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Treatment regimens for chronic hepatitis C virus genotype 1
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Treatment regimens for chronic hepatitis C virus genotype 1

Disclosures: Sanjiv Chopra, MD, MACP Nothing to disclose. Andrew J Muir, MD, MHS Grant/Research/Clinical Trial Support: AbbVie [HCV (ABT-450, ombitasvir, dasabuvir)]; Achillion [HCV (ACH-0143102)]; BMS [HCV (Daclatasvir, asunaprevir)]; Gilead [HCV (Sofosbuvir, ledipasvir)]; GSK [HCV (Eltrombopag)]; Janssen [HCV (Simeprevir)]; Merck [HCV (Boceprevir, MK-5172, MK-8742)]; Vertex [HCV (Telaprevir)]. Consultant/Advisory Boards: AbbVie [HCV (ABT-450, ombitasvir, dasabuvir)]; BMS [HCV (Daclatasvir, asunaprevir)]; Gilead [HCV (Sofosbuvir, ledipasvir)]; Janssen [HCV (Simeprevir)]; Merck [HCV (Boceprevir, MK-5172, MK-8742)]. Adrian M Di Bisceglie, MD Grant/Research/Clinical Trial Support: Genentech [Hepatitis C (Pegylated interferon)]; Gilead Sciences [Hepatitis B and C (Treatment)]; Bristol-Myers Squibb [Hepatitis C (Novel agents for hepatitis C)]; AbbVie [Viral hepatitis (Treatment)]; Transgene [Hepatitis C (Novel agents for hepatitis C)]. Consultant/Advisory Board: Gilead Sciences [Hepatitis C (Novel agents for hepatitis C)]; AbbVie [Liver cancer, viral hepatitis (Treatment)]; Novartis (Deferasirox); Bayer [Liver cancer (Treatment)]; BTG [Liver cancer (Treatment)]. Allyson Bloom, MD Nothing to disclose.

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Literature review current through: Apr 2015. | This topic last updated: Apr 28, 2015.

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 three to six months 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 'Goal of antiviral therapy'.)

This topic will review the treatment of patients with chronic genotype 1 HCV infection. Treatment of patients with other genotypes, experimental agents for the treatment of HCV, the treatment of acute HCV, the selection of patients for treatment, the management of treatment-induced side effects, and factors that predict a response to treatment 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".)

(See "Investigational therapies for hepatitis C virus infection".)

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

(See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection".)

(See "Predictors of a sustained virologic response following treatment with peginterferon and ribavirin for chronic hepatitis C virus infection".)

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 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), which was published in 2014 [3], and United Kingdom consensus guidelines, which were updated in 2014 [4]. 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 [5].

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

Prior relapsers: Patients who had an undetectable viral load at the end of a prior attempt at treatment (end of treatment response) but who did not achieve a sustained virologic response (negative HCV RNA 24 weeks after completing treatment)

Partial responders: Patients who achieved a 2 log10 drop in HCV RNA by week 12 of treatment with peginterferon and ribavirin but who did not achieve an end of treatment response

Null responders: Patients who did not achieve a 1 log10 reduction in HCV RNA by week 4 or a 2 log10 drop in HCV RNA by week 12 of treatment with peginterferon and ribavirin

Protease inhibitor failures: Patients who did not respond to treatment with boceprevir, telaprevir, or simeprevir in combination with peginterferon and ribavirin

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 is 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 whom and 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 in patients for whom the decision to treat has been made (algorithm 1). (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 [6-15]. 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.)

Certain DAAs that are not available in the United States and are thus not discussed in this topic may be available in other resource-rich countries, such as daclatasvir in European countries and daclatasvir and asunaprevir in Japan. Clinicians in those locations are advised to check local guidelines on the optimal use of such 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, ombitasvir-paritaprevir-ritonavir plus dasabuvir with or without ribavirin, and simeprevir 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 regimen of ledipasvir-sofosbuvir for its favorable adverse effect profile, its minimal drug interactions, and its ease of administration (a single pill once daily) (algorithm 1).

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 8 weeks. For patients who meet these criteria but have multiple traditional negative predictors of response (ie, male, older age, obesity, black race), we aim to treat for 12 weeks, although there are not ample data to support this practice and insurers may not allow the extra 4 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 94 percent [13,16,17]. (See 'Ledipasvir-sofosbuvir' below.)

