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      2017 KASL clinical practice guidelines management of hepatitis C: Treatment of chronic hepatitis C

      The Korean Association for the Study of the Liver (KASL)

      Clinical and Molecular Hepatology

      The Korean Association for the Study of the Liver

      Chronic hepatitis C, Treatment, Direct acting antivirals, Guidelines

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          Abstract

          INTRODUCTION Guidelines on the management of hepatitis C were first developed in 2004 and revised in 2013 and 2015 by the Korean Association for the Study of the Liver (KASL). Recently, paradigms for the treatment of chronic hepatitis C have changed from interferon (IFN) alpha–based treatment to direct-acting antiviral agents (DAA). Compared with IFN, the higher sustained virologic response rate (SVR) of around 95%, lower adverse events, and convenience of DAAs for hepatitis C approaches the ideal goals of antiviral treatment. However, treatment for individual patients remains complex because treatment regimens and durations can differ depending on previous treatment experience, virus genotype and subtype, and the presence or absence of underlying liver cirrhosis. Furthermore, re-treatment options for patients who failed on previous DAA are limited. Since the first release of DAA, there have been many developments, including the introduction of pan-genotypic DAAs, new antivirals against resistance-associated substitutions (RASs), and the publication of many novel research results from Korea and other countries. Therefore, this clinical practice guideline, Management of hepatitis C: Treatment of chronic hepatitis C, has been revised in the areas of treatment, research, and education. These recommendations are not absolute standards of care, and adoption of the guidelines in clinical practice might need to differ among individual patients. Target populations The target groups for these guidelines are newly or previously diagnosed patients with hepatitis C virus infection (HCV), including patients with chronic hepatitis C with cirrhosis, hepatitis C patients with chronic kidney disease, and those co-infected with human immunodeficiency virus (HIV) or hepatitis B virus (HBV). Intended users These guidelines are intended to provide useful information and guidance to physicians and healthcare providers involved in the diagnosis and treatment of hepatitis C, along with resident physicians, practitioners, and trainers. Development, funding, and revision process The Clinical Practice Guidelines Committee for the Management of Hepatitis C, comprising 10 hepatologists, was organized according to a proposal by and the approval of the KASL Board of Executives. Funding for the revision was provided by KASL. Each committee member collected and analyzed the source data in his or her own field, and the members then wrote the manuscript together. Literature review for evidence collection The committee systematically collected and reviewed the international and domestic literature published before September 2017 in PubMed, MEDLINE, KoreaMed, and other databases. The keywords used were ‘hepatitis C virus’, ‘hepatitis C’, ‘liver cirrhosis’, ‘liver cancer’, and other specific related keywords. Level of evidence and grades of recommendations The quality of evidence is classified using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system (Table 1) [1]. Based on the types of study, randomized controlled studies were approached as providing a high level of evidence, whereas observational studies were approached as providing a low level of evidence. Then, the levels of evidence were adjusted by accounting for the factors that influence study quality. The levels of evidence are defined as follows: A, the highest level of evidence with the smallest possibility of changes in the conclusion; B, a moderate risk of potential changes; and C, the lowest level of evidence with the greatest possibility of changes. The strength of each recommendation is also classified according to the GRADE system. Each study was classified as a strong recommendation (1) or weak recommendation (2) based on the quality of evidence, the balance between the desirable and undesirable effects of an intervention, and socioeconomic aspects, including cost and availability. A strong recommendation indicates that the intervention could be applied for most patients with a strong certainty that desirable effects are highly possible with high-quality evidence, presumed patient-important outcomes, cost-effectiveness, preference, and compliance. A weak recommendation indicates a suggestion made with less certainty but that still could be considered favorable for many patients based on the level of evidence and the cost or preferences of patients or medical practitioners. List of key questions The revision committee considered the following clinical questions as the key components to be covered in these guidelines. 1. What are the characteristics and indications of new kinds of DAAs? 2. What are the recent updates in drug–drug interactions? 3. What is the definition, detection method, and clinical application of resistance associated substitutions (RASs)? 4. How should patients with genotype 1 chronic hepatitis and compensated cirrhosis be treated? 5. How should patients with genotype 2 chronic hepatitis and compensated cirrhosis be treated? 6. How should patients with genotype 3 chronic hepatitis and compensated cirrhosis be treated? 7. How should patients with genotype 4 chronic hepatitis and compensated cirrhosis be treated? 8. How should patients with genotype 5 or 6 chronic hepatitis and compensated cirrhosis be treated? 9. How should patients with decompensated cirrhosis be treated? 10. How should patients who underwent liver or extrahepatic organ transplantation be treated? 11. How should patients with special conditions (people who inject drug, chronic kidney disease, coinfection with HIV or HBV, hemophilia or thalassemia, immunosuppressive therapy or cytotoxic chemotherapy, and pediatric patients) be treated? 12. How should patients who failed on previous direct antiviral agents be treated? Review of the manuscript and approval process Each manuscript written by committee members was reviewed, agreed, and approved through meetings of the committee. The quality of the manuscript was evaluated based on the standards suggested by Appraisal of Guidelines for Research and Evaluation II (AGREE II), along with the academic integrity of the contents. The guidelines were reviewed and revised based on counsel from an infection specialist, a meeting of an external review board of 7 KASL members, opinions at a public hearing, and a symposium open to all KASL members. The final manuscript was approved by the KASL Board of Executives. Release of the guidelines and plan for updates The Korean version of the KASL Clinical Practice Guidelines for the Management of Hepatitis C: Treatment of Chronic Hepatitis C was released in November 2017 at a KASL meeting and published in November 2017 on the KASL website (http://www.kasl.org). Future plans for revision will be made when the accumulation of research on the management of hepatitis C makes revision necessary for the promotion of health in South Korea. In addition, the use of new DAAs will be allowed in South Korea in the near future, which might warrant updates or revisions to the guidelines. DIRECT ACTING ANTIVIRALS (DAAS) Recently, the paradigm for treating hepatitis C changed rapidly as newly developed oral antiviral agents, DAAs, became available. DAAs show antiviral effects by directly acting on the life cycle of the hepatitis C virus (HCV). DAAs are classified into HCV nonstructural protein (NS) 3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors, depending on their site of action. NS3/4A protease inhibitors are first-generation DAAs that block the polyprotein processing essential for HCV replication. Following the first-generation protease inhibitors (boceprevir and telaprevir), simeprevir, asunaprevir, paritaprevir, grazoprevir, voxilaprevir, and glecaprevir were developed [2]. NS5A inhibitors affect HCV replication and assembly, showing a synergistic effect in combination with other DAAs. They include daclatasvir, ledipasvir, ombitasvir, elbasvir, velpatasvir, and pibrentasvir. NS5B polymerase inhibitors include sofosbuvir and dasabuvir. As of 2017, the DAAs sofosbuvir, ledipasvir/sofosbuvir, daclatasvir, asunaprevir, ombitasvir/paritaprevir/ritonavir, dasabuvir, elbasvir/grazoprevir were approved in Korea (Table 2). In the United States and Europe, sofosbuvir/velpatasvir was approved in 2016, and sofosbuvir/velpatasvir/voxilaprevir and glecaprevir/pibrentasvir were approved in 2017. Given an understanding of the basic characteristics, doses, and posology of each DAA, the selection and use of appropriate drugs should consider hepatic and renal function. DAA regimens can interact with other medications used by patients. Prior to starting treatment, patients should be evaluated for potential drug–drug interactions with selected DAAs (Table 3, 4). A comprehensive list of drug–drug interactions is available at several websites, such as www.hep-druginteractions.org, and in the prescribing information for each drug [2-8]. [Recommendations] 1. Clinicians should understand the characteristics of each DAA and choose the most appropriate drug for each patient, with consideration of hepatic and renal function (A1). 2. The potential for drug–drug interactions must be considered before and during treatment with DAAs. Full prescribing information must be consulted prior to the use of DAAs because of the potential for drug–drug interactions (A1). Sofosbuvir Sofosbuvir is an HCV NS5B polymerase inhibitor. Dosage and administration Sofosbuvir should be administered orally at the dose of 400 mg (one tablet) once daily, with or without food. Pharmacokinetics Sofosbuvir is metabolized in the liver by the cathepsin A, carboxylesterase 1, histidine triad nucleotide-binding protein 1, and pyrimidine nucleotide biosynthesis pathway. GS-331007 is a major metabolite of sofosbuvir, of which approximately 80% is excreted in urine, and 15% is excreted in feces. No dosage adjustment of sofosbuvir is required for patients with hepatic impairment. Compared to subjects with normal renal function (eGFR >80 mL/min), the area under the curve (AUC) of sofosbuvir and GS-331007 were 1.7-fold and 4.5-fold higher, respectively, in patients with severe renal impairment (eGFR <30 mL/min) and that of GS-331007 was increased up to 20-fold in patients with end-stage renal disease (ESRD). Thus, no dosage adjustment of sofosbuvir is required for patients with mild or moderate renal impairment (eGFR 30-80 mL/min). Sofosbuvir is not recommended for use in patients with severe renal impairment (eGFR <30 mL/min) or ESRD requiring dialysis. Drug–drug interactions Sofosbuvir is a substrate of the drug transporter P-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP). Strong P-gp inducers, including anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), antituberculosis drugs (rifampin, rifabutin, rifapentine), and the herbal product St. John’s wort, could decrease the plasma concentration of sofosbuvir, causing reduced therapeutic efficacy. Thus, concomitant use of those substances with sofosbuvir is not recommended. In addition, because serious symptomatic bradycardia can occur, co-administration of amiodarone with sofosbuvir is contraindicated. Adverse reactions and safety The most common adverse reactions observed with sofosbuvir in combination with ribavirin were fatigue and headache, insomnia, pruritus, and anemia. Ledipasvir/sofosbuvir Ledipasvir is an HCV NS5A inhibitor, and sofosbuvir is an HCV NS5B polymerase inhibitor. Dosage and administration Ledipasvir/sofosbuvir is a fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) in a single tablet and should be administered at the dose of one tablet orally once a day, with or without food. Pharmacokinetics Ledipasvir is subject to slow oxidative metabolism via a still unknown mechanism. Ledipasvir is mainly excreted in feces, whereas, sofosbuvir is extensively excreted via the kidneys. No dosage adjustment of ledipasvir/sofosbuvir is required for patients with hepatic impairment due to minimal effects in the plasma concentration of the drug. No dose adjustment is required for patients with mild or moderate renal impairment (eGFR 30-80 mL/min), but it is not recommended for use in patients with severe renal impairment (eGFR <30 mL/min) or ESRD because its safety is not established in that population. Drug–drug interactions Ledipasvir and sofosbuvir are substrates of the drug transporters P-gp and BCRP. Strong P-gp inducers, such as antituberculosis drugs (rifampin, rifapentine, rifabutin), anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), and the herbal product St. John’s wort, could decrease the plasma concentration of ledipasvir/sofosbuvir and cause reduced therapeutic efficacy. Thus, concomitant use of those substances with ledipasvir/sofosbuvir is not recommended. Ledipasvir is an inhibitor of drug transporters such as P-gp, BCRP, and organic anion transporting polypeptide (OATP). Co-administration of ledipasvir/sofosbuvir with P-gp substrates (digoxin, dabigatran) could increase the concentration of each drug, requiring careful monitoring for therapeutic concentration or side effects. Co-administration with rosuvastatin is contraindicated because ledipasvir inhibits OATP, leading to a significant increase in the concentration of rosuvastatin. In addition, caution about adverse reactions is warranted if other HMGCoA reductase inhibitors (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin) are used. Co-administration of amiodarone (and possibly dronedarone) with ledipasvir/sofosbuvir is contraindicated due to serious risk of symptomatic bradycardia. Because the solubility of ledipasvir decreases with increasing pH, drugs that increase gastric pH are expected to decrease the concentration of ledipasvir. It is therefore recommended to separate antacids and ledipasvir/sofosbuvir by 4 hours. H2-receptor antagonists may be administered simultaneously with or 12 hours apart from ledipasvir/sofosbuvir at a dose that does not exceed doses comparable to famotidine 40 mg twice daily. Protonpump inhibitors can be administered at doses comparable to omeprazole 20 mg or lower, but at higher doses, they might decrease the efficacy of ledipasvir/sofosbuvir. Because ledipasvir/sofosbuvir increases the tenofovir concentration when a pharmacokinetic enhancer (ritonavir or cobicistat) is included in an antiretroviral regimen, combinations such as atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, elvitegravir/cobicistat, atazanavir/cobicistat, or