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Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults
Authors:
Sanjiv Chopra, MD, MACP
Camilla S Graham, MD
Section Editor:
Adrian M Di Bisceglie, MD
Deputy Editor:
Allyson Bloom, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Aug 23, 2017.

INTRODUCTION — Hepatitis C virus (HCV) can cause both acute and chronic hepatitis. The acute process is self-limited, rarely causes hepatic failure, and usually leads to chronic infection. Chronic HCV infection often follows a progressive course over many years and can ultimately result in cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection".)

The goal of treatment is to eradicate HCV RNA, which is predicted by the achievement of a sustained virologic response (SVR) as defined by the absence of HCV RNA by polymerase chain reaction (PCR) 12 weeks after stopping treatment. An SVR is associated with a 99 percent chance of being HCV RNA negative during long-term follow-up and can therefore be considered cure of the HCV infection [1]. Achievement of an SVR has also been associated with improved clinical outcomes. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Goals of therapy'.)

This topic will review the treatment of patients with chronic genotype 2 and 3 HCV infection. General management of chronic HCV, the selection of patients for treatment, antiviral treatment of patients with other genotypes, and the treatment of acute HCV infection are discussed elsewhere:

(See "Overview of the management of chronic hepatitis C virus infection".)

(See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection".)

(See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults".)

(See "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults".)

(See "Clinical manifestations, diagnosis, and treatment of acute hepatitis C virus infection in adults".)

GUIDELINES — Guidelines for the diagnosis and management of HCV infection were released jointly by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) in 2014, are continuously updated, and can be accessed at www.hcvguidelines.org [2]. The discussion in this topic is generally consistent with those guidelines.

Other guidelines include treatment recommendations from the European Association for the Study of the Liver (EASL) [3]. The World Health Organization (WHO) also released guidelines in 2014 on screening and treatment of HCV intended primarily for clinicians and policy-makers in low- and middle-income countries [4].

Links to these and other guidelines can be found below. (See 'Society guideline links' below.)

DEFINITIONS — Specific terms have been used to define genotype 2 and 3 patient populations based on their exposure and prior response to therapy:

Treatment-naïve – Patients who have never received any treatment for HCV

Treatment-experienced – Patients who have failed prior treatment for HCV. This refers to:

Peginterferon and ribavirin failure – Patients who did not respond to or relapsed after treatment with peginterferon and ribavirin (without direct-acting antiviral exposure)

Sofosbuvir failures – Patients who did not respond to or relapsed after treatment with a regimen that contained sofosbuvir (but did not contain an NS5A inhibitor)

NS5A inhibitor failures – Patients who did not respond to or relapsed after treatment with a regimen containing an NS5A inhibitor (such as daclatasvir)

Throughout the topic, the terms interferon and peginterferon refer to interferon-alfa and peginterferon-alfa, specifically.

EPIDEMIOLOGY AND NATURAL HISTORY OF GENOTYPES 2 AND 3 INFECTION — In the United States, HCV genotypes 2 and 3 are less prevalent than genotype 1 infection, with genotype 2 comprising approximately 15 percent of infections and genotype 3 representing less than 10 percent. Genotypes 2 and 3 are more common in Europe than in the United States, and genotype 3 is very common in South Asia (figure 1). (See "Epidemiology and transmission of hepatitis C virus infection" and "Characteristics of the hepatitis C virus", section on 'Genotypes'.)

The natural history of genotypes 2 and 3 is similar to genotype 1 in that patients are at risk for development of cirrhosis, decompensated liver disease, and hepatocellular carcinoma. Genotype 3 is also uniquely associated with an increase in hepatic steatosis, which is believed to be related to direct effects on lipid metabolism in liver cells [5]. In general, management of liver disease and evaluation for treatment is similar for all HCV genotypes. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection" and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection" and "Overview of the management of chronic hepatitis C virus infection", section on 'General management'.)

SELECTION OF TREATMENT REGIMEN — There have been remarkable advances in HCV drug development over the last few years, and the goals of many regimens in development have been to increase sustained virologic response (SVR) rates, improve tolerability, eliminate interferon and ribavirin, shorten duration of treatment, and improve the convenience of regimen administration. An all-oral regimen that meets many of these objectives for most patients with genotype 2 and 3 infection became possible with the introduction of sofosbuvir, a nucleotide analogue that potently inhibits HCV viral replication through interference with RNA-dependent RNA polymerase function (NS5B polymerase inhibitor).

