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), 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 [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 antiviral treatment of patients with chronic genotype 1 HCV infection. General management of chronic HCV infection, evaluation and selection of patients for antiviral 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 genotypes 2 and 3 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 originally released jointly by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) in 2014 and are updated on a continuous basis, following availability of new medications or release of major treatment trials. These guidelines 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]. 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 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)
•Protease inhibitor failures – Patients who did not respond to or relapsed after treatment with boceprevir, telaprevir, or simeprevir in combination with peginterferon and ribavirin
•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 ledipasvir, daclatasvir, elbasvir, or ombitasvir)
Throughout this topic, peginterferon refers specifically to peginterferon-alfa.
DECIDING WHOM AND WHEN TO TREAT — With the growing availability of highly effective interferon-free regimens for genotype 1 infection, a curative all-oral treatment is becoming a possibility for the vast-majority of patients. However, the cost of these new agents prevents universal delivery of antiviral therapy. When resources are constrained, prioritizing patients who may benefit most from antiviral treatment may be warranted. These issues are discussed in detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Deciding when to treat'.)
SELECTION OF TREATMENT REGIMENS — Regimen selection for patients with genotype 1 infection should take into account the efficacy, duration, and adverse effect profile of the regimen, potential drug interactions, the patient's history of prior treatment, and the stage of fibrosis. For the individual patient, insurance and financial issues will also likely be an important consideration. This section discusses regimen selection by treatment history (algorithm 1 and algorithm 2). (See 'Treatment-naïve patients' below and 'Treatment-experienced patients' below.)
The various direct-acting antiviral (DAA)-containing regimens (including interferon-free and interferon-containing regimens) available for treatment of genotype 1 infection have not been studied head to head, but in trials are associated with sustained virologic response (SVR) rates in excess of 80 percent among treatment-naïve patients. Interferon-free combination regimens have reported SVR rates in excess of 90 percent. In general, we recommend an interferon-free DAA combination regimen, as it avoids the substantial toxicity associated with interferon use. Of note, a DAA should not be used as monotherapy because of the strong likelihood of treatment failure and the potential to develop resistance. Additional details on the administration and efficacy of the various regimens are found elsewhere. (See 'Interferon-free regimens' below.)
Other DAAs that are not available in the United States and are thus not discussed in this topic may be available in other countries. Clinicians in those locations are advised to check local guidelines on the optimal use of these agents.
Treatment-naïve patients — For patients who have never undergone antiviral therapy for HCV infection and are initiating antiviral therapy now, several interferon-free options have comparably high expected efficacy and safety. These are ledipasvir-sofosbuvir, sofosbuvir-velpatasvir, glecaprevir-pibrentasvir, elbasvir-grazoprevir, ombitasvir-paritaprevir-ritonavir plus dasabuvir with or without ribavirin, simeprevir plus sofosbuvir, and daclatasvir plus sofosbuvir. The choice between them depends primarily on the potential for drug interactions and drug toxicity (eg, if the addition of ribavirin is warranted). Additionally, in the United States, the options will be limited by the individual's insurance provider.
If cost or insurance coverage is not an issue, we generally favor the regimens of ledipasvir-sofosbuvir, sofosbuvir-velpatasvir, or glecaprevir-pibrentasvir for their favorable adverse effect profile and ease of administration (once-daily dosing without the need for testing for preexisting viral polymorphisms) (algorithm 1). Drug interactions are generally manageable but should be evaluated prior to initiation, particularly with NS3/4A protease inhibitor-containing regimens (such as glecaprevir-pibrentasvir).
The following discusses treatment regimens for patients without cirrhosis or with compensated cirrhosis. Options for decompensated cirrhosis are discussed elsewhere. (See 'Decompensated' below.)
●Ledipasvir-sofosbuvir – For treatment-naïve patients, the duration of this regimen depends on the viral load and the presence of cirrhosis. For patients with a viral load <6 million international units/mL and without cirrhosis, treatment duration is generally eight weeks. For patients who meet these criteria but have multiple traditional negative predictors of response (ie, being male, obese, a Black person) or HIV infection, we aim to treat for 12 weeks, although there are not ample data to support this practice, and insurers may not allow the extra four weeks. For treatment-naïve patients with a viral load >6 million international units/mL or with cirrhosis, ledipasvir-sofosbuvir is given for 12 weeks. In patients with and without cirrhosis, these regimens result in SVR rates greater than 95 percent [5-7]. (See 'Ledipasvir-sofosbuvir' below.)
●Sofosbuvir-velpatasvir – For treatment-naïve patients, sofosbuvir-velpatasvir is given for 12 weeks, regardless of the presence of cirrhosis. This regimen results in SVR rates of approximately 98 to 99 percent [8-10]. (See 'Sofosbuvir-velpatasvir' below.)
●Glecaprevir-pibrentasvir – For treatment-naïve patients, glecaprevir-pibrentasvir is given for eight weeks, regardless of the presence of cirrhosis. For patients with compensated cirrhosis, the duration had previously been 12 weeks, but updated data suggested that eight weeks is sufficient for this population as well. This regimen results in SVR rates of approximately 98 to 99 percent [11-14]. (See 'Glecaprevir-pibrentasvir' below.)
●Elbasvir-grazoprevir – For treatment-naïve patients, use of this regimen depends on the infecting subtype and the presence of pre-existing NS5A resistance-associated substitutions (RASs). Patients with subtype 1a infection should undergo testing for NS5A RASs prior to receiving elbasvir-grazoprevir; those who have RASs should use another regimen. For those with subtype 1a infection without RASs or subtype 1b infection, the regimen is given for 12 weeks. Duration is the same in patients with and without cirrhosis, among whom they result in SVR rates greater than 95 percent [15-17]. This regimen is contraindicated in Child-Pugh classes B and C cirrhosis. (See 'Elbasvir-grazoprevir' below.)
Ombitasvir-paritaprevir-ritonavir plus dasabuvir is not available in the United States but may be available elsewhere. For treatment-naïve patients, the duration of this regimen and the addition of weight-based ribavirin (daily dose 1000 mg for those <75 kg and 1200 mg for those ≥75 kg) depend on the infecting subtype and the presence of cirrhosis. For patients with subtype 1a infection, the regimen is given with ribavirin for 12 weeks in patients without cirrhosis and for 24 weeks in patients with cirrhosis. For patients with subtype 1b infection, the regimen is given without ribavirin for 12 weeks, regardless of the presence of cirrhosis. If used in patients with cirrhosis, close monitoring for hepatic decompensation is warranted; the regimen is contraindicated in Child-Pugh classes B and C cirrhosis. These regimens result in SVR rates greater than 95 percent [18-20]. SVR rates are especially high for subtype 1b (99 to 100 percent). (See 'Ombitasvir-paritaprevir-ritonavir plus dasabuvir' below.)
