KASL clinical practice guidelines: management of hepatitis C

Abstract

PREAMBLE Aims The Korean Association for the Study of the Liver (KASL) Practice Guidelines for Management of Hepatitis C were first established in 2004, and revised in 2013, when direct-acting antivirals (DAA) were not approved in Korea. Since then, numerous studies of the efficacy, adverse effects and drug-drug interactions (DDI) of interferon-free DAA combination therapy have been published. With all oral DAA therapy showing a sustained virologic response (SVR) rate of 80-90% with minimal adverse events, hepatitis C virus (HCV) eradication is a realistic goal of treatment. Therefore, a screening strategy for HCV-infected populations according to each country’s epidemiology and disease burden is required. DAA combination therapeutics were approved and adapted to practice in Korea in 2015, and KASL revised the guidelines based on a systematic approach that reflects evidence-based medicine and expert opinions. The clinical practice guidelines for the management of hepatitis C have been revised to be useful for treatment, research and education. These recommendations are not absolute standards of care, and adoption of the guidelines in clinical practice may differ among individual patients. Target population The target groups of these guidelines are newly or previously diagnosed patients with hepatitis C virus (HCV) infection, including not only chronic hepatitis C and cirrhosis but also acute hepatitis C patients, hepatitis C patients with chronic kidney diseases, and those patients coinfected with human immunodeficiency virus (HIV) or hepatitis B virus (HBV). Intended users The guidelines are intended to provide useful information and guidance to physicians and healthcare providers involved in the diagnosis and treatment of hepatitis C, and resident physicians, practitioners, and trainers. Development, funding, and revision process The Clinical Practice Guidelines Committee for the Management of Hepatitis C (Committee) comprising 14 hepatologists, was organized according to the proposal and 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 in PubMed, MEDLINE, KoreaMed, and other databases. The key words used were ‘hepatitis C virus’, ‘hepatitis C’, ‘liver cirrhosis’, ‘liver cancer’ and other related specific key words. Levels of evidence and grades of recommendations The quality of evidence was classified according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system (Table 1) [1]. Based on the types of study, randomized control studies were approached from a high level of evidence, while observational studies were approached from a low level of evidence. Then, the level of evidence was adjusted by accounting for the factors influencing the quality of the studies. Through follow-up studies, the level of evidence was defined as follows: A, the highest level of evidence with the smallest possibility of changes in the conclusion; B, a moderate level of potential changes; and C, the lowest level of evidence with the greatest possibility of changes. The strength of a recommendation was also classified according to the GRADE system. Each study was classified as strong recommendation (1) or weak recommendation (2) based on the quality of evidence, the balance between the desirable and undesirable effect of an intervention, and socioeconomic aspects including cost or availability. A strong recommendation indicated that the interventions could be applied in most patients with strong certainty and that there was a greater possibility of desirable effects, high-quality evidence, and presumed patient-important outcomes, cost-effectiveness, preference, and compliance. A weak recommendation indicated a suggestion made with less certainty but that could be considered favorable for many patients, based on the level of evidence, the cost or preferences of the 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 is the epidemiology, natural history and prevention strategy of hepatitis C in Korea? 2. How should diagnosis and evaluation of severity of chronic hepatitis C be made? 3. What is the goal of treatment and who are the targets for antiviral treatment of hepatitis C? 4. How to define the treatment response and what are the predictors of the response? 5. How to treat patients with genotype 1 chronic hepatitis C and compensated cirrhosis? 6. How to treat patients with genotype 2 chronic hepatitis C and compensated cirrhosis? 7. How to treat patients with genotype 3 chronic hepatitis C and compensated cirrhosis? 8. How to treat patients with genotype 4 chronic hepatitis C and compensated cirrhosis? 9. How to treat patients with genotypes 5 and 6 chronic hepatitis C and compensated cirrhosis? 10. How to treat patients with decompensated cirrhosis? 11. How to treat patients who underwent liver or extrahepatic organ transplantation? 12. How to treat patients with acute hepatitis C? 13. How to monitor the patients and the adverse effects of antiviral drugs during and after antiviral treatment? 14. How to treat patients with special conditions (people who inject drugs, chronic kidney diseases, coinfection with HIV or HBV, hemophilia or thalassemia, immunosuppressive therapy or cytotoxic chemotherapy, and pediatric patients)? 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 AGREE II (Appraisal of Guidelines for Research and Evaluation II) along with the academic integrity of the contents. The guidelines were reviewed after counsel from an infection specialist, at a meeting of an external review board composed of 14 KASL members, and were further modified following opinions aired 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 was released in November 2015 at a KASL meeting and published in January 2016 on the KASL website (http://www.kasl.org). Future plans for revision will be conducted under the judgment that the revision is necessary for promotion of health in South Korea with accumulation of research on the management of hepatitis C. In addition, use of DAA is to be allowed in South Korea in the near future, so that updating or partial revision of the guidelines, as appropriate, is warranted. EPIDEMIOLOGY HCV is one of the main causes of acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma [2]. Hepatitis C is on the list of National Notifiable Infectious Disease in South Korea and has been under surveillance since 2000. An effective HCV vaccine is yet to be discovered, so that understanding of national epidemiology and a preventive strategy to block routes of HCV infection is important for public health. Prevalence of HCV infection The worldwide prevalence of HCV infection was 2.8% in 2005 and 1.6% in 2014, equating to about 115 million persons positive for antibody to hepatitis C (anti-HCV) and 1.1% equating to about 80 million persons positive for HCV RNA [3]. The prevalence varies among geographic regions; regions with a high prevalence of over 3.5% include Central Asia (including Mongolia and China), SouthEast Asia (including Pakistan and Thailand), and North Africa (including Egypt). Low prevalence (below 1.5%) regions are Asia (including South Korea and Japan), North America (including the United States), and South America [4]. 1. Prevalence in adult health check examinees The prevalace of HCV infection in adult health check examinees was reported to be 1.7% using a first-generation enzyme immunoassay (EIA) in the early 1990s soon after HCV was discovered [5]. The estimated age-standardized prevalence of anti-HCV in adult health check examinees in > 40 years of age was reported to be 1.29% (95% confidence interval, 1.12-1.48) and was over 193,000 persons in a collective study of health checkup examinees from Seoul, Ulsan, Jeollanam-do, and Daegu between 1995 and 2000 [6-10]. In 2009, the anti-HCV prevalence in health examinations of 291,314 adults ≥20 years of age from 29 health examination centers was 0.78% using third-generation EIA after adjusting for age, sex, and area [11]. The anti-HCV prevalence was higher in females (0.83%) than in males (0.75%) and increased with age (20-29 years: 0.34%, 30-39 years: 0.41%, 40-49 years: 0.60%, 50-59 years: 0.80%, 60-69 years: 1.53%, ≥70 years: 2.31%). In addition, the anti-HCV prevalence varied geographically; in comparison with the prevalence of 0.50-1.20% in most regions, including Seoul and Gyeonggi-do, the prevalence in Pusan and Jeollanamdo were 1.53% and 2.07%, respectively, while the Jeju Special Self-Governing Province had the lowest rate of 0.23% (Fig. 1). And also, there was a significant geographic difference in the potential risk factors for HCV infection in Korea [12]. An update of the national HCV infection prevalence in South Korea is expected to be released at the end of 2015, and the Korea National Health and Nutrition Examination Survey has included anti-HCV testing since 2012. 2. Prevalence of anti-HCV in blood donors, pregnant women, and children The anti-HCV prevalence in 2,040,151 blood donors in 1997 in South Korea was 0.34%, as determined by third-generation EIA [13]. From 2005 to 2009, the anti-HCV prevalence in 11,064,532 blood donors was 0.16%, and the HCV RNA-positive rate was 8.4 (0.0084%) of 100,000 donors, among whom 81% were young people aged 10-30 years [14]. In South Korea, the risk of blood transfusion-related HCV infection decreased from 1 in 81,431 in 2000/2001 to 1 in 2,984,415 after implementation of nucleic acid testing for HCV screening of donated blood in February 2005 [15]. The anti-HCV prevalence in pregnant women was reported to be 0.49-1.7% [16-18], and a domestic report investigating over 5,000 pregnant women reported rates of 0.42-0.44% [19,20]. Among anti-HCV-positive pregnant women, 57-60% of the patients positive for HCV RNA [19,20]. Domestic studies on anti-HCV prevalence in children and adolescents are insufficient. A 0.82% anti-HCV-positive rate tested by third-generation EIA in 2,080 children between 6 and 11 years of age living in Seoul was reported [21]. However there have been no other reports or studies on children and adolescents, hindering the accurate assessment of the HCV infection prevalence in the pediatric population of South Korea. 3. Prevalence of anti-HCV in high-risk groups The high-risk groups for HCV infection include people who inject drugs (PWID), patients under hemodialysis, and those with HIV infection, hemophilia, and leprosy. However, the HCV prevalences in this group have been reported mostly before 2000; few studies were performed thereafter. The domestic anti-HCV prevalence in the intravenous drug user (IVDU) group was 48.4-79.2% [22-25]. Among anti-HCV-positive persons, 98.1% were HCV RNA-positive [24]. The anti-HCV prevalence in those who share cocaine suction pipes was similar to that in the IVDU group [26]. The anti-HCV prevalence was 5.9-14.7% in previous studies of >200 patients with chronic kidney diseases [27,28], 2.2% in the 2014 report of the Korean Society of Nephrology [29] and was significantly correlated with hemodialysis duration. The HCV coinfection rate was high in those infected with HIV; ~25% of westerners and 5.0-6.3% of HIV-infected individuals in South Korea were coinfected with HCV [30-32]. The anti-HCV prevalence in 104 hemophilia patients tested by third-generation EIA was 42.3% in 2002, and the risk of infection was correlated with age and severity of hemophilia [33]. In their 2012 annual report, the Korea Hemophilia Foundation (KHF) reported that 430 of 2,148 (20.0%) hemophilia patients were anti-HCV-positive and 118 of 2,148 (5.5%) were HCV RNA-positive [34]. Leprosy patients can be considered at high risk of HCV infection due to their skin lesions and long-term cohabitation in limited areas. The anti-HCV prevalence of 96 leprosy patients tested by second-generation EIA was 67.7% in 1997; 82% of these individuals were immunoblot-positive [35]. HCV incidence rate Studies on HCV infection incidence rate are rare, since only 20-30% of those with acute HCV infection develop symptoms. HCV incidence rates are decreasing in Western countries [36]. In the US the incidence rate decreased from 7.4 of 100,000 people from 1982-1989 to 0.7 of 100,000 people from 1994-2006 [37], and in Italy, it decreased from 2.02 of 100,000 people in 1996 to 0.55 of 100,000 people in 2006 [38]. The HCV infection incidence rate in South Korean blood donors was reported to be 13.8 per 100,000 according to a survey conducted on those who donated blood at least twice from 1994-1996 [39]. The recent HCV infection incidence rates among blood donors who donated at least twice in 2 years between 2000 and 2010 were estimated to be 6.80 in 2001, 3.19 in 2003, 2.69 in 2005, 1.83 in 2007, and 0.80 in 2009 per 100,000 person-years, showing significant decrease in the incidence of HCV in this population in South Korea [15]. According to surveillance sample data from the Korea Centers for Disease Control and Prevention (KCDC), the number of reported hepatitis C cases was 1,927 in 2002, 6,407 in 2008, and 4,280 in 2012. Future studies should evaluate the nationwide incidence of HCV in Korea. Distribution of HCV genotypes Globally, HCV genotypes 1, 2, and 3 are common and genotypes 4, 5, and 6 are localized to limited regions [40,41]. Genotype 1a is the most common in Northern Europe and North America, and 1b is the most common in Far East Asia and Europe. Genotype 2 is less common than genotype 1. Genotype 3 is common in Southeast Asia and genotype 4 is common in the Middle East, Egypt, and Central Africa. Genotype 5 is commonly found in South Africa and genotype 6 is common in Hong Kong, Macau, and Vietnam. Common HCV genotypes in South Korea are genotype 1b (45- 59%) and 2a (26-51%); types 1a, 2b, 3, 4, and 6 are rare in South Korea [42,43]. Whether genotype 1 HCV infection provokes faster progression of hepatic disease than the other genotypes is controversial. A recent meta-analysis reported that genotype 1b patients showed a 1.78-fold higher risk of developing HCC (95% CI, 1.36-2.32) compared to non-1 genotype patients [44]. Nevertheless, the HCV genotype is the most crucial factor in determining the efficacy of antiviral therapy [45]. PREVENTION Route of transmission HCV transmission occurs by parenteral exposure. The main routes of transmission include transfusion of contaminated blood or blood products, organ transplantation, PWID, unsafe injection or medical procedures, stabs by contaminated syringe or needle, sexual contact with HCV-infected person, or perinatal transmission from an infected mother to her newborn. Transmission via transfusion was a main route of infection until 1991, but the possibility has become extremely low since introduction of a screening test for blood donors [46-48]. Recently, in developed regions such as the US and Europe which have low HCV prevalence, the most common route of HCV transmission has been the use of illicit drugs [49], and anti-HCV prevalence in the PWID group was reported to be up to 50-90% [50]. Meanwhile, unsafe injection with multiple-use medication vials or reused syringes, or unsanitary medical procedures including surgery, endoscopy, and dental treatment without proper disinfection are the main causes of HCV transmission in developing countries [51-53]. In addition, meta-analyses have reported that risk factors for HCV transmission include piercing, acupuncture, or tattooing without proper disinfection [54-56]. The risk of HCV infection due to percutaneous exposure to a small dose, such as needle sticks, is 1.8% (0-7%) [57-60] in other countries and 0.92% in South Korea [61]. Heterosexual persons with chronic HCV infection in long-term monogamous relationships with a partner had little evidence of sexual transmission of HCV. However, the risk becomes higher with multiple sex partners, and unsafe sex including anal sex, sex accompanying wounds, sex with carriers of other sexually transmitted diseases such as HIV, or in homosexuals [62,63]. The percentage of perinatal transmission was 1-6.2% [64,65]. It was reported to be 1.7% when the mothers were positive for anti-HCV regardless of HCV RNA-positivity, and 4.3% (3.9-7.1%) in the case of HCV RNA-positive mothers [65,66]. The risk of perinatal transmission increased in female infants, HIV-positive mothers, and mothers with high blood HCV RNA levels [67]. Cesarean section reportedly does not prevent HCV transmission [67,68], and the frequency of transmission via nursing was very low. Thus, it is not necessary to limit breast-feeding unless nipples are injured or bleeding [69]. Reports of horizontal transmission between siblings or family members of HCV-infected persons are based on a low level of evidence [70]. A comparative study of 1,173 HCV patients and 534 controls in five university hospitals between 2007 and 2011 in South Korea reported several independent risk factors of infection, including use of illicit drugs, needle-stick injury, transfusion before 1995, tattoo, and age [71]. Counseling for prevention Since an effective vaccine has not been developed, the main strategy for prevention is to educate people on the risk factors for HCV infection and to maintain strict sanitation standards in all locations performing percutaneous procedures. HCV-infected persons should be counseled not to donate blood, organs, tissues, or semen, and not to share any instrument penetrating skin. They should use their own instruments including toothbrushes, oral hygiene devices, razors, or nail clippers so other people are not exposed to his/her blood. Finger-stabbing needles commonly used for Korean home remedies should not be shared. IVDU should be persuaded to stop drug abuse and they should not reuse syringes, needles, injection solution, cotton swab, or alcohol sponges. They must be reminded that other people can be infected via recklessly disposed needles. Since the risk of infection among monogamous couples is very low, use of barrier protection by these couples is not necessarily recommended. Nevertheless, if the partner of the infected individual requests, or if the infected person has multiple sex partners, it is recommended to use condoms. Routine screening for HCV is not recommended for all pregnant women. However, for those with a risk factor, prenatal testing for HCV is required. HCV infection does not mean a restriction of breast-feeding or recommendation for a specific means of delivery, such as Cesarean section. Healthcare facilities should take precautions to prevent HCV transmission. Proper disinfection, cleaning, and management of materials and instruments are essential in medical and invasive procedures including tattooing, piercing, and acupuncture. [Recommendations] 1. HCV-infected persons should not donate blood, organs, tissues, or semen (A1). HCV-infected persons should avoid sharing toothbrushes, oral hygiene devices, razors, nail clippers, or any instrument penetrating skin, so as not to expose other people to his/her blood (C1). 2. People who inject drugs should be counseled to stop abuse of illicit drugs (A1). They should be educated about routes of infection and tested regularly for HCV infection (B1). 3. Proper disinfection, cleaning, and management of materials and instruments are essential in medical and invasive procedures including tattooing, piercing, and acupuncture (B1). 4. As the risk of infection among monogamous sexual partners is very low, use of barrier protection is not advised in these couples (B1). However, for those with multiple sex partners, it is recommended to use condoms (B1). 