darunavir/cobicistat in combination with tenofovir disoproxil fumarate/emtricitabine should be used with caution and frequent renal monitoring. Adverse reactions and safety The most common adverse reactions observed with ledipasvir/sofosbuvir were fatigue, headache, diarrhea, and insomnia. Daclatasvir Daclatasvir is an HCV NS5A inhibitor. Dosage and administration Daclatasvir is orally administered at the dose of 60 mg (one tablet) once daily with or without food. Dose modification of daclatasvir is needed if a CYP3A inhibitor or inducer is co-administered. If a strong CYP3A inhibitor is co-administered, the dose of daclatasvir should be reduced to one 30 mg tablet once daily. If a moderate CYP3A inducer is co-administered, the dose of daclatasvir should be increased to one 90 mg tablet once daily. Co-administration with a strong CYP3A inducer is contraindicated. Pharmacokinetics Daclatasvir is metabolized by CYP3A. Approximately 90% of daclatasvir is eliminated in feces, with less than 10% excreted in urine. Hepatic impairment does not have a clinically significant effect on the free drug concentration of daclatasvir. Thus, no dosage adjustment of daclatasvir is required for patients with any degree of hepatic or renal impairment. Drug–drug interactions Co-administration of daclatasvir with substances that are moderate or strong inducers or inhibitors of CYP3A4 is not recommended because it can significantly alter the exposure to daclatasvir. Strong CYP3A inducers, including anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), the herbal product St. John’s wort, and the antituberculosis drug rifampin, are contraindicated. Strong CYP3A inhibitors, including antiretrovirals (atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, atazanavir/cobicistat, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate), antifungals (itraconazole, ketoconazole, posaconazole, voriconazole), macrolides (clarithromycin, telithromycin), the antidepressant nefazodone, and calcium channel blockers (diltiazem, verapamil), can increase the plasma concentration of daclatasvir. Thus, the dose of daclatasvir should be decreased, or co-administration is not recommended. Moderate CYP3A inducers, including antibiotics (nafcillin, rifapentine), the endothelin receptor antagonist bosentan, the systemic steroid dexamethasone, antiretrovirals (efavirenz, etravirine, nevirapine), and the stimulant drug modafinil, can decrease the plasma concentration of daclatasvir. Thus, the dose of daclatasvir should be increased, or co-administration is not recommended. Daclatasvir is an inhibitor of P-gp, OATP1B1 and 1B3, and BCRP. Therefore, co-administration with the antiarrhythmic digoxin or HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) increases the plasma concentration of each drug, requiring caution for adverse reactions. Co-administration of daclatasvir and sofosbuvir with amiodarone is contraindicated due to a serious risk of severe bradycardia. Adverse reactions and safety The most common adverse reactions observed with daclatasvir in combination with asunaprevir were headache, fatigue, diarrhea, nausea, and alanine aminotransferase (ALT) elevation. Asunaprevir Asunaprevir is an HCV NS3/4A protease inhibitor. Dosage and administration Asunaprevir should be orally administered at the dose of 100 mg (one capsule) twice a day with or without food. Pharmacokinetics Asunaprevir is metabolized by CYP3A in the liver and mostly eliminated via bile. Compared to subjects with normal hepatic function, the plasma concentration of asunaprevir is not significantly altered in patients with Child-Turcotte-Pugh (CTP) class A cirrhosis, whereas, it can be increased 5-fold and 23-fold in CTP class B and C patients, respectively. Thus, asunaprevir is contraindicated for patients with moderate or severe hepatic impairment (CTP class B or C). No dosage adjustment is required for patients with mild or moderate renal impairment (eGFR 30–80 mL/min). A dosage adjustment of asunaprevir to 100 mg once daily is recommended for patients with severe renal impairment (eGFR <30 mL/min) not receiving hemodialysis because the AUC of asunaprevir in those patients increases 2-fold compared with subjects with normal renal function. Drug–drug interactions The drug–drug interactions of asunaprevir with co-medications can be found in the prescribing information of asunaprevir. Coadministration of asunaprevir, an inhibitor of CYP2D6, with antiarrhythmics (flecainide, propafenone) or the antipsychotic thioridazine can cause severe arrhythmia and is thus contraindicated. Strong or moderate CYP3A inducers, including anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), antituberculosis drugs (rifampin, rifabutin), the endothelin receptor antagonist bosentan, the systemic steroid dexamethasone, the herbal product St. John’s wort, antiretrovirals (efavirenz, etravirine, nevirapine), and the stimulant drug modafinil, can decrease the plasma concentration of asunaprevir, with possible loss of efficacy. Thus, co-administration is contraindicated. In addition, strong inhibitors of OATP1B1 or 2B1, such as the antituberculosis drug rifampin, the immunosuppressive drug cyclosporine, and the lipid lowering drug gemfibrozil, can decrease the therapeutic effect of asunaprevir by reducing its intrahepatic levels. Thus, coadministration is not recommended. Strong or moderate CYP3A inhibitors, including antifungals (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole), macrolides (clarithromycin, erythromycin), calcium channel blockers (diltiazem, verapamil), antiretrovirals (atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, saquinavir), and pharmacokinetic enhancers (cobicistat, ritonavir), can increase plasma levels of asunaprevir and cause severe adverse events. Thus, co-administration is contraindicated. Asunaprevir is a moderate inhibitor of CYP2D6 and an inhibitor of OATP 1B1/1B3 and P-gp. Therefore, co-administration of asunaprevir with substrates of those transporters, including the anticoagulant dabigatran, antiarrhythmics (digoxin, flecainide), HMGCoA reductase inhibitors (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), the antidepressant amitriptyline, and the antitussive dextromethorphan, can increase the plasma levels of each drug. Thus, close clinical monitoring and caution are warranted. Adverse reactions and safety The most common adverse events observed with asunaprevir in combination with daclatasvir were headache, fatigue, diarrhea, nausea, and ALT elevation. The frequency of ALT elevation more than 5 times the upper limit of normal was 3 to 4%, and the frequency of bilirubin elevation more than 2.6 times the upper limit of normal was 1%. Therefore, frequent monitoring of liver function is required to consider possible hepatotoxicity in patients receiving asunaprevir-containing regimens. Ombitasvir/paritaprevir/ritonavir, dasabuvir Ombitasvir is an inhibitor of HCV NS5A; paritaprevir is an HCV NS3/4A protease inhibitor; and ritonavir, a pharmacokinetic enhancer, is an inhibitor of CYP3A4. Dasabuvir is an HCV NS5B polymerase inhibitor. Dosage and administration Ombitasvir/paritaprevir/ritonavir is a fixed-dose combination containing ombitasvir (12.5 mg), paritaprevir (75 mg), and ritonavir (50 mg) in a single tablet that should be orally administered at the dose of two tablets once a day with food. Dasabuvir is orally administered at the dose of 250 mg (one tablet) twice a day with food. Pharmacokinetics Ombitasvir is predominantly metabolized by amide hydrolysis followed by oxidative metabolism. Paritaprevir is predominantly metabolized by CYP3A4, and dasabuvir is metabolized by CYP2C8. Ombitasvir, paritaprevir, and dasabuvir are excreted extensively into the feces. The AUC of paritaprevir increases 1.6-fold in patients with moderate hepatic impairment (CTP class B). The AUC of paritaprevir and dasabuvir increase 9-fold and 3-fold, respectively, in patients with severe hepatic impairment (CTP class C). Therefore, no dosage adjustment is required in patients with mild hepatic impairment (CTP class A). However, this regimen is not recommended for patients with moderate or severe hepatic impairment (CTP class B or C). No dosage adjustment is required in patients with any degree of renal impairment not on dialysis. This regimen has not been studied in patients on dialysis. Drug–drug interactions Moderate or strong CYP3A4 inducers and CYP2C8 inducers decrease the plasma concentration of ombitasvir/paritaprevir/ritonavir and dasabuvir, leading to reduced therapeutic efficacy. Thus, co-administration with anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), the antituberculosis drug rifampin, the herbal product St. John’s wort, the antiretroviral efavirenz, and the endothelin receptor antagonist bosentan is contraindicated. Strong CYP2C8 inhibitors increase the plasma concentration of dasabuvir, which is associated with the risk of QT prolongation; thus, antifungals (itraconazole, ketoconazole, posaconazole, voriconazole), macrolides (clarithromycin, telithromycin), and the lipid lowering drug gemfibrozil are contraindicated. Ritonavir strongly inhibits CYP3A4; paritaprevir inhibits OATP1B1, OATP1B3, BRCP, and P-gp; and dasabuvir and ritonavir inhibit P-gp and BRCP. Co-administration with substrate drugs of those enzymes can increase the plasma concentration of each drug, causing severe adverse events, and is thus not recommended. Those substrate drugs include the angiotensin inhibitor aliskiren, the alpha-adrenoreceptor antagonist alfuzosin, the anti-angina drug ranolazine, antiarrhythmics (amiodarone, dronedarone), the antiplatelet ticagrelor, HMG-CoA reductase inhibitors (atorvastatin, lovastatin, simvastatin), antipsychotics (luracidone, pimozide, quetiapine), the gastrointestinal motility stimulant cisapride, sedatives (triazolam, midazolam), and the ergot agonist ergotamine. Furthermore, serum ALT elevation frequently developed when ombitasvir/paritaprevir/ritonavir and dasabuvir were administered to women using the oral contraceptive ethinylestradiol; thus, co-administration is not recommended. Some other drugs also require caution for dose modification, rescheduling of administration times, or monitoring for adverse reactions caused by drug–drug interactions. Adverse reactions and safety The most common adverse reactions observed with ombitasvir/paritaprevir/ritonavir and dasabuvir were nausea, pruritus, and insomnia. When it is administered with ribavirin, the most commonly reported adverse reactions were fatigue, nausea, pruritus, other skin reactions, and insomnia. Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported, mostly in patients with advanced cirrhosis, warranting close monitoring for clinical signs and symptoms. In addition, ALT elevation more than 5 times the upper normal limit at treatment week 4 was reported in about 1% of patients; thus monitoring of liver enzymes is required. Elbasvir/grazoprevir Elbasvir is an inhibitor of HCV NS5A, and grazoprevir is an HCV NS3/4A protease inhibitor. Dosage and administration Elbasvir/grazoprevir is a fixed dose combination of elbasvir (50 mg) and grazoprevir (100 mg) in a single tablet and should be orally administered at the dose of one tablet once a day with or without food. Pharmacokinetics Elbasvir and grazoprevir are partially metabolized by CYP3A4 and are mainly eliminated through bile and feces. No dosage adjustment is recommended in patients with mild hepatic impairment (CTP class A). However, the AUC of grazoprevir increases 5-fold and 12-fold in patients with moderate and severe hepatic impairment (CTP class B and C), respectively. Thus, elbasvir/grazoprevir is contraindicated in patients with moderate or severe hepatic impairment (CTP class B or C). No dosage adjustment is recommended in patients with any degree of renal impairment, including patients receiving hemodialysis. Drug–drug interactions Moderate or strong CYP3A inducers, including anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), the antituberculosis drug rifampin, the herbal product St. John’s wort, antiretrovirals (efavirenz, etravirine), the antibiotic nafcillin, the endothelin receptor antagonist bosentan, and the stimulant drug modafinil, decrease the plasma concentration of elbasvir and grazoprevir; thus, co-administration is contraindicated. Inhibitors of CYP3A or OATP1B1/3, including antiretrovirals (cobicistat-containing regimens, atazanavir, darunavir, lopinavir, saquinavir, tipranavir) and the immunosuppressive drug cyclosporine, can increase the plasma concentration of elbasvir and grazoprevir and are thus contraindicated. Grazoprevir is a weak inhibitor of CYP3A, and elbasvir is a weak inhibitor of P-gp; therefore, the possibility that elbasvir/grazoprevir will affect the plasma levels of other drugs is relatively low. However, co-administration with substrate drugs of CYP3A or P-gp (tacrolimus, statins, dabigatran, ticagrelor) warrants caution for drug–drug interactions. Adverse reactions and safety The most common adverse reactions observed with elbasvir/grazoprevir were fatigue, headache, and nausea. Serum ALT elevation more than 5 times the upper normal limit at treatment week 8 was reported in about 1% of patients; thus monitoring for liver function is required. Glecaprevir/pibrentasvir Glecaprevir is an HCV NS3/4A protease inhibitor, and pibrentasvir is an HCV NS5A inhibitor. Dosage and administration Glecaprevir/pibrentasvir is a fixed dose combination of glecaprevir (100 mg) and pibrentasvir (40 mg) in a single tablet and should be orally administered at the dose of three tablets once a day with food. Pharmacokinetics Glecaprevir/pibrentasvir is metabolized by CYP3A and mainly eliminated in bile, with less than 1% excreted in urine. The AUC of glecaprevir is 2-fold higher in patients with moderate hepatic impairment (CTP class B) compared to normal subjects, and the AUC of glecaprevir and pibrentasvir is 11-fold and 2-fold higher, respectively, in patients with severe hepatic impairment (CTP class C). Therefore, glecaprevir/pibrentasvir is contraindicated in patients with severe hepatic impairment (CTP class C) and is also not recommended in patients with moderate hepatic impairment (CTP class B). No dosage adjustment is recommended in patients with any degree of renal impairment, including patients receiving hemodialysis. Drug–drug interactions Strong or moderate inducers of P-gp and CYP significantly reduce the AUC of glecaprevir/pibrentasvir with loss of therapeutic efficacy. Thus, anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), antituberculosis drugs (rifampin, rifapentine, rifabutin), the herbal product St. John’s wort, the antiretroviral efavirenz, and the endothelin receptor antagonist bosentan are contraindicated. Glecaprevir