been approved by the EASL Governing Board.
      Table 1Evidence grading used (adapted from the GRADE system).
      Evidence qualityNotesGrading
      HighFurther research is very unlikely to change our confidence in the estimate of effectA
      ModerateFurther research is likely to have an important impact on our confidence in the estimate of effect and may change the estimateB
      LowFurther research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Any change of estimate is uncertainC
      RecommendationNotesGrading
      StrongFactors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and cost1
      WeakVariability in preferences and values, or more uncertainty. Recommendation is made with less certainty, higher cost or resource consumption2

      Available drugs in Europe

      The HCV drug combinations available in Europe are listed in this paragraph and in Table 2. Their known pharmacokinetic and safety profiles are presented.
      Table 2HCV DAAs approved in Europe recommended in this document and yet unapproved paediatric formulations (information provided by Abbvie and Gilead on request from the panel).
      ProductPresentationPosology
      SofosbuvirTablets containing 400 mg of sofosbuvirOne tablet once daily
      Half-strength tablets containing 200 mg of sofosbuvir
      Paediatric formulation.
      One tablet once daily
      Sofosbuvir/velpatasvirTablets containing 400 mg of sofosbuvir and 100 mg of velpatasvirOne tablet once daily
      Half-strength tablets containing 200 mg of sofosbuvir and 50 mg of velpatasvir
      Paediatric formulation.
      ,
      Approval pending.
      One tablet once daily
      Granules containing 50 mg of sofosbuvir and 12.5 mg of velpatasvir
      Paediatric formulation.
      ,
      Approval pending.
      Three or four granules once daily, according to body weight
      Sofosbuvir/velpatasvir/voxilaprevirTablets containing 400 mg of sofosbuvir, 100 mg of velpatasvir and 100 mg of voxilaprevirOne tablet once daily with food
      Glecaprevir/pibrentasvirTablets containing 100 mg of glecaprevir and 40 mg of pibrentasvirThree tablets once daily with food
      Film-coated granules of glecaprevir and pibrentasvir in sachets containing 50 mg of glecaprevir and 20 mg of pibrentasvir mixed together in a small amount of food
      Paediatric formulation.
      ,
      Approval pending.
      Three to five sachets once daily, according to body weight
      Grazoprevir/elbasvirTablets containing 100 mg of grazoprevir and 50 mg of elbasvirOne tablet once daily
      DAAs, direct-acting antivirals.
      a Paediatric formulation.
      b Approval pending.

       Sofosbuvir

      Sofosbuvir should be administered at the dose of 400 mg (1 tablet) once per day, with or without food.
      Approximately 80% of sofosbuvir is renally excreted, whereas 15% is excreted in faeces. The majority of the sofosbuvir dose recovered in urine is the dephosphorylation-derived nucleoside metabolite GS-331007 (78%), while 3.5% is recovered as sofosbuvir. Renal clearance is the major elimination pathway for GS-331007, with a large part actively secreted. No dose adjustment of sofosbuvir is required for patients with mild to moderate renal impairment. Sofosbuvir-containing regimens were shown to be safe in patients with moderate to severe renal impairment, including those with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 and those with end-stage renal disease requiring haemodialysis, with or without hepatic decompensation.
      • Eletreby R.
      • El-Serafy M.
      • Anees M.
      • Kasem G.
      • Salama M.
      • Elkhouly R.
      • et al.
      Sofosbuvir-containing regimens are safe and effective in the treatment of HCV patients with moderate to severe renal impairment.
      A recent study has confirmed the safety of sofosbuvir in patients with stage 4–5 kidney disease who were not on dialysis.
      • Lawitz E.
      • Landis C.S.
      • Flamm S.L.
      • Bonacini M.
      • Ortiz-Lasanta G.
      • Huang J.
      • et al.
      Sofosbuvir plus ribavirin and sofosbuvir plus ledipasvir in patients with genotype 1 or 3 hepatitis C virus and severe renal impairment: a multicentre, phase 2b, non-randomised, open-label study.
      Sofosbuvir exposure is not significantly changed in patients with mild liver impairment (Child-Pugh A cirrhosis), but it is increased 2.3-fold in those with moderate liver impairment (Child-Pugh B cirrhosis).
      Sofosbuvir is well tolerated over 12 to 24 weeks of administration.

       Sofosbuvir/velpatasvir

      Sofosbuvir and velpatasvir are available in a two-drug fixed-dose combination containing 400 mg of sofosbuvir and 100 mg of velpatasvir in a single tablet. The recommended dose of the combination is 1 tablet taken orally once daily with or without food.
      Velpatasvir is metabolised in vitro by cytochrome P450 (CYP) 2B6, CYP2C8 and CYP3A4. However, because of the slow turnover, the vast majority of drug in plasma is the parent drug. Importantly, velpatasvir is transported by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and, to a limited extent, by organic anion transporting polypeptide (OATP) 1B1. Biliary excretion of the parent drug is the major route of elimination. The median terminal half-life of velpatasvir following administration of sofosbuvir and velpatasvir is approximately 15 hours.
      Velpatasvir plasma exposure (area under curve, AUC) is similar in patients with moderate and severe hepatic impairment (Child-Pugh B and C cirrhosis, respectively) compared to those with normal hepatic function. Cirrhosis, including decompensated cirrhosis, had no clinically relevant effect on velpatasvir exposure in a population-level pharmacokinetic analysis in HCV-infected individuals.
      • Mogalian E.
      • Brainard D.M.
      • Osinusi A.
      • Moorehead L.
      • Murray B.
      • Ling K.H.J.
      • et al.
      Pharmacokinetics and safety of velpatasvir and sofosbuvir/velpatasvir in subjects with hepatic impairment.
      The pharmacokinetics of velpatasvir have been studied in HCV-negative patients with severe renal impairment (eGFR <30 ml/min/1.73 m2). Relative to individuals with normal renal function, the AUC of velpatasvir was 50% higher, which was not considered to be clinically relevant.
      • Smolders E.J.
      • de Kanter C.T.
      • van Hoek B.
      • Arends J.E.
      • Drenth J.P.
      • Burger D.M.
      Pharmacokinetics, efficacy, and safety of hepatitis C virus drugs in patients with liver and/or renal impairment.
      Treatment with sofosbuvir/velpatasvir for 12 weeks was reported to be safe in patients with end-stage renal disease undergoing haemodialysis.
      • Borgia S.M.
      • Dearden J.
      • Yoshida E.M.
      • Shafran S.D.
      • Brown A.
      • Ben-Ari Z.
      • et al.
      Sofosbuvir/velpatasvir for 12 weeks in hepatitis C virus-infected patients with end-stage renal disease undergoing dialysis.
      The safety assessment of sofosbuvir and velpatasvir was based on pooled phase III and real-world data.
      • Lawitz E.
      • Feld J.J.
      • Jacobson I.M.
      • Weiland O.
      • Sood A.
      • Gordon S.C.
      • et al.
      Efficacy and safety of sofosbuvir/velpatasvir for the treatment of patients with chronic hepatitis C genotype 1-6 infection: integrated analysis of eight Phase 3 clinical trials.
      ,
      • Mangia A.
      • Milligan S.
      • Khalili M.
      • Fagiuoli S.
      • Shafran S.
      • Carrat F.
      • et al.
      Global real-world evidence of sofosbuvir/velpatasvir as a simple, effective regimen for the treatment of chronic hepatitis C patients: integrated analysis of 12 clinical practice cohorts.
      Headache, fatigue and nausea were the most commonly reported adverse events, at a similar frequency to placebo-treated patients.

       Sofosbuvir/velpatasvir/voxilaprevir

      Sofosbuvir, velpatasvir and voxilaprevir are available in a three-drug fixed-dose combination containing 400 mg of sofosbuvir, 100 mg of velpatasvir and 100 mg of voxilaprevir in a single tablet. The recommended dose of the combination is 1 tablet taken orally once daily with food, as voxilaprevir plasma exposure (AUC) and maximum concentration (Cmax) were 112% to 435%, and 147% to 680% higher, respectively, in the presence of food.
      Voxilaprevir is metabolised in vitro by CYP3A4, with the vast majority of drug in plasma being the parent drug. Velpatasvir and voxilaprevir are both inhibitors of drug transporters P-gp, BCRP, OATP1B1 and OATP1B3. Biliary excretion of the parent drug is the major route of elimination for voxilaprevir. The median terminal half-life of voxilaprevir following administration of sofosbuvir, velpatasvir and voxilaprevir is approximately 33 hours.
      Population pharmacokinetic analysis of voxilaprevir in HCV-infected patients indicated that patients with compensated (Child-Pugh A) cirrhosis had 73% higher exposure to voxilaprevir than those without cirrhosis. Thus, no dose adjustment of sofosbuvir, velpatasvir and voxilaprevir is required for patients with compensated (Child-Pugh A) cirrhosis. The pharmacokinetics of single-dose voxilaprevir were also studied in patients with moderate and severe hepatic impairment (Child-Pugh B and C cirrhosis, respectively). Relative to patients with normal hepatic function, the voxilaprevir AUC was 3-fold and 5-fold higher in patients with moderate and severe hepatic impairment, respectively. Thus, the combination of sofosbuvir, velpatasvir and voxilaprevir should not be used in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.
      The pharmacokinetics of voxilaprevir have been studied in HCV-negative patients with severe renal impairment (eGFR <30 ml/min/1.73 m2). Relative to patients with normal renal function, the AUC of voxilaprevir was 71% higher in those with severe renal impairment, which was not considered to be clinically relevant.
      The safety data of sofosbuvir, velpatasvir and voxilaprevir was based on data from phase II and III clinical trials and real-world studies.
      • Bourliere M.
      • Gordon S.C.
      • Flamm S.L.
      • Cooper C.L.
      • Ramji A.
      • Tong M.
      • et al.
      Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection.
      • Jacobson I.M.
      • Lawitz E.
      • Gane E.J.
      • Willems B.E.
      • Ruane P.J.
      • Nahass R.G.
      • et al.
      Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials.
      • Belperio P.S.
      • Shahoumian T.A.
      • Loomis T.P.
      • Backus L.I.
      Real-world effectiveness of sofosbuvir/velpatasvir/voxilaprevir in 573 direct-acting antiviral experienced hepatitis C patients.
      • Llaneras J.
      • Riveiro-Barciela M.
      • Lens S.
      • Diago M.
      • Cachero A.
      • Garcia-Samaniego J.
      • et al.
      Effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C previously treated with DAAs.
      • Degasperi E.
      • Spinetti A.
      • Lombardi A.
      • Landonio S.
      • Rossi M.C.
      • Pasulo L.
      • et al.
      Real-life effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients with previous DAA failure.
      Headache, diarrhoea and nausea were the most commonly reported adverse events. The incidence of gastrointestinal side effects was greater than with the combination of sofosbuvir and velpatasvir alone.

       Glecaprevir/pibrentasvir

      Glecaprevir and pibrentasvir are available in a two-drug fixed-dose combination containing 100 mg of glecaprevir and 40 mg of pibrentasvir. The recommended dose is 3 tablets taken orally once daily with food, as glecaprevir plasma exposure increases 83%–163% in the presence of food compared to the fasted state.
      Biliary excretion is the major route of elimination for both glecaprevir and pibrentasvir. Their half-lives are approximately 6 and 23 hours, respectively.
      Population-level pharmacokinetic analysis in HCV-infected individuals showed that following administration of glecaprevir/pibrentasvir in HCV-infected patients with compensated (Child-Pugh A) cirrhosis, exposure to glecaprevir was approximately 2-fold higher whilst pibrentasvir exposure was similar to that in patients without cirrhosis. When compared to patients with normal hepatic function, the AUC of glecaprevir was 33% higher in patients with compensated (Child-Pugh A) cirrhosis, 100% higher in those with moderate hepatic impairment (Child-Pugh B cirrhosis), and increased to 11-fold in those with severe hepatic impairment (Child-Pugh C cirrhosis). Thus, glecaprevir/pibrentasvir should not be used in patients with Child-Pugh B or C cirrhosis.
      Glecaprevir/pibrentasvir was studied in HCV-negative individuals with mild, moderate, severe, or end-stage renal impairment not on dialysis and compared to those with normal renal function. AUCs were increased by less than 56% in all patients with any stage of renal disease, which was not clinically significant. The AUC of glecaprevir/pibrentasvir was also similar in patients on dialysis; thus, this combination can be recommended in patients with mild, moderate, severe and end-stage renal impairment.
      • Lawitz E.
      • Gane E.J.
      • Zadeikis N.
      • Sise M.
      • Zamor P.J.
      • Persico M.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV infection and moderate to severe renal impairment: an integrated analysis.
      The safety of pibrentasvir and glecaprevir was evaluated in phase II and III clinical trials and real-world studies.
      • Flamm S.
      • Mutimer D.
      • Asatryan A.
      • Wang S.
      • Rockstroh J.
      • Horsmans Y.
      • et al.
      Glecaprevir/pibrentasvir in patients with chronic HCV genotype 3 infection: an integrated phase 2/3 analysis.
      • Puoti M.
      • Foster G.R.
      • Wang S.
      • Mutimer D.
      • Gane E.
      • Moreno C.
      • et al.
      High SVR12 with 8-week and 12-week glecaprevir/pibrentasvir therapy: an integrated analysis of HCV genotype 1-6 patients without cirrhosis.
      • Berg T.
      • Naumann U.
      • Stoehr A.
      • Sick C.
      • John C.
      • Teuber G.
      • et al.
      Real-world effectiveness and safety of glecaprevir/pibrentasvir for the treatment of chronic hepatitis C infection: data from the German Hepatitis C-Registry.
      • D'Ambrosio R.
      • Pasulo L.
      • Puoti M.
      • Vinci M.
      • Schiavini M.
      • Lazzaroni S.
      • et al.
      Real-world effectiveness and safety of glecaprevir/pibrentasvir in 723 patients with chronic hepatitis C.
      Headache and fatigue were the most commonly reported adverse events.

       Grazoprevir/elbasvir

      Grazoprevir and elbasvir are available in a two-drug fixed-dose combination containing 100 mg of grazoprevir and 50 mg of elbasvir in a single tablet. The recommended dose of the combination is 1 tablet taken orally once daily with or without food.
      Grazoprevir and elbasvir are partially metabolised by CYP3A4, but no circulating metabolites are detected in plasma. The principal route of elimination is biliary and faecal, with <1% recovered in urine. Grazoprevir is transported by P-gp and OATP1B1, while elbasvir is a substrate for P-gp. Both elbasvir (>99.9%) and grazoprevir (98.8%) are extensively bound to plasma proteins. The terminal half-life values are approximately 24 and 31 hours, respectively.
      Pharmacokinetic data from hepatic impairment studies in non-HCV-infected individuals have demonstrated a decrease in the AUC of elbasvir in patients with Child-Pugh A (40%), Child-Pugh B (28%) and Child-Pugh C (12%) cirrhosis. In contrast, grazoprevir exposure is increased in Child-Pugh A (70%), Child-Pugh B (5-fold) and Child-Pugh C (12-fold) cirrhosis. Based on these data, elbasvir/grazoprevir should not be used in patients with decompensated (Child-Pugh B or C) cirrhosis.
      No dose adjustment is required in patients with mild, moderate or severe renal impairment (including patients on haemodialysis or peritoneal dialysis). There is an increase in elbasvir (65%) and grazoprevir (86%) exposure in non-HCV-infected individuals with an eGFR <30 ml/min/1.73 m2, but this is not considered to be clinically significant.
      The safety of elbasvir/grazoprevir is based on phase II and III clinical trials and real-world studies, with the most commonly reported adverse reactions being fatigue and headache.
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      • Lawitz E.
      • Kwo P.Y.
      • Hezode C.
      • Peng C.Y.
      • Howe A.Y.M.
      • et al.
      Safety and efficacy of elbasvir/grazoprevir in patients with hepatitis C virus infection and compensated cirrhosis: an integrated analysis.
      • Zeuzem S.
      • Serfaty L.
      • Vierling J.
      • Cheng W.
      • George J.
      • Sperl J.
      • et al.
      The safety and efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 1b infection.
      • Kramer J.R.
      • Puenpatom A.
      • Erickson K.F.
      • Cao Y.
      • Smith D.
      • El-Serag H.B.
      • et al.
      Real-world effectiveness of elbasvir/grazoprevir in HCV-infected patients in the US Veterans Affairs Healthcare System.
      • Flamm S.L.
      • Bacon B.
      • Curry M.P.
      • Milligan S.
      • Nwankwo C.U.
      • Tsai N.
      • et al.
      Real-world use of elbasvir-grazoprevir in patients with chronic hepatitis C: retrospective analyses from the TRIO network.
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      • Fernandez I.
      • Perello C.
      • Gallego A.
      • Bonacci M.
      • Pascasio J.M.
      • et al.
      Effectiveness and safety of elbasvir/grazoprevir therapy in patients with chronic HCV infection: results from the Spanish HEPA-C real-world cohort.
      • Jacobson I.M.
      • Poordad F.
      • Firpi-Morell R.
      • Everson G.T.
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      • Bhanja S.
      • et al.
      Elbasvir/grazoprevir in people with hepatitis C genotype 1 infection and Child-Pugh class B cirrhosis: the C-SALT study.
      Rare cases (0.8%) of substantial elevations in alanine aminotransferase (ALT) level were reported, slightly more frequently in female, Asian and elderly patients.