5. For pregnant women, if a risk factor for HCV infection is detected or HCV infection is suspected otherwise, prenatal testing for HCV infection is recommended (B1). HCV infection does not mean a restriction of breast-feeding or a recommendation of specific delivery, such as Cesarean section (B2). NATURAL HISTORY Acute HCV infection After 1-3 weeks of HCV infection, HCV RNA becomes detectable in blood and the level rapidly increases [72,73]. The serum alanine transaminase (ALT) level increases due to hepatocyte damage after 4-12 weeks of infection. Most infections are asymptomatic (70-80%), but symptoms including flu-like symptoms, fatigue, vomiting, nausea, right upper quadrant pain, muscle pain, or pruritus may develop within 2-12 weeks. About 20% of acute infection accompanies jaundice with serum bilirubin level <3-8 mg/dL, and acute liver failure occurs in <1% of cases. Acute hepatitis progressed to chronic infection in 54-85% of patients, and 20-50% of patients recovered spontaneously within 3-4 months [74-76]. The spontaneous recovery rate differs according to route of infection; the spontaneous recovery rate in post-transfusion cases was 12%, while in the cases not related to transfusion it was 29-52% [76-78]. Factors related to spontaneous recovery are hepatitis accompanying jaundice, female gender, low viral load, and genotype 3 [77-79]. A Korean study reported that among 18 acute hepatitis C patients (17 patients showed symptoms), 12 patients spontaneously recovered and 6 patients progressed to chronic hepatitis [80]. Another study including 47 acute hepatitis C patients with a mean age of 45.8 years in seven Korean institutions reported that 21 of 47 (44.7%) patients recovered spontaneously, and 16 patients received antiviral therapy. All 12 patients who were treated and followed-up achieved a sustained virological response (SVR). Ten patients who did not receive antiviral therapy progressed to chronic hepatitis [81]. A single nucleotide polymorphism (SNP) of the interleukin 28B (IL28B) gene is strongly related to spontaneous recovery from acute hepatitis C infection [82-84]. IL28B is located on chromosome 19 and encodes interferon-lamda-3. One study reported a spontaneous recovery rate of 53% in cases with genotype CC of IL28B SNP rs12979860 and of 28% in genotype CT or TT (Odds ratio (OR)=0.33, P<10-12) [85]. However, future studies are needed as there has been no Korean study of the role of IL28B SNP in acute HCV infection. Chronic HCV infection About 50-80% of HCV-infected patients progress to chronic infection. Chronic hepatitis can cause persistent liver injury without spontaneous recovery, leading to cirrhosis and HCC. Most (60- 80%) patients with chronic hepatitis show no symptoms, but some can experience abdominal discomfort, fatigue, nausea, muscle pain, arthritis, or weight loss. About 60-70% of chronic HCV-infected patients show chronic hepatitis accompanying steady or intermittent elevation of serum ALT. About 15-56% of chronic hepatitis may progress to cirrhosis through a period of 20-25 years [73,86-88]. Among patients with liver cirrhosis, the annual incidence of HCC is reported as 1-4.9% [89-91], that of decompensated liver cirrhosis is 3-6% [73,90-92], and the overall annual mortality rate is 2-4% [73,90-92]. An observational study including 1,137 Korean chronic HCV infected patients for an average follow-up of 55.2 months reported a 14.2% rate of disease progression, defined as development of HCC, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy, and death due to hepatic diseases, and the overall annual mortality rate was 2.0-2.5% [93]. The cumulative probability of disease progression was 6.3%, 12.9%, and 26.1% at 1, 2, and 3 years, respectively. Among 1,137 patients, 490 (43.0%) received antiviral treatment and 60.4% showed an SVR. Chronic infection without antiviral treatment showed a significantly higher risk of disease progression compared to chronic infection with antiviral treatment (37.4% vs. 10.7%, respectively, P<0.05). The 5-year cumulative probability of disease progression was higher in a non-SVR group compared to a group with SVR (13.0% vs. 3.7%, respectively, P<0.05). According to prospective cohort data from 196 patients with HCV-related cirrhosis in Korea, during a mean follow-up period of 39.2 months, 31 (15.8%) patients developed HCC, and 33 (16.8%) patients died or underwent liver transplantation. The estimated HCC incidence was 5.8 per 100 person-years, and the independent factors for HCC were absence of anti-HBV surface antibody (HBs hazard ratio [HR], 5.018; 95% confidence interval [CI], 1.710-14.726; P=0.003) and serum albumin<3.8g/dL (HR, 3.051; 95% CI, 1.318-7.067; P=0.009). The overall mortality rate was 5.1 per 100 person-years, and the related independent factors were the presence of ascites (HR, 2.448; 95% CI, 1.142-5.210; P=0.022), serum albumin < 3.8 g/dL (HR, 3.067; 95% CI, 1.254-8.139, P=0.014), and nonachievement of SVR (HR, 0.066; 95% CI, 0.001-0.484, P=0.002) [94]. Factors affecting disease progression include duration of infection, age at the time of infection (≥40 years of age), male gender, alcohol intake, coinfection with other viruses (HBV or HIV), insulin resistance, obesity, immune-depressed patients, organ transplantees, elevation of ALT, and genetic factors such as IL28B [73]. Excessive alcohol intake by chronic hepatitis C patients is strongly related to occurrence of cirrhosis, and increases the risk of HCC [88,95-98]. Fatty liver, insulin resistance, and obesity increase the risks of hepatic fibrosis and HCC development in chronic hepatitis C patients [99-102]. Coinfection with HIV or HBV accelerates progression of liver diseases and increases the risk of HCC compared to HCV single infection [103-105]. In addition, coinfection with hepatitis A virus (HAV) in chronic hepatitis C increases the risk of hepatic failure [106]. The pathologic stage of hepatic fibrosis at the time of chronic hepatitis C diagnosis is the most important predictor of progression to cirrhosis (refer to the Diagnosis section of this paper) [88,103]. Stage 1 hepatic fibrosis has a 10-30% incidence of cirrhosis over a period of 15 years, while most cases of stage 3 hepatic fibrosis are expected to progress to cirrhosis within 15 years. Therefore, patients diagnosed as having hepatic fibrosis over stage 2 must be considered for active antiviral treatment. [Recommendations] 1. Continuous management and surveillance for development of cirrhosis and HCC is necessary in chronic hepatitis C patients (A1). 2. Chronic hepatitis C patients should abstain from alcohol or drink in moderation, and maintain suitable body weight through physical exercise and dietary control, since disease progression is related to alcohol, obesity, and insulin resistance (B1). 3. Patients with chronic HCV infection without antibodies against HAV and HBV should be vaccinated for HAV and HBV (C1). Screening test for HCV infection Routine screening for HCV infection is recommended in populations at risk, such as those with a history of blood transfusions or organ transplantation prior to 1992; persons who have injected illicit drugs; persons with HIV infection, hemophilia, or Hansen’s disease; persons who have been on hemodialysis; children born to mothers infected with HCV; and health care providers after a needle stick injury or mucosal exposure to HCV-positive blood (Table 2) [107]. In 2012, the US Centers for Disease Control and Prevention expanded the screening population to the birth cohort born between 1945-1965 and recommended screening for HCV once in a life-time, based on cost effectiveness [108-110]. A Japanese study revealed that hepatitis C screening appears cost-effective in the general population as well as in high-risk groups [111], but a European study showed that screening of the general population is cost-effective only in HCV prevalent areas [112]. Therefore, since the epidemiologic characteristics and healthcare systems differ among nations, further research on cost effectiveness is needed to determine the optimal screening strategy for Korea. According to anti-HCV prevalence rates in Korea, the estimated number of anti-HCV infected persons over 20 years old was about 320,000 in 2009. However, the number of patients who were treated under coverage of Health Insurance Review and Assessment Service (HIRA) due to liver disease associated with HCV infection was 64,501 in 2009 [113]. These data suggest the possibility that only about 20% of the patients were diagnosed and treated. An online survey in 2013 about awareness of HCV infection showed that about 90% of the general population had not been tested for hepatitis C or did not know whether they had been tested for hepatitis C, which implies that awareness of HCV infection in the general population was low. According to HIRA data, the direct annual medical cost per patient in South Korea was markedly higher for liver cirrhosis (1,522 USD), hepatocellular carcinoma (6046 USD) or liver transplantation (57,940 USD) compared to in chronic hepatitis (842 USD) [113]. Such results demonstrate that every effort to intervene disease progression should be exerted to reduce the HCV disease burden. The high accuracy rate and low cost of testing for anti-HCV as a screening tool, and the >90% cure rate of DAA in early stage liver disease, should also be taken into consideration. One-time screening for HCV infection in the South Korean population aged 40-70 years is likely to be more cost-effective compared to current practice [114]. Therefore, a nationwide screening and therapeutic strategy to diagnose and cure hepatitis C patients prior to progression to advanced liver disease would not only decrease the disease burden but also be a successful model for HCV elimination. Diagnosis of HCV infection Biochemical tests, serologic assays, and HCV RNA testing are needed to confirm HCV infection. Physical examination and history taking should be performed to understand the routes of transmission and prevent further reinfection. HCV genotyping is essential for treatment, and radiologic examination, liver biopsy, or noninvasive evaluation of hepatic fibrosis can be performed to determine the necessity of treatment, and to assess liver disease severity. Interpretation of serological and virological test results is summarized in Table 3. DIAGNOSIS Serologic assays: Anti-HCV test Detection of anti-HCV in serum or plasma is used for screening of high-risk groups and for diagnosis of acute or chronic hepatitis C [115]. The third-generation EIA uses recombinant core, NS3, NS4, and NS5 HCV proteins, and its sensitivity and specificity are 97.2- 99% and 99.8-100%, respectively, when tested in immune-competent individuals [116-118]. If signal/cutoff (S/CO) ratios of third-generation EIA exceed 3.8, a positive result will be apparent in 95% of recombinant immunoblot assays (RIBA) [119-121]. However, the cut-off S/CO ratio can differ according to the type of equipment, so that high S/CO ratios do not always mean true positive [122]. Recently, use of enhanced chemiluminescent immunoassay (CLIA) or electrochemiluminescence immunoassay (ECLIA) is increasing since those assays detect antigen-antibody reaction more sensitively compared to the third-generation EIAs. Meanwhile, pointof-care tests using saliva or fingerstick blood that produce results within 20 minutes can also be employed [123,124]. Average time between HCV infection and seroconversion is 8-9 weeks, and anti-HCV is detectable in >97% of patients with HCV infection within 6 months [107,125]. Anti-HCV is not a neutralizing antibody and persists indefinitely in chronic hepatitis C patients and after recovery. Therefore, the differentiation of current from past infection after recovery is impossible using anti-HCV positivity. Anti-HCV can be tested repeatedly in high-risk persons because hepatitis C virus can reinfect after recovery. Negative result for anti-HCV in combination with a positive result for HCV RNA may represent an early stage of acute infection or chronic infection in the setting of severe immunosuppression, such as patients on hemodialysis, HIV coinfection, solid organ transplantation recipients, hypo-/ a-gammaglobulinemia, and patients with HCV-associated essential mixed cryoglobulinemia [126-128]. In these patients, HCV RNA testing is necessary for diagnosis of HCV infection. In contrast, false-positive result for anti-HCV and negative result for HCV RNA can occur in patients with autoimmune diseases [129]. Virological assays 1. HCV RNA assays HCV RNA assays are classified as quantitative and qualitative. Since the detection cutoff of qualitative assays is 50 IU/mL, and these are more sensitive than previous-generation quantitative assays, HCV RNA qualitative assays have been used for diagnostic confirmation of HCV infection, and HCV RNA quantification is used for pretreatment assessment and monitoring of a virological response during and after antiviral therapy [115,121,130]. However, recently available quantitative HCV RNA assays use real-time polymerase chain reaction (PCR) and transcription-mediated amplification (TMA), and are highly sensitive with lower detection limits of 12-15 IU/mL, while they have a broad measuring range with an upper limit of 7-8 log IU/mL and 98-99% diagnostic specificity irrespective of HCV genotype [115,131-135]. Therefore, quantitative HCV RNA tests are now widely used for both diagnosis and evaluation of the treatment response [127,136]. In 1997, the World Health Organization established an international standard for HCV RNA quantification unit, IU, rather than HCV copy number [137,138]. However, since viral quantification results can differ among laboratories [139], it is recommended to use the same laboratory test before, during, and after-treatment for monitoring, if possible [107,127]. Blood HCV RNA is detectable as early as 2 weeks after infection [76], rapidly increases to reach a plateau, and decreases along with ALT after ALT has peaked [140]. HCV RNA levels remain steady in patients with chronic hepatitis C [140,141]. HCV RNA levels are not significantly correlated with the severity of hepatic inflammation or fibrosis, and change little during chronic infection without antiviral treatment [142,143]. 2. Genotyping/subgenotyping assays HCV genotyping is useful for epidemiologic studies as well as for predicting treatment response. Therefore, HCV genotype should be assessed before treatment to determine the optimal therapeutic duration and dose of ribavirin [144]. HCV is classified into six major genotypes (1-6) and is subdivided into subtypes identified by lower-case letters, such as 1a or 1b. Differences of 31-33% at the nucleotide level differentiate the genotypes, compared with 20-25% for the subtypes [145]. HCV genotype does not change within a person unless reinfected. HCV genotypes and subtypes can be determined by direct sequence analysis, reverse hybridization, or restriction fragment mass polymorphism (RFMP) [146]. Most genotyping assays analyze both the 5’-untranslated region (UTR) and HCV core regions, the nucleotide sequences of which are highly conserved [147-150]. Subtyping is not necessary in antiviral therapy using interferon alpha and ribavirin, but in treatment that includes DAAs, subtypes may need to be confirmed since DAAs act differently according to subgenotype [148-153]. Genotyping is not possible in <5% of patients, because of low HCV RNA levels, problems with PCR amplification, or the high nucleotide variability of the HCV genome [154]. 3. HCV drug-resistance mutation tests As various DAAs began to be used for therapy, amino acid sequence variants associated with resistance to DAA have been found (Table 4) [155-166]. HCV resistance-associated variants (RAV) can be selected during the HCV life cycle, or during DAA therapy. Naturally occurring RAV has been found more commonly in HCV 1a than in HCV 1b [167]. RAV to protease inhibitors (PI) were found in 9-48% of patients infected with HCV 1a and 0.5-4.9% of those with HCV 1b [168-170], while RAV to daclatasvir, an NS5A inhibitor, are found in 11.2% of patients infected with HCV 1b. RAVs to both NA5A inhibitor and NS3/4 PI are found in only 0.4% of patients [170]. Asunaprevir-resistant substitutions found during therapy can disappear within a few weeks, but daclatasvir-resistant substitutions can persist up to 48 weeks post-treatment [160]. Therefore, patients who failed the first DAA therapy should be retreated with drugs showing no cross-resistance with the drugs already administered [171]. RAVs can be detected using several methods, including population sequencing, clonal sequencing and deep sequencing, by which variants with frequencies less than approximately 25%, 5% and 0.5% respectively, cannot be detected [172]. HCV RAV testing prior to first-line therapy is not generally required. However, the Q80K polymorphism should be tested in HCV 1a-infected patients who were previously treated with boceprevir or telaprevir, and will be treated with a simeprevir-containing regimen. In patients with HCV genotype 1a who have the Q80K variant, simeprevir is not recommended. In HCV 1b patients with baseline NS5A polymorphisms such as L31 or Y93H, daclatasvir plus asunaprevir combination therapy showed a significantly lower SVR than that in those without NS5A RAVs. Therefore, HCV NS5A RAV testing should be performed prior to treatment of HCV patients with daclatasvir plus asunaprevir. Otherwise, HCV RAV testing is not recommended during DAA therapy [173]. Diagnosis in case of accidental exposure The average incidence of anti-HCV seroconversion in healthcare providers after accidental percutaneous exposure to HCV-infected blood is 1.8% (0-7%) in various countries [59,60,174-178], and 0.92% in South Korea [61]. When a person is exposed to an HCV-positive source, baseline testing for anti-HCV and serum ALT level should be performed. If anti-HCV is negative, HCV RNA assay should be performed 4-6 weeks after exposure for early diagnosis. Even if all baseline tests for HCV infection are negative, follow-up testing for anti-HCV and serum ALT level should be performed 4-6 months after exposure [127,175]. If anti-HCV is positive, a confirmative test is needed. Assessment of liver disease severity To decide the treatment for HCV-infected patients, the severity of liver disease must be evaluated through liver biopsy and/or noninvasive tests. It is important to confirm whether the patient has liver cirrhosis or not before treatment since the existence of liver cirrhosis can affect the treatment response, prognosis, and necessity of surveillance for HCC. Liver cirrhosis can be diagnosed using clinical characteristics, histologic findings and/or noninvasive tests for evaluation of liver fibrosis. Liver biopsy Liver biopsy is performed to assess the grade and stage of the hepatic injury [107,179]. The Metavir [180] and Ishak [181] scoring systems are most widely used, and the scoring system proposed by the South Korean Study Group for the Pathology of Digestive Diseases [182] is used in South Korea (Table 5). Although liver biopsy is not mandatory prior to treatment, it can help to determine when to start treatment and to provide information regarding the treatment response and prognosis. Considering the natural history of the disease, the cost of treatment and its possible adverse effects, treatment can be postponed if liver histopathology shows minimal to moderate fibrosis, state <2 (Metavir stage 2 or periportal fibrosis of the South Korean Study Group for the Pathology of Digestive Diseases, F2) [76,183,184]. In this case, a liver biopsy should be repeated 4-5 years later to reassess the necessity of treatment according to the progression of liver disease [185]. About 5-30% of patients with genotype 1 with consistently normal serum ALT may have severe fibrosis [186-188] and liver biopsy would be useful to determine treatment initiation in this group [88,189,190]. Although hepatic steatosis [179,191,192] and liver iron load overload [193] might impede the treatment response, these findings are not contraindications for treatment [194-196]. If a liver biopsy is not conducted and treatment is not undertaken, continuous monitoring is needed. Liver biopsy and treatment initiation should be considered when there is elevation of the serum ALT level and evidence of liver disease progression [107]. Noninvasive tests for evaluation of liver fibrosis Although liver biopsy is accepted as the gold standard test for evaluation of liver fibrosis [197,198], it is associated with serious complications [199,200], sampling errors [201], high costs, and interobserver variations. Therefore, various blood marker panels have been developed—including aspartate aminotransferase (AST)-platelet ratio index (APRI) and AST/ALT ratio (AAR), and Fibrosis-4 score (FIB-4)—that use combinations of AST, ALT, and platelet count. FibroTest, Hepascore, FibroMeter, Fibrospect II, and Enhanced Liver Fibrosis tests can also be used [202-213]. APRI is calculated by the formula (AST/upper limit of normal for AST) × 100/platelet count (×109/L) (www.kasl.org). This formula is accurate for predicting both significant fibrosis (Ishak score ≥3) defined as APRI >1.5 (AUROC=0.8) and cirrhosis defined as APRI>2 (AUROC=0.89) [214]. A normal value of AAR is <0.8, but it increases with hepatic fibrosis progression, so that an AAR value >1.0 has a 73.7-100% positive predictive value for diagnosis [207,215-217]. FIB-4 is calculated using the formula: age (yr) × AST (IU/L)/platelet count (109/L × [ALT (IU/L)1/2] (www.kasl.org). A FIB-4 score <1.45 has a negative predictive value of 90% for advanced fibrosis (Ishak fibrosis score 4-6). In contrast, a FIB-4 score of >3.25 has a positive predictive value of 65% for advanced fibrosis [218]. Liver stiffness measurement using transient elastography can be used to assess hepatic fibrosis [219-222]. However, transient elastography cannot totally replace liver biopsy, because it often cannot produce reliable measurements in obese patients, and tends to give falsely high results in cases of acute hepatitis with severe inflammation and necrosis with mild fibrosis [223,224]. In the case of chronic hepatitis C, cutoff values determining significant fibrosis (≥F2) vary among studies, ranging from 7.1 to 8.8 kPa, with an AUROC of 0.79-0.83 [225]. The AUROC for diagnosis of liver cirrhosis ranged from 0.95-0.97, with cutoff values of 12.5-14.6 kPa (77-78% positive predictive value, 95-97% negative predictive value) [202,209,219,225-228]. Other newly developed noninvasive tests include acoustic radiation force impulse (ARFI) imaging, real-time elastography, magnetic resonance (MR) elastography, diffusion-weighted MR image, and MR spectroscopy. However, their effectiveness remains to be validated [229-231]. [Recommendations] 1. Screening for HCV infection could be considered in populations at risk as well as those over 40 years old with increasing prevalence of HCV infection (C1). 2. Anti-HCV should be tested in patients suspected of having acute or chronic HCV infection (A1). 3. HCV RNA should be tested in patients with a positive anti-HCV test to confirm the diagnosis (A1). 4. Even if anti-HCV is negative, HCV RNA testing is required when acute HCV infection is suspected or in the presence of unexplained liver disease in immunosuppressed patients (B1). 5. HCV RNA quantitative assay and genotyping/subgenotyping (1a/1b) should be performed prior to antiviral treatment (A1). 6. Immediately following exposure to infected blood or body fluids, anti-HCV and serum ALT level testing should be performed. If anti-HCV is negative, an HCV RNA assay should be conducted 4-6 weeks after exposure for early diagnosis. If all baseline tests are negative, follow-up testing for anti-HCV and serum ALT level should be performed 4-6 months after the exposure (B2). 7. Assessment of liver disease severity is essential prior to antiviral treatment (A1). 8. Liver biopsy and/or noninvasive tests for assessment of hepatic fibrosis can be performed to make treatment decision and predict prognosis (B1). TREATMENT GOALS The goals of hepatitis C treatment are to eradicate HCV and to prevent complications of liver cirrhosis, hepatocellular carcinoma, extrahepatic manifestations of HCV infection and death. It is difficult to evaluate the treatment goal in a short period of time due to the gradual progression of chronic hepatitis C over several decades. Therefore, the short-term goal of hepatitis C treatment is to achieve an SVR, defined as undetectable serum HCV RNA by a sensitive assay 12 or 24 weeks after the end of treatment. SVR was determined 24 weeks after the end of treatment using an assay with a lower limit of detection of <50 IU/mL in studies of combination therapy with Peginterferon (PegIFN)-α and ribavirin [232], whereas it was determined 12 weeks after the end of treatment using an assay with a lower limit of detection of 10-25 IU/mL in studies on DAA therapy [233,234]. Since HCV does not reappear in 99% of patients who achieve an SVR [232], the SVR is considered as eradication of HCV. Histological hepatic fibrosis improves or does not get worse [235,236], complications of cirrhosis significantly decrease [237], occurrence of hepatocellular carcinoma decreases [238,239], and survival rate improves [240,241]. SVR also improves the extrahepatic manifestations of HCV infection, such as mixed cryoglobulinemia and glomerulonephritis [242,243]. [Recommendations] 1. The goals of hepatitis C treatment are to eradicate HCV and to prevent complications of liver cirrhosis, hepatocellular carcinoma, extrahepatic manifestations of HCV infection and death (A1). 