Ombitasvir-paritaprevir-ritonavir plus dasabuvir — 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 in patients without cirrhosis and with ribavirin for 12 weeks in patients with 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 and dasabuvir' below.)

Simeprevir plus sofosbuvir — This regimen is given for 12 weeks in patients without cirrhosis and for 24 weeks in patients with cirrhosis. There is no clear efficacy benefit to balance the additional cost or potential side effects of adding ribavirin to the regimen, although it is reasonable to use weight-based ribavirin in select populations. The regimen of simeprevir plus sofosbuvir also has an expected SVR rate that exceeds 90 percent, although it has been formally studied in fewer patients [12,21]. (See 'Simeprevir plus sofosbuvir' below.)

We do not use the regimen of sofosbuvir and ribavirin for 24 weeks in genotype 1 infected patients because of the longer treatment duration and lower expected SVR rates compared with other regimens.

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, ombitasvir-paritaprevir-ritonavir plus dasabuvir with or without ribavirin, and simeprevir 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 regimen of ledipasvir-sofosbuvir for its favorable adverse effect profile, its minimal drug interactions, and its ease of administration (a single pill once daily) (algorithm 1).

Ledipasvir-sofosbuvir — Among treatment-experienced patients, the duration of ledipasvir-sofosbuvir 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, which was not substantially improved by increasing the duration to 24 weeks [15]. In contrast, for those with cirrhosis, the regimen is given for 24 weeks. This results in an approximately 100 percent SVR rate, compared with 86 percent with only 12 weeks [15]. Alternatively, ledipasvir-sofosbuvir plus weight-based ribavirin (daily dose 1000 mg for those ≤75 kg and 1200 mg for those >75 kg) given for 12 weeks has comparable efficacy to ledipasvir-sofosbuvir for 24 weeks in patients with cirrhosis. (See 'Ledipasvir-sofosbuvir' below.)

Ombitasvir-paritaprevir-ritonavir plus dasabuvir — The duration of this regimen and the addition of weight-based ribavirin 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 in patients without cirrhosis and with ribavirin for 12 weeks in patients with cirrhosis. These regimens result in SVR rates greater than 94 percent [19,22,23]. (See 'Ombitasvir-paritaprevir-ritonavir and dasabuvir' below.)

Simeprevir plus sofosbuvir — This regimen is given for 12 weeks in treatment-experienced patients without cirrhosis and for 24 weeks in those with cirrhosis. In patients with prior null response, this regimen resulted SVR rates in excess of 90 percent, even in the setting of advanced fibrosis [12,21]. Patients with prior partial response are expected to have comparable response rates. There is no clear efficacy benefit to balance the additional cost or potential side effects of adding ribavirin to the regimen, although it is reasonable to use weight-based ribavirin in select populations. (See 'Simeprevir plus sofosbuvir' below.)

We do not use the regimen of sofosbuvir and ribavirin for 24 weeks in genotype 1 infected patients because of the lower expected SVR rates compared with other regimens.

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 favor ledipasvir-sofosbuvir (algorithm 1). In such patients, ledipasvir-sofosbuvir is given for 12 weeks to those without cirrhosis and 24 weeks to those with cirrhosis. For patients with cirrhosis who are expected to tolerate ribavirin (ie, no anemia or renal impairment), an equally effective regimen is ledipasvir-sofosbuvir plus weight based ribavirin for 12 weeks. These regimens result in SVR rates from 96 to 100 percent [15,24]. They are discussed in greater detail elsewhere. (See 'Ledipasvir-sofosbuvir' below.)

If a patient has failed one protease inhibitor, treatment with another protease inhibitor (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-based regimen failure — Patients who relapsed following treatment with certain sofosbuvir-containing regimens may be successfully retreated with a ledipasvir-sofosbuvir regimen, based on results of small studies [25,26]. For patients who have failed prior sofosbuvir plus ribavirin with or without peginterferon and cannot wait for additional data (ie, in patients with advanced liver disease who are deemed to warrant imminent treatment), we attempt retreatment with ledipasvir-sofosbuvir plus ribavirin for 24 weeks [2]. (See 'Ledipasvir-sofosbuvir' below.)

Although there are no data yet on using ledipasvir-sofosbuvir in patients who have failed simeprevir plus sofosbuvir, it plausibly would have similar efficacy in this population. An alternative is to wait for additional data or for other novel interferon-free regimens that could potentially have activity in this setting.