and pibrentasvir are substrates of P-gp and BCRP, and glecaprevir is a substrate of OATP 1B1/3. Because P-gp, BCRP, and OATP 1B1/3 inhibitors increase the AUC of glecaprevir and pibrentasvir, antiretrovirals (atazanavir, darunavir, lopinavir, ritonavir) are contraindicated, and co-administration with cyclosporine at a dose above 100 mg per day is not recommended. Glecaprevir and pibrentasvir are inhibitors of P-gp, BCRP, and OATP 1B1/3 and can increase the plasma concentrations of drugs that are substrates of those transporters. The angiotensin inhibitor aliskiren, the anticoagulant dabigatran, and HMG-CoA reductase inhibitors (atorvastatin, lovastatin, simvastatin) are contraindicated. Co-administration with other HMG-CoA reductase inhibitors (fluvastatin, pitavastatin, pravastatin, rosuvastatin), the antiarrhythmic digoxin, or immunosuppressive drugs (everolimus, sirolimus, tacrolimus) can increase the plasma concentration of each drug, warranting dose adjustment or monitoring for adverse reactions. Furthermore, serum ALT elevations frequently developed when glecaprevir/pibrentasvir was administered to women using the oral contraceptive ethinylestradiol; thus, glecaprevir/pibrentasvir is not recommended in that condition. Adverse reactions and safety The most common adverse reactions observed with glecaprevir/pibrentasvir were headache and fatigue. Sofosbuvir/velpatasvir Velpatasvir is an HCV NS5A inhibitor, and sofosbuvir is an HCV NS5B polymerase inhibitor. Dosage and administration Sofosbuvir/velpatasvir is a fixed dose combination of sofosbuvir (400 mg) and velpatasvir (100 mg) in a single tablet and should be orally administered at the dose of one tablet once a day with or without food. Pharmacokinetics Velpatasvir is metabolized by CYP2B6, CYP2C8, and CYP3A4 and mainly excreted via bile. The AUC of velpatasvir in patients with moderate or severe hepatic impairment is similar to that in subjects with normal hepatic function. Thus, no dosage adjustment is required for patients with cirrhosis, including decompensated disease. No dosage adjustment is required for patients with mild or moderate renal impairment (eGFR 30–80 mL/min), but it is not recommended for use in patients with severe renal impairment (eGFR <30 mL/min) or ESRD requiring dialysis because the AUC of GS-331007, a metabolite of sofosbuvir, is significantly increased. Drug–drug interactions Strong or moderate inducers of P-gp, CYP2B6, CYP2C8, or CYP3A4 decrease the plasma concentration of sofosbuvir and velpatasvir with loss of therapeutic efficacy. Thus, anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), antituberculosis drugs (rifampin, rifapentine, rifabutin), the herbal product St. John’s wort, the antiretroviral efavirenz, the stimulant modafinil, and the endothelin receptor antagonist bosentan are contraindicated. Because drugs increasing gastric pH reduce the solubility of sofosbuvir/velpatasvir, caution is needed when antacids, an H2 receptor antagonist, or a proton pump inhibitor is coadministered. Velpatasvir is an inhibitor of P-gp, BCRP, OATP1B1/B3, and OATP2B1. Co-administration of sofosbuvir/velpatasvir with substrates of those transporters can increase the plasma concentration of each drug. Sofosbuvir/velpatasvir increases the plasma concentration of topotecan, an anticancer drug; thus, co-administration is not recommended. Co-administration with tenofovircontaining regimens of antiretrovirals or HMG-CoA reductase inhibitors (atorvastatin, rosuvastatin) can increase the plasma levels of each drug, requiring dose adjustment or monitoring for adverse reactions. Co-administration of sofosbuvir/velpatasvir with amiodarone is contraindicated due to a risk of serious bradycardia. Frequent monitoring for digoxin levels is recommended if it is used. Adverse reactions and safety The most common adverse reactions observed with sofosbuvir/velpatasvir were headache and fatigue. When it is administered with ribavirin, the most commonly reported adverse reactions were fatigue, anemia, nausea, headache, insomnia, and diarrhea. Sofosbuvir/velpatasvir/voxilaprevir Voxilaprevir is an HCV NS3/4A protease inhibitor, velpatasvir is an HCV NS5A inhibitor, and sofosbuvir is an HCV NS5B polymerase inhibitor. Dosage and administration Sofosbuvir/velpatasvir/voxilaprevir is a fixed dose combination of sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg) in a single tablet and should be orally administered at the dose of one tablet once a day with food. Pharmacokinetics Voxilaprevir is metabolized by CYP3A4 and mainly eliminated via bile. Compared to subjects with normal hepatic function, the AUC of voxilaprevir is 1.7-fold higher in patients with mild hepatic impairment (CTP class A) and 3-fold and 5-fold higher, respectively, in patients with moderate and severe hepatic impairment (CTP class B and C). Therefore, sofosbuvir/velpatasvir/voxilaprevir is contraindicated in decompensated cirrhotic patients with moderate or severe hepatic impairment (CTP class B or C). No dose adjustment is required for patients with mild or moderate renal impairment (eGFR 30–80 mL/min), but it is not recommended for use in patients with severe renal impairment (eGFR <30 mL/min) or ESRD requiring dialysis because the AUC of GS-331007 is significantly increased. Drug–drug interactions Sofosbuvir, velpatasvir, and voxilaprevir are substrates of P-gp and BCRP, and voxilaprevir is a substrate of OATP1B1/1B3. Strong or moderate P-gp, CYP inducers significantly decrease the AUC of sofosbuvir/velpatasvir/voxilaprevir with loss of therapeutic efficacy. Thus, anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), antituberculosis drugs (rifampin, rifapentine, rifabutin), the herbal product St. John’s wort, the antiretroviral efavirenz, and the endothelin receptor antagonist bosentan are contraindicated. OATP inhibitors can markedly increase the plasma concentration of voxilaprevir; thus, antiretrovirals (atazanavir, lopinavir) and the immunosuppressive drug cyclosporine are contraindicated. Because drugs increasing gastric pH reduce the solubility of sofosbuvir/velpatasvir/voxilaprevir, caution is warranted when antacids, an H2 receptor antagonist, or a proton pump inhibitor are co-administered. Velpatasvir and voxilaprevir are inhibitors of P-gp, BCRP, and OATP 1B1/1B3, and velpatasvir is an inhibitor of OATP 2B1. Therefore, co-administration with drugs that are substrates of those transporters can change the plasma levels of each drug. HMGCoA reductase inhibitors (atorvastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatin), anticancer drugs (methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, topotecan), and the anticoagulant dabigatran are contraindicated. Co-administration of sofosbuvir/velpatasvir/voxilaprevir with amiodarone can cause serious bradycardia and is thus contraindicated. Frequent monitoring for digoxin levels is required when it is used. Co-administration with a tenofovir-containing regimen of antiretrovirals or lipid lowering drugs (ezetimibe, pravastatin) can increase the plasma levels of each drug, requiring dose adjustment or monitoring for adverse reactions. Furthermore, serum ALT elevations frequently developed when sofosbuvir/velpatasvir/voxilaprevir was administered to women using the oral contraceptive ethinylestradiol; thus, sofosbuvir/velpatasvir/voxilaprevir is contraindicated in that condition. Adverse reactions and safety The most common adverse reactions observed with sofosbuvir/velpatasvir/voxilaprevir were headache, fatigue, diarrhea, and nausea. HCV RESISTANCE-ASSOCIATED SUBSTITUTION (RAS) TESTING While a variety of DAAs were being tested, amino acid sequence substitutions associated with resistance to DAAs were found (Table 5) [9]. Thus, some DAAs require RAS testing before treatment. HCV RASs can appear spontaneously during the HCV life cycle without previous DAA therapy. The frequency of naturally occurring RASs varies among genotypes: for an NS3 RAS, it is 75.0% and 2.0% in genotypes 1a and 1b, respectively; for an NS5A RAS, it is 3.5% and 14.1% in genotypes 1a and 1b, respectively [10]. In contrast, the frequency of naturally occurring NS5B RASs is very low: in phase 2 and 3 clinical trials of sofosbuvir (n=8,598), S282T was not detected when measured by the deep sequencing method (with 1% cutoff) [11]. Viruses resistant to NS3 protease inhibitors or NS5B inhibitors disappear from peripheral blood within a few weeks to months, whereas NS5A inhibitor-resistant viruses persist for years [9]. There are several RAS testing methods: population sequencing, clonal sequencing, and deep sequencing. The sensitivity of each method is 10–25%, 5%, and 0.5-1%, respectively. Resistant viruses present in low proportions (less than 15%) at baseline do not appear to significantly influence the treatment response. Also, a 15% cutoff better predicts treatment failure through the selection of resistant viruses. Thus, a 15% cutoff is widely recommended to report the presence of RASs [9]. However, RAS testing methods are not yet well standardized, and HCV RAS testing prior to DAA therapy is not generally required in clinical practice. Exceptionally, several conditions do necessitate RAS testing prior to DAA therapy. For example, in HCV genotype 1b-infected patients with a baseline NS5A RAS at position L31 or Y93, daclatasvir and asunaprevir combination therapy showed a significantly lower SVR than in those without NS5A RASs [12]. Therefore, NS5A RAS testing should be performed prior to daclatasvir and asunaprevir combination therapy. If NS5A RASs are detected, an alternative regimen should be considered. In HCV genotype 1a-infected patients with a baseline NS5A RAS at position M28, Q30, L31, or Y93, elbasvir/grazoprevir treatment had a significantly lower SVR than in those without RASs [13]. Therefore, HCV genotype 1ainfected patients should be tested for NS5A RASs prior to elbasvir/grazoprevir treatment. If NS5A RASs are detected, the prolongation of treatment duration and the addition of ribavirin should be considered. In addition, RAS testing could help clinicians choose the best drugs for patients who failed with initial DAA therapy. When the HCV titer is very low in serum or a mutation is at the position where the primer binds, a RAS test can be “undetermined.” In that case, it is reasonable to regard it as RAS-positive and treat accordingly. [Recommendations] 1. Patients with HCV genotype 1b chronic hepatitis C or compensated cirrhosis should be tested for NS5A RASs prior to daclatasvir and asunaprevir combination treatment. If NS5A RASs are detected, an alternative regimen should be considered (A1). 2. Patients with HCV genotype 1a chronic hepatitis C or compensated cirrhosis should be tested for NS5A RASs prior to elbasvir/grazoprevir treatment. If NS5A RASs are detected, prolonging the treatment duration and adding ribavirin should be considered (A1). TREATMENT OF CHRONIC HEPATITIS C OR COMPENSATED CIRRHOSIS PATIENTS Treatment of chronic hepatitis C or compensated cirrhosis patients with HCV genotype 1 infection Several potent DAA oral combination regimens are recommended for patients with genotype 1 infection. However, the regimens differ based on the HCV subtype, the existence of baseline RASs, and liver cirrhosis status. Some regimens have demonstrated higher treatment failure rates in genotype 1a patients. Therefore, genotype 1 patients whose subtype cannot be identified should be treated as if they had a genotype 1a infection. Few Korean HCV patients have been treated with 1st generation protease inhibitors (PIs) such as boceprevir or telaprevir, except those enrolled in clinical trials. In these guidelines, “treatment-experienced patients” refer to people treated with interferon-based treatments (pegylated or conventional) with or without ribavirin. Those patients might have failed to achieve an SVR for various reasons, including non-response to the treatment or intolerance to or ineligibility for the interferon-based treatment. Initial treatment of genotype 1b patients Ledipasvir/sofosbuvir: In a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection (n=865, genotype 1b 33%, cirrhosis 16%), the SVR following 12 weeks of ledipasvir/sofosbuvir treatment was 99% (211/214) [14]. The addition of ribavirin or treatment extension to 24 weeks did not affect the outcome. In addition, an integrated safety and efficacy analysis of ledipasvir/sofosbuvir in previously untreated patients with genotype 1 HCV infection and compensated cirrhosis (n=161) concluded that the addition of ribavirin or extension of treatment duration did not affect the SVR in those patients either [13]. In a phase 3, open-label study involving 647 previously untreated patients with HCV genotype 1 infection without cirrhosis, the SVR were similar among those who received 8 weeks of ledipasvir/sofosbuvir treatment (94%, 202/215), 8 weeks of ledipasvir/sofosbuvir plus ribavirin (93%, 201/216), and 12 weeks of ledipasvir/sofosbuvir treatment (95%, 206/216) [15]. In that study, the degree of fibrosis was assessed by liver biopsy, and cirrhotic patients were excluded. Virologic relapse rates were higher in the 8-week arms with or without ribavirin than in the 12-week treatment group (5% [20/431] vs. 1% [3/216]). Post hoc analyses assessed baseline predictors of relapse and identified lower relapse rates in patients receiving 8 weeks of ledipasvir/sofosbuvir who had baseline HCV RNA levels of less than 6,000,000 IU/mL (2/123; 2%). In another cohort study, SVRs in patients receiving 8 weeks of ledipasvir/sofosbuvir were not inferior to those in the 12-week treatment group if the patients were non-cirrhotic and had baseline HCV RNA of less than 6,000,000 IU/mL, providing the possibility of shortening therapy for some patients [16]. In a recent observational study involving HCV genotype 1b infected patients without cirrhosis, the SVR rate in the 8-week ledipasvir/sofosbuvir treatment group (97%, 62/64) was similar to that in the 12 week-treatment group (97%, 61/63) (cirrhotic patients were excluded based on clinical evidence and results from at least two imaging tools, i.e., abdominal ultrasonography, FibroScan®, computed tomography, or magnetic resonance imaging) [17]. On the other hand, another observational cohort study found that treatmentnaïve patients with HCV genotype 1 without cirrhosis (FIB-4≤3.25 or APRI ≤2) and baseline HCV RNA of less than 6,000,000 IU/mL who completed 8 weeks of ledipasvir/sofosbuvir treatment had an SVR of 93% (1,020/1,094), whereas those who completed 12 weeks of therapy showed an SVR of 97% (875/906) [18]. However, that study assessed cirrhosis using laboratory markers, FIB-4 or APRI, so the possibility that patients with advanced fibrosis or cirrhosis were recruited cannot be excluded. In another study, in