The introductions of sofosbuvir-velpatasvir and subsequently glecaprevir-pibrentasvir, each a highly effective once-daily pangenotypic combination regimen, offer the opportunity to streamline antiviral treatment for most patients. Antiviral selection among patients without cirrhosis or with compensated cirrhosis is discussed by genotype in the sections that follow. (See 'Genotype 2' below and 'Genotype 3' below.)

Treatment of patients with decompensated cirrhosis is discussed elsewhere. (See 'Patients with decompensated cirrhosis' below.)

Genotype 2

No prior direct-acting antiviral exposure — For genotype 2-infected patients who are treatment naïve or have failed prior treatment with peginterferon and ribavirin, we suggest sofosbuvir-velpatasvir (for 12 weeks for all patients) or glecaprevir-pibrentasvir (for 8 weeks for patients without cirrhosis and 12 weeks for patients with compensated cirrhosis) (algorithm 1). These regimens are extremely effective against genotype 2 and do not require the addition of ribavirin. The choice between them depends primarily on the potential for drug interactions and patient preference regarding dosing (eg, glecaprevir-pibrentasvir is three pills once daily with food but can be given for 8 rather than 12 weeks in the absence of cirrhosis).

The following studies illustrate their efficacy:

Sofosbuvir-velpatasvir – In the initial trials, there were no cases of virologic failure or relapse among genotype 2-infected patients treated with sofosbuvir-velpatasvir for 12 weeks [6-8]. As an example, a randomized, placebo-controlled trial reported SVR in 100 percent of the 104 genotype 2-infected individuals, 10 of whom had cirrhosis and 25 of whom had previously failed treatment (predominantly with peginterferon and ribavirin) [6]. In a separate trial that included 266 patients with genotype 2 infection (14 percent with cirrhosis and 14 percent with prior treatment failure), the SVR rate was 99 percent with sofosbuvir-velpatasvir for 12 weeks compared with 95 percent with sofosbuvir plus ribavirin for 12 weeks [7]. The one patient who did not achieve SVR with sofosbuvir-velpatasvir had discontinued therapy early on for adverse effects. (See 'Sofosbuvir-velpatasvir' below.)

Glecaprevir-pibrentasvir – In a trial of 145 patients with genotype 2 infection without cirrhosis, glecaprevir-pibrentasvir for eight weeks resulted in an SVR rate of 98 percent [9]. A 12-week course for such patients was not associated with a higher SVR rate [10]. In a separate study of patients with compensated cirrhosis that included 31 genotype 2-infected patients, the SVR rate was 100 percent with glecaprevir-pibrentasvir for 12 weeks [11]. (See 'Glecaprevir-pibrentasvir' below.)

For patients who do not have access to sofosbuvir-velpatasvir or glecaprevir-pibrentasvir, daclatasvir plus sofosbuvir for 12 to 24 weeks appears to be effective (with the longer duration used for patients with cirrhosis), although this regimen has been studied in only a small number of genotype 2-infected patients [12,13].

In regions that do not have access to newer direct-acting antivirals (DAAs), such as sofosbuvir, treatment with peginterferon and ribavirin (800 mg daily dose) for 24 weeks is a fairly effective and relatively inexpensive treatment choice for those who can tolerate interferon. In a meta-analysis of eight trials that included 1050 genotype 2 patients who received peginterferon and ribavirin for 24 weeks, the overall SVR was 74 percent, with a range of 64 to 93 percent [14]. Nevertheless, because of the extensive adverse events associated with interferon, if all-oral regimens are available, we recommend that these be selected for use instead.

Prior DAA failure — For genotype 2-infected patients with prior failure with a direct-acting antiviral (DAA)-based regimen, potential options for retreatment depend on the precise treatment history.

Prior sofosbuvir (without NS5A inhibitor) – For patients with genotype 2 infection who have failed sofosbuvir plus ribavirin, we suggest glecaprevir-pibrentasvir (for 8 weeks for patients without cirrhosis and 12 weeks for patients with compensated cirrhosis) or sofosbuvir-velpatasvir for 12 weeks. The choice between them primarily depends on the potential for drug interactions and patient preference regarding dosing (eg, glecaprevir-pibrentasvir is three pills once daily with food but can be given for 8 rather than 12 weeks in the absence of cirrhosis).

Data evaluating the use of glecaprevir-pibrentasvir in sofosbuvir-experienced patients are limited since there were very few such genotype 2-infected patients in the registration trials [9,11]. However, the mechanism of action is distinct from that of sofosbuvir, so efficacy is expected to be intact.

