Hepatitis C Organism-Specific Therapy 

Updated: Dec 09, 2020
  • Author: David C Wolf, MD, FACP, FACG, AGAF, FAASLD; Chief Editor: Michael Stuart Bronze, MD  more...
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Therapeutic Regimens

The primary goal of therapy for patients infected with hepatitis C (HCV) is viral eradication. Secondary goals of therapy include reduction of symptoms and prevention or delay of progression to cirrhosis or hepatocellular carcinoma (HCC). [1] The duration of therapy is determined by the HCV genotype. The quantitative HCV ribonucleic acid (RNA) level is used to assess response to therapy and as a guide to discontinuation of treatment.

Institution of therapy for hepatitis C is rarely an emergency. Exceptions include cases of fibrosing cholestatic hepatitis after liver transplantation and some cases of severely symptomatic HCV-induced cryoglobulinemic vasculitis. In the latter situation, other treatments (eg, plasmapheresis) may be instituted before contemplating anti-HCV therapy. [1]

Viral loads and SVR

Typically, HCV viral loads are checked during treatment at weeks 4, 8, 12, and 24, and then every 3 months after the conclusion of treatment. [1, 2, 3, 4, 5] Sustained virologic response (SVR) is defined as the absence of detectable HCV RNA on blood testing 6 months after the completion of antiviral therapy; SVR can be equated with cure. A retrospective review of HCV treatment trials noted that only 2% of patients with an undetectable HCV RNA 12 weeks after conclusion of treatment relapsed by week 24. The Food and Drug Administration now utilizes SVR12 as a primary endpoint for registrational trials evaluating therapies for HCV. [6]

Pegylated interferon and ribavirin

Regimens containing pegylated interferon and ribavirin were the backbone of HCV therapy from 2001 until 2014. Since 2014, interferon-free therapy has been the norm. However, interferon may still play a role in particular treatment situations (eg, therapy for treatment-experienced patients infected with genotype 3). [7] Ribavirin continues to play a key role in a wide variety of HCV treatment regimens.

Below, the term pegylated interferon refers to either peginterferon alfa-2a 180 µg subcutaneously (SC) once weekly or peginterferon alfa-2b 1.5 µg/kg SC once weekly. Note that peginterferon is contraindicated for use in patients with hepatic decompensation (eg, the presence of ascites). Such patients may be at risk for worsening liver function or sepsis if treated with peginterferon.

The ribavirin dose is based on weight. The initial clinical trials with peginterferon alfa-2a utilized ribavirin at a dose of 1000-1200 mg per day (in two divided doses), [8] whereas the initial clinical trials with peginterferon alfa-2b utilized ribavirin at a dose of 800-1400 mg per day. [9] Trials published in relatively recent years that studied sofosbuvir utilized ribavirin using the following schedule: for individuals weighing less than 75 kg, ribavirin 400 mg in AM and 600 mg in PM; for individuals weighing 75 kg or more, ribavirin 600 mg twice per day. Trials that studied the elbasvir/grazoprevir combination used a different schedule: for individuals weighing less than 66 kg, ribavirin 800 mg per day; for individuals weighing 66 to 80 kg, ribavirin1000 mg per day; for individuals weighing 81 to 105 kg, ribavirin1200 mg per day; for individuals weighing more than 105 kg, ribavirin 1400 mg per day.

Ribavirin is contraindicated in women who are or may become pregnant and in men whose female partner is pregnant; this is due to the drug’s potential teratogenicity.

Monotherapy with pegylated interferon, ribavirin, or any direct-acting antiviral agent (eg, simeprevir, sofosbuvir) is not recommended, due to their lack of efficacy.

The first HCV protease inhibitors

In May 2011, the HCV NS3/4A protease inhibitors boceprevir and telaprevir received FDA approval for patients infected with HCV genotype 1. However, treatment with either of these agents is no longer recommended because of the higher efficacy and improved safety profile of other regimens. The sale and distribution of telaprevir was discontinued in the United States in 2014. The sale and distribution of boceprevir was discontinued in the United States in 2015.

