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Updates, Authorship, and Related Guidelines
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Developer and funding source
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New York State Department of Health AIDS Institute (NYSDOH AI)
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Intended users
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Clinicians in New York State who treat adults with chronic HCV
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Development
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See Supplement: Guideline Development and Recommendation Ratings
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Updates
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April 17, 2023
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Recommended DAA Treatment Regimens: The recommendation on how to choose an anti-HCV regimen was revised; choosing a regimen is based on findings from the pretreatment assessment and history of HCV treatment and not HCV genotype. Accordingly, the tables of recommended treatment regimens were revised. Post-Treatment Care: A recommendation was added for clinicians to refer patients with cirrhosis to a liver disease specialist for continued care. Note: The NYSDOH AI guideline Treatment of Chronic HCV with Direct-Acting Antivirals (July 2017 through October 2020) was replaced with 3 guidelines: 1) Hepatitis C Virus Screening, Testing and Diagnosis in Adults; 2) Pretreatment Assessment in Adults With Chronic Hepatitis C Virus Infection; and 3) Treatment of Chronic Hepatitis C Virus Infection in Adults
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Author and writing group conflict of interest disclosures
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See Conflict of Interest statement*
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Related NYSDOH AI guidelines
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Purpose of This Guideline
Date of current publication: April 17, 2023
Lead author: David E. Bernstein, MD
Writing group: Joshua S. Aron, MD; Christine A. Kerr, MD; Colleen Flanigan, RN, MS; Christopher J. Hoffmann, MD, MPH; Charles J. Gonzalez, MD
Committee:
Hepatitis C Virus (HCV) Guideline Committee
Date of original publication: July 31, 2017
This guideline for treatment of chronic hepatitis C virus (HCV) infection was developed by the New York State Department of Health AIDS Institute (NYSDOH AI) to guide primary care providers and other practitioners in New York State in treating patients with chronic HCV infection. The guideline aims to achieve the following goals:
Provide clinicians with current clinical evidence-based recommendations on treating and curing chronic HCV to 1) increase the number of New York State residents treated for and cured of chronic HCV and 2) reduce the growing burden of morbidity and mortality associated with chronic HCV infection.
Educate clinicians on safely and correctly prescribing anti-HCV medications.
Educate clinicians on the effects of HCV infection during pregnancy and the risk of vertical HCV transmission during the perinatal period.
Advise clinicians on the risks associated with HCV treatment in pregnant individuals.
Treatment and cure of chronic HCV: The availability of safe and effective regimens of oral direct-acting antivirals (DAAs) revolutionized HCV care, and DAA regimens are the standard of care for treating and curing chronic HCV. DAAs are molecules that work at different stages of the HCV lifecycle, targeting and inhibiting specific nonstructural proteins of HCV to disrupt viral replication and infection [UpToDate 2021]. The classes of DAAs are defined by their mechanism of action and therapeutic target.
Current DAAs for treatment of chronic HCV:
Protease inhibitors (-previrs): glecaprevir, voxilaprevir, grazoprevir
NS5A inhibitors (-asvirs): ledipasvir, velpatasvir, pibrentasvir, elbasvir
NS5B nucleoside polymerase inhibitor (-buvir): sofosbuvir
The goal of HCV therapy is a sustained virologic response (SVR), which is defined as the absence of detectable HCV RNA at least 12 weeks after treatment completion. An SVR is the equivalent of a cure. DAA regimens have been associated with an SVR rate of ≥90% and have excellent tolerability in both treatment-naive and treatment-experienced patients with and without cirrhosis [Falade-Nwulia, et al. 2017].
See the tables in the guideline section Recommended DAA Treatment Regimens for options for initial treatment of chronic HCV or retreatment of chronic HCV after treatment failure.
HCV Treatment Goals and Considerations
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| RECOMMENDATIONS |
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Considerations in HCV Treatment
Clinicians new to HCV treatment should consult a specialist in treatment of liver disease or viral hepatitis when treating patients who:
Clinicians should prescribe RBV with caution for patients with a CrCl <50 mL/min. (A1)
If prescribed, a reduced dose of 200 mg per day is required. Non-RBV-containing regimens can be prescribed without dose adjustments for patients with CrCl ≥30 mL/min.
Contraindications
Clinicians should not prescribe RBV for treatment of the following patients:
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Abbreviations: CrCl, creatinine clearance; DAA, direct-acting antiviral; HBV, hepatitis B virus; HCV, hepatitis C virus; RBV, ribavirin.
Goals
The goal of treatment in patients with chronic HCV infection is to attain a virologic cure, as evidenced by a sustained viral response, in order to reduce all-cause mortality and liver-related complications, including end-stage liver disease, hepatocellular carcinoma, and the morbidity and mortality associated with the extrahepatic manifestation of chronic HCV infection. With the significant advances in treatment, all patients with chronic HCV infection, regardless of fibrosis stage, are considered candidates for antiviral therapy [Simmons, et al. 2015; Smith-Palmer, et al. 2015; van der Meer, et al. 2012].