Sofosbuvir-velpatasvir is supported by a study that included 32 genotype 2-infected patients who had previously failed sofosbuvir plus ribavirin, of whom 97 percent achieved SVR with sofosbuvir-velpatasvir for 12 weeks [15].

Daclatasvir plus sofosbuvir with or without weight-based ribavirin for 24 weeks is another potential option, although data are extremely limited.

Prior sofosbuvir plus NS5A inhibitor – For the rare genotype 2-infected patient who fails a sofosbuvir-velpatasvir (or other NS5A inhibitor) -based regimen, we suggest sofosbuvir-velpatasvir-voxilaprevir for 12 weeks, which resulted in SVR in all five genotype 2 patients with prior NS5A exposure in one trial [15]. Sofosbuvir-velpatasvir plus weight-based ribavirin for 24 weeks is an alternative [16].

Genotype 3

Treatment-naive — For treatment–naïve genotype 3-infected patients, we suggest sofosbuvir-velpatasvir or glecaprevir-pibrentasvir (algorithm 2). For patients without cirrhosis, daclatasvir plus sofosbuvir is an equally effective alternative. The choice between them depends primarily on the potential for drug interactions, whether the addition of ribavirin is warranted, reimbursement priorities, and patient preference regarding dosing (eg, glecaprevir-pibrentasvir is three pills once daily with food but can be given for 8 rather than 12 weeks in the absence of cirrhosis). Administration of each regimen depends on the presence of cirrhosis:

No cirrhosis – For treatment-naïve patients without cirrhosis, the regimen durations and expected efficacies are as follows:

Glecaprevir-pibrentasvir for eight weeks – Among 157 such patients, this regimen resulted in an SVR rate of 95 percent [17]. The response rate was equivalent to that with a 12-week course of glecaprevir-pibrentasvir, which resulted in an SVR rate of 95 percent among 233 patients and was, in turn, not statistically different than the SVR rate with 12 weeks of daclatasvir plus sofosbuvir (97 percent among 115 patients).

Sofosbuvir-velpatasvir for 12 weeks – Among 163 such patients, this regimen resulted in an SVR rate of 98 percent [7].

Daclatasvir plus sofosbuvir for 12 weeks – Among 76 and 115 such patients in two separate trials, this regimen resulted in SVR rates of 95 and 97 percent, respectively [17,18].

Other options are less preferable because they are of longer duration, include interferon, are more expensive without improved efficacy or safety, or have not been as well studied. The regimen of sofosbuvir plus ribavirin requires a duration of 24 weeks for optimal efficacy for genotype 3, with SVR rates of 90 to 95 percent in trials of treatment-naïve patients without cirrhosis [19,20], but lower rates have been reported in real-world cohorts [21,22]. Furthermore, sofosbuvir plus ribavirin for 24 weeks does not appear to be as effective as sofosbuvir plus peginterferon plus weight-based ribavirin for 12 weeks [20]. Although studies have suggested that ledipasvir-sofosbuvir with ribavirin for 12 weeks is effective for treatment-naïve genotype 3-infected patients without cirrhosis [23,24], concerns about the in vitro potency of ledipasvir against genotype 3 virus and the availability of superior regimens preclude recommending its use.

Cirrhosis – Treatment-naïve patients with compensated cirrhosis should undergo testing for the Y93H mutation, which has been associated with worse response to sofosbuvir-velpatasvir (and daclatasvir plus sofosbuvir). If glecaprevir-pibrentasvir is definitely going to be used, Y93H mutation testing is not necessary.

For treatment-naïve patients with compensated cirrhosis, regimen administration and expected efficacies are as follows:

Glecaprevir-pibrentasvir for 12 weeks – Among 40 such patients, this regimen resulted in an SVR rate of 98 percent [25].

Sofosbuvir-velpatasvir for 12 weeks, with weight-based ribavirin if the Y93H mutation is present – Among 43 such patients, sofosbuvir-velpatasvir (without ribavirin) for 12 weeks resulted in an SVR rate of 93 percent [7]. Among all genotype 3-infected participants in the study (including those without cirrhosis and those with prior treatment failure), the presence of baseline RASs in the NS5A gene, in particular the Y93H mutation, predicted a lower likelihood of SVR (97 percent without baseline RASs versus 88 and 84 percent with any RAS and the Y93H mutation, respectively). Thus, ribavirin is added when this mutation is present to try to improve the suboptimal SVR rate.