2. A short-term goal of hepatitis C treatment is to achieve an SVR, defined as an undetectable serum HCV RNA using a sensitive assay at 12 or 24 weeks after the end of treatment (A1). INDICATIONS FOR TREATMENT All hepatitis C patients who have no contraindications to treatment can be considered for antiviral treatment. However, treatment would be applicable in cases in which the benefits of treatment outweigh the risks. Generally, treatment is strongly recommended for patients with significant hepatic fibrosis (≥ stage F2). Treatment for patients with advanced fibrosis (stage F3-4) who are at high risk of cirrhotic complications and hepatocellular carcinoma should be prioritized [90]. Treatment of patients in the pre- and post-liver transplant setting should be a priority as successful eradication of HCV increases patient and graft survival [244,245]. Treatment of patients with HCV-related mixed cryoglobulinemia and glomerulonephritis should also be a priority since HCV eradication can improve the prognosis of those patients [242,243]. With advent of DAA, patients with decompensated liver cirrhosis (LC), which is a contraindication to the combination of PegIFN-α and ribavirin are candidates for antiviral treatment. HCV eradication can reduce the recurrence of hepatocellular carcinoma (HCC) and improve survival in patients with HCC [246,247]. Therefore, patients with HCC can be treated using the rules applicable to those without HCC, taking into consideration the prognosis of HCC and life expectancy. In cases of mild hepatic fibrosis, treatment can be determined after considering patients’ age, willingness to undergo treatment, and perspectives regarding new drugs. Contraindications of DAA are limited due to the few adverse effects. Sofosbuvir is contraindicated in patients with several renal impairment (Glomerular filtration rate [GFR] <30 mL/min) in whom the serum sofosbuvir concentration is markedly increased. Safety of daclatasvir, ledipasvir, and asunaprevir has not been fully evaluated in patients with severe renal impairment (GFR <30 mL/min). Paritaprevir, dasabuvir, and asunaprevir are contraindicated in patients with decompensated cirrhosis in whom the serum concentrations of these drugs are markedly increased. Absolute contraindications to the combination of PegIFN-α and ribavirin include uncontrolled depression or psychiatric illness, uncontrolled autoimmune diseases, transplantation of solid organs except the liver, untreated thyroid illness, pregnancy or unwillingness to comply with adequate contraception, severe concurrent medical illness such as poorly controlled hypertension, heart failure, significant coronary heart disease, poorly controlled diabetes mellitus, and chronic obstructive pulmonary disease, age ≤2 years, and hypersensitivity to PegIFN-α or ribavirin. [Recommendations] 1. All HCV-infected patients with no contraindication to treatment should be considered for treatment (A1). 2. Patients with advanced fibrosis ≥F3 (including compensated and decompensated cirrhosis) should be given priority for treatment (A1). 3. Treatment should be prioritized in the pre- and post-liver transplant setting (A1). 4. Treatment should be prioritized for patients with severe extrahepatic manifestations, including HCV-related mixed cryoglobulinemia and glomerulonephritis (A1). 5. Treatment should be individualized taking into consideration the severity of liver disease, probability of treatment success, risks of severe adverse effects, accompanying diseases, and patients’ willingness to undergo treatment (B1). 6. HCV treatment is not recommended in patients with limited life expectancy due to extrahepatic diseases (B1). DEFINITION OF TREATMENT RESPONSE An end-of-treatment response (ETR) is defined as undetectable HCV RNA at the end of treatment using a sensitive assay. An SVR is defined as undetectable HCV RNA by a sensitive assay at 12 or 24 weeks after completion of treatment. The concordance of SVR 12 and SVR 24 is 98% irrespective of treatment regimen [248]. Viral breakthrough refers to the reappearance of HCV RNA during treatment after a virological response, and relapse is defined as the reappearance of HCV RNA after treatment has been completed. The combination of PegIFN-α and ribavirin is associated with considerable cost and adverse effects. The likelihood of SVR increases as the time of HCV RNA disappearance is shorter [249]. Response-guided therapy is a strategy to modify the duration of treatment based on the time of HCV RNA disappearance by measuring serum HCV RNA at weeks 4, 12, and 24 of treatment. However, treatment with DAA does not comply with this strategy. A rapid virological response (RVR) is defined as undetectable HCV RNA using a sensitive assay with a lower limit of detection of <50 IU/mL at week 4 of treatment. The SVR rate is expected to be 87.5-100% in HCV genotype 1 patients with a RVR and 33.3-63.8% in those without a RVR [250-252]. The SVR rate is expected to be 85-86.5% in HCV genotypes 2 and 3 patients with a RVR and 54-58.3% in those without a RVR [251,253]. An early virological response (EVR) is defined as undetectable HCV RNA using a sensitive assay with a lower limit of detection of <50 IU/mL or a ≥ 2 log reduction in HCV RNA compared with the baseline level. The SVR rate is as low as 3% in HCV genotype 1 patients without an EVR [254-256]. Therefore, medical cost and adverse effects can be reduced by discontinuing therapy in cases without an EVR. An EVR is classified as a complete EVR (cEVR), which is defined as undetectable HCV RNA, and a partial EVR (pEVR), which is defined as an EVR with detectable HCV RNA at week 12. A delayed virological response (DVR) is defined as a pEVR that results in undetectable HCV RNA at week 24 [257,258]. A null response is defined as a <2 log reduction in HCV RNA level from baseline at week 12 of therapy, whereas a partial nonresponse is defined as a ≥ 2 log reduction in HCV RNA level from baseline but detectable HCV RNA at week 12 and 24 (Table 6). PREDICTORS OF TREATMENT RESPONSES HCV genotype 3 [259], liver cirrhosis [259], previous treatment failure [259], and RAV [233,260] are predictive factors for decreased SVR when treated with DAAs. In cases of combination treatment of PegIFN-α and ribavirin, the strongest pretreatment predictors of an SVR include HCV genotype [254,261,262], degree of hepatic fibrosis [263], and IL28B genetic polymorphism [263,264]. The SVR rates are 40-60% in HCV genotype 1 patients and 70-80% in HCV genotypes 2 and 3 patients [254,265]. Patients with F0-F2 fibrosis have a 2.7-fold higher SVR rate than those with F3-F4 fibrosis [263]. The SVR rates are 2.4-2.7-fold higher in patients with a viral load of <400,000-800,000 IU/mL compared to those with a viral load of >800,000 IU/mL [250,263,266]. SVR rates are lower in older patients (>40 years) [254], African-Americans [267], body weight >70 kg [254,261], and insulin resistance [268,269]. SVR rates vary depending on SNP of IL28B, in other words, a C or T allele at the rs12979869 locus [270]. The SVR rates of HCV genotype 1 Caucasian patients are 69%, 33%, and 27% in CC homozygotes, CT heterozygotes, and TT homozygotes, respectively. The SVR rates of HCV genotype 1 African-American patients are 48%, 15%, and 13% [263,271]. The SVR rates of HCV genotype 1 Korean patients are 73-88% in CC homozygotes and 0-40% in CT heterozygotes [272-274]. The prevalence of the IL28B genetic polymorphism varies among ethnicities. CC homozygotes in Korea account for 88-89% [272-274], compared to 17% in African-Americans, and 37% in Caucasians [263]. Therefore, the usefulness of the IL28B genetic polymorphism as a predictive factor is limited as over 90% of the population of Korea are CC homozygotes. During combination treatment with PegIFN-α and ribavirin, a RVR is the strongest on-treatment predictor for an SVR [250-252], and an SVR rate increases ninefold with a RVR [263]. Meanwhile, an EVR is a strong negative predictor for an SVR. Without EVR, the SVR rate is only 3% [255]. In addition, SVR rates increase when medication adherence is higher than 80% [275], so assessment and maintenance of medication adherence can increase the SVR rate. NEW DRUGS, DIRECT-ACTING ANTIVIRALS (DAA) DAA acts at a specific step of the viral life cycle. DAAs include NS3/4A protease inhibitors (PI), NS5A inhibitors, and NS5B polymerase inhibitors. NS3/4A PI is a first-generation DAA and blocks the polyprotein processing essential for HCV replication. To date, available drugs are boceprevir, telaprevir, simeprevir, asunaprevir, and paritaprevir. NS5A inhibitors, such as daclatasvir, ledipasvir or ombitasvir, affect various HCV genotypes and show a synergistic effect in combination with other DAAs. The NS5B polymerase inhibitors are divided into nucleoside polymerase inhibitors (sofosbuvir) and non-nucleoside polymerase inhibitors (dasabuvir, beclabuvir). Because the basic characteristics of each DDA differ, selection and use of the appropriate drugs should take into consideration hepatic and renal function. DAA regimens may have a risk of interactions with other medications used by patients. Prior to starting treatment, patients should be evaluated for potential drug-drug interactions with selected DAAs. A more comprehensive list of drug-drug interactions is available at several websites, such as www.hep-druginteractions.org. [Recommendations] 1. The characteristics of the DAAs should be understood, and the appropriate drugs selected taking into consideration hepatic and renal function (A1). 2. The potential for drug-drug interactions must be considered before and during treatment with DAAs. The full prescribing information must be consulted prior to use of DAAs due to the potential for drug-drug interactions (A1). Simeprevir Simeprevir is a HCV NS3/4A protease inhibitor. 1. Dosage and administration One 150 mg capsule is taken orally once daily with food. 2. Pharmacokinetics Simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A system. Elimination of simeprevir occurs via biliary excretion. Renal clearance plays an insignificant role in its elimination. Therefore, no dose adjustment of simeprevir is needed in patients with mild, moderate or severe renal impairment. Compared to HCV-uninfected subjects with normal hepatic function, the mean steady-state AUC of simeprevir was higher in HCV-uninfected subjects with moderate hepatic impairment (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C). Simeprevir has not been extensively studied in such patients, but has been used in real-life settings. 3. Drug-drug interactions Co-administration of simeprevir with substances that are moderate or strong inducers or inhibitors of CYP3A4 is not recommended as this may lead to significantly lower or higher exposure to simeprevir, respectively. A number of compounds are contraindicated in patients receiving simeprevir, including anticonvulsants (carbamazepine, phenobarbital, phenytoin), antibiotics (erythromycin, clarithromycin), antimycobacterials (rifampin, rifabutin, rifapentine), antifungals (itraconazole, ketoconazole, fluconazole, voriconazole), dexamethasone, cisapride, herbal products (milk thistle, St John’s wort) and antiretroviral drugs (cobicistat-based regimens, efavirenz, etravirine, nevirapine, ritonavir). Simeprevir does not require dose changes in combination with the immunosuppressants tacrolimus and sirolimus. In contrast, it is not recommended to co-administer simeprevir with cyclosporine, as this can result in significantly increased plasma concentrations of simeprevir. Dose adjustments are needed with some antiarrhythmics, warfarin, calcium-channel blockers, HMG Co-A reductase inhibitors and sedative/anxiolytics. 4. Adverse reactions and safety Most common adverse reactions in patients receiving simeprevir, PegIFN-α and ribavirin were rash (including photosensitivity), pruritus and nausea. Transient hyperbilirubinemia was observed, but it was not associated with elevations in liver transaminase levels. Asunaprevir Asunaprevir is a HCV NS3/4A protease inhibitor. 1. Dosage and administration One 100 mg capsule is taken orally twice daily with or without food. 2. Pharmacokinetics Asunaprevir undergoes oxidative metabolism primarily mediated by CYP3A. Following single-dose oral administration in healthy subjects, 84% of it was recovered in feces and less than 1% was recovered in the urine. No dosage adjustment is required for patients with mild and moderated renal impairment (eGFR 30-80 mL/min/1.73 m2). Dosage adjustment of asunaprevir to 100mg once daily is recommended for patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) not receiving hemodialysis. No dose adjustment of asunaprevir is required for patients with mild hepatic impairment. Asunaprevir is contraindicated for patients with moderate or severe hepatic impairment (Child Pugh B or C), because steady state exposure was markedly higher in those patients. 3. Drug-drug interactions Co-administration asunaprevir with moderate or strong inducers or inhibitors of CYP3A is not recommended, as this may decrease or increase the plasma levels of asunaprevir. Furthermore, co-administration of asunaprevir with strong inhibitors of organic anion-transporting polypeptide (OATP)-mediated transport (e.g. rifampin, cyclosporine, sirolimus, gemfibrozil) is not recommended because this may increase the plasma concentration of asunaprevir and decrease its therapeutic effect. 4. Adverse reactions and safety The most common adverse events were headache, fatigue, diarrhea, and nausea. ALT or AST elevations (3-4%) were reported in clinical trials of asunaprevir-containing regimens. Daclatasvir Daclatasvir is a HCV NS5A inhibitor. 1. Dosage and administration One 60 mg tablet is taken orally once daily with or without food. If a reduced dose is needed, one 30 mg tablet is taken once daily. 2. Pharmacokinetics Daclatasvir is a substrate of CYP3A. Following single-dose oral administration in healthy subjects, 88% of the dose was recovered in feces and 6.6% was excreted in the urine. No dosage adjustment of daclatasvir is required for patients with any degree of renal impairment. Hepatic impairment does not have a clinically significant effect on the free drug concentrations of daclatasvir. Thus, no dosage adjustment of daclatasvir is required for patients with any degree of hepatic impairment. 3. Drug-drug interactions Co-administration of daclatasvir with substances that are moderate or strong inducers or inhibitors of CYP3A4 is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively. 4. Adverse reactions and safety The most common adverse reactions observed with daclatasvir in combination with asunaprevir were headache, fatigue, diarrhea, nausea and elevation of ALT. Sofosbuvir Sofosbuvir is a HCV nucleotide analog NS5B polymerase inhibitor. 1. Dosage and administration One 400 mg tablet is taken orally once daily with or without food. 2. Pharmacokinetics Sofosbuvir is extensively metabolized in the liver. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Following a single 400 mg oral dose, approximately 80% and 14% is respectively recovered in urine and feces. No dosage adjustment of sofosbuvir is required for patients with mild or moderate renal impairment (eGFR 30-80 mL/min/1.73 m2). No dosage recommendation can be provided for patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) or end-stage renal disease. No dosage adjustment of sofosbuvir is required for patients with hepatic impairment. 3. Drug-drug interactions Sofosbuvir is a substrate of the drug transporter P-gp. Drugs that are P-gp inducers in the intestine (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) may decrease sofosbuvir plasma concentration, leading to a reduced therapeutic effect, and thus concomitant use with sofosbuvir is not recommended. In addition, since serious symptomatic bradycardia may occur, co-administration of amiodarone with sofosbuvir in combination with another DAA, such as daclatasvir, simeprevir or ledipasvir, is contraindicated. 4. Adverse reactions and safety The most common adverse reactions observed with sofosbuvir in combination with ribavirin were fatigue and headache. The most common adverse events observed with sofosbuvir, PegIFN-α and ribavirin were fatigue, headache, nausea, insomnia and anemia. Ledipasvir/Sofosbuvir Ledipasvir/sofosbuvir is a fixed-dose combination of ledipasvir, a HCV NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor. 1. Dosage and administration One tablet (90 mg of ledipasvir and 400 mg of sofosbuvir) is taken orally once daily with or without food. 2. Pharmacokinetics In vitro, no detectable metabolism of ledipasvir by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 was observed. Evidence of slow oxidative metabolism via an unknown mechanism has been reported. Biliary excretion of unchanged ledipasvir is a major route of elimination, with renal excretion being a minor pathway. No dose adjustment is required for patients with mild or moderate renal impairment (eGFR 30-80 mL/min/1.73 m2), but no dose recommendation can currently be provided for patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) or with end-stage renal disease (ESRD). No dosage adjustment of ledipasvir/sofosbuvir is required for patients with hepatic impairment. 3. Drug-drug interactions Ledipasvir is an inhibitor of the drug transporter P-gp and may increase intestinal absorption of co-administered substrates of these transporters. Thus, caution is needed with P-gp substrates such as digoxin and dabigatran such as digoxin and dabigatran, but also potentially with other drugs that are, in part, transported by these proteins (e.g. aliskiren, amlodipine, buprenorphine, carvedilol, cyclosporine). Co-administration of amiodarone (and possibly dronedarone) with sofosbuvir/ledipasvir is contraindicated due to a serious risk of symptomatic bradycardia. Co-administration of sofosbuvir/ledipasvir with rosuvastatin may significantly increase the concentration of rosuvastatin, which is associated with an increased risk of myopathy, including rhabdomyolysis. Co-administration of sofosbuvir/ledipasvir with rosuvastatin is not recommended. The solubility of ledipasvir decreases with increasing pH. Drugs that increase gastric pH (e.g., antacids, H2-receptor antagonists, or proton pump inhibitors) are expected to decrease the concentration of ledipasvir. Because sofosbuvir/ledipasvir increases the tenofovir concentration when a pharmacokinetic enhancer (ritonavir or cobicistat) is present in an antiretroviral regimen, these combinations should be used with caution, with frequent renal monitoring if other alternatives are not available. 4. Adverse reactions and safety The most common adverse reactions observed with ledipasvir/sofosbuvir were fatigue, headache, nausea, diarrhea and insomnia. Ombitasvir/paritaprevir/ritonavir and dasabuvir Ombitasvir/paritaprevir/ritonavir and dasabuvir (Opr+D) includes ombitasvir, a HCV NS5A inhibitor, paritaprevir, a HCV NS3/4A protease inhibitor, ritonavir, a CYP3A inhibitor and dasabuvir, a HCV non-nucleoside NS5B palm polymerase inhibitor. 1. Dosage and administration Two ombitasvir, paritaprevir, ritonavir 12.5/75/50 mg tablets once daily (in the morning) and one dasabuvir 250 mg tablet twice daily (morning and evening) are taken orally with a meal. 2. Pharmacokinetics Ombitasvir is predominantly metabolized by amide hydrolysis followed by oxidative metabolism. Paritaprevir is predominantly metabolized by CYP3A4 and dasabuvir is predominantly metabolized by CYP2C8. Paritaprevir and ombitasvir are excreted predominantly into the feces. Dasabuvir is metabolized in the liver, and its predominant metabolite is cleared mainly via biliary excretion and fecal elimination with minimal renal clearance. No dosage adjustment is required in patients with mild, moderate or severe renal impairment. It has not been studied in patients on dialysis. No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh A). However, it is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C). 3. Drug-drug interactions Co-administration of Opr+D can alter the plasma concentrations of some drugs and some drugs may alter the plasma concentrations of Opr+D. The potential for drug interactions must be considered before and during treatment. Co-administration of Opr+D with drugs that are highly dependent on CYP3A for clearance; moderate or strong inducers of CYP3A and strong inducers of CYP2C8; and strong inhibitors of CYP2C8 is not recommended. 