Guideline sources The following summarized guidelines for the evaluation and management of hepatitis C are prepared by our editorial team based on guidelines from the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2022), the World Health Organization (WHO 2022), the American College of Emergency Physicians (ACEP 2021), the Infectious Diseases Society of America (IDSA/AASLD 2020), and the U.S. Preventive Services Task Force (USPSTF 2013). 1 2 3 4 5 6 6 6 7 8 8 9 Definition Hepatitis C is an infectious disease caused by HCV that is characterized by progressive liver damage and polymorphous extrahepatic manifestations. 6 Epidemiology HCV, an RNA virus of the Flaviviridae family, infects hepatocytes and evades the immune system, causing oxidative stress, inflammation and fibrosis, which can progress to cirrhosis, hepatic decompensation, HCC, and death. 6 Pathophysiology https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 1/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway Pathophysiology The prevalence of hepatitis C in the United States adult population is estimated at 1.0% (current infection) and 1.7% (current or past infection). 7 Disease course Approximately 15-20% of patients who are infected will progress to cirrhosis over a 20-year period. The risk of HCC in cirrhotic patients (without successful treatment) is 3% per year. 8 8 Prognosis and risk of recurrence The mortality rate ratio of patients with HCV infection, as compared with the general population, is estimated at 2.3 (95% CI, 2.2-2.5). Cure rates with modern antiviral therapy are > 90% for chronic HCV infection. 6 9 CalculatorChild Pugh score for mortality in Guidelines 1. Screening and diagnosis Indications for screening: As per AASLD 2020 guidelines, obtain one-time, routine opt-out HCV testing in all persons 18 years of age. B Show 4 more As per USPSTF 2013 guidelines: Screen for HCV infection in patients at high risk for infection. B Offer one-time screening for HCV infection in patients born between 1945 and 1965. B 2. Diagnostic investigations Initial laboratory tests: As per WHO 2022 guidelines, obtain quantitative or qualitative nucleic acid testing directly following a positive HCV antibody serological test result for the detection of HCV RNA as the preferred strategy to diagnose viremic infection. B Show 7 more As per AASLD 2020 guidelines, obtain HCV antibodies with reflex HCV-RNA PCR for initial HCV testing. B https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 2/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway Show 4 more Viral genotyping: As per ACEP 2021 guidelines, do not obtain HCV genotyping when treating with pangenotypic medications unless planning glecaprevir-pibrentasvir therapy. D As per AASLD 2020 guidelines, consider obtaining HCV genotyping if it may alter treatment recommendations. B Evaluation for liver fibrosis: As per ACEP 2021 guidelines: Do not obtain invasive testing to establish the degree of fibrosis. D Consider obtaining inexpensive laboratory tests to identify patients with cirrhosis. C As per AASLD 2020 guidelines, obtain evaluation for advanced fibrosis using noninvasive tests (serum panels, elastography) or liver biopsy, if required, in all patients with HCV infection to facilitate an appropriate decision regarding HCV treatment strategy, and to determine the need for initiating additional measures for cirrhosis management (such as HCC screening). B Evaluation for other coinfections: obtain evaluation for other conditions accelerating liver fibrosis, including hepatitis B and human immunodeficiency virus in all patients with active HCV infection. B Evaluation of renal function: Assess all patients for kidney disease (with urinalysis and estimated GFR) at the time of HCV infection diagnosis. B Obtain repeated screening in patients remaining nucleic acid testing-positive if there is no evidence of kidney disease at initial evaluation. Pretreatment evaluation: evaluate potential drug-drug interactions with concomitant medications before starting direct-acting antiviral therapy. Discontinue an interaction co-medication or switch to an alternative with less risk for potential interaction during HCV treatment, if possible. B Show 4 more Resistance-associated substitution testing: obtain non-structural protein 5A resistance- associated substitution testing in genotype 1a-infected, treatment-na ve or -experienced patients being candidates for elbasvir/grazoprevir therapy. Consider switching to a different regimen if present. B Show 2 more 3. Diagnostic procedures Kidney biopsy: consider managing patients with HCV infection with a typical presentation of immune-complex proliferative glomerulonephritis without a confirmatory kidney biopsy. Consider performing a biopsy in certain clinical circumstances. 