Hepatitis C Guidance: AASLD‐IDSA Recommendations for Testing, Managing, and Treating Adults Infected with Hepatitis C Virus

Potential conflict of interest: Listed at the end of the article for all authors. These recommendations have been approved by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. Potential conflict of interest: Listed at the end of the article for all authors. All AASLD Practice Guidelines are updated annually. If you are viewing a Practice Guideline that is more than 12 months old, please visit www.aasld.org for an update in the material. Preamble The pace of hepatitis C virus (HCV) drug development in recent years has accelerated dramatically. For patients to benefit from these impressive advances, practitioners need access to the most up‐to‐date data and to advice from experienced experts. Such information and advice can be difficult to access readily given the diverse sources from which information is available and the sometimes lengthy time needed for publication of original articles and scholarly perspectives. Traditional practice guidelines for more established areas of medicine and care often take years to develop and bring to publication. In the new era in hepatitis C treatment, such a process would not be nimble or timely enough to address the needs of patients with HCV infection, practitioners caring for these patients, or payers approving therapies for use. A living document made available in a web‐based system, such as that used by the US Department of Health and Human Services for human immunodeficiency virus (HIV) treatment recommendations (http://aidsinfo.nih.gov/guidelines), was selected as the best model to provide timely recommendations for hepatitis C management. In 2013, the two major membership societies supporting liver and infectious disease specialists (American Association for the Study of Liver Diseases [AASLD] and Infectious Diseases Society of America [IDSA]) joined forces to develop guidance for the management of hepatitis C in this rapidly moving field. The International Antiviral Society‐USA, which has experience in developing treatment guidelines in HIV disease, was invited to join the effort as a collaborating partner responsible for managing the panel and the guidance development process. The goal of the hepatitis C guidance is to provide up‐to‐date recommendations for HCV care practitioners on the optimal screening, management, and treatment for adults with HCV infection in the United States, using a rigorous review process to evaluate the best available evidence. This review provides a condensed summary of recommendations from the guidance. The complete guidance, which is updated regularly, is available at www.hcvguidelines.org. Process This was conceived to be a living document that would reside online and undergo real‐time revisions as the field evolved. To lead the process, two cochairs selected by the governing boards of each founding society were joined by a fifth cochair representing the International Antiviral Society‐USA. These cochairs selected 10 panel members from each society. The panel members were chosen to represent expertise in the diagnosis, management, treatment, research, and patient care from the fields of hepatology and infectious diseases. At least 51% of the panelists could have no substantive industry support other than research advisory boards, data safety monitoring boards, or research funding that went to the member's employer. The panel first convened in person in October 2013. Panel members were divided into teams to review available data and to propose preliminary guidance in three areas: (1) testing and linkage to care, (2) initial treatment of HCV infection, and (3) retreatment of patients in whom prior HCV treatment had failed. The treatment section teams also reviewed data for special considerations in patients with hepatitis C, including those with HCV/HIV coinfection, with decompensated cirrhosis, and who had undergone liver transplantation. The teams and cochairs met regularly by conference call. All panel members reviewed and approved the final recommendations. Each society's governing board peer‐reviewed the final recommendations. The first version of the guidance was uploaded (www.hcvguidelines.org) on January 29, 2014. By September 2014, three additional sections were developed: (1) treatment of acute HCV infection, (2) monitoring during and after therapy, and (3) when and whom to treat. In October 2014, the panel reconvened in person to update recommendations to consider data on pending new treatments. The updated recommendations (and appropriate revisions of all current guidance) were uploaded on December 20, 2014. This report was prepared on May 20, 2015. Funding for the guidance itself was provided by the AASLD and the IDSA. No industry funding was solicited or accepted. The Centers for Disease