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 velpatasvir or pibrentasvir)
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 overall than genotype 1 infection, with genotype 2 comprising approximately 15 percent of infections and genotype 3 representing less than 10 percent. However, among younger individuals and people who use injection drugs, the prevalence of genotype 3 infection is higher [5,6]. 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 [7]. 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 eight weeks for most patients but 12 weeks for patients with compensated cirrhosis who had failed prior peginterferon and ribavirin) (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 eight 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 breakthrough or relapse among genotype 2-infected patients treated with sofosbuvir-velpatasvir for 12 weeks [8-10]. 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) [8]. 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 [9]. 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 [11]. A 12-week course for such patients was not associated with a higher SVR rate [12]. For treatment-naïve patients with compensated cirrhosis, eight weeks of therapy resulted in an SVR rate of 100 percent among 26 such patients with genotype 2 infection in a trial [13,14]. Only 12 weeks of therapy have been evaluated among patients with compensated cirrhosis who had failed prior therapy with peginterferon and ribavirin [15]. (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) [16-19].
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 12 weeks 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 eight 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 [11,15]. 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 [20].
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 inhibitor exposure in one trial [20]. Sofosbuvir-velpatasvir plus weight-based ribavirin for 24 weeks is an alternative [21].
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 and is used primarily in regions that do not have access to other options. 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 eight rather than 12 weeks). 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 [22]. 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 [9].
•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 [22,23].
Other options (including sofosbuvir plus ribavirin) are less preferable because they are of longer duration, have more associated side effects, are more expensive without improved efficacy or safety, or have not been as well studied [24-29].
●Cirrhosis – Treatment-naïve patients with compensated cirrhosis should undergo testing for the Y93H variant, which has been associated with worse response to sofosbuvir-velpatasvir (and daclatasvir plus sofosbuvir). If glecaprevir-pibrentasvir is definitely going to be used, Y93H variant testing is not necessary.
For treatment-naïve patients with compensated cirrhosis, regimen administration and expected efficacies are as follows:
•Glecaprevir-pibrentasvir for eight weeks – Among 63 such patients, this regimen resulted in an SVR rate of 95 percent in a trial [13,14].
•Sofosbuvir-velpatasvir for 12 weeks if the Y93H variant is absent – Among 43 treatment-naïve patients with compensated cirrhosis, sofosbuvir-velpatasvir (without ribavirin) for 12 weeks resulted in an SVR rate of 93 percent [9]. Among all genotype 3-infected participants in the study (including those without cirrhosis and those with prior treatment failure), the presence of baseline resistance-associated substitutions (RASs) in the NS5A gene, in particular the Y93H variant, predicted a lower likelihood of SVR (97 percent without baseline RASs versus 88 and 84 percent with any RAS and the Y93H variant, respectively).
If the Y93H variant is present, we use sofosbuvir-velpatasvir-voxilaprevir instead of sofosbuvir-velpatasvir. It is highly effective for patients with cirrhosis [30]; although the optimal duration is uncertain in this setting, 12 weeks is generally recommended [2,3]. An alternative is to add weight-based ribavirin to sofosbuvir-velpatasvir for 12 weeks when the Y93H variant is present to try to improve the suboptimal SVR rate [31].
Daclatasvir plus sofosbuvir is another alternative when access to other options is limited, but the optimal duration is uncertain. For patients with cirrhosis, we give it for 24 weeks. With 12 weeks of treatment, SVR rates were only 73 percent among treatment-naïve patients with METAVIR F4 disease [23]. In a large French cohort, daclatasvir plus sofosbuvir for 24 weeks resulted in SVR rates of approximately 86 percent among patients with cirrhosis [32]. The addition of ribavirin was not associated with improved SVR rates, as had been suggested with 12-week courses [33-35].