which fibrosis stage was assessed by transient elastography, serum biomarkers (fibro-SURE, Hepascore), or liver biopsy, the SVR of treatment-naïve, HCV genotype 1b infected patients without cirrhosis treated with ledipasvir/sofosbuvir was 99% (200/202) [19]. In addition, a meta-analysis of six additional cohorts comprising 5,637 patients demonstrated comparable relapse rates after 8-week and 12-week treatments of ledipasvir/sofosbuvir (relative risk [RR] 0.99, 95% confidence interval [CI] 0.98–1.00) [19]. In treatment-naïve HCV genotype 1b infected patients, the presence of baseline NS5A RASs did not affect the treatment outcome after ledipasvir/sofosbuvir treatment, which provided an SVR of 99% in every group, including those with liver cirrhosis [20]. However, in a recent cohort study (n=772, treatment naïve 61%), NS5A RASs undermined the virological response in HCV genotype 1b infected patients with cirrhosis [21]. In that study, the SVR12 in cirrhotic patients with NS5A RASs (88%, 49/56) was statistically lower than the SVR12 in the other three groups: non-cirrhosis without NS5A RASs (100%, 405/405), non-cirrhosis with NS5A RASs (99%, 125/126), and cirrhosis without NS5A RASs (99%, 154/155). Although, the researchers did not analyze the SVR according to treatment experience, those findings suggest that baseline RASs could affect treatment outcomes in genotype 1b cirrhotic patients. Elbasvir/grazoprevir: In a phase 3 study, treatment-naïve HCV genotype 1b infected patients were treated with elbasvir/grazoprevir for 12 weeks and showed an SVR of 99% (129/131) [13]. The presence of compensated cirrhosis did not affect the SVR rates [13]. The SVR in patients with and without baseline RASs was 94% (17/18), and 100% (112/112), respectively. In another phase 3 study, patients infected with HCV genotype 1 or 4 were treated with elbasvir/grazoprevir for 12 weeks (genotype 1b 85%, PR experience 22%) and showed an SVR rate of 99% (128/129) [22]. In that study, HCV genotype 1b infected patients with baseline RASs had an SVR of 100% (11/11) [22]. In a study conducted in Japan, the SVR after patients with genotype 1b infection with and without cirrhosis received a 12-week treatment of elbasvir/grazoprevir was 97% (34/35) and 97% (219/227), respectively [23]. In a pooled analysis, HCV genotype 1b patients with baseline NS5A RASs who received 12 weeks of elbasvir/grazoprevir had an SVR of 94% (48/51), and those without baseline RASs had an SVR of 99% (247/248) (P< =0.017) [24]. Ombitasvir/paritaprevir/ritonavir plus dasabuvir: Treatment-naïve HCV genotype 1b infected patients without liver cirrhosis who received ombitasvir/paritaprevir/ritonavir plus dasabuvir combined with ribavirin for 12 weeks showed an SVR of 99% (209/210), and those who did not receive the ribavirin combination had an SVR of 99% (207/209) [25]. In another study of patients with genotype 1b infection without cirrhosis, the SVR after 12 weeks of therapy with ombitasvir/paritaprevir/ritonavir and dasabuvir with and without ribavirin was 99% (83/84) and 98% (81/83), respectively [26]. In another study, treatment-naïve genotype 1b infected patients without liver cirrhosis treated with ombitasvir/paritaprevir/ritonavir plus dasabuvir and ribavirin showed an SVR of 100% (22/22) [27], as did treatment-naïve genotype 1b patients without cirrhosis in a different study who were treated ombitasvir/paritaprevir/ritonavir plus dasabuvir without ribavirin SVR of 100% (60/60) [28]. Daclatasvir and sofosbuvir: In a study of 101 patients with HIV/HCV co-infection treated with daclatasvir and sofosbuvir, a post hoc analysis showed that treatment-naïve patients with genotype 1b infection without cirrhosis who were treated for 12 weeks showed an SVR of 100% (12/12) [29,30]. In a study of treatment-naïve patients with genotype 1 infection, the SVR after 24 weeks of treatment with daclatasvir and sofosbuvir was 100% (29/29), regardless of ribavirin combination, and the SVR after 12 weeks of therapy with daclatasvir and sofosbuvir with and without ribavirin was 95% (39/41) and 100% (41/41), respectively [31]. That study included only 11 patients with cirrhosis, making it inappropriate for evaluating the influence of cirrhosis on SVR [31]. A cohort study that recruited 768 genotype 1 infected patients (liver cirrhosis 73%, genotype 1b 46%, treatment naïve 16%) assessed SVR according to the treatment duration (12 weeks vs. 24 weeks of daclatasvir plus sofosbuvir) with and without ribavirin. In cirrhotic patients, the SVR rates after 12-week, 12-week+ribavirin, 24-week, and 24-week+ribavirin treatments were 87% (82/94), 92% (23/25), 94% (323/343), and 98% (100/102), respectively (P< =0.0152). That study suggests that cirrhosis status and treatment experience influence SVR [32]. In a phase 3 study that treated patients with genotype 1b infection and decompensated cirrhosis with daclatasvir and sofosbuvir for 12 weeks in combination with ribavirin, the SVR was 100% (11/11) [33]. Daclatasvir and asunaprevir: Daclatasvir and asunaprevir treatment for 24 weeks in 203 treatment-naïve genotype 1b patients produced an SVR of 90% [12]. The SVRs did not differ by the baseline factors of gender, age, race, IL28B genotype, or cirrhosis status. However, the presence of baseline NS5A RASs (L31 or Y93) significantly reduced the SVR. A pooled data analysis from 5 phase 2 and 3 studies (n=979, treatment naïve 30%, liver cirrhosis 22%) demonstrated an SVR of 39% in patients with NS5A RASs compared to an SVR rate of 94% in patients without RASs after 24 weeks of daclatasvir and asunaprevir treatment [34]. Baseline NS5A RASs were identified in 13–14% of the patients included in this analysis. A post hoc analysis of a phase 3 clinical study investigated the efficacy of 24 weeks of asunaprevir and daclatasvir treatment in Asian genotype 1b patients (n=747, including 78 Koreans). The SVR was 92% among treatment-naïve patients. SVR12 varied little according to the baseline factors of age, viral load, IL28 genotype, and cirrhosis status [35]. A multivariate regression analysis showed that NS5A RAS had a significant influence on SVR (odds ratio [OR] 19.64, 95% CI 4.72–81.75). Glecaprevir/pibrentasvir: In a phase 2 study, DAA-naïve noncirrhotic patients with HCV genotype 1 infection treated with glecaprevir (200 mg) plus pibrentasvir (120 mg) for 12 weeks, glecaprevir (200 mg) plus pibrentasvir (40 mg) for 12 weeks, or glecaprevir (300 mg) plus pibrentasvir (120 mg) for 8 weeks showed SVRs of 100%, 97%, and 97%, respectively (n=133, treatment experience 30%) [36]. A phase 3 study that assessed the efficacy and safety of 8 and 12 weeks of glecaprevir (300 mg)/pibrentasvir (120 mg) in HCV genotype 1 monoinfected and HIV/HCV co-infected patients without cirrhosis (n=703, interferon-based treatment experience 28%, sofosbuvir-based treatment experience 0.4%, genotype 1a 43%) showed SVR of 99% and 99.7%, respectively [37]. In a pooled analysis of phase 2 and 3 studies of patients with genotype 1–6 chronic HCV infection without cirrhosis (interferon-based treatment experience 23%, sofosbuvir-based treatment experience 1%), the SVR rates among patients with genotype 1 infection (n=788, genotype 1b 56%) after 8 or 12 weeks of treatment with glecaprevir (300 mg) and pibrentasvir (120 mg) were 99% and 100%, respectively [38]. A phase 2 study among DAA-naïve HCV genotype 1 infected patients with compensated cirrhosis (n=27, genotype 1b 26%, interferon-based treatment experience 22%) treated with glecaprevir (200mg) plus pibrentasvir (120mg) for 12 weeks showed an SVR of 96% [39]. A phase 3 study of HCV genotype 1, 2, 4, 5, and 6 infected patients with compensated cirrhosis (n=146, interferon-based treatment experience 17%, sofosbuvir-based treatment experience 8%) treated with glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks showed an SVR of 100% in patients with genotype 1b infection (n=39) [40]. A phase 3 study conducted in Japan among DAA-naive HCV genotype 1 infected patients without cirrhosis (n=129, genotype 1b 97%, treatment experience 27%) treated with glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks found an SVR of 99% [41]. On the other hand, treatment-naive HCV genotype 1 infected patients with cirrhosis (n=38, genotype 1b 100%, treatment experience 32%) were treated with glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks and showed an SVR of 100% [41]. Sofosbuvir/velpatasvir: In a phase 3, double-blind, placebocontrolled study among untreated and previously treated HCV genotype 1, 2, 4, 5, and 6 infected patients (including 20% cirrhotic patients), the SVR of HCV genotype 1b infected patients following 12 weeks of treatment with sofosbuvir (400 mg)/velpatasvir (100 mg) was 99% (117/118) [42]. The SVR was 100% (94/94) in patients without cirrhosis and 96% (23/24) in compensated cirrhotic patients. In that study, the SVR of treatment-naïve HCV genotype 1b infected patients was 100% (86/86). Sofosbuvir/velpatasvir/voxilaprevir: In a phase 3, openlabel trial, HCV infected patients who had not been previously treated with DAAs were randomly assigned to groups given sofosbuvir/velpatasvir/voxilaprevir for 8 weeks or sofosbuvir/velpatasvir for 12 weeks (n=941, conventional or pegylated interferon experienced patients 23%) [43]. The overall SVR rate following treatment with sofosbuvir/velpatasvir/voxilaprevir for 8 weeks or sofosbuvir/velpatasvir for 12 weeks was 95% (476/501) and 98% (432/440), respectively. Although the 8-week treatment of sofosbuvir/velpatasvir/voxilaprevir seems to be inferior to the 12-week treatment of sofosbuvir/velpatasvir, the HCV genotype 1b infected patients treated with sofosbuvir/velpatasvir/voxilaprevir for 8 weeks had an SVR of 97% (61/63), and those treated with sofosbuvir/velpatasvir for 12 weeks also had an SVR of 97% (57/59). On the other hand, the HCV genotype 1a infected patients treated for 8 weeks had an SVR of only 92% (155/169), whereas those treated for 12 weeks had an SVR of 99% (170/172). The SVRs following an 8-week treatment of sofosbuvir/velpatasvir/voxilaprevir or 12-week treatment of sofosbuvir/velpatasvir were 96% (395/411) and 98% (349/356), respectively, in non-cirrhotic patients and 91% (82/90) and 99% (83/84) in cirrhotic patients. In HCV genotype 1b infected patients, virologic relapse rates were 3% (2/63) after an 8-week treatment of sofosbuvir/velpatasvir/voxilaprevir and 2% (1/59) after a 12-week treatment of sofosbuvir/velpatasvir. Baseline NS3 or NS5A RASs were found in 50% (250/501) of patients in the 8-week sofosbuvir/velpatasvir/voxilaprevir treatment group, and those patients had an SVR of 94% (234/250). On the other hand, baseline NS3 or NS5A RASs were found in 50% (220/440) of the patients in the sofosbuvir/velpatasvir 12-week treatment group, and their SVR was 99% (217/220). Re-treatment of treatment-experienced patients with genotype 1b Ledipasvir/sofosbuvir: In a phase 3, randomized, open-label study among previously treated chronic HCV genotype 1 infected patients (n=440, genotype 1b 21%, cirrhosis 20%, protease inhibitor-experienced patients 53%), 12 weeks of ledipasvir/sofosbuvir, 12 weeks of ledipasvir/sofosbuvir plus ribavirin, 24 weeks ledipasvir/sofosbuvir, and 24 weeks of ledipasvir/sofosbuvir plus ribavirin provided SVR rates of 87% (20/23), 100% (23/23), 100% (24/24), and 100% (23/23), respectively [44]. Baseline viral load, age, IL28B genotype, and sub-genotype had no significant effects on treatment response. In this study, among HCV genotype 1 infected patients with compensated cirrhosis, 12 weeks of ledipasvir/sofosbuvir treatment, 12 weeks of ledipasvir/sofosbuvir plus ribavirin treatment, 24 weeks of ledipasvir/sofosbuvir treatment, and 24 weeks of ledipasvir/sofosbuvir plus ribavirin treatment provided SVR rates of 86% (19/22), 82% (18/22), 95% (21/22), and 100% (22/22), respectively (P< =0.007). In another study where treatment-experienced HCV genotype 1 infected patients with compensated cirrhosis that were enrolled in phase 2 or 3 clinical trials were analyzed (n=352, genotype 1b 37%), 12 weeks of ledipasvir/sofosbuvir treatment, 12 weeks ledipasvir/sofosbuvir plus ribavirin treatment, 24 weeks of ledipasvir/sofosbuvir treatment, and 24 weeks of ledipasvir/sofosbuvir plus ribavirin treatment provided SVR rates of 90% (64/71), 96% (152/159), 98% (98/100), and 100% (22/22), respectively, showing that the addition of ribavirin and extended treatment duration improved the virologic response [13]. On the other hand, in a study involving PI-experienced cirrhotic patients (n=155, genotype 1b 55%), the SVR of the 12-week ledipasvir/sofosbuvir plus ribavirin treatment group (96%, 74/77) was similar to that of the 24-week ledipasvir/sofosbuvir plus ribavirin treatment group (97%, 75/77) [45]. However, a phase 3 Japanese study (n=341, genotype 1b 97%, cirrhosis 22%, treatment experience 51%) found that patients treated for 12 weeks with ledipasvir/sofosbuvir without ribavirin and those treated for 12 weeks with ledipasvir/sofosbuvir plus ribavirin showed SVR rates of 100% (171/171) and 98% (167/170), respectively [46]. Therefore, HCV genotype 1b infected patients treated with ledipasvir/sofosbuvir without ribavirin for 12 weeks showed a high SVR irrespective of their treatment experience or cirrhosis status. In a phase 3 Korean study, treatment-experienced, HCV genotype 1 infected patients (n=47, genotype 1b 98%, cirrhosis 28%) treated with ledipasvir/sofosbuvir for 12 weeks showed an SVR of 98% (46/47) [47]. It has been recognized that the presence of NS5A RASs might not affect the SVRs in genotype 1b patients [46,48]. However, a recent study reported that the presence of NS5A RASs did affect the SVR in genotype 1b patients [21] and a study reported that among treatment-experienced patients. the SVR was 89% (41/46) in NS5A RAS-positive patients and 98% (267/272) in NS5A RASnegative patients [20]. Elbasvir/grazoprevir: In a phase 3 study, treatment-experienced genotype 1 infected patients (genotype 1b 35%, liver cirrhosis 35%) treated with elbasvir/grazoprevir without ribavirin for 12 weeks had an SVR of 100% (34/34), and those treated with elbasvir/grazoprevir plus ribavirin for 12 weeks had an SVR of 97% (28/29), whereas those treated with elbasvir/grazoprevir without ribavirin for 16 weeks had an SVR of 100% (36/36), and those treated for 16 weeks with elbasvir/grazoprevir plus ribavirin had an SVR of 98% (46/47) [49]. The presence of baseline NS5A RASs did not affect the SVRs in patients with genotype 1b infection treated with 12 weeks of elbasvir/grazoprevir [49]. In a pooled analysis, HCV genotype 1b patients with baseline NS5A RASs treated with 12 weeks of elbasvir/grazoprevir had an SVR of 94% (48/51), and those without baseline RASs had an SVR of 99% (247/248) (P< =0.017) [24]. Ombitasvir/paritaprevir/ritonavir