Control and Prevention (CDC) provided separate funding for identifying and reviewing data pertaining to testing and linkage to care. Collecting, Evaluating, and Rating the Evidence The panel, comprising experts in the fields of hepatology and infectious diseases, used an evidence‐based approach to review available information for the guidance. Information sources considered were research published in peer‐reviewed journals or presented at major national or international research conferences; safety warnings from the US Food and Drug Administration (FDA), other regulatory agencies, or the manufacturer; drug interaction data; prescribing information from FDA‐approved products; and registration data for new products under FDA review. An initial search of the literature yielded 3939 unique citations on November 4, 2013. To be considered, articles needed to be published in English from 2010 to the present. Review studies, studies using mice or rats, and in vitro studies were excluded. Panel members monitor the literature and other sources regularly and update the guidance as new evidence warrants. Each recommendation is rated in terms of the level of evidence (depicted by Roman numeral I, II, or III) and the strength of the recommendation (depicted by letter A, B, or C) using a scale (Table 1) adapted from the American College of Cardiology and the American Heart Association Practice Guidelines.1 Table 1 - Rating by Classification and Level of Evidence Classification Description Class I Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure, or treatment is beneficial, useful, and effective Class II Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness and efficacy of a diagnostic evaluation, procedure, or treatment Class IIa Weight of evidence and/or opinion is in favor of usefulness and efficacy Class IIb Usefulness and efficacy are less established by evidence and/or opinion Class III Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure, or treatment is not useful and effective or if it in some cases may be harmful Level of Evidence Description Level Aa Data derived from multiple randomized clinical trials, meta‐analyses, or equivalent Level Ba Data derived from a single randomized trial, nonrandomized studies, or equivalent Level C Consensus opinion of experts, case studies, or standard of care aIn some situations, such as for PEG‐IFN–sparing HCV treatments, randomized clinical trials with an existing standard‐of‐care arm cannot ethically or practicably be conducted. The FDA has suggested alternative study designs, including historical controls or immediate versus deferred, placebo‐controlled trials. For additional examples and definitions see http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225333.pdf. In those instances for which there was a single predetermined, FDA‐approved equivalency established, panel members considered the evidence as equivalent to a randomized controlled trial for levels A and B.Adapted from the American College of Cardiology and the American Heart Association Practice Guidelines.1 HCV Testing and Linkage to Care Of the estimated 2.2 million to 3.2 million persons3 chronically infected with HCV in the United States, half are unaware that they are infected.4 Identification of those with active infection is the first step toward improving health outcomes and preventing transmission.5 Accordingly, HCV testing is recommended in select populations based on demography, prior exposures, risk behaviors, and medical conditions (Table 2). In 2012, the CDC expanded its risk‐based HCV testing guidelines originally issued in 19987 with a recommendation to offer a one‐time HCV test to all persons born from 1945 through 1965, regardless of whether HCV risk factors have been identified. This recommendation was supported by the failure of the risk‐based screening strategy to identify more than 50% of HCV infections. Furthermore, persons in the 1945 to 1965 birth cohort accounted for nearly three‐fourths of all HCV infections, with a five times higher prevalence (3.25%) than other cohorts. A retrospective review showed that 68% of persons with HCV infection would have been identified through a birth cohort testing strategy, whereas only 27% would have been screened with the risk‐based approach.8 The cost‐effectiveness of one‐time birth cohort testing is comparable to that of current risk‐based screening strategies.5 Table 2 - Summary of Recommendations for Screening for HCV Infection 1. Birth cohort • Persons born between the years of 1945 and 1965 2 Risk behaviors • Injection‐drug use (current or ever, including those who injected once) • Intranasal illicit drug use 3. Risk exposures • Long‐term hemodialysis (ever) • Getting a tattoo in an unregulated setting • Health care, emergency medical, and public safety workers after needlesticks, sharps, or mucosal exposures to HCV‐infected