Hepatitis C Organism-Specific Therapy 

Updated: Nov 22, 2015
  • 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 weight based (ie, 1000 mg [<75 kg] to 1200 mg [≥75 kg]).

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 initial clinical trials with peginterferon alfa-2a utilized ribavirin at a dose of 1000-1200 mg per day (in 2 divided doses). [8] The initial clinical trials with peginterferon alfa-2b utilized ribavirin at a dose of 800-1400 mg per day. [9] Trials published in 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.

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 will be discontinued in the United States by December 2015.

A third protease inhibitor, simeprevir, received FDA approval in November 2013 for use in patients infected with HCV genotype 1. Simprevir's initial approval specified that medication be used in combination with peginterferon and ribavirin in patients with compensated liver disease. However, the naturally-occuring 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). Ledipasivr 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 ledipasir/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]

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] The dose was 60 mg PO once daily plus sofosbuvir 400 mg once daily. [25] In the ALLY-3 study, SVR12 was achieved in 98% of treatment-naïve patients and 92% of treatment-experienced patients without cirrhosis. Patients with cirrhosis had reduced SVR rates of 58% and 69%, respectively, in treatment-naïve and treatment-experienced patients. [25]  However, improved SVR rates were seen when ribavirin was added to the regimen of daclatasvir plus sofosbuvir. As an example, the SVR rate in treatment-experienced cirrhotic patients increased to 87%. [26]

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). [27] 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-naive patients

The following options have similar efficacy [27] :

  1. Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  2. Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus  twice-daily dasabuvir (250 mg) and ribavirin for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis)
  3. Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without ribavirin, for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis without Q80 polymorphism)
  4. Daily daclatasvir (60 mg) and sofosbuvir (400 mg), for 12 weeks (no cirrhosis) or 24 weeks with or without ribavirin (cirrhosis)

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 [27] :

  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus  twice-daily dasabuvir (250 mg) and ribavirin for 12 weeks
  • Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without ribavirin for 12 weeks
  • Daily daclatasvir (60 mg) plus sofosbuvir (400 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 [27] :

  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks.
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) plus ribavirin for 12 weeks
  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dasabuvir (250 mg) and ribavirin for 24 weeks
  • Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without ribavirin, for 24 weeks (HCV genotype 1a infection negative for Q80K variant)
  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg), with or without ribavirin, for 24 weeks

Patients without advanced fibrosis, in whom a previous sofosbuvir plus RBV or sofosbuvir plus RBV with PEG-INF treatment have failed

The recommended regimens are as follows [27] :

  • Patients with no cirrhosis: Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Patients with cirrhosis: Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg), with or without ribavirin, for 24 weeks

Patients without cirrhosis who have HCV genotype 1 infection, regardless of subtype, in whom a prior treatment with an HCV NS3 protease inhibitor plus PEG-IFN, and RBV has failed

The recommended regimens are as follows [27] :

  • Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Patients without cirrhosis in whom prior treatment with simeprevir plus sofosbuvir has failed: Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) plus ribavirin for 12 weeks

Patients with cirrhosis who have HCV genotype 1 infection, regardless of subtype, in whom prior PEG-IFN, RBV, and an HCV protease inhibitor regimen has failed

The recommended regimens are as follows [27] :

  • Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks; addition of ribavirin to ledipasvir/sofosbuvir is recommended for patients with cirrhosis in whom prior treatment with the HCV protease inhibitor simeprevir plus sofosbuvir has failed
  • Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) plus ribavirin for 12 weeks; patients with cirrhosis who have HCV genotype 1 infection, in whom prior treatment with the HCV protease inhibitor simeprevir plus sofosbuvir has failed should not be treated with this 12-week regimen

 

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HCV Genotype 1b Infection

Treatment-naïve patients

There are generally three options with similar efficacy recommended for treatment-naive patients with HCV genotype 1b infection, as follows [27] :