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Clinicians can increase their patients’ ability to understand treatment-related information and participate in decision-making if they communicate with clear, easily understood, jargon-free, and culturally sensitive language. Patient preferences are central to all treatment decisions.
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Considerations
This guideline includes recommendations for treating patients with chronic HCV infection, with consideration of individual characteristics such as viral genotype, presence of cirrhosis, and previous treatment history. Concurrent medical conditions, potential drug-drug interactions, and cost/coverage influence are factors in selecting HCV treatment regimens; sex, age, viral load levels, substance use disorders, mental health disorders, and HIV coinfection are not factors in choosing regimens.
The tables in the guideline section Recommended DAA Treatment Regimens present several options for treatment in each category. No regimen is prioritized or recommended over another; regimens are listed alphabetically.
Renal impairment: For patients with a CrCl <50 mL/min, RBV should be used with caution; if used, a reduced dose of 200 mg per day is recommended [FDA 2011]. No dose adjustment of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or glecaprevir/pibrentasvir is required in patients with mild, moderate, or severe renal impairment [FDA(a) 2019; FDA(b) 2019; FDA 2017; FDA(a) 2016].
Resistance testing: At present, testing for resistance-associated substitutions (RASs) is not universally recommended. RASs are also referred to as resistance analysis populations and resistance-associated variants. RAS testing is performed when retreatment is considered for patients for whom treatment with a DAA regimen containing an NS5A or NS5B inhibitor has failed (see guideline section Recommended DAA Regimens After PEG-IFN Treatment Failure).
NS5A testing is recommended in patients with HCV genotype 3 who are being considered for 12 weeks of sofosbuvir/velpatasvir and are treatment-naive and have cirrhosis or are treatment-experienced [Hezode, et al. 2018; Foster, et al. 2015]. If the Y93H RAS is present, weight-based RBV should be added to the regimen or another regimen should be selected.
For more information on HCV resistance, see the Infectious Diseases Society of America/American Association for the Study of Liver Disease HCV Resistance Primer.
HCV Testing and Management in Pregnant Adults
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| RECOMMENDATIONS |
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HCV Testing and Management in Pregnant Adults
Clinicians should perform HCV testing in all patients who are planning to get pregnant (A2) or are currently pregnant (B3), and screening should be repeated with each pregnancy (B3). Clinicians should advise pregnant patients diagnosed with chronic HCV (a positive HCV antibody test result and detectable HCV RNA) to defer treatment with DAAs until they are no longer pregnant or breastfeeding. (A2) If an individual with HCV becomes pregnant during DAA treatment, the clinician should:
Clinicians should refer pregnant patients diagnosed with HCV to a specialist experienced in managing HCV in pregnancy, e.g., hepatologist, gastroenterologist, infectious disease specialist, or high-risk obstetrician. (A3) If a pregnant patient with HCV has a substance use disorder, the clinician should provide or refer the patient for substance use treatment, including harm reduction services. (A3) Clinicians should advise pregnant and postpartum individuals with HCV monoinfection that HCV is not transmitted through breast milk and breastfeeding is considered safe. (B3) Clinicians should advise patients to discontinue breastfeeding if they have or develop cracked or bleeding nipples and to express and discard milk until the bleeding has resolved. (B3) Clinicians should refer infants born to mothers with HCV to pediatricians with experience in HCV care. (A3)
Contraceptive Use With HCV Treatment Containing RBV
Before initiating RBV as part of an HCV treatment regimen in a patient of childbearing potential, clinicians should confirm a negative pregnancy test and advise patients to use 2 methods of birth control for the duration of DAA therapy and 6 months after completion. (A2) If a patient becomes pregnant while taking RBV, the clinician should discontinue the RBV. (A1) Contraindication: Clinicians should not prescribe RBV for any patient planning pregnancy within 6 months of the last RBV dose or any male patient with a pregnant partner. (A2)
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Abbreviations: AASLD, American Association for the Study of Liver Diseases; CDC, Centers for Disease Control and Prevention; DAA, direct-acting antiviral; HCV, hepatitis C virus; IDSA, Infectious Diseases Society of America; RBV, ribavirin.
HCV screening during pregnancy: In New York State, excluding New York City, 2,416 cases of HCV were reported in 2020 among individuals of childbearing age, 15 to 44 years old [NYSDOH 2022]. In New York City, in 2020, 447 cases of HCV were reported among individuals of childbearing age [NYCDOHMH 2021].
These data raise concerns about reaching and treating this population and the potential for perinatal HCV transmission. Data indicate that in areas of high HCV prevalence, 10% to 28% of pregnant individuals with HCV infection are not identified through risk-based screening [Andes, et al. 2021; Koniares, et al. 2020; Fernandez, et al. 2016; Waruingi, et al. 2015; Thomas 2013]. Thus, in alignment with Centers for Disease Control and Prevention [Schillie, et al. 2020] and American College of Obstetricians and Gynecologists (ACOG) [ACOG 2022] recommendations, the NYSDOH and this committee recommend universal testing for HCV infection in individuals who are pregnant or planning to become pregnant and that screening be repeated with each pregnancy (see NYSDOH Dear Colleague Letter (11/1/2021): HCV Testing in Pregnant Persons). Identifying HCV presents an opportunity to ensure linkage to care and guide obstetric clinicians on the maternal and fetal risks in pregnant patients with HCV. In addition, universal HCV testing during pregnancy appears to be cost-effective [Chaillon, et al. 2021; Tasillo, et al. 2019].