4. Adverse reactions and safety The most commonly reported adverse reactions were nausea, pruritus, and insomnia. TREATMENT OF CHRONIC HEPATITIS C Recently, there has been marked improvement in the treatment of chronic hepatitis C, which is sufficient to be called a paradigm shift. The effectiveness of the combined administration of PegIFN-α and ribavirin, which was the previous standard treatment, has been decreased due to its relatively low treatment effects and severe side effects. Furthermore, the combined administration of PegIFN-α/ribavirin and the first-generation NS3/4A PI (boceprevir, telaprevir) was also limited due to high cost, drug resistance and exacerbated side effects. DAA acts on a specific part of the HCV non-structural (non-structural, NS) protein, blocking HCV replication and it is classified as a NS3/4A PI, NS5A inhibitor and NS5B nucleos(t)ide/non-nucleoside polymerase inhibitor based on its mechanism and target. Since drugs show advantages and disadvantages, use of a combination of two or more DAAs with different targets or addition of ribavirin in a difficult-to-treat patient shows an SVR rate of ~90% after 12 weeks of treatment or expanded treatment for 24 weeks. In Korea, boceprevir was approved in May 2014 by the Ministry of Food and Drug Safety as a DAA for the treatment of chronic hepatitis C. Daclatasvir (NS5A inhibitor), asunaprevir (second-generation PI), sofosbuvir (NS5B nucleotide polymerase inhibitor), and ledipasvir (NS5A inhibitor)/sofosbuvir, which administered as a fixed-dose in a single tablet, have been approved up to November 2015. Various types of DAA are awaiting approval which will improve the treatment of chronic hepatitis C. However, high costs, drug resistance and interactions between various drugs remain to be overcome. Initially, the combined administration of PegIFN-α and ribavirin showed good treatment effects in some genotypes, is less expensive than DAA and is useful in situations where DAAs cannot be used. Hopefully, DAAs with excellent cost-effectiveness, shorter treatment duration, effective in broad spectrum of patients, less side effects and minimal drug-drug interactions will be available in the near future. TREATMENT OF HCV GENOTYPE 1 INFECTION Initial treatment The SVR rate was 99% in 865 treatment-naïve patients with HCV genotype 1 infection who received ledipasvir/sofosbuvir for 12 weeks. There were no additional benefits when ribavirin was added or the duration of treatment was extended to 24 weeks [276]. No significant difference in SVR rate was found according to age, baseline HCV RNA level, presence of cirrhosis, IL28B genotype, or HCV gene sub-genotype (1a or 1b). RAVs of ledipasvir at baseline were detected in 16% of the patients, but had no significant effect on the treatment result [277]. In a study involving patients with baseline HCV RNA levels of <6,000,000 IU/mL, the SVR rates were 97% in those who received 8 weeks of combination therapy with ledipasvir/sofosbuvir plus ribavirin and 96% in those who received 12 weeks of ledipasvir/sofosbuvir, suggesting a shortened treatment duration in some patients [278]. In an integrated analysis of 513 patients with genotype 1 compensated liver cirrhosis who received a combination of ledipasvir/sofosbuvir plus ribavirin or ledipasvir/sofosbuvir, the SVR rates were 95% in those who received the therapy for 12 weeks and 98% in those who received it for 24 weeks, showing no additional benefit in previously untreated patients with liver cirrhosis of ribavirin addition or extension of treatment duration to 24 weeks [279]. In treatment-naïve patients without cirrhosis treated with ombitasvir/paritaprevir/ritonavir and dasabuvir (Opr+D) together with ribavirin for 12 weeks, the SVR rates were 95% (307/322) in genotype 1a and 98% (148/151) in genotype 1b patients [280]. To evaluate the importance of ribavirin administration with Opr+D, phase 3 trials were conducted in treatment-naïve, non-cirrhotic patients with genotype 1a and 1b [281]. Patients with HCV genotype 1b were randomly assigned to receive Opr+D alone (n=209) or with ribavirin (n=210) for 12 weeks. Only three of 419 patients in the trial failed treatment; the SVR rate was 99% in both groups. On the other hand, of 205 patients with HCV genotype 1a randomly assigned to receive Opr+D alone for 12 weeks, 185 (90%) achieved SVR; this rate was significantly lower than that observed in patients treated with Opr+D plus ribavirin (97%), emphasizing the importance of ribavirin co-administration when Opr+D is prescribed to patients with HCV genotype 1a. In treatment-naïve patients with compensated cirrhosis, SVR rates were 92% and 93% in patients infected with genotype 1a and 100% in patients infected with genotype 1b when treated with Opr+D plus ribavirin for 12 and 24 weeks, respectively [282]. Recently, the Opr+D regimen, without ribavirin, for 12 weeks achieved a 100% SVR in 60 genotype 1b patients with compensated cirrhosis, including treatment-experienced patients [283]. On the basis of this study, treating patients infected with genotype 1b with Opr+D without ribavirin for 12 weeks is recommended, irrespective of the presence of cirrhosis or prior treatment experience. In treatment-naïve HCV genotype 1b patients treated with daclatasvir and asunaprevir for 24 weeks, the SVR rate was 90% [233]. Among Korean patients, 95% (20/21) achieved a SVR [284]. There were no differences in SVR rates based on sex, age, race, IL28B genotype, or presence of cirrhosis. However, multivariate regression analysis of baseline factors identified the presence of NS5A RAVs L31F/I/M/V and/or Y93H as negative predictors of SVR. Also, pooled data from five clinical studies of DCV and ASV in HCV genotype 1b patients show that the presence of the NS5A RAVs L31F/I/M/V and/or Y93H at baseline was associated with a reduced SVR (range: 36.9-41.9%), while SVR rates in the absence of these RAVs were high (range: 88.0-93.9%) [163]. Pretreatment NS5A RAVs L31F/I/M/V and/or Y93H were present in 12.6-14.4% of HCV genotype 1b patients. Therefore, this combination is not recommended in patients with detectable NS5A RAVs L31F/I/M/V and/or Y93H at baseline. In a study carried of combination treatment of sofosbuvir and simeprevir for 12 weeks or 24 weeks, the SVR rate of all patients was 92% (154/167 patients), and there was no difference in SVR rate according to treatment duration (12 or 24 weeks), addition of ribavirin or fibrotic stage. However, the treatment effect of genotype 1a patients with Q80K RAV was lower in comparison to patients with no RAV (88% vs. 94%) [285]. In a recent phase 3 study, the SVR rate of genotype 1 patients without liver cirrhosis was 97% (150/155), and there was no difference according to the subgenotype [286]. In a study carried out on 103 patients with liver cirrhosis, the SVR rate was 84% (86/103), and there was no difference according to sub-genotype [287]. In a real-life study, the SVR rate of 276 (including 132 treatment-naïve) patients was 82%, and among them, the SVR rate of those with liver cirrhosis was ~10% lower (88% vs. 75%) [288]. In an open-label study of 111 treatment-naïve patients receiving treatment with daclatasvir and sofosbuvir with or without ribavirin, SVR was achieved in 98% irrespective of treatment duration [234]. Treatment with a combination of sofosbuvir and PegIFN-α plus ribavirin for 12 weeks resulted in an 89% SVR rate among 291 previously untreated patients with genotype 1 [259]. In a study that compared combination therapy with sofosbuvir and PegIFN-α plus ribavirin using treatment durations of 12 and 24 weeks, the SVR rate in both groups was 89%. Treatment for 24 weeks had no additional benefit compared with treatment for 2 weeks [289]. When combination treatment of simeprevir with PegIFN-α and ribavirin was carried out for 12 weeks, followed by combination treatment of PegIFN-α and ribavirin for 12 or 36 weeks according to the therapeutic response (response-guided therapy) in a study of 305 (including 60 Korean) patients, the SVR rate was 90%. In another study of 264 patients, the SVR rate was 80% (1b: 90% [105/117], 1a: 71% [105/147]) using the same regimen. Among genotype 1a patients, the SVR rate of those with Q80K RAV was 52% (31/60), and that of patients with no RAV was 85% (73/86), which was similar to the result of genotype 1b patients. However, the SVR rate of 31 patients with liver cirrhosis was 58% (18/31) [290,291]. SVR rates in Europe and the US were reported as 40-50% when HCV genotype 1 patients were treated with PegIFN-α and ribavirin [292]. SVR rates in South Korea were reported higher; 53.6-69.5% [293-297] and 62.7% in a pooled analysis of 10 studies [298]. This is related to the higher frequency of favorable IL28B genotypes in Koreans than in Caucasians or African-Americans [83]. Patients with genotype 1 who achieve a RVR and had a low baseline viral load (<400,000 IU/mL) may have their duration of therapy shortened to 24 weeks if there are no negative predictors of response, such as advanced liver fibrosis, cirrhosis, obesity, or insulin resistance [249]. Treatment should be stopped in patients who do not achieve an EVR, as the SVR rate in these patients using the standard treatment duration is <3%, and in patients with pEVR and detectable HCV RNA at week 24, as the SVR rate is 2-4% [254,299]. Retreatment of treatment-experienced patients Few Korean HCV patients have experience of PI, except for those who participated in clinical trials. Therefore, in the current guidelines, “treatment-experienced patients” refer to the patients treated with conventional interferon or PegIFN-α in combination with ribavirin, not including DAAs. These include patients who previously received treatment but failed to achieve an SVR due to various factors (e.g., non-response or partial response to treatment, relapse, virological breakthrough, and drug adverse events or low compliance). In addition, in the case of genotype 1 with an undistinguishable sub-genotype, treatment is to be given in accordance with genotype 1a and drugs that can be used unrelated to sub-genotypes are recommended. Of 440 patients treated with ledipasvir/sofosbuvir for 12 weeks, 44% were un-responsive to prior treatment and 53% had prior PI treatment failure, resulting in a 94% SVR rate, showing no significant difference between treatment with a combination of ledipasvir/sofosbuvir plus ribavirin for 12 weeks (SVR rate 96%) and treatment with ledipasvir/sofosbuvir for 24 weeks (SVR rate 99%) [300]. NS5A RAVs at baseline were detected in 14% of the patients, of whom 89% showed a treatment response. Baseline viral load, age, presence of liver cirrhosis, IL28B genotype, and subgenotype had no significant effect on treatment response. In a Korean study of 93 patients (46 treatment-naïve patients and 47 patients with prior treatment failure), including previously treated patients, the SVR rates were 99% (92/93) when they were given ledipasvir/sofosbuvir for 12 weeks and 100% (17/17) among patients with cirrhosis who received the same regimen. In that study, NS5A RAVs at baseline were detected in 22% of the patients, of whom 95% showed a treatment response [301]. In addition, in another study, treatment with ledipasvir/sofosbuvir for 12 weeks resulted in a treatment response in all 341 previously treated patients, including patients with cirrhosis [302]. In an integrated analysis of patients with compensated cirrhosis, the SVR rates were 90% (162/171) when ledipasvir/sofosbuvir was administered for 12 weeks, 96% (174/181) when a combination of ledipasvir/sofosbuvir plus ribavirin was administered for 12 weeks, 98% (98/100) when ledipasvir/sofosbuvir was administered for 24 weeks, and 100% (22/22) when ledipasvir/sofosbuvir plus ribavirin was administered for 24 weeks. Therefore, addition of ribavirin or extension of treatment duration was more effective [279]. Treatment with a combination of ledipasvir/sofosbuvir plus ribavirin for 12 weeks resulted in a 96% SVR rate among 155 patients with cirrhosis who had treatment failure after the treatment with combination of PegIFN-α and ribavirin, followed by retreatment failure, including PI. This is similar to the results of treatment with ledipasvir/sofosbuvir for 24 weeks, which resulted in a 97% SVR rate [303]. The combination of ombitasvir/paritaprevir/ritonavir and dasabuvir (Opr+D) plus ribavirin for 12 weeks was evaluated in 297 non-cirrhotic patients in whom previous PegIFN-α and ribavirin therapy failed [304]. The SVR rate was 96%, and did not differ according to sub-genotypes, or types of treatment failure. To evaluate the importance of ribavirin in non-cirrhotic, treatment-experienced patients with HCV genotype 1b infection, 179 patients in whom previous therapy with PegIFN-α and ribavirin failed were treated with Opr+D with or without ribavirin for 12 weeks [305]. SVR rates were high in both arms: 100% (91/91) in the ribavirin-free arm and 96.6% (85/88) in the ribavirin-containing arm, supporting the recommendation that Opr+D may be used without ribavirin for patients with HCV genotype 1b infection. Among treatment-experienced patients with compensated cirrhosis, SVR rates were 86% and 93% in those infected with genotype 1a and 98% and 100% in patients infected with genotype 1b when treated with Opr+D plus ribavirin for 12 and 24 weeks, respectively [282]. Recently, treatment using the Opr+D regimen, without ribavirin, for 12 weeks achieved a 100% SVR in 60 genotype 1b patients with compensated cirrhosis, including treatment-experienced patients [283]. In treatment-experienced HCV sub-genotype 1b patients treated with daclatasvir and asunaprevir for 24 weeks, the SVR rates were 82% in non-responder patients and 82% in interferon-ineligible/intolerant patients [233]. The SVR rate was higher in treatment-naïve patients versus experienced patients. In 44 Korean treatment-experienced HCV genotype 1b patients, an SVR was achieved by 70% of non-responder patients and 86% of interferon-ineligible/intolerant patients [284]. In an open-label, phase 3, Japanese study, an SVR was achieved in 87% of patients who were ineligible or intolerant to interferon-based therapy and in 81% of patients who had not responded to treatment previously [306]. There were no differences in SVR rates based on sex, age, race, IL28B genotype, or presence of cirrhosis. The SVR rate of patients who showed no response to the previous combination treatment of PegIFN-α and ribavirin was 91-95%, similar to that of patients without experience of combination treatment with sofosbuvir and simeprevir. However, the treatment-experienced patients with liver cirrhosis showed a lower SVR rate than treatment-naïve patients (79% vs. 88%) [285-287]. In an open-label study, 41 patients for whom treatment including PegIFN-α –based therapy and a first-generation PI had failed were treated for 24 weeks with daclatasvir and sofosbuvir without ribavirin (n = 20) and with ribavirin (n = 21) [234]. The SVR rate was 98%. In a real-life French cohort, 409 HCV genotype 1 patients (307 treatment-experienced including a first-generation PIs, 319 patients with cirrhosis) were treated with daclatasvir and sofosbuvir with or without ribavirin for 12 or 24 weeks [307]. Overall, SVR rates for daclatasvir and sofosbuvir without ribavirin were 85% after 12 weeks of treatment and 93% following 24 weeks of treatment. The SVR rates for daclatasvir and sofosbuvir with ribavirin were 100% and 98% after 12 and 24 weeks, respectively. When combination treatment of simeprevir with PegIFN-α and ribavirin was carried out for 12 weeks in relapsed patients, followed by combination treatment of PegIFN-α and ribavirin for 12 or 36 weeks according to the therapeutic responses (response-guided therapy), the SVR rate was 79% (206/260), and among them, genotype 1b showed 86% and 1a showed 70% [260]. The SVR rate of patients who showed a partial response to previous treatments was 70% (101/145), and that of patients who showed no response to previous treatments (non-responders) was 44% (102/234), indicating that this regimen showed a very low therapeutic effect in patients who did not respond to previous treatments [308]. [Recommendations] (Table 7) Initial treatment of HCV genotype 1 infection 1. Patients infected with HCV genotype 1 with or without cirrhosis should be treated with daily ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks, regardless of sub-genotype (A1). 2. Patients infected with HCV genotype 1b with or without cirrhosis should be treated with daily ombitasvir (25 mg)/paritaprevir (150 mg)/ritonavir (100 mg) plus dasabuvir (500 mg) for 12 weeks (A1). 3. Patients infected with HCV genotype 1a without cirrhosis should be treated with daily ombitasvir (25 mg)/paritaprevir (150 mg)/ritonavir (100 mg) plus dasabuvir (500 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 12 weeks (A1). Duration of therapy should be extended to 24 weeks in patients with liver cirrhosis (A1). 4. Patients infected with HCV genotype 1b with or without cirrhosis should be treated with daily daclatasvir (60 mg) and asunaprevir (200 mg) for 24 weeks. Patients infected with HCV genotype 1b in whom treatment with daclatasvir and asunaprevir is considered must be tested for NS5A RAVs L31F/I/M/V and/or Y93H prior to treatment. Patients with NS5A RAVs L31F/I/M/V and/or Y93H should be treated with an alternative regimen (A1). 5. Patients infected with HCV genotype 1 without cirrhosis should be treated with daily sofosbuvir (400 mg) and simeprevir (150 mg) for 12 weeks, regardless of sub-genotype (A1). Addition of daily weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) is recommended in patients with cirrhosis (B1). Extending treatment to 24 weeks is recommended for patients with cirrhosis in whom use of ribavirin is contraindicated (B1). 6. Patients infected with HCV genotype 1 without cirrhosis should be treated with daily daclatasvir (60 mg) and sofosbuvir (400 mg) for 12 weeks, regardless of sub-genotype (A1). Adding daily weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) is recommended for patients with cirrhosis (B1). Extending treatment to 24 weeks is recommended for patients with cirrhosis in whom use of ribavirin is contraindicated (B1). 7. Patients infected with HCV genotype 1 with or without cirrhosis should be treated with daily sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) plus weekly PegIFN-α for 12 weeks (A2). 8. Treatment with one of two PegIFN-α molecules in combination with ribavirin should be planned for 48 weeks (A2). PegIFN-α 2a should be injected 180 μg subcutaneous once a week, regardless of patient body weight with ribavirin using doses of 1,000 mg/d for those ≤ 75 kg in weight and 1,200 mg/day for those > 75 kg. PegIFN-α 2b is to be injected 1.5 μg/kg/week with ribavirin using doses of 800 mg for those < 65 kg in weight, 1,000 mg for 65-85 kg, 1,200 mg for 85-105 kg, and 1,400 mg for > 105 kg. In patients with a RVR and low baseline HCV viral load (<400,000 IU/mL), and without any negative predictors of SVR (advanced liver fibrosis, cirrhosis, obesity or insulin resistance), shortening of treatment duration to 24 weeks can be considered (B1). Treatment should be stopped in patients who fail to achieve an EVR (A1). Patients who achieve a cEVR can be treated for 48 weeks (A1). Patients with a pEVR should be re-tested at week 24; if HCV RNA remains positive, treatment should be stopped (A1). Retreatment of treatment-experienced patients with HCV genotype 1 (In this guideline, “treatment-experienced patients” refer to patients who have been treated with conventional interferon or PegIFN-α and ribavirin, not including DAAs. These include patients who previously underwent treatment but failed to reach SVR due to various factors (e.g., non-response or partial response to treatment, relapse, virological breakthrough, and drug adverse events or low compliance). In addition, in the case of genotype 1 with an undistinguishable sub-genotype, treatment is to be given in accordance with genotype 1a and drugs that can be used unrelated to sub-genotype are recommended.) 1. Treatment-experienced patients infected with HCV genotype 1 without cirrhosis should be treated with daily ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks, regardless of sub-genotype (A1). Duration of therapy should be extended to 24 weeks in patients with liver cirrhosis (A1). Addition of daily weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) without extending treatment duration can also be recommended (B1). 2. Treatment-experienced patients infected with HCV genotype 1b with or without cirrhosis should be treated with daily ombitasvir (25 mg)/paritaprevir (150 mg)/ritonavir (100 mg) plus dasabuvir (500 mg) for 12 weeks (A1). 3. Treatment-experienced patients infected with HCV genotype 1a without cirrhosis should be treated with daily ombitasvir (25 mg)/paritaprevir (150 mg)/ritonavir (100 mg) plus dasabuvir (500 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 12 weeks (A1). Duration of therapy should be extended to 24 weeks in patients with cirrhosis (A1). 4. Treatment-experienced patients infected with HCV genotype 1b with or without cirrhosis should be treated with daily daclatasvir (60 mg) and asunaprevir (200 mg) for 24 weeks. Patients infected with HCV genotype 1b in whom treatment with daclatasvir and asunaprevir is considered must be tested for the NS5A RAVs L31F/I/M/V and/or Y93H prior to treatment. Patients with the NS5A RAVs L31F/I/M/V and/or Y93H should be treated with an alternative regimen (A1). 5. Treatment-experienced patients infected with HCV genotype 1 without cirrhosis should be treated with daily sofosbuvir (400 mg) and simeprevir (150 mg) for 12 weeks, regardless of sub-genotype (A1). Addition of daily weightbased ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 12 weeks is recommended (B1). Extending treatment to 24 weeks is recommended for patients with cirrhosis in whom use of ribavirin is contraindicated (B1). 