Daclatasvir plus sofosbuvir plus weight-based ribavirin is an alternative, but the optimal duration is uncertain. For patients with cirrhosis, we give it for 24 weeks with weight-based ribavirin, regardless of treatment history. With 12 weeks of treatment, SVR rates were only 73 percent among treatment-naïve patients with METAVIR F4 disease [18]. Other data suggest that adding ribavirin and/or extending the course to 24 weeks improves outcomes [26-29].

In regions that do not have access to these DAAs, treatment with peginterferon and ribavirin (800 mg daily dose) for 24 weeks is a modestly effective and relatively inexpensive treatment choice for those who can tolerate interferon. Genotype 3 HCV is less responsive than genotype 2 to this regimen. In a meta-analysis of eight trials that included 1225 genotype 3 patients who received peginterferon and ribavirin for 24 weeks, the overall SVR was 69 percent, with a range of 60 to 80 [14]. Among those with cirrhosis, SVR rates were less than 50 percent. Extension of treatment duration to 48 weeks does not appear to improve response rates [30]. Because of the extensive adverse events associated with interferon and the longer duration of interferon used, if DAA-based regimens are available, we recommend that these be selected for use instead.

Prior interferon/ribavirin failure — For genotype 3-infected patients who have failed prior treatment with peginterferon and ribavirin, we suggest sofosbuvir-velpatasvir or glecaprevir-pibrentasvir (algorithm 2). For patients without cirrhosis, daclatasvir plus sofosbuvir is likely an equally effective alternative. The choice between them depends primarily on the potential for drug interactions, whether the addition of ribavirin is warranted, and patient preference regarding dosing (eg, glecaprevir-pibrentasvir is three pills once daily with food). Administration of each regimen depends on the presence of cirrhosis:

No cirrhosis – Patients without cirrhosis who have failed prior treatment with peginterferon and ribavirin should undergo testing for the Y93H mutation, which has been associated with worse response to sofosbuvir-velpatasvir (and daclatasvir plus sofosbuvir). If glecaprevir-pibrentasvir is definitely going to be used, Y93H mutation testing is not necessary.

For patients without cirrhosis who have failed prior peginterferon and ribavirin, regimen administration and expected efficacies are as follows:

Glecaprevir-pibrentasvir for 16 weeks – In a randomized trial of 44 such patients, SVR rates were higher when this regimen was given for 16 compared with 12 weeks (96 versus 91 percent) [25].

Sofosbuvir-velpatasvir for 12 weeks, with weight-based ribavirin if the Y93H mutation is present – Among 34 such patients, sofosbuvir-velpatasvir (without ribavirin) for 12 weeks resulted in an SVR rate of 91 percent, and the presence of baseline NS5A RASs (and particularly the Y93H mutation) was associated with lower SVR rates [7]. Since the addition of ribavirin to sofosbuvir-velpatasvir was associated with higher SVR rates in a difficult-to-cure genotype 3-infected population in a separate small study [31], weight-based ribavirin is recommended when the Y93H mutation is detected in order to improve the relatively low response rates in treatment-experienced patients.

Daclatasvir plus sofosbuvir for 12 weeks, with weight-based ribavirin if the Y93H mutation is present – In a trial that included 43 treatment-experienced patients with METAVIR F0-F3, daclatasvir plus sofosbuvir (without ribavirin) for 12 weeks resulted in an SVR rate of 91 percent [18]. The presence of NS5A RASs is associated with lower SVR rates with this regimen as well, and the rationale for adding ribavirin is the same as for sofosbuvir-velpatasvir.

Other options for genotype 3 are less preferable because they are of longer duration, include interferon, are more expensive without improved efficacy or safety, or have not been as well studied. The regimen of sofosbuvir plus ribavirin requires a duration of 24 weeks for optimal efficacy for genotype 3, with SVR rates of 81 to 87 percent in trials of peginterferon and ribavirin-experienced patients without cirrhosis [19,20], but lower rates have been reported in real-world cohorts [21,22]. Furthermore, sofosbuvir plus ribavirin for 24 weeks does not appear to be as effective as sofosbuvir plus peginterferon plus weight-based ribavirin for 12 weeks [20].

Cirrhosis – For patients with cirrhosis who have failed prior treatment with peginterferon and ribavirin, the regimen administration and expected efficacies are as follows:

Glecaprevir-pibrentasvir for 16 weeks – Among 47 such patients, this regimen resulted in an SVR rate of 96 percent [25].