      Diagnosis of recently acquired hepatitis C, chronic hepatitis C and HCV reinfection

      Anti-HCV antibodies are detectable in serum or plasma by enzyme immunoassay (EIA) in the vast majority of patients with HCV infection, but may be undetectable in the early phase of acute infection and in patients with chronic hepatitis C who are profoundly immunosuppressed. Following spontaneous or treatment-induced viral clearance, anti-HCV antibodies persist in the absence of HCV RNA, but titres may wane and finally disappear in some individuals.
      • Chevaliez S.
      • Pawlotsky J.M.
      Diagnosis and management of chronic viral hepatitis: antigens, antibodies and viral genomes.
      • Kamili S.
      • Drobeniuc J.
      • Araujo A.C.
      • Hayden T.M.
      Laboratory diagnostics for hepatitis C virus infection.
      • Takaki A.
      • Wiese M.
      • Maertens G.
      • Depla E.
      • Seifert U.
      • Liebetrau A.
      • et al.
      Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C.
      Anti-HCV antibody testing is not helpful to determine reinfection after treatment, as the antibodies are already present before reinfection in the vast majority of cases.
      The diagnosis of recently acquired and chronic HCV infection is based on the detection of HCV RNA in serum or plasma by a sensitive, exclusively qualitative or both qualitative and quantitative molecular method. An assay with a lower limit of detection ≤15 IU/ml is recommended. However, the vast majority of patients with an indication for anti-HCV therapy have an HCV RNA level above 50,000 IU/ml.
      • Terrault N.A.
      • Pawlotsky J.M.
      • McHutchison J.
      • Anderson F.
      • Krajden M.
      • Gordon S.
      • et al.
      Clinical utility of viral load measurements in individuals with chronic hepatitis C infection on antiviral therapy.
      There is an important need for affordable (less than US$5–US$10) point-of-care or near-care nucleic acid testing assays to ascertain viraemia, which would be applicable for large-scale diagnosis where sensitive HCV RNA assays are not available and/or not affordable, i.e. in low-to middle-income areas, as well as in specific settings in high-income countries. For widespread population testing, a qualitative HCV RNA assay needs only to have a lower limit of detection ≤1,000 IU/ml (3.0 Log10 IU/ml). In such settings, the low incidence of a false-negative test for viraemia with these assays is outweighed by the benefit of scaling up access to diagnosis and care. Indeed, a study in patients with chronic hepatitis C due to HCV genotype 1 found only 4 patients out of 2,472 (0.16%) with an HCV RNA level below 1,000 IU/ml.
      • Ticehurst J.R.
      • Hamzeh F.M.
      • Thomas D.L.
      Factors affecting serum concentrations of hepatitis C virus (HCV) RNA in HCV genotype 1-infected patients with chronic hepatitis.
      In a report from the Swiss Hepatitis C Cohort, 88 out of 2,533 (3.5%) treatment-naïve patients with chronic hepatitis C and available quantitative HCV RNA testing results ever had an HCV RNA level less than or equal to 1,000 IU/ml.
      • Bertisch B.
      • Brezzi M.
      • Negro F.
      • Mullhaupt B.
      • Ottiger C.
      • Kunzler-Heule P.
      • et al.
      Very low hepatitis C viral loads in treatment-naive persons: do they compromise hepatitis C virus antigen testing?.
      Young age, excessive alcohol consumption and absence of intravenous drug use were independently associated with an HCV RNA level ≤1,000 IU/ml. Among patients from this study with a very low viral level who had another HCV RNA level measurement available more than 6 months after their initial very low viral level, the vast majority had an HCV RNA level >1,000 IU/ml.
      • Bertisch B.
      • Brezzi M.
      • Negro F.
      • Mullhaupt B.
      • Ottiger C.
      • Kunzler-Heule P.
      • et al.
      Very low hepatitis C viral loads in treatment-naive persons: do they compromise hepatitis C virus antigen testing?.
      HCV core antigen in serum or plasma is a marker of HCV replication. Thus, HCV core antigen detection can be used to diagnose viraemia in recently acquired HCV infection, in chronic infection, or after HCV reinfection.
      • van Tilborg M.
      • Al Marzooqi S.H.
      • Wong W.W.L.
      • Maan R.
      • Vermehren J.
      • Maasoumy B.
      • et al.
      HCV core antigen as an alternative to HCV RNA testing in the era of direct-acting antivirals: retrospective screening and diagnostic cohort studies.
      HCV core antigen assays are less sensitive than HCV RNA assays for the diagnosis of viraemia (lower limit of detection equivalent to approximately 500 to 3,000 HCV RNA IU/ml, depending on the HCV genotype
      • Chevaliez S.
      • Feld J.
      • Cheng K.
      • Wedemeyer H.
      • Sarrazin C.
      • Maasoumy B.
      • et al.
      Clinical utility of HCV core antigen detection and quantification in the diagnosis and management of patients with chronic hepatitis C receiving an all-oral, interferon-free regimen.
      • Chevaliez S.
      • Soulier A.
      • Poiteau L.
      • Bouvier-Alias M.
      • Pawlotsky J.M.
      Clinical utility of hepatitis C virus core antigen quantification in patients with chronic hepatitis C.
      • Heidrich B.
      • Pischke S.
      • Helfritz F.A.
      • Mederacke I.
      • Kirschner J.
      • Schneider J.
      • et al.
      Hepatitis C virus core antigen testing in liver and kidney transplant recipients.
      ). They detect HCV core antigen in serum or plasma a few days after HCV RNA becomes detectable during acute HCV infection. In rare cases of chronic infection, HCV core antigen is undetectable in the presence of HCV RNA.
      • Freiman J.M.
      • Tran T.M.
      • Schumacher S.G.
      • White L.F.
      • Ongarello S.
      • Cohn J.
      • et al.
      Hepatitis C core antigen testing for diagnosis of hepatitis C virus infection: a systematic review and meta-analysis.
      The diagnosis of recently acquired hepatitis C can only be made confidently if recent seroconversion to anti-HCV antibodies can be documented. Not all patients with recently acquired hepatitis C test positive for anti-HCV antibodies at diagnosis. In these cases, recently acquired hepatitis C can be suspected if the clinical signs and symptoms are compatible with an acute hepatitis (ALT level >10 times the upper limit of normal and/or jaundice), in the absence of a history of chronic liver disease or other causes of acute hepatitis, and/or if a likely recent source of transmission is identifiable. In all cases, HCV RNA or HCV core antigen can be detected during the acute phase, although their concentrations may fluctuate with interludes (up to several weeks) of undetectable HCV RNA or HCV core antigen.
      • Arase Y.
      • Ikeda K.
      • Chayama K.
      • Murashima N.
      • Tsubota A.
      • Suzuki Y.
      • et al.
      Fluctuation patterns of HCV-RNA serum level in patients with chronic hepatitis C.
      ,
      • Cividini A.
      • Cerino A.
      • Muzzi A.
      • Furione M.
      • Rebucci C.
      • Segagni L.
      • et al.
      Kinetics and significance of serum hepatitis C virus core antigen in patients with acute hepatitis C.
      Thus, HCV RNA-negative or HCV core antigen-negative individuals should be retested for HCV RNA or HCV core antigen 12 and 24 weeks after a negative result to confirm definitive clearance.
      HCV reinfection can occur after spontaneous or treatment-induced HCV clearance when re-exposure to HCV has occurred in those with risk factors for infection. Reinfection is diagnosed based on the reappearance of HCV RNA or HCV core antigen after an SVR and the demonstration (by sequencing followed by phylogenetic analysis) that infection is caused by a different genotype or by a distantly related strain of the same genotype from the initial infection. Reinfection should be suspected in cases of a recurrence of HCV infection occurring more than 12 or 24 weeks post-SVR, if risk behaviours have continued.
      Recommendations
      • All patients with suspected de novo recently acquired HCV infection should be tested for anti-HCV antibodies and either HCV RNA or HCV core antigen in serum or plasma (A1).
      • Anti-HCV antibody-positive, HCV RNA-negative or HCV core antigen-negative patients with suspected de novo recently acquired HCV infection should be retested for HCV RNA 12 and 24 weeks later to confirm definitive clearance (A1).
      • All patients with suspected chronic HCV infection should be tested for anti-HCV antibodies in serum or plasma as first-line diagnostic test (A1).
      • If anti-HCV antibodies are detected in patients with suspected chronic HCV infection, either HCV RNA or HCV core antigen should be determined (A1).
      • HCV reinfection should be suspected in case of reappearance of HCV RNA or HCV core antigen after an SVR in individuals with risk factors for infection, and confirmed by the demonstration that infection is caused by a different genotype or, using sequencing followed by phylogenetic analysis, by a distantly related strain of the same genotype from the initial infection (A1).
      • Anti-HCV antibodies should be determined in serum or plasma by enzyme immunoassay (A1).
      • HCV RNA should be determined in serum or plasma by a sensitive molecular method with a lower limit of detection ≤15 IU/ml (A1).
      • HCV core antigen in serum or plasma by enzyme immunoassay is a marker of HCV replication that can be used as an alternative to HCV RNA to diagnose HCV viraemia (A1).
      • Where sensitive HCV RNA assays are not available and/or not affordable, a qualitative HCV RNA assay with a lower limit of detection ≤1,000 IU/ml (3.0 Log10 IU/ml) can be used to broaden access to HCV diagnosis and care (B1).

      Screening for chronic hepatitis C

      A major barrier to HCV elimination still results from the fact that a substantial proportion of patients with chronic HCV infection are unaware of their infection, with large variations across different regions, countries and risk populations.
      • Cooke G.S.
      • Andrieux-Meyer I.
      • Applegate T.L.
      • Atun R.
      • Burry J.R.
      • Cheinquer H.
      • et al.
      Accelerating the elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission.
      Accurate HCV prevalence and incidence data are needed to analyse the epidemiology in different regions and to design apposite public health interventions. Thus, HCV screening is required to identify infected individuals and to engage them in care. The optimal regional or national screening approaches should be determined based on the local epidemiology.
      Screening for HCV infection is based on the detection of anti-HCV antibodies. Either EIA or rapid diagnostic tests (RDTs) can be used to screen for anti-HCV antibodies. RDTs use various matrices, including serum and plasma, and can also utilise fingerstick capillary whole blood or oral (crevicular) fluid to facilitate screening without the need for venipuncture, sample centrifugation, freezing and skilled labour. RDTs for anti-HCV antibodies are simple to perform at room temperature without specific instrumentation or extensive training. They have been shown to have excellent sensitivity and specificity compared to EIAs.
      • Chevaliez S.
      • Poiteau L.
      • Rosa I.
      • Soulier A.
      • Roudot-Thoraval F.
      • Laperche S.
      • et al.
      Prospective assessment of rapid diagnostic tests for the detection of antibodies to hepatitis C virus, a tool for improving access to care.
      • Khuroo M.S.
      • Khuroo N.S.
      • Khuroo M.S.
      Diagnostic accuracy of point-of-care tests for hepatitis C virus infection: a systematic review and meta-analysis.
      • Shivkumar S.
      • Peeling R.
      • Jafari Y.
      • Joseph L.
      • Pant Pai N.
      Accuracy of rapid and point-of-care screening tests for hepatitis C: a systematic review and meta-analysis.
      • Tang W.
      • Chen W.
      • Amini A.
      • Boeras D.
      • Falconer J.
      • Kelly H.
      • et al.
      Diagnostic accuracy of tests to detect hepatitis C antibody: a meta-analysis and review of the literature.
      • Pallares C.
      • Carvalho-Gomes A.
      • Hontangas V.
      • Conde I.
      • Di Maira T.
      • Aguilera V.
      • et al.
      Performance of the OraQuick Hepatitis C virus antibody test in oral fluid and fingerstick blood before and after treatment-induced viral clearance.
      • Chevaliez S.
      • Pawlotsky J.M.
      New virological tools for screening, diagnosis and monitoring of hepatitis B and C in resource-limited settings.
      If anti-HCV antibodies are detected, the presence of HCV RNA by a molecular assay or, alternatively, HCV core antigen by EIA should be determined to identify patients with ongoing infection.
      Currently, most laboratories use a two-step approach including an antibody test in step 1, followed by phlebotomy and a test for HCV RNA in step 2. This procedure lessens the prospect of a confirmatory HCV RNA test. Reflex testing, i.e. testing for HCV RNA in the sample obtained for anti-HCV antibody testing, has been shown to substantially increase the proportion of anti-HCV antibody-positive patients who are tested for viraemia and receive subsequent linkage to care.
      • Chapko M.K.
      • Dufour D.R.
      • Hatia R.I.
      • Drobeniuc J.
      • Ward J.W.
      • Teo C.G.
      Cost-effectiveness of strategies for testing current hepatitis C virus infection.
      • Howes N.
      • Lattimore S.
      • Irving W.L.
      • Thomson B.J.
      Clinical care pathways for patients with hepatitis C: reducing critical barriers to effective treatment.
      • Sena A.C.
      • Willis S.J.
      • Hilton A.
      • Anderson A.
      • Wohl D.A.
      • Hurt C.B.
      • et al.
      Efforts at the frontlines: implementing a hepatitis C testing and linkage-to-care program at the local public health level.
      • Coyle C.
      • Kwakwa H.
      • Viner K.
      Integrating routine HCV testing in primary care: lessons learned from five federally qualified health centers in Philadelphia, Pennsylvania, 2012-2014.
      • Kapadia S.N.
      • Marks K.M.
      Hepatitis C management simplification from test to cure: a framework for primary care providers.
      Therefore, reflex testing should be applied whenever possible when anti-HCV antibodies are detected.
      Dried blood spots (DBSs) can be used to collect and transport whole blood specimens for both detection of anti-HCV antibodies by EIA (on the first spot) and reflex HCV RNA testing (on a second spot) in a central laboratory.
      • Poiteau L.
      • Soulier A.
      • Rosa I.
      • Roudot-Thoraval F.
      • Hezode C.
      • Pawlotsky J.M.
      • et al.
      Performance of rapid diagnostic tests for the detection of antibodies to hepatitis C virus in whole blood collected on dried blood spots.
      • Soulier A.
      • Poiteau L.
      • Rosa I.
      • Hezode C.
      • Roudot-Thoraval F.
      • Pawlotsky J.M.
      • et al.
      Dried blood spots: a tool to ensure broad access to hepatitis C screening, diagnosis, and treatment monitoring.
      • Tuaillon E.
      • Mondain A.M.
      • Meroueh F.
      • Ottomani L.
      • Picot M.C.
      • Nagot N.
      • et al.
      Dried blood spot for hepatitis C virus serology and molecular testing.
      • Shepherd S.J.
      • Baxter R.E.
      • Gunson R.N.
      Evaluation of the Abbott m2000 system for dried blood spot detection of hepatitis C virus RNA.
      • Vazquez-Moron S.
      • Ardizone Jimenez B.
      • Jimenez-Sousa M.A.
      • Bellon J.M.
      • Ryan P.
      • Resino S.
      Evaluation of the diagnostic accuracy of laboratory-based screening for hepatitis C in dried blood spot samples: a systematic review and meta-analysis.
      • Wlassow M.
      • Poiteau L.
      • Roudot-Thoraval F.
      • Rosa I.
      • Soulier A.
      • Hezode C.
      • et al.
      The new Xpert HCV viral load real-time PCR assay accurately quantifies hepatitis C virus RNA in serum and whole-blood specimens.
      The methodology is less sensitive than HCV RNA testing in serum or plasma, as quantitative HCV RNA is underestimated by approximately 1.6–1.8 Log10 IU/ml on average on DBSs.
      • Soulier A.
      • Poiteau L.
      • Rosa I.
      • Hezode C.
      • Roudot-Thoraval F.
      • Pawlotsky J.M.
      • et al.
      Dried blood spots: a tool to ensure broad access to hepatitis C screening, diagnosis, and treatment monitoring.
      Confirmation of viraemia by testing for HCV core antigen from whole blood sampled on DBSs is not recommended, as DBSs are insufficiently sensitive for HCV core antigen detection. Indeed, false-negative tests occur in 7%–36% of viraemic patients with anti-HCV antibodies.
      • Soulier A.
      • Poiteau L.
      • Rosa I.
      • Hezode C.
      • Roudot-Thoraval F.
      • Pawlotsky J.M.
      • et al.
      Dried blood spots: a tool to ensure broad access to hepatitis C screening, diagnosis, and treatment monitoring.
      ,
      • Mohamed Z.
      • Mbwambo J.
      • Shimakawa Y.
      • Poiteau L.
      • Chevaliez S.
      • Pawlotsky J.M.
      • et al.
      Clinical utility of HCV core antigen detection and quantification using serum samples and dried blood spots in people who inject drugs in Dar-es-Salaam, Tanzania.
      • Lamoury F.M.J.
      • Hajarizadeh B.
      • Soker A.
      • Martinez D.
      • Quek C.
      • Cunningham P.
      • et al.
      Evaluation of a hepatitis C virus core antigen assay in plasma and dried blood spot samples.
      • Catlett B.
      • Lamoury F.M.J.
      • Bajis S.
      • Hajarizadeh B.
      • Martinez D.
      • Mowat Y.
      • et al.
      Evaluation of a hepatitis C virus core antigen assay from venepuncture and dried blood spot collected samples: a cohort study.
      • Biondi M.J.
      • van Tilborg M.
      • Smookler D.
      • Heymann G.
      • Aquino A.
      • Perusini S.
      • et al.
      Hepatitis C core-antigen testing from dried blood spots.
      A cartridge-based point-of-care HCV RNA assay has received World Health Organization (WHO) prequalification. This assay can be used with serum, plasma or fingerstick capillary whole blood, with equal performance.
      • McHugh M.P.
      • Wu A.H.B.
      • Chevaliez S.
      • Pawlotsky J.M.
      • Hallin M.
      • Templeton K.E.
      Multicenter evaluation of the Cepheid Xpert hepatitis C virus viral load assay.
      • Grebely J.
      • Lamoury F.M.J.
      • Hajarizadeh B.
      • Mowat Y.
      • Marshall A.D.
      • Bajis S.
      • et al.
      Evaluation of the Xpert HCV Viral Load point-of-care assay from venepuncture-collected and finger-stick capillary whole-blood samples: a cohort study.
      • Lamoury F.M.J.
      • Bajis S.
      • Hajarizadeh B.
      • Marshall A.D.
      • Martinello M.
      • Ivanova E.
      • et al.
      Evaluation of the Xpert HCV viral load Finger-Stick point-of-care assay.
      The test can be used for reflex testing, but it is too expensive to be used instead of anti-HCV antibody testing for first-line screening.
      Inexpensive direct tests for HCV RNA or HCV core antigen should be developed to replace screening based on anti-HCV antibody testing by a 1-step direct identification of viraemic individuals, in order to simplify testing algorithms and facilitate shorter pathways to treatment. These tests will require validation for sensitivity and specificity, as well as demonstrable cost-effectiveness, before replacing anti-HCV antibody testing in low-incidence populations.
      Recommendations
      • Screening strategies for HCV infection should be defined according to the local epidemiology of HCV infection, ideally within the framework of local, regional or national action plans (A1).
      • Anti-HCV antibody screening and diagnosis should be linked to prevention, care and treatment (A1).
      • Screening for HCV infection should be based on the detection of anti-HCV antibodies in serum or plasma by means of EIA (A1).
      • Whole blood sampled on DBSs can be used as an alternative to serum or plasma obtained by venipuncture for anti-HCV antibody testing, after shipment to a central laboratory where the EIA will be performed (A1).
      • Rapid diagnostic tests using serum, plasma, fingerstick whole blood or crevicular fluid (saliva) as matrices can be used instead of classical EIAs as point-of-care tests to facilitate anti-HCV antibody screening and improve access to care (A1).
      • If anti-HCV antibodies are detected, the presence of HCV RNA by molecular assay or HCV core antigen by EIA in serum or plasma should be determined to identify patients with viraemia (A1).
      • Whole blood sampled on DBSs can be used as an alternative to serum or plasma obtained by venipuncture for HCV RNA testing, after shipment to a central laboratory where the molecular test will be performed (A1).
      • Whole blood sampled on DBSs should not be used as an alternative to serum or plasma obtained by venipuncture for HCV core antigen testing, as a substantial proportion of viraemic patients will be missed due to insufficient sensitivity (B1).
      • Reflex testing for HCV RNA or HCV core antigen in patients found to be anti-HCV antibody-positive should be applied to shorten pathways to care (A1).
      • Anti-HCV antibody screening for HCV infection can be replaced by low-cost point-of-care tests for viraemia with a lower limit of detection ≤1,000 IU/ml (3.0 Log10 IU/ml) or for HCV core antigen testing when such tests are available, if less costly than anti-HCV antibody testing in low-incidence populations (C2).