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. 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 [27,28]. 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 [27]. 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 [21]. Overall, the interferon-based regimen was less effective (75 versus 93 percent 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 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. The American Association for the Study of Liver Disease (AASLD) recommends caution with the use of peginterferon in such patients, which should only be undertaken by experienced clinicians. Interferon-free regimens are being evaluated in these patients. As an example, one study randomly assigned patients with decompensated cirrhosis (Child class B or C) and creatinine clearance >40 mL/min to receive ledipasvir-sofosbuvir plus ribavirin for 12 or 24 weeks [29]. SVR rates were high (87 to 89 percent), and although serious adverse events were common (10 to 42 percent, depending on the level of decompensation and duration of the regimen), few were deemed related to the treatment.

Of note, because of increased levels of simeprevir in the setting of Child B and C cirrhosis, the agent is not recommended in patients with hepatic impairment.

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 "Liver transplantation for hepatitis C virus infection", section on 'Treatment of recurrence'.)

Patients with renal impairment — The selection of a 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. Levels of sofosbuvir and its metabolite are substantially higher in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) or end stage renal disease on dialysis than in patients who have normal renal functions, so the safety of sofosbuvir-containing regimens in such patients has not been established. Antiviral treatment in such patients is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C infection in adults with renal impairment".)

HIV-HCV co-infection — All human immunodeficiency virus (HIV) infected patients should undergo screening for HCV. Patients with HIV infection have increased rates of HCV infection due to shared transmission routes and coinfection is associated with an accelerated course of HCV. (See "Epidemiology, natural history, and diagnosis of hepatitis C in the HIV-infected patient".)

Treatment with peginterferon and ribavirin resulted in lower SVR rates among coinfected compared with monoinfected patients [30,31], but studies of direct acting antivirals (either in interferon-based or interferon-free combinations) have demonstrated similar SVR rates among both groups [32-35]. However, drug-drug interactions between antiretroviral agents and HCV antiviral agents may be significant. These data suggest that patients with HIV infection and preserved immune function should not be thought of as a special population that has lower response rates compared with the monoinfected population, but instead as a group with particular drug-drug interaction concerns.

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

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 a 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 [13,14,16,17] and experienced [15] patients:

Treatment-naïve — 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 [13]. 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 [14]. 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.

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). (See "Investigational therapies for hepatitis C virus infection", section on 'Sofosbuvir and ledipasvir combinations'.)

Treatment-experienced — 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 [15]. 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) [24]. 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 [36].

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) [26]. 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 [25]. 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-sofoabuvir 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 [13-15]. Fatigue, headache, insomnia, and nausea were the most common effects. Important drug interactions to avoid include P-gp inducers, such as rifampin and St. John’s wort, which can reduce concentrations of both ledipasvir and sofosbuvir. 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 'Nucleot(s)ide polymerase inhibitors (NPIs)' and "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'NS5A inhibitors'.)

Ombitasvir-paritaprevir-ritonavir and 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. (See 'Selection of treatment regimens' above.)

Support for the use of this regimen is based on several large clinical trials [18-20,22,23,37]:

Patients without cirrhosis — In the absence of cirrhosis, 12 weeks of ombitasvir-paritaprevir-ritonavir and 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 [22]. 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 [37]. 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. 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 [23]. 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.

Other combinations of these agents also appear to be effective in certain genotype 1 populations, but not quite as effective as the above combinations [37-39].

Ombitasvir-paritaprevir-ritonavir and dasabuvir with or without ribavirin is generally well tolerated. In the large studies of the combination regimen, adverse events were common but typically mild [18,19,22,37]. The most common adverse effects included headache, fatigue, pruritus, asthenia, and insomnia. Overall, discontinuation of treatment for adverse events was rare. The most common serious lab abnormalities 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 B to C) cirrhosis [40]. 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 co-administered 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 Lexi-Interact 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 plus dasabuvir'.)

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, but the data to support its use are overall more limited than for ledipasvir-sofosbuvir and ombitasvir-paritaprevir-ritonavir plus dasabuvir. 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 not other factors such as marginal hemoglobin level or renal impairment that increase the risk of ribavirin-associated anemia.

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.

Evidence for the use of this regimen comes from the COSMOS trial, which included two cohorts of genotype 1 infected patients: one with 80 prior null responders without advanced liver disease and one with 87 patients with advanced fibrosis or cirrhosis who were either treatment-naïve or prior null responders [12]. Patients from each cohort were randomly assigned to receive simeprevir plus