4. Medical management https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 3/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway General principles: As per WHO 2022 guidelines, initiate any of the following pangenotypic direct-acting antiviral regimens in all adult, B adolescent, B and 3 years old pediatric patients with chronic hepatitis C infection, regardless of the disease stage: sofosbuvir/daclatasvir for 12 weeks sofosbuvir/velpatasvir for 12 weeks glecaprevir/pibrentasvir for 8 weeks. B As per ACEP 2021 guidelines, ensure simplification of treatment and monitoring to enable patients with uncomplicated HCV infection to receive treatment in primary care settings. B As per AASLD 2020 guidelines, set a goal of treatment to reduce all-cause mortality and liver- related health adverse consequences, including end-stage liver disease and HCC, by the achievement of virologic cure as evidenced by a sustained virologic response in patients with HCV infection. B Show 5 more Antiviral therapy, genotype 1a: Administer any of the following daily fixed-dose combination regimens in patients with na ve genotype 1a HCV infection without cirrhosis: elbasvir 50 mg/grazoprevir 100 mg for 12 weeks in patients without baseline non-structural protein 5A resistance-associated substitutions for elbasvir B glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks B ledipasvir 90 mg/sofosbuvir 400 mg for 12 weeks B ledipasvir 90 mg/sofosbuvir 400 mg for 8 weeks in patients without human immunodeficiency virus infection and if HCV-RNA level is < 6 million IU/mL B sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks. B Show 3 more Antiviral therapy, genotype 1b: Administer any of the following daily fixed-dose combination regimens in patients with na ve genotype 1b HCV infection without cirrhosis: elbasvir 50 mg/grazoprevir 100 mg for 12 weeks B glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks B ledipasvir 90 mg/sofosbuvir 400 mg for 12 weeks B ledipasvir 90 mg/sofosbuvir 400 mg for 8 weeks in patients without human immunodeficiency virus and if HCV-RNA level is < 6 million IU/mL B sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks. B Show 3 more Antiviral therapy, genotype 2: Administer any of the following daily fixed-dose combination regimens in patients with na ve genotype 2 HCV infection without cirrhosis: glecaprevir 300 mg/pibrentasvir 120 mg for 8weeks sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks. B Show 3 more https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 4/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway Antiviral therapy, genotype 3: Administer any of the following daily fixed-dose combination regimens in patients with na ve genotype 3 HCV infection without cirrhosis: glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks. B Show 4 more Antiviral therapy, genotype 4: Administer any of the following daily fixed-dose combination regimens in patients with na ve genotype 4 without cirrhosis: elbasvir 50 mg/grazoprevir 100 mg for 12 weeks glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks ledipasvir 90 mg/sofosbuvir 400 mg for 12 weeks sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks. B Show 3 more Antiviral therapy, genotype 5 or 6: Administer any of the following daily fixed-dose combination regimens in patients with na ve genotype 5 or 6 HCV infection with or without compensated cirrhosis: glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks B sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks B ledipasvir 90 mg/sofosbuvir 400 mg 12 weeks. B Show 2 more Antiviral therapy, prior failures: administer daily fixed-dose combination of sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100 mg for 12 weeks in patients with HCV infection with or without compensated cirrhosis failed sofosbuvir-based treatment. B Show 4 more Indications for treatment discontinuation: discontinue direct-acting antiviral therapy in patients with an increase in ALT 10-fold from baseline at any time during treatment (especially with signs or symptoms of liver inflammation or increasing conjugated bilirubin, ALP, or INR). B Show 2 more 5. Specific circumstances Pediatric patients (laboratory testing): obtain HCV antibodies in all 18 months pediatric patients born to females with HCV infection. B Show 6 more Pediatric patients (preventative measures and counseling): inform parents that HCV is not transmitted by casual contact and pediatric patients with HCV infection do not pose a risk to other children and can participate in school, sports, and athletic activities, and engage in all other regular childhood activities without restrictions. B Show 5 more https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 5/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway Pediatric patients (antiviral therapy): initiate direct-acting antiviral treatment with an approved regimen in all 3 years old pediatric and adolescent patients with HCV infection regardless of disease severity. B Show 5 more Pediatric patients (follow-up): obtain disease severity assessment using routine laboratory testing and physical examination and evolving noninvasive modalities (elastography, imaging, or serum fibrosis markers) in all pediatric patients with chronic HCV infection. B Show 2 more Patients contemplating pregnancy: counsel female patients with HCV infection and cirrhosis about the increased risk of adverse maternal and perinatal outcomes. B Show 6 more Pregnant patients: obtain HCV infection testing with each pregnancy, ideally at the initial visit in all pregnant patients as part of prenatal care. B Show 7 more Men who have sex with men: obtain annual HCV testing in sexually active adolescent and adult MSM with human immunodeficiency virus. Consider obtaining more frequent testing depending on the precedence of high-risk sexual or drug use practices. B Show 4 more Patients injecting drugs: obtain annual HCV testing in patients injecting