Sofosbuvir-velpatasvir plus weight-based ribavirin for 12 weeks – Among 37 such patients, sofosbuvir-velpatasvir (without ribavirin) for 12 weeks resulted in an SVR rate of 89 percent [7]. However, in a separate study that included 42 similar patients, there was a trend towards higher SVR rates with the addition of ribavirin (96 versus 88 percent without ribavirin) [31].

Daclatasvir plus sofosbuvir plus weight-based ribavirin is an alternative, but the optimal duration is uncertain. For patients with cirrhosis, we give it for 24 weeks with weight-based ribavirin, regardless of treatment history. With 12 weeks of treatment, SVR rates were only 73 percent among treatment-naïve patients with METAVIR F4 disease [18]. Other data suggest that adding ribavirin and/or extending the course to 24 weeks improves outcomes [26-29].

Prior DAA failure — For genotype 3-infected patients with prior failure with a direct-acting antiviral (DAA)-based regimen, potential options for retreatment depend on the precise treatment history (algorithm 2):

Prior sofosbuvir failure (without NS5A inhibitor) – For patients who failed a sofosbuvir-containing regimen but had no NS5A inhibitor exposure, we suggest sofosbuvir-velpatasvir-voxilaprevir for 12 weeks or glecaprevir-pibrentasvir for 16 weeks. The choice between them depends primarily on the potential for drug interactions and patient preference regarding dosing.

In a randomized trial that included 106 genotype 3-infected patients who had failed a sofosbuvir-containing regimen (without an NS5A inhibitor), sofosbuvir-velpatasvir-voxilaprevir resulted in a higher SVR rate than sofosbuvir-velpatasvir alone (96 versus 85 percent) [15].

Support for glecaprevir-pibrentasvir for 16 weeks in this population comes from a trial of 69 treatment-experienced patients, nearly half of whom had failed prior sofosbuvir plus ribavirin (with or without interferon); the SVR rate with this regimen was 96 percent among those with and without cirrhosis [25].

Prior sofosbuvir plus NS5A inhibitor – Options for genotype 3-infected patients who have failed an NS5A inhibitor-containing regimen are limited to sofosbuvir-velpatasvir-voxilaprevir for 12 weeks. In a study that included 78 genotype 3-infected patients who had previously received an NS5A-containing DAA regimen (56 of whom had compensated cirrhosis), sofosbuvir-velpatasvir-voxilaprevir for 12 weeks resulted in SVR in 95 percent [15]. Preexisting NS3 and NS5A resistance-associated substitutions (RASs) had no effect on outcomes [32]. Other available regimens (such as sofosbuvir-velpatasvir plus weight-based ribavirin for 24 weeks) do not appear to be as effective [16].

TREATMENT CONSIDERATION IN SPECIFIC POPULATIONS

HIV and HCV coinfection — Although studies with peginterferon and ribavirin therapy suggested that HIV/hepatitis C virus (HCV)-coinfected patients had lower response rates compared with HCV-monoinfected patients, SVR rates with regimens that contain a direct-acting antiviral (DAA) appear to be comparable. Thus, HIV/HCV-coinfected patients are treated with the same regimens recommended for monoinfected patients, although potential interactions with antiretroviral agents and DAA agents must be taken into consideration when selecting regimens.

The treatment of HCV in HIV/HCV-coinfected patients is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C virus infection in the HIV-infected patient".)

Patients with impaired renal function — The selection of an HCV antiviral regimen for patients with renal disease depends upon the extent of renal impairment in addition to the genotype, extent of underlying liver disease, and history of past antiviral treatment. Antiviral treatment in such patients is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C infection in adults with renal impairment".)

Patients with decompensated cirrhosis — Antiviral treatment of patients with decompensated cirrhosis (ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage) should only be undertaken by or in close consultation with an expert in the management of such patients, preferably at a transplant center. Patients with decompensated cirrhosis or a Model of End-Stage Liver Disease (MELD) score greater than 10 should be evaluated for liver transplantation prior to initiation of HCV therapy.

For patients with genotype 2 and 3 infection and decompensated cirrhosis, sofosbuvir-velpatasvir plus ribavirin for 12 weeks [33] or daclatasvir plus sofosbuvir plus ribavirin for 12 to 24 weeks [27] are effective options. Neither sofosbuvir nor daclatasvir require dose reduction in the setting of moderate to severe hepatic impairment (Childs class B or C). In patients with decompensated cirrhosis, anemia is common, so we recommend that ribavirin be initiated at a dose of 600 mg daily and slowly increased as tolerated (to a maximum of 1000 mg for <75 kg or 1200 mg for ≥75 kg).