plus dasabuvir: In treatment-experienced patients with genotype 1b infection without cirrhosis, the SVR after a 12-week treatment with ombitasvir/paritaprevir/ritonavir plus dasabuvir with ribavirin was 97% (119/123) [50]. In another study of treatment-experienced patients with genotype 1b infection, the SVR after a 12-week treatment of ombitasvir/paritaprevir/ritonavir plus dasabuvir with and without ribavirin was 97% (85/88) and 97% (85/88), respectively. The addition of ribavirin was thus not beneficial in treatment-experienced genotype 1b infected patients [51]. In a phase 3 study of 380 patients with genotype 1 infection and cirrhosis (treatment experience 58%, genotype 1b 31%), the SVR of genotype 1b infected patients treated with ombitasvir/paritaprevir/ritonavir plus dasabuvir with ribavirin for 12 or 24 weeks was 99% (67/68) and 100% (51/51), respectively [27]. In another study of 60 genotype 1b infected patients with cirrhosis (treatment experience 55%), the SVR of ombitasvir/paritaprevir/ritonavir plus dasabuvir treatment for 12 weeks was 100% (60/60) [28]. Daclatasvir and sofosbuvir: In a study of treatment-experienced patients with HIV/HCV co-infection, genotype 1b infected patients treated with daclatasvir and sofosbuvir for 12 weeks showed an SVR of 98% (43/44) [30]. That study included 15 patients with cirrhosis whose subtypes were not analyzed [30]. In a phase 2 study of 41 treatment-experienced patients with genotype 1 infection (genotype 1b 24%, cirrhosis 14%), the SVR from a 24-week treatment of daclatasvir and sofosbuvir with and without ribavirin were 100% (21/21) and 95% (19/20), respectively [31]. A cohort study of 768 genotype 1 infected patients (liver cirrhosis 73%, genotype 1b 46%, treatment experience 84%) assessed SVR by treatment duration (12 weeks vs. 24 weeks of daclatasvir and sofosbuvir) with and without ribavirin. In cirrhotic patients, the SVR following 12 weeks, 12 weeks+ribavirin, 24 weeks, and 24 weeks+ribavirin was 87% (82/94), 92% (23/25), 94% (323/343), and 98% (100/102), respectively [32]. That study revealed that cirrhosis and treatment experience influenced SVR [32]. A phase 3 study treated patients with genotype 1b infection and decompensated cirrhosis with daclatasvir and sofosbuvir for 12 weeks in combination with ribavirin and found an SVR of 100% (11/11) [33]. Daclatasvir and asunaprevir: A phase 3 study that evaluated the efficacy of 24 weeks of treatment with daclatasvir and asunaprevir in previous non-responders to peginterferon alpha plus ribavirin and those ineligible for or intolerant to peginterferon alpha plus ribavirin demonstrated an SVR of 82% (168/205) and 82% (192/235), respectively, whereas the SVR in treatment-naïve patients following the same protocol was 90% (182/203) [12]. A post hoc analysis of that study to determine the efficacy of that treatment in Korean patients (n=44) showed an SVR of 70% (16/23) in non-responders and 86% (15/21) in patients ineligible for or intolerant to peginterferon-based treatment [35]. The presence of NS5A RASs appeared to be the single most important predictor of treatment failure in that study. Another phase 3 study conducted in Japan among 87 non-responders and 135 patients ineligible for or intolerant to peginterferon-based treatment received daclatasvir and asunaprevir treatment for 24 weeks and provided an overall SVR of 85% (188/222) [52]. In that study, non-responders showed an SVR of 81% (70/87), and patients ineligible for or intolerant to peginterferon-based treatment had an SVR of 87% (118/135). Baseline cirrhosis status had no effect on SVR, and baseline NS5A RASs were not tested in that study. A meta-analysis of 9 trials (n=1690) that provide 24 week treatment of asunaprevir and daclatasvir showed an SVR of 90% (336/374) in treatment-naïve patients and 82% (316/386) and 85% (514/607) in non-responders and patients ineligible for or intolerant to peginterferon-based treatments, respectively [53]. However, that study did not analyze the presence of baseline NS5A RASs, so enrolled patients might have had baseline NS5A RASs. Recently, Korean genotype 1b patients without baseline NS5A RASs (treatment experience 25%, cirrhosis 29%) were treated with daclatasvir and asunaprevir for 24 weeks. The patients without liver cirrhosis had an SVR of 98% (102/104), and those with compensated liver cirrhosis had an SVR of 92% (44/48) (P< =0.080) [54]. Asunaprevir and daclatasvir were given for 24 weeks in Korean genotype 1b patients without baseline NS5A RASs (n=251, treatment experience 36%, cirrhosis 22%) and provided an overall SVR of 98% (246/251), whereas patients with liver cirrhosis showed an SVR of 96% (49/51) [55]. Glecaprevir/pibrentasvir: In a phase 2 study recruiting DAA-naïve genotype 1–6 infected patients without cirrhosis, genotype 1 infected patients (n=133, treatment experience 30%) treated with glecaprevir (200 mg) plus pibrentasvir (120 mg) for 12 weeks, glecaprevir (200 mg) plus pibrentasvir (40 mg) for 12 weeks, or glecaprevir (300 mg) plus pibrentasvir (120 mg) for 8 weeks showed SVR rates of 100%, 97%, and 97%, respectively [36]. In a phase 3 study that assessed the efficacy and safety of 8 or 12 weeks of glecaprevir (300 mg)/pibrentasvir (120 mg) in genotype 1 mono-infected or HIV/HCV co-infected patients without cirrhosis (n=703, interferon-based treatment experience 28%, sofosbuvir-based treatment experience 0.4%, genotype 1a 43%), the SVRs were 99% and 99.7%, respectively [37]. In a pooled analysis of phase 2 and 3 studies of genotype 1–6 HCV infected patients without cirrhosis (interferon-based treatment experience 23%, sofosbuvir-based treatment experience 1%), HCV genotype 1 infected patients (n=788, genotype 1b 56%) treated with glecaprevir (300 mg) and pibrentasvir (120 mg) for 8 or 12 weeks had SVRs of 99% and 100%, respectively [38]. In a phase 2 study recruiting DAA-naïve genotype 1 infected patients with compensated cirrhosis (n=27, genotype 1b 26%, interferon-based treatment experience 22%), the SVR rate after 12 weeks of glecaprevir (200 mg) plus pibrentasvir (120 mg) was 96% [39]. In a phase 3 study that assessed the efficacy and safety of 12 weeks of glecaprevir (300 mg)/pibrentasvir (120 mg) in genotype 1, 2, 4, 5, and 6 HCV patients with compensated cirrhosis (n=146, interferon-based treatment experience 17%, sofosbuvirbased treatment experience 8%), genotype 1b infected patients (n=39) had an SVR of 100% [40]. In a phase 3 study conducted in Japan among DAA-naive genotype 1 infected patients, patients without cirrhosis (n=129, genotype 1b 97%, treatment experience 27%) were treated with glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks and showed an SVR of 99%, whereas those with cirrhosis (n=38, genotype 1b 100%, treatment experience 32%) were treated with glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks and showed an SVR of 100% [41]. Sofosbuvir/velpatasvir: Treatment-experienced HCV genotype 1 infected patients were treated with sofosbuvir plus velpatasvir (25 mg or 100 mg) with or without ribavirin for 12 weeks.In this study, HCV genotype 1 patients treated with sofosvuvir plus velpatasvir (100 mg) with or without ribavirn showed SVRs of 100% (27/27) and 96% (27/28), respectively [56]. In a phase 3, double-blind, placebo-controlled study involving untreated and previously treated HCV genotype 1, 2, 4, 5, or 6 infected patients with or without compensated cirrhosis, previously treated HCV genotype 1b patients treated with sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks showed an SVR of 97% (31/32) [42]. Sofosbuvir/velpatasvir/voxilaprevir: In a phase 3, openlabel trial, HCV infected patients who had not previously been treated with a DAA were randomly assigned to groups given 8 weeks of sofosbuvir/velpatasvir/voxilaprevir treatment or 12 weeks of sofosbuvir/velpatasvir treatment (n=941, conventional or pegylated interferon experience 23%) [43]. The overall SVR in the 8-week sofosbuvir/velpatasvir/voxilaprevir group and 12-week sofosbuvir/velpatasvir group was 95% (476/501) and 98% (432/440), respectively. Although the 8-week treatment of sofosbuvir/velpatasvir/voxilaprevir seems to be inferior to the 12-week treatment of sofosbuvir/velpatasvir, the HCV genotype 1b infected patients treated with sofosbuvir/velpatasvir/voxilaprevir for 8 weeks had an SVR of 97% (61/63), and those treated with sofosbuvir/velpatasvir for 12 weeks also showed an SVR of 97% (57/59). On the other hand, HCV genotype 1a infected patients treated for 8 weeks had an SVR of only 92% (155/169), and those treated for 12 weeks had an SVR of 99% (170/172). The SVR rates following the 8-week treatment of sofosbuvir/velpatasvir/voxilaprevir and 12-week treatment of sofosbuvir/velpatasvir were 96% (395/411) and 98% (349/356), respectively, in non-cirrhotic patients, and 91% (82/90) and 99% (83/84) in cirrhotic patients. In HCV genotype 1b infected patients, virologic relapse rates were 3% (2/63) after the 8-week treatment of sofosbuvir/velpatasvir/voxilaprevir and 2% (1/59) after the 12-week treatment of sofosbuvir/velpatasvir. [Recommendations] (Table 6) Initial treatment of chronic hepatitis C or compensated cirrhosis patients with HCV genotype 1b infection 1. Ledipasvir/sofosbuvir should be administered for 12 weeks (A1). Treatment could be shortened to 8 weeks in patients without liver cirrhosis and without HIV co-infection whose baseline HCV RNA level is less than 6,000,000 IU/mL (B1). 2. Elbasvir/grazoprevir should be administered for 12 weeks (A1). 3. Ombitasvir/paritaprevir/ritonavir plus dasabuvir should be administered for 12 weeks (A1). 4. Daclatasvir and sofosbuvir should be administered for 12 weeks to patients without liver cirrhosis (A1). Daclatasvir, sofosbuvir, and ribavirin could be administered for 12 weeks to patients with liver cirrhosis, or they could receive daclatasvir and sofosbuvir for 24 weeks (B1). 5. Daclatasvir and asunaprevir could be administered for 24 weeks to patients without baseline NS5A RASs (A2). Patients with baseline NS5A RASs should be treated with other regimens (A1). 6. Glecaprevir/pibrentasvir should be administered for 8 weeks to patients without liver cirrhosis (A1). Glecaprevir/pibrentasvir should be administered for 12 weeks to patients with liver cirrhosis (A1). 7. Sofosbuvir/velpatasvir should be administered for 12 weeks (A1). Retreatment of treatment-experienced chronic hepatitis C or compensated cirrhosis patients with HCV genotype 1b infection 1. Ledipasvir/sofosbuvir should be administered for 12 weeks to patients without liver cirrhosis (A1). Ledipasvir/sofosbuvir and ribavirin could be administered for 12 weeks to patients with liver cirrhosis, or they could receive ledipasvir/sofosbuvir for 24 weeks (B1). 2. Elbasvir/grazoprevir should be administered for 12 weeks (A1). 3. Ombitasvir/paritaprevir/ritonavir plus dasabuvir should be administered for 12 weeks (A1). 4. Daclatasvir and sofosbuvir sould be administered for 12 weeks to patients without liver cirrhosis (A1). Daclatasvir, sofosbuvir, and ribavirin could be administered for 12 weeks to patients with liver cirrhosis, or they could receive daclatasvir and sofosbuvir for 24 weeks (B1). 5. Daclatasvir and asunaprevir could be administered to patients without baseline NS5A RASs for 24 weeks (A2). Patients with baseline NS5A RASs should be treated with other regimens (A1). 6. Glecaprevir/pibrentasvir should be administered for 8 weeks to patients without liver cirrhosis (A1). Glecaprevir/pibrentasvir should be administered for 12 weeks to patients with liver cirrhosis (A1). 7. Sofosbuvir/velpatasvir should be administered for 12 weeks (A1). Initial treatment of HCV genotype 1a patients Ledipasvir/sofosbuvir In a phase 3, open-label study recruiting previously untreated HCV genotype 1 infected patients (n=865, genotype 1a 67%, cirrhosis 16%), the SVR after a 12-week treatment with ledipasvir/sofosbuvir, 12-week treatment with ledipasvir/sofosbuvir plus ribavirin, 24-week treatment of ledipasvir/sofosbuvir, and 24-week treatment of ledipasvir/sofosbuvir plus ribavirin were 99% (211/214), 97% (211/217), 98% (212/217), and 99% (215/217), respectively [14]. No significant differences in SVR were found according to age, baseline HCV RNA level, cirrhosis status, IL28B genotype, or HCV sub-genotype (1a vs. 1b). A post hoc analysis of data from seven clinical trials to evaluate the efficacy and safety of ledipasvir/sofosbuvir with and without ribavirin included 161 treatment-naïve patients with genotype 1 and compensated cirrhosis (genotype 1a 53%) [57]. The SVR following a 12-week treatment of ledipasvir/sofosbuvir, 12-week treatment of ledipasvir/sofosbuvir plus ribavirin, 24-week treatment of ledipasvir/sofosbuvir, and 24-week treatment of ledipasvir/sofosbuvir plus ribavirin were 96% (45/47), 98% (44/45), 97% (32/33), and 100% (36/36), respectively. SVR did not vary significantly with treatment duration (12 weeks 97% [89/92] vs. 24 weeks 99% [68/69]), presence/absence of ribavirin (99% [80/81] vs. 96% [77/80]), HCV sub-genotype (1a 98% [84/86] vs. 1b 97% [72/74]), or IL28B genotype (CC 98% (56/57) vs. non-CC 97% [101/104]). Twelve- or 24-week treatment with ledipasvir/sofosbuvir with or without ribavirin provided an overall SVR of 91% (42/46) in patients with baseline ledipasvir-specific RASs (NS5A positions 24, 28, 30, 31, 32, 38, 58, 92, 93) and an SVR of 99% (539/546) in those without ledipasvir-specific RASs [20]. In cirrhotic patients, the SVR was 86% (6/7) in patients with baseline ledipasvir-specific RASs and 99% (71/73) in those without ledipasvir-specific RASs. In a phase 3, open-label study of 647 previously untreated HCV genotype 1 infected patients without cirrhosis (genotype 1a 80%), the SVR following an 8-week treatment of ledipasvir/sofosbuvir, 8-week treatment of ledipasvir/sofosbuvir plus ribavirin, or 12-week treatment of ledipasvir/sofosbuvir were 94% (202/215), 93% (201/216), and 95% (206/216), respectively [15]. Virologic relapse rates were higher in the 8-week treatment arms than in the 12-week treatment arm (5% [20/431] vs. 1% [3/216]). Post hoc analyses assessed baseline predictors of relapse and identified a low relapse rate in patients receiving 8 weeks of ledipasvir/sofosbuvir who had baseline HCV RNA levels < 6,000,000 IU/mL (2/123; 2%). The same held true for patients with similar baseline HCV RNA levels who received 12 weeks of treatment (2/131; 2%). Treatment-naïve HCV genotype 1 infected patients without cirrhosis (defined as FIB-4 ≤ 3.25) and with baseline HCV RNA< 6,000,000 IU/mL (genotype 1a > 70%) showed a lower SVR [93.2% (1,020/1,094)] when treated with ledipasvir/sofosbuvir for 8 weeks compared to those treated with ledipasvir/sofosbuvir for 12 weeks (97% [875/906]) [18]. However, another study