      Goal of HCV therapy

      The goal of therapy is to cure HCV infection in order to: (i) prevent the complications of HCV-related liver and extrahepatic diseases, including hepatic necroinflammation, fibrosis, cirrhosis, decompensation of cirrhosis, HCC, severe extrahepatic manifestations and death; (ii) improve quality of life and remove stigma; (iii) prevent onward transmission of HCV (treatment as prevention or “TasP”).
      Recommendations
      • The goal of therapy is to cure HCV infection, in order to: (i) prevent the complications of HCV-related liver and extrahepatic diseases, including hepatic necroinflammation, fibrosis, cirrhosis, decompensation of cirrhosis, HCC, severe extrahepatic manifestations and death; (ii) improve quality of life and remove stigma; (iii) prevent onward transmission of HCV through treatment as prevention (A1).

      Endpoint of HCV therapy

      The endpoint of HCV therapy is an SVR, defined by undetectable HCV RNA in serum or plasma 12 weeks (SVR12) or 24 weeks (SVR24) after the end of therapy, as assessed by a sensitive molecular method with a lower limit of detection ≤15 IU/ml. Both SVR12 and SVR24 have been accepted as endpoints by regulators in Europe and the United States, given that their concordance is >99%.
      • Martinot-Peignoux M.
      • Stern C.
      • Maylin S.
      • Ripault M.P.
      • Boyer N.
      • Leclere L.
      • et al.
      Twelve weeks post-treatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated interferon and ribavirin.
      Undetectable HCV core antigen 12 or 24 weeks after the end of therapy can be used as an alternative to HCV RNA testing to define SVR12 and SVR24, respectively, in patients with detectable HCV core antigen before treatment.
      • Chevaliez S.
      • Feld J.
      • Cheng K.
      • Wedemeyer H.
      • Sarrazin C.
      • Maasoumy B.
      • et al.
      Clinical utility of HCV core antigen detection and quantification in the diagnosis and management of patients with chronic hepatitis C receiving an all-oral, interferon-free regimen.
      ,
      • Chevaliez S.
      • Soulier A.
      • Poiteau L.
      • Bouvier-Alias M.
      • Pawlotsky J.M.
      Clinical utility of hepatitis C virus core antigen quantification in patients with chronic hepatitis C.
      ,
      • Freiman J.M.
      • Tran T.M.
      • Schumacher S.G.
      • White L.F.
      • Ongarello S.
      • Cohn J.
      • et al.
      Hepatitis C core antigen testing for diagnosis of hepatitis C virus infection: a systematic review and meta-analysis.
      ,
      • Aghemo A.
      • Degasperi E.
      • De Nicola S.
      • Bono P.
      • Orlandi A.
      • D'Ambrosio R.
      • et al.
      Quantification of core antigen monitors efficacy of direct-acting antiviral agents in patients with chronic hepatitis C virus infection.
      ,
      • Lucejko M.
      • Tomasiewicz K.
      • Olczak A.
      • Tudrujek-Zdunek M.
      • Halota W.
      • Jelski W.
      • et al.
      Hepatitis C virus core antigen as a possible alternative for evaluation of treatment effectiveness after treatment with direct acting antivirals.
      In settings where sensitive HCV RNA assays are not available and/or not affordable, a qualitative assay with a lower limit of detection ≤1,000 IU/ml (3.0 Log10 IU/ml) can be used to assess SVR12 or SVR24.
      Long-term follow-up studies have shown that an SVR corresponds to a definitive cure of HCV infection in the vast majority of cases.
      • Sarrazin C.
      • Isakov V.
      • Svarovskaia E.S.
      • Hedskog C.
      • Martin R.
      • Chodavarapu K.
      • et al.
      Late relapse versus hepatitis C virus reinfection in patients with sustained virologic response after sofosbuvir-based therapies.
      ,
      • Swain M.G.
      • Lai M.Y.
      • Shiffman M.L.
      • Cooksley W.G.
      • Zeuzem S.
      • Dieterich D.T.
      • et al.
      A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin.
      In patients with advanced fibrosis (METAVIR score F3) and cirrhosis (F4), an SVR reduces the rate of decompensation and will also reduce, but not abolish, the risk of HCC.
      • Nahon 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.
      Thus, in these patients, surveillance for HCC must be continued.
      Recommendations
      • The endpoint of therapy is undetectable HCV RNA in serum or plasma by an assay with a lower limit of detection ≤15 IU/ml, 12 weeks (SVR12) or 24 weeks (SVR24) after the end of treatment (A1).
      • Undetectable HCV core antigen in serum or plasma 12 weeks (SVR12) or 24 weeks (SVR24) after the end of treatment can be used as an alternative endpoint of therapy in patients with detectable HCV core antigen prior to therapy (A1).
      • Undetectable HCV RNA in serum or plasma 12 weeks (SVR12) or 24 weeks (SVR24) after the end of treatment, using a qualitative HCV RNA assay with a lower limit of detection ≤1,000 IU/ml (3.0 Log10 IU/ml), can be used as an alternative endpoint of therapy where sensitive HCV RNA assays are not available and/or not affordable (B1).
      • In patients with advanced fibrosis (METAVIR score F3) and cirrhosis (METAVIR score F4), surveillance for HCC must be continued because an SVR will reduce, but not abolish, the risk of HCC (A1).

      Indications for treatment: who should be treated?

      All treatment-naïve and treatment-experienced patients with recently acquired or chronic HCV infection should be treated without delay.
      Urgent treatment must be considered in patients with significant fibrosis (METAVIR score F2 or F3) or cirrhosis (METAVIR score F4), including decompensated cirrhosis; patients with clinically significant extrahepatic manifestations (e.g. symptomatic vasculitis associated with HCV-related mixed cryoglobulinaemia, HCV immune complex-related nephropathy and non-Hodgkin B cell lymphoma); patients with HCV recurrence after liver transplantation; patients at risk of a rapid evolution of liver disease because of concurrent comorbidities (non-liver solid organ or stem cell transplant recipients, HBV and human immunodeficiency virus [HIV] coinfections, diabetes); and individuals at high risk of transmitting HCV (people who inject drugs [PWIDs], men who have sex with men with high-risk sexual practices, women of childbearing age who wish to get pregnant, patients on haemodialysis, incarcerated individuals). PWIDs and men who have sex with men with high-risk sexual practices should be made aware of the risk and routes of reinfection and transmission and should apply preventive measures after successful treatment.
      Treatment is generally not recommended in patients with limited life expectancy because of non-liver-related comorbidities.
      Recommendations
      • All treatment-naïve and treatment-experienced patients with recently acquired or chronic HCV infection must be offered treatment without delay (A1).
      • Urgent treatment should be considered: in patients with significant fibrosis or cirrhosis (METAVIR score F2, F3 or F4), including compensated (Child-Pugh A) and decompensated (Child-Pugh B or C) cirrhosis; in patients with clinically significant extrahepatic manifestations (e.g. symptomatic vasculitis associated with HCV-related mixed cryoglobulinaemia, HCV immune complex-related nephropathy and non-Hodgkin B cell lymphoma); in patients with HCV recurrence after liver transplantation; in patients at risk of a rapid evolution of liver disease because of concurrent comorbidities (non-liver solid organ or stem cell transplant recipients, HBV and HIV coinfections, diabetes); and in individuals at risk of transmitting HCV (PWIDs, men who have sex with men with high-risk sexual practices, women of childbearing age who wish to get pregnant, patients on haemodialysis, incarcerated individuals) (A1).
      • Treatment is generally not recommended in patients with limited life expectancy due to non-liver-related comorbidities (B2).

      Contraindications to therapy

      Few contraindications to treatment with HCV direct-acting antiviral (DAA) drug combinations exist. The use of certain CYP/P-gp-inducing agents (such as carbamazepine, phenytoin and phenobarbital) are contraindicated with all regimens, due to the risk of significantly reduced concentrations of DAAs and therefore the high risk of virological failure (see below). Patients on these anticonvulsants who cannot switch anticonvulsant therapy remain problematic and further data is required in the treatment of such patients with DAAs. Other concomitant medicine-related contraindications are discussed below.
      Treatment regimens comprising an NS3-4A protease inhibitor, such as grazoprevir, glecaprevir or voxilaprevir, are contraindicated in patients with decompensated (Child-Pugh B or C) cirrhosis and in patients with previous episodes of decompensation, because of the substantially higher protease inhibitor concentrations in these patients and the related risk of toxicity.
      Recommendations
      • There are few contraindications to current DAA-based treatments (A1).
      • The use of certain cytochrome P450/P-gp-inducing agents (such as carbamazepine, phenytoin and phenobarbital) contraindicates all HCV DAA regimens if they cannot be switched to other medications, due to the risk of significantly reduced concentrations of HCV DAAs (A1).
      • Treatment regimens comprising an HCV protease inhibitor, such as grazoprevir, glecaprevir or voxilaprevir, are contraindicated in patients with decompensated (Child-Pugh B or C) cirrhosis and in patients with previous episodes of decompensation (A1).

      Pre-therapeutic assessment

      Liver disease severity must be assessed, and baseline virological parameters that will be useful for tailoring therapy should be determined.

       Search for liver comorbidities

      Other causes of chronic liver disease, or factors which are likely to affect the natural history or progression of liver disease and therapeutic choices, should be systematically investigated. All patients should be tested for past or current HBV infection (HBs antigen, anti-HBc antibodies and anti-HBs antibodies), for anti-HIV antibodies and for total antibody to hepatitis A virus (HAV). HBV and HAV vaccination should be proposed for patients who are not immune. Alcohol consumption and substance abuse should be assessed and quantified, and counselling given. In addition, HCV may cause a variety of extrahepatic manifestations which need to be considered in the work-up of HCV-infected patients. Renal function, the presence of diabetes mellitus, obesity and the possibility of drug-induced hepatotoxicity require assessment.
      Recommendations
      • The contribution of comorbidities to the progression of liver disease must be evaluated and appropriate corrective measures implemented (A1).
      • Alcohol consumption and substance abuse should be assessed and quantified, with specific counselling given (A1).
      • Extrahepatic manifestations of HCV infection should be identified (A1).
      • Renal function, including creatinine and eGFR, should be ascertained (A1).
      • All patients should be tested for past or current HBV infection, for HIV infection and for immunity to HAV (A1).
      • HBV and HAV vaccination should be proposed to patients who are not immune (A1).

       Assessment of liver disease severity

      Assessment of liver disease severity is necessary prior to therapy. Diagnosing clinically inapparent cirrhosis (METAVIR score F4) or advanced (bridging) fibrosis (METAVIR score F3) is required, as the choice of treatment regimen and the post-treatment prognosis and surveillance for HCC every 6 months depend on the stage of fibrosis. Patients with cirrhosis need to be assessed for portal hypertension, including oesophageal varices.
      In chronic hepatitis C, non-invasive methods should be used instead of liver biopsy to assess liver disease severity prior to therapy. Liver stiffness measurement can be used to assess liver fibrosis and the presence of portal hypertension in patients with chronic hepatitis C. Consideration must be given to factors that may adversely affect liver stiffness measurement, such as obesity, high ALT levels, or post-prandial testing. Well established panels of fibrosis biomarkers can also be applied. Among them, aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4) are generally available, simple and inexpensive, and the information they provide is reliable, but they may lack sensitivity in African populations. Both liver stiffness measurement and biomarkers perform well in the identification of cirrhosis vs. no fibrosis, but they perform less well in resolving intermediate degrees of fibrosis.
      European Association for Study of the Liver, Asociacion Latinoamericana para el Estudio del Higado
      EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis.
      Cut-offs used with common non-invasive markers to establish the different stages of fibrosis in patients with chronic hepatitis C prior to therapy are shown in Table 3.
      • Afdhal N.H.
      • Bacon B.R.
      • Patel K.
      • Lawitz E.J.
      • Gordon S.C.
      • Nelson D.R.
      • et al.
      Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study.
      • Chou R.
      • Wasson N.
      Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review.
      • Degos F.
      • Perez P.
      • Roche B.
      • Mahmoudi A.
      • Asselineau J.
      • Voitot H.
      • et al.
      Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study).
      • Herrmann E.
      • de Ledinghen V.
      • Cassinotto C.
      • Chu W.C.
      • Leung V.Y.
      • Ferraioli G.
      • et al.
      Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography: an individual patient data-based meta-analysis.
      • Hu X.
      • Qiu L.
      • Liu D.
      • Qian L.
      Acoustic Radiation Force Impulse (ARFI) elastography for noninvasive evaluation of hepatic fibrosis in chronic hepatitis B and C patients: a systematic review and meta-analysis.
      • Zarski J.P.
      • Sturm N.
      • Desmorat H.
      • Melin P.
      • Raabe J.J.
      • Bonny C.
      • et al.
      Non-invasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized study.
      The combination of blood biomarkers or the combination of liver stiffness measurement and a blood test improve accuracy.
      • Castera L.
      • Sebastiani G.
      • Le Bail B.
      • de Ledinghen V.
      • Couzigou P.
      • Alberti A.
      Prospective comparison of two algorithms combining non-invasive methods for staging liver fibrosis in chronic hepatitis C.
      ,
      • Castera L.
      • Vergniol J.
      • Foucher J.
      • Le Bail B.
      • Chanteloup E.
      • Haaser M.
      • et al.
      Prospective comparison of transient elastography, fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C.
      Notably, non-invasive tools should not be used to assess fibrosis stage after therapy, as they are unreliable in this setting.
      Table 3Non-invasive markers cut-offs for prediction of stages of fibrosis, including F3 (advanced fibrosis) and F4 (cirrhosis).
      TestStage of fibrosisNumber of patientsCut-off(s)AUROCSensitivitySpecificityPositive predictive valueNegative predictive valueReferences
      FibroScan®F3560 HCV-positive10 kPa
      Scales for liver stiffness cut-offs (in kPa) are different between FibroScan® and Aixplorer®.
      0.8372%80%62%89%
      • Afdhal N.H.
      • Bacon B.R.
      • Patel K.
      • Lawitz E.J.
      • Gordon S.C.
      • Nelson D.R.
      • et al.
      Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study.
      F41,855 HCV-positive13 kPa
      Scales for liver stiffness cut-offs (in kPa) are different between FibroScan® and Aixplorer®.
      0.90–0.9372–77%85–90%42–56%95–98%
      • Afdhal N.H.
      • Bacon B.R.
      • Patel K.
      • Lawitz E.J.
      • Gordon S.C.
      • Nelson D.R.
      • et al.
      Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study.
      ,
      • Degos F.
      • Perez P.
      • Roche B.
      • Mahmoudi A.
      • Asselineau J.
      • Voitot H.
      • et al.
      Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study).
      ,
      • Zarski J.P.
      • Sturm N.
      • Desmorat H.
      • Melin P.
      • Raabe J.J.
      • Bonny C.
      • et al.
      Non-invasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized study.
      ARFI (VTQ®)F32,691 (including 1,428 HCV-positive)1.60–2.17 m/sec0.94