blood • Children born to HCV‐infected women • Prior recipients of transfusions or organ transplants, including persons who — were notified that they received blood from a donor who later tested positive for HCV infection — received a transfusion of blood or blood components or underwent an organ transplant before July 1992 — received clotting factor concentrates produced before 1987 — were ever incarcerated 4. Other • HIV infection • Unexplained chronic liver disease and chronic hepatitis including elevated ALT levels • Solid organ donors (deceased and living) Recommendation 1. Consistent with the CDC and the US Preventive Services Task Force, a one‐time HCV test is recommended in asymptomatic persons in the 1945‐1965 birth cohort and other persons based on exposures, behaviors, and conditions that increase risk for HCV infection. (I‐B) Testing for HCV antibody (anti‐HCV) should be performed using FDA‐approved methods such as testing for anti‐HCV9,10 with laboratory‐based assays or a point‐of‐care assay.11 A positive anti‐HCV test result indicates current (active) HCV infection (acute or chronic), past infection that has resolved, or a false‐positive test result.12 Therefore, FDA‐approved quantitative or qualitative nucleic acid testing with a detection level of 25 IU/mL or lower should be used to detect HCV RNA to confirm active HCV infection and guide clinical management. Testing for HCV RNA should also be performed in persons with a negative anti‐HCV test who are immunocompromised (e.g., persons receiving chronic hemodialysis)13 or who might have been exposed to HCV in the prior 6 months because these persons may be anti‐HCV‐negative. An HCV RNA test is also needed to detect reinfection in anti‐HCV‐positive persons after previous spontaneous or treatment‐related viral clearance. Further details for interpreting results of different antibody and nucleic acid testing can be found in the CDC testing algorithm at www.hcvguidelines.org. Recommendation 2. All persons recommended for HCV testing should first be tested for anti‐HCV using an FDA‐approved test. Positive results should be confirmed by nucleic acid testing for HCV RNA. (I‐A) Evidence regarding the optimal frequency of testing in persons at risk for ongoing exposure to HCV is lacking; therefore, clinicians should determine the periodicity of testing based on the risk of reinfection. Because of the high incidence of HCV infection among persons who inject drugs and among HIV‐infected men who have sex with men who have unprotected sex,14 at least annual HCV testing is recommended in these subgroups. Recommendation 3. Annual HCV testing is recommended for persons who inject drugs and for HIV‐seropositive men who have unprotected sex with men. Periodic testing should be offered to other persons at ongoing risk of HCV exposure. (IIa‐C) Persons infected with HCV should be educated about preventing further damage to their liver. Most important is prevention of the potential deleterious effect of alcohol, which may lead to more rapid progression of liver fibrosis and the development of hepatocellular carcinoma (HCC).20 Persons with HCV should be tested for HIV antibody and hepatitis B surface antigen as coinfection with hepatitis B virus or HIV has been associated with poorer prognosis of HCV,27 they share overlapping risk factors, and additional benefits accrue from their diagnosis and treatment29 (http://www.aafp.org/afp/200/0315/p819.html and http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5708a1.htm). Patients with obesity and metabolic syndrome who have underlying insulin resistance are more prone to have nonalcoholic fatty liver disease, which may accelerate fibrosis progression in HCV‐infected persons.31 Therefore, HCV‐infected persons who are overweight or obese (defined by a body mass index of 25 kg/m2 or higher or 30 kg/m2 or higher, respectively) should be counseled regarding strategies to reduce weight and improve insulin resistance through diet, exercise, and medical therapies.33 Recommendation 4. Persons infected with HCV should be educated about their disease and how to prevent further damage to their liver. (IIa‐B) Improvements in identification of current hepatitis C and advances in treatment will have limited impact on HCV‐related morbidity and mortality unless patients have access to appropriate medical care. In the United States, it is estimated that only 13%‐18% of persons with chronic HCV infection receive treatment.35 Indeed, in many cases referral to practitioners who are able and willing to evaluate such patients and provide treatment is delayed or never occurs.36 Thus, it is crucial that all patients with current hepatitis C and a positive HCV RNA test result be referred to and evaluated by a practitioner with expertise in the assessment of liver disease severity and HCV treatment. Further, those with advanced