These agents appear to be generally safe in patients with decompensated cirrhosis, although close monitoring is essential [27,28]. In a trial of sofosbuvir-velpatasvir with or without ribavirin in patients with decompensated cirrhosis, serious adverse events occurred in approximately 15 to 20 percent of patients, most commonly hepatic encephalopathy and sepsis [33]. In one study of 60 patients with advanced cirrhosis who were treated with 12 weeks of daclatasvir plus sofosbuvir plus ribavirin, grade 3 or 4 adverse events occurred in 11 patients (18 percent), but only four were attributed to the study medication [28]. Hemoglobin <9 g/dL occurred in 8 percent and total bilirubin >2.5 times the upper limit of normal in 15 percent; ribavirin was discontinued in 17 percent and the entire regimen in 2 percent because of adverse events.

Glecaprevir-pibrentasvir and sofosbuvir-velpatasvir-voxilaprevir are contraindicated in patients with Child-Pugh classes B and C cirrhosis because of increased drug levels in the setting of such hepatic impairment.

Patients with decompensated cirrhosis who are undergoing HCV antiviral therapy should have frequent clinical and laboratory monitoring, including monitoring of liver synthetic function. General management issues for patients with decompensated cirrhosis are discussed elsewhere. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Major complications'.)

Recurrence after liver transplantation — Recurrence of HCV occurs in more than 95 percent of patients after liver transplantation. However, the therapeutic options are limited in this population, and rigorous clinical trials are difficult to conduct. (See "Recurrence of hepatitis C virus infection following liver transplantation", section on 'Treatment of recurrence'.)

ADMINISTRATION OF TREATMENT REGIMENS

Sofosbuvir-velpatasvir — Sofosbuvir-velpatasvir is one of our preferred treatment regimens for most patients with genotype 2 and 3 infection. It is typically given for 12 weeks. For genotype 3-infected patients whether weight-based ribavirin (1000 mg daily dose for patients who weigh <75 kg or 1200 mg daily dose for ≥75 kg) is added depends on the presence of cirrhosis, the treatment history, and the presence of the NS5A resistance-associated variant Y93H. (See 'Genotype 2' above and 'Genotype 3' above.)

Sofosbuvir-velpatasvir is administered as a single combination pill once daily with or without food. Increased gastric pH levels may decrease absorption of velpatasvir. Although acid suppressing agents can be coadministered if necessary, if used with proton pump inhibitors, sofosbuvir-velpatasvir should be administered without food and taken four hours prior to a low dose of a proton pump inhibitor. Because of other expected and observed drug interactions, co-administration of sofosbuvir-velpatasvir is not recommended with several agents, including amiodarone, rifampin, rifabutin, rifapentine, St. John’s wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, and efavirenz.

The regimen is well tolerated, with the most common adverse effects being headache, nausea, nasopharyngitis, and insomnia [34]. If ribavirin is also used, precautions include potential for anemia and teratogenic effects. Additional details on the dosing, adverse effects, and drug interactions of velpatasvir-sofosbuvir are discussed elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Sofosbuvir-velpatasvir'.)

Glecaprevir-pibrentasvir — Glecaprevir-pibrentasvir is one of our preferred treatment regimens for most patients with genotype 2 and 3 infection. For genotype 2-infected and treatment-naïve genotype 3-infected patients it is given for 8 weeks for those without cirrhosis and for 12 weeks for those with cirrhosis. For genotype 3-infected patients who have failed peginterferon and ribavirin, it is given for 16 weeks. It is also effective in patients who have had prior sofosbuvir failure. (See 'Selection of treatment regimen' above.)

Glecaprevir-pibrentasvir is administered as three combination tablets once daily with food. It can be used in patients with any degree of renal impairment, but should not be used in patients with decompensated cirrhosis (Child Pugh Class B or C). Because of expected and observed drug interactions, coadministration is contraindicated with rifampin and atazanavir and not recommended with carbamazepine, oral contraceptive agents, St. John's wort, cyclosporine, and certain other antiretrovirals.

The regimen is well tolerated. In an analysis of pooled data from multiple clinical trials, including over 2000 patients with chronic HCV infection, most adverse effects were mild, with headache and fatigue the most common complaints [35]. Additional details on the dosing, adverse effects, and drug interactions of glecaprevir-pibrentasvir are discussed elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Glecaprevir-pibrentasvir'.)