HCV infection during pregnancy: There are no published large-scale studies on DAA treatment for HCV during pregnancy, and treatment of pregnant individuals is not currently recommended. Clinical trials are underway to evaluate the use of DAAs for the treatment of HCV during pregnancy [Chappell, et al. 2020; Yattoo 2018], and the clinician could discuss the possibility of clinical trial participation and refer the patient as appropriate (see Clinical Trials.gov).
If an individual becomes pregnant during DAA treatment, the clinician and patient should discuss the risks (e.g., no information on the effects of the medication on the fetus) and benefits (e.g., probable HCV cure) of continuing treatment and refer the patient to a specialist experienced in managing HCV in pregnancy, such as a hepatologist, gastroenterologist, infectious disease specialist, or high-risk obstetrician. Clinicians with patients who have been exposed to DAA treatment during pregnancy can contact the Treatment in Pregnancy for Hepatitis C Registry.
HCV infection, compared with no HCV infection, is associated with a higher incidence of intrahepatic cholestasis in pregnancy. Intrahepatic cholestasis in pregnancy has significant maternal and fetal morbidity [Wijarnpreecha, et al. 2017], and patients with HCV and this condition should be followed by a liver specialist or an obstetrician experienced in managing high-risk pregnancies [Wijarnpreecha, et al. 2017]. HCV infection during pregnancy has been associated with other adverse maternal and fetal outcomes, including gestational diabetes, low birth weight, small for gestational age, impaired intrauterine fetal growth, preterm delivery, miscarriage, and congenital anomalies [Connell et al. 2011]. Researchers note that the specific role of HCV in determining these outcomes is unclear because the data may be confounded by comorbid polysubstance use [Connell, et al. 2011]. Patients with HCV and recent or active substance use during pregnancy should be referred to care providers experienced in managing substance use during pregnancy for evaluation, treatment, and harm reduction services.
Perinatal transmission: Approximately 1.0% to 3.6% of pregnant individuals in the United States have HCV infection [Edlin, et al. 2015; Floreani 2013], and the risk of perinatal transmission is estimated at 6% for patients with HCV monoinfection and >10% for patients with HIV/HCV coinfection [Pawlowska 2015; Arshad, et al. 2011]. Currently, no antiviral treatment is available to reduce HCV transmission during pregnancy.
Intrauterine, intrapartum, and postpartum HCV transmission to the fetus have been reported, but postpartum transmission is believed to be rare [Gibb, et al. 2000]. In utero transmission may occur during all 3 trimesters, and the risk of transmission may be associated with high maternal HCV RNA levels [Elrazek, et al. 2017]. When an individual’s immune response is altered during pregnancy, HCV RNA levels usually increase during the second and third trimesters, and there is a synchronous decrease in maternal alanine transaminase levels [Gervais, et al. 2000]. HCV RNA levels decline after delivery; spontaneous postpartum clearance of the HCV infection has been reported and should be considered when evaluating postpartum patients for treatment [Hashem, et al. 2017; Prasad and Honegger 2013].
Data are limited on intrauterine HCV transmission during invasive procedures, such as fetal scalp monitoring, intrauterine pressures, chorionic villi sampling, and amniocentesis. Conditions such as premature rupture of membranes during pregnancy have been associated with increased risk of HCV transmission [Mast, et al. 2005]. However, observational studies have demonstrated that mode of delivery (Cesarean section [C-section] or vaginal) is not associated with the rate of perinatal HCV transmission [Ghamar Chehreh, et al. 2011; Mast, et al. 2005; European Paediatric Hepatitis C Virus Network 2001]. The Society for Maternal-Fetal Medicine/ACOG guidelines recommend against performing a C-section simply to reduce the risk of HCV transmission [Hughes, et al. 2017; Cottrell, et al. 2013].
Breastfeeding: For postpartum individuals with HCV, breastfeeding is an option and is not associated with an increased risk of HCV transmission to the infant [Cottrell et al. 2013]. However, it should be noted that if the postpartum individual has cracked or bleeding nipples, HCV transmission may occur during breastfeeding through blood or nonintact skin exposure [CDC 2021]. Early discussion with lactation consultants during or after pregnancy may be helpful to minimize difficulties with breastfeeding. For pregnant patients with HIV/HCV coinfection, clinicians should consult ACOG: Labor and Delivery Management of Women With Human Immunodeficiency Virus Infection.
Contraceptive use with HCV treatment containing RBV: For all female and male patients planning conception within 6 months of treatment, use of RBV is contraindicated due to the teratogenic effects of the drug [Sinclair, et al. 2017; FDA 2011]. Before prescribing an RBV-containing regimen for a patient of childbearing potential, a negative pregnancy test is required immediately before initiation of therapy, and using 2 forms of contraception or abstinence is advised during therapy and for 6 months after. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in female patients and female partners of male patients taking RBV.