found that the SVR of treatment-naïve HCV genotype 1a infected patients without cirrhosis whose baseline HCV RNA< 6,000,000 IU/mL was 98% (372/381) [19]. Elbasvir/grazoprevir In a phase 3 study that evaluated the efficacy of a 12-week treatment with elbasvir/grazoprevir in treatment-naïve genotype 1a infected patients, the SVR was 92% [13]. The SVR in patients with compensated cirrhosis was 97%, which did not differ from that in patients without cirrhosis [13,58]. SVR did not differ by age, gender, race, or IL28B genetic polymorphism, but it was higher in patients with HCV RNA ≤ 800,000 IU/mL than in those with HCV RNA > 800,000 IU/mL (100% vs. 92%). NS5A RASs were detected in 12% of the genotype 1a infected patients, and the SVR was significantly lower in patients with RASs than in those without them (58% vs. 99%). However, the SVR was 100% (17/17) even in patients with RASs when pretreatment HCV RNA was ≤ 800,000 IU/mL [13]. A pooled analysis of phase 2 and 3 clinical trials revealed that the SVR was 100% in genotype 1a infected patients with baseline NS5A RASs treated with elbasvir/grazoprevir and ribavirin for 16 or 18 weeks [59,60]. Another pooled analysis reported that NS5A RASs (M29, Q30, L31, or Y93 mutation) were detected in 11% (92/825) of treatment-naïve genotype 1a infected patients. The SVR was significantly lower in patients with RASs (73% [33/45]) than in those without them (98% [364/371]) following treatment with elbasvir/grazoprevir for 12 weeks. Treatment with elbasvir/grazoprevir plus ribavirin for 16 or 18 weeks provided an SVR of 100% in treatment-naïve HCV genotype 1a infected patients with baseline RASs [24]. Ombitasvir/paritaprevir/ritonavir plus dasabuvir In treatment-naïve patients with genotype 1a infection but not cirrhosis, the SVR after treatment for 12 weeks with a combination of ombitasvir/paritaprevir/ritonavir plus dasabuvir with ribavirin was 95% (306/322) [61]. In another study of treatment-naïve HCV genotype 1 infected patients without cirrhosis, the SVR after ombitasvir/paritaprevir/ritonavir and dasabuvir treatment without ribavirin for 12 weeks was 99% in genotype 1b patients, whereas it was 90% in genotype 1a patients [25]. The SVR after receiving a combination of ombitasvir/paritaprevir/ritonavir, dasabuvir, and ribavirin for 12 or 24 weeks was 89% (124/140) and 94% (114/121), respectively, in treatment-naïve and treatment-experienced HCV genotype 1a patients with compensated cirrhosis [27]. Daclatasvir and sofosbuvir In a phase 3 study that assessed the efficacy of a 12-week treatment of daclatasvir and sofosbuvir in treatment-naïve HCV genotype 1 infected patients (genotype 1a 71, 1b 12, compensated cirrhosis 9), the SVR was 96% [30]. In a phase 2 study of treatment-naïve genotype 1 infected patients (n=126, genotype 1a 99, 1b 27), the SVR after 12 or 24 weeks of daclatasvir and sofosbuvir treatment was 100% (41/41) and 100% (29/29) respectively, and the SVR after 12 or 24 weeks of treatment with daclatasvir and sofosbuvir with ribavirin was 95% (39/41) and 100% (15/15), with no statistical differences by treatment duration or the addition of ribavirin [31]. However, only 14 genotype 1 infected patients with compensated cirrhosis were included in that study. In a cohort study of 768 genotype 1 infected patients (liver cirrhosis 73%, CTP classification B or C decompensated cirrhosis 3%, genotype 1a 50%, treatment naïve 16%), the SVR after 12 or 24 weeks of treatment with daclatasvir and sofosbuvir was 92% (147/160) and 95% (417/439), respectively, and the SVR after 12 or 24 weeks of treatment with daclatasvir and sofosbuvir with ribavirin was 94% (32/34) and 99% (133/135), respectively, with no statistical differences among treatment groups. However, the SVR was lower in patients with cirrhosis than in those without cirrhosis (88% [105/119] vs. 95% [423/444], P< =0.0054) [32]. Although studies on the combination of daclatasvir and sofosbuvir are insufficient in treatment-naïve genotype 1a infected patients with compensated cirrhosis, given the lower SVR in cirrhotic patients and risk of emerging NS5A RASs in cases of treatment failure, 12-week treatment with daclatasvir and sofosbuvir with ribavirin or 24-week treatment with daclatasvir and sofosbuvir can be considered. Glecaprevir/pibrentasvir In a phase 2 study for DAA-naïve, HCV genotype 1–6 infected patients without cirrhosis, the SVR after treatment with glecaprevir (200 mg) plus pibrentasvir (120 mg) for 12 weeks, glecaprevir (200 mg) plus pibrentasvir (40 mg) for 12 weeks, or glecaprevir (300 mg) plus pibrentasvir (120 mg) for 8 weeks was 100%, 97%, and 97%, respectively, in genotype 1 infected patients (n=133, treatment experience 30%) [36]. In a phase 3 study that assessed the efficacy and safety of 8- and 12-week treatment with glecaprevir (300 mg)/pibrentasvir (120 mg) in genotype 1 monoinfected or HIV/HCV co-infected patients without cirrhosis (n=703, interferon-based treatment experience 28%, sofosbuvir-based treatment experience 0.4%), the SVR was 99% and 99.7%, respectively [37]. In a pooled analysis of phase 2 and 3 studies of genotype 1–6 chronic HCV infected patients without cirrhosis (interferon-based treatment experience 23%, sofosbuvir-based treatment experience 1%), the SVR after treatment with glecaprevir (300 mg) plus pibrentasvir (120 mg) for 8 or 12 weeks was 99% and 100%, respectively, in HCV genotype 1 infected patients without cirrhosis (n=788, genotype 1a 44%) [38]. In a phase 2 study of DAA-naïve HCV genotype 1 infected patients with compensated cirrhosis (n=27, interferon-based treatment experience 22%), the SVR after a 12-week treatment with glecaprevir (200 mg) plus pibrentasvir (120 mg) was 96% [39]. In a phase 3 study that assessed the efficacy and safety of a 12-week treatment with glecaprevir (300 mg)/pibrentasvir (120 mg) in patients infected with HCV genotype 1, 2, 4, 5, or 6 and compensated cirrhosis (n=146, interferon-based treatment experience 17%, sofosbuvir-based treatment experience 8%), the SVR was 99% in HCV genotype 1a infected patients (n=48) [40]. Sofosbuvir/velpatasvir In a phase 3, double-blind, placebo-controlled study recruiting untreated and previously treated patients with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis, the SVR after a 12-week treatment with sofosbuvir (400 mg)/velpatasvir (100 mg) was 98% (157/161) in HCV genotype 1a infected patients without cirrhosis and 100% (49/49) in those with compensated cirrhosis. The SVR of treatment-naïve HCV genotype 1a infected patients was 97% (128/132) [42]. Sofosbuvir/velpatasvir/voxilaprevir In a phase 3, open-label trial, HCV infected patients who had not previously been treated with DAAs were assigned randomly to an 8-week sofosbuvir/velpatasvir/voxilaprevir treatment arm or a 12-week sofosbuvir/velpatasvir treatment arm (n=941, conventional or pegylated interferon experience 23%) [43]. In genotype 1a patients, the SVR after the 8-week sofosbuvir/velpatasvir/voxilaprevir or 12-week sofosbuvir/velpatasvir treatment were 92% (155/169) and 99% (170/172), respectively. Among HCV genotype 1a infected patients without cirrhosis, the virologic relapse rates were 8% and 0% in the 8-week sofosbuvir/velpatasvir/voxilaprevir and 12-week sofosbuvir/velpatasvir treatment groups, respectively. Among HCV genotype 1a infected patients with cirrhosis, the virologic relapse rates were 10% and 2% in the 8-week sofosbuvir/velpatasvir/voxilaprevir and 12-week sofosbuvir/velpatasvir treatment groups, respectively. Therefore, among HCV genotype 1a infected patients, treatment responses after 8 weeks of sofosbuvir/velpatasvir/voxilaprevir were inferior to those after 12 weeks of sofosbuvir/velpatasvir. In addition, the SVR following treatment with sofosbuvir/velpatasvir/voxilaprevir for 8 weeks was 89% and 95% in HCV genotype 1a infected patients with and without baseline NS5A RASs, respectively. Retreatment of treatment-experienced genotype 1a patients Ledipasvir/sofosbuvir In a phase 3, randomized, open-label study of previously treated HCV genotype 1 infected patients (n=440, genotype 1a 79%, cirrhosis 20%, protease inhibitor experience 53%), the SVR following 12 weeks of ledipasvir/sofosbuvir, 12 weeks of ledipasvir/ sofosbuvir plus ribavirin, 24 weeks of ledipasvir/sofosbuvir, or 24 weeks of ledipasvir/sofosbuvir plus ribavirin were 94% (102/109), 96% (107/111), 99% (108/109), and 99% (110/111), respectively [44]. Virologic relapse rates were 6% (7/109), 4% (4/111), 0% (0/109), and 0% (0/111), respectively. Baseline viral load, age, IL28B genotype, and sub-genotype had no significant effect on treatment responses. In cirrhotic patients, the SVR following a 12-week ledipasvir/sofosbuvir treatment, 12-week ledipasvir/sofosbuvir plus ribavirin treatment, 24-week ledipasvir/sofosbuvir treatment, or 24-week ledipasvir/sofosbuvir plus ribavirin treatment were 86% (19/22), 82% (18/22), 95% (21/22), and 100% (22/22), respectively. A post hoc analysis of data from seven clinical trials to evaluate the efficacy and safety of ledipasvir/sofosbuvir with and without ribavirin included 352 treatment-experienced HCV genotype 1 infected patients with compensated cirrhosis (genotype 1a 63%, protease inhibitor experience 68%) [57]. The SVR following a 12-week ledipasvir/sofosbuvir treatment, 12-week ledipasvir/sofosbuvir plus ribavirin treatment, 24-week ledipasvir/sofosbuvir treatment, and 24-week ledipasvir/sofosbuvir plus ribavirin treatment were 90% (64/71), 96% (152/159), 98% (98/100), and 100% (22/22), respectively. The relatively lower SVR in treatment-experienced patients treated with ledipasvir/sofosbuvir for 12 weeks raised the question of whether those patients would benefit from adding ribavirin or extending treatment duration to 24 weeks. Among treatment-experienced HCV genotype 1a patients, the overall SVR following ledipasvir/sofosbuvir with or without ribavirin treatment for 12 or 24 weeks was 76% (22/29) in patients with baseline ledipasvir-specific RASs (K24G/N/R, M28T/A/G, Q30L/T/E/G/H/K, L31F/I/M/V, P32L, S38F, H58D, A92T/K, Y93F/C/H/N/S) and 97% (409/420) in those without ledipasvir-specific RASs [20]. In cirrhotic patients, the SVR was 77% (10/13) in patients with baseline ledipasvir-specific RASs and 98% (193/196) in those without ledipasvir-specific RASs. That is, treatment-experienced HCV genotype 1a patients with baseline ledipasvir-specific RASs had a lower response irrespective of their cirrhosis status. Elbasvir/grazoprevir In a phase 3 study that assessed the efficacy and safety of a 12-week treatment of elbasvir/grazoprevir in treatment-experienced HCV genotype 1a patients, the SVR was 92% (55/60) [49]. The SVR was 93% (56/60) in patients treated with elbasvir/grazoprevir plus ribavirin for 12 weeks, 94% (45/48) in those treated with elbasvir/grazoprevir for 16 weeks without ribavirin, and 100% (55/55) in those treated with elbasvir/grazoprevir plus ribavirin for 16 weeks. SVR did not differ significantly depending on the addition of ribavirin or the extension of the treatment duration [49]. The SVR after 12 or 16 weeks of treatment with elbasvir/grazoprevir with and without ribavirin was 94% (135/144) in patients with compensated cirrhosis (genotype 1a [n=77], genotype 1b [n=50], genotype 4 [n=17], genotype 6 [n=3]), which did not differ from that in patients without cirrhosis (97% [255/264]) [49]. The presence of baseline NS5A RASs was a predictive factor for treatment failure, and amino acid substitutions at positions M28, Q30, L31, and Y93 were associated with lower SVR. The SVR after a 12-week treatment with elbasvir/grazoprevir was 99% in HCV genotype 1a patients without NS5A RASs but only 68% (21/31) in those with baseline NS5A RASs. The SVR after a 16- or 18-week treatment with elbasvir/grazoprevir plus ribavirin was 100% (6/6) in genotype 1a patients with baseline NS5A RASs [49]. In another study, baseline NS5A RASs were detected in 21% of HCV genotype 1a patients, and the SVR after a 12-week treatment with elbasvir/grazoprevir was significantly lower in patients with baseline NS5A RASs (64% [9/14]) than in those without them (96% [52/54]) [59]. However, the SVR was 100% (8/8) in patients with NS5A RASs after a 16- or 18-week treatment with elbasvir/grazoprevir plus ribavirin [59]. In a pooled analysis of phase 2 and 3 studies of DAAnaïve patients, the SVR after a 12-week treatment with elbasvir/grazoprevir was 97% (77/79) among PR-experienced HCV genotype 1a patients without NS5A RASs and 55% (6/11) in those with NS5A RASs. The SVR after 16 or 18 weeks of treatment with elbasvir/grazoprevir plus ribavirin was 100% (6/6), even in those with NS5A RASs [24]. Because the treatment response in patients with NS5A RASs is inferior, NS5A resistance testing is recommended for genotype 1a infected patients before elbasvir/grazoprevir treatment, and treatment duration should be extended to 16 weeks and ribavirin should be added if baseline NS5A RASs are identified. Ombitasvir/paritaprevir/ritonavir and dasabuvir Among treatment-experienced HCV genotype 1a patients without cirrhosis, the SVR after a 12-week treatment of ombitasvir/paritaprevir/ritonavir plus dasabuvir with ribavirin was 96% (166/173) [50,54]. Among treatment-experienced HCV genotype 1 patients with compensated cirrhosis (genotype 1a 262, 1b 119), the SVR after 12 and 24 weeks of treatment with ombitasvir/paritaprevir/ritonavir plus dasabuvir with ribavirin was 90% (110/122) and 97% (95/98), respectively, with no statistical differences between the groups (P< =0.09). However, the SVR was significantly lower in HCV genotype 1a infected patients (OR 0.12, P< =0.04) and genotype 1 patients who showed null response to prior PR therapy (OR 0.39, P< =0.04) [27]. Daclatasvir and sofosbuvir In a phase 2 study of treatment-experienced HCV genotype 1 patients (genotype 1a 33, 1b 8, cirrhosis 9), the SVR after a 24-week treatment of daclatasvir and sofosbuvir with and without ribavirin was 100% (21/21) and 95% (19/20), respectively [31]. In a cohort study of 768 genotype 1 infected patients (genotype 1a 50%, liver cirrhosis 73%, CTP classification B or C decompensated cirrhosis 3%, PR experience 41%, 1st generation PI+PR experience 41%), the SVR after a 12- or 24-week treatment of daclatasvir and sofosbuvir was 92% (147/160) and 95% (417/439), respectively, and the SVR after a 12- or 24-week treatment of daclatasvir and sofosbuvir with ribavirin was 94% (32/34) and 99% (133/135), respectively, without statistical difference among treatment groups. However, the SVR was lower in cirrhotic patients than in those without cirrhosis (88% [105/119] vs. 95% [423/444], P< =0.0054) [32]. Glecaprevir/pibrentasvir In a phase 3 study that assessed the efficacy and safety of 8 or 12 weeks of treatment with glecaprevir (300 mg)/pibrentasvir (120 mg) in