6. Treatment-experienced patients infected with HCV genotype 1 without cirrhosis can be treated with daily daclatasvir (60 mg) and sofosbuvir (400 mg) for 12 weeks, regardless of sub-genotype (B1). Addition of daily weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) is recommended for patient with cirrhosis (B1). Extending treatment to 24 weeks is recommended for patients with cirrhosis in whom use of ribavirin is contraindicated (B1). TREATMENT OF HCV GENOTYPE 2 INFECTION Initial treatment In the FISSION study in which treatment-naïve chronic HCV genotype 2 patients were treated with sofosbuvir and weight-based ribavirin for 12 weeks, the SVR rate was 97% (68/70) [259]. This was significantly higher than that of 24 weeks of treatment using PegIFN-α and ribavirin, which showed an SVR rate of 78% (52/67) [259]. In addition, the results of a Korean phase III trial of 12 weeks of sofosbuvir and ribavirin treatment demonstrated an SVR rate of 97% [309]. Extending treatment in patient with advanced fibrosis is short of solid evidences. Although the FISSION study reported liver cirrhosis to be a significant adverse factor for an SVR, the analysis was not stratified for genotype 2 patients [259]. On the hands, another study suggested that treatment-experienced genotype 2 patients may benefit from extending treatment to 16 weeks, overcoming the negative effect of liver cirrhosis [310]. Another Korean phase III trial reported an SVR rate of 100% in 13 cirrhotic genotype 2 patients [309]. However, since liver cirrhosis inhibits achieving an SVR in many cases, extending treatment to 16 weeks in cirrhotic genotype 2 HCV patients is recommended until more data are available. Reports of daclatasvir and sofosbuvir treatment in chronic HCV genotype 2 patients are scarce. Two recent studies involving treatment of HIV and HCV genotype 2 co-infected treatment-naïve patients for 12 or 24 weeks reported 100% SVR rates [234,311]. Since the numbers of patients in these studies were 11 and 14, respectively, evidence supporting the use of daclatavir and sofosbuvir is insufficient. However, in treatment-naïve HCV genotype 2 patients in whom ribavirin cannot be used, 12 weeks of treatment with daclatavir and sofosbuvir may be an alternative regimen. PegIFN-α based therapy in treatment naïve genotype 2 patients consists of any one of two PegIFN-α combined with ribavirin for 24 weeks [254,261,262,312-314]. PegIFN-α 2a 180 μg should be injected subcutaneously once a week, regardless of body weight, whereas PegIFN-α 2b is to be injected 1.5 μg/kg subcutaneously once a week. Ribavirin is to be given at a flat dose of 800 mg daily, regardless of the type of PegIFN-α used [261,262,312]. There is a lack of evidence showing that a weight-based dose of ribavirin is more effective in achieving SVR for HCV genotype 2 patients. The SVR rate of HCV genotype 2 Korea patients treated with PegIFN-α and ribavirin exceeded 80% [296,315]. Regarding factors predicting relapse after treatment other than duration of therapy, existence of cirrhosis, baseline high viral load, body weight, gender, and old age have been suggested [266,316-318]. However, studies contradicting these results also exist, and further research is required [319-321]. Due to the high SVR rate after PegIFN-α and ribavirin combination treatment in genotype 2 patients, studies on factors predicting an SVR may require a relatively large sample size [322]. A recent large-scale study reported that advanced liver fibrosis had a significant effect on achieving an SVR [323]. Studies of shortened treatment duration in PegIFN-α and ribavirin combination therapy are of heterogeneous design regarding treatment duration, ribavirin dose and use of RVR, and thus should not be compared directly [266,316,317,319,320,324-326]. A study comparing 16 and 24 weeks of therapy in which each group contained ~350 patients, reported an SVR rate of 65% in the 16-week treatment group compared to 82% in the 24-week treatment group [320]. However, shortening of the treatment duration was not performed according to the on-treatment response, RVR, instead being randomly assigned in this study. Another study compared 16- and 24-week treatment groups of 200 HCV genotype 2 patients each, and reported an SVR rate of 81% in the 16-week group and 92% in the 24-week group, with no significant difference [316]. However, the 16-week treatment group had a relapse rate of 17%, which was significantly higher than that of the 24-week treatment group, 5% [316]. In addition, it should be noted that this study used weight-based dose of ribavirin, which still resulted in a higher relapse rate when the treatment was shortened. In conclusion, patients with genotype 2 who achieve a RVR may have their duration of therapy shortened to 16 weeks only if there are no adverse predictors of response, such as advanced liver fibrosis, cirrhosis, and high baseline viral load, at the expense of a higher probability of post-treatment relapse. In patients with advanced liver fibrosis or cirrhosis, little evidence supports equal efficacy of shortened therapy. Studies of the efficacy of extended treatment up to 48 weeks in patients with negative predictors of a response have been performed. One study involving 1,311 HCV genotype 2 or 3 patients with negative predictors for SVR reported no benefit of extension of the treatment duration to 48 weeks in terms of achieving SVR [262]. Retreatment of treatment-experienced patients HCV genotype 2 patients in whom prior treatment with PegIFN-α and ribavirin failed can be retreated with sofosbuvir plus weight-based ribavirin. In a study in which treatment-experienced patients were given 12 weeks of sofosbuvir and ribavirin, the SVR rate was 93% (68/73) [327]. This study reported no significant difference in SVR rate according to the existence of liver cirrhosis or pre-treatment serum HCV RNA level. Another study compared 12 and 16 weeks of treatment, and reported SVR rates of 86.1% (31/36) and 93.8% (30/32) (95% confidence interval (CI), -24%-9%), respectively [310]. When cirrhotic patients were analyzed separately, the SVR rates after 12 and 16 weeks of treatment were 60.0% (6/10) and 77.8% (7/9) (95% CI, -58.0%-26.8%), respectively, whereas those in non-cirrhotic patients were 96.2% (25/26) and 100% (23/23) (95% CI, -20.2-11.3%) [310]. The BOSON study, in which sofosbuvir and ribavirin were given 16 or 24 weeks, reported an SVR rate of 94% (15/16) and 100% (17/17) [337]. In contrast, a phase III from Korea and Taiwan reported an SVR rate of 100% (66/66) after 12 weeks of sofosbuvir and ribavirin treatment, regardless of accompanying liver cirrhosis [309]. A Japanese study of 12-week treatment of sofosbuvir plus ribavirin showed an SVR rate of 95% (60/63) in treatment-experienced HCV genotype 2 patients [328]. This was comparable with the result in treatment-naïve Japanese patients, which was 98% (88/90) [328]. The presence of liver cirrhosis did not significantly affect the SVR rate. Current studies do not provide strong support for extending treatment duration in treatment-experienced, cirrhotic genotype 2 patients undergoing sofosbuvir plus ribavirin treatment. However, both experiencing treatment failure in prior therapy and having liver cirrhosis are important adverse factors for achieving an SVR, and extending treatment for 16-24 weeks is recommended until more data contradicting the benefit of this extension accumulate. Data on daclatavir plus sofosbuvir combination therapy in treatment-experienced genotype 2 patients are limited. Achievement of an SVR in two HIV and HCV genotype 2 co-infected patients whose prior treatment failed has been reported [311]. However, in cases in which ribavirin cannot be administered, 12 weeks of daclatavir plus sofosbuvir may be considered. Another treatment option for HCV genotype 2 patients with a prior treatment failure is PegIFN, sofosbuvir and weight-based ribavirin for 12 weeks. A study on this combination reported an SVR rate of 96% (22/23), which was not affected by the presence of liver cirrhosis [310]. Retreatment with PegIFN plus ribavirin can be considered in patients treated previously with conventional interferon with or without ribavirin, or PegIFN-α without ribavirin, and who failed to achieve SVR [329-335]. The SVR rate after retreatment with PegIFN and ribavirin in relapsers is reported to be ~50-70% [329,330,332,334,335]. The treatment is recommended for 24 weeks and the benefit of extending treatment to 48 weeks in these patients is unclear. For those who fail to achieve a SVR after PegIFN and ribavirin treatment, retreatment using the same regimen is not recommended as the SVR rate is reported to be as low as 10% [336]. Patients treated with either a conventional interferon-based regimen or PegIFN without ribavirin and failed to achieve an SVR can be retreated with the same DAA-containing regimen as can those in whom prior treatment with PegIFN plus ribavirin has failed. [Recommendations] (Table 8) Initial treatment of HCV genotype 2 infection 1. Patients infected with HCV genotype 2 without cirrhosis should be treated with daily weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) and sofosbuvir (400 mg) for 12 weeks (A1). Extension of treatment to 16 weeks is recommended for patients with cirrhosis (C1). 2. Patients infected with HCV genotype 2 with or without cirrhosis can be treated with daily daclatavir (60 mg) and sofosbuvir (400 mg) for 12 weeks (C1). 3. Treatment with PegIFN-α in combination with ribavirin can be given for 24 weeks. (A2) PegIFN-α 2a should be injected 180 μg subcutaneous once a week, regardless of patient body weight and PegIFN-α 2b is to be injected 1.5 μg/kg/week (A1). Daily administration of 800 mg of ribavirin can be performed, regardless of body weight (A2). In patients with an RVR who lack negative predictors for SVR, shortening of treatment duration to 16 weeks can be considered (B2). However, shortening of treatment duration should be done with caution, since this can result in a higher relapse rate (A2). Retreatment of treatment-experienced patients with HCV genotype 2 1. Treatment-experienced patients with HCV genotype 2 without cirrhosis should be treated with daily sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 12 weeks (A1). Duration of therapy should be extended to 16-24 weeks in patients with cirrhosis (A1). 2. Treatment-experienced patients with HCV genotype 2 with or without cirrhosis can be treated with daily daclatavir (60 mg) and sofosbuvir (400 mg) for 12 weeks (C1). 3. Treatment-experienced patients with HCV genotype 2 with or without cirrhosis can be treated with daily sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) plus weekly PegIFN-α for 12 weeks (B1). TREATMENT OF CHRONIC HCV GENOTYPE 3 INFECTION Initial treatment In a phase III study, 12 weeks of a daily sofosbuvir and weight-based ribavirin regimen for treatment-naïve patients with HCV genotype 3 infection was compared with a PegIFN-α and ribavirin combination regimen. The SVR rates were 56% (102/183) and 63% (110/176), respectively, which was not significantly different [259]. In contrast, in another phase III study, 105 treatment-naïve patients with HCV genotype 3 infection were administered sofosbuvir and ribavirin for 24 weeks, and showed an SVR of 94% (99/105) [327], which was superior to that of 12 or 16 weeks of treatment (62-63%) [259,337]. Since there were no differences in SVR rates according to the existence of liver cirrhosis in treatment-naïve patients with HCV genotype 3 infection, extension of the treatment duration might not be necessary [327]. A daily daclatasvir and sofosbuvir combination regimen for 12 weeks showed an SVR of 89% (16/19) in a phase II study of 19 treatment-naïve patients with HCV genotype 3 infection [234]. In a phase III study of 75 treatment-naïve genotype 3 patients, this regimen showed a good SVR of 97% (73/75) [338]. However, extension of the treatment period was to be considered in treatment-naïve patients with cirrhosis due to a significantly lower SVR of 58% (11/19) [339]. A recent European cohort study reported that a daclatavir and sofosbuvir regimen for 24 weeks resulted in a significantly higher SVR of 88% (52/59) than did 12 weeks of treatment, which had an SVR rate of 76% (22/29) [339]. Therefore, it was suggested that extension of treatment is beneficial in treatment-naïve cirrhotic patients. In addition, this study allowed addition of ribavirin to daclatavir and sofosbuvir according to the practitioner’s demand, and addition of ribavirin to patients with negative predictors of SVR might be beneficial [339]. Ledipasvir/sofosbuvir plus ribavirin for 12 weeks showed an excellent SVR of 100%, compared to ledipasvir/sofosbuvir without ribavirin for 12 weeks, which had an SVR rate of 64% [340]. However, since an in vitro pharmacodynamic study of ledipasvir reported lower suppression of HCV genotype 3, further research on this regimen is warranted [340]. PegIFN, sofosbuvir and weight-based ribavirin for 12 weeks showed an SVR of 90% in a phase II study of 10 non-cirrhotic and treatment-naïve HCV genotype 3 patients [341,342]. In a phase III study of 123 treatment-naïve patients, this regimen showed a high SVR of 95% (117/123) [340]. Moreover, since there was no significant difference in SVR rate between patients with and without liver cirrhosis (SVR of 91% vs. 96%, respectively), this regimen could be a treatment option for cirrhotic patients [342]. The combination one of two PegIFN-α and ribavirin for 24 weeks in treatment-naïve HCV genotype 3 patients could be an alternative treatment regimen [254,261]. PegIFN-α 2a 180 μg should be injected subcutaneously once a week, regardless of body weight, whereas PegIFN-α 2b should be injected 1.5 μg/kg subcutaneously once a week. Ribavirin is to be given at a flat dose of 800 mg daily, regardless of the type of PegIFN-α used. Evidence that a weight-based dose of ribavirin is more effective in achieving SVR in HCV genotype 3 patients is lacking [262,314]. Although the SVR rate of HCV genotype 3 Korean patients has rarely been reported, HCV genotype 3 patients of other ethnicities showed a 10-20% lower SVR rate than genotype 2 patients [319,320,325]. Retreatment of treatment-experienced patients In a phase III study, sofosbuvir plus ribavirin treatment for 12 weeks was compared with that for 16 weeks in treatment-experienced HCV genotype 3 patients. The SVR rate was 30% (19/64) after 12 weeks of treatment and 62% (39/62) after 16 weeks of treatment [310]. Furthermore, only 5 of 26 cirrhotic patients achieved an SVR (19%) [310]. Although extending treatment to 24 weeks increased the SVR rate to 85% (213/250), cirrhotic and treatment-experienced patients exhibited a low SVR rate of 62% (29/47) in a sub-group analysis [327]. Thus a better treatment option is needed, especially for treatment-experienced, cirrhotic patients. In a phase II study, treatment-experienced patients with genotype 3 infection received PegIFN, sofosbuvir and weight-based ribavirin for 12 weeks, and achieved an SVR rate of 83% (20/24) [343]. Of note, more than 50% of the patients in this study had liver cirrhosis and an 83% (10/12) SVR was obtained, which was comparable to that of non-cirrhotic patients [343]. In a phase III study of 544 treatment-experienced patients, PegIFN, sofosbuvir and weight-based ribavirin for 12 weeks resulted in an SVR rate of 93% (166/181) [337]. This was higher than the SVR rate of sofosbuvir and ribavirin for 24 weeks which was 85% (153/182). Of note, cirrhotic and treatment-experienced patients showed an SVR rate of 91% (21/23), which was comparable to that 96% (68/71) of non-cirrhotic and treatment-experienced patients [337]. Daily daclatasvir and sofosbuvir combination therapy for 12 weeks showed a SVR rate of 94% (32/34) in a phase III study of 34 treatment-experienced patients with HCV genotype 3 infection [338]. However, cirrhotic and treatment-experienced patients achieved a lower SVR rate, 69% (9/13) [338]. Consequently, when cirrhotic and treatment-experienced patients are treated, additional management such as add-on ribavirin or extension of the treatment period should be considered. A recent European cohort study reported that a daclatavir and sofosbuvir combination regimen for 24 weeks demonstrated a significantly higher SVR of 88% (52/59) compared to 76% (22/29) after 12 weeks of treatment. It was suggested that extension of treatment duration would benefit cirrhotic patients [339]. Ledipasvir/sofosbuvir plus ribavirin combination therapy, which was suggested as an alternative treatment for treatment-experienced HCV genotype 3 patients, demonstrated an SVR rate of 82% (41/50). However, this regimen resulted in a lower SVR rate of 73%, and so further studies are needed [340]. Retreatment with PegIFN plus ribavirin can be considered in patients previously treated with conventional interferon with or without ribavirin, or PegIFN-α without ribavirin, who failed to achieve SVR [329-332,344]. Patients treated with either a conventional interferon-based regimen or PegIFN without ribavirin and who failed to achieve an SVR can be retreated with the same DAA containing regimen as those in whom prior treatment with PegIFN plus ribavirin failed. [Recommendations] (Table 9) Initial treatment of HCV genotype 3 infection 1. Patients infected with HCV genotype 3 without cirrhosis should be treated with daily sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 24 weeks (A1). The same regimen is recommended for patients with cirrhosis (B1). 2. Patients infected with HCV genotype 3 without cirrhosis should be treated with daily daclatasvir (60 mg) and sofosbuvir (400 mg) for 12 weeks (A1). Extending treatment to 24 weeks with or without adding ribavirin is recommended for patients with cirrhosis (B2). 3. Patients infected with HCV genotype 3 without cirrhosis should be treated with daily sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) plus weekly PegIFN-α for 12 weeks (A1). The same regimen is recommended for patients with cirrhosis (B1). 4. Treatment with PegIFN-α in combination with ribavirin can be given for 24 weeks (A2). PegIFN-α 2a should be injected 180 μg subcutaneous once a week, regardless of patient body weight and PegIFN-α 2b is to be injected 1.5 μg/kg/week (A1). Daily administration of 800 mg of ribavirin can be performed, regardless of body weight (A2). Retreatment of treatment-experienced patients with HCV genotype 3 infection 1. Treatment-experienced patients with HCV genotype 3 with or without liver cirrhosis should be treated with daily sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) plus weekly PegIFN-α for 12 weeks (A1). 2. Treatment-experienced patients with HCV genotype 3 without cirrhosis should be treated with daily daclatasvir (60 mg) and sofosbuvir (400 mg) for 12 weeks. (A1) Extending treatment to 24 weeks with or without adding ribavirin is recommended for patients with cirrhosis (B2). 3. Treatment-experienced patients with HCV genotype 3 without cirrhosis can be treated with daily sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 24 weeks (B2). Due to the suboptimal sustained virological response for treatment-experienced patients with cirrhosis, an alternative regimen should be considered in these patients (B1). TREATMENT OF CHRONIC HCV GENOTYPE 4 INFECTION There are no reports of the therapeutic outcome of patients infected with HCV genotype 4 in South Korea. The SVR rate was reported to be 72% in patients infected with HCV genotype 4 treated with the combination of PegIFN-α and ribavirin for 48 weeks [345]. Several IFN-free regimens were evaluated for treatment of patients infected with HCV genotype 4. Three trials, in which patients infected with HCV genotype 4 treated for 24 weeks with sofosbuvir and weight-based ribavirin exhibited SVR rates of 93% (27/29), 90% (46/51) and 84% (26/31), respectively [346-348]. The SVR rate was decreased to 78% in cirrhotic patients treated with the same regimen [347]. Another interferon-free regimen comprising ledipasvir/sofosbuvir for 12 weeks showed a 95% SVR in 21 patients infected with HCV genotype 4, including 7 cirrhotic patients [349]. SVR rates were 100% (42/42) and 100% (49/49) in treatment-naïve and treatment-experienced patients infected with HCV genotype 4 treated for 12 weeks with ombitasvir/paritaprevir/ritonavir and weight-based ribavirin, respectively [350]. The triple combination of daclatasvir, asunaprevir and beclabuvir resulted in a 100% SVR in 21 treatment-naïve and non-cirrhotic patients infected with HCV genotype 4 [350]. Although the evidence is weak, it is likely that the results of several trials involving patients infected with genotype 1 can be extrapolated. Interferon-free regimens for the treatment of cirrhotic patients infected with HCV genotype 4 could be prolonged to 24 weeks or weight-based ribavirin added to improve the SVR rates. The combination of PegIFN-α, weight-based ribavirin and sofosbuvir for 12 weeks as an interferon-containing regimen showed a 96% SVR rate in 28 treatment-naïve patients infected with HCV genotype 4 [259]. Another interferon-containing regimen comprising PegIFN-α 2a, weight-based ribavirin and simeprevir for 24 or 48 weeks showed an overall 65% (70/107) SVR rate in patients infected with HCV genotype 4. Indeed, an SVR was achieved with this regimen in 83% (29/35) of treatment-naïve patients, 86% (19/22) of prior relapsers, 60% (6/10) of prior partial responders, and 40% (16/40) of prior null responders [351]. If DAAs are not available, the previous standard therapy such as the combination of PegIFN-α and ribavirin for 48 weeks remains acceptable. [Recommendations] (Table 10) Initial treatment of HCV genotype 4 infection 1. Patients infected with HCV genotype 4 without cirrhosis can be treated with daily ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks (B1). Duration of therapy can be extended to 24 weeks or daily weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) can be added without extending treatment duration in patients with cirrhosis (C1). 2. Patients infected with HCV genotype 4 without cirrhosis can be treated with daily ombitasvir (25 mg)/paritaprevir (150 mg)/ritonavir (100 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 12 weeks (B1). Treatment can be extended to 24 weeks in patients with cirrhosis (C1). 3. Patients infected with HCV genotype 4 without cirrhosis can be treated with daily sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 24 weeks (B1). 4. Patients infected with HCV genotype 4 with or without cirrhosis can be treated with daily sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) plus weekly PegIFN-α for 12 weeks (B1). 