Sofosbuvir-velpatasvir-voxilaprevir — Sofosbuvir-velpatasvir-voxilaprevir is a regimen option for genotype 2-infected patients who have failed an NS5A-containing regimen and for genotype 3-infected patients who have failed a sofosbuvir-containing regimen with or without an NS5A inhibitor. It is given for 12 weeks in such patients. (See 'Selection of treatment regimen' above.)

Sofosbuvir-velpatasvir-voxilaprevir is well tolerated, with <1 percent of trial participants discontinuing a 12-week regimen for adverse events. The most common adverse events are headache, fatigue, diarrhea, and nausea [15]. Coadministration is contraindicated with rifampin and is not recommended with amiodarone, anticonvulsants, St. John's wort, certain antiretrovirals, and cyclosporine. Increased gastric pH levels may decrease absorption of velpatasvir. Although acid suppressing agents can be coadministered if necessary, if used with proton pump inhibitors, sofosbuvir-velpatasvir-voxilaprevir should be administered without food and taken four hours prior to a low dose of a proton pump inhibitor. For other specific drug interactions, refer to the Lexi-Interact program included with UpToDate.

Additional adverse effects and drug information, including pharmacokinetics and potential drug interactions, for sofosbuvir-velpatasvir-voxilaprevir are discussed elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Sofosbuvir-velpatasvir-voxilaprevir'.)

Daclatasvir plus sofosbuvir — The interferon-free combination of daclatasvir and sofosbuvir is a highly effective alternate treatment regimen patients with genotype 2 infection and for patients with genotype 3 infection who do not have cirrhosis. It is not as effective in genotype 3-infected patients with cirrhosis. It is typically given for 12 to 24 weeks and for genotype 3-infected patients with or without weight-based ribavirin (1000 mg daily dose for patients who weigh <75 kg or 1200 mg daily dose for ≥75 kg), depending on the presence of cirrhosis, the treatment history, and the presence of the NS5A resistance-associated variant Y93H. (See 'Genotype 2' above and 'Genotype 3' above.)

Daclatasvir and sofosbuvir are initiated together. Daclatasvir is dosed as 60 mg orally once daily and sofosbuvir is dosed as 400 mg orally once daily; both can be taken with or without food. Because of observed and expected drug interactions, coadministration of daclatasvir plus sofosbuvir is not recommended with several agents, including amiodarone, rifampin, rifabutin, rifapentine, St. John’s wort, carbamazepine, phenytoin, phenobarbital, and oxcarbazepine. Daclatasvir is a CYP3A substrate and warrants dose adjustments when used with strong CYP3A inhibitors or moderate CYP3A inducers.

The regimen is well tolerated, with headache, fatigue, and nausea as the most commonly reported adverse effects [12,18]. If ribavirin is also used, precautions include potential for anemia and teratogenic effects. Additional details on the dosing, adverse effects, and drug interactions of daclatasvir and sofosbuvir can be found elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Daclatasvir' and "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Sofosbuvir'.)

Interferon-containing regimens — These are generally used only when other options are not available.

Peginterferon and ribavirin – We reserve the use of this regimen for patients who warrant treatment for genotype 2 or 3 HCV infection in regions where newer direct-acting antivirals (DAAs), such as sofosbuvir and daclatasvir, are not available.

Two formulations of peginterferon alfa are available worldwide, but local availability is variable. Although data are mixed regarding comparable efficacy, meta-analyses suggest a slight advantage for peginterferon alfa-2a [36,37]. For all these reasons, we suggest peginterferon alfa-2a rather than peginterferon alfa-2b when using an interferon-based regimen in patients with chronic HCV genotype 2 or 3 infection.

For peginterferon alfa-2a, the dose is 180 mcg subcutaneously per week

For peginterferon alfa-2b, the dose is 1.5 mcg/kg subcutaneously per week

Ribavirin is not weight-based for the treatment of genotypes 2 or 3 when administered with peginterferon only. All patients receive 800 mg in daily divided doses (typically 400 mg twice daily). Dosing in the setting of renal impairment is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C infection in adults with renal impairment", section on 'Regimen selection'.)

Treatment with peginterferon plus ribavirin should be administered for 24 weeks in patients with genotype 2 or 3. Data on shorter periods of treatment have been mixed; thus, routine treatment for less than 24 weeks cannot be recommended [38-41].

Monitoring, adverse effects, and precautions associated with the use of peginterferon and ribavirin are discussed elsewhere. (See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection" and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Contraindications/precautions with anti-HCV agents'.)