Simeprevir plus sofosbuvir and daclatasvir plus sofosbuvir are other effective regimens but are generally used only in regions where access to the fixed-combination regimens above are limited. Each regimen is given for 12 weeks without cirrhosis. They are not recommended regimens for patients with cirrhosis, in part because a prolonged 24-week course is necessary for acceptable SVR rates. (See 'Simeprevir plus sofosbuvir' below and 'Daclatasvir plus sofosbuvir' below.)
Treatment-experienced patients
Prior peginterferon and ribavirin failure — For patients who have failed prior treatment with peginterferon and ribavirin and are initiating antiviral therapy now, several interferon-free regimens have comparably high expected efficacy and safety. The options are the same as for treatment-naïve patients and are ledipasvir-sofosbuvir, elbasvir-grazoprevir, ombitasvir-paritaprevir-ritonavir plus dasabuvir with or without ribavirin, simeprevir plus sofosbuvir, and daclatasvir plus sofosbuvir. The choice between them depends primarily on the potential for drug interactions and drug toxicity (eg, if the addition of ribavirin is warranted). Additionally, in the United States, the options will be limited by the individual's insurance provider.
If cost or insurance coverage is not an issue, we generally favor the regimens of ledipasvir-sofosbuvir, sofosbuvir-velpatasvir, or glecaprevir-pibrentasvir for their favorable adverse effect profile and ease of administration (once-daily dosing without the need for testing for preexisting viral polymorphisms) (algorithm 2). Drug interactions are generally manageable but should be evaluated prior to initiation, particularly with NS3/4A protease inhibitor-containing regimens (such as glecaprevir-pibrentasvir).
The following discusses treatment regimens for patients without cirrhosis or with compensated cirrhosis. Options for decompensated cirrhosis are discussed elsewhere. (See 'Decompensated' below.)
●Ledipasvir-sofosbuvir – For patients who have failed prior therapy with peginterferon and ribavirin, the specific ledipasvir-sofosbuvir regimen depends on the presence of cirrhosis. For those without cirrhosis, the regimen is given for 12 weeks. This results in an approximately 95 percent SVR rate [21]. For those with cirrhosis, ledipasvir-sofosbuvir is given with weight-based ribavirin (daily dose 1000 mg for those <75 kg and 1200 mg for those ≥75 kg) for 12 weeks, which results in an approximate 96 to 97 percent SVR rate in most patients [21-23]. However, patients with cirrhosis who have baseline NS5A RASs appear to have lower SVR rates [24]; thus some experts, including other UpToDate contributors, check for NS5A RASs in genotype 1a-infected treatment-experienced patients with cirrhosis and choose a different regimen (such as sofosbuvir-velpatasvir or elbasvir-grazoprevir with ribavirin) if present. Data to inform an optimal approach in this setting are limited. (See 'Ledipasvir-sofosbuvir' below.)
●Sofosbuvir-velpatasvir – For patients who have failed prior therapy with peginterferon and ribavirin, sofosbuvir-velpatasvir is given for 12 weeks, regardless of the presence of cirrhosis. This regimen results in SVR rates of approximately 98 to 99 percent [8-10]. (See 'Sofosbuvir-velpatasvir' below.)
●Glecaprevir-pibrentasvir – For patients who have failed prior therapy with peginterferon and ribavirin, the duration of this regimen depends on the presence of cirrhosis. For patients without cirrhosis, glecaprevir-pibrentasvir is given for eight weeks; for patients with cirrhosis, it is given for 12 weeks. This regimen results in SVR rates of approximately 99 percent [11-13]. (See 'Glecaprevir-pibrentasvir' below.)
●Elbasvir-grazoprevir – For patients who have failed prior therapy with peginterferon and ribavirin, the duration of this regimen and the addition of weight-based ribavirin (daily dose 1000 mg for those <75 kg and 1200 mg for those ≥75 kg) depend on the infecting subtype and the presence of preexisting NS5A RASs. Patients with subtype 1a infection should undergo testing for NS5A RASs prior to receiving elbasvir-grazoprevir; the regimen is given for 12 weeks to those without RASs but is given for 16 weeks with weight-based ribavirin to those with RASs. For patients with subtype 1b infection, the regimen is given for 12 weeks without ribavirin. Duration of these regimens is the same in patients with and without cirrhosis, among whom they result in SVR rates greater than 95 percent [16,17,25]. This regimen is contraindicated in Child-Pugh classes B and C cirrhosis. (See 'Elbasvir-grazoprevir' below.)
Ombitasvir-paritaprevir-ritonavir plus dasabuvir is not available in the United States but may be available elsewhere. For patients with subtype 1a infection without cirrhosis and for patients with subtype 1b infection, the regimen is given with ribavirin for 12 weeks. This regimens result in SVR rates greater than 94 percent [19,26,27]. It is not recommended for patients with subtype 1a and cirrhosis because 24 weeks of therapy is necessary for high SVR rates. If used in patients with compensated cirrhosis, close monitoring for hepatic decompensation is warranted; the regimen is contraindicated in Child-Pugh classes B and C cirrhosis. (See 'Ombitasvir-paritaprevir-ritonavir plus dasabuvir' below.)
Simeprevir plus sofosbuvir and daclatasvir plus sofosbuvir are other effective regimens but are generally used only in regions where access to the fixed-combination regimens above are limited. Each regimen is given for 12 weeks without cirrhosis. They are not recommended regimens for patients with cirrhosis, in part because a prolonged 24-week course is necessary for acceptable SVR rates. (See 'Simeprevir plus sofosbuvir' below and 'Daclatasvir plus sofosbuvir' below.)
Prior protease inhibitor failures — For patients who have failed prior treatment with a protease inhibitor-containing regimen (ie, simeprevir, telaprevir, or boceprevir plus peginterferon and ribavirin) and are initiating antiviral therapy now, we suggest sofosbuvir-velpatasvir, ledipasvir-sofosbuvir, or glecaprevir-pibrentasvir (algorithm 2). In such patients, sofosbuvir-velpatasvir and glecaprevir-pibrentasvir are given for 12 weeks; ledipasvir-sofosbuvir is given for 12 weeks to those without cirrhosis and with ribavirin for 12 weeks to those with compensated cirrhosis. These regimens result in SVR rates from 96 to 100 percent [8-10,21,22,28]. They are discussed in greater detail elsewhere. (See 'Ledipasvir-sofosbuvir' below and 'Sofosbuvir-velpatasvir' below and 'Glecaprevir-pibrentasvir' below.)
Elbasvir-grazoprevir plus weight-based ribavirin (daily dose 1000 mg for those <75 kg and 1200 mg for those ≥75 kg) is also effective for such protease-inhibitor failures [29]. Although grazoprevir is also a protease inhibitor, it has a high threshold for resistance. The manufacturer recommended duration of elbasvir-grazoprevir plus ribavirin for this population is 12 weeks [30]. However, given the concern for decreased efficacy in the setting of preexisting NS5A RASs, we check for these RASs in patients with genotype 1a infection and extend treatment to 16 weeks if any are present, if possible.