If an individual with HCV becomes pregnant while taking an HCV treatment regimen containing RBV, RBV should be discontinued.
Recommended DAA Treatment Regimens
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Recommended DAA Treatment Regimens
Clinicians and patients should choose an anti-HCV regimen based on the pretreatment assessment and the patient’s previous treatment experience. (A2) See the tables listed below:
Clinicians and patients should choose an anti-HCV regimen based on the pretreatment assessment and any previous HCV treatment. (A2)
Treatment-naive patients (see Tables 2 and 3). Patients previously treated with PEG-IFN (see Tables 4 and 5). Patients previously treated with DAAs (see Tables 6 and 7).
If a regimen that includes weight-based RBV is prescribed, clinicians should dose as follows (A1):
<75 kg: RBV 400 mg once daily plus 600 mg once daily (total daily dose: 1,000 mg) ≥75 kg: RBV 600 mg twice daily (total daily dose: 1,200 mg)
In patients with genotype 3 HCV and compensated cirrhosis, clinicians should perform NS5A RAS testing before initiating therapy. (A2) Clinicians new to HCV treatment should consult a specialist in treatment of liver disease or viral hepatitis when retreating patients in whom any prior DAA treatment has failed. (B3) Failure is defined as detectable HCV RNA 12 weeks after the conclusion of HCV treatment.
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Abbreviations: DAA, direct-acting antiviral; HCV, hepatitis C virus; PEG-IFN, pegylated interferon; RAS, resistance-associated substitution; RBV, ribavirin.
All regimens listed in this guideline were available as of October 2022.
These recommendations for treatment of chronic HCV in adults ≥18 years old were developed by the NYSDOH AI HCV Guideline Committee to guide primary care providers and other clinicians in New York State in treating patients with chronic HCV infection. Treatment guidelines for patients ≤17 years old are available at the American Association of the Study of Liver Diseases/Infectious Disease Society of America HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. All available DAA regimens are pangenotypic. As such, these recommendations are based on a patient’s treatment experience instead of genotype.
HIV/HCV coinfection: Recommendations for treatment of chronic HCV infection in patients with HIV are the same as those for patients who do not have HIV, but attention to potential drug-drug interactions between DAAs and antiretrovirals is needed (see Box 1, below). Clinicians are encouraged to consult a specialist in the treatment of liver disease or viral hepatitis and an experienced HIV care provider as needed.
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The choice of regimen should be based on individual pretreatment assessment findings, HCV treatment history, and insurance coverage. The recommended regimens within each list are in alphabetical order, not in order of preference; no single regimen is recommended over another within each list of options.
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Undetectable or indeterminate genotype: Rarely, laboratories report the results of an HCV genotype test as “undetectable” or “indeterminate” for a patient with detectable HCV viral load [Germer, et al. 2011]. These HCV genotype reports are consistent with active HCV infection. The laboratory may be able to clarify the specific reason for the result. For example, an “undetectable” result may be due to the lower sensitivity of the genotype test compared with the HCV RNA test or a level of HCV RNA that is too low to perform the assay for genotype.
Data on treating patients with HCV who have an undetectable or indeterminate genotype are limited. Patients who have an undetectable or indeterminate HCV genotype can be treated with a pangenotypic regimen such as glecaprevir/pibrentasvir or sofosbuvir/velpatasvir.
Table 1, below, lists recommended oral DAAs. All regimens listed in drug regimen tables for all HCV genotypes refer to oral medications.
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| Table 1: Recommended Oral Direct-Acting Antiviral Drug Regimens for Adults [a] With Chronic HCV (October 2022) |
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Drug/Combination
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Trade Name
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| Glecaprevir/pibrentasvir | Mavyret [b] |
| Ledipasvir/sofosbuvir | Multiple brands [c] |
| Sofosbuvir/velpatasvir | Multiple brands |
| Sofosbuvir/velpatasvir/voxilaprevir | Vosevi |
- a
- b
Glecaprevir/pibrentasvir (GLE/PIB; Mavyret) is indicated for individuals ≥3 years old or weighing ≥45 kg with chronic HCV genotype 1, 2, 3, 4, 5, or 6. See prescribing information for full indications, dosing regimens, and information.
- c
Ledipasvir/sofosbuvir (LED/SOF; Harvoni; multiple brands) is indicated for individuals ≥3 years old with chronic HCV genotype 1, 4, 5, or 6. See prescribing information for full indications, dosing regimens, and information.
Drug-drug interactions: It is essential to check current resources for potential drug-drug interactions before prescribing direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) treatment.
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| Box 1: Online Resources for Identifying Drug-Drug Interactions Associated With DAAs |
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Recommended Treatment Regimens for Treatment-Naive Patients
Recommended regimens: The recommendations are organized by whether or not the patient has compensated cirrhosis. All drugs in the recommended regimens listed below are oral medications.
Treatment interruption and adherence: To achieve HCV cure, strict adherence to the medications as prescribed is essential. Before initiating treatment with a DAA regimen, develop an adherence plan with the patient, address potential barriers, and make support available if it is needed. Clinicians are advised to consult an HCV treatment specialist if a patient’s DAA treatment is interrupted.