genotype 1 monoinfected or HIV/HCV co-infected patients without cirrhosis (n=703, interferon-based treatment experience 28%, sofosbuvir-based treatment experience 0.4%), the SVR rates were 99% and 99.7%, respectively [37]. In a pooled analysis of phase 2 and 3 studies of patients with HCV genotypes 1–6 without cirrhosis (interferon-based treatment experience 23%, sofosbuvir-based treatment experience 1%), the SVR after an 8- or 12-week treatment with glecaprevir (300 mg) plus pibrentasvir (120 mg) was 99% and 100%, respectively, in HCV genotype 1 patients (n=788, genotype 1a 44%) [38]. In a phase 3 study that assessed the efficacy and safety of a 12-week treatment with glecaprevir (300 mg)/pibrentasvir (120 mg) in patients infected with HCV genotype 1, 2, 4, 5, or 6 and compensated cirrhosis (n=146, interferon-based treatment experience 17%, sofosbuvir-based treatment experience 8%), the SVR was 99% in HCV genotype 1a infected patients (n=48) [40]. Sofosbuvir/velpatasvir In a phase 3, double-blind, placebo-controlled study of untreated and previously treated patients infected with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis, the SVR following a 12-week treatment with sofosbuvir (400 mg)/velpatasvir (100 mg) was 100% (78/78) in previously treated HCV genotype 1a patients [42]. Sofosbuvir/velpatasvir/voxilaprevir In a phase 3 open-label trial, HCV infected patients who had not been previously treated with DAAs were randomly assigned to an 8-week treatment with sofosbuvir/velpatasvir/voxilaprevir or a 12-week treatment with sofosbuvir/velpatasvir (n=941, conventional or pegylated interferon experience 23%) [43]. Among genotype 1a patients, the SVR of the 8-week sofosbuvir/velpatasvir/voxilaprevir and 12-week sofosbuvir/velpatasvir treatment groups were 92% (155/169) and 99% (170/172), respectively. In HCV genotype 1a patients without cirrhosis, the virologic relapse rates were 8% and 0% in the 8-week sofosbuvir/velpatasvir/voxilaprevir and 12-week sofosbuvir/velpatasvir treatment groups, respectively. Among HCV genotype 1a patients with cirrhosis, virologic relapse rates were 10% and 2% in the 8-week sofosbuvir/velpatasvir/voxilaprevir and 12-week sofosbuvir/velpatasvir treatment groups, respectively. Therefore, among HCV genotype 1a patients, treatment responses after 8 weeks of sofosbuvir/velpatasvir/voxilaprevir treatment were inferior to those after 12 weeks of sofosbuvir/velpatasvir treatment. In addition, the SVR after the 8-week treatment with sofosbuvir/velpatasvir/voxilaprevir was 89% and 95%, respectively, in HCV genotype 1a patients with and without baseline NS5A RASs. [Recommendations] (Table 7) Initial treatment of chronic hepatitis C or compensated cirrhosis patients with HCV genotype 1a infection 1. Ledipasvir/sofosbuvir should be administered for 12 weeks (A1). Treatment could be shortened to 8 weeks in patients without liver cirrhosis and without HIV co-infection whose baseline HCV RNA level is less than 6,000,000 IU/mL (B1). 2. Elbasvir/grazoprevir should be administered for 12 weeks to patients without NS5A RASs (A1). Elbasvir/grazoprevir and ribavirin could be administered for 16 weeks to patients with NS5A RASs (B1). 3. Ombitasvir/paritaprevir/ritonavir plus dasabuvir and ribavirin should be administered for 12 weeks to patients without liver cirrhosis (A1). Ombitasvir/paritaprevir/ritonavir plus dasabuvir and ribavirin should be administered for 24 weeks to patients with compensated cirrhosis (A1). 4. Daclatasvir and sofosbuvir should be administered for 12 weeks to patients without liver cirrhosis (A1). Daclatasvir, sofosbuvir, and ribavirin could be administered for 12 weeks to patients with compensated cirrhosis, or they could receive daclatasvir and sofosbuvir for 24 weeks (B1). 5. Glecaprevir/pibrentasvir should be administered for 8 weeks to patients without liver cirrhosis (A1). Glecaprevir/pibrentasvir should be administered for 12 weeks to patients with compensated cirrhosis (A1). 6. Sofosbuvir/velpatasvir should be administered for 12 weeks (A1). Retreatment of treatment-experienced chronic hepatitis C or compensated cirrhosis patients with HCV genotype 1a infection 1. Ledipasvir/sofosbuvir and ribavirin should be administered for 12 weeks, or ledipasvir/sofosbuvir should be administered for 24 weeks (A1). 2. Elbasvir/grazoprevir should be administered for 12 weeks to patients without NS5A RASs (A1). Elbasvir/grazoprevir and ribavirin could be administered for 16 weeks to patients with NS5A RASs (B1). 3. Ombitasvir/paritaprevir/ritonavir plus dasabuvir and ribavirin should be administered for 12 weeks to patients without liver cirrhosis (A1). Ombitasvir/paritaprevir/ritonavir plus dasabuvir and ribavirin should be administered for 24 weeks to patients with compensated cirrhosis (A1). 4. Daclatasvir and sofosbuvir could be administered for 12 weeks to patients without liver cirrhosis (B1). Daclatasvir, sofosbuvir, and ribavirin could be administered for 12 weeks to patients with compensated cirrhosis, or they could receive daclatasvir and sofosbuvir for 24 weeks (B1). 5. Glecaprevir/pibrentasvir should be administered for 8 weeks to patients without liver cirrhosis (A1). Glecaprevir/pibrentasvir should be administered for 12 weeks to patients with compensated cirrhosis (A1). 6. Sofosbuvir/velpatasvir should be administered for 12 weeks (A1). TREATMENT OF CHRONIC HEPATITIS C OR COMPENSATED CIRRHOSIS PATIENTS WITH HCV GENOTYPE 2 INFECTION Initial treatment of genotype 2 patients Sofosbuvir and ribavirin According to a study comparing 12 weeks of sofosbuvir and ribavirin with 24 weeks of peginterferon alpha and ribavirin in treatment-naïve patients with chronic hepatitis C genotype 2, the SVR were 97% (68/70) and 78% (52/67), respectively. The SVR following 12 weeks of sofosbuvir and ribavirin in patients with and without liver cirrhosis was 91% (10/11) and 98% (58/59), respectively [62]. In a phase 3 study of patients ineligible for peginterferon therapy (including 8% of enrolled patients who discontinued therapy due to an adverse event), the SVR following 12 weeks of sofosbuvir and ribavirin therapy was 93% (101/109). The SVR in patients with and without liver cirrhosis was 94% (16/17) and 92% (85/92), respectively [62]. In a phase 3 study of Korean and Taiwanese patients, the SVR following 12 weeks of sofosbuvir and ribavirin treatment was 96% (101/105), and all 6 patients with liver cirrhosis showed an SVR [63]. In a Japanese study, the SVR rate following 12 weeks of sofosbuvir and ribavirin was 98% (88/90), and all 8 patients with liver cirrhosis showed an SVR [64]. In a phase 3 study of 12 weeks of sofosbuvir and ribavirin therapy, the SVR in treatment-naive patients was 97% (31/32), and the SVR in patients with and without liver cirrhosis were 100% (2/2) and 97% (29/30), respectively [65]. Studies on the optimal treatment duration of sofosbuvir and ribavirin therapy are very limited in treatment-naïve patients with chronic HCV infection and liver cirrhosis. In a Korean real life study, the SVR following 12 weeks of sofosbuvir and ribavirin was 98% (177/181) in treatment-naïve patients without liver cirrhosis. The SVR after 16 weeks of sofosbuvir and ribavirin therapy was 96% (50/52) in patients with liver cirrhosis, although it is not possible to distinguish between treatment-naive and experienced patients in that analysis [66]. In a real life study of sofosbuvir and ribavirin therapy among treatment-naïve and experienced patients, the SVR of treatmentnaïve patients with or without liver cirrhosis was 72% (23/32) and 92% (159/173), respectively, after 12 weeks of therapy and 100% (7/7) and 91% (10/11), respectively, after 16 weeks of therapy [67]. Another real life study (treatment naïve 56%, liver cirrhosis 58%) included patients with advanced fibrosis, who received 12 weeks of sofosbuvir and ribavirin (n=123), and patients with liver cirrhosis, who received 16 or 20 weeks of sofosbuvir and ribavirin, (n=168, CTP class A 89%). The overall SVR in treatment-naïve patients was 98%. Although it is not possible to distinguish between treatment-naive and experienced patients, the SVR following 16 and 20 weeks of treatment in patients with cirrhosis were 95% (86/91) and 91% (75/82), respectively [68]. Daclatasvir and sofosbuvir Only a few studies have considered daclatasvir and sofosbuvir combination therapy in patients with HCV genotype 2. In a phase 2 study of daclatasvir and sofosbuvir therapy for treatment-naïve patients, the SVR was 92% (24/26). That study conducted daclatasvir and sofosbuvir therapy with and without ribavirin for 23 weeks (sofosbuvir monotherapy for 1 week followed by 23 consecutive weeks of daclatasvir and sofosbuvir with or without ribavirin) or 24 weeks, and 40% of the included patients had liver cirrhosis [31]. In a study of daclatasvir and sofosbuvir for 8 or 12 weeks in patients with HIV/HCV coinfection, the SVR in treatment-naïve patients without liver cirrhosis was 83% (5/6) and 100% (11/11), respectively [30]. Based on a sub-group analysis of genotype 2 patients from a real life study of genotypes 1–4 (total n=2,612, treatment naïve 47%), 12 weeks of daclatasvir and sofosbuvir combination therapy yielded 100% SVR in all patients with (n=29) and without (n=17) cirrhosis, although it is not possible to distinguish between treatment-naive and experienced patients in that subpopulation [69]. Glecaprevir/pibrentasvir According to integrated analyses of seven phase 2 and 3 studies of glecaprevir/pibrentasvir treatment for 8 and 12 weeks in patients with genotypes 1–6 without cirrhosis (treatment-naive 79% and 74%, respectively), the SVR of patients with genotype 2 was 99% (193/195) and 100% (232/232), respectively [38]. In a phase 3 study (treatment naïve 75%) of a 12-week regimen of glecaprevir/pibrentasvir given to cirrhotic patients with genotypes 1, 2, 4, 5, or 6, the SVR in patients with genotype 2 HCV infection was 100% (31/31) [40]. Sofosbuvir/velpatasvir In a phase 3 study comparing 12 weeks of sofosbuvir/velpatasvir with placebo in patients with genotype 1, 2, 4, 5, or 6 infection (treatment naive 68%, liver cirrhosis 19%), the SVR of patients with genotype 2 who received sofosbuvir/velpatasvir therapy was 100% (104/104) [42]. According to a phase 3 study comparing treatment with sofosbuvir/velpatasvir for 12 weeks and sofosbuvir and ribavirin for 12 weeks (treatment naive 85%, liver cirrhosis 14%), the SVR were 99% (133/134) and 94% (124/132), respectively (P< =0.02) [70]. An integrated study of 12 weeks of sofosbuvir/velpatasvir showed an SVR of 99% (193/194) among treatment-naïve patients with genotype 2. The SVR of patients with liver cirrhosis was 100% (29/29), although it is not possible to distinguish between treatment-naive and experienced patients in that subpopulation [71]. Sofosbuvir/velpatasvir/voxilaprevir In a phase 3 study comparing 8 weeks of sofosbuvir/velpatasvir/voxilaprevir with 12 weeks of sofosbuvir/velpatasvir in patients with genotypes 1– 6 (treatment naïve 77%, liver cirrhosis 18%), the SVR of patients with genotype 2 was 97% (61/63) and 100% (53/53), respectively [43]. Peginterferon alpha and ribavirin The SVR of peginterferon alpha and ribavirin therapy among Korean patients with genotype 2 is reported to be 80% or more [72,73]. Peginterferon-α 2a should be injected at a subcutaneous dose of 180 μg once a week, regardless of patient body weight, and peginterferon-α 2b is to be injected at a dose of 1.5 μg/kg/week. Ribavirin should be administered as an 800 mg fixed dose, regardless of body weight or type of peginterferon [74-79]. Retreatment of treatment-experienced patients Sofosbuvir and ribavirin In one phase 3 study of sofosbuvir and ribavirin for 12 weeks, the SVR of treatment-experienced patients was 90% (37/41): 78% (7/9) and 94% (30/32) with and without liver cirrhosis, respectively [65]. In a Korean real life study, the SVR following 12 weeks of sofosbuvir and ribavirin was 97% (32/33) among treatment-experienced patients without liver cirrhosis. The SVR following 16 weeks of sofosbuvir and ribavirin was 96% (50/52) among patients with liver cirrhosis, although it is not possible to distinguish between treatment-naive and experienced patients in that subpopulation [66]. In a phase 3 study of sofosbuvir and ribavirin therapy for treatment-experienced patients, the SVR with and without liver cirrhosis was 87% (26/30) and 88% (42/48), respectively, following 12 weeks of therapy and 77% (13/17) and 100% (3/3), respectively, following 16 weeks of therapy [62]. In a real life study of sofosbuvir and ribavirin for treatment-naïve and experienced patients, the SVR of treatment-experienced patients with and without liver cirrhosis was 72% (23/32) and 92% (159/173), respectively, following 12 weeks of therapy and 100% (7/7) and 91% (10/11), respectively, following 16 weeks of therapy [67]. In a study comparing 12 weeks and 16 weeks of sofosbuvir and ribavirin therapy, the SVR of treatment experienced patients with liver cirrhosis was 87% (13/15) and 100% (17/17), respectively [80]. In phase 3 study of Korean and Taiwanese patients, the SVR in treatment-experienced patients after 12 weeks of sofosbuvir and ribavirin therapy was 100% (24/24, including 7 liver cirrhosis patients) [63]. In a Japanese study, the SVR following 12 weeks of sofosbuvir and ribavirin therapy was 95% (60/63, including SVR of 8/9 with liver cirrhosis) [64]. In a real life study of 16 or 20 weeks of sofosbuvir and ribavirin therapy for patients with liver cirrhosis (treatment-experienced 51%), the SVR in patients with previous non-response and relapse was 91% and 100%, respectively. Although it is not possible to distinguish between treatment-naive and experienced patients in this analysis, the SVR following 16 and 20 weeks of treatment in patients with cirrhosis was 95% (86/91) and 91% (75/82), respectively [68]. Daclatasvir and sofosbuvir In a study of 12 weeks of daclatasvir and sofosbuvir for patients with HIV/HCV co-infection, 2 treatment-experienced patients had an SVR, including one patient with liver cirrhosis [30]. Based on a sub-group analysis of patients with HCV genotype 2 in a real life study (genotypes 1–4, n=2,612, treatment experience 53%), daclatasvir and sofosbuvir combination therapy for 12 weeks yielded 100% SVR in all 17 patients without cirrhosis and all 29 patients with cirrhosis, although it is not possible to distinguish between treatment-naive and experienced patients in that analysis [69]. Glecaprevir/pibrentasvir According to an integrated analysis of seven phase 2 and 3 studies of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with genotypes 1–6 without cirrhosis (treatment-experienced 21% and 26%, respectively), the SVR in patients with genotype 2 was 99% (193/195) and 100% (232/232), respectively [38]. In a phase 3 study of 12 weeks of glecaprevir/pibrentasvir for cirrhotic patients with genotypes 1, 2, 4, 5, or 6 (treatment-experienced 25%), the SVR of patients with genotype 2 was 100% (31/31) [40]. Sofosbuvir/velpatasvir In a phase 3 study comparing a 12-week course of sofosbuvir/velpatasvir with placebo in patients with genotypes 1, 2, 4, 5, or 6 (treatment experienced 32%, liver cirrhosis 19%), the SVR of patients with genotype 2 was 100% (104/104) [42]. According to a phase 3 study comparing 12 weeks of treatment with sofosbuvir/velpatasvir with 12 weeks of sofosbuvir and ribavirin therapy (treatment experienced 15%, liver cirrhosis 14%), the SVR were 99% (133/134) and 94% (124/132), respectively [70]. In an integrated study of sofosbuvir/velpatasvir for 12 weeks, the SVR was 100% (44/44) among treatment-experienced patients with genotype 2. The SVR of patients with liver cirrhosis was also 100% (29/29) [71]. Sofosbuvir/velpatasvir/voxilaprevir In a phase 3 study comparing 8 weeks of sofosbuvir/velpatasvir/voxilaprevir with 12 weeks of sofosbuvir/velpatasvir in patients with genotypes 1–6 (treatment experienced 23%, liver cirrhosis 18%), the SVR of patients with genotype 2 was 97% (61/63) and 100% (53/53), respectively [43]. [Recommendations] (Table 8) Initial treatment of chronic hepatitis C or compensated cirrhosis patients with HCV genotype 2 infection 1. Sofosbuvir and ribavirin should be administered for 12 weeks to patients without liver cirrhosis (A1). Sofosbuvir and ribavirin could be administered for 16 weeks to patients with liver cirrhosis (B1). 