fibrosis or cirrhosis require specialized management, including consideration of liver transplantation as indicated. Recommendation 5. Evaluation by a practitioner who is prepared to provide comprehensive management, including consideration of antiviral therapy, is recommended for all persons with current (active) HCV infection. (IIa‐C) When and in Whom to Initiate HCV Therapy Successful hepatitis C treatment is achievable in nearly all infected patients and is reflected by a sustained virological response (SVR), defined as the continued absence of detectable HCV RNA for 12 or more weeks after completion of therapy. SVR is a marker for virological cure of HCV infection and has been shown to be durable in large prospective studies in more than 99% of patients followed up for at least 5 years.39 Patients who are cured of their HCV infection experience numerous health benefits, including a decrease in liver inflammation, regression of fibrosis in most cases, and resolution of cirrhosis in half.41 Among the latter group, portal hypertension, splenomegaly, and other clinical manifestations of advanced liver disease also improve. An SVR is associated with a more than 70% reduction in the risk of liver cancer (HCC) and a 90% reduction in the risk of liver‐related mortality and liver transplantation.42 Cure of HCV infection may also reduce symptoms and mortality from severe extrahepatic manifestations, including cryoglobulinemic vasculitis, a condition affecting up to 15% of HCV‐infected individuals.45 Persons infected with HCV with non‐Hodgkin lymphoma and other lymphoproliferative disorders achieve complete or partial remission in up to 75% of cases following successful HCV treatment.47 These reductions in disease severity contribute to dramatic reductions in all‐cause mortality.43 Lastly, patients achieving an SVR have substantially improved quality of life, including physical, emotional, and social health.53 Evidence clearly supports treatment for all HCV‐infected persons, except those with limited life expectancy (less than 12 months) due to non–liver‐related comorbid conditions. Although treatment is best administered early in the course of the disease before fibrosis progression and the development of complications, the most immediate benefits of treatment will be realized by populations at highest risk for liver‐related complications. Thus, where resources limit the ability to treat all infected patients immediately as recommended, it is most appropriate to treat first those at greatest risk of disease complications and those at risk for transmitting HCV or in whom treatment may reduce transmission risk. Where such limitations exist, prioritization of immediate treatment for those listed in Tables 3 and 4 is recommended, including patients with progressive liver disease (Metavir stage F3 or F4), transplant recipients, or those with severe extrahepatic manifestations. Table 3 - Settings of Liver‐Related Complications and Extrahepatic Disease in Which HCV Treatment Is Most Likely to Provide the Most Immediate and Impactful Benefits* Highest priority for treatment owing to highest risk for severe complications • Advanced fibrosis (Metavir F3) or compensated cirrhosis (Metavir F4) Rating: Class I, Level A • Organ transplant recipients Rating: Class I, Level B • Type 2 or 3 cryoglobulinemia with end‐organ manifestations (e.g., vasculitis) Rating: Class I, Level B • Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis Rating: Class IIa, Level B High priority for treatment owing to high risk for complications • Fibrosis (Metavir F2) Rating: Class I, Level B • HIV‐1 coinfection Rating: Class I, Level B • Hepatitis B virus coinfection Rating: Class IIa, Level C • Other coexistent liver disease (e.g., nonalcoholic steatohepatitis) Rating: Class IIa, Level C • Debilitating fatigue Rating: Class IIa, Level B • Type 2 Diabetes mellitus (insulin‐resistant) Rating: Class IIa, Level B • Porphyria cutanea tarda Rating: Class IIb, Level C Ratings refer to the strength and level of evidence with regard to benefits of treatment in these settings. Table 4 - Persons With Risk of HCV Transmissiona or in Whom Treatment May Reduce Transmission • Men who have sex with men with high‐risk sexual practices • Active injection‐drug users • Incarcerated persons • Persons on long‐term hemodialysis • HCV‐infected women of childbearing potential wishing to get pregnant • Infected health care workers who perform exposure‐prone procedures Rating: Class IIa, Level C aPatients at substantial risk of transmitting HCV should be counseled on ways to decrease transmission and minimize the risk of reinfection. Recent reports suggest that initiating therapy in patients with lower‐stage fibrosis may extend the benefits of an SVR. In a long‐term follow‐up study, 820 patients with Metavir stage F0 or F1 fibrosis confirmed by biopsy were followed for