Drug names: A “/” between 2 drug names indicates a co-formulated tablet.
Rating of regimens: All regimen choices listed below are rated A1 (strong recommendation, with high-quality evidence from at least 1 randomized trial with clinical outcomes or validated laboratory endpoints) except where indicated.
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Table 2: Preferred Regimens for HCV Treatment-Naive Patients
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Genotype
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Regimen
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Treatment Duration
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| No
Cirrhosis | Compensated
Cirrhosis |
| 1a, 1b, 2, 4, 5, 6 | Glecaprevir 300 mg/pibrentasvir 120 mg once daily | 8 weeks [a] | 8 weeks [b] |
| Sofosbuvir 400 mg/velpatasvir 100 mg once daily | 12 weeks [c] | 12 weeks [c] |
| 3 | Glecaprevir 300 mg/pibrentasvir 120 mg once daily | 12 weeks [d] | 12 weeks [e] |
| Sofosbuvir 400 mg/velpatasvir 100 mg once daily | 12 weeks [f] | 12 weeks [g,h] |
Abbreviations: HCV, hepatitis C virus; RAS, resistance-associated substitution; RBV, ribavirin.
- a
- b
- c
- d
- e
- f
- g
- h
Patients with genotype 3 and compensated cirrhosis require baseline NS5A RAS testing. Those without Y93H can be treated with 12 weeks of sofosbuvir/velpatasvir, and those with the Y93H RAS can be treated with sofosbuvir/velpatasvir plus weight-based RBV [Esteban, et al. 2018].
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Table 3: Alternative Regimens for HCV Treatment-Naive Patients
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Genotype/Patient Characteristics
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Regimen
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Treatment Duration
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| No
Cirrhosis | Compensated
Cirrhosis |
| 1a or 1b, non-Black, HIV-negative, HCV RNA <6 mil copies/mL (A2) | Ledipasvir 90 mg/sofosbuvir 400 mg once daily | 8 weeks [a] | 12 weeks [b] |
| 1a or 1b, Black, HIV-positive or HCV RNA >6 mil copies/mL (A2) | Ledipasvir 90 mg/sofosbuvir 400 mg once daily | 12 weeks [a] | 12 weeks [c] |
| 4, 5, 6 | Ledipasvir 90 mg/sofosbuvir 400 mg once daily | 12 weeks [d] | 12 weeks [d] |
Abbreviation: HCV, hepatitis C virus.
- a
- b
- c
- d
Recommended DAA Regimens After PEG-IFN Treatment Failure
Recommended regimens: The recommendations are organized by whether or not the patient has compensated cirrhosis. All drugs in the recommended regimens listed below are oral medications.
Treatment interruption and adherence: To achieve HCV cure, strict adherence to the medications as prescribed is essential. Before initiating treatment with a DAA regimen, develop an adherence plan with the patient, address potential barriers, and make support available if it is needed. Clinicians are advised to consult an HCV treatment specialist if a patient’s DAA treatment is interrupted.
Drug names: A “/” between 2 drug names indicates a co-formulated tablet.
Rating of regimens: All regimen choices listed below are rated A1 (strong recommendation, with high-quality evidence from at least 1 randomized trial with clinical outcomes or validated laboratory endpoints) except where indicated.
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Table 4: Preferred Regimens After PEG-IFN Plus RBV Treatment Failure
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Genotype
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Regimen
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Treatment Duration
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| No
Cirrhosis | Compensated
Cirrhosis |
| 1a, 1b, 2, 4, 5, 6 | Glecaprevir 300 mg/pibrentasvir 120 mg once daily | 8 weeks [a] | 12 weeks [b] |
| Sofosbuvir 400 mg/velpatasvir 100 mg once daily | 12 weeks [c] | 12 weeks [c] |
| 3 | Glecaprevir 300 mg/pibrentasvir 120 mg once daily | 16 weeks [a] | 16 weeks [b] |
| Sofosbuvir 400 mg/velpatasvir 100 mg once daily | 12 weeks [d] | 12 weeks [d,e] |
Abbreviations: PEG-IFN, pegylated interferon; RAS, resistance-associated substitution; RBV, ribavirin.
- a
- b
- c
- d
- e
Patients with genotype 3 and compensated cirrhosis require baseline NS5A RAS testing. Those without Y93H can be treated with 12 weeks of sofosbuvir/velpatasvir, and those with the Y93H RAS can be treated with sofosbuvir/velpatasvir plus weight-based RBV [Esteban, et al. 2018].
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Table 5: Alternative Regimens After PEG-IFN Plus RBV Treatment Failure
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Genotype
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Regimen
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Treatment Duration
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| No
Cirrhosis | Compensated
Cirrhosis |
| 1a, 1b | Ledipasvir 90 mg/sofosbuvir 400 mg once daily | 12 weeks [a] | 12 weeks [a] |
| Ledipasvir 90 mg/sofosbuvir 400 mg once daily plus weight-based RBV twice daily | Not indicated | 12 weeks [a] |
| 4, 5, 6 | Ledipasvir 90 mg/sofosbuvir 400 mg once daily | 12 weeks [b] | 12 weeks [b] |
Abbreviations: PEG-IFN, pegylated interferon; RBV, ribavirin.