Otherwise, if a patient has failed one protease inhibitor, treatment with other protease inhibitors (eg, paritaprevir or simeprevir) is not recommended due to likely resistance development and thus subsequent treatment failure. Thus, the regimens of ombitasvir-paritaprevir-ritonavir plus dasabuvir or simeprevir plus sofosbuvir are not options for these patients. Sofosbuvir and ribavirin has not been studied in such patients, but presumably would achieve a similarly suboptimal response rate as seen in treatment-naïve individuals.
Prior sofosbuvir failure (no NS5A inhibitor exposure) — For patients who have failed a sofosbuvir-based regimen (but have had no NS5A inhibitor exposure), new combination regimens of DAA agents that have high barriers to resistance and are active against common resistance-associated substitutions offer potential options. Nevertheless, data on treatment options are relatively limited.
For patients who have only had sofosbuvir exposure without other DAAs (eg, sofosbuvir plus peginterferon and/or ribavirin), the options include:
●Glecaprevir-pibrentasvir for 8 weeks (for those without cirrhosis) or 12 weeks (for those with cirrhosis)
●Sofosbuvir-velpatasvir-voxilaprevir for 12 weeks (for genotype 1a with or without cirrhosis) or sofosbuvir-velpatasvir for 12 weeks (for genotype 1b with or without cirrhosis)
For patients who have had sofosbuvir and NS3/4A protease inhibitor exposure (eg, sofosbuvir plus simeprevir), the options include:
●Glecaprevir-pibrentasvir for 12 weeks
●Sofosbuvir-velpatasvir-voxilaprevir for 12 weeks (for genotype 1a) or sofosbuvir-velpatasvir for 12 weeks (for genotype 1b)
These two regimens have not been compared directly, but studies suggest they result in SVR rates greater than 95 percent [31,32]. However, the efficacy estimates were based on relatively small numbers of patients (ie, fewer than 50 for each regimen studied) with prior sofosbuvir exposure. (See 'Glecaprevir-pibrentasvir' below and 'Sofosbuvir-velpatasvir-voxilaprevir' below.)
Prior failure with an NS5A inhibitor regimen — For patients who have failed an NS5A inhibitor regimen, new combination regimens of DAA agents that have high barriers to resistance and are active against common resistance-associated substitutions offer potential options. Nevertheless, data on treatment options are relatively limited.
For those who have failed an NS5A inhibitor regimen, we use sofosbuvir-velpatasvir-voxilaprevir for 12 weeks, which in one study resulted in SVR rates of 96 and 100 percent in NS5A inhibitor-experienced genotype 1a- and 1b-infected patients, respectively [31].
For patients who have failed an NS5A inhibitor regimen that did not include an NS3/4A protease inhibitor, glecaprevir-pibrentasvir for 16 weeks is another option [32-34]. In one study that evaluated this regimen among 49 patients without cirrhosis and 29 patients with compensated cirrhosis, the SVR rates were 94 and 97 percent, respectively [34]. (See 'Glecaprevir-pibrentasvir' below and 'Sofosbuvir-velpatasvir-voxilaprevir' below.)
Other DAA combinations that are not typically used might have efficacy in the setting of prior NS5A inhibitor failure. As an example, sofosbuvir plus elbasvir-grazoprevir plus ribavirin for 16 to 24 weeks was highly effective in a small study [35].
ADDITIONAL TREATMENT CONSIDERATIONS
Patients with cirrhosis
Compensated — Because of the risk of progression to more severe liver disease, we treat patients with advanced fibrosis or compensated cirrhosis promptly if highly effective interferon-free direct-acting antiviral (DAA) regimens are available. Although interferon-free regimens appear effective and safe for such patients, treatment should generally be undertaken in consultation with an expert in managing patients with cirrhosis. Patients with cirrhosis who are treated with an ombitasvir-paritaprevir-ritonavir-based regimen should be monitored closely because of a reported risk of hepatic decompensation [36]. The regimen selection depends on the prior treatment history, as discussed above. (See 'Selection of treatment regimens' above.)
In locations where interferon-free regimens are not available, however, the decision to treat with an interferon-based regimen depends on the balance between the risk of deferring therapy and the risk of serious adverse effects of such a regimen, which can be substantial in this population. Treatment with an interferon-containing regimen should be undertaken in consultation with an expert in managing patients with cirrhosis. Some studies have suggested an excess of serious adverse events, including decompensating events and death, among patients with cirrhosis when peginterferon and ribavirin were given with first-generation HCV protease inhibitors [37,38]. In the CUPIC study, which included 455 patients with HCV genotype 1 and compensated cirrhosis, 45 percent of those treated with telaprevir and 33 percent of those treated with boceprevir experienced serious adverse events, including death [37]. Predictors of serious adverse events included platelet count ≤100,000/microL and albumin <3.5 g/dL. In another study of treatment-naïve and experienced patients with compensated cirrhosis comparing simeprevir plus sofosbuvir with sofosbuvir plus peginterferon and ribavirin for 12 weeks, of the 31 patients randomly assigned to the interferon-based regimens, four withdrew because of refusal to take interferon and three discontinued treatment because of an adverse event, one of which was liver decompensation [39]. Overall, the interferon-based regimen was less effective (75 versus 93 percent sustained virologic response [SVR] with simeprevir plus sofosbuvir).
Other absolute and relative contraindications to interferon are discussed elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Contraindications/precautions with anti-HCV agents'.)
Decompensated — Options are limited for patients with decompensated cirrhosis (ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage), and antiviral treatment 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 MELD score greater than 10 should be evaluated for liver transplantation prior to initiation of HCV therapy. We agree with the AASLD/IDSA guidelines that recommend against the use of peginterferon in such patients [2].
Several interferon-free regimens appear effective and relatively safe in these patients. For genotype 1-infected patients, these include ledipasvir-sofosbuvir, sofosbuvir-velpatasvir, and daclatasvir plus sofosbuvir, each with weight-based ribavirin [40-43]. As an example, in one study that randomly assigned patients with decompensated cirrhosis (Child-Pugh class B or C) and creatinine clearance >40 mL/min to receive ledipasvir-sofosbuvir plus ribavirin for 12 or 24 weeks, SVR rates were high (87 to 89 percent) [40]. In another study that included 68 patients with genotype 1 infection and Child-Pugh class B cirrhosis, SVR rates with sofosbuvir-velpatasvir plus ribavirin for 12 weeks were 94 and 100 percent for subtypes 1a and 1b, respectively [42]. Although serious adverse events were common in these studies (10 to 42 percent, depending on the level of decompensation and on the precise regimen administered), few were deemed related to the treatment.