more than 20 years. The 15‐year survival rate was significantly better in those who experienced an SVR than in those whose treatment had failed or those who were untreated (93%, 82%, and 88%, respectively; P = 0.003) and argues for consideration of earlier initiation of treatment.55 Several other modeling studies suggest greater mortality benefit if treatment is initiated at stages prior to F3.56 Recommendations 6. Antiviral treatment is recommended for all patients with chronic HCV infection, except those with limited life expectancy due to nonhepatic causes. (I‐A) 7. If resources limit the ability to treat all infected patients immediately as recommended, then it is most appropriate to treat those at greatest risk of disease complications before treating those with less advanced disease (see Tables3and4for ratings). An accurate assessment of fibrosis is vital in assessing the urgency for treatment, in some instances the duration of treatment, and the need for more intensive clinical monitoring. The degree of hepatic fibrosis is one of the most robust prognostic factors used to predict disease progression and clinical outcomes.59 In addition to being in more urgent need for antiviral therapy, individuals with severe fibrosis require screening for HCC and esophageal varices.60 There are several acceptable approaches to staging. Individuals with clinically apparent cirrhosis, such as those with endoscopic evidence of varices or imaging showing cirrhosis or portal hypertension, do not require additional staging. However, the majority of patients require testing to determine stage. Although liver biopsy is the diagnostic standard, sampling error and observer variability limit test performance, particularly when inadequate sampling occurs.62 In addition, the test is invasive and minor complications are common, limiting patient and practitioner acceptance. Serious complications such as bleeding, although rare, are well recognized. Recently, noninvasive tests to stage the degree of fibrosis in patients with chronic HCV infection include models incorporating indirect serum biomarkers (routine tests such as aspartate transaminase, alanine transaminase [ALT], and platelet count), direct serum biomarkers (components of the extracellular matrix produced by activated hepatic stellate cells), and vibration‐controlled transient liver elastography.63 No single method is recognized to have high accuracy alone, and the results of each test must be interpreted carefully. The most efficient approach to fibrosis assessment is to combine direct biomarkers and vibration‐controlled transient liver elastography.67 Recommendation 8. Use of noninvasive testing or liver biopsy is recommended in order to assess the degree of hepatic fibrosis and, hence, the urgency of immediate treatment. (I‐A) Initial Treatment of HCV Infection This section addresses treatment of patients with chronic hepatitis C who are naive to any type of therapy. Although regimens containing peginterferon (PEG‐IFN) and ribavirin (RBV) plus direct‐acting antiviral (DAA) drugs are approved by the FDA for many HCV genotypes, the initial regimen for patients who are treatment‐naive with HCV genotype 1 generally has been superseded by treatments incorporating regimens using only DAAs. Recommended treatments are viewed as equivalent, and the decision of which to use may involve consideration of drug interactions between the DAAs and concomitant medications (see http://www.hcvguidelines.org/full-report/initial-treatment-hcv-infection#drug-interactions). For example, the daily fixed‐dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) (hereafter ledipasvir/sofosbuvir) has a potential interaction with proton pump inhibitors. Similarly, the daily fixed‐dose combination of paritaprevir (150 mg), ritonavir (100 mg), and ombitasvir (25 mg) plus twice‐daily dosed dasabuvir (250 mg) (hereafter paritaprevir/ritonavir/ombitasvir plus dasabuvir [PrOD]) has a substantial interaction with the long‐acting inhaled beta‐adrenoceptor agonist salmeterol and other drugs that interface with the cytochrome P450 3A4 isoenzyme. Genotype 1a Patients with HCV genotype 1a tend to have higher relapse rates than patients with HCV genotype 1b with certain regimens. Genotype 1 HCV infection that cannot be subtyped should be treated as genotype 1a infection. For HCV genotype 1a–infected, treatment‐naive patients, there are three regimens of comparable efficacy: ledipasvir/sofosbuvir,68 PrOD and weight‐based RBV,70 and sofosbuvir plus simeprevir.72 For PrOD, the use of RBV and the length of therapy differ for those with compensated cirrhosis versus those who do not have cirrhosis. The standard weight‐based dosing of RBV is 1000 mg for individuals who weigh less than 75 kg to 1200 mg for those who weigh 75 kg or more. The known safety profiles of each of these recommended regimens are