- a
- b
Recommended DAA Retreatment Regimens
Recommended regimens: The recommendations are organized by whether or not the patient has compensated cirrhosis. All drugs in the recommended regimens listed below are oral medications.
Treatment interruption and adherence: To achieve HCV cure, strict adherence to the medications as prescribed is essential. Before initiating treatment with a DAA regimen, develop an adherence plan with the patient, address potential barriers, and make support available if it is needed. Clinicians are advised to consult an HCV treatment specialist if a patient’s DAA treatment is interrupted.
Drug names: A “/” between 2 drug names indicates a co-formulated tablet.
Rating of regimens: All regimen choices listed below are rated A1 (strong recommendation, with high-quality evidence from at least 1 randomized trial with clinical outcomes or validated laboratory endpoints) except where indicated.
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Table 6: Recommended Regimens After Sofosbuvir or Elbasvir/Grazoprevir Treatment Failure
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Genotype
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Regimen
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Treatment Duration
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| No
Cirrhosis | Compensated
Cirrhosis |
| 1a, 1b, 2, 4, 5, 6 | Glecaprevir 300 mg/pibrentasvir 120 mg once daily | 16 weeks [a,b] | 16 weeks [b] |
| Sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100 mg once daily | 12 weeks [c] | 12 weeks [c] |
| 3 | Sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100 mg once daily plus weight-based RBV twice daily | 12 weeks [d] | 12 weeks [d] |
Abbreviations: DAA, direct-acting antiviral; RBV, ribavirin.
- a
- b
Not recommended for NS3/4 protease inhibitor inclusive combination DAA regimens.
- c
- d
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Table 7: Recommended Regimens After Glecaprevir/Pibrentasvir Treatment Failure
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Genotype
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Regimen
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Treatment Duration
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| No
Cirrhosis | Compensated
Cirrhosis |
| 1a, 1b, 2, 3, 4, 5, 6 | Glecaprevir 300 mg/pibrentasvir 120 mg plus sofosbuvir 400 mg once daily plus weight-based RBV twice daily | 16 weeks [a] | 16 weeks [b] |
| Sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100 mg once daily | 12 weeks [c] | 12 weeks [d,e] |
Abbreviation: RBV, ribavirin.
- a
- b
- c
- d
- e
Addition of weight-based RBV is recommended.
Monitoring During DAA Treatment
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| RECOMMENDATIONS |
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Monitoring of Patients Taking RBV
Monitoring for HBV Reactivation
In patients who are HBsAg-positive and have no detectable HBV DNA, clinicians should monitor for HBV reactivation by performing AST, ALT, and HBV DNA tests every 4 weeks during HCV treatment. (A3) Clinicians new to HCV treatment should consult a liver disease or experienced viral hepatitis specialist for further evaluation of patients who develop detectable HBV DNA. (A3)
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Abbreviations: ALT, alanine transaminase; AST, aspartate aminotransferase; HBsAg, HBV surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; RBV, ribavirin.
The adverse events associated with direct-acting antiviral (DAA) treatment are listed in Table 8, below, and most are manageable. Patients who are taking RBV and experience insomnia may need to adjust the timing of the dose to earlier in the afternoon to avoid any sleep disruption.
Transient transaminase and bilirubin elevations may occur during the normal course of DAA therapy. However, severe laboratory value elevations and rare hepatic decompensation have been reported with protease inhibitors during the treatment of patients with cirrhosis [FDA(b) 2019; FDA 2017; FDA(b) 2016; Hayashi, et al. 2016]. Therefore, if the ALT level is elevated above baseline 4 weeks after treatment is initiated, testing should be repeated and levels monitored according to the drug’s prescribing information [FDA(b) 2019; FDA 2017; FDA(b) 2016; Hayashi, et al. 2016].
HBV reactivation and HBV-related hepatic flares have occurred both during and after DAA therapy in patients not receiving HBV treatment [Wang, et al. 2017; Sulkowski, et al. 2016; Collins, et al. 2015; Ende, et al. 2015]. The U.S. Food and Drug Administration has issued a drug safety warning regarding these risks.
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Table 8: Adverse Events Associated with Direct-Acting Antivirals
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| Drug or Combination
(brand name) |
Most Common Adverse Reactions (proportion observed)
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| Glecaprevir/pibrentasvir
(GLE/PIB; Mavyret) | Headache and fatigue (>10%) |
| Ledipasvir/sofosbuvir
(LED/SOF; Harvoni; multiple brands) | Asthenia, headache, and fatigue (≥10%) |
| Ribavirin(Copegus) | Fatigue/asthenia, pyrexia, myalgia, and headache in adults receiving combination therapy (>40%) |
| Sofosbuvir/velpatasvir
(SOF/VEL; Epclusa; multiple brands) |
With SOF/VEL: headache and fatigue (≥10%, all grades) With SOF/VEL and ribavirin in patients with decompensated cirrhosis: fatigue, anemia, nausea, headache, insomnia, and diarrhea (≥10%, all grades)
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| Sofosbuvir/velpatasvir/voxilaprevir
(SOF/VEL/VOX; Vosevi) | Headache, fatigue, diarrhea, and nausea (≥10%) |
Post-Treatment Care
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| RECOMMENDATIONS |
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Evaluating the Response to HCV Treatment
Post-Treatment Monitoring
Patients With Persistent Liver Disease
Clinicians should evaluate patients with persistent abnormal transaminase levels after SVR for other causes of liver disease and consult with a liver disease specialist. (A3) For patients with bridging fibrosis or cirrhosis at the onset of treatment, clinicians should continue screening for HCC with ultrasound and alpha-fetoprotein testing every 6 months indefinitely. (A1) Clinicians should refer patients with cirrhosis to a liver disease specialist for continued care. (A3)
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Abbreviations: DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; RBV, ribavirin; SVR, sustained viral response.