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'.)
Of note, glecaprevir-pibrentasvir, elbasvir-grazoprevir, sofosbuvir-velpatasvir-voxilaprevir, and simeprevir are contraindicated in patients with Child-Pugh classes B and C cirrhosis because of increased drug levels in the setting of such hepatic impairment. Ombitasvir-paritaprevir-ritonavir-based regimens are also contraindicated in patients with Child-Pugh classes B and C cirrhosis because of the risk of worsened hepatic decompensation.
Recurrence after liver transplantation — Recurrence of HCV occurs in more than 95 percent of patients after liver transplantation. Management of HCV recurrence post-transplant is discussed elsewhere. (See "Hepatitis C virus infection in liver transplant candidates and recipients", section on 'Assessment of HCV recurrence'.)
Patients with renal impairment — 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".)
HIV-HCV coinfection — Although studies with peginterferon and ribavirin therapy suggested that HIV-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 between antiretroviral agents and DAA agents must be taken into consideration when selecting regimens.
Treatment of HCV/HIV-infected patients is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C virus infection in the patient with HIV".)
Genotype 1a versus 1b — Although direct-acting antiviral (DAA)-based regimens result in dramatically higher sustained virologic response (SVR) rates for genotype 1-infected patients, one of the themes of the DAA era has been the slightly lower response rates observed with genotype 1a compared with 1b infection.
In studies of the first generation protease inhibitors boceprevir and telaprevir, each combined with peginterferon and ribavirin, lower SVR rates were observed for genotype 1a-infected patients [44,45]. Additionally, different patterns of resistance were reported, with genotype 1a-infected patients more likely to develop resistant substitutions, including those that had high-level resistance leading to virologic failure. These subtype differences are also relevant to other interferon-free regimens for genotype 1 virus. As an example, 99 percent of genotype 1b-infected patients without cirrhosis achieved SVR with a 12-week regimen of ombitasvir-paritaprevir-ritonavir plus dasabuvir without ribavirin [20]. In contrast, only 90.2 percent of genotype 1a-infected patients without cirrhosis achieved SVR with this regimen, but the SVR rate increased to 97 percent when ribavirin was added. With both the ombitasvir-paritaprevir-ritonavir plus dasabuvir and simeprevir-sofosbuvir regimens, the addition of ribavirin is recommended for genotype 1a but not genotype 1b infections [2]. With the elbasvir-grazoprevir regimen, preexisting resistance-associated substitutions (RASs) are associated with lower SVR rates among patients with subtype 1a but not 1b infection [17]. The impact of subtype on outcomes and the role of resistance will be important to monitor with the development of future therapies. (See 'Selection of treatment regimens' above.)
REGIMEN OPTIONS
Interferon-free regimens — For patients with chronic genotype 1 HCV infection, we recommend an interferon-free regimen instead of an interferon-containing regimen. Most interferon-free regimens are highly effective for all patient populations and are well tolerated, without the well-known toxicity associated with interferon.
Ledipasvir-sofosbuvir — The regimen of ledipasvir-sofosbuvir is one of our preferred antiviral regimen for the vast majority of patients with chronic HCV infection. It is available in a once-daily fixed-dose combination tablet of the NS5A inhibitor ledipasvir (90 mg) and the NS5B inhibitor sofosbuvir (400 mg) and is highly effective for both treatment-naïve and experienced patients with genotype 1 infection, even in the setting of cirrhosis. The duration of therapy is 12 weeks for treatment-naïve and noncirrhotic treatment-experienced patients and 24 weeks for cirrhotic treatment-experienced patients. Eight weeks of therapy appears to be sufficient for noncirrhotic treatment-naïve patients with viral levels <6 million international units/mL. The efficacy of ledipasvir-sofosbuvir does not appear to be significantly improved by the addition of ribavirin. (See 'Selection of treatment regimens' above.)
Support for the use of ledipasvir-sofosbuvir is based on data from several clinical trials in both treatment-naïve [5-7,46,47] and experienced [21,47] patients. Real-world observational studies have also demonstrated high efficacy [48,49].
●Treatment-naïve patients – In the open-label ION-1 trial, SVR rates among 865 treatment-naïve patients with genotype 1 infection randomly assigned to receive ledipasvir-sofosbuvir with or without weight-based ribavirin for 12 or 24 weeks ranged from 97 to 99 percent across all four groups [7]. SVR rates were similarly high among subgroups that have been historically considered "difficult to treat". As an example, SVR rates ranged from 94 to 100 percent among patients with cirrhosis and from 91 to 100 percent among Black patients across the four treatment groups. Overall, only three patients experienced virologic failure, including one who had breakthrough during treatment in the setting of undetectable drug concentrations thought to reflect nonadherence.
Among those without cirrhosis, an even shorter duration of therapy appears highly effective. In the open-label ION-3 trial, 647 such patients with genotype 1 infection were randomly assigned to receive ledipasvir-sofosbuvir for 8 or 12 weeks or ledipasvir-sofosbuvir with ribavirin for 8 weeks [46]. SVR rates ranged from 93 to 95 across all groups. Among those with a baseline HCV RNA <6 million international units/mL, SVR rates with ledipasvir-sofosbuvir alone were 97 and 96 percent for 8 and 12 weeks of therapy, respectively. Among Black patients, a traditional predictor of poor response to interferon-based therapy, 8 versus 12 weeks of therapy also appear to result in similarly high SVR rates as long as other criteria are met [50].
Fewer than 8 weeks of treatment with ledipasvir-sofosbuvir appears to be less effective, although such shorter durations of therapy may become a possibility with the addition of other investigational direct-acting antivirals (DAA).
●Treatment-experienced patients – In the open-label ION-2 trial, 440 patients with genotype 1 infection who had failed prior treatment with peginterferon plus ribavirin, with or without a protease inhibitor, were randomly assigned to receive a once-daily fixed-dose combination tablet of ledipasvir-sofosbuvir with or without weight-based ribavirin for 12 or 24 weeks [21]. SVR rates ranged from 94 to 96 percent with 12 weeks of therapy (with or without ribavirin) and were 99 percent with 24 weeks. Overall, 11 patients had a documented virologic relapse after treatment; all had received 12 weeks of therapy. Response rates did not differ by type of prior treatment failure (ie, relapse versus nonresponse) or prior regimen (ie, with versus without a protease inhibitor).
Among the 44 patients with cirrhosis who received ledipasvir-sofosbuvir without ribavirin, SVR rates were improved with 24 weeks compared to 12 weeks of treatment (100 versus 86 percent). In a subsequent trial of patients with cirrhosis who had failed peginterferon, ribavirin, and a protease inhibitor, treatment with ledipasvir-sofosbuvir plus ribavirin for 12 weeks resulted in similar SVR rates as ledipasvir-sofosbuvir plus placebo for 24 weeks (96 and 97 percent, respectively) [22]. This finding was supported by an analysis of the treatment-experienced patients with cirrhosis included in several initial trials of ledipasvir-sofosbuvir, which also showed the two regimens were comparable in this population [23].