Prior interferon/ribavirin failure — For genotype 3-infected patients who have failed prior treatment with peginterferon and ribavirin, the preferred regimens depend on the presence of a Y93H variant or cirrhosis (algorithm 2):
●No cirrhosis – Patients without cirrhosis who have failed prior treatment with peginterferon and ribavirin should undergo testing for the Y93H variant, which has been associated with worse response to sofosbuvir-velpatasvir (and daclatasvir plus sofosbuvir). For those without the Y93H variant, we suggest sofosbuvir-velpatasvir for 12 weeks. Glecaprevir-pibrentasvir is also highly effective, but is most effective at a longer 16-week course, which may be difficult to access. For those with a Y93H variant, we suggest sofosbuvir-velpatasvir-voxilaprevir for 12 weeks or glecaprevir-pibrentasvir for 16 weeks; an alternative is sofosbuvir-velpatasvir plus weight-based ribavirin for 12 weeks.
For patients without cirrhosis who have failed prior peginterferon and ribavirin, regimen administration and expected efficacies are as follows:
•Sofosbuvir-velpatasvir for 12 weeks if the Y93H variant is absent – Among 34 patients without cirrhosis who had failed peginterferon and ribavirin, sofosbuvir-velpatasvir (without ribavirin) for 12 weeks resulted in an SVR rate of 91 percent [9]. The presence of baseline NS5A RASs (and particularly the Y93H variant) was associated with lower SVR rates. Thus, when the Y93H variant is present, we use sofosbuvir-velpatasvir-voxilaprevir for 12 weeks instead of sofosbuvir-velpatasvir; it is highly effective for treatment-experienced patients [20]. An alternative is to add weight-based ribavirin to sofosbuvir-velpatasvir for 12 weeks when the Y93H variant is present; 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 [36].
•Glecaprevir-pibrentasvir for 16 weeks – In a randomized trial of 44 patients without cirrhosis who had failed peginterferon and ribavirin, SVR rates were higher when this regimen was given for 16 compared with 12 weeks (96 versus 91 percent) [37].
Daclatasvir plus sofosbuvir is another alternative when access to other options is limited. It is given for 12 weeks, and if the Y93H variant is present, weight-based ribavirin is added. 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 [23]. 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 (including sofosbuvir plus ribavirin) are less preferable because they are of longer duration, have more associated side effects, are more expensive without improved efficacy or safety, or have not been as well studied [24-27].
●Cirrhosis – For patients with cirrhosis who have failed prior treatment with peginterferon and ribavirin, we suggest glecaprevir-pibrentasvir or sofosbuvir-velpatasvir-voxilaprevir. 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 [37].
•Sofosbuvir-velpatasvir-voxilaprevir for 12 weeks – Support for this specific regimen is somewhat indirect. In a trial of 61 genotype 3-infected patients with cirrhosis who had failed peginterferon and ribavirin, sofosbuvir-velpatasvir-voxilaprevir given for eight weeks resulted in a lower SVR rate compared with sofosbuvir-velpatasvir for 12 weeks (89 versus 94 percent). However, in a separate trial of patients who had failed a direct-acting antiviral-containing regimen, among whom 106 had genotype 3 infection, sofosbuvir-velpatasvir-voxilaprevir for 12 weeks resulted in a higher SVR rate than sofosbuvir-velpatasvir alone for 12 weeks among those with cirrhosis (98 versus 86 percent) [20,30]. It is likely that the 12-week regimen will result in similarly high SVR rates for patients who had failed peginterferon and ribavirin. An alternative is sofosbuvir-velpatasvir plus weight-based ribavirin for 12 weeks, which is associated with improved SVR rates (96 versus 88 percent without ribavirin) [36].
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 [23]. Other data suggest that adding ribavirin and/or extending the course to 24 weeks improves outcomes [33-35,38].
Prior DAA failure — For genotype 3-infected patients with prior failure with a direct-acting antiviral (DAA)-based regimen, a sofosbuvir-velpatasvir-voxilaprevir-based regimen is the main option. It is given for 12 weeks; if the patient has compensated cirrhosis and had failed a prior NS5A inhibitor-containing regimen, it is given with weight-based ribavirin (algorithm 2).
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) [20].