      (95% CI 0.91–0.95)
      84%

      (95% CI 80–88%)
      90%

      (95% CI 86–92%)
      n.a.n.a.
      • Hu X.
      • Qiu L.
      • Liu D.
      • Qian L.
      Acoustic Radiation Force Impulse (ARFI) elastography for noninvasive evaluation of hepatic fibrosis in chronic hepatitis B and C patients: a systematic review and meta-analysis.
      F42,691 (including 1,428 HCV-positive)2.19–2.67 m/sec0.91

      (95% CI 0.89–0.94)
      86%

      (95% CI 80–91%)
      84%

      (95% CI 80–88%)
      n.a.n.a.
      • Hu X.
      • Qiu L.
      • Liu D.
      • Qian L.
      Acoustic Radiation Force Impulse (ARFI) elastography for noninvasive evaluation of hepatic fibrosis in chronic hepatitis B and C patients: a systematic review and meta-analysis.
      Aixplorer®F3379 HCV-positive9 kPa
      Scales for liver stiffness cut-offs (in kPa) are different between FibroScan® and Aixplorer®.
      0.9190%

      (95% CI 72–100%)
      77%

      (95% CI 78–92%)
      n.a.n.a.
      • Herrmann E.
      • de Ledinghen V.
      • Cassinotto C.
      • Chu W.C.
      • Leung V.Y.
      • Ferraioli G.
      • et al.
      Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography: an individual patient data-based meta-analysis.
      F4379 HCV-positive13 kPa
      Scales for liver stiffness cut-offs (in kPa) are different between FibroScan® and Aixplorer®.
      0.9386%

      (95% CI 74–95%)
      88%

      (95% CI 72–98%)
      n.a.n.a.
      • Herrmann E.
      • de Ledinghen V.
      • Cassinotto C.
      • Chu W.C.
      • Leung V.Y.
      • Ferraioli G.
      • et al.
      Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography: an individual patient data-based meta-analysis.
      Fibrotest®F41,579 (including 1,295 HCV-positive)0.740.82–0.8763–71%81–84%39–4093–94
      • Afdhal N.H.
      • Bacon B.R.
      • Patel K.
      • Lawitz E.J.
      • Gordon S.C.
      • Nelson D.R.
      • et al.
      Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study.
      ,
      • Degos F.
      • Perez P.
      • Roche B.
      • Mahmoudi A.
      • Asselineau J.
      • Voitot H.
      • et al.
      Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study).
      ,
      • Zarski J.P.
      • Sturm N.
      • Desmorat H.
      • Melin P.
      • Raabe J.J.
      • Bonny C.
      • et al.
      Non-invasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized study.
      FIB-4F42,297 HCV-positive1–45
      Two cut-offs are provided for FIB-4 and for APRI, respectively, with their own sensitivities and specificities.


      3.25
      Two cut-offs are provided for FIB-4 and for APRI, respectively, with their own sensitivities and specificities.
      0.87
      median (range).
      (0.83–0.92)
      90%

      55%
      58%

      92%
      n.a.n.a.
      • Chou R.
      • Wasson N.
      Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review.
      APRIF416,694 HCV-positive1.0
      Two cut-offs are provided for FIB-4 and for APRI, respectively, with their own sensitivities and specificities.


      2.0
      Two cut-offs are provided for FIB-4 and for APRI, respectively, with their own sensitivities and specificities.
      0.84
      median (range).
      (0.54–0.97)
      77%

      48%
      75%

      94%
      n.a.n.a.
      • Chou R.
      • Wasson N.
      Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review.
      n.a., not applicable.
      a Scales for liver stiffness cut-offs (in kPa) are different between FibroScan® and Aixplorer®.
      b Two cut-offs are provided for FIB-4 and for APRI, respectively, with their own sensitivities and specificities.
      median (range).
      Liver biopsy may be required in cases of known or suspected mixed aetiologies (e.g. metabolic syndrome, alcoholism or autoimmunity).
      Recommendations
      • Liver disease severity must be assessed prior to therapy (A1).
      • Cirrhosis must be identified, as some treatment regimens must be adjusted and post-treatment surveillance for HCC is mandatory (A1).
      • Post-treatment surveillance for HCC must also be performed in patients with advanced fibrosis (METAVIR score F3) (B1).
      • Fibrosis stage must initially be assessed by non-invasive methods, including liver stiffness measurement or serum biomarkers, including APRI and FIB-4 that are inexpensive and reliable biomarker panels (A1).
      • Liver biopsy should be reserved for cases where there is uncertainty or potential additional aetiologies (A1).
      • Non-invasive methods should not be used to assess fibrosis stage after therapy, as they are unreliable in this setting (B1).

       HCV RNA or HCV core antigen detection/quantification

      Detection or detection/quantification of HCV RNA or HCV core antigen in serum or plasma must be available prior to initiating therapy. HCV RNA assessment should be performed with a reliable and sensitive assay, and HCV RNA levels should be expressed in IU/ml. HCV core antigen quantification should be carried out with a reliable EIA assay and core antigen levels should be expressed in fmol/L.
      Recommendations
      • The presence of viraemia, reflected by the presence of HCV RNA or HCV core antigen, must be demonstrated prior to initiating therapy (A1).
      • HCV RNA detection and quantification in serum or plasma should be made by a sensitive assay with a lower limit of detection of ≤15 IU/ml (A1).
      • HCV core antigen detection and quantification should be made by EIA (A1).
      • HCV RNA detection can be made by a low-cost point-of-care test with a lower limit of detection ≤1,000 IU/ml (3.0 Log10 IU/ml) where sensitive HCV RNA assays are not available and/or not affordable (B1).

       HCV genotype determination

      Pan-genotypic HCV drug regimens, including sofosbuvir/velpatasvir and glecaprevir/pibrentasvir, can be used to treat individuals without identifying their HCV genotype and subtype, simplifying therapy.
      Nevertheless, identifying certain genotypes before starting first-line therapy remains useful and may be required where drug procurement or pricing dictates genotype-specific treatment, or to optimise treatment regimens. Genotyping/subtyping should be performed with an assay that accurately discriminates subtype 1a from 1b, i.e. an assay using the sequence of the 5′untranslated region plus a portion of another genomic region, generally the core-coding or the NS5B-coding regions.
      • Chevaliez S.
      • Bouvier-Alias M.
      • Brillet R.
      • Pawlotsky J.M.
      Hepatitis C virus (HCV) genotype 1 subtype identification in new HCV drug development and future clinical practice.
      The most widely used, CE-IVD-marked method is based on reverse hybridisation with the second-generation line probe assay.
      • Yang R.
      • Wei L.
      Profile of the VERSANT HCV genotype 2.0 assay.
      A commercial CE-IVD-marked assay based on deep sequencing is also available.
      • Rodriguez C.
      • Soulier A.
      • Demontant V.
      • Poiteau L.
      • Mercier-Darty M.
      • Bouvier-Alias M.
      • et al.
      A novel standardized deep sequencing-based assay for hepatitis C virus genotype determination.
      ,
      • Dirani G.
      • Paesini E.
      • Mascetra E.
      • Farabegoli P.
      • Dalmo B.
      • Bartolini B.
      • et al.
      A novel next generation sequencing assay as an alternative to currently available methods for hepatitis C virus genotyping.
      Recently, distinct subtypes of genotypes 1 to 8 that are infrequent in Europe, North America, Japan and Australia (defined as genotype 1 non-1a/1b, genotype 2 non-2a/2b, genotype 3 non-3a, genotype 4 non-4a/4d, and subtypes of genotypes 5 to 8) have been shown to be highly prevalent in certain regions of Africa and Asia and in migrants from these regions.
      • Childs K.
      • Davis C.
      • Cannon M.
      • Montague S.
      • Filipe A.
      • Tong L.
      • et al.
      Suboptimal SVR rates in African patients with atypical genotype 1 subtypes: implications for global elimination of hepatitis C.
      • Wasitthankasem R.
      • Vongpunsawad S.
      • Siripon N.
      • Suya C.
      • Chulothok P.
      • Chaiear K.
      • et al.
      Genotypic distribution of hepatitis C virus in Thailand and Southeast Asia.
      • Wei L.
      • Lim S.G.
      • Xie Q.
      • Van K.N.
      • Piratvisuth T.
      • Huang Y.
      • et al.
      Sofosbuvir-velpatasvir for treatment of chronic hepatitis C virus infection in Asia: a single-arm, open-label, phase 3 trial.
      • Pawlotsky J.M.
      DAA failures in African patients with “unusual” HCV subtypes: Hey! Didn't you know there was another world?.
      Some (for instance genotypes 1l, 4r, 3b, 3g, 6u, 6v among others) harbour natural polymorphisms that confer inherent resistance to NS5A inhibitors, resulting in unacceptably frequent virological failures in both the resident populations as well as in migrants from these regions.
      • Childs K.
      • Davis C.
      • Cannon M.
      • Montague S.
      • Filipe A.
      • Tong L.
      • et al.
      Suboptimal SVR rates in African patients with atypical genotype 1 subtypes: implications for global elimination of hepatitis C.
      ,
      • Wei L.
      • Lim S.G.
      • Xie Q.
      • Van K.N.
      • Piratvisuth T.
      • Huang Y.
      • et al.
      Sofosbuvir-velpatasvir for treatment of chronic hepatitis C virus infection in Asia: a single-arm, open-label, phase 3 trial.
      • Pawlotsky J.M.
      DAA failures in African patients with “unusual” HCV subtypes: Hey! Didn't you know there was another world?.
      • Fourati S.
      • Rodriguez C.
      • Hezode C.
      • Soulier A.
      • Ruiz I.
      • Poiteau L.
      • et al.
      Frequent antiviral treatment failures in patients infected with hepatitis C virus genotype 4, subtype 4r.
      • Gupta N.
      • Mbituyumuremyi A.
      • Kabahizi J.
      • Ntaganda F.
      • Muvunyi C.M.
      • Shumbusho F.
      • et al.
      Treatment of chronic hepatitis C virus infection in Rwanda with ledipasvir-sofosbuvir (SHARED): a single-arm trial.
      • Smith D.
      • Magri A.
      • Bonsall D.
      • Ip C.L.C.
      • Trebes A.
      • Brown A.
      • et al.
      Resistance analysis of genotype 3 hepatitis C virus indicates subtypes inherently resistant to nonstructural protein 5A inhibitors.
      • Nguyen D.
      • Smith D.
      • Vaughan-Jackson A.
      • Magri A.
      • Barnes E.
      • Simmonds P.
      • et al.
      Efficacy of NS5A inhibitors against unusual and potentially difficult-to-treat HCV subtypes commonly found in sub Saharan Africa and South East Asia.
      Thus, HCV genotype and subtype should ideally be determined before treatment in regions where these HCV subtypes are present in substantial proportions, or in migrants from these regions, to optimise treatment regimens. Reverse hybridisation with the line probe assay accurately identifies only genotypes 1 to 6 and subtypes 1a and 1b, but misclassifies most of these infrequent, less treatment-susceptible subtypes.
      • Yang R.
      • Wei L.
      Profile of the VERSANT HCV genotype 2.0 assay.
      Their accurate determination requires sequence analysis of the NS5B or another coding region of the HCV genome followed by phylogenetic analysis. A commercial CE-IVD-marked assay based on deep sequencing can be used for this purpose, but it requires specific equipment and skills.
      • Rodriguez C.
      • Soulier A.
      • Demontant V.
      • Poiteau L.
      • Mercier-Darty M.
      • Bouvier-Alias M.
      • et al.
      A novel standardized deep sequencing-based assay for hepatitis C virus genotype determination.
      ,
      • Dirani G.
      • Paesini E.
      • Mascetra E.
      • Farabegoli P.
      • Dalmo B.
      • Bartolini B.
      • et al.
      A novel next generation sequencing assay as an alternative to currently available methods for hepatitis C virus genotyping.
      If this assay is not available and/or not affordable, only in-house population sequencing (Sanger sequencing) or deep sequencing technologies can be used. These technologies are not available in low- and middle-income settings where these subtypes are prevalent. Virological studies are required in countries in Africa, Asia and South America to determine the epidemiology, distribution and prevalence of HCV subtypes inherently resistant to NS5A inhibitors and thus to optimise treatment decisions without the need for individual HCV genotype and subtype determination.
      • Pawlotsky J.M.
      DAA failures in African patients with “unusual” HCV subtypes: Hey! Didn't you know there was another world?.
      Recommendations
      • Treatment with pangenotypic regimens, including sofosbuvir/velpatasvir or glecaprevir/pibrentasvir, can be initiated without knowledge of the genotype and subtype with a high probability of success (A1).
      • It is still useful to determine the HCV genotype and subtype where such determination is available and does not limit access to care, to identify patients who may benefit from treatment tailoring (A1).
      • Migrants from countries where distinct, less treatment-susceptible HCV subtypes are known to be prevalent may benefit from determination of genotype and subtype by means of population or deep sequencing of the NS5B or another coding region followed by phylogenetic analysis, to identify HCV subtypes inherently resistant to NS5A inhibitors (such as subtypes 1l, 4r, 3b, 3g, 6u, 6v and other undetermined subtypes) in order to avoid treatment failure (B1).
      • In geographical areas or settings where HCV subtypes inherently resistant to NS5A inhibitors (such as subtypes 1l, 4r, 3b, 3g, 6u, 6v and other undetermined subtypes) are present, the HCV genotype and subtype should be determined whenever possible by means of population or deep sequencing of the NS5B or another coding region followed by phylogenetic analysis (but population or deep sequencing methods are not available for patients in most low- and middle-income countries where these HCV subtypes are present) (B2).

       HCV resistance testing

      Only 1 standardised semi-automated, deep sequencing-based test for HCV resistance to approved DAAs is available as a purchasable kit. This test is CE-IVD-marked for resistance testing in the NS3 (protease), NS5A and NS5B (polymerase) regions of HCV genotypes 1a, 1b and 3a; sequence information is also generated and interpretable for most of the other HCV genotypes and subtypes.
      • Papaluca T.
      • O'Keefe J.
      • Bowden S.
      • Doyle J.S.
      • Stoove M.
      • Hellard M.
      • et al.
      Prevalence of baseline HCV NS5A resistance associated substitutions in genotype 1a, 1b and 3 infection in Australia.
      ,
      • Rodriguez C.
      • Mercier-Darty M.
      • Soulier A.
      • Poiteau L.
      • Wlassow M.
      • Fourati S.
      • et al.
      Performance assessment of a fully automated deep sequencing platform for HCV resistance testing.
      Alternatively, resistance testing relies on in-house techniques based on population sequencing (Sanger sequencing) or deep sequencing.
      • Fourati S.
      • Pawlotsky J.M.
      Virologic tools for HCV drug resistance testing.
      A limited number of laboratories have made such tests available in Europe and elsewhere. HCV resistance testing may be technically difficult, particularly for genotypes other than 1 and 4, and the performance of the available in-house assays varies widely.
      Access to resistance testing is limited and there is no consensus on the techniques, interpretation and reporting of these tests. In addition, highly efficacious treatments are now available that are effective in patients with detectable pre-existing resistance-associated substitutions (RAS) at baseline. Thus, systematic testing for HCV resistance prior to treatment in DAA-naïve individuals is not recommended.
      • Pawlotsky J.M.
      Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-free regimens.
      The current EASL recommendations suggest treatment regimens that do not necessitate any resistance testing prior to first-line therapy. In areas where these regimens are not available or not reimbursed, physicians who have easy access to reliable resistance tests can use these results to guide their decisions, according to the 2016 EASL Recommendations on Treatment of Hepatitis C.
      European Association for the Study of the Liver
      EASL recommendations on treatment of hepatitis C 2016.
      Recommendations
      • Testing for HCV resistance prior to first-line treatment is not recommended (A1).
      • In areas where only regimens that require optimisation based on pre-treatment resistance testing are available, and physicians have easy access to a reliable test that evaluates HCV resistance to NS5A inhibitors (spanning amino acids 24 to 93), these analyses can guide decisions, as specified in the 2016 version of the EASL Recommendations on Treatment of Hepatitis C (B2).