Even patients who had relapsed on a prior sofosbuvir-containing regimen can be successfully retreated with ledipasvir-sofosbuvir, with or without ribavirin. In a study of 51 patients who had previously failed sofosbuvir plus peginterferon and ribavirin for 12 weeks or sofosbuvir with or without ribavirin for 24 weeks, SVR rates were 98 percent following 12 weeks of ledipasvir-sofosbuvir plus ribavirin (and the one failure was a genotype 3-infected individual inadvertently included in the study) [51]. Similarly, in a study of 14 genotype 1-infected patients who had relapsed following sofosbuvir plus ribavirin for 24 weeks, all achieved SVR with 12 weeks of ledipasvir-sofosbuvir [52]. Patients with stage 3 to 4 fibrosis were well-represented in both studies. There are no data yet on ledipasvir-sofosbuvir as retreatment of patients who previously failed sofosbuvir plus simeprevir.
Overall, ledipasvir-sofosbuvir is well tolerated. Although the majority of participants experienced at least one adverse event in the large ION trials, these were generally of mild to moderate severity [7,21,28,46,53]. Fatigue, headache, insomnia, and nausea were the most common effects. Important drug interactions to avoid include P-glycoprotein inducers, such as rifampin and St. John's wort, which can reduce concentrations of both ledipasvir and sofosbuvir, and amiodarone. Also, drugs that increase gastric pH (ie, acid reducers) can decrease ledipasvir concentrations, so the lowest possible dose of these agents should be used if necessary.
Additional adverse effects and drug information, including pharmacokinetics and potential drug interactions, for ledipasvir and sofosbuvir are discussed elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Ledipasvir-sofosbuvir'.)
Sofosbuvir-velpatasvir — The pangenotypic regimen of sofosbuvir-velpatasvir is one of our preferred antiviral regimens for the vast majority of patients with chronic HCV infection. It is available in a once-daily fixed-dose combination tablet of the NS5B inhibitor sofosbuvir (400 mg) and the NS5A inhibitor velpatasvir (100 mg). It is given for 12 weeks and is highly effective for both treatment-naïve and experienced patients with genotype 1 infection [8-10]. (See 'Selection of treatment regimens' above.)
In a randomized, placebo-controlled trial that included 328 genotype 1-infected patients who received sofosbuvir-velpatasvir for 12 weeks, 98 and 99 percent of 1a- and 1b-infected patients achieved SVR [8]. Response rates were similar regardless of treatment history or the presence of cirrhosis. Among patients who had previously failed treatment with a protease inhibitor plus peginterferon and ribavirin, the SVR rates in two studies were 100 percent (of 37 patients) and 96 percent (of 28 patients) [8,10].
Sofosbuvir-velpatasvir is well tolerated, with <1 percent of trial participants discontinuing a 12-week regimen for adverse events. The most common adverse events are fatigue, headache, nausea, and insomnia [8,54]. Coadministration is not recommended with amiodarone, anticonvulsants, rifamycins, certain antiretrovirals, and St. John's wort.
Additional adverse effects and drug information, including pharmacokinetics and potential drug interactions, for sofosbuvir-velpatasvir are discussed elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Ledipasvir-sofosbuvir'.)
Glecaprevir-pibrentasvir — The pangenotypic once-daily fixed-dose combination of the NS3/4A protease inhibitor glecaprevir (300 mg) and the NS5A inhibitor pibrentasvir (120 mg) is one of our preferred regimens for treatment-naïve and -experienced genotype 1-infected patients with and without compensated cirrhosis. Among patients without prior NS3/4A or NS5A inhibitor exposure, the regimen is given for 8 weeks in patients without cirrhosis and 12 weeks in patients with cirrhosis. It is given for 12 weeks for prior NS3/4A protease inhibitor exposure and 16 weeks for prior NS5A inhibitor exposure. (See 'Selection of treatment regimens' above.)
Several trials have demonstrated high efficacy of this regimen among genotype 1-infected patients who have had no prior NS3/4A or NS5A inhibitor exposure [11-13,55]. As an example, in a randomized trial of 700 genotype 1-infected patients without cirrhosis (about 8 percent of whom had F3 fibrosis), glecaprevir-pibrentasvir resulted in comparably high SVR rates when given for 8 versus 12 weeks (99 versus 99.7 percent) [11]. Of those who did not achieve SVR with eight weeks of treatment, one had virologic failure and two discontinued early or were lost to follow-up. In a separate trial of patients with cirrhosis, 89 of 90 genotype 1-infected patients achieved SVR with 12 weeks of treatment [13]. However, in a subsequent trial, eight weeks of treatment also resulted in a 98 percent SVR rate among 231 genotype 1-infected patients with compensated cirrhosis [14,56].
Trials in NS3/4A or NS5A inhibitor-experienced patients also demonstrate high efficacy with longer treatment courses than eight weeks, but not in patients who have both NS3/4A and NS5A inhibitor exposure [32,33]. In a randomized trial that included 27 patients with prior NS3/4A inhibitor exposure, 100 percent achieved SVR with either 12 or 16 weeks of glecaprevir-pibrentasvir. However, among 34 patients with prior NS5A inhibitor exposure, SVR rates were lower with 12 versus 16 weeks (88 versus 94 percent), and among 30 patients with prior exposure to both NS3/4A and NS5A inhibitors, SVR rates were suboptimal with both 12 and 16 weeks (79 and 81 percent) [32]. Only five of nine patients (56 percent) who had key baseline NS3/4A (at 155, 156, or 168) and NS5A resistance-associated substitution (RAS; at 24, 28, 30, 31, 58, 92, 93) achieved SVR, and all of these had prior failure with both NS3/4A and NS5A inhibitors.
Glecaprevir-pibrentasvir 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 [57]. Less than 0.5 percent of patients discontinued therapy because of adverse effects. Elevations in aminotransferase or bilirubin levels were rare and not clearly related to the drug.
Pharmacologic issues may limit the use of this regimen. Although it can be used in patients with any degree of renal impairment, it is contraindicated in patients with moderate to severe (Child-Pugh class B or C) cirrhosis. Drug interactions are considerable. Coadministration is contraindicated with rifampin and atazanavir and not recommended with carbamazepine, oral contraceptive agents, St. John's wort, cyclosporine, and certain other antiretrovirals. 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 glecaprevir-pibrentasvir are discussed in detail elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection".)