5. Patients infected with HCV genotype 4 with or without cirrhosis can be treated with PegIFN-α and weight-based ribavirin for 48 weeks (A2). PegIFN-α 2a should be injected 180 μg subcutaneous once a week, regardless of patient body weight with ribavirin using doses of 1,000 mg/d for those ≤ 75 kg in weight and 1,200 mg/day for those > 75 kg. PegIFN-α 2b is to be injected 1.5 μg/kg/week with ribavirin using doses of 800 mg for those < 65 kg in weight, 1,000 mg for 65-85 kg, 1,200 mg for 85-105 kg, and 1,400 mg for > 105 kg (A1). TREATMENT OF CHRONIC HCV GENOTYPE 5 OR 6 INFECTION There is no report of HCV genotype 5 in South Korea, which is limited mostly to South Africa. HCV genotype 6 is limited mostly to Southeast Asia, Southern China, Hong Kong, and Macau. It comprises about 1% of total chronic HCV patients in South Korea [352]. SVR rate of chronic HCV genotype 5 or 6 treated with a combination of PegIFN-α and ribavirin is 70-86%, which is comparable with that of HCV genotype 3 and higher than that of HCV genotype 1 [353-355]. Studies for HCV genotype 5 or 6 are limited because of the small number of patients infected with HCV genotype 5 or 6. The combination of ledipasvir/sofosbuvir for 12 weeks as an IFN-free DAA regimen showed a 96% SVR in 25 treatment-naïve and -experienced patients infected with HCV genotype 6 [340]. This result can be extrapolated for treatment of HCV genotype 5, although there are no data regarding use of this combination in patients infected with HCV genotype 5, because ledipasvir is active against both genotypes 5 and 6 in vitro. Treatment with PegIFN-α, weight-based ribavirin and sofosbuvir for 12 weeks achieved a 100% SVR in one patient infected with HCV genotype 5 and six patients infected with HCV genotype 6 [259]. Due to the weak evidence, the results of several trials involving patients infected with genotype 1 can be extrapolated. IFN-free regimens for the treatment of cirrhotic patients infected with HCV genotype 5 or 6 could be prolonged to 24 weeks or weight-based ribavirin added to improve the SVR rate. If DAAs are not available, the previous standard therapy such as the combination of PegIFN-α and ribavirin for 24 weeks remains acceptable. [Recommendations] (Table 10) Initial treatment of HCV genotype 5 or 6 1. Patients infected with HCV genotype 5 or 6 without cirrhosis can be treated with daily ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks (B1). Duration of therapy can be extended to 24 weeks or daily weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) can be added without extending treatment duration in patients with cirrhosis (C1). 2. Patients infected with HCV genotype 5 or 6 with or without cirrhosis can be treated with daily sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) plus weekly PegIFN-α for 12 weeks (B1). 3. Patients infected with HCV genotype 5 or 6 with or without cirrhosis can be treated with PegIFN-α and weight-based ribavirin for 24 weeks (A2). PegIFN-α 2a should be injected 180 μg subcutaneous once a week, regardless of patient body weight with ribavirin using doses of 1,000 mg/d for those ≤ 75 kg in weight and 1,200 mg/day for those > 75 kg. PegIFN-α 2b is to be injected 1.5 μg/kg/week with ribavirin using doses of 800 mg for those < 65 kg in weight, 1,000 mg for 65-85 kg, 1,200 mg for 85-105 kg, and 1,400 mg for > 105 kg (A1). TREATMENT OF PATIENTS WITH DECOMPENSATED CIRRHOSIS In the SOLAR-2 study, which was a multicenter randomized controlled trial of 108 patients with HCV genotypes 1 and 4 with decompensated cirrhosis (Child-Pugh Turcotte [CTP] class B or C, CTP scores ≤ 12), participants were randomly assigned to receive daily fixed-dose combination ledipasvir (90 mg) and sofosbuvir (400 mg) and ribavirin (initial dose of 600 mg, increased as tolerated) for 12 or 24 weeks [356]. SVR was achieved in 87% and 89% of patients given the 12- and 24-week treatment courses, respectively. Baseline CTP and Model for End-Stage Liver Disease (MELD) scores improved in more than 50% of the patients, but some patients experienced worsening of hepatic function. During the treatment, five (5%) patients died of variceal bleeding. Grade 3 or 4 adverse events occurred in 15% and 34% in the 12- and 24-week arms, respectively. In the phase III ALLY-1 study, daclatasvir (60 mg) was administered daily in combination with sofosbuvir (400 mg) and a low initial dose of ribavirin (600 mg) for 12 weeks to 60 patients with decompensated cirrhosis (mostly CTP class B and C, HCV genotype 1:3:2/4/6=45:6:9) [357]. The overall SVR rate was 83%. SVR rates were 76% and 100% among patients with HCV genotypes 1a and 1b, respectively. In patients with HCV genotype 1, SVR rates were 92% and 50% among patients with CTP classes B and C, respectively. Among subjects with HCV genotype 3 and 2/4/6, SVR12 rates were 83% and 89%, respectively. The efficacy and safety of simeprevir plus sofosbuvir with or without ribavirin for 12 weeks were assessed in patients with CTP class B/C (n=55) versus CTP class A (n=101) cirrhosis and compared to matched untreated controls [358]. SVR was achieved by 73% of CTP class B/C versus 91% of CTP class A (P<0.01) patients. CTP class B/C vs. CTP class A patients had more early treatment discontinuations (11% vs. 1%), adverse events requiring hospitalization (22% vs. 2%), infections requiring antibiotics (20% vs. 1%), and hepatic decompensating events (20% vs. 3%; all P<0.01). Adverse events requiring hospitalization (9% vs. 13%; P=0.55), infections (8% vs. 6%; P=0.47), and events of decompensation (9% vs. 10%; P=0.78) occurred at similar frequency in simeprevir plus sofosbuvir-treated patients and matched untreated controls. Use of ribavirin with simeprevir plus sofosbuvir was not associated with an SVR. Among DAAs, paritaprevir, dasabuvir and asunaprevir are contraindicated in patients with decompensated cirrhosis due to the higher drug concentrations observed. Efficacy and safety data in patients with more advanced liver disease (Child-Pugh ≥ 13) are limited and require verification. Also, the long-term clinical benefit of antiviral therapy in patients with decompensated cirrhosis without consideration for liver transplantation is unclear; thus it should be individualized. Therapeutic outcome with PegIFN-α plus ribavirin in decompensated cirrhotic patients is very poor, with frequent treatment-related complications. A small study (n=10, 8 genotype 1 HCV patients, 2 genotype non-1 HCV patients) reported a SVR rate of 20.0% in treating decompensated cirrhotic patients using combination therapy of PegIFN-α plus ribavirin [359]. Therefore, antiviral treatment of CTP class B cirrhotic patients can be attempted by experienced specialists with careful monitoring. A relatively good therapeutic outcome is expected in cases of low HCV RNA concentrations, or HCV genotype 2 or 3. Although drug administration can be started with standard doses, more than half of the patients experienced drug discontinuation or dose reduction. Thus, a careful approach starting with a low accelerated dose regimen (starting with 90 μg/week of PegIFN-α 2a or 0.5 μg/kg/week of PegIFN-α 2b and 600 mg/day of ribavirin, and a gradual increase in dose every 2 weeks up to the maximum tolerable dose) was assessed, and showed a similar efficacy to a standard dose regimen [244]. The combination treatment with PegIFN-α plus ribavirin is contraindicated in patients with CTP class C due to the likelihood of severe complications, including death [244]. [Recommendations] (Table 11) Interferon-free regimen 1. Treatment of patients infected with HCV genotypes 1, 4, 5 or 6 who have decompensated cirrhosis 1) Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) and a low initial dose of ribavirin (600 mg, increased as tolerated) for 12 weeks is recommended for patients with HCV genotype 1, 4, 5 or 6 infection who have decompensated cirrhosis (B1). Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks can be used for patients who are ribavirin intolerant or ineligible (C1). 2) Daily daclatasvir (60 mg), sofosbuvir (400 mg), and a low initial dose of ribavirin (600 mg, increased as tolerated) for 12 weeks is recommended for patients with HCV genotype 1, 4, 5 or 6 infection who have decompensated cirrhosis (B1). Daily daclatasvir (60 mg) and sofosbuvir (400 mg) for 24 weeks can be used for patients who are ribavirin intolerant or ineligible (C1). 3) Daily sofosbuvir (400 mg) and simeprevir (150 mg) for 12 weeks can be used for patients with HCV genotype 1, 4, 5 or 6 infection who have decompensated cirrhosis (C2). 2. Treatment of patients infected with HCV genotype 2 who have decompensated cirrhosis 1) Daily sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 16-24 weeks can be used for patients with HCV genotype 2 infection with decompensated cirrhosis (C1). 2) Daily daclatasvir (60 mg), sofosbuvir (400 mg), and a low initial dose of ribavirin (600 mg, increased as tolerated) for 12 weeks can be used for patients with HCV genotype 2 infection with decompensated cirrhosis (C1). Daily daclatasvir (60 mg) and sofosbuvir (400 mg) for 24 weeks can be used for patients who are ribavirin intolerant or ineligible (C1). 3. Treatment of patients with HCV genotype 3 who have decompensated cirrhosis 1) Daily daclatasvir (60 mg), sofosbuvir (400 mg), and a low initial dose of ribavirin (600 mg, increased as tolerated) for 12 weeks can be used for patients with HCV genotype 3 infection with decompensated cirrhosis (C1). Daily daclatasvir (60 mg) and sofosbuvir (400 mg) for 24 weeks can be used for patients who are ribavirin intolerant or ineligible (C1). 2) Daily sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 24-48 weeks can be used for patients with HCV genotype 3 infection with decompensated cirrhosis (C2). Interferon-containing regimen In CTP class B cirrhotic patients, combination treatment with PegIFN-α plus ribavirin can be attempted by experienced specialists with careful monitoring (C2). Combination treatment with PegIFN-α plus ribavirin is contraindicated in patients of CTP class C due to the likelihood of severe complications, including death (B1). LIVER TRANSPLANTATION AND OTHER ORGAN TRANSPLANTS Treatment before liver transplantation HCV reinfection occurs within several hours after transplantation in most patients with detectable HCV RNA at the time of the transplantation [360]. Thus, patients with HCV infection at the time of liver transplantation have a higher graft failure rate (hazard ratio (HR), 1.30; 95% CI, 1.21-1.39) and mortality rate (HR, 1.23; 95% CI, 1.12-1.35) compared to patients without HCV infection [361]. HCV-related liver diseases rapidly deteriorate following liver transplantation and around one-third of patients progress to cirrhosis within 5 years after transplantation [361,362]. Therefore, successful elimination of HCV before or after transplantation is critical to improve the prognosis of the graft and patient. Treatment of HCV infection in patients awaiting a liver transplantation has two goals: i) preventing liver graft infection after transplantation, and ii) improving liver function before transplantation in patients with decompensated cirrhosis. Improvement of liver function may lead to delisting of some of patients awaiting transplantation [363]. However, the duration of antiviral therapy cannot be predicted in a patient on the waiting list. Curry et al. reported a study in which 61 patients infected with HCV genotype 1, 2, 3 or 4 were treated with sofosbuvir and ribavirin up to 48 weeks prior to transplantation; 46 of them were transplanted [364]. Among 43 patients with an HCV RNA level <25 IU/ml at the time of transplantation, 30 (70%) had an SVR post-transplantation. The duration of undetectable HCV RNA pretransplant was the best predictor of a response. HCV recurrence occurred in 64% (9/14) vs. 4% (1/26) in patients with undetectable HCV RNA for less than 30 continuous days vs. more than 30 days before transplantation, respectively. Treatment following liver transplantation All patients with post-transplant recurrence of HCV infection should be prioritized for antiviral therapy. In particular, antiviral treatment should be started as soon as possible when advanced fibrosis or portal hypertension is noted, since these conditions predict a rapid progression of liver diseases and graft failure. The SOLAR-1 study was a large, multicenter, randomized controlled trial that included liver transplant recipients (n=222) infected with HCV genotype 1 or 4. Study participants were randomly assigned to receive fixed-dose combination ledipasvir (90 mg) and sofosbuvir (400 mg) and weight-based ribavirin (1,000 mg [<75 kg] to 1,200 mg [>75 kg]) for either 12 weeks or 24 weeks [359]. In patients with Metavir fibrosis stages F0 to F3, SVR was achieved in 96% and 98% of patients in the 12- and 24-week arms, respectively. In patients with compensated cirrhosis, SVR was achieved in 96% of patients in both the 12- and 24-week arms. Efficacy was lower in patients with CTP class B cirrhosis (SVR 85% vs. 88% in the 12- and 24-week arms) or CTP class C cirrhosis (60% vs. 75% in the 12- and 24-week arms). A total of 123 patients infected with HCV genotype 1 received simeprevir and sofosbuvir with or without ribavirin treatment for 12 weeks [365]. An SVR was achieved in 90% of patients, and the addition of ribavirin did not impact the SVR rate. Because of significantly increased plasma concentrations of simeprevir, the concomitant use of simeprevir and cyclosporine is not recommended in liver transplant recipients. No simeprevir dose changes are required with tacrolimus and sirolimus. In the phase III ALLY-1 study, daclatasvir (60 mg daily) was administered in combination with daily sofosbuvir (400 mg) and ribavirin (initial dose, 600 mg) for 12 weeks to patients with recurrent HCV infection post-transplant (n=53, HCV genotype 1:3:2/4/6=41:11:1) [360]. The SVR rate was 94%. SVR rates were 95%, 91% and 100% in patients infected with genotypes 1, 3 and 2/4/6, respectively. In a multicenter study of 34 liver transplant recipients with mild recurrence (Metavir fibrosis stage F0-F2) of HCV genotype 1 infection, fixed-dose combination paritaprevir (150 mg), ritonavir (100 mg), and ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and weight-based ribavirin was given for 24 weeks, and achieved an SVR rate of 97% [366]. Two patients (6%) had serious adverse events, and there were no deaths during the study. Because of interactions with ritonavir and paritaprevir, adjustments of the cyclosporine and tacrolimus dose were needed. When interferon-containing treatment is considered in patients with HCV reinfection following liver transplantation, it is recommended after histological confirmation of chronic hepatitis C at least 6 months after transplantation. This is because shortly after transplantation, patients are heavily immunosuppressed and incompletely recovered from the surgery, resulting in a high probability of drug intolerability as well as allograft rejection during interferon use. The SVR rate of interferon-containing antiviral treatment after transplantation is 30-40%, and genotypes 2 and 3 show better therapeutic outcomes than genotype 1 [245,367,368]. Post-transplant patients reportedly show similar therapeutic outcomes (33% and 38% SVR rates, respectively) using PegIFN-α plus ribavirin combination therapy or PegIFN-α monotherapy, which may be due to frequent dose reduction or discontinuation of ribavirin due to complications [369]. Anemia is the most common cause of treatment discontinuation and recombinant erythropoietin is recommended in this case [367,368]. Allograft rejection related to interferon alpha use can occur, and liver biopsy is required to differentiate the cause of liver function deterioration during antiviral treatment. Treatment following other organ transplants Renal transplant patients with HCV infection display rapidly progressing hepatic fibrosis and show high mortality related to hepatic failure; thus, antiviral treatment was recommended prior to renal transplantation in the past [370]. However, with the introduction of DAAs, successful elimination of HCV after renal transplantation could be achieved. It remains to be determined whether patients with chronic hepatitis C should optimally proceed to renal transplantation, with the expectation that their hepatitis C can be cured post-transplant to improve the outcome. Combination therapy with PegIFN-α plus ribavirin causes graft rejection in over 30% of patients, leading to graft failure and death. Thus, DAA therapy is preferred over interferon-containing therapy in renal transplant patients [371,372]. No data on the situation of transplants of the heart, lung, pancreas, small intestine, or cornea are available. When antiviral therapy is needed, DAA therapy is preferred over interferon-containing therapy. [Recommendations] (Table 12) 1. Antiviral therapy can prevent graft infection in patients awaiting liver transplantation, and should follow the recommendations according to liver function and HCV genotype (B1). 2. All patients who develop recurrent HCV infection after liver transplantation should be prioritized for antiviral therapy (A1). Antiviral treatment should be started as soon as possible when fibrosing cholestatic fibrosis, advanced fibrosis or portal hypertension is noted, since these conditions predict a rapid progression of liver diseases and graft failure (A1). 3. Treatment of patients who develop recurrent HCV infection after liver transplantation: HCV genotype 1 or 4 1) Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 12 weeks is recommended for post-liver transplantation patients infected with HCV genotypes 1 or 4 (B1). A low initial dose of ribavirin (600 mg, increased as tolerated) is recommended for patients with decompensated cirrhosis (B1). Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks can be used for patients who are ribavirin intolerant or ineligible (C1). 2) Daily daclatasvir (60 mg), sofosbuvir (400 mg), and a low initial dose of ribavirin (600 mg, increased as tolerated) for 12 weeks is recommended for post-liver transplantation patients infected with HCV genotypes 1 or 4 (B1). Daily daclatasvir (60 mg) and sofosbuvir (400 mg) for 24 weeks can be used for patients who are ribavirin intolerant or ineligible (C1). 3) Daily sofosbuvir (400 mg) and simeprevir (150 mg) for 12 weeks is recommended for post-liver transplantation patients infected with HCV genotypes 1 or 4 (B1). Weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) can be added (B1). 4) A daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 24 weeks is recommended for post-liver transplantation patients infected with HCV genotypes 1, who have early stage fibrosis (Metavir stage F0-F2) (B1). 5) A daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 12-24 weeks can be used for post-liver transplantation patients infected with HCV genotype 4 (C1). 4. Treatment of patients who develop recurrent HCV infection after liver transplantation: HCV genotype 2 1) Daily sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 12-24 weeks can be used for post-liver transplantation patients infected with HCV genotype 2 (C1). 2) Daily daclatasvir (60 mg), sofosbuvir (400 mg), and low initial dose of ribavirin (600 mg, increased as tolerated) for 12 weeks can be used for post-liver transplantation patients infected with HCV genotype 2 (C1). Daily daclatasvir (60 mg) and sofosbuvir (400 mg) for 24 weeks can be used for patients who are ribavirin intolerant or ineligible (C1). 5. Treatment of patients who develop recurrent HCV infection after liver transplantation: HCV genotype 3 1) Daily daclatasvir (60 mg), sofosbuvir (400 mg), and a low initial dose of ribavirin (600 mg, increased as tolerated) for 12 weeks can be used for post-liver transplantation patients infected with HCV genotype 3 (C1). Daily daclatasvir (60 mg) and sofosbuvir (400 mg) for 24 weeks can be used for patients who are ribavirin intolerant or ineligible (C1). 2) Daily sofosbuvir (400 mg) and weight-based ribavirin (1,200 mg in patients ≥ 75 kg, 1,000 mg in patients < 75 kg) for 24-48 weeks can be used for patients who are ribavirin intolerant or ineligible (C1). 6. When DAAs are administered to patients after transplantation, drug-drug interactions with immunosuppressants should be considered. The concomitant use of simeprevir and cyclosporine A is not recommended in this setting (A2). When using the combination of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir, tacrolimus and cyclosporine dose must be adjusted, and the use of mTOR inhibitors is not recommended (A2). 7. Interferon-containing treatment for HCV reinfection after liver transplantation is recommended with histological confirmation of chronic hepatitis C (B2). The treatment regimen could be either combination therapy with PegIFN-α plus ribavirin or monotherapy with PegIFN-α (B2). Liver biopsy is often required to differentiate causes of liver function deterioration during antiviral treatment (C1). 8. When antiviral therapy is considered in non-hepatic solid organ transplant recipients, DAA therapy is preferred over interferon-containing therapy (C1). TREATMENT OF ACUTE HEPATITIS C Acute hepatitis C is defined as hepatitis C presenting within 6 months of the exposure. The spontaneous recovery rate of acute hepatitis C varies from 20-50% [74,82,373-375]. Before the DAA era, although treatment could be initiated immediately after the diagnosis of acute hepatitis C, evidence supports a therapeutic strategy of delaying treatment for 8-12 weeks to allow spontaneous remission [74,376,377]. According to a randomized controlled study comparing immediate with delayed treatment for 12 weeks, the SVR rate of the delayed treatment was not inferior to that of the immediate treatment in terms of the spontaneous recovery rate and treatment-induced SVR [378]. Nevertheless, diagnosis of acute hepatitis C has not always been straightforward. Anti-HCV antibody starts to appear at the time of highest ALT and when the blood HCV RNA level is declining, which is ~8-12 weeks after infection when most patients do not show specific symptoms [140]. Therefore, testing for serum HCV RNA is useful for diagnosis and treatment when acute hepatitis C is suspected but anti-HCV antibody is negative. The SVR rate can reach 80-90% when acute hepatitis C is treated with conventional interferon alpha or by PegIFN-α monotherapy for 24 weeks [379-385]. PegIFN-α 2b and ribavirin combination therapy did not increase the SVR rate compared to that of PegIFN-α 2b monotherapy [378,381]. No clear additional benefit of combining ribavirin with interferon alpha or PegIFN-α is apparent to date. The optimal treatment duration for acute hepatitis C remains unclear. A randomized controlled study (n=34 per group) reported no significant difference in SVR rates (82.4% in the 12-week treatment group and 91.2% in the 24-week treatment group) irrespective of HCV genotypes [385]. In addition, studies reporting good therapeutic outcomes of acute hepatitis C have tended to adopt a 24-week treatment [379,380,384-386]. However, a recently published randomized controlled study of 120 patients that compared 12 weeks of PegIFN-α monotherapy, 12 weeks of PegIFN-α and ribavirin combination therapy and 24 weeks of PegIFN-α monotherapy reported no significant difference in SVR rates [387], and recommended 12 weeks of PegIFN-α monotherapy. Data on neither the efficacy nor the cost-effectiveness of treating acute hepatitis C with DAAs are available. However, currently available DAA-containing treatments for chronic HCV, which are highly effective with very few adverse effects, markedly reduce the advantage of treating HCV at the acute stage. Therefore, persons with acute HCV infection can be monitored for ≥6 months for spontaneous HCV clearance and then treated according to the recommendations for chronic infection if indicated. In cases in which a DAA-containing regimen is recommended and deferring treatment would be a threat to the patient’s health, immediate treatment can be initiated using the same recommendations as for chronic infection. [Recommendations] 1. When the treatment is started at the acute stage, initiation of treatment can be postponed for 8-12 weeks after onset of acute hepatitis C to allow spontaneous recovery (A2). 