      Assessment of drug-drug interactions prior to starting therapy

      Prior to starting treatment with a DAA, a full and detailed drug history should be taken including all prescribed medications, over-the-counter drugs, herbal and vitamin preparations and any illicit drug use discussed and documented. The pre-treatment appointment can be used to rationalise prescribing.
      The pharmacokinetic profiles and how HCV drugs impact key drug-drug interactions is presented below. For a more comprehensive listing of drug-drug interactions, see Table 4A, Table 4B, Table 4C, Table 4D, Table 4E, Table 4F, Table 4G, Table 4H to 4H, and www.hep-druginteractions.org for a list of 800 co-medications. For additional information on the disposition of individual DAAs, refer to the Summary of Product Characteristics.
      Table 4ADrug-drug interactions between HCV DAAs and antiretroviral drugs.
      DAAs, direct-acting antivirals; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
      Colour Legend No clinically significant interaction expected. Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring. These drugs should not be co-administered.
      Notes:
      • o
        Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice.
      • o
        The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.
      ∗Known or anticipated increase in tenofovir concentrations in regimens containing tenofovir disoproxil fumarate. Caution and frequent renal monitoring.
      Table 4BDrug-drug interactions between HCV DAAs and illicit/recreational drugs or drugs of abuse.
      DAAs, direct-acting antivirals; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
      Colour Legend No clinically significant interaction expected. Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring. These drugs should not be co-administered.
      Notes:
      • o
        Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice.
      • o
        The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.
      Table 4CDrug-drug interactions between HCV DAAs and lipid-lowering drugs.
      DAAs, direct-acting antivirals; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
      Colour Legend No clinically significant interaction expected. Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring.These drugs should not be co-administered.
      Notes:
      • o
        Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice.
      • o
        The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.
      Table 4DDrug-drug interactions between HCV DAAs and central nervous system drugs.
      DAAs, direct-acting antivirals; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
      Colour Legend No clinically significant interaction expected. Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring. These drugs should not be co-administered.
      Notes:
      • o
        Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice.
      • o
        The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.
      Table 4EDrug-drug interactions between HCV DAAs and cardiovascular drugs.
      DAAs, direct-acting antivirals; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
      Colour Legend No clinically significant interaction expected. Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring. These drugs should not be co-administered.
      Notes:
      • o
        Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice.
      • o
        The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.
      Table 4FDrug-drug interactions between HCV DAAs and immunosuppressants.
      DAAs, direct-acting antivirals; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
      Colour Legend No clinically significant interaction expected. Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring. These drugs should not be co-administered.
      Notes:
      • o
        Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice.
      • o
        The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.
      Table 4GDrug-drug interactions between HCV DAAs and antiplatelets and anticoagulants.
      DAAs, direct-acting antivirals; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
      Colour Legend No clinically significant interaction expected. Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring. These drugs should not be co-administered.
      Notes:
      • o
        Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice.
      • o
        The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.
      Table 4HDrug-drug interactions between HCV DAAs and anticonvulsants.
      DAAs, direct-acting antivirals; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
      Colour Legend No clinically significant interaction expected. Potential interaction which may require a dosage adjustment, altered timing of administration or additional monitoring. These drugs should not be co-administered.
      Notes:
      • o
        Some drugs may require dose modifications dependent on hepatic function. Please refer to the product label for individual drugs for dosing advice.
      • o
        The symbol (green, amber, red) used to rank the clinical significance of the drug interaction is based on www.hep-druginteractions.org (University of Liverpool). For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer to the above-mentioned website.

       Sofosbuvir

      Sofosbuvir is not metabolised by CYP, but is transported by P-gp. Drugs that are potent P-gp inducers significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect. Thus, sofosbuvir should not be administered with known inducers of P-gp, such as rifampicin, carbamazepine, phenobarbital, phenytoin or St John's wort. Other potential interactions may occur with moderate inducers such as rifabutin, oxcarbazepine, rifapentine and modafinil. No significant drug-drug interactions have been reported in studies with the antiretroviral agents emtricitabine, tenofovir, rilpivirine, efavirenz, darunavir/ritonavir and raltegravir, and there are no potential drug-drug interactions with other antiretroviral drugs.
      • Kirby B.J.
      • Symonds W.T.
      • Kearney B.P.
      • Mathias A.A.
      Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir.
      Sofosbuvir-based regimens are contraindicated in patients treated with the anti-arrhythmic amiodarone because of the risk of life-threatening arrhythmias. Bradycardia has been observed within hours to days of starting the DAA, but cases have been observed up to 2 weeks after initiating HCV treatment. A number of potential mechanisms have been proposed involving P-gp inhibition, protein binding displacement and direct effects of sofosbuvir and/or other DAAs on cardiomyocytes or ion channels. Toxicity is likely the result of a combination of mechanisms. Because of the long half-life of amiodarone, an interaction is possible for several months after discontinuation of amiodarone. If the patient has no cardiac pacemaker in situ, waiting 3 months after discontinuing amiodarone before starting a sofosbuvir-based regimen is recommended. Sofosbuvir-containing regimens have also been implicated in cardiac toxicity in the absence of amiodarone, but this remains controversial. In the absence of specific drug-drug interaction data, caution should be exercised with anti-arrhythmics other than amiodarone.
      • Back D.J.
      • Burger D.M.
      Interaction between amiodarone and sofosbuvir-based treatment for hepatitis C virus infection: potential mechanisms and lessons to be learned.

       Sofosbuvir/velpatasvir

      Drugs that are potent P-gp or potent CYP inducers (e.g., rifampicin, rifabutin, carbamazepine, phenobarbital, phenytoin, St John's wort) are contraindicated, because of the decrease in sofosbuvir and/or velpatasvir exposure with a potential loss in efficacy. However, there are also drugs that are moderate P-gp or CYP inducers (such as modafinil) which can reduce velpatasvir exposure. Currently, this combination would not be recommended with sofosbuvir and velpatasvir.
      There is an increase in exposure of co-medications that are substrates for P-gp and/or BCRP with velpatasvir. The sofosbuvir and velpatasvir combination may be co-administered with P-gp, BCRP, OATP and CYP substrates.
      • Mogalian E.
      • German P.
      • Kearney B.P.
      • Yang C.Y.
      • Brainard D.
      • McNally J.
      • et al.
      Use of multiple probes to assess transporter- and cytochrome P450-mediated drug-drug interaction potential of the pangenotypic HCV NS5A inhibitor velpatasvir.
      Caution is required with co-medications that have a narrow therapeutic window, as reflected by the colour coding for sofosbuvir/velpatasvir in Table 4A, Table 4B, Table 4C, Table 4D, Table 4E, Table 4F, Table 4G, Table 4H to 4H (e.g. for digoxin, dabigatran and ticagrelor).
      The solubility of velpatasvir decreases as pH increases. Therefore, it is important to be aware of the recommendations concerning the co-administration of antacids, H2-receptor antagonists and proton pump inhibitors. For most patients, proton pump inhibitors should be avoided during sofosbuvir/velpatasvir treatment. If considered necessary, sofosbuvir/velpatasvir should be given with food and taken 4 hours before the proton pump inhibitor, at a maximum dose comparable to omeprazole 20 mg (Table 5).
      Table 5Dose equivalence among proton pump inhibitors and H2 antagonists.
      Drug familyDrugDose
      Proton pump inhibitors (dose equivalent to omeprazole 20 mg once daily)Omeprazole20 mg once daily
      Lansoprazole30 mg once daily
      Esomeprazole20 mg once daily
      Pantoprazole40 mg once daily
      Rabeprazole20 mg once daily
      H2 antagonists (dose equivalent to famotidine 20 mg twice daily)Famotidine20 mg twice daily
      Ranitidine150 mg twice daily
      Cimetidine300 mg three-four times daily
      Nizatidine150 mg twice daily
      The proton pump inhibitor doses shown in the Table are considered equivalent. The H2 antagonist doses shown in the Table are considered equivalent.
      Sofosbuvir/velpatasvir may be given with most antiretroviral drugs, the exceptions being the inducing drugs efavirenz, etravirine and nevirapine. Efavirenz causes a 50% decrease in velpatasvir exposure. Sofosbuvir/velpatasvir also increases tenofovir exposure by inhibiting P-gp. Patients on a regimen containing tenofovir disoproxil fumarate (TDF), particularly if prescribed with the pharmacokinetic enhancers ritonavir or cobicistat, require monitoring of renal function.
      • Mogalian E.
      • Stamm L.M.
      • Osinusi A.
      • Brainard D.M.
      • Shen G.
      • Hiing K.
      • et al.
      Drug-drug interaction studies between hepatitis C virus antivirals sofosbuvir/velpatasvir and boosted and unboosted human immunodeficiency virus antiretroviral regimens in healthy volunteers.

       Sofosbuvir/velpatasvir/voxilaprevir

      Because velpatasvir and voxilaprevir are both inhibitors of P-gp, BCRP, OATP1B1 and OATP1B3, co-administration of sofosbuvir, velpatasvir and voxilaprevir with medicinal products that are substrates of these transporters may increase exposure to these co-medications.

      Kirby BJ, Taylor J, Stamm LM, Song Q, Wei H, Li Y, et al. Evaluation of transporter and cytochrome P450-mediated drug-drug interactions with the pangenotypic HCV NS3/4A protease inhibitor voxilaprevir (GS-9857) or sofosbuvir/velpatasvir/voxilaprevir and phenotypic probe drugs. 17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, Washington, DC, June 8-10, 2016.

      Dose adjustment or additional monitoring is required. Rosuvastatin is contraindicated because of a 19-fold increase in plasma exposure of the statin. As this effect is likely to be attributed more to the BCRP transporter, other drugs that are BCRP substrates, including methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, sulfasalazine and topotecan, are also not recommended. Dabigatran is contraindicated because of a near 3-fold increase in AUC. This is caused by P-gp inhibition by both velpatasvir and voxilaprevir. Other substrates of P-gp may need to be dose-adjusted or monitored for increased exposure, including digoxin, ticagrelor and carvedilol. Similar caution is required with OATP1B inhibitors, such as cyclosporin, as voxilaprevir plasma exposure increases 19-fold, or with OATP1B substrates, such as edoxaban, as voxilaprevir inhibition is expected to increase exposure to the factor Xa inhibitor. Neither of these combinations are recommended.
      Concomitant use with medicinal products that are strong P-gp and/or strong CYP inducers, such as rifampicin, rifabutin, St John's wort, carbamazepine, phenobarbital or phenytoin, are contraindicated due to the decrease in sofosbuvir, velpatasvir and/or voxilaprevir exposure with the potential loss in efficacy. Moderate P-gp or CYP inducers (such as modafinil, efavirenz, oxcarbazepine and others) which can also reduce exposure of this DAA are not currently recommended.
      For women of childbearing age, concomitant use with ethinylestradiol-containing contraception is contraindicated because of the risk of ALT elevations. Progestogen-containing contraception is allowed.
      The solubility of velpatasvir decreases as pH increases. Therefore, it is important to be aware of the recommendations concerning the co-administration of antacids, H2-receptor antagonists and proton pump inhibitors. Proton pump inhibitors can be given with sofosbuvir/velpatasvir/voxilaprevir at a dose that does not exceed doses comparable to omeprazole 20 mg (Table 5). Sofosbuvir/velpatasvir/voxilaprevir should be given with food and taken 4 hours before the proton pump inhibitor if possible.
      Sofosbuvir/velpatasvir/voxilaprevir is not recommended with the inducing HIV drugs efavirenz, etravirine and nevirapine, and the protease inhibitors atazanavir/ritonavir and lopinavir/ritonavir. Caution is required with twice daily darunavir/ritonavir, darunavir/cobicistat and atazanavir/cobicistat as there are no data. Efavirenz causes a 50% decrease in velpatasvir exposure and atazanavir causes a 4-fold increase in voxilaprevir exposure. Sofosbuvir/velpatasvir/voxilaprevir also increases tenofovir exposure by inhibiting P-gp, and renal function should be monitored in patients on an antiretroviral regimen containing TDF.

       Glecaprevir/pibrentasvir

      Glecaprevir and pibrentasvir are inhibitors of P-gp, BCRP and OATP1B1 and OATP1B3. Co-administration with glecaprevir/pibrentasvir may increase the concentration of co-medications that are substrates of P-gp (e.g., dabigatran etexilate which is contraindicated because of a 2.4-fold increase in dabigatran exposure), BCRP (e.g. rosuvastatin which requires a dose reduction), or OATP1B1/3 (e.g. atorvastatin or simvastatin which are contraindicated). For other P-gp, BCRP, or OATP1B1/3 substrates, dose adjustment should be considered, particularly in narrow therapeutic index drugs.
      Glecaprevir/pibrentasvir concentrations may be decreased by strong P-gp- and CYP3A-inducing drugs such as rifampicin, carbamazepine, St John's wort or phenytoin, leading to reduced therapeutic effect or loss of virologic response. Co-administration with these or other potent inducers is contraindicated. Prescription of moderate inducers, such as oxcarbazepine and eslicarbazepine, is not recommended. Co-medications that inhibit P-gp and BCRP may increase plasma exposure of glecaprevir/pibrentasvir. Similarly, OATP1B1/3 inhibitors, such as cyclosporin, darunavir and lopinavir, may also increase glecaprevir concentrations.
      The potential for glecaprevir/pibrentasvir to affect other medications is relatively low, although glecaprevir is a weak CYP3A inhibitor (approximately 27% increase in midazolam exposure). There needs to be some caution when co-administering drugs metabolised by CYP3A with a narrow therapeutic index (e.g. tacrolimus) or drugs with large dose ranges such as quetiapine, whereas patients on higher doses may need additional monitoring, dose reduction and/or an electrocardiogram.
      For women of childbearing age, concomitant use with ethinylestradiol-containing contraception is contraindicated because of the risk of ALT elevations. Progestogen-containing contraception is allowed.
      Similar to other DAAs, the solubility of glecaprevir decreases as pH increases. The Cmax of glecaprevir decreases on average by 64% when co-administered with omeprazole 40 mg. Data indicate that this does not affect SVR and license states that no dose changes are recommended. However, prescribing doses of omeprazole greater than 40 mg or equivalent (Table 5) with glecaprevir and pibrentasvir have not been studied and may lead to a greater decrease in glecaprevir concentrations. As with any DAA, reviewing the need for proton pump inhibitor in the first instance must be considered.
      Because of the mechanisms described above, glecaprevir/pibrentasvir is contraindicated with atazanavir-containing regimens and is not recommended with other HIV protease inhibitors. Similarly, the non-nucleoside reverse transcriptase inhibitors efavirenz, etravirine and nevirapine are not recommended because of an expected reduction in plasma exposure of glecaprevir/pibrentasvir. All other antiretroviral drugs can be co-administered, including cobicistat when used with the integrase inhibitor elvitegravir.
      • Rockstroh J.K.
      • Lacombe K.
      • Viani R.M.
      • Orkin C.
      • Wyles D.
      • Luetkemeyer A.F.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir in patients coinfected with hepatitis C virus and human immunodeficiency virus type 1: the EXPEDITION-2 study.

       Grazoprevir/elbasvir

      Since elbasvir and grazoprevir are substrates of CYP3A and P-gp, inducers of these proteins such as efavirenz, etravirine, phenytoin, carbamazepine, bosentan, modafinil and St John's wort may cause a marked decrease in plasma exposure to both DAAs and are therefore contraindicated. Strong inhibitors of CYP3A (e.g. boosted protease inhibitors, some azole antifungals), which may markedly increase plasma concentrations, are either contraindicated or not recommended. In addition to inhibition of CYP3A, grazoprevir plasma concentrations may also be markedly increased by inhibitors of OATP1B1 (including boosted protease inhibitors, cobicistat, cyclosporin, single-dose rifampicin). However, there is no effect of acid-reducing agents on the absorption of either DAA.
      The potential for grazoprevir/elbasvir to affect other medications is relatively low, although grazoprevir is a weak CYP3A inhibitor (34% increase in midazolam exposure) and elbasvir a weak inhibitor of P-gp. Caution is required when co-administering drugs metabolised by CYP3A and P-gp, especially with a narrow therapeutic index (e.g. tacrolimus, some statins, dabigatran, ticagrelor), or drugs with large ranges such as quetiapine.
      There are limitations on which antiretrovirals can be co-administered with elbasvir/grazoprevir. The nucleotide reverse transcriptase inhibitors abacavir, lamivudine, tenofovir (either as TDF or as tenofovir alafenamide [TAF]), emtricitabine, along with rilpivirine, raltegravir, dolutegravir, maraviroc, doravirine, bictegravir and cabotegravir can be used (Table 4A).
      Recommendations
      • A thorough drug-drug interaction risk assessment prior to starting HCV therapy and before starting other medications during treatment is required in all patients undergoing treatment with DAAs, based on the prescribing information for each DAA (summary data on key interactions can be found in Table 4A, Table 4B, Table 4C, Table 4D, Table 4E, Table 4F, Table 4G, Table 4HA to 4H in this document; a key internet resource is www.hep-druginteractions.org where recommendations are regularly updated) (A1).
      • Drug-drug interactions are a key consideration in treating HIV-HCV-coinfected patients, and close attention must be paid to anti-retroviral drugs that are contraindicated, not recommended or require dose adjustment with particular DAA regimens (A1).
      • Patients should be educated on the importance of adherence to therapy, following the dosing recommendations and reporting the use of other prescribed medications, over-the-counter medications, medications bought via the internet, and use of party or recreational drugs (A1).