Elbasvir-grazoprevir — The once-daily fixed-dose combination of the NS5A inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is highly effective among treatment-naïve and experienced genotype 1-infected patients with and without cirrhosis; however, certain NS5A RASs that confer high-level resistance to elbasvir reduce the efficacy of a 12-week regimen. Thus, the duration of treatment and the addition of ribavirin to the regimen depend on the subtype and the presence of any preexisting RASs. Patients with genotype 1a who are treatment-naïve or have failed prior treatment with peginterferon and ribavirin should undergo testing for NS5A RASs prior to receiving elbasvir-grazoprevir. For those without RASs, the regimen is given for 12 weeks; for those with RASs, the regimen is given for 16 weeks with weight-based ribavirin. The regimen is given for 12 weeks for patients with genotype 1b who are treatment-naïve or have failed prior treatment with peginterferon and ribavirin. (See 'Selection of treatment regimens' above.)
Several trials have demonstrated high efficacy among genotype 1-infected patients [15,25,29,58-62]. As an example, in a multicenter trial that included 283 treatment-naïve genotype 1-infected patients with or without cirrhosis and randomly assigned them to 12 weeks of elbasvir-grazoprevir or placebo, SVR rates with the active drug were 92 and 99 percent for 1a (n = 157) and 1b (n = 131) subtypes, respectively [15]. SVR rates among the approximately 70 patients with cirrhosis were comparable with those among patients without cirrhosis. In a separate trial of 123 treatment-naïve patients with cirrhosis and 130 patients with or without cirrhosis who had failed prior therapy with peginterferon and ribavirin, elbasvir-grazoprevir given for 12 or 18 weeks with or without ribavirin resulted in SVR rates ranging from 90 to 100 percent [25]. Additionally, the regimen appears safe and effective in specific populations, such as HIV/HCV coinfected patients [58,63], patients with ongoing injection drug use on methadone or buprenorphine [60], and patients with severe renal impairment, including those who are hemodialysis dependent [61]. (See "Treatment of chronic hepatitis C virus infection in the patient with HIV" and "Treatment of chronic hepatitis C infection in adults with kidney function impairment".)
Elbasvir-grazoprevir, when given with weight-based ribavirin for 12 weeks, is also highly effective in patients who had failed prior treatment with peginterferon, ribavirin, and a protease inhibitor (simeprevir, telaprevir, or boceprevir), with a 96 percent SVR rate in one trial of 79 patients [29].
Among patients with subtype 1a infection, SVR rates with only 12 weeks of therapy are lower among patients with preexisting RASs in the NS5A gene (polymorphisms at positions M28, Q30, L31, and Y93), which are estimated to occur in approximately 11 percent of subtype 1a viruses. As an example, in a pooled analysis of results among subtype 1a-infected patients who were treatment-naïve or had previously relapsed after peginterferon and ribavirin, SVR rates with 12 weeks of elbasvir-grazoprevir were 91 and 98 percent, respectively, among those with (n = 150) and without (n = 439) preexisting RASs [17]. However, extension of therapy to 16 to 18 weeks with the addition of weight-based ribavirin appears to improve SVR rates to 100 percent among 14 prior nonresponders with NS5A RASs. RASs in the NS3 gene are not associated with lower SVR rates, and NS5A RASs do not affect response rates in subtype 1b-infected patients.
Overall, elbasvir-grazoprevir is well tolerated. In large trials, the most common adverse events were headache, fatigue, and nausea [15,25]. Rarely, patients developed late aminotransferase elevations without associated bilirubin increases that resolved once the regimen was stopped. Monitoring aminotransferases with this regimen is recommended. (See 'Monitoring during treatment' below.)
Pharmacologic issues may limit the use of this regimen. Although it can be used in patients with any degree of renal impairment, it is contraindicated in patients with moderate to severe (Child-Pugh class B or C) cirrhosis. Drug interactions are considerable. Drugs that are contraindicated with elbasvir-grazoprevir include anticonvulsants, rifampin, St. John's wort, cyclosporine, and certain antiretrovirals. 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 elbasvir-grazoprevir are discussed in detail elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Elbasvir-grazoprevir'.)
Ombitasvir-paritaprevir-ritonavir plus dasabuvir — Another interferon-free regimen for genotype 1 infection is the combination of the ritonavir-boosted protease inhibitor paritaprevir and the NS5A inhibitor ombitasvir (all coformulated in a single tablet) plus the non-nucleotide NS5B inhibitor dasabuvir. It is given with or without weight-based ribavirin (1000 mg/day if <75 kg or 1200 mg/day if ≥75 kg) for 12 or 24 weeks, depending on the population. It is highly effective in treatment-naïve patients and in those who have failed prior treatment with peginterferon and ribavirin, even in the setting of cirrhosis. The regimen is particularly effective for subtype 1b infection. It is not available in the United States but may be available elsewhere. (See 'Selection of treatment regimens' above.)
Support for the use of this regimen is based on several large clinical trials [18-20,26,27,64,65]. Real-world observational studies have also demonstrated high efficacy [66]:
●Patients without cirrhosis – In the absence of cirrhosis, 12 weeks of ombitasvir-paritaprevir-ritonavir plus dasabuvir with weight-based ribavirin results in SVR rates in excess of 95 percent, regardless of treatment history. In the double-blind SAPPHIRE-I trial, treatment-naïve patients without cirrhosis were randomly assigned to receive 12 weeks of this regimen (n = 473) or placebo (n = 158) [18]. The SVR rate was 96 percent with this regimen, with only one virologic breakthrough during treatment and seven post-treatment relapses. All of the patients who had virologic failure had at least one baseline mutation that was associated with resistance to one of the antiviral agents. Similarly, in the SAPPHIRE-II trial of non-cirrhotic patients who had failed prior peginterferon plus ribavirin therapy, 96 percent of the 297 patients who received the regimen for 12 weeks achieved SVR [26]. Response rates were 95, 100, and 95 percent among those with prior relapse, prior partial response, and prior null response, respectively.
These findings confirm the results of the open label AVIATOR study of patients without cirrhosis, in which 12 weeks of ombitasvir-paritaprevir-ritonavir plus dasabuvir with weight-based ribavirin resulted in SVR rates of 96 percent in treatment-naïve patients and 93 percent in prior null responders [64]. These outcomes were not different from those after treatment for 24 weeks. However, there were a higher number of virologic relapsers following eight weeks of therapy, suggesting that shorter duration is not sufficient.
Among genotype 1b patients, who are generally more responsive to DAA-based regimens, 12 weeks of ombitasvir-paritaprevir-ritonavir plus dasabuvir is similarly effective with or without ribavirin [20,27,67]. In the PEARL-III trial of over 400 treatment-naïve, noncirrhotic genotype 1b-infected patients, SVR rates were 99 percent, regardless of whether ribavirin was used with this regimen [20]. Similarly, in the PEARL-II trial of 179 treatment-experienced, noncirrhotic genotype 1b-infected patients, the SVR rate was 100 percent with 12 weeks of ombitasvir-paritaprevir-ritonavir plus dasabuvir without ribavirin [27]. In contrast, among over 300 treatment-naïve noncirrhotic genotype 1a-infected patients in the PEARL-IV trial, SVR rates were higher when ribavirin was included (97 versus 90 percent without ribavirin) [20].