A third protease inhibitor, simeprevir, received FDA approval in November 2013 for use in patients infected with HCV genotype 1. Initial approval specified that simeprevir (now discontinued in the United States) be used in combination with peginterferon and ribavirin in patients with compensated liver disease. However, the naturally-occurring NS3/4A Q80K amino acid substitution was problematic for patients with genotype 1a. This resistance-associated variant (RAV) was seen in about 30% of patients with genotype 1a infection. If present, the polymorphism was associated with a lower SVR in simeprevir-treated patients. SVR rates in previously untreated patients were reported as 84% in genotype 1a patients without the Q80K polymorphism, 58% in genotype 1a patients with the Q80K polymorphism, and 85% in genotype 1b patients. [10] Accordingly, it was recommended that patients with genotype 1a and the Q80K polymorphism not receive combination therapy with peginterferon, ribavirin, and simeprevir.

All-oral regimens

Sofosbuvir is an orally administered nucleotide analogue inhibitor of the HCV NS5B polymerase. [11] It received FDA approval in December 2013 for use in patients infected with HCV genotypes 1, 2, 3, and 4. At that time, the FDA's approval of combination therapy with sofosbuvir and ribavirin for patients with genotypes 2 and 3 marked the first time that all-oral therapy was available for HCV-infected patients in the United States.

In October 2014, the FDA approved the first oral combination drug for chronic hepatitis C, ledipasvir/sofosbuvir (Harvoni). Ledipasvir was the first NS5A replication complex inhibitor to receive approval for use in the United States. Combination ledipasvir/sofosbuvir treatment of genotype 1 patients for 12 weeks was associated with an SVR of 96-99% in noncirrhotic patients and 94% in cirrhotic patients. An SVR of 97% was achieved when ledipasvir/sofosbuvir was administered for 8 weeks in patients with genotype 1 and a viral load below 6 million IU/mL. In previously treated patients, SVR rates of rates of 94% were seen in noncirrhotic patients who were treated with ledipasvir/sofosbuvir for 12 weeks and 99% in cirrhotic patients who were treated with ledipasvir/sofosbuvir for 24 weeks. [12, 13, 14] Ledipasvir/sofosbuvir subsequently received FDA approval for use in patients with genotypes 4, 5, and 6, patients with HCV/HIV coinfection; liver transplant recipients infected with genotype 1 or 4; and patients with genotype 1 and decompensated cirrhosis.

In November 2014, the FDA approved an all-oral regimen of simeprevir plus sofosbuvir for treatment-naïve or treatment-experienced patients (with or without cirrhosis). [15] The approval for simeprevir plus sofosbuvir was based on the COSMOS study, an open-label, randomized phase II clinical trial. For all patients (treatment-naïve and treatment-experienced, with or without cirrhosis), 93% achieved SVR12 after 12 weeks of treatment, and 97% achieved SVR12 after 24 weeks of treatment. [15]

In December 2014, the FDA approved for patients with genotype 1 infection the combination of paritaprevir (an NS3/4A protease inhibitor), ritonavir (a protease inhibitor that functions as a CYP3A inhibitor to boost the level of paritaprevir), ombitasvir (an NS5A replication complex inhibitor), and dasabuvir (a non-nucleoside NS5B polymerase inhibitor).

This combination, known by the brand name Viekira Pak or as PrOD (in the American Association for the Study of Liver Diseases/Infectious Diseases Society of America [AASLD/IDSA] guidelines), is often used in combination with ribavirin. It is FDA approved for use in noncirrhotic patients and in patients with compensated cirrhosis. Studies were conducted using two tablets of paritaprevir/ritonavir/ombitasvir once daily (in the morning) plus one tablet of dasabuvir 250 mg twice daily (morning and evening) with a meal with ribavirin (up to 6 pills divided into two daily doses) for 12 weeks (no cirrhosis or compensated cirrhosis with genotype 1b infection) or 24 weeks (compensated cirrhosis with genotype 1a infection). SVR rates of 89-99% were reported, depending on the genotype subtype and the presence of cirrhosis. [16, 17, 18, 19, 20]

The Viekira Pak package insert was amended in October 2015. Several cases of hepatic decompensation and death were reported after PrOD therapy was initiated in patients with moderate to severe hepatic impairment (Child-Pugh B and C). The use of PrOD is now contraindicated in these groups. [21]

In July 2015, the combination product paritaprevir/ritonavir/ombitasvir (Technivie) received FDA approval. [22] It is used in combination with ribavirin for the treatment of patients with genotype 4 patients without cirrhosis. In the PEARL-1 study, treatment with PrO plus ribavirin resulted in an SVR rate of 100%. Patients treated with PrO without ribavirin achieved an SVR rate of 91%. [23]

Also in July 2015, daclatasvir (Daklinza), an NS5A inhibitor, received FDA approval for use with sofosbuvir in patients with genotype 3 infection. [24, 25, 26] Daclatasvir was discontinued from the worldwide market 2018 after highly effective, shorter duration HCV regimens emerged.