2. Patients with acute hepatitis C can be treated with PegIFN monotherapy for 12 weeks (A2). 3. If a delay in treatment initiation is acceptable, spontaneous HCV clearance can be monitored for at least 6 months (C1). 4. Treatment after the 6-month monitoring should follow the recommendations for chronic infection (C1). MONITORING AND MANAGEMENT OF ADVERSE EFFECTS DURING ANTIVIRAL TREATMENT FOR HCV INFECTION Monitoring during and after antiviral treatment Poor adherence to therapies increases the rate of treatment failure due to virologic breakthrough, relapse after treatment, occurrence of RAV, etc. Therefore, patients should be educated prior to antiviral treatment regarding the importance of compliance and adverse reactions to the antiviral drugs. During the period of antiviral treatment, efforts should be made to increase adherence through regular follow-up visits for monitoring and management of side effects. Because excessive drinking has an impact on treatment adherence [388], patients should be recommended to stop or reduce alcohol consumption before and during the treatment. Also, DAAs have potential drug-drug interactions with clinically relevant drugs used for underlying concurrent co-morbid diseases of patients with chronic hepatitis C. Therefore, clinicians should advise patients on potential drug-drug interactions. To estimate the effect of DAA-containing regimens as antiviral treatments for chronic hepatitis C, virologic response is assessed by measuring HCV RNA levels at weeks 4, 8, and 12-24 of treatment or at the end of treatment, and 12 or 24 weeks after treatment. To evaluate each individual therapeutic response and to set the treatment duration of the dual combination of peginterferon alpha and ribavirin, virologic responses are assessed by measuring HCV RNA levels at week 4, 12, and 24 of treatment or at the end of treatment, and 24 weeks after treatment, depending on the HCV genotype. Stopping rules have been defined for combination therapy with simeprevir, peginterferon alpha and ribavirin; if the HCV RNA value is higher than 25 IU/mL at week 4 of treatment with good compliance, treatment should be stopped [290,291]. Also, with combination therapy with sofosbuvir, peginterferon alpha and ribavirin for 12 weeks, if HCV RNA is detected at week 4 of treatment with good compliance, treatment may be stopped [259,389-391]. There are no clear criteria for stopping treatment with IFN-free DAA regimens, but if the HCV RNA level exceeds 25 IU/mL in week 4 of treatment, it should be tested again in week 6. If at that time the HCV RNA concentration is ≥10-fold higher than that in week 4, treatment should be stopped [124,392]. If HCV RNA is not elevated but remains detectable at week 6 or 8 of treatment, treatment may be stopped [124,392]. If HCV RNA is not detected at week 4 of treatment, virologic breakthrough can occur at weeks 4-12 of treatment; therefore, HCV RNA should be measured at week 8 of treatment and if is detected or elevated, and compliance is good, treatment should be stopped [233]. Continuous observation of undetectable HCV RNA after achieving an SVR can be regarded as complete eradication of HCV. HCV re-infection is possible even after achieving an SVR, mainly in PWID [393-397]. Therefore, follow-up is needed to assess re-infection or relapse of HCV after achieving an SVR. A risk of HCC remained even after achieving an SVR in cases with accompanying cirrhosis or advanced hepatic fibrosis prior to treatment [241]. In these patients, monitoring for HCC according to the surveillance strategy and management of general complications of cirrhosis are needed. If an SVR is not achieved, the incidence of HCC and disease progression are significantly higher compared to cases with an SVR [241,393], and continuous management of chronic hepatitis is necessary in cases without an SVR. [Recommendations] 1. The patient should be informed before treatment that adherence is important for achieving an SVR. The patient’s adherence should be checked regularly during the treatment. Also drug- drug interactions should be checked upon prescription of a new drug for a comorbid and underlying disease (A1). 2. Serum HCV RNA levels should be measured at weeks 4, 8, and 12-24 of treatment or at the end of treatment depending on the regimen (B1). If HCV RNA is detected at week 4 of DAA treatment (HCV RNA > 25 IU/mL), it should be retested at week 6 and if it is elevated by greater than 10-fold at week 6, discontinuation of treatment should be considered (C1). 3. To evaluate each individual’s therapeutic response and to modify the duration of treatment during PegIFN-α and ribavirin combination therapy, serum HCV RNA assays should be performed at weeks 4, 12, and 24 of treatment or at the end of treatment, depending on the HCV genotype (B1). In cases of genotype 1, treatment should be stopped in patients who fail to achieve an EVR (A1). Patients who achieve a cEVR can be treated for 48 weeks (A1). Patients with a pEVR should be re-tested at week 24; if HCV RNA remains positive, treatment should be stopped (A1). 4. HCV RNA should be measured at 12 or 24 weeks after the cessation of treatment to evaluate therapeutic effects and to identify the achievement of an SVR (A1). 5. Continuous undetectable HCV RNA after achieving an SVR can be regarded as complete eradication of HCV (C1). 6. Risks of hepatocellular carcinoma and complications of chronic liver disease remain after achieving an SVR in patients with cirrhosis or advanced hepatic fibrosis, and continuous management and surveillance following the strategies for chronic liver disease are needed (B1). 7. If an SVR is not achieved, continuous management of chronic liver disease is necessary (B1). Adverse effects of antiviral therapy and their management A thorough education about the process of treatment, and expected adverse reactions and their management encourages patients to continue treatment. Adverse reactions should be assessed at week 2-4 of treatment, and progress should be monitored at about 4-12-week intervals. DAA has fewer adverse reactions and tends to be well tolerated. Commonly reported adverse reactions are fatigue, headache, nausea, etc.; however, less than 1% of patients stop treatment due to adverse reactions. Adverse reactions of each drug are described in detail in the section ‘New drugs, direct-acting antivirals (DAA)’. A liver function test is performed within 4 weeks of treatment, and stopping of treatment may be considered when ALT is over 10-fold higher than the upper limit of the normal range, or when there is a risk of acute liver failure, such as an elevated bilirubin level or extended prothrombin time, even if the elevation of ALT is insignificant. More than 20% of patients treated with PegIFN-α and ribavirin combination therapy experience headache, fever, myalgia, muscular rigidity, arthralgia, nausea, anorexia, weight loss, diarrhea, hair loss, skin rash, pruritus, inflammation at sites of injection, dyspnea, fatigue, insomnia, irritability, or depression (Table 13) [254,261,262,398]. However, the severity and/or frequency of these adverse effects may vary, as these were reported by patients enrolled in clinical trials [398]. Adverse effects after PegIFN-α injection can be classified as flulike symptoms, myelosuppression, neuropsychological problems, and autoimmune dysfunction. Flu-like symptoms including fever, fatigue, myalgia, or nausea occur in ~37% of patients,254,261,262,398 but these symptoms can be alleviated by administration of analgesics and usually improve 4-6 weeks after treatment [398]. Myelosuppression causes neutropenia and thrombocytopenia, the main causes of dose reduction, and often set the therapeutic limit in patients with cirrhosis. Dose of PegIFN-α should be reduced or skipped in cases of severe adverse effects. Especially, when the absolute neutrophil count decreases to <750/mm3 or platelet count decreases to <50,000/mm3, dose reduction should be considered; when the absolute neutrophil count decreases to <500/mm3 or platelet count decreases to <25,000/mm3, drug discontinuation should be considered. Later, re-administration of the drugs can be considered following adequate recovery of absolute neutrophil count and platelet count; for example, 50% of the previous dose can be administered if the absolute neutrophil count recovers to ≥1,000/mm3, and platelet count to ≥75,000/mm3, with continuous monitoring of these cell counts. Although evidence for the role of granulocyte colony stimulating factor (G-CSF) in terms of reducing the infection rate and improving SVR is insufficient, use of G-CSF can be considered in some patients with cirrhosis [399]. Treatment should be halted in cases of acute deterioration of hepatitis with elevation of ALT to over 10-fold the upper-normal level or severe bacterial infection, such as sepsis. There is a report that thrombopoietin receptor agonist can raise platelet count in cirrhosis prior to treatment [400]. However, this drug should be used very carefully, since evidence for improvement of the SVR rate by this drug remains insufficient, whereas it has a risk of portal vein thrombosis [401]. Neuropsychological problems including insomnia, difficulty in concentrating, memory impairment, irritability, or apathy can be caused by PegIFN-α. Especially, severe depression can provoke a suicide attempt, and so careful observation is required during antiviral treatment [402]. Past history of depression should be checked, since uncontrolled depression is a contraindication to treatment. Depression occurs in about 28% of patients during treatment [403], and antidepressants such as serotonin uptake inhibitors can be used to maintain the treatment [404]. Preventive administration of antidepressants may reduce the occurrence of depression during treatment although there is a lack of evidence that this would increase the SVR rate [403-405]. Thyroid complications can occur in ~15-20% of patients, due to immunomodulatory function of PegIFN-α [398,406], which may be due to autoimmune or non-autoimmune causes; autoimmune thyroid diseases are classified as Graves’ disease, Hashimoto’s disease, and auto-antibody generation against the thyroid gland [407] and non-autoimmune thyroid disease results from thyroid damage mediated by HCV itself [406-408]. Hashimoto’s disease is the most common; it begins with hyperthyroidism and may progress to hypothyroidism. Thyroid function may not recover after the cessation of treatment [409-411]. Discontinuation of treatment should be considered in cases of severe hyperthyroidism during interferon administration, while treatment can be maintained with careful observation if hyperthyroidism is not severe [412]. In cases of hypothyroidism at the beginning, interferon therapy can be maintained by administering thyroxine [406]. Meanwhile, thyroid gland dysfunction can occur even after the end of treatment [398] and thyroid-stimulating hormone (TSH) and free thyroxine levels should be assessed at 2-4-month intervals during treatment and regularly for 1 year after the termination of treatment. Various autoimmune diseases, such as systemic lupus erythematosus, type 1 diabetes mellitus, asthma, interstitial pulmonary fibrosis, or thyroid diseases, can be induced by interferon therapy [413]. Therefore, baseline evaluation of these diseases is necessary prior to the initiation of treatment, although their presence is not an absolute contraindication to treatment especially, particularly if they are well controlled [398,406]. Other adverse effects related to PegIFN-α, such as visual-field defect, retinal hemorrhage and edema, hearing defect, tinnitus, vomiting, nausea, pruritus, weight loss and hair loss, improve after termination of treatment [398]. The frequency of retinal defect is ~3.8-30.9% [414-418] and the clinical course varies from severe visual field defect to no symptoms. The retina should be checked prior to treatment in cases with risk factors such as old age, hypertension, or diabetes [418-420] despite the fact that pretreatment and regular follow-up evaluation of the retina remains debatable. Hearing loss occurs in <1% of patients and it cannot be recovered completely even after termination of treatment [421]. A common adverse effect of ribavirin is hemolytic anemia due to dose-dependent direct toxicity to erythrocytes; this can be a barrier to successful treatment [422]. Anemia due to ribavirin can worsen existing ischemic heart or pulmonary diseases [422]. Immediate dose reduction by 200 mg should be considered if the hemoglobin level decreases to <10 g/dL and drug discontinuation should be considered in cases with <8.5 g/dL hemoglobin. Re-administration of the reduced dose is possible when anemia improves. Recombinant erythropoietin can be used in cases of severe anemia in order to prevent dose reduction or not to stop ribavirin, although the evidence for erythropoietin increasing the SVR rate is lacking [399,423]. Meanwhile, ribavirin can cause congenital deformity during pregnancy, therefore thorough contraception is essential during treatment and for 6 months after treatment for both male and female patients [424]. Other adverse effects related to ribavirin include fatigue, pruritus, rashes, sinusitis, and gout. Educating patients on treatment-related adverse effects and their management facilitates maintenance of the therapy. Detection of adverse reactions during the first 2-4 weeks of the treatment is important, and monitoring at 4-12-week intervals thereafter is required even if the patients are tolerating the antiviral therapy. [Recommendations] 1. Attention should be paid to the adverse reactions of individual drugs in DAA regimens, and interactions with concurrent drugs for underlying diseases should be monitored (A1). 2. For management of adverse reactions to PegIFN-α and ribavirin combination therapy, the following are recommended: 1) Pretreatment evaluation of depression, cardiac and pulmonary diseases, hypertension, diabetes mellitus, thyroid diseases, or anemia is required to monitor adverse effects of treatment (B1). 2) Monitoring of adverse effects at 2-4-week intervals after treatment initiation and thereafter at 4-12-week intervals during the treatment (C1). 3) If the absolute neutrophil count decreases to <750/mm3 or platelet count decreases to <50,000/mm3, dose reduction of PegIFN-α should be considered; if the absolute neutrophil count decreases to <500/mm3 or platelet count decreases to <25,000/mm3, discontinuation of PegIFN-α should be considered. Later, re-administration of PegIFN-α at a reduced dose can be considered following adequate recovery of absolute neutrophil count and platelet count; those counts should be monitored continuously (C2). 4) Dose reduction of ribavirin should be considered when anemia with hemoglobin level <10 g/dL occurs and discontinuation of ribavirin should be considered in cases of a hemoglobin level of <8.5 g/dL. Later, when anemia improves, re-administration of ribavirin at a reduced dose is possible, and the hemoglobin level should be monitored continuously (C2). 5) Monitoring of TSH and free thyroxine levels at 2-4-month intervals is recommended to detect thyroid abnormalities (C1). 6) Appropriate management is needed when depression develops during antiviral treatment, and antiviral treatment should be halted in cases of severe depression (C1). 7) Regardless of sex, under treatment that includes ribavirin, contraception is essential during treatment and for 6 months thereafter (A1). TREATMENT OF SPECIAL POPULATIONS Because clinical trials on patients in specific medical conditions have many limitations, individualized antiviral treatment should be used in these populations. Person who inject drugs Injection drug abuse is the main route of HCV transmission, and the abusers show a significantly higher HCV infection rate compared to those without a history of drug abuse [37,425,426]. Anti-HCV positive rate of Korean intravenous drug users has been reported to be 48.4-79.2% [23-25,427]. Psychotropic agents (ecstasy and methamphetamine), cannabis, and narcotics are major causes of drug crimes, and psychotropic medicine, the proportion of which increased steadily after 2011, accounted for 81.3% according to the Annual Narcotics Crime White Paper published by the Supreme Prosecutor’s Office (SPO). Treatment of persons who inject drugs (PWID) with chronic HCV infection makes a significant contribution to reducing liver-related complications and transmission to other healthy persons. However, active PWID tends to have an increased likelihood of treatment failure and reinfection if they do not receive adequate support for drug abuse. For this reason, multidisciplinary cooperative treatment among medical and psychiatric counseling services and social support resulted in a significant increase in adherence during therapy. A meta-analysis including over 2,800 injection drug users showed SVR rates of 44.9% in HCV genotype 1 and 70.0% in HCV genotype 2 and 3 patients treated with PegIFN-α and ribavirin [428]. DAA-based safety and treatment outcomes have not been fully evaluated; however, drug-drug interaction studies reported no clinically important interactions between sofosbuvir and simeprevir, methadone, buprenorphine [429,430] and daclatasvir [431,432], ombitasvir/paritaprevir/ritonavir with dasabuvir and methadone, and buprenorphine [433,434]. In addition to opioid substitution therapy, antidepressants, antipsychotics and sedatives are frequently used in patients or used by patients with addiction problems, and no significant drug-drug interactions with sofosbuvir has been reported. Simeprevir increases the blood concentration of midazolam after oral administration, and possibly also triazolam. Little data are available for daclatasvir [429]. [Recommendations] 1. PWID should be treated following the treatment rules for persons without drug abuse after managing drug-drug interactions (B1). 2. Multidisciplinary cooperative treatment among medical and psychiatric counseling services, social support by specialists on drug abuse and improvement of social environment can increase compliance with treatment in intravenous drug users (B2). Chronic kidney disease HCV infection rates in dialysis patients differ among regions from 3% to 80% [435], anti-HCV positivity rates from the late 1990s to early 2000s in Korea were 5.9-14.7% [27,28,436]. In contrast, the Dialysis Registry, ESRD Registry Committee of Korean Society of Nephrology reported a rate of 2.2% in 2014 [29]. The HCV infection rate is high in chronic kidney disease patients. However, anti-HCV screening may not be needed for these patients. Screening should be selectively conducted when HCV-related glomerulonephritis clinically presenting as hematuria, albuminuria, or cryoglobulinemia is suspected. However, anti-HCV should be tested in patients undergoing maintenance dialysis for the first time or who were transferred from other dialysis units. In addition, when unexplained abnormal liver-related biochemical tests is found or HCV exposure is suspected, anti-HCV antibodies should be tested and patients who are contiguously anti-HCV–negative should undergo HCV RNA assays [245,437]. The optimal interval for surveillance of HCV infection in anti-HCV negative patients in dialysis units is 6-12 months, taking into consideration the HCV infection rate of the dialysis unit in question. Dialysis patients infected with HCV show a higher mortality rate and more rapid progression to cirrhosis or hepatocellular carcinoma compared to non-dialysis patients [438-440]. Patients scheduled for kidney transplantation should receive an anti-HCV assay and consider HCV treatment because the survival rate after kidney transplantation tends to be low with a possibility of graft rejection and increased occurrence of diabetes and membranous nephritis compared with patients without HCV [429]. Interferon-based antiviral therapy is not recommended after kidney transplantation due to possible graft rejection [441-447]; however, DAA-based antiviral therapy can be safely applied after kidney transplantation. Indications for HCV treatment in chronic kidney disease patients should be determined considering liver disease condition and therapeutic complications. Simeprevir, asunaprevir, daclatasvir, ledipasvir, sofosbuvir and ombitasvir/paritaprevir/ritonavir with dasabuvir are administered at the same dose as in those without kidney disease in patients with mild to moderate renal impairment (creatinine clearance 30-80 mL/min). Safety and efficacy are not fully evaluated in patients with creatinine clearance (CrCl) <30 mL/min, and asunaprevir should be applied at 100 mg daily in non-dialysis patients with <30 mL/min. For non-cirrhotic patients with CrCl <30 mL/min for whom the urgency to treat (or retreat) is high and renal transplant is not an immediate option, a daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) with twice-daily dosed dasabuvir (250 mg) (for HCV genotype 1b infection) is recommended [448]. For patients with HCV genotypes 2 and 3 infection and CrCl <30 mL/min, PEG-IFN and dose-adjusted ribavirin is recommended. However, this recommendation is based on limited safety and efficacy data. Dose adjustment is needed depending on the severity of kidney disease, since PegIFN-α and ribavirin clearance is reduced according to the degree of impaired kidney function. Moreover, ribavirin should be carefully used in patients with creatinine clearance under 50 mL/min since ribavirin can cause severe hemolytic anemia [449]. Patients with mild kidney disease (glomerular filtration rate (GFR) ≥60 mL/min) can be administered the same doses of therapeutic drugs as those without kidney disease. If the patient has severe kidney disease (GFR of 15-59 mL/min), 135 μg of PegIFN-α -2a or 1 μg/kg of PegIFN-α -2b along with 200-800 mg/day of ribavirin twice a day with a gradual increase in dose is recommended [436]. Patients on dialysis can take either interferon alpha or PegIFN-α, although combination with ribavirin is not recommended. The SVR rates varied from 7-97% in a study of combination therapy with PegIFN-α (135 μg/week) and low-dose ribavirin (200 mg/day) in patients on dialysis, and most studies reported a high rate of treatment discontinuation. Antiviral therapy for HCV can be conducted in patients with HCV-related cryoglobulinemia or membranous glomerulonephritis. Immunosuppressive therapy or plasma exchange can be performed prior to antiviral treatment in such patients with nephrotic syndrome or a rapid decrease in kidney function [450-452]. Recommendations 1. Testing for anti-HCV should be performed in patients with chronic kidney disease who is under or planning to undergo kidney replacement therapy such as dialysis or kidney transplantation (B1). 