●Patients with cirrhosis – High SVR rates can also be achieved with ombitasvir-paritaprevir-ritonavir plus dasabuvir with weight-based ribavirin even in the setting of cirrhosis. In the open-label TURQUOISE-II trial, 380 treatment-naïve and experienced patients with cirrhosis were randomly assigned to receive 12 or 24 weeks of this regimen [19]. SVR rates were 92 and 96 percent for 12 and 24 weeks of treatment, respectively, and the difference between the two was not significant. Overall, more patients in the 12-week treatment arm had documented virologic failure (5.9 versus 0.6 percent with 24 weeks). SVR rates for 12 and 24 weeks of treatment were 89 and 92 percent, respectively, among patients with subtype 1a infection and were 99 and 100 percent among those with subtype 1b infection. Subtype 1a infection, a history of prior null response, and former injection drug use were independently associated with failure to achieve SVR.
Among genotype 1b-infected patients with cirrhosis, ombitasvir-paritaprevir-ritonavir plus dasabuvir remains highly effective, even without the addition of ribavirin [67,68]. As an example, in an open-label study of 60 such patients with cirrhosis, about half of whom had failed prior treatment with peginterferon and ribavirin, all achieved SVR with 12 weeks of this regimen [68].
Other combinations of these agents also appear to be effective in certain genotype 1 populations, but not quite as effective as the above combinations [64,69,70].
Ombitasvir-paritaprevir-ritonavir plus dasabuvir with or without ribavirin is generally well tolerated. In the large studies of the combination regimen, adverse events were common but typically mild [18,19,26,64]. However, in patients with underlying cirrhosis, there have been subsequent reports of hepatic decompensation that occurred within one to four weeks of drug initiation and thus, this regimen should be used cautiously in such patients [51]. Otherwise, the most common adverse effects overall included headache, fatigue, pruritus, asthenia, and insomnia, and discontinuation of treatment for adverse events was rare. The most common serious lab abnormalities reported in studies were hyperbilirubinemia (primarily unconjugated) and elevations in the alanine aminotransferases, which resolved during or immediately after treatment. Mild to moderate reductions in hemoglobin also occurred and occasionally warranted ribavirin dose reduction.
Pharmacologic issues may limit the use of this regimen. It should not be used in patients with moderate to severe (Child-Pugh class B or C) cirrhosis [71]. Because components of ombitasvir-paritaprevir-ritonavir plus dasabuvir are both substrates and inhibitors of major metabolic enzymes, drug interactions are considerable. Common drugs that should not be coadministered with ombitasvir-paritaprevir-ritonavir plus dasabuvir include anticonvulsants, rifampin, St. John's wort, ethinyl estradiol-containing products (ie, certain oral contraceptives), and salmeterol. 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 ombitasvir-paritaprevir-ritonavir plus dasabuvir are discussed elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Ombitasvir-paritaprevir-ritonavir with or without dasabuvir'.)
Sofosbuvir-velpatasvir-voxilaprevir — The pangenotypic once-daily fixed-dose combination of the NS5B inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor voxilaprevir is a highly effective option for patients who have failed prior therapy with NS5A inhibitor-containing regimens and subtype 1a patients who have failed prior therapy with a sofosbuvir-containing regimen. It is given for 12 weeks in such patients. (See 'Prior sofosbuvir failure (no NS5A inhibitor exposure)' above and 'Prior failure with an NS5A inhibitor regimen' above.)
In a trial of patients who had previously failed an NS5A inhibitor-containing regimen, sofosbuvir-velpatasvir-voxilaprevir for 12 weeks resulted in SVR rates of 96 and 100 percent for genotypes 1a (n = 101) and 1b (n = 45), respectively [31]. The majority of patients had NS3/4A or NS5A RAS at baseline, which were not associated with lower SVR rates. Approximately 40 percent of the patients in this study had compensated cirrhosis. The addition of ribavirin does not improve response rates [72].
In a separate trial of patients who had previously failed a sofosbuvir-containing regimen (without an NS5A inhibitor), sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was superior to sofosbuvir-velpatasvir for 12 weeks among 98 genotype 1a-infected patients (98 versus 89 percent) but not among 46 genotype 1b-infected patients (96 versus 95 percent) [31].
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 [31]. Coadministration is contraindicated with rifampin and is not recommended with amiodarone, anticonvulsants, St. John's wort, certain antiretrovirals, and cyclosporine. 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".)
Simeprevir plus sofosbuvir — The interferon-free combination of the protease inhibitor simeprevir (150 mg orally once daily) plus the NS5B inhibitor sofosbuvir (400 mg orally once daily) appears highly effective for the majority of patients with chronic HCV infection [73-77], but the data to support its use are somewhat more limited than for other options. The regimen is given for 12 weeks to those without cirrhosis and for 24 weeks to those with cirrhosis. There is no clear efficacy benefit with the addition of weight-based ribavirin (1000 mg/day if <75 kg or 1200 mg/day if ≥75 kg) to simeprevir plus sofosbuvir and we do not routinely use it. Nevertheless, given the overall limited data for this regimen, it is reasonable to add ribavirin in patients who have characteristics traditionally associated with suboptimal response to antiviral therapy (eg, cirrhosis, obesity, Black race, unfavorable IL28B genotype) as long as there are no other factors such as marginal hemoglobin level or renal impairment that increase the risk of ribavirin-associated anemia. Given lower response rates, is not recommended for subtype 1a patients who have cirrhosis and the Q80K viral variant.
Simeprevir plus sofosbuvir is not an option for the following patients: those with a history of treatment failure with a protease inhibitor, those who use an essential drug that cannot be administered with simeprevir (or sofosbuvir) because of drug interactions, or those with some other contraindication to these agents. Additionally, in the United States, although the individual agents are available, the regimen has not been approved by the Food and Drug Administration, so some insurers may not be willing to pay for this regimen.
Trial-based evidence for the use of this regimen comes from the COSMOS and OPTIMIST studies. In the OPTIMIST-1 trial, 310 genotype 1-infected patients without cirrhosis were randomly assigned to 12 versus 8 weeks of treatment with simeprevir plus sofosbuvir [74]. Overall SVR rates were greater with 12 weeks of therapy (97 versus 83 percent with 8 weeks), which resulted in similar outcomes regardless of treatment history (97 and 95 percent in treatment-naïve and experienced patients, respectively). Among patients with subtype 1a infection, the presence of the Q80K viral variant, which had been associated with decreased response rates to simeprevir plus peginterferon and ribavirin, was not associated with variable SVR rates. In contrast, in the OPTIMIST-2 study of 103 patients with cirrhosis, overall SVR rates with 12 weeks of simeprevir plus sofosbuvir were lower at 83 percent (88 and 79 percent in treatment-naïve and experienced patients, respectively) [75]. In particular, among the 34 subtype 1a-infected patients with the Q80K variant, the SVR rate was only 74 percent.