2. Daclatasvir and sofosbuvir could be administered for 12 weeks (B1). 3. Glecaprevir/pibrentasvir should be administered for 8 weeks to patients without liver cirrhosis (A1). Glecaprevir/pibrentasvir should be administered for 12 weeks to patients with liver cirrhosis (A1). 4. Sofosbuvir/velpatasvir should be administered for 12 weeks (A1). 5. Peginterferon alpha and ribavirin could be administered for 24 weeks (A2). Retreatment of treatment-experienced chronic hepatitis C or compensated cirrhosis patients with HCV genotype 2 infection 1. Sofosbuvir and ribavirin should be administered for 12 weeks to patients without liver cirrhosis (A1). Sofosbuvir and ribavirin could be administered for 16–24 weeks to patients with liver cirrhosis (B1). 2. Daclatasvir and sofosbuvir could be administered for 12 weeks (B1). 3. Glecaprevir/pibrentasvir should be administered for 8 weeks to patients without liver cirrhosis (A1). Glecaprevir/pibrentasvir should be administered for 12 weeks to patients with liver cirrhosis (A1). 4. Sofosbuvir/velpatasvir should be administered for 12 weeks (A1). TREATMENT OF CHRONIC HEPATITIS C OR COMPENSATED CIRRHOSIS PATIENTS WITH HCV GENOTYPE 3 INFECTION Initial treatment of genotype 3 patients Daclatasvir and sofosbuvir Although daclatasvir was more potent than ledipasvir for viral suppression in a pharmacodynamic study of HCV genotype 3 [81,82]. studies on daclatasvir and sofosbuvir combination therapy are very limited. In a phase 3 study of 12 weeks of daclatasvir and sofosbuvir, the overall SVR for treatment-naïve patients was 90% (91/101), with an SVR of 58% (11/19) and 97% (73/75) in patients with and without liver cirrhosis, respectively [83]. Based on a sub-group analysis of patients with genotype 3 in a real life study of patients with genotype 1–4 infection (n=2,612, treatment naïve 47%), 12 weeks of daclatasvir and sofosbuvir showed an SVR of 95% (18/19) in patients without cirrhosis, and 12 weeks of daclatasvir, sofosbuvir, and ribavirin showed an SVR of 92% (121/131) in patients with liver cirrhosis, although it is not possible to distinguish between treatment-naive and -experienced patients [69]. In a study evaluating the efficacy of 12 and 16 weeks of a daclatasvir and sofosbuvir combination regimen in patients with genotype 3 (treatment naïve 26%, liver cirrhosis 72%), the overall SVR was 80% (21/24) and 92% (24/26), respectively; the corresponding SVR in treatment-naïve patients were 83% (5/6) and 100% (7/7), respectively [84]. In a phase 2 study of 24 weeks of daclatasvir or sofosbuvir with or without ribavirin, the SVR was 89% (16/18) [31]. In a study of 12 and 24 weeks of daclatasvir and sofosbuvir therapy in patients with liver cirrhosis (combined use of ribavirin in 86% and 78% of patients, respectively), the SVR was 92% (34/37) and 95% (89/94), respectively, with an overall SVR of 93% (68/73) in treatment-naïve patients [85]. In a real life study of 24 weeks of daclatasvir and sofosbuvir with or without ribavirin (27% with liver cirrhosis), the SVR in treatment naïve patients was 100% (12/12) and 92% (23/25), respectively, though it is not possible to distinguish the presence or absence of liver cirrhosis in that analysis [86]. The effects of RASs on daclatasvir and sofosbuvir combination therapy were tested in a phase 3 study of 12 weeks of daclatasvir and sofosbuvir. Although the researchers did not complete a subanalysis between treatment-naïve and -experienced patients, the SVR in RASs-positive patients with and without liver cirrhosis was 30% (3/10) and 83% (15/18), respectively [83]. Glecaprevir/pibrentasvir In a phase 3 study comparing 8 and 12 weeks of glecaprevir/pibrentasvir and 12 weeks of daclatasvir and sofosbuvir in treatment-naïve patients without liver cirrhosis, the SVR was 95% (149/157), 95% (222/233), and 97% (111/115), respectively [87]. According to an integrated analysis of seven phase 2 and 3 studies of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with genotypes 1–6 without cirrhosis (all patients with genotype 3 were treatment-naive), the SVR of patients with genotype 3 was 97% (177/183) and 98% (258/262), respectively [38]. In a phase 2 study comparing 12 weeks of combination therapy with glecaprevir (300 mg) and pibrentasvir (120 mg) with glecaprevir (300 mg), pibrentasvir (120 mg), and ribavirin (800 mg), the SVR in treatment-naïve patients were 100% (24/24) and 100% (24/24), respectively [39]. Sofosbuvir/velpatasvir In a phase 3 study comparing 12 weeks of sofosbuvir/velpatasvir with 12 weeks of sofosbuvir and ribavirin, the SVR in treatment-naïve patients were 97% (200/206) and 87% (174/201), respectively [70]. Although the SVR with sofosbuvir and ribavirin combination therapy for 12 weeks differed significantly between patients with and without liver cirrhosis (73% [33/45] and 90% [141/156], respectively), the SVR of sofosbuvir/velpatasvir for 12 weeks was similar between patients with and without liver cirrhosis (93% [40/43] and 98% [160/163], respectively). Although the researchers provide no detailed data according to treatment experience, the SVR in patients with and without an NS5A RAS (16%) was 88% (38/43) and 97% (225/231), respectively. Moreover, the SVR in patients with Y93H was 84% (21/25). Given the current situation in Korea, where genotype 3-specific RAS testing is unavailable, the combined use of ribavirin is highly recommended in patients with liver cirrhosis. Sofosbuvir/velpatasvir/voxilaprevir A phase 3 study compared 8 weeks of sofosbuvir/velpatasvir/voxilaprevir with 12 weeks of sofosbuvir/velpatasvir in patients with genotypes 1–6 (among patients with genotype 3, treatment naïve 77%, none of liver cirrhosis). The SVR of patients with genotype 3 was 99% (91/92) and 97% (86/89), respectively [43]. In a phase 3 study comparing 8 weeks of sofosbuvir/velpatasvir/voxilaprevir and 12 weeks of sofosbuvir/velpatasvir for cirrhotic patients with genotype 3 (69% treatment naïve), the SVR was 96% (106/110) and 96% (105/109), respectively. Sofosbuvir, peginterferon alpha, and ribavirin In a phase 2 study of 12 weeks of sofosbuvir, pegylated interferon, and ribavirin in treatment-naïve patients without liver cirrhosis, the SVR was 92–100% [88,89]. In a phase 3 study of 12 weeks of sofosbuvir, pegylated interferon, and ribavirin, the SVR in treatment-naïve patients was 95% (89/94), and that in patients with and without liver cirrhosis was 91% (21/23) and 96% (68/71), respectively [80]. Peginterferon alpha and ribavirin Genotype 3 chronic HCV infection is very rare in Korea, and information about the efficacy of peginterferon therapy is lacking. Studies from Western countries show that the SVR following a 24-week combination therapy of peginterferon alpha and ribavirin for genotype 3 HCV infection was 60–70%, 10–20% lower than that for genotype 2 chronic hepatitis C [90-92]. Peginterferon-α 2a should be injected at a subcutaneous dose of 180 μg once a week, regardless of patient body weight, and peginterferon-α 2b should be injected at a dose of 1.5 μg/kg/week. Ribavirin should be administered at a fixed dose of 800 mg, regardless of body weight or type of peginterferon [74,76]. Retreatment of treatment-experienced patients Daclatasvir and sofosbuvir In a phase 3 study of 12 weeks of daclatasvir and sofosbuvir, the overall SVR was 86% (44/51) for treatment-experienced patients, with an SVR of 69% (9/13) and 94% (32/34) in patients with and without liver cirrhosis, respectively [83]. Based on a sub-group analysis of patients with genotype 3 in a real life study of patients with genotypes 1–4 (total n=2,612, treatment experience 53%), 12 weeks of daclatasvir and sofosbuvir produced an SVR of 95% (18/19) in patients without cirrhosis, and 12 weeks of daclatasvir, sofosbuvir, and ribavirin produced an SVR of 92% (121/131) in patients with liver cirrhosis, although it is not possible to distinguish between treatment-naive and -experienced patients in that analysis [69]. In a study of 12 and 16 weeks of daclatasvir and sofosbuvir combination therapy in patients with genotype 3 (treatment experienced 74%, liver cirrhosis 72%), the SVR rate in treatment-experienced patients was 88% (14/16) and 86% (12/14), respectively. The SVR in patients with and without liver cirrhosis, including treatment-naïve patients, was 83% (15/18) and 89% (16/18), respectively [84]. In a real life study of 12 and 24 weeks of daclatasvir and sofosbuvir therapy (ribavirin combination in 86% and 78%, respectively) among patients with liver cirrhosis, the overall SVR was 92% (34/37) and 95% (89/94), respectively, with an SVR of 94% (55/58) among treatment-experienced patients [85]. In another real life study of 24 weeks of daclatasvir and sofosbuvir combination therapy with and without ribavirin (liver cirrhosis 27%), the SVR in treatment-experienced patients was 84% (21/25) and 84% (26/31), respectively [86]. The SVR rate with a combination regimen of daclatasvir, sofosbuvir, and ribavirin in patients with liver cirrhosis, including treatment-naïve patients, was 88% (29/33). An additional real life study conducted compassionate daclatasvir and sofosbuvir therapy for 12 or 24 weeks with and without ribavirin (treatment experienced 72%, liver cirrhosis 77%) in patients with liver cirrhosis or pre/post-liver transplantation. The SVR was 73% (48/66), 60% (6/10), 89% (174/196), and 82% (50/61) following daclatasvir and sofosbuvir for 12 weeks, daclatasvir, sofosbuvir, and ribavirin for 12 weeks, daclatasvir and sofosbuvir for 24 weeks, and daclatasvir, sofosbuvir, and ribavirin for 24 weeks, respectively [93]. Elbasvir/grazoprevir and sofosbuvir In a phase 2 study comparing 12 weeks of elbasvir/grazoprevir and sofosbuvir, 12 weeks of elbasvir/grazoprevir, sofosbuvir, and ribavirin, and 16 weeks of elbasvir/grazoprevir and sofosbuvir in cirrhotic patients with genotype 3 HCV, the SVR were 100% (17/17), 94% (17/18), and 94% (17/18), respectively [94]. Glecaprevir/pibrentasvir In a phase 2 study of 12 and 16 weeks of glecaprevir/pibrentasvir in patients without liver cirrhosis and 16 weeks of glecaprevir/pibrentasvir in treatment-experienced patients with liver cirrhosis (peginterferon and ribavirin experienced 54%, sofosbuvir and ribavirin experienced with or without peginterferon 46%), the SVR were 91% (20/22), 96% (21/22), and 96% (45/47), respectively [95]. In a phase 2 study comparing 12 weeks of combination therapy of glecaprevir (300 mg) and pibrentasvir (120 mg) with 12 weeks of glecaprevir (300 mg), pibrentasvir (120 mg), and ribavirin (800 mg), the SVR in treatment-experienced patients was 75% (3/4) and 100% (3/3), respectively [39]. Sofosbuvir/velpatasvir In a phase 3 study comparing 12 weeks of sofosbuvir/velpatasvir and 12 weeks of sofosbuvir and ribavirin, the SVR of treatment-experienced patients was 90% (64/71) and 64% (44/69), respectively (P<0.001) [70]. The SVR following 12 weeks of sofosbuvir and ribavirin in patients with and without liver cirrhosis was 58% (22/38) and 71% (22/31), respectively. The SVR rates from 12 weeks of sofosbuvir/velpatasvir in patients with and without liver cirrhosis were 89% (33/37) and 91% (31/34), respectively. Sofosbuvir/velpatasvir/voxilaprevir In a phase 3 study comparing 8 weeks of sofosbuvir/velpatasvir/voxilaprevir with 12 weeks of sofosbuvir/velpatasvir in patients with genotypes 1–6 (among patients with genotype 3, treatment experienced 23%, none of liver cirrhosis), the SVR of patients with genotype 3 was 99% (91/92) and 97% (86/89), respectively [43]. In a phase 3 study comparing 8 weeks of sofosbuvir/velpatasvir/voxilaprevir and 12 weeks of sofosbuvir/velpatasvir in cirrhotic patients with genotype 3 (treatment experience 31%), the SVR was 96% (106/110) and 96% (105/109), respectively. Sofosbuvir, peginterferon alpha, and ribavirin In a phase 3 study of 12 weeks of sofosbuvir, pegylated interferon, and ribavirin, the SVR in treatment-experienced patients was 93% (166/181). The SVR in patients with and without liver cirrhosis was 86% (30/35) and 94% (49/52), respectively [80]. [Recommendations] (Table 9) Initial treatment of chronic hepatitis C or compensated cirrhosis patients with HCV genotype 3 infection 1. Daclatasvir and sofosbuvir could be administered for 12 weeks to patients without liver cirrhosis (B1). Daclatasvir, sofosbuvir, and ribavirin could be administered for 24 weeks to patients with liver cirrhosis (B1). 2. Glecaprevir/pibrentasvir should be administered for 8 weeks to patients without liver cirrhosis (A1). Glecaprevir/pibrentasvir should be administered for 12 weeks to patients with liver cirrhosis (B1). 3. Sofosbuvir/velpatasvir should be administered for 12 weeks to patients without liver cirrhosis (A1). Sofosbuvir/velpatasvir and ribavirin should be administered for 12 weeks to patients with liver cirrhosis (A1). 4. Sofosbuvir/velpatasvir/voxilaprevir should be administered for 8 weeks to patients with liver cirrhosis (A1). 5. Peginterferon alpha and ribavirin could be administered for 24 weeks (A2). Retreatment of treatment-experienced chronic hepatitis C or compensated cirrhosis patients with HCV genotype 3 infection 1. Daclatasvir, sofosbuvir, and ribavirin could be administered for 12 weeks to pa