In January 2016, a fixed-dose combination pill of elbasvir (an NS5A replication complex inhibitor) and grazoprevir (an NS3/4A protease inhibitor) received FDA approval for use in patients with genotype 1 or 4 infection. [27] The elbasvir/grazoprevir combination (Zepatier)—with or without ribavirin— was also approved for use in patients with HCV/HIV coinfection and in patients with compensated cirrhosis. Use in patients with decompensated cirrhosis was contraindicated owing to concerns that such patients could experience high grazoprevir plasma concentrations, putting them at risk for liver dysfunction. Importantly, elbasvir/grazoprevir received approval for use in patients with severe renal impairment, including patients underoging hemodialysis.

AASLD/IDSA guidelines

Treatment for chronic HCV is based on guidelines from the AASLD and the IDSA, in collaboration with the International Antiviral Society-USA (IAS-USA). [28] These guidelines are constantly being updated. For more information, see HCV Guidelines: Recommendations for Testing, Managing, and Treating Hepatitis C.

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HCV Genotype 1a Infection

Treatment-naïve patients

The following options have similar efficacy [28] :

HCV genotype 1a treatment-naïve patients without cirrhosis

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks if no baseline nonstructural protein 5A (NS5A) resistance-associated substitutions (RASs) for elbasvir are detected
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 8 weeks for non-Black patients, non-HIV-infected persons, and those whose HCV RNA level is below 6 million IU/mL
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

HCV genotype 1a treatment-naïve patients with compensated cirrhosis

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks for those with no baseline NS5A RASs for elbasvir
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Treatment-experienced patients with previous treatment failure

Patients with HCV genotype 1a infection who do not have cirrhosis, in whom prior PEG-IFN and RBV treatment has failed

The recommended regimens are as follows [28] :

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks (without baseline NS5A RASs for elbasvir)
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Patients with HCV genotype 1a infection who have compensated cirrhosis, in whom prior PEG-IFN and RBV treatment has failed

The recommended regimens are as follows [28] :

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks (without baseline NS5A RASs for elbasvir)
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks
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HCV Genotype 1b Infection

Treatment-naïve patients

There are several options with similar efficacy recommended for treatment-naive patients with HCV genotype 1b infection, as follows [28] :

HCV genotype 1b treatment-naïve patients without cirrhosis

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 8 weeks for non-Black persons, non-HIV-infected patients, and those whose HCV RNA level is below 6 million IU/mL
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

HCV genotype 1b treatment-naïve patients with compensated cirrhosis

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Treatment-experienced patients with previous treatment failure

Patients with HCV genotype 1b infection who do not have cirrhosis, in whom prior PEG-IFN and RBV treatment has failed

The recommended regimens are as follows [28] :

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks 
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks 
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Patients with HCV genotype 1b infection who have compensated cirrhosis, in whom prior PEG-IFN and RBV treatment has failed

The recommended regimens are as follows [28] :

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks
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HCV Genotype 2 Infection

Treatment-naïve patients

HCV genotype 2 treatment-naïve patients without cirrhosis or with compensated cirrhosis

The recommended regimens are as follows [28] :

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Treatment-experienced patients with previous IFN or RBV treatment failure

HCV genotype 2 PEG-IFN/ribavirin treatment-experienced patients with or without compensated cirrhosis

The recommended regimens are as follows [28] :

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks (without cirrhosis) or for 12 weeks (with compensated cirrhosis)
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Patients with genotype 2 in whom a prior treatment with sofosbuvir and ribavirin has failed

The recommended regimens are as follows:

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks
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HCV Genotype 3 Infection

Treatment-naïve patients

HCV genotype 3 treatment-naïve patients without cirrhosis or with compensated cirrhosis

The recommended regimens are as follows [28] :

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Treatment-experienced patients with previous PEG-IFN and RBV treatment failure

Patients without cirrhosis [28]

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks

Patients with compensated cirrhosis [28]

  • Daily fixed-dose elbasvir (50 mg)/grazoprevir (100 mg) plus sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks

Patients with sofosbuvir and RBV treatment failures [28]