drugs with no prior testing or past negative testing and subsequent injection drug use. Consider obtaining more frequent testing depending on the level of risk. B Show 5 more Patients in jails and prisons: jails and prisons should implement opt-out HCV testing consisting of HCV antibody testing followed by confirmatory HCV-RNA testing if the antibody is positive. B Show 4 more Patients with chronic kidney disease (screening for HCV infection): screen all patients for HCV infection at the time of initial evaluation of CKD. B Obtain an immunoassay followed by nucleic acid testing if the immunoassay is positive. B Show 8 more Patients with chronic kidney disease (screening for other infections): screen for HAV, HBV, and human immunodeficiency virus in all patients with HCV infection (whether nucleic acid testing-positive or not) and CKD. Offer vaccination against HAV and HBV if appropriate. B Show 3 more Patients with chronic kidney disease (liver testing): assess for liver fibrosis in patients with CKD and HCV infection, B initially with noninvasive methods. B Show 2 more Patients with chronic kidney disease, antiviral regimens: As per KDIGO 2022 guidelines, assess all patients with CKD (G1-G5), on dialysis (G5D), and kidney transplant recipients (G1T-G5T) with HCV for direct-acting antiviral-based therapy. B Show 4 more https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 6/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway As per IDSA/AASLD 2020 guidelines, do not adjust doses of direct-acting antiviral therapy when using recommended regimens in patients with stage 1, 2, or 3 D and 4 or 5 CKD, except consider adjusting ribavirin dose in patients with stage 3, 4, or 5 CKD. D Patients with chronic kidney disease (management of glomerular disease): consider managing patients with HCV infection with a typical presentation of immune-complex proliferative glomerulonephritis without a confirmatory kidney biopsy. Consider performing a biopsy in certain clinical circumstances. Show 6 more Patients with chronic kidney disease (kidney transplantation): offer kidney transplantation as the best therapeutic option in patients with CKD stage G5 irrespective of the presence of HCV infection. B Show 6 more Patients with chronic kidney disease (follow-up): obtain regular monitoring to assess kidney disease progression in all patients with CKD with a history of HCV infection, whether nucleic acid testing-positive or not. B Kidney transplant recipients: As per KDIGO 2022 guidelines, evaluate kidney transplant recipients being treated with direct- acting antivirals for the need for dose adjustment of concomitant immunosuppressants. B Show 4 more As per AASLD 2020 guidelines, administer any of the following daily fixed-dose combination regimens in treatment-na ve and non-direct-acting-antiviral-experienced patients with kidney transplant with genotype 1-6 HCV infection with or without compensated cirrhosis: glecaprevir 300 mg/pibrentasvir 120 mg for 12 weeks B ledipasvir 90 mg/sofosbuvir 400 mg for 12 weeks in patients with genotype 1, 4, 5, or 6 HCV infection B sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks. B Show 2 more Patients receiving organs of HCV-infected patients: As per KDIGO 2022 guidelines, screen all kidney donors for HCV infection with both immunoassay and nucleic acid testing (if available). B Show 4 more As per AASLD 2020 guidelines, include the following elements in the informed consent: risk of transmission from an HCV-viremic donor (and with a public health service-defined increased risk donor, the potential risks for other viral infections) risk of liver disease if HCV treatment is not available or treatment is unsuccessful risk of graft failure risk of extrahepatic complications, such as HCV-associated renal disease risk of HCV transmission to a partner benefits, specifically reduced waiting time and possibly lower waiting list mortality https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 7/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway other unknown long-term consequences (hepatic and extrahepatic) of HCV exposure (even if cure is attained). B Show 5 more Patients with acute HCV infection: obtain HCV antibodies and HCV-RNA in patients with suspected acute HCV infection due to exposure, clinical presentation, or elevated aminotransferase levels. B Show 5 more Patients with HBV coinfection: obtain HBsAg for assessment of active HBV coinfection and HBV core antibodies and HBV surface antibodies for assessment of prior infection in all patients initiating direct-acting antiviral therapy for HCV infection. B Show 2 more Patients with HIV coinfection: treat and re-treat patients with human immunodeficiency and HCV coinfection the same as patients without human immunodeficiency virus infection after recognizing and managing interactions with antiretroviral medications. B Show 23 more 6. Patient education General counseling: provide education and interventions in all patients with HCV infection aimed at reducing liver disease progression and preventing HCV transmission. B Show 3 more 7. Preventative measures Immunizations: Administer vaccination against hepatitis A and hepatitis B in all susceptible patients with HCV infection. B Administer vaccination against pneumococcal infection in all patients with cirrhosis. B Prevention of transmission in hemodialysis