2. HCV RNA should be tested to confirm HCV infection in patients with idiopathic liver disease despite negative anti-HCV results or in anti-HCV–positive patients (B1). 3. Simeprevir, asunaprevir, daclatasvir, ledipasvir, sofosbuvir and ombitasvir/paritaprevir/ritonavir with dasabuvir can be used without dose adjustment in patients with mild to moderate renal impairment (creatinine clearance 30-80 mL/min) (B1). 4. Safety and efficacy data of DAA-based antiviral therapy are not available in patients with CrCl < 30 mL/min (B1). 5. Combination therapy using PegIFN-α (135 μg of alpha-2a or 1 μg/kg alpha-2b) and ribavirin (200-800 mg/day) or interferon alpha and ribavirin can be used in chronic hepatitis C patients with severe kidney disease not undergoing hemodialysis (15-59 mL/min glomerular filtration rate) (C2). 6. Treatment of HCV in patients on dialysis may be considered with either interferon alpha (2a or 2b, 3,000,000 units, three times a week), or a reduced dose of PegIFN-α (2a, 135 μg/week or 2b, 1 μg/kg/week) (C2). Treatment of patients with HIV or HBV coinfection Chronic hepatitis C patients with HIV coinfection The HIV and HCV coinfection rate is reported to be 25% in western countries [30], and 5.0-6.6% in South Korea [31,32,453]. Since the frequency of coinfection is relatively high, all HIV-infected patients should receive HCV testing, which consists primarily of an anti-HCV assay. However, antibody may not be present in 6% of HIV-infected patients and an HCV RNA assay should be conducted in patients with idiopathic liver disease who are negative for anti-HCV [454,455]. Chronic hepatitis C patients with risk factors for HIV infection should be tested for HIV. HIV-coinfected patients show rapid progress of liver disease, higher incidence of cirrhosis and mortality, and generally higher serum HCV RNA levels compared to those with HCV monoinfection [262,456-462]. Especially, progression of liver disease tends to accelerate with decreasing CD4+ lymphocyte count and deterioration of immune system [463]. In contrast, recovery of immune function by antiretroviral therapy can delay the progression of liver disease by reducing HIV-related immune activation and inflammation [464-466]. Therefore, antiretroviral therapy is generally recommended in HIV/HCV-coinfected patients regardless of their CD4+ lymphocyte count. However, antiretroviral therapy should be conducted carefully due to high risk of liver toxicity, especially in HIV/HCV-coinfected patients with progressed liver disease [467,468]. Antiretroviral therapy can be delayed in HIV treatment-naïve patients and a CD4+ lymphocyte count >500/mm3 to avoid drug-drug interactions until HCV treatment is completed. In patients with a CD4 lymphocyte count <200/mm3, antiretroviral therapy should be initiated promptly, but HCV therapy may be delayed until the patient is stable on HIV treatment [469]. HIV/HCV-coinfected patients should be treated identically to HCV-monoinfected patients, and DAA treatment is recommended with priority because of the lower treatment efficacy of interferon-based regimens. To decide on the regimen, considerations include drug-drug interactions with antiretroviral agents (Table 14), prior treatment history and drug tolerance; moreover, expert consultation regarding HIV treatment is recommended [470]. 1) Therapeutic agents Simeprevir: Simeprevir can be administered with raltegravir, rilpivirine, maraviroc, enfuvirtide, tenofovir, emtricitabine, lamivudine, abacavir, and dolutegravir; these have no drug-drug interactions. Coadministration with efavirenz, etravirine, nevirapine, cobicistat, or HIV PI is not recommended. Ribavirin: Anemia related to ribavirin is an increasingly important problem in treatment of HIV coinfection, is more frequent and severe in patients taking zidovudine (AZT), and should be avoided [471]. Ribavirin can deteriorate didanosine (ddI) toxicity by inhibiting inosine-5-monophosphate dehydrogenase and severe lactic acidosis, steatosis, pancreatitis have been reported in patients taking ddI along with ribavirin; therefore, concomitant use of these two agents is contraindicated [472-474]. Therefore, patients receiving AZT and especially ddI should be switched to an equivalent antiretroviral agent before beginning a combination therapy that includes ribavirin. Asunaprevir: Among antiretroviral agents, PI is not recommended because the blood asunaprevir concentration may be increased, and non-nucleoside reverse transcriptase inhibitors (NNRTIs) other than rilpivirine are not recommended because may decrease the therapeutic effect of asunaprevir. Daclatasvir: Dose adjustment of daclatasvir is not required when used with ritonavir-boosted darunavir or ritonavir-boosted lopinavir. The dose of daclatasvir should be reduced to 30 mg once daily with ritonavir-boosted atazanavir and cobicistat-containing antiretroviral regimens, and an increased dose (90 mg daily) of daclatasvir is recommended when used with efavirenz or etravirine. Sofosbuvir: No clinically significant drug-drug interactions with most antiretroviral drugs (efavirenz, tenofovir, emtricitabine, rilpivirine, ritonavir-boosted darunavir and raltegravir) have been identified, but coadministration with tipranavir is not recommended. Ledipasvir and sofosbuvir: When rilpivirine or efavirenz is used with tenofovir as an antiretroviral agent for treatment of HCV-HIV coinfection, tenofovir levels are increased with ledipasvir/sofosbuvir, which may increase the risk of renal toxicity. Concomitant use with ledipasvir/sofosbuvir in patients at high risk for renal toxicity (those with a CrCl rate 30-60 mL/min or pre-existing evidence of Fanconi syndrome) or those taking tenofovir and a ritonavir-boosted PI, should be monitored for potential renal injury by assessing renal function every 2-4 weeks [392,475]. Ombitasvir/paritaprevir/ritonavir and dasabuvir: Paritaprevir is an inhibitor of OATP1B1 and can increase indirect bilirubin. Ombitasvir/paritaprevir/ritonavir plus dasabuvir should be used with antiretroviral drugs with which they do not have drug-drug interactions; i.e., raltegravir, enfuvirtide, tenofovir, emtricitabine, lamivudine, atazanavir, dolutegravir. As ritonavir has anti-HIV activity, HIV/HCV-coinfected patients should have achieved HIV RNA suppression prior to initiation of this regimen due to the potential for low-dose ritonavir to select for HIV PI resistance in patients not undergoing antiretroviral therapy. Especially, because this combination contains 100 mg of ritonavir, the dose of ritonavir used for boosting of HIV protease inhibitors may need to be adjusted (or held) when administered with ombitasvir/paritaprevir/ritonavir plus dasabuvir and then restored upon completion of HCV treatment. Concomitant use with efavirenz, rilpivirine, darunavir, and ritonavir-boosted lopinavir is not recommended. When this combination is used with ribavirin, unboosted HIV PI, rilpivirine, and efavirenz should not be used. When this combination is used with efavirenz, emtricitabine, tenofovir, gastrointestinal and neurologic adverse events, elevations of ALT can occur [392,476]. 2) Treatment efficacy In 50 patients with HCV genotype 1 and HIV co-infection never before treated for HCV and without cirrhosis, the SVR rate was 98% after 12 weeks of ledipasvir/sofosbuvir treatment [475]. After 12 weeks of ledipasvir/sofosbuvir treatment in 335 patients coinfected with HIV and genotype 1 or 4 HCV who had been previously treated or untreated for HCV, 20% of whom were cirrhotic, the SVR rate was 96% [477]. In 63 patients with HCV genotype 1 and HIV co-infection who were HCV treatment-naïve or had a history of prior treatment failure including cirrhotic patients, the SVR rate was 91-94% after 12 or 24 weeks of ombitasvir/paritaprevir/ritonavir plus dasabuvir and ribavirin [476]. After 24 weeks of sofosbuvir plus weight-based ribavirin in 112 treatment-naïve and 114 retreatment genotype 1 HCV coinfected patients including those with compensated cirrhosis, the SVR rates were 85% and 76%, respectively [348,478]. After 12 weeks of daclatasvir plus sofosbuvir treatment in 153 previously untreated and treated HIV/HCV coinfected (genotypes 1-4) patients, which included cirrhotic patients, the SVR rate was 97-98% [311]. In HCV genotype 2 or 3 patients including those with compensated cirrhosis, sofosbuvir plus weight-based ribavirin treatment for 12 weeks in 68 treatment-naïve patients and 24 weeks in 41 retreatment patients resulted in SVR rates of 88% for genotype 2 and 67% in genotype 3 HCV [478]. Using the same regimen, 163 HIV-coinfected patients (including cirrhotic patients) were treated for 12 weeks (genotype 2 treatment-naïve) or 24 weeks (genotype 3 or 4 and retreated genotype 2 patients); SVR rates were 88% for genotype 2, 89% for genotype 3 and 84% for genotype 4 HCV [348]. Clinical information regarding sofosbuvir treatment in patients with HIV and HCV genotype 5 and 6 coinfection is limited, and information about retreatment in HIV-coinfected patients, or in simeprevir- or sofosbuvir-experienced patients is also insufficient. Peginterferon alpha can be used at the same dose recommended for treating HCV monoinfection, and the ribavirin dose can be adjusted depending on body weight (1,000 mg/day for under 75 kg, 1,200 mg/day for over 75 kg), regardless of HCV genotype in HIV coinfection [479]. Treatment duration is usually recommended as 48 weeks, regardless of HCV genotype. A shortened duration of therapy to 24 weeks can be effective in genotype 2 and 3 with RVR, and an extended duration of therapy to 60-72 weeks can be helpful in genotype 1 and 4 with pEVR and no RVR [479-483]. [Recommendations] 1. All HIV infected patients should be tested for anti-HCV (B1). 2. HCV RNA assays should be conducted in patients with idiopathic liver disease, including those anti-HCV negative and positive (B1). 3. Antiretroviral treatment interruption to allow HCV therapy is not recommended (B1). 4. Interferon-free DAA treatment is recommended as a priority for HIV/HCV-coinfected patients, who should be treated identically HCV-monoinfected patients (B1). 5. When HIV/HCV-coinfected patients are treated with DAAs, drug-drug interactions should be carefully considered and consultation with an HIV treatment expert is recommended if the antiretroviral therapy regimen is to be modified (A1). 6. PegIFN-α can be used at the same dose recommended for treating HCV monoinfection and the ribavirin dose can be adjusted depending on body weight for 48 weeks, regardless of HCV genotype, in HIV-coinfected patients (B2). Chronic hepatitis C patients with HBV coinfection The number of HBV/HCV coinfected patients worldwide is estimated to be 15,000,000 [484], and 2.37% of anti-HCV positive patients are reported to be coinfected with HBV in South Korea [485]. A 10-year follow-up study of HCV-monoinfected patients reported an HCC occurrence rate of 28%, whereas HCV/HBV-coinfected patients showed an occurrence rate of 45%, which was significantly higher [486]. In addition, risks of severe and fulminant hepatitis increase and the incidence of cirrhosis and HCC increases in HBV/HCV-coinfected patients compared to those with HBV monoinfection [487-489]. In patients with HBV/HCV coinfection, blood HCV RNA and HBV DNA levels, which are indicators of the replicative status of each virus, should be evaluated, and if HCV infection is the dominant cause of the liver disease, the same antiviral therapy as for HCV monoinfection is recommended. Indeed, the SVR rate of PegIFN-α and ribavirin is similar to that in HCV monoinfection [490-492]. Treatment of patients with HBV/HCV coinfection is identical to that of HCV-monoinfected patients. The risk of drug-drug interactions between DAA and anti-HBV agents is low, with the exception of asunaprevir, for which information is lacking. Renal function monitoring is warranted if ledipasvir is used with tenofovir because renal toxicity can be increased (Table 15). Reactivation of HBV is possible during or after HCV treatment [485,493], and administration of oral antiviral agents may be indicated if significant proliferation of HBV is confirmed [494]. [Recommendations] 1. After confirming the dominant cause of liver diseases in HBV/HCV coinfection, treatment following the same rules as HCV monoinfection is recommended, and oral administration of anti-HBV agents may be indicated if significant proliferation of HBV is confirmed (B1). Hemophilia or thalassemia Accompanying HCV infection in patients with hemophilia or thalassemia causes significant increases in morbidity and mortality rates compared to patients without HCV infection [495-499]. Therefore, aggressive treatment of HCV infection should be considered. Hemophilia A and B caused by deficiency of factor VIII or IX may have increased chance of exposure to HCV due to multiple transfusion caused by spontaneous and traumatic bleeds. Coinfection with HIV/HCV is not a contraindication to liver transplantation in hemophilia, and indications for liver transplantation in patients with hemophilia are the same as those in non-hemophilic individuals [429]. Therapeutic outcomes in HCV-infected cases with or without hemophilia were similar, and there was no increase in complications regarding bleeding tendency [500,501]. Severe anemia can occur due to ribavirin in thalassemia, and up to 30-40% of cases may require blood transfusion at 3-4-week intervals to maintain 9-10 g/dL hemoglobin. Therefore careful monitoring is required to confirm hematological complications. However, the frequency of treatment discontinuation and the incidence of other main complications did not increase in these patients [495]. [Recommendations] 1. Patients with hemophilia should be treated following the same rules as persons without bleeding disorders (A1). 2. Patients with thalassemia should be treated following the same rules as persons without hemoglobinopathy (B1). Patients receiving immunosuppressants or cytotoxic chemotherapy Although one study defined HCV reactivation as re-emergence of or increase in HCV RNA plus elevation of ALT up to threefold the upper limit of normal [502], there is no universal consensus on definition of HCV reactivation; blood ALT and HCV RNA levels are commonly used as the criteria. The incidence of HCV reactivation in patients taking immunosuppressants or under cytotoxic chemotherapy is lower than that of HBV [502-506]. For example, the reactivation rate of HCV was 0% (0/11) compared to 38% (3/8) for HBV in a study including 98 non-Hodgkin’s lymphoma patients receiving chemotherapy [507]. However, another study of B cell non-Hodgkin’s lymphoma reported a higher incidence (26.3% vs. 2.1%) of significant elevation of ALT level in HCV-infected patients compared to patients without HCV infection, indicating that HCV reactivation does occur and may cause clinically significant morbidity [508]. Risk factors for HCV reactivation have not been clearly identified. However, reactivation has been reported to occur more frequently in patients with hematological malignancies [504,509]. HCV reactivation has also been reported in patients with solid cancer or who underwent stem cell transplantation [510-513]. Although death due to HCV reactivation is rare [514], the mortality is similar to that of HBV once severe hepatitis occurs due to HCV reactivation [515-517]. Strategies to prevent HCV reactivation in these patients have not been established. Conservative therapy and discontinuation of offending drugs are currently recommended. However, one should take into account hepatic morbidity from HCV reactivation and the disadvantages of immunosuppressive drug discontinuation, and decisions should be individualized. Further studies are needed to explore methods of preventing and treating HCV reactivation using DAAs. Children From a Korean study reported in 1996, 2,080 children were recruited and an anti-HCV positive rate was 0.82% [518]. Transfusion of infected blood components or vertical transmission is the most common cause of HCV infection in children [519], although transfusion-related HCV transmission has been reported only rarely after introduction of the screening test in 1991 in South Korea. The global HCV infection rate in pregnant females has been reported to be 0.49-1.7% [16-18]. A Korean study involving 5,000 pregnant females and another study with 20,000 pregnant females reported anti-HCV positivity rates of 0.42-0.44%, where 57-60% of anti-HCV positive pregnant females were also positive for HCV RNA [19,20]. The frequency of HCV transmission was reported as 1-6.2% during the perinatal period [67,69,520,521], and the evidence that Cesarean section reduces the risk of vertical HCV transmission is weak [522]. Although HCV RNA has been detected in human milk, acquisition of HCV infection from human milk has not been documented, and children with chronic HCV infection should not be prevented from attending school or participating in routine activities, including sports [522]. An anti-HCV assay in children is recommended after 18 months of age, since maternal antibodies can be delivered to newborns [522-524]. An HCV RNA assay may be performed at 1 or 2 months of age if earlier diagnosis is desired, although the sensitivity is as low as 22% at that time; therefore, HCV RNA assays should be conducted at the age over 6 months, when the sensitivity reaches 85% [523,525]. Spontaneous recovery is more frequent in children, and tends to show a normal ALT level [526], In addition, HCV infection in children often shows slow progression of hepatic fibrosis and rarely results in severe hepatic damage. However, aggressive treatment instead of waiting until the children reach the age of adult has been suggested, since children usually have a regular life cycle and show higher therapeutic compliance. Aggressive treatment is considered in cases of continuously elevated serum AST/ALT levels or when progressed hepatic fibrosis is confirmed by liver biopsy. In addition, treatment can also be considered when serum AST/ALT is normal or mild fibrosis is detected by liver biopsy since the tools used to predict disease progression are not sufficient in children [527]. Little data are available in children [528]. Although in previous studies on HCV-infected children was limited to interferon-α monotherapy due to the potential teratogenic effects of ribavirin, higher SVR rates have recently been reported with the addition of ribavirin to treatment [529-533]. Therefore, most studies have adapted combination therapy to children, since this approach is standard in adults. Use of PegIFN-α in children over 3 years of age has been approved in North America and Europe [527]. The dose of PegIFN-α is 60 μg/m2/week for PegIFN-α 2b, and 180 μg/1.73 m2/week for PegIFN-α 2a and the dose of ribavirin is 15 mg/kg twice a day. Genotype 1 and 4 patients should be treated for 48 weeks and genotype 2 and 3 patients should be treated for 24 weeks, similar to adults [527]. The SVR rate after combination therapy of PegIFN-α and ribavirin (47-53% in genotype 1 and 80-100% in genotypes 2 and 3) is superior to that of combination therapy with interferon alpha and ribavirin [531-533]. Factors predictive of an SVR include infection by genotypes 2 and 3, and an HCV RNA titer <600,000 IU/mL [529,532,533]. [Recommendations] 1. Diagnosis and evaluation of HCV in children should proceed following the same rules as in adults (B1). 2. Anti-HCV assay in children is recommended at age >18 months since maternal antibodies can be delivered to newborns. If an earlier assay is required, HCV RNA assay may be considered after 6 months of age (B2). 3. HCV infected children aged 3-17 years should be considered appropriate candidates for treatment according to the same criteria used in adults (B1). 4. The dose of PegIFN-α is 60 μg/1.73 m2/week for 2b and 180 μg/1.73 m2/week for 2a, and the dose of ribavirin is 15 mg/kg/day. Genotype 1 and 4 patients should be treated for 48 weeks and genotype 2 and 3 patients should be treated for 24 weeks (B1).