  1. Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  2. Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dasabuvir (250 mg) for 12 weeks; addition of ribavirin is recommended in patients with cirrhosis
  3. Daily sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis), with or without weight-based ribavirin
  4. Daily daclatasvir (60 mg) and sofosbuvir (400 mg) for 12 weeks (no cirrhosis) or 24 weeks, with or without weight-based ribavirin, (cirrhosis) for treatment-naive patients with HCV genotype 1b infection

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 [27] :

  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis)
  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dasabuvir (250 mg) for 12 weeks
  • Daily sofosbuvir (400 mg) plus simeprevir (150 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 [27] :

  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) plus ribavirin for 12 weeks
  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus  twice-daily dasabuvir (250 mg) and ribavirin for 12 weeks
  • Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without ribavirin, for 24 weeks

Patients in whom a previous sofosbuvir plus RBV or sofosbuvir plus RBV with PEG-INF treatment has failed

The recommended regimens are as follows:

  • Patients with no cirrhosis: Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Patients with cirrhosis: Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg), with or without ribavirin, for 24 weeks

Patients without cirrhosis who have HCV genotype 1 infection, regardless of subtype, in whom a prior treatment with an HCV NS3 protease inhibitor plus PEG-IFN and RBV have failed

The recommended regimens are as follows [27] :

  • Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Patients without cirrhosis in whom prior treatment with simeprevir plus sofosbuvir has failed: Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) plus ribavirin for 12 weeks

Patients with cirrhosis who have HCV genotype 1 infection, regardless of subtype, in whom prior PEG-IFN, RBV, and an HCV protease inhibitor regimen has failed

The recommended regimens are as follows [27] :

  • Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks
  • In patients with failed treatment with simprevir plus sofosbuvir, daily fixed dose ledipasvir (90 mg) plus  sofosbuvir 400 mg plus weight-based ribavirin for 12 weeks
  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg), with or without weight-based ribavirin, for 24 weeks

Patients with cirrhosis who have HCV genotype 1 infection, regardless of subtype, in whom prior PEG-IFN, RBV, sofosbuvir or simprevir plus sofosbuvir has failed

The recommended regimens are as follows  [27] :

  • Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks
  • Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based ribavirin for 12 weeks
  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg), with or without weight-based ribavirin, for 24 weeks
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HCV Genotype 2 Infection

Treatment-naive patients

The recommended regimens are as follows:

  • Daily sofosbuvir 400 mg plus  ribavirin for 12 weeks [27] (NOTE: This regimen, described in the phase III VALENCE trial, may be utilized in both treatment-naïve and treatment-experienced patients. [28] The SVR rate was 97% in treatment-naïve patients and 90% in treatment-experienced patients.) The regimen may be extended up to 16 weeks for treatment-naïve patients with cirrhosis.
  • Daily daclatasvir (60 mg ) plus sofosbuvir (400 mg) for 12 weeks, in patients who cannot tolerate ribavirin

Treatment-experienced patients with previous treatment failure

The recommended regimens are as follows:

  • Daily sofosbuvir (400 mg) and  ribavirin for 16 to 24 weeks [27]
  • Daily sofosbuvir (400 mg) plus  ribavirin plus weekly pegylated interferon for 12 weeks, in interferon-eligible patients

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

The recommended regimens are as follows:

  • Daily sofosbuvir (400 mg) plus  weight-based ribavirn plus weekly pegylated interferon for 12 weeks
  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg), with or without weight-based ribavirin, for 24 weeks

 

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HCV Genotype 3 Infection

Treatment-naive patients

Daclatasvir (Daklinza), an NS5A inhibitor, was FDA approved in July 2015 for use with sofosbuvir for chronic HCV genotype 3 infection. [24]

The recommended regimens are as follows:

  • Daily sofosbuvir 400 mg PO once per day plus    daily ribavirin plus  weekly pegylated interferon for 24 weeks (NOTE: This regimen, described in the phase III VALENCE trial, may be utilized in both treatment-naïve patients and treatment-experienced patients. [28] The SVR rate was 93% in treatment-naïve patients and 77% in treatment-experienced patients.)
  • Daily sofosbuvir (400 mg) plus weight-based ribavirin for 24 weeks
  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks (no cirrhosis) or 24 weeks, with or without weight-based RBV (cirrhosis)