units: ensure that hemodialysis facilities adhere to standard infection control procedures including hygienic precautions effectively preventing the transfer of blood and blood-contaminated fluids between patients to prevent transmission of blood-borne pathogens. B Show 7 more 8. Follow-up and surveillance Treatment monitoring: As per ACEP 2021 guidelines: Consider limiting laboratory monitoring to the beginning and end of the treatment in adult patients without cirrhosis or with compensated cirrhosis. C https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 8/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway Obtain closer monitoring in patients with decompensated cirrhosis. B As per AASLD 2020 guidelines, ensure clinic visits or telephone contact as clinically indicated during treatment to ensure medication adherence, and to monitor for adverse events and potential drug-drug interactions, especially with newly prescribed medications. B Show 6 more Post-treatment follow-up (patients achieved sustained virologic response): monitor patients without cirrhosis in the same way as persons never infected with HCV. B Show 6 more Post-treatment follow-up (patients failed sustained virologic response): initiate retreatment with recommended regimens in patients with chronic HCV. B Show 3 more Management of recurrence after liver transplantation: Administer any of the following daily fixed-dose combination regimens in treatment-na ve and -experienced patients with genotype 1-6 HCV infection in the allograft without cirrhosis: glecaprevir 300 mg/pibrentasvir 120 mg for 12 weeks ledipasvir 90 mg/sofosbuvir 400 mg for 12 weeks in patients with genotype 1, 4, 5, or 6 HCV infection sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks. B Show 3 more References 1. Kidney Disease: Improving Global Outcomes KDIGO Hepatitis C Work Group. KDIGO 2022 Clinical Practice Guideline FOR the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease. Kidney Int. 2022 Dec;102 6S S129 S205. Open 2. Marc G Ghany, Timothy R Morgan, AASLD IDSA Hepatitis C Guidance Panel. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Hepatology. 2020 Feb;71 2 686 721. Open 3. George M Abraham, Adam J Obley, Linda L Humphrey et al. World Health Organization Guidelines on Treatment of Hepatitis C Virus Infection: Best Practice Advice From the American College of Physicians. Ann Intern Med. 2021 Jan;174 1 98 100. Open 4. No authors listed. Updated recommendations on treatment of adolescents and children with chronic HCV infection, and HCV simplified service delivery and diagnostics. Geneva: World Health Organization; 2022. Open 5. Moyer VA. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013 Sep 3;159 5 349 57. Open 6. Manns MP, Buti M, Gane E et al. Hepatitis C virus infection. Nat Rev Dis Primers. 2017 Mar 2;3 17006. Open 7. Hofmeister MG, Rosenthal EM, Barker LK et al. Estimating Prevalence of Hepatitis C Virus Infection in the United States, 2013 2016. Hepatology. 2019 Mar;69 3 1020 1031. Open https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 9/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway 8. Kim A. Hepatitis C Virus. Ann Intern Med. 2016 Sep 6;165 5 ITC33 ITC48. Open 9. Ireland G, Mandal S, Hickman M et al. Mortality rates among individuals diagnosed with hepatitis C virus HCV ; an observational cohort study, England, 2008 to 2016. Euro Surveill. 2019 Jul;24 30 . Open 10. Kidney Disease: Improving Global Outcomes KDIGO . KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int Suppl. 2008 Apr; 109 S1 99. Open 11. Grad R, Thombs BD, Tonelli M et al. Recommendations on hepatitis C screening for adults. CMAJ. 2017 Apr 24;189 16 E594 E604. Open 12. Kaplan JE, Benson C, Holmes KK et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009 Apr 10;58 RR 4 1 207. Open 13. American Society for Clinical Pathology. Choosing Wisely ASCP recommendations. Choosing Wisely. 2019. Open 14. Muir AJ, Gong L, Johnson SG et al. Clinical Pharmacogenetics Implementation Consortium CPIC guidelines for IFNL3 IL28B genotype and PEG interferon- -based regimens. Clin Pharmacol Ther. 2014 Feb;95 2 141 6. Open 15. Paul Martin, Andrea DiMartini, Sandy Feng et al. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014 Mar;59 3 1144 65. Open 16. Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Department of Health and Human Services. 2023. Open 17. Kidney Disease: Improving Global Outcomes KDIGO Hepatitis C Work Group. KDIGO 2018 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease. Kidney Int Suppl 2011 . 2018 Oct;8 3 91 165. Open 18. European Association for the Study of the Liver, Clinical Practice Guidelines Panel: Chair, EASL Governing Board representative. EASL recommendations on treatment of hepatitis C Final update of the series. J Hepatol. 2020 Nov;73 5 1170 1218. Open 19. Tram T Tran, Joseph Ahn, Nancy S Reau. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111 2 176 94; quiz 196. Open 20. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open 21. Monika Sarkar, Carla W Brady, Jaquelyn Fleckenstein et al. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Jan;73 1 318 365. Open 22. R Douglas Wilson. Guideline No. 409 Intrauterine Fetal Diagnostic Testing in Women with Chronic Viral Infections. J Obstet Gynaecol Can. 2020 Dec;42 12 1555 1562.e1. Open https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 10/10