It is also effective in patients with NS5A inhibitor exposure. In a study that included 78 genotype 3-infected patients who had previously received an NS5A inhibitor-containing DAA regimen (56 of whom had compensated cirrhosis), sofosbuvir-velpatasvir-voxilaprevir for 12 weeks resulted in SVR in 95 percent [20]. The four patients who failed to achieve SVR all had cirrhosis; thus ribavirin is added in the setting of compensated cirrhosis.
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 patient with HIV".)
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 kidney function 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 [39] or daclatasvir plus sofosbuvir plus ribavirin for 12 to 24 weeks [34] 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 [34,35]. 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 [39]. 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 [35]. 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 (of the protease inhibitor component) 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 "Hepatitis C virus infection in liver transplant candidates and recipients", section on 'Evaluation of HCV infection post-transplant'.)
ADMINISTRATION OF TREATMENT REGIMENS
Sofosbuvir-velpatasvir — Sofosbuvir-velpatasvir is one of our preferred treatment regimens for most patients with genotype 2 and many patients with genotype 3 infection (algorithm 1 and algorithm 2). 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 inhibitor 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 decrease absorption of velpatasvir; and the manufacturer's instructions should be carefully followed. Coadministration with proton pump inhibitors is ideally avoided, but if necessary, omeprazole 20 mg can be coadministered, with sofosbuvir-velpatasvir taken with food and four hours prior to the omeprazole (other proton pump inhibitors have not been studied) [40]. Care with dosing antacids or H2-receptor antagonists is also important; we counsel patients to avoid over-the-counter products that may contain stomach acid neutralizers until they discuss it with a clinician. Because of other expected and observed drug interactions, coadministration 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 [41]. 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 many patients with genotype 3 infection (algorithm 1 and algorithm 2). For treatment-naïve patients, it is given for eight weeks. For patients who have failed peginterferon and ribavirin, it is given for eight weeks to genotype 2-infected patients without cirrhosis, for 12 weeks to genotype 2-infected patients with cirrhosis, and for 16 weeks for genotype 3-infected patients. (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 [42]. 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 inhibitor-containing regimen and for certain genotype 3-infected patients (algorithm 1 and algorithm 2). It is given for 12 weeks with food. (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 [20]. Coadministration is contraindicated with rifampin and is not recommended with amiodarone, anticonvulsants, St. John's wort, certain antiretrovirals, and cyclosporine. Increased gastric pH levels decrease absorption of velpatasvir. If a proton pump inhibitor is necessary, it can be coadministered, but it is important to follow the manufacturer's instructions: sofosbuvir-velpatasvir-voxilaprevir should be administered with food and taken four hours prior to omeprazole 20 mg (other proton pump inhibitors have not been studied) [43]. For other specific drug interactions, refer to the Lexicomp drug interactions 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 inhibitor resistance-associated variant Y93H. In locations where fixed combination regimens are available, daclatasvir plus sofosbuvir does not offer an advantage and is likely more costly or difficult to access. However, it is the main option in many resource-limited settings. (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 [16,23]. 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'.)
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.)
●With the 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 eight weeks for most patients and 12 weeks for treatment-experienced patients with compensated 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, glecaprevir-pibrentasvir, or sofosbuvir-velapatasvir-voxilaprevir (algorithm 2) (Grade 2B). The choice among them depends on treatment history, the presence of cirrhosis, and the presence of a Y93H variant. Sofosbuvir-velpatasvir is given for 12 weeks; ribavirin is added for treatment-naïve patients with cirrhosis with a Y93H variant, treatment-experienced patients without cirrhosis but with a Y93H variant, and treatment-experienced patients with cirrhosis. Glecaprevir-pibrentasvir is given for eight weeks for treatment-naïve patients and 16 weeks for treatment-experienced patients. Sofosbuvir-velpatasvir-voxilaprevir is given for 12 weeks. 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 patient with HIV".)
●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 kidney function 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 Lexicomp drug interactions 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 males and females of child-conceiving potential during and for six (for males) and nine (for females) months after treatment with ribavirin-containing regimens. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Ribavirin'.)