Prior limited data had suggested that 24 weeks of therapy might be more effective for patients with cirrhosis. In a pooled analysis of the cohorts in the COSMOS trial, which included 187 patients who were randomly assigned to simeprevir plus sofosbuvir with or without weight-based ribavirin for 12 or 24 weeks, there was a somewhat greater SVR rate with 24 versus 12 weeks of treatment among patients with cirrhosis (100 versus 86 percent), but the numbers were very small [73,76]. The potential to improve on SVR rates with the 12 week regimen in cirrhotics had also been suggested by observational studies in which simeprevir plus sofosbuvir for 12 weeks resulted in SVR in 75 to 87 percent in the presence and 88 to 92 percent in the absence of cirrhosis [78-80]. Results from the COSMOS trial also suggested that there was not a benefit to the addition of ribavirin [73]; the OPTIMIST studies did not evaluate ribavirin [74,75].
The regimen was well tolerated in these studies, even among patients with compensated cirrhosis (Child-Pugh class A). The most commonly reported adverse effects were fatigue, headache, and nausea. When observed, anemia and hyperbilirubinemia occurred predominantly in patients who also received ribavirin. In other studies of simeprevir containing regimens, photosensitivity and rash have been reported and patients should thus be cautioned about this risk and instructed to use sun protective measures and limit sun exposure.
Pharmacologic issues with simeprevir may limit the use of this regimen. The elimination of simeprevir is by the liver [76], and it should not be used in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment because of increases in exposure of two- to fivefold. Additionally, simeprevir is oxidatively metabolized by CYP3A subfamily, which consists mainly of hepatic and intestinal CYP3A4 metabolism [81]. Therefore, coadministered drugs that are significant inducers or inhibitors of CYP3A4 are expected to alter concentrations of simeprevir (table 1). Sofosbuvir should not be used with Pg-p inducers, such as rifampin and St. John's wort, which can reduce its concentration.
Additional adverse effects and drug information, including pharmacokinetics and potential drug interactions, for sofosbuvir and simeprevir are discussed elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Simeprevir' and "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Sofosbuvir'.)
Daclatasvir plus sofosbuvir — The combination of the NS5A inhibitor daclatasvir plus the NS5B inhibitor sofosbuvir is effective for genotype 1 infection, although data are limited for patients with cirrhosis. Additionally, in the United States, the regimen is not FDA approved for genotype 1 infection so may not be accessible to many patients.
In an open label trial that included 82 treatment-naïve genotype 1-infected patients treated with daclatasvir plus sofosbuvir for 12 weeks, SVR rates were high (95 and 100 percent with or without ribavirin, respectively) [82]. Similarly, in a study of HIV and HCV coinfected patients, 12 weeks of daclatasvir plus sofosbuvir resulted in SVR rates of 97 and 98 percent among treatment-naïve (n = 83) and experienced patients (n = 44), respectively [83]. Daclatasvir plus sofosbuvir for 24 weeks with or without ribavirin has also been demonstrated to be effective among patients who failed prior therapy with a protease inhibitor combined with peginterferon and ribavirin (98 percent of 42 individuals) [82].
The efficacy is less certain in patients with cirrhosis because of the small number included in these studies. Other data, mainly retrospective or indirect, have suggested that adding weight-based ribavirin and/or extending treatment to 24 weeks in patients with cirrhosis is associated with acceptably high SVR rates [84-86].
The regimen is well tolerated; dose modifications of daclatasvir may be warranted when used with certain other medications. More details on adverse effects and drug information, including pharmacokinetics and potential drug interactions, for daclatasvir and sofosbuvir are discussed 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'.)
MAINTENANCE THERAPY IN NONRESPONDERS — Long term maintenance therapy with peginterferon does not halt liver disease progression [87], and maintenance therapy is not recommended for nonresponders.
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 growing availability of highly effective interferon-free regimens for genotype 1 infection, a curative all-oral treatment is becoming a possibility for the vast-majority of patients. However, the cost of these new agents prevents universal delivery of antiviral therapy. When resources are constrained, prioritizing patients who benefit most from antiviral treatment may be warranted. These issues are discussed in detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Deciding when to treat'.)
●For patients with chronic genotype 1 HCV infection who are initiating antiviral therapy, we recommend an interferon-free regimen instead of an interferon-containing regimen (Grade 1A). Interferon-free regimens achieve SVR rates of approximately 95 percent or higher and are well tolerated, without the well-known toxicity associated with interferon. (See 'Selection of treatment regimens' above.)
●For treatment-naïve patients and those who have failed treatment with peginterferon and ribavirin, regimens based on the following drug combinations have comparably high expected efficacy and safety:
•Elbasvir-grazoprevir with or without ribavirin
•Ombitasvir-paritaprevir-ritonavir plus dasabuvir with or without ribavirin
•Simeprevir plus sofosbuvir
•Daclatasvir plus sofosbuvir
The patient characteristics that impact regimen specifics (eg, the duration and need to add ribavirin) vary by regimen and include treatment history, presence of cirrhosis, infecting subtype, and the presence of certain preexisting resistance-associated substitutions (RASs) (algorithm 1 and algorithm 2). The choice between these combination regimens depends primarily on the potential for drug interactions and drug toxicity. Additionally, in the United States, the options will be limited by the individual's insurance provider. If cost or insurance coverage is not an issue, we suggest ledipasvir-sofosbuvir, sofosbuvir-velpatasvir, or glecaprevir-pibrentasvir (Grade 2B). (See 'Treatment-naïve patients' above and 'Treatment-experienced patients' above.)
●For patients who have failed prior DAA regimens, options depend on the precise regimen that was previously used. (See 'Prior protease inhibitor failures' above and 'Prior sofosbuvir failure (no NS5A inhibitor exposure)' above and 'Prior failure with an NS5A inhibitor regimen' above.)
●Interferon-free regimens are generally effective and safe in patients with compensated cirrhosis but should be undertaken in consultation with an expert in managing patients with cirrhosis. Glecaprevir-pibrentasvir, elbasvir-grazoprevir, sofosbuvir-velpatasvir-voxilaprevir, ombitasvir-paritaprevir-ritonavir plus dasabuvir, and simeprevir are contraindicated in patients with Child-Pugh class B or C cirrhosis. (See 'Additional treatment considerations' above.)
●Ribavirin is teratogenic, so two effective forms of contraception should be used by both males and females of child-conceiving potential during treatment 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'.)