excellent. Across numerous phase 3 studies, fewer than 1% of patients without cirrhosis discontinued treatment early and adverse events were mild. Most adverse events occurred in RBV‐containing arms. Patients with cirrhosis and HCV genotype 1a who were harboring the nonstructural protein 3 (NS3) Q80K polymorphism had lower SVR rates after treatment with sofosbuvir and simeprevir than those who did not harbor the Q80K polymorphism;73 in these patients, one of the other recommended regimens for cirrhosis should be used. Recommendation 9. Treatment options for treatment‐naive patients with HCV genotype 1a who are initiating therapy (regimens are listed in alphabetical order): Daily fixed‐dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. (I‐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 RBV for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis). (I‐A) Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight‐based RBV for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis) for patients with a negative test result for the Q80K variant using commercially available resistance assays. In patients with HCV genotype 1a and cirrhosis who have the Q80K variant, one of the other regimens for cirrhosis detailed above is recommended. (IIa‐B) Genotype 1b For HCV genotype 1b–infected, treatment‐naive patients, there are three regimens of comparable efficacy: ledipasvir/sofosbuvir for 12 weeks, PrOD for 12 weeks70 and sofosbuvir plus simeprevir with or without weight‐based RBV for 12 weeks (or 24 weeks for patients with cirrhosis).72 Recommendation 10. Treatment options for treatment‐naive patients with HCV genotype 1b who are initiating therapy (regimens are listed in alphabetical order): Daily fixed‐dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. (I‐A) Daily fixed‐dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice‐daily dosed dasabuvir (250 mg) for 12 weeks. (I-A) Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight‐based RBV for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis). (IIa‐B) Genotype 2 Sofosbuvir plus weight‐based RBV is the recommended therapy for treatment‐naive patients with HCV genotype 2 infection.75 Until more data are available, extending treatment to 16 weeks in HCV genotype 2–infected patients with cirrhosis is recommended. Recommendation 11. Regimen for treatment‐naive patients with HCV genotype 2 infection: Daily sofosbuvir (400 mg) and weight‐based RBV for 12 weeks. (I‐A) Extending treatment to 16 weeks is recommended for patients with cirrhosis. (IIb‐C) Genotype 3 Genotype 3 is the most difficult genotype to treat with available DAAs. Sofosbuvir plus weight‐based RBV for 24 weeks is the recommended DAA‐only regimen in the United States.76 Based on recent data from a randomized trial demonstrating higher SVR rates than those seen with sofosbuvir and RBV for 24 weeks, the combination of sofosbuvir plus PEG‐IFN and RBV for 12 weeks is recommended for interferon (IFN)–eligible patients,80 although the adverse effects and increased monitoring requirements of PEG‐IFN may make this a less attractive therapeutic option. Daclatasvir plus sofosbuvir for 12 weeks has been studied, but daclatasvir is not FDA‐approved.81 Recommendation 12. Treatment for treatment‐naive patients with HCV genotype 3 infection: Daily sofosbuvir (400 mg) and weight‐based RBV plus weekly PEG‐IFN for 12 weeks for IFN‐eligible patients. (I‐A) Daily sofosbuvir (400 mg) and weight‐based RBV for 24 weeks for IFN‐ineligible patients. (I‐B) Genotype 4 For the treatment of therapy‐naive patients with HCV genotype 4, three therapeutic options are recommended: daily combination of paritaprevir/ritonavir/ombitasvir with weight‐based RBV,82 ledipasvir/sofosbuvir,83 or sofosbuvir plus weight‐based RBV.85 Given the demonstrated activity in vitro and in vivo of simeprevir against HCV genotype 4, simeprevir plus sofosbuvir may be considered; but supportive clinical data are limited. Recommendation 13. Treatment options for treatment‐naive patients with HCV genotype 4 infection (listed in alphabetical order): Daily fixed‐dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. (IIb‐B) Daily fixed‐dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight‐based RBV for 12 weeks. (I‐B) Daily sofosbuvir (400 mg) and weight‐based RBV for 24 weeks. (IIa‐B) Alternatives Daily sofosbuvir (400 mg) and weight‐based RBV plus weekly PEG‐IFN for 12 weeks. (II‐B) Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight‐based RBV for 12 weeks. (IIb‐B) Genotype 5 or 6 Few data are available to help guide decision making for patients infected with HCV genotype 5 or 6. Nonetheless, based on emerging data, sofosbuvir plus ledipasvir is recommended.83,84,88 Recommendation 14. Treatment for treatment‐naive patients with HCV genotype 5 or 6 infection: Daily fixed‐dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. (IIa‐B)