MONITORING DURING TREATMENT — Monitoring during treatment is discussed in detail elsewhere. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Monitoring during antiviral therapy'.)

FOLLOW-UP AFTER TREATMENT — Follow-up after treatment includes checking the viral load 12 weeks after the cessation of therapy to evaluate for a sustained virologic response. Patients with advanced fibrosis or cirrhosis also warrant ongoing screening for hepatocellular carcinoma, regardless of antiviral treatment outcome. These issues are discussed in detail elsewhere. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Follow-up after antiviral therapy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatitis C virus infection".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Treatment for hepatitis C (The Basics)")

SUMMARY AND RECOMMENDATIONS

The goal of treatment is to eradicate hepatitis C virus (HCV) RNA, which is predicted by the achievement of a sustained virologic response (SVR), defined by the absence of HCV RNA by polymerase chain reaction 12 weeks after stopping treatment. An SVR is associated with a 99 percent chance of being HCV RNA negative during long-term follow-up and can therefore be considered cure of the HCV infection. (See 'Introduction' above.)

Despite relatively high SVR rates with only 24 weeks of peginterferon and ribavirin among most patients with genotype 2 or 3 HCV infection, many still did not receive antiviral therapy because of absolute and relative contraindications to interferon, provider reluctance to use interferon in patients with mild liver disease, or personal patients decisions because of interferon's effects on quality of life. With the successive introduction of direct-acting antiviral (DAA) regimens, a highly effective, well-tolerated, all-oral, interferon-free regimen is now possible for the vast majority of genotype 2- and 3-infected patients. (See 'Selection of treatment regimen' above.)

For patients with genotype 2 infection who have not previously been treated with a DAA regimen, we suggest sofosbuvir-velpatasvir (for 12 weeks) or glecaprevir-pibrentasvir (for 8 weeks for patients without cirrhosis and 12 weeks for patients with cirrhosis) (algorithm 1) (Grade 2B). They are both highly effective for such patients. The choice between them depends primarily on the potential for drug interactions and patient preference regarding dosing. Daclatasvir plus sofosbuvir is an alternative. (See 'Genotype 2' above and 'Sofosbuvir-velpatasvir' above and 'Glecaprevir-pibrentasvir' above.)

For patients with genotype 3 infection who have not previously been treated with a DAA regimen, we suggest sofosbuvir-velpatasvir or glecaprevir-pibrentasvir (algorithm 2) (Grade 2B). Sofosbuvir-velpatasvir is given for 12 weeks; ribavirin is added for treatment-naïve patients with cirrhosis with a Y93H mutation, treatment-experienced patients without cirrhosis but with a Y93H mutation, and treatment-experienced patients with cirrhosis. Glecaprevir-pibrentasvir is given for 8 weeks for treatment-naïve patients without cirrhosis, for 12 weeks for treatment-naïve patients with cirrhosis, and 16 weeks for treatment-experienced patients. The choice between them depends primarily on the potential for drug interactions and patient preference regarding dosing. Daclatasvir plus sofosbuvir is an equally effective option for patients without cirrhosis. (See 'Genotype 3' above and 'Sofosbuvir-velpatasvir' above and 'Glecaprevir-pibrentasvir' above.)

For patients who have failed a DAA-containing regimen, the options for retreatment depend on the specific DAAs previously used. (See 'Prior DAA failure' above and 'Prior DAA failure' above.)

Selection of DAA regimens for patients with HIV and genotypes 2 or 3 HCV coinfection are the same as those for HCV-monoinfected patients, but potential for drug interactions with antiretroviral agents is an important consideration. (See 'HIV and HCV coinfection' above and "Treatment of chronic hepatitis C virus infection in the HIV-infected patient".)

Sofosbuvir-containing regimens should generally not be used in patients with an estimated creatinine clearance <30 mL/min. Antiviral treatment in such patients is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C infection in adults with renal impairment".)

Combination DAA regimens are general well tolerated. Headache, fatigue, and nausea are the most commonly reported adverse effects. Potential drug interaction are relevant for all combinations. For specific drug interactions, refer to the Lexi-Interact program included with UpToDate. (See 'Administration of treatment regimens' above and "Direct-acting antivirals for the treatment of hepatitis C virus infection".)

Ribavirin is teratogenic, so two effective forms of contraception should be used by both men and women of child-conceiving potential during and six months after treatment with ribavirin-containing regimens. (See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection", section on 'Teratogenicity'.)

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