      Virological results of clinical trials and real-world studies that support the present recommendations on treatment of chronic hepatitis C in patients without cirrhosis and in patients with compensated (Child-Pugh A) cirrhosis

       Sofosbuvir/velpatasvir

      The below recommendations are based on the results of the phase III ASTRAL-1, ASTRAL-2, ASTRAL-3 and ASTRAL-5 trials, additional phase III or IV trials and post-approval real-world studies.

       Patients infected with HCV genotypes 1, 2, 4, 5 and 6

      In ASTRAL-1, in patients with HCV genotype 1 infection (22% with cirrhosis; 66% treatment-naïve; 34% treatment-experienced, of whom 44% were exposed to previous DAAs) treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks, an SVR12 was observed in 98% (206/210; 1 relapse) of patients infected with genotype 1a and in 99% (117/118; 1 relapse) of those infected with genotype 1b.
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.
      The SVR12 rate was 100% (104/104) in treatment-naïve (approximately two-thirds) and treatment-experienced (one-third) patients infected with HCV genotype 2, of whom approximately 30% had cirrhosis.
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.
      In the phase III ASTRAL-2 trial in patients with HCV genotype 2 infection (14% with compensated cirrhosis, 86% treatment-naïve, 14% treatment-experienced) receiving sofosbuvir/velpatasvir for 12 weeks, the SVR12 rate was 99% (133/134; no virological failure).
      • Foster G.R.
      • Afdhal N.
      • Roberts S.K.
      • Brau N.
      • Gane E.J.
      • Pianko S.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.
      In ASTRAL-1, patients with HCV genotype 4 infection (23% with cirrhosis, 55% treatment-naïve, 45% treatment-experienced) treated with the same regimen for 12 weeks achieved SVR12 in 100% (116/116) of cases, those with HCV genotype 5 (14% with cirrhosis, 69% treatment-naïve, 31% treatment-experienced) in 97% (34/35) of cases, and those with HCV genotype 6 (15% with cirrhosis, 93% treatment-naïve, 17% treatment-experienced) in 100% (41/41) of cases.
      • Feld J.J.
      • Jacobson I.M.
      • Hezode C.
      • Asselah T.
      • Ruane P.J.
      • Gruener N.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.
      The latter results were confirmed by a 97% (35/36; 1 relapse) SVR12 rate in a phase III trial in patients infected with genotype 6 from Singapore, Malaysia, Thailand and Vietnam.
      • Lim S.G.
      • Mohamed R.
      • Le P.
      • Tee H.P.
      • McNabb B.L.
      • Lu S.
      • et al.
      Safety and efficacy of sofosbuvir/velpatasvir in a genotype 1-6 HCV-infected population from Singapore, Malaysia, Thailand, and Vietnam: results from a phase 3 clinical trial.
      In the ASTRAL-1 trial, 1 patient subsequently found to be infected with HCV genotype 7 achieved SVR12 after 12 weeks of sofosbuvir/velpatasvir.
      • Schreiber J.
      • McNally J.
      • Chodavarapu K.
      • Svarovskaia E.
      • Moreno C.
      Treatment of a patient with genotype 7 hepatitis C virus infection with sofosbuvir and velpatasvir.

       Patients infected with HCV genotype 3

      Patients with HCV genotype 3 infection were studied in the phase III ASTRAL-3 trial (29% with compensated cirrhosis, 74% treatment-naïve, 26% treatment-experienced). After treatment with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks, the SVR12 rate was 98% (160/163; 1 relapse) in treatment-naïve patients without cirrhosis. An overall 90% (104/116; 10 virological failures) SVR12 rate was observed in patients who were treatment-experienced or had cirrhosis with this regimen, including 93% (40/43; 3 relapses) in treatment-naïve patients with compensated cirrhosis, 91% (31/34; 3 relapses) in treatment-experienced patients without cirrhosis and 89% (33/37; 4 relapses) in treatment-experienced patients with compensated cirrhosis.
      • Foster G.R.
      • Afdhal N.
      • Roberts S.K.
      • Brau N.
      • Gane E.J.
      • Pianko S.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.
      The SVR12 rates after 12 weeks of sofosbuvir/velpatasvir were 97% (225/231) in patients without NS5A RASs at baseline vs. 88% (38/43) in those with detectable NS5A RASs at baseline in this study. Treatment failures associated with NS5A RASs were observed in both treatment-experienced patients without cirrhosis and treatment-naïve and treatment-experienced patients with compensated cirrhosis.
      • Foster G.R.
      • Afdhal N.
      • Roberts S.K.
      • Brau N.
      • Gane E.J.
      • Pianko S.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.
      In the POLARIS-3 trial, which assessed the safety and efficacy of the fixed-dose combination of sofosbuvir, velpatasvir and voxilaprevir in patients infected with HCV genotype 3, the SVR rate was 96% (105/109) after 12 weeks of sofosbuvir/velpatasvir in the control arm. There were only 4 patients with the NS5A Y93H RAS (who all achieved SVR) in this arm.
      • Jacobson I.M.
      • Lawitz E.
      • Gane E.J.
      • Willems B.E.
      • Ruane P.J.
      • Nahass R.G.
      • et al.
      Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials.
      In a randomised controlled trial, genotype 3-infected patients with compensated cirrhosis were assigned to receive sofosbuvir and velpatasvir for 12 weeks, or sofosbuvir and velpatasvir plus ribavirin for 12 weeks.
      • Esteban R.
      • Pineda J.A.
      • Calleja J.L.
      • Casado M.
      • Rodriguez M.
      • Turnes J.
      • et al.
      Efficacy of sofosbuvir and velpatasvir, with and without ribavirin, in patients with hepatitis C virus genotype 3 infection and cirrhosis.
      Although the study was not powered to show a significant difference, there were 6/101 (6%) virological failures in the no ribavirin arm vs. 2/103 (2%) in the ribavirin-containing arm. In the sofosbuvir and velpatasvir without ribavirin arm, the proportion of patients with baseline NS5A RASs who achieved an SVR was lower than that of patients without NS5A RASs (84% vs. 96%, respectively). In the sofosbuvir and velpatasvir plus ribavirin arm, baseline NS5A RASs had less effect on the proportion of patients with an SVR (96% vs. 99%, respectively).
      • Esteban R.
      • Pineda J.A.
      • Calleja J.L.
      • Casado M.
      • Rodriguez M.
      • Turnes J.
      • et al.
      Efficacy of sofosbuvir and velpatasvir, with and without ribavirin, in patients with hepatitis C virus genotype 3 infection and cirrhosis.
      When pooling the results of ASTRAL-3, POLARIS-3 and the randomised controlled trial in patients with cirrhosis, the SVR rates after sofosbuvir/velpatasvir without ribavirin were 73/81 (90%) in patients with any NS5A RAS, but only 27/33 (82%) in patients with the Y93H RAS.
      • Jacobson I.M.
      • Lawitz E.
      • Gane E.J.
      • Willems B.E.
      • Ruane P.J.
      • Nahass R.G.
      • et al.
      Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials.
      ,
      • Foster G.R.
      • Afdhal N.
      • Roberts S.K.
      • Brau N.
      • Gane E.J.
      • Pianko S.
      • et al.
      Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.
      ,
      • Esteban R.
      • Pineda J.A.
      • Calleja J.L.
      • Casado M.
      • Rodriguez M.
      • Turnes J.
      • et al.
      Efficacy of sofosbuvir and velpatasvir, with and without ribavirin, in patients with hepatitis C virus genotype 3 infection and cirrhosis.

       Patients coinfected with HIV

      In the ASTRAL-5 trial in treatment-naïve or treatment-experienced patients with or without cirrhosis coinfected with HCV and HIV, the SVR12 rates with the fixed-dose combination of sofosbuvir and velpatasvir were 95% (63/66; 2 relapses) in patients with genotype 1a, 92% (11/12; no virological failure) in patients with genotype 1b, 100% (11/11) in patients with genotype 2, 92% (11/12; no virological failure) in patients with genotype 3, and 100% (4/4) in patients with genotype 4.
      • Wyles D.
      • Brau N.
      • Kottilil S.
      • Daar E.S.
      • Ruane P.
      • Workowski K.
      • et al.
      Sofosbuvir and velpatasvir for the treatment of hepatitis C virus in patients coinfected with human immunodeficiency virus type 1: an open-label, phase 3 study.

       Pooled resistance analysis

      In a pooled resistance analysis from phase III trials with sofosbuvir/velpatasvir, virological failure was observed in 20/1,778 patients (1.1%), including 7/694 (1.0%) infected with genotype 1, 0/316 infected with genotype 2, 12/478 (2.5%) infected with genotype 3, 1/197 (0.5%) infected with genotype 4 and 0/93 infected with genotypes 5 to 7.
      • Hezode C.
      • Reau N.
      • Svarovskaia E.S.
      • Doehle B.P.
      • Shanmugam R.
      • Dvory-Sobol H.
      • et al.
      Resistance analysis in patients with genotype 1-6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies.

       Real-world studies

      The high SVR rates achieved with sofosbuvir/velpatasvir have been confirmed in a large number of real-world studies. In particular, the real-world efficacy of the fixed-dose combination of sofosbuvir and velpatasvir administered for 12 weeks has been reported in a very large and heterogeneous population from 12 cohorts originating from 7 countries across the European Union and North America.
      • Mangia A.
      • Milligan S.
      • Khalili M.
      • Fagiuoli S.
      • Shafran S.
      • Carrat F.
      • et al.
      Global real-world evidence of sofosbuvir/velpatasvir as a simple, effective regimen for the treatment of chronic hepatitis C patients: integrated analysis of 12 clinical practice cohorts.
      The intent-to-treat SVR12/24 rate was 93% (5,134/5,541), while the per protocol SVR12/24 rate was 98% (5,134/5,214) due to a 6% non-virological failure rate (lost-to-follow-up, early discontinuation, death, etc). Overall, the virological failure rate was 1.4% (80/5,541). Per protocol, the SVR12/24 rates were 99% (1,595/1,615) for genotype 1, 99% (1,535/1,553) for genotype 2, 98% (1,646/1,686) for genotype 3, 99% (238/239) for genotype 4, 98% (67/68) for genotypes 5 and 6, and 100% (36/36) for mixed/unknown genotypes, with no difference according to the stage of fibrosis or the presence of cirrhosis. The results for populations known to be more “difficult-to-cure” were 98% (753/766) for treatment-experienced patients, 98% (678/693) for historic or current intravenous drug users, 96% (297/308) for patients infected with genotype 3 with compensated cirrhosis, 98% (263/268) for patients using proton pump inhibitors at baseline, 99% (443/447) for patients aged more than 70 years, and 96% (181/188) for patients coinfected with HIV.
      • Mangia A.
      • Milligan S.
      • Khalili M.
      • Fagiuoli S.
      • Shafran S.
      • Carrat F.
      • et al.
      Global real-world evidence of sofosbuvir/velpatasvir as a simple, effective regimen for the treatment of chronic hepatitis C patients: integrated analysis of 12 clinical practice cohorts.
      In another large, non-selective real-world cohort study based on the English HCV Treatment Registry, SVR12 rates with sofosbuvir/velpatasvir plus ribavirin were significantly higher than those with sofosbuvir/velpatasvir without ribavirin in patients infected with HCV genotype 3 with compensated cirrhosis (98.0% [192/196] vs. 92% [200/218], p = 0.005). The addition of ribavirin did not make a significant difference in genotype 3 patients with no, mild or moderate fibrosis (F0–F3).
      • Drysdale K.
      • Townley C.
      • Mahomed F.
      • Foster G.R.
      Effectiveness of therapy in 16,567 directly-acting antiviral treated people in England: high response rates in genotype 3 hepatitis C infection regardless of degree of fibrosis, but ribavirin improves response in cirrhosis.

       Patients infected with “unusual” HCV subtypes inherently resistant to NS5A inhibitors

      Limited data are available on the efficacy of the fixed-dose combination of sofosbuvir and velpatasvir in patients with so-called “unusual” (denoting less common in Western countries) HCV subtypes that are inherently resistant to NS5A inhibitors. However, the intrinsic presence of several polymorphisms in the NS5A region of the genome of these viruses is likely to impact SVR rates, as suggested by in vitro studies.
      • Smith D.
      • Magri A.
      • Bonsall D.
      • Ip C.L.C.
      • Trebes A.
      • Brown A.
      • et al.
      Resistance analysis of genotype 3 hepatitis C virus indicates subtypes inherently resistant to nonstructural protein 5A inhibitors.
      ,
      • Nguyen D.
      • Smith D.
      • Vaughan-Jackson A.
      • Magri A.
      • Barnes E.
      • Simmonds P.
      • et al.
      Efficacy of NS5A inhibitors against unusual and potentially difficult-to-treat HCV subtypes commonly found in sub Saharan Africa and South East Asia.
      ,
      • Gottwein J.M.
      • Pham L.V.
      • Mikkelsen L.S.
      • Ghanem L.
      • Ramirez S.
      • Scheel T.K.H.
      • et al.
      Efficacy of NS5A inhibitors against hepatitis C virus genotypes 1-7 and escape variants.
      In a single-arm, open-label phase III study performed in Asia (China, Thailand, Vietnam, Singapore and Malaysia) in patients infected with HCV genotypes 1 to 6, an overall SVR12 rate of 96% (362/375) was achieved. Notably, 42 of the 375 patients included (11%) were infected with HCV subtype 3b and had baseline RASs in the NS5A region, generally A30K + L31M. Among patients with subtype 3b infection, 89% (25/28) of those without cirrhosis and only 50% (7/14) of those with cirrhosis achieved SVR12.
      • Wei L.
      • Lim S.G.
      • Xie Q.
      • Van K.N.
      • Piratvisuth T.
      • Huang Y.
      • et al.
      Sofosbuvir-velpatasvir for treatment of chronic hepatitis C virus infection in Asia: a single-arm, open-label, phase 3 trial.
      Data is required on other “unusual” subtypes inherently resistant to NS5A inhibitors, including subtypes 1l, 4r, 3g, 6u, 6v and others that remain to be determined. From 114 patients who failed to achieve SVR after a course of sofosbuvir/velpatasvir sent to the French National Reference Center for Viral Hepatitis B, C and D for subtyping and resistance analysis, 6 were infected with a non-1a/1b genotype 1 subtype, 16 with a non-2a/2c subtype and 6 with a non-4a/4d subtype (Slim Fourati and Jean-Michel Pawlotsky, personal communication to the panel).

       Glecaprevir/pibrentasvir

      The below recommendations are based on the phase II SURVEYOR-2 trial, on phase III studies (ENDURANCE-1, ENDURANCE-3, ENDURANCE-4, EXPEDITION-1, EXPEDITION-2, EXPEDITION-8, CERTAIN-1, CERTAIN-2, VOYAGE-1, and VOYAGE-2), on integrated analyses of phase II and III trials and on real-world data.