After treatment for chronic HCV infection, follow-up care is based on individual patient factors, including response to recent treatment, previous treatment history, degree of hepatic fibrosis, comorbidities, and cofactors for other sources of liver injury, such as alcohol use or fatty liver disease.
Evaluating the Response to HCV Treatment
All treated individuals should have HCV RNA testing performed 12 weeks after treatment. If there is no detectable HCV RNA at 12 weeks, HCV infection has been cured. In the absence of recurrent risk factors, subsequent HCV testing is not required. However, with late relapse reported in rare (<0.5%) cases, some clinicians may choose to retest at 24 and/or 48 weeks after the end of treatment [Jacobson, et al. 2017].
Successful treatment of chronic HCV infection results in no detectable HCV RNA, but antibodies to HCV are typically retained for life. It is important for treated individuals to understand that they will continue to have antibodies but not active HCV infection. It is also important for patients to understand that, although antibodies to HCV will continue to be present after treatment, HCV antibodies do not offer protection from HCV reinfection. All individuals with no detectable HCV RNA are susceptible to reinfection if re-exposed to HCV. Although the overall rate of reinfection is low, it is elevated among populations at higher risk [Martinello, et al. 2017]. A meta-analysis of 59 studies reporting recurrence after an SVR in 9,049 patients found that the summary 5-year risk of HCV reinfection among high-risk populations was 10.67% [Simmons, et al. 2016]. High risk was defined as having 1 or more risk factors, currently or formerly, for reinfection (injection drug use, imprisonment, and being a man who has sex with other men). Among low-risk populations, defined as those with no known risk factors, the summary 5-year recurrence risk was 0.95% [Simmons, et al. 2016]. For discussion of risk factors, see the NYSDOH AI guideline Hepatitis C Virus Screening, Testing, and Diagnosis in Adults.
Post-Treatment Monitoring
It is important to monitor the resolution of patients’ HCV treatment-related adverse events. RBV-containing regimens are teratogenic; patients receiving RBV-containing regimens and their partners should be counseled to avoid pregnancy during treatment and up to 6 months post-treatment. Two forms of effective birth control should be used [FDA 2011].
provides a list of adverse events associated with DAA regimens. During treatment with RBV, patients may experience hemolytic anemia, nausea, cough, shortness of breath, rash, dry skin, pruritus, lactic acidosis, or pancreatitis [FDA 2011]. Patients should be monitored through the follow-up period for resolution of any symptoms.
Hepatitis B virus (HBV) reactivation: HBV-related hepatic flares have been reported during and after DAA therapy in patients who were not receiving concurrent HBV treatment [Wang, et al. 2017; De Monte, et al. 2016; Hayashi, et al. 2016; Sulkowski, et al. 2016; Takayama, et al. 2016; Collins, et al. 2015; Ende, et al. 2015]. The U.S. Food and Drug Administration has issued a drug safety warning regarding these risks. Although data are insufficient to make a definitive recommendation regarding monitoring in patients with isolated hepatitis B core antibody [AASLD/IDSA 2021], it is important to consider HBV reactivation as part of the differential diagnosis for patients with HBV infection who experience unexplained increases in liver enzymes during or after completion of DAA treatment.
Patients With Persistent Liver Disease
Cessation of fibrosis progression and histological improvement are among the benefits of treating chronic HCV infection. However, patients should still be monitored for potential post-treatment decompensation [Jacobson, et al. 2017]. Individuals cured of HCV infection remain at risk of liver disease progression if they have advanced baseline fibrosis, other chronic liver conditions (e.g., chronic HBV, non-alcoholic fatty liver disease), comorbidities (e.g., metabolic syndrome, alcohol use, uncontrolled coinfection with HIV), or at risk of liver injury from drugs or dietary supplements [Vandenbulcke, et al. 2016].
There is wide individual variation in the time needed for fibrosis progression in patients with chronic liver disease. It is important to maintain an elevated suspicion for progression and the complications associated with hepatic decompensation, particularly in individuals with bridging fibrosis or cirrhosis before the initiation of DAA therapy and HCV cure.
In patients with bridging fibrosis or cirrhosis, an ultrasound and alpha-fetoprotein testing should be performed every 6 months, regardless of SVR, to screen for HCC [Jacobson, et al. 2017]. The risk of HCC for patients with stage 3 or higher fibrosis is 1.5% to 5% per year, but it is not known whether the histologic improvement after successful treatment mitigates this risk [Bruix and Sherman 2011].
All Recommendations
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Considerations in HCV Treatment
Clinicians new to HCV treatment should consult a specialist in treatment of liver disease or viral hepatitis when treating patients who:
Clinicians should prescribe RBV with caution for patients with a CrCl <50 mL/min. (A1)
If prescribed, a reduced dose of 200 mg per day is required. Non-RBV-containing regimens can be prescribed without dose adjustments for patients with CrCl ≥30 mL/min.
Contraindications
Clinicians should not prescribe RBV for treatment of the following patients:
HCV Testing and Management in Pregnant Adults
Clinicians should perform HCV testing in all patients who are planning to get pregnant (A2) or are currently pregnant (B3), and screening should be repeated with each pregnancy (B3). Clinicians should advise pregnant patients diagnosed with chronic HCV (a positive HCV antibody test result and detectable HCV RNA) to defer treatment with DAAs until they are no longer pregnant or breastfeeding. (A2) If an individual with HCV becomes pregnant during DAA treatment, the clinician should:
Clinicians should refer pregnant patients diagnosed with HCV to a specialist experienced in managing HCV in pregnancy, e.g., hepatologist, gastroenterologist, infectious disease specialist, or high-risk obstetrician. (A3) If a pregnant patient with HCV has a substance use disorder, the clinician should provide or refer the patient for substance use treatment, including harm reduction services. (A3) Clinicians should advise pregnant and postpartum individuals with HCV monoinfection that HCV is not transmitted through breast milk and breastfeeding is considered safe. (B3) Clinicians should advise patients to discontinue breastfeeding if they have or develop cracked or bleeding nipples and to express and discard milk until the bleeding has resolved. (B3) Clinicians should refer infants born to mothers with HCV to pediatricians with experience in HCV care. (A3)
Contraceptive Use With HCV Treatment Containing RBV
Before initiating RBV as part of an HCV treatment regimen in a patient of childbearing potential, clinicians should confirm a negative pregnancy test and advise patients to use 2 methods of birth control for the duration of DAA therapy and 6 months after completion. (A2) If a patient becomes pregnant while taking RBV, the clinician should discontinue the RBV. (A1) Contraindication: Clinicians should not prescribe RBV for any patient planning pregnancy within 6 months of the last RBV dose or any male patient with a pregnant partner. (A2)
Recommended DAA Treatment Regimens
Clinicians and patients should choose an anti-HCV regimen based on the pretreatment assessment and the patient’s previous treatment experience. (A2) See the tables listed below:
Clinicians and patients should choose an anti-HCV regimen based on the pretreatment assessment and any previous HCV treatment. (A2)
Treatment-naive patients (see Tables 2 and 3). Patients previously treated with PEG-IFN (see Tables 4 and 5). Patients previously treated with DAAs (see Tables 6 and 7).
If a regimen that includes weight-based RBV is prescribed, clinicians should dose as follows (A1):
<75 kg: RBV 400 mg once daily plus 600 mg once daily (total daily dose: 1,000 mg) ≥75 kg: RBV 600 mg twice daily (total daily dose: 1,200 mg)
In patients with genotype 3 HCV and compensated cirrhosis, clinicians should perform NS5A RAS testing before initiating therapy. (A2) Clinicians new to HCV treatment should consult a specialist in treatment of liver disease or viral hepatitis when retreating patients in whom any prior DAA treatment has failed. (B3) Failure is defined as detectable HCV RNA 12 weeks after the conclusion of HCV treatment.
Monitoring of Patients Taking RBV
Monitoring for HBV Reactivation
In patients who are HBsAg-positive and have no detectable HBV DNA, clinicians should monitor for HBV reactivation by performing AST, ALT, and HBV DNA tests every 4 weeks during HCV treatment. (A3) Clinicians new to HCV treatment should consult a liver disease or experienced viral hepatitis specialist for further evaluation of patients who develop detectable HBV DNA. (A3)
Evaluating the Response to HCV Treatment
Post-Treatment Monitoring
Patients With Persistent Liver Disease
Clinicians should evaluate patients with persistent abnormal transaminase levels after SVR for other causes of liver disease and consult with a liver disease specialist. (A3) For patients with bridging fibrosis or cirrhosis at the onset of treatment, clinicians should continue screening for HCC with ultrasound and alpha-fetoprotein testing every 6 months indefinitely. (A1) Clinicians should refer patients with cirrhosis to a liver disease specialist for continued care. (A3)
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Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALT, alanine transaminase; AST, aspartate aminotransferase; CDC, Centers for Disease Control and Prevention; CrCl, creatinine clearance; DAA, direct-acting antiviral; HBsAg, HBV surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IDSA, Infectious Diseases Society of America; PEG-IFN, pegylated interferon; RAS, resistance-associated substitution; RBV, ribavirin; SVR, sustained viral response.
Conflict of Interest: There are no author or writing group conflict of interest disclosures.
Created: July 2017; Last Update: April 2023.