Treatment-experienced patients with previous treatment failure

The recommended regimens are as follows for patients without cirrhosis [27] :

  • Daily sofosbuvir (400 mg) plus  weight-based ribavirin plus weekly pegylated interferon for 12 weeks
  • Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks

The recommended regimens are as follows for patients with cirrhosis [27] :

  • Daily sofosbuvir (400 mg) plus  weight-based ribavirin plus weekly pegylated interferon for 12 weeks
  • Daily daclatasvir (60 mg) plus  sofosbuvir (400 mg) plus weight-based ribavirin for 24 weeks
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HCV Genotype 4 Infection

New treatment for HCV genotype 4

The combination product ombitasvir/paritaprevir/ritonavir (Technivie) was FDA approved in July 2015. [22]  It is indicated for genotype 4 chronic HCV infection without cirrhosis in patients who were either treatment naïve or did not achieve a virologic response with prior treatment with pegylated interferon/ribavirin (peg-IFN/RBV).

Treatment-naïve patients

Three options with similar efficacy are typically recommended for treatment-naive patients with HCV genotype 4 infection, as follows [27] :

  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin for 12 weeks
  • Daily sofosbuvir (400 mg) plus weight-based ribavirin for 24 weeks

An alternate regimen is the following [27] :

  • Daily sofosbuvir (400 mg) plus  weight-based ribavirin plus weekly pegylated interferon for 12 weeks

Treatment-experienced patients with previous treatment failure

The recommended regimens are as follows [27] :

  • Daily sofosbuvir (400 mg)  plus weight-based ribavirin for 24 weeks
  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  • Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin for 12 weeks
  • Daily sofosbuvir (400 mg) plus  weight-based ribavirin plus weekly pegylated interferon for 12 weeks
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HCV Genotypes 5 or 6 Infection

Treatment-naïve patients

The recommended regimen is:

  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks [27]

An alternative regimen is [27] :

  • Daily sofosbuvir (400 mg) plus  weight-based ribavirin plus weekly pegylated interferon for 12 weeks

Treatment-experienced patients with previous treatment failure

The recommended regimen is:

  • Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks [27]

An alternative regimen is [27] :

  • Daily sofosbuvir (400 mg) plus  weight-based ribavirin plus weekly pegylated interferon for 12 weeks
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Drug Dosage Adjustments in Patients With Renal Insufficiency

Peginterferon alfa-2a

Note the following:

  • Creatinine clearance (CrCl) <50 mL/min: Caution is advised
  • End-stage renal disease on hemodialysis: Reduce dose to 135 µg SC once weekly

Peginterferon alfa-2b

Note the following:

  • CrCl 30-50 mL/min: Reduce the dose by 25%
  • CrCl <30 mL/min: Reduce the dose by 50% [8]

Ribavirin

Current AASLD/ISDA guidelines recommend the following regarding use of ribavirin in patients with renal impairment [27] :

  • CrCl 30-50 mL/min/1.73 m 2: Reduce the dose of ribavirin to 200 mg PO alternating with 400 mg PO every other day
  • For patients with CrCl <30 mL/min/1.73 m 2: Reduce the dose of ribavirin to 200 mg PO per day
  • Hemodialysis: Consider treatment with ribavirin 200 mg PO per day

Simeprevir or ombitasvir/paritaprevir/ritonavir and dasabuvir

Dose adjustments are not required for patients with mild, moderate, or severe renal impairment. Simeprevir is highly bound to plasma proteins; dialysis is not likely to result in significant removal of simeprevir. [10]

Sofosbuvir or ledipasvir/sofosbuvir

Dose adjustments are not required for patients with mild or moderate renal impairment. Dosing has not been established for patients with CrCl less than 30 mL/min or for patients with end-stage renal disease on hemodialysis. [11]

Daclatasvir

Dose adjustments are not required for patients with mild, moderate, or severe renal impairment. Daclatasvir is highly protein bound to plasma proteins; dialysis is not likely to result in significant removal of daclatasvir. [29]

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