       Patients infected with HCV genotypes 1 to 6 without cirrhosis

      In the ENDURANCE-1 phase III trial, the SVR12 rate was 99% (150/152; 1 virological breakthrough) in genotype 1a-infected and 100% (198/198) in genotype 1b-infected treatment-naïve or treatment-experienced patients without cirrhosis receiving 8 weeks of glecaprevir/pibrentasvir, including 13 and 2 patients who were HIV-coinfected, respectively.
      • Zeuzem S.
      • Foster G.R.
      • Wang S.
      • Asatryan A.
      • Gane E.
      • Feld J.J.
      • et al.
      Glecaprevir-pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection.
      These results were confirmed in the CERTAIN-1 phase III trial, showing an SVR rate of 99% (128/129, no virological failure) in Japanese patients infected with genotype 1 (97% of whom were infected with genotype 1b) receiving the same treatment regimen for 8 weeks.
      • Chayama K.
      • Suzuki F.
      • Karino Y.
      • Kawakami Y.
      • Sato K.
      • Atarashi T.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 1 hepatitis C virus infection with and without cirrhosis.
      In the phase II SURVEYOR-2 study, the SVR12 rate was 98% (53/54; no virological failure) in treatment-naïve and treatment-experienced patients infected with HCV genotype 2 without cirrhosis after 8 weeks of glecaprevir/pibrentasvir.
      • Kwo P.Y.
      • Poordad F.
      • Asatryan A.
      • Wang S.
      • Wyles D.L.
      • Hassanein T.
      • et al.
      Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis.
      These results were confirmed in the CERTAIN-2 trial, showing an SVR rate of 98% (88/90, no virological failure) in Japanese patients infected with genotype 2 without cirrhosis receiving the same treatment regimen for 8 weeks.
      • Toyoda H.
      • Chayama K.
      • Suzuki F.
      • Sato K.
      • Atarashi T.
      • Watanabe T.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 2 hepatitis C virus infection.
      In the phase III ENDURANCE-3 trial, SVR12 was achieved in 95% (149/157; 5 relapses, 1 virological breakthrough) of treatment-naïve patients, infected with HCV genotype 3 without cirrhosis, receiving glecaprevir/pibrentasvir for 8 weeks. However, only 17% of patients in this study had advanced fibrosis (METAVIR score F3), the remaining 83% having mild to moderate fibrosis (F0–F2).
      • Foster G.R.
      • Gane E.
      • Asatryam A.
      • Asselah T.
      • Ruane P.J.
      • Pol S.
      • et al.
      ENDURANCE-3: safety and efficacy of glecaprevir/pibrentasvir compared to sofosbuvir plus daclatasvir in treatment-naïve HCV genotype 3-infected patients without cirrhosis.
      An integrated analysis of phase II and III trials in patients infected with genotype 3 showed an SVR12 rate of 95% (198/208; 6 virological failures) after 8 weeks of glecaprevir/pibrentasvir in treatment-naïve patients infected with genotype 3 without cirrhosis.
      • Flamm S.L.
      • Wyles D.L.
      • Wang S.
      • Mutimer D.J.
      • Rockstroh J.K.
      • Horsmans Y.J.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir for 8 or 12 weeks in treatment-naïve patients with chronic HCV genotype 3: an integrated Phase 2/3 analysis.
      In the SURVEYOR-2 study, the SVR12 rates were 91% (20/22; 2 relapses) and 95% (21/22; 1 relapse) in treatment-experienced patients with HCV genotype 3 without cirrhosis treated for 12 or 16 weeks, respectively.
      • Kwo P.Y.
      • Poordad F.
      • Asatryan A.
      • Wang S.
      • Wyles D.L.
      • Hassanein T.
      • et al.
      Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis.
      A pooled analysis of phase II and III clinical trials in patients infected with genotype 3 showed SVR12 rates of 96% (258/270) in treatment-naïve patients without cirrhosis and 90% (44/49) in treatment-experienced patients without cirrhosis treated for 12 weeks with glecaprevir/pibrentasvir.
      • Krishnan P.
      • Schnell G.
      • Tripathi R.
      • Ng T.
      • Reisch T.
      • Beyer J.
      • et al.
      Pooled resistance analysis in HCV genotype 1-6-infected patients treated with glecaprevir/pibrentasvir in phase 2 and 3 clinical trials.
      In the phase II SURVEYOR-2 trial, the SVR12 rate was 93% (43/46; no virological failure) in treatment-naïve and treatment-experienced patients infected with HCV genotype 4 without cirrhosis receiving glecaprevir/pibrentasvir for 8 weeks,
      • Kwo P.Y.
      • Poordad F.
      • Asatryan A.
      • Wang S.
      • Wyles D.L.
      • Hassanein T.
      • et al.
      Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis.
      while in ENDURANCE-4, similar patients achieved SVR12 in 99% (75/76; no virological failures) of cases after 12 weeks of treatment.
      • Asselah T.
      • Kowdley K.V.
      • Zadeikis N.
      • Wang S.
      • Hassanein T.
      • Horsmans Y.
      • et al.
      Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis.
      Two out of 2 patients without cirrhosis infected with HCV genotype 5 achieved SVR12 after 8 weeks of treatment in SURVEYOR-2,
      • Kwo P.Y.
      • Poordad F.
      • Asatryan A.
      • Wang S.
      • Wyles D.L.
      • Hassanein T.
      • et al.
      Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis.
      while in ENDURANCE-4, genotype 5 patients without cirrhosis treated for 12 weeks achieved SVR in 100% (26/26) of cases.
      • Asselah T.
      • Kowdley K.V.
      • Zadeikis N.
      • Wang S.
      • Hassanein T.
      • Horsmans Y.
      • et al.
      Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis.
      In patients infected with genotype 6, 90% (9/10; no virological failure) of treatment-naïve and treatment-experienced individuals without cirrhosis achieved SVR12 after 8 weeks of treatment in SURVEYOR-2,
      • Kwo P.Y.
      • Poordad F.
      • Asatryan A.
      • Wang S.
      • Wyles D.L.
      • Hassanein T.
      • et al.
      Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis.
      and 100% (19/19) achieved SVR12 after 12 weeks of treatment in ENDURANCE-4.
      • Asselah T.
      • Kowdley K.V.
      • Zadeikis N.
      • Wang S.
      • Hassanein T.
      • Horsmans Y.
      • et al.
      Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis.
      In the VOYAGE-1 phase III trial, 362 Asian patients without cirrhosis, infected with HCV genotypes 1 to 6 (genotype 1a: 5%; genotype 1b: 45%; genotype 2: 38%; genotype 3a: 4%; genotype 3b: 3%; genotype 6: 5%) were treated with the fixed-dose combination of glecaprevir and pibrentasvir for 8 weeks.
      • Wei L.
      • Wang G.
      • Alami N.N.
      • Xie W.
      • Heo J.
      • Xie Q.
      • et al.
      Glecaprevir-pibrentasvir to treat chronic hepatitis C virus infection in Asia: two multicentre, phase 3 studies - a randomised, double-blind study (VOYAGE-1) and an open-label, single-arm study (VOYAGE-2).
      The global SVR12 rate was 97% (352/362; 2 on-treatment virological failures and 6 relapses), including 99.4% (178/179; no virological failure) in patients infected with genotype 1 and 98% (136/139) in patients infected with genotype 2. All 8 patients who experienced virological failure were from China: the 2 patients who had on-treatment virological failure were infected with genotype 3b; among the 6 patients who experienced post-treatment relapse, 3 were infected with genotype 3b, 2 with genotype 2 and 1 with genotype 3a.
      • Wei L.
      • Wang G.
      • Alami N.N.
      • Xie W.
      • Heo J.
      • Xie Q.
      • et al.
      Glecaprevir-pibrentasvir to treat chronic hepatitis C virus infection in Asia: two multicentre, phase 3 studies - a randomised, double-blind study (VOYAGE-1) and an open-label, single-arm study (VOYAGE-2).

       Patients infected with HCV genotypes 1 to 6 with compensated (Child-Pugh A) cirrhosis

      The phase III EXPEDITION-1 trial included treatment-naïve and treatment-experienced patients infected with HCV genotypes 1, 2, 4, 5 or 6 with compensated (Child-Pugh A) cirrhosis who received glecaprevir/pibrentasvir for 12 weeks. The SVR12 rates were 98% (47/48; 1 relapse) in genotype 1a patients, 100% (39/39) in genotype 1b patients, 100% (31/31) in genotype 2 patients, 100% (16/16) in genotype 4 patients, 100% (2/2) in genotype 5 patients and 100% (7/7) in genotype 6 patients.
      • Forns X.
      • Lee S.S.
      • Valdes J.
      • Lens S.
      • Ghalib R.
      • Aguilar H.
      • et al.
      Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial.
      These results were confirmed in Japanese patients in the phase III CERTAIN-1 and CERTAIN-2 trials for genotypes 1 and 2, with SVR12 rates of 100% (38/38) and 100% (18/18), respectively.
      • Chayama K.
      • Suzuki F.
      • Karino Y.
      • Kawakami Y.
      • Sato K.
      • Atarashi T.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 1 hepatitis C virus infection with and without cirrhosis.
      ,
      • Toyoda H.
      • Chayama K.
      • Suzuki F.
      • Sato K.
      • Atarashi T.
      • Watanabe T.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 2 hepatitis C virus infection.
      In an integrated analysis of phase II and III trials, the SVR12 rate after 12 weeks of glecaprevir/pibrentasvir in treatment-naïve patients, infected with genotype 3 with compensated cirrhosis, was 97% (67/69; 1 virological breakthrough).
      • Flamm S.L.
      • Wyles D.L.
      • Wang S.
      • Mutimer D.J.
      • Rockstroh J.K.
      • Horsmans Y.J.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir for 8 or 12 weeks in treatment-naïve patients with chronic HCV genotype 3: an integrated Phase 2/3 analysis.
      In the SURVEYOR-2 study, the SVR12 rates were 97% (39/40; no virological failure) in treatment-naïve patients with cirrhosis treated for 12 weeks and 96% (45/47; 2 virological failures) in treatment-experienced patients with cirrhosis treated for 16 weeks.
      • Wyles D.
      • Poordad F.
      • Wang S.
      • Alric L.
      • Felizarta F.
      • Kwo P.Y.
      • et al.
      Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: a partially randomized phase 3 clinical trial.
      A pooled analysis of phase II and III clinical trials in patients infected with genotype 3 showed SVR12 rates of 98% (64/65) in treatment-naïve patients with compensated cirrhosis treated for 12 weeks, and 94% (48/51) in treatment-experienced patients with compensated cirrhosis treated for 16 weeks.
      • Krishnan P.
      • Schnell G.
      • Tripathi R.
      • Ng T.
      • Reisch T.
      • Beyer J.
      • et al.
      Pooled resistance analysis in HCV genotype 1-6-infected patients treated with glecaprevir/pibrentasvir in phase 2 and 3 clinical trials.
      No data have been generated on 12 weeks of treatment with glecaprevir and pibrentasvir in treatment-experienced patients with compensated cirrhosis.
      In the phase III EXPEDITION-8 trial, 343 treatment-naïve patients (95 with genotype 1a, 136 with genotype 1b, 26 with genotype 2, 63 with genotype 3, 13 with genotype 4, 1 with genotype 5 and 9 with genotype 6) with compensated cirrhosis (median Fibroscan score in 295 patients: 20.2 [16.4–26.6]) have been treated with 8 weeks of glecaprevir/pibrentasvir. Among them, 171 (50%) had a platelet count <150 × 109/L and 63 (18%) a platelet count <100 × 109/L. The global SVR rate was 98% (335/343). The SVR12 rates by genotype were: 98% (226/231; no virological failure) for genotype 1, 100% (26/26) for genotype 2, 95% (60/63; 1 relapse) for genotype 3, 100% (13/13) for genotype 4, 100% (1/1) for genotype 5 and 100% (9/9) for genotype 6.
      • Brown Jr., R.S.
      • Buti M.
      • Rodrigues L.
      • Chulanov V.
      • Chuang W.L.
      • Aguilar H.
      • et al.
      Glecaprevir/pibrentasvir for 8 weeks in treatment-naive patients with chronic HCV genotypes 1-6 and compensated cirrhosis: the EXPEDITION-8 trial.
      In the VOYAGE-2 phase III trial, 160 Asian patients with compensated (Child-Pugh A) cirrhosis, infected with HCV genotypes 1 to 6 (genotype 1a: <1%; genotype 1b: 53%; genotype 2: 33%; genotype 3a: 4%; genotype 3b: 5%; genotype 4: <1%; genotype 6: 4%), were treated with the fixed-dose combination of glecaprevir and pibrentasvir for 12 weeks, except treatment-experienced patients infected with genotype 6 who received treatment for 16 weeks.
      • Wei L.
      • Wang G.
      • Alami N.N.
      • Xie W.
      • Heo J.
      • Xie Q.
      • et al.
      Glecaprevir-pibrentasvir to treat chronic hepatitis C virus infection in Asia: two multicentre, phase 3 studies - a randomised, double-blind study (VOYAGE-1) and an open-label, single-arm study (VOYAGE-2).
      The SVR12 rate was 99% (159/160; 1 relapse). The patient who relapsed was from China and infected with genotype 3b.
      • Wei L.
      • Wang G.
      • Alami N.N.
      • Xie W.
      • Heo J.
      • Xie Q.
      • et al.
      Glecaprevir-pibrentasvir to treat chronic hepatitis C virus infection in Asia: two multicentre, phase 3 studies - a randomised, double-blind study (VOYAGE-1) and an open-label, single-arm study (VOYAGE-2).

       Patients coinfected with HIV

      One hundred and fifty-three patients coinfected with HIV, including 16 (10%) with compensated cirrhosis, were enrolled in the phase III EXPEDITION-2 study. The 137 patients without cirrhosis (66 with genotype 1a, 21 with genotype 1b, 9 with genotype 2, 22 with genotype 3, 16 with genotype 4 and 3 with genotype 6) received 8 weeks of glecaprevir/pibrentasvir, while the 16 patients with cirrhosis (5 with genotype 1a, 5 with genotype 1b, 1 with genotype 2, 4 with genotype 3, 1 with genotype 4) were treated for 12 weeks. The SVR12 rate was 98% (150/153; no virological failures) in 137 patients treated for 8 weeks. One genotype 3-infected patient with cirrhosis had on-treatment virological failure.
      • Rockstroh J.K.
      • Lacombe K.
      • Viani R.M.
      • Orkin C.
      • Wyles D.
      • Luetkemeyer A.F.
      • et al.
      Efficacy and safety of glecaprevir/pibrentasvir in patients coinfected with hepatitis C virus and human immunodeficiency virus type 1: the EXPEDITION-2 study.

       Pooled resistance analysis

      In a pooled resistance analysis from phase II and III trials with glecaprevir/pibrentasvir, virological failure was observed in 22/2,256 patients (1.0%), including 2/889 (0.2%) infected with genotype 1, 2/466 (0.4%) infected with genotype 2, 18/643 (2.8%) infected with genotype 3, and 0/258 infected with genotypes 4 to 6.
      • Krishnan P.
      • Pilot-Matias T.
      • Schnell G.
      • Tripathi R.
      • Ng T.I.
      • Reisch T.
      • et al.
      Pooled resistance analysis in patients with hepatitis C virus genotype 1 to 6 infection treated with glecaprevir-pibrentasvir in phase 2 and 3 clinical trials.
      The higher frequency of glecaprevir/pibrentasvir failure in patients infected with genotype 3 was confirmed in a meta-analysis including 3,302 patients from 17 studies.
      • Singh A.D.
      • Maitra S.
      • Singh N.
      • Tyagi P.
      • Ashraf A.
      • Kumar R.
      • et al.
      Systematic review and meta-analysis: impact of baseline resistance-associated substitutions on the efficacy of glecaprevir/pibrentasvir among chronic hepatitis C patients.
      Among 50 patients with a virological failure, 48% were infected with genotype 3 vs. 44% with genotype 1. Baseline RASs were present in 44/50 patients (88%). The presence of NS5A RASs Y93H and A30K at baseline significantly impacted SVR12 rates in patients infected with genotype 3; in contrast, the presence of NS5A RASs at baseline had no effect in those infected with genotype 1.
      • Singh A.D.
      • Maitra S.
      • Singh N.
      • Tyagi P.
      • Ashraf A.
      • Kumar R.
      • et al.
      Systematic review and meta-analysis: impact of baseline resistance-associated substitutions on the efficacy of glecaprevir/pibrentasvir among chronic hepatitis C patients.

       Real-world studies

      The high SVR rates achieved with glecaprevir/pibrentasvir have been confirmed in a large number of real-world studies. One of the reports included 16 real-world cohorts including 11,101 adults treated with glecaprevir/pibrentasvir for 8 or 12 weeks. The global intent-to-treat and modified intent-to-treat (mITT: excluding non-virological failures) SVR rates were 97% (7,808/8,082 from 14 cohorts) and 98% (5,757/5,863 from 12 cohorts), with a 2.4% rate of virological failure (143/5,863 mITT patients).
      • Cornberg M.
      • Negro F.
      • Lampertico P.
      • Turnés J.
      • Curry M.
      • Brown A.
      • et al.
      Real-world effectiveness and safety of glecaprevir/pibrentasvir in adults with chronic hepatitis C virus infection: a meta-analysis.
      The intent-to-treat and mITT SVR12 rates by genotype were, respectively: 95% (1,609/1,685 from 6 cohorts) and 98% (2,288/2,335 from 5 cohorts) for genotype 1; 96% (361/375 from 6 cohorts) and 98% (359/368 from 5 cohorts) for genotype 2; 95% (1,032/1,084 from 6 cohorts) and 96% (651/679 from 7 cohorts) for genotype 3; and 99% (212/214 from 4 cohorts) and 98% (194/197 from 3 cohorts) for genotype 4. There was no difference in SVR12 rates according to the presence or absence of cirrhosis (intent-to-treat: 98% vs. 97%; mITT: 98% vs. 98%, respectively) or to the duration of treatment of 8 or 12 weeks (intent-to-treat: 96% vs. 96%; mITT: 98% vs. 97%, respectively). mITT SVR12 was achieved in more than 99% (3,267/3,280 from 8 cohorts) of treatment-naïve patients without cirrhosis who underwent 8 weeks of treatment and in 99% (295/298 from 7 cohorts) of treatment-naïve patients with compensated cirrhosis who underwent 12 weeks of treatment. The mITT results for populations known to be more “difficult-to-cure” were 98% for patients with F3 fibrosis (180/183 from 4 cohorts), 96% for patients with alcohol abuse or dependence (111/115 from 2 cohorts), 99% in patients with chronic kidney disease stage 4 or 5 (58/59 from 2 cohorts), 97% in patients using drugs or on opioid substitution (227/233 from 3 cohorts), 98% in patients with psychiatric disorders (103/105 from 2 cohorts) and 98% in patients using proton pump inhibitors (179/183 from 3 cohorts).
      • Cornberg M.
      • Negro F.
      • Lampertico P.
      • Turnés J.
      • Curry M.
      • Brown A.
      • et al.
      Real-world effectiveness and safety of glecaprevir/pibrentasvir in adults with chronic hepatitis C virus infection: a meta-analysis.