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) for 12 weeks
  • Weight-based ribavirin for 12 weeks for individuals with prior NS5A inhibitor failure and cirrhosis
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HCV Genotype 4 Infection

Treatment-naïve patients

HCV genotype 4 treatment-naïve patients without cirrhosis or with compensated cirrhosis [28]

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

Treatment-experienced patients with previous IFN and RBV treatment failure

The recommended regimens are as follows [28] :

HCV genotype 4 PEG-IFN/ribavirin treatment-experienced patients without cirrhosis

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks for patients who had virologic relapse after previous PEG-IFN/ribavirn treatment
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

HCV genotype 4 PEG-IFN/ribavirin treatment-experienced patients with compensated cirrhosis

  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks for individuals who had virologic relapse after previous PEG-IFN/ribavirin treatment
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks
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HCV Genotypes 5 or 6 Infection

Treatment-naïve patients

The recommended regimen is [28] :

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

Treatment-experienced patients with previous IFN and RBV treatment failure

The recommended regimen is [28] :

  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) for 8 weeks for patients without cirrhosis OR for 12 weeks for patients with compensated cirrhosis
  • Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks
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Drug Dosage Adjustments in Patients With Renal Insufficiency

No dose adjustment in direct-acting antivirals is required when using recommended regimens. [28]

Drug regimens that do not require dosage adjustment if eGFR ≥30 mL/min

See the following regimens:

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) [29]
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) [30]
  • Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) [31]
  • Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) [32]
  • Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) [33]

Recommended regimens for eGFR < 30 mL/min or end-stage renal disease

See the regimens below:

  • Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) [29]
  • Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) [30]
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Questions & Answers

Overview

What are the goals of treatment for hepatitis C virus (HCV) infection?

How is sustained virologic response (SVR) defined in the treatment of hepatitis C virus (HCV) infection?

What is the role of pegylated interferon and ribavirin in the treatment of hepatitis C virus (HCV) infection?

What is the role of protease inhibitors in the treatment of hepatitis C virus (HCV) infection?

What is the role of sofosbuvir in the treatment of hepatitis C virus (HCV) infection?

What is the role of Viekira Pak in the treatment of hepatitis C virus (HCV) infection?

What is the role of paritaprevir/ritonavir/ombitasvir (Technivie) in the treatment of hepatitis C virus (HCV) infection?

What is the role of daclatasvir (Daklinza) in the treatment of hepatitis C virus (HCV) infection?

What is the role of combined elbasvir/grazoprevir (Zepatier)in the treatment of hepatitis C virus (HCV) infection?

Which organizations have issued guidelines on the treatment of hepatitis C virus (HCV) infection?

What are the treatment regimens for hepatitis C virus (HCV) genotype 1a in treatment-naïve patients?

What are the treatment regimens for hepatitis C virus (HCV) genotype 1a following prior PEG-IFN and RBV treatment failure?

What are the treatment regimens for hepatitis C virus (HCV) genotype 1b in treatment-naïve patients?

What are the treatment regimens for hepatitis C virus (HCV) genotype 1b following prior PEG-IFN and RBV treatment failure?

What are the treatment regimens for hepatitis C virus (HCV) genotype 2 in treatment-naïve patients?

What are the treatment regimens for hepatitis C virus (HCV) genotype 2 following prior PEG-IFN and RBV treatment failure?

What are the treatment regimens for hepatitis C virus (HCV) genotype 3 in treatment-naïve patients?

What are the treatment regimens for hepatitis C virus (HCV) genotype 3 following prior PEG-IFN and RBV treatment failure?

What are the treatment regimens for hepatitis C virus (HCV) genotype 4 in treatment-naïve patients?

What are the treatment regimens for hepatitis C virus (HCV) genotype 4 following prior PEG-IFN and RBV treatment failure?

What are the treatment regimens for hepatitis C virus (HCV) genotype 5 or 6 in treatment-naïve patients?

What are the treatment regimens for hepatitis C virus (HCV) genotype 5 or 6 following prior PEG-IFN and RBV treatment failure?

When is a dose adjustment required in direct acting antivirals for the treatment of hepatitis C virus (HCV) infection?

Which regimens do not require dose adjustment for the treatment of hepatitis C virus (HCV) infection in patients with eGFR 30 mL/min or higher?

What are the recommended treatment regimens for the treatment of hepatitis C virus (HCV) infection in patients with eGFR <30 mL/min?

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