       Patients infected with HCV subtypes inherently resistant to NS5A inhibitors

      Few data are available on the efficacy of the fixed-dose combination of glecaprevir and pibrentasvir in patients with “unusual” HCV subtypes inherently resistant to NS5A inhibitors. Pibrentasvir has a higher barrier to resistance than other NS5A inhibitors against several NS5A RASs intrinsically present in the genome of these viruses.
      • Smith D.
      • Magri A.
      • Bonsall D.
      • Ip C.L.C.
      • Trebes A.
      • Brown A.
      • et al.
      Resistance analysis of genotype 3 hepatitis C virus indicates subtypes inherently resistant to nonstructural protein 5A inhibitors.
      ,
      • Nguyen D.
      • Smith D.
      • Vaughan-Jackson A.
      • Magri A.
      • Barnes E.
      • Simmonds P.
      • et al.
      Efficacy of NS5A inhibitors against unusual and potentially difficult-to-treat HCV subtypes commonly found in sub Saharan Africa and South East Asia.
      ,
      • Gottwein J.M.
      • Pham L.V.
      • Mikkelsen L.S.
      • Ghanem L.
      • Ramirez S.
      • Scheel T.K.H.
      • et al.
      Efficacy of NS5A inhibitors against hepatitis C virus genotypes 1-7 and escape variants.
      From 24 patients who failed to achieve SVR after a course of glecaprevir/pibrentasvir sent to the French National Reference Center for Viral Hepatitis B, C and D for subtyping and resistance analysis (the introduction of glecaprevir/pibrentasvir is more recent in France than that of sofosbuvir/velpatasvir, at least partly explaining the small number of cases observed thus far), 1 was infected with a non-1a/1b genotype 1 subtype, 2 with a non-2a/2c subtype, 6 with a non-4a/4d subtype and 1 with a non-6a subtype (Slim Fourati and Jean-Michel Pawlotsky, personal communication to the panel). Among the 20 patients infected with HCV genotype 3b included in the VOYAGE-1 and VOYAGE-2 Asian phase III trials, 6 patients (30%) experienced a virological failure (out of a total of 9 with virological failure among 522 patients treated with glecaprevir and pibrentasvir).
      • Wei L.
      • Wang G.
      • Alami N.N.
      • Xie W.
      • Heo J.
      • Xie Q.
      • et al.
      Glecaprevir-pibrentasvir to treat chronic hepatitis C virus infection in Asia: two multicentre, phase 3 studies - a randomised, double-blind study (VOYAGE-1) and an open-label, single-arm study (VOYAGE-2).

       Grazoprevir/elbasvir for genotype 1b

      In the phase III C-EDGE-TN trial, in treatment-naïve patients infected with genotype 1b receiving grazoprevir and elbasvir for 12 weeks, the SVR12 rate was 98% (129/131; 1 relapse).
      • Zeuzem S.
      • Ghalib R.
      • Reddy K.R.
      • Pockros P.J.
      • Ben Ari Z.
      • Zhao Y.
      • et al.
      Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial.
      In the C-CORAL trial, performed in Russia and the Asia-Pacific region, the SVR12 rate was 98% with the same regimen (382/389; 5 relapses).
      • Wei L.J.
      • Zhdanov K.
      • Burnevich E.
      • Sheen I.S.
      • Heo J.
      • Nguyen V.K.
      • et al.
      Efficacy and safety of elbasvir/grazoprevir in treatment-naïve patients with chronic HCV GT 1, GT 4 and GT 6 infection (C-CORAL): a phase III randomized multinational clinical trial.
      In treatment-experienced patients included in the C-EDGE-TE phase III trial, in which approximately one-third of patients had compensated cirrhosis, the SVR12 rate in genotype 1b patients was 100% (34/34) after 12 weeks of grazoprevir/elbasvir.
      • Kwo P.
      • Gane E.J.
      • Peng C.Y.
      • Pearlman B.
      • Vierling J.M.
      • Serfaty L.
      • et al.
      Effectiveness of elbasvir and grazoprevir combination, with or without ribavirin, for treatment-experienced patients with chronic hepatitis C infection.
      A pooled analysis of all phase II and III trials showed an SVR rate of 97% (1,040/1,070; 15 relapses and 15 non-virological failures) in patients infected with genotype 1b treated for 12 weeks with this regimen.
      • Zeuzem S.
      • Serfaty L.
      • Vierling J.
      • Cheng W.
      • George J.
      • Sperl J.
      • et al.
      The safety and efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 1b infection.
      In the open-label C-EDGE-COINFECTION trial, the SVR12 rate was 95% (42/44) in genotype 1b-infected treatment-naïve patients coinfected with HIV, with or without compensated cirrhosis, treated with grazoprevir and elbasvir for 12 weeks.
      • Rockstroh J.K.
      • Nelson M.
      • Katlama C.
      • Lalezari J.
      • Mallolas J.
      • Bloch M.
      • et al.
      Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial.
      In the STREAGER study, treatment-naïve genotype 1b-infected patients with F0–F2 fibrosis (excluding patients with advanced fibrosis or cirrhosis) treated with grazoprevir/elbasvir for 8 weeks achieved an SVR12 in 97% (109/112; 3 relapses) and an SVR24 in 95% (106/111; 5 relapses) of cases.
      • Abergel A.
      • Asselah T.
      • Mallat A.
      • Chanteranne B.
      • Faure F.
      • Larrey D.
      • et al.
      Phase 3, multicenter open-label study to investigate the efficacy of elbasvir and grazoprevir fixed-dose combination for 8 weeks in treatment-naive, HCV GT1b-infected patients, with non-severe fibrosis.
      In the Chinese EGALITE study, 8 weeks and 12 weeks of treatment yielded SVR12 rates of 88% (36/41, 4 relapses) and 100% (41/41), respectively, in treatment-naïve patients infected with genotype 1b with mild fibrosis.
      • Huang C.F.
      • Hung C.H.
      • Cheng P.N.
      • Bair M.J.
      • Huang Y.H.
      • Kao J.H.
      • et al.
      An open-label, randomized, active-controlled trial of 8 versus 12 weeks of elbasvir/grazoprevir for treatment-naive patients with chronic hepatitis C genotype 1b infection and mild fibrosis (EGALITE study): impact of baseline viral loads and NS5A resistance-associated substitutions.

       Sofosbuvir/velpatasvir/voxilaprevir for genotype 3a

      Patients infected with HCV genotype 3 have been treated with sofosbuvir/velpatasvir/voxilaprevir in 2 phase III trials: POLARIS-2 and POLARIS-3. In POLARIS-2, in which approximately three-quarters of patients were treatment-naïve and one-quarter treatment-experienced and approximately 20% of individuals had cirrhosis, the SVR12 rate was 99% (91/92; no virological failure) after 8 weeks of the triple combination of sofosbuvir, velpatasvir and voxilaprevir in genotype 3-infected patients.
      • Jacobson I.M.
      • Lawitz E.
      • Gane E.J.
      • Willems B.E.
      • Ruane P.J.
      • Nahass R.G.
      • et al.
      Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials.
      In POLARIS-3, 8 weeks of the triple combination yielded a 96% SVR12 rate (106/110; 2 relapses) in treatment-naïve and treatment-experienced patients with compensated cirrhosis.
      • Jacobson I.M.
      • Lawitz E.
      • Gane E.J.
      • Willems B.E.
      • Ruane P.J.
      • Nahass R.G.
      • et al.
      Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials.
      No data with 12 weeks of therapy have been generated in these phase III trials.

      Treatment of chronic hepatitis C in patients without cirrhosis and in patients with compensated (Child-Pugh A) cirrhosis

       General principles of treatment of chronic hepatitis C in patients without cirrhosis and in patients with compensated (Child-Pugh A) cirrhosis

      Because of their virological efficacy, ease of use, safety and tolerability, interferon (IFN)-free, ribavirin-free, pangenotypic DAA-based regimens (including sofosbuvir/velpatasvir, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir) are the recommended options in HCV-infected patients without cirrhosis and in those with compensated (Child-Pugh A) cirrhosis, including “treatment-naïve” patients (defined as patients who have never been treated for their HCV infection) and “treatment-experienced” patients (defined as patients who were previously treated with pegylated IFN-α and ribavirin; pegylated IFN-α, ribavirin and sofosbuvir; or sofosbuvir and ribavirin).
      The indications are the same in HCV-monoinfected and HIV-coinfected patients. However, treatment alterations or dose adjustments may be needed in the latter, owing to drug-drug interactions (see above and Table 4A).
      Generic drugs and their combinations produced by companies under the license of the Medicines Patent Pool and prequalified by WHO and/or other regulatory authorities have been shown to generate similar results to the original compounds, with similar safety and tolerability.
      • Freeman J.A.
      • Hill A.
      The use of generic medications for hepatitis C.
      • Bwa A.H.
      • Nangia G.
      • Win S.T.S.
      • Maung S.T.
      • Han K.A.W.
      • Htar S.S.
      • et al.
      Strategy and efficacy of generic and pan-genotypic sofosbuvir/velpatasvir in chronic hepatitis C virus: a Myanmar experience.
      • Hlaing N.K.T.
      • Nangia G.
      • Tun K.T.
      • Lin S.
      • Maung M.Z.
      • Myint K.T.
      • et al.
      High sustained virologic response in genotypes 3 and 6 with generic NS5A inhibitor and sofosbuvir regimens in chronic HCV in Myanmar.
      • Lashen S.A.
      • Shamseya M.M.
      • Madkour M.A.
      • Aboufarrag G.A.
      Tolerability and effectiveness of generic direct-acting antiviral drugs in eradication of hepatitis C genotype 4 among Egyptian patients.
      • Scotto R.
      • Buonomo A.R.
      • Moriello N.S.
      • Maraolo A.E.
      • Zappulo E.
      • Pinchera B.
      • et al.
      Real-world efficacy and safety of pangenotypic direct-acting antivirals against hepatitis C virus infection.
      • Abozeid M.
      • Alsebaey A.
      • Abdelsameea E.
      • Othman W.
      • Elhelbawy M.
      • Rgab A.
      • et al.
      High efficacy of generic and brand direct acting antivirals in treatment of chronic hepatitis C.
      • Goel A.
      • Chen Q.
      • Chhatwal J.
      • Aggarwal R.
      Cost-effectiveness of generic pan-genotypic sofosbuvir/velpatasvir versus genotype-dependent direct-acting antivirals for hepatitis C treatment.
      • Liu C.H.
      • Chen Y.S.
      • Wang S.S.
      • Liu C.J.
      • Su T.H.
      • Yang H.C.
      • et al.
      Sofosbuvir-based interferon-free direct acting antiviral regimens for heart transplant recipients with chronic hepatitis C virus infection.
      • Liu C.H.
      • Huang Y.J.
      • Yang S.S.
      • Chang C.H.
      • Yang S.S.
      • Sun H.Y.
      • et al.
      Generic sofosbuvir-based interferon-free direct acting antiviral agents for patients with chronic hepatitis C virus infection: a real-world multicenter observational study.
      • Morrison C.
      Gilead injects own generics into shrinking HCV drug market.
      • Zeng Q.L.
      • Xu G.H.
      • Zhang J.Y.
      • Li W.
      • Zhang D.W.
      • Li Z.Q.
      • et al.
      Generic ledipasvir-sofosbuvir for patients with chronic hepatitis C: a real-life observational study.
      The panel recognises the heterogeneity of per capita incomes and health insurance systems across Europe and in other regions, and therefore the constraints that may necessitate continued utilisation of regimens described in previous versions of these recommendations but no longer recommended. In settings where none of the IFN-free, ribavirin-free options proposed in this document are available, options proposed in previous versions of these recommendations remain acceptable for patients likely to respond to these regimens until new DAAs become available and affordable; see prior EASL Recommendations on Treatment of Hepatitis C.
      European Association for the Study of the Liver
      EASL recommendations on treatment of hepatitis C 2016.
      ,
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines: management of hepatitis C virus infection.
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines: management of hepatitis C virus infection.
      European Association for the Study of the Liver
      EASL recommendations on treatment of hepatitis C 2015.
      European Association for the Study of the Liver
      EASL recommendations on treatment of hepatitis C 2018.
      In particular, in many low- and middle-income countries where the pangenotypic DAA combinations recommended in the present document are not available and/or not affordable, the combination of generic sofosbuvir and daclatasvir is safe and well tolerated and provides high SVR rates at a very low price. This combination should be used according to the 2016 EASL Recommendations on Treatment of Hepatitis C.
      European Association for the Study of the Liver
      EASL recommendations on treatment of hepatitis C 2016.
      Recommendations
      • Because of their virological efficacy, ease of use, safety and tolerability, IFN-free, ribavirin-free, pangenotypic DAA-based regimens are preferred in HCV-infected patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis, including “treatment-naïve” patients (defined as patients who have never been treated for their HCV infection) and “treatment-experienced” patients (defined as patients who were previously treated with pegylated IFN-α and ribavirin; or pegylated IFN-α, ribavirin and sofosbuvir; or sofosbuvir and ribavirin) (A1).
      • The following pangenotypic regimens are recommended for the treatment of patients infected with HCV, according to the below recommendations (A1):
        • the fixed-dose combination of sofosbuvir (400 mg) and velpatasvir (100 mg) in a single tablet administered once daily;
        • the fixed-dose combination of glecaprevir (300 mg) and pibrentasvir (120 mg) in 3 tablets containing 100 mg of glecaprevir and 40 mg of pibrentasvir, administered once daily with food;
        • the fixed-dose combination of sofosbuvir (400 mg), velpatasvir (100 mg) and voxilaprevir (100 mg) in a single tablet administered once daily with food.
      • The non-pangenotypic fixed-dose combination of grazoprevir (100 mg) and elbasvir (50 mg) in a single tablet administered once daily can also be used in patients infected with HCV genotype 1b (A1).
      • The same IFN-free, ribavirin-free treatment regimens should be used in HIV-coinfected patients as in patients without HIV infection, because the virological results of therapy are identical (A1).
      • In HIV-coinfected patients, treatment alterations or dose adjustments should be performed in case of interactions with antiretroviral drugs (A1).
      • In settings where none of the IFN-free, ribavirin-free options proposed in this document are available, options proposed in previous versions of these recommendations remain acceptable for patients likely to respond to these regimens until pangenotypic DAA regimens become available and affordable (A1).
      • Generic drugs can be used, provided that quality controls are met and guaranteed by the provider (A1).
      • In low- and middle-income countries where the IFN-free, ribavirin-free options proposed in this document are not available and/or not affordable, the pangenotypic combination of generic sofosbuvir and generic daclatasvir is safe, highly efficacious and affordable, and should be used according to the 2016 EASL Recommendations on Treatment of Hepatitis C (A1).
      • In patients with advanced fibrosis (F3) or compensated (Child-Pugh A) cirrhosis (F4), post-SVR surveillance for the diagnosis of HCC and linkage to care must be provided when treatment for HCC is available (A1).

       Simplified, genotyping/subtyping-free treatment of chronic hepatitis C with pangenotypic drug regimens in patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis

      Improving access to anti-HCV therapy has become a worldwide priority. Many obstacles remain that reduce the global benefit of HCV treatment, including the numbers of infected individuals, the cost of diagnostic tests, the amount of information needed to inform treatment decisions, and the relative complexity of treatment strategies based on genotype. Thus, wherever genotype/subtype determination is not available, not affordable and/or limits access to HCV care, simplified treatment without knowledge of the HCV genotype and subtype should be used to facilitate the cascade of care. Populations who are historically less engaged in healthcare, such as PWIDs, prisoners, homeless individuals, migrants, people living in rural communities with poor access to care, patients struggling with mental health or substance use disorders, men who have sex with men, sex workers, or indigenous populations are those who will benefit more from a streamlined care pathway.
      The only information needed to start treatment with either sofosbuvir/velpatasvir or glecaprevir/pibrentasvir in patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis, including treatment-naïve or treatment-experienced patients (as defined above), is the presence of HCV replication (as assessed by HCV RNA or HCV core antigen testing, as described above) and possible drug-drug interactions. The presence of advanced fibrosis (F3) or cirrhosis (F4) must be checked prior to therapy as it will determine the duration of treatment (8 or 12 weeks) with certain HCV genotypes and regimens, and whether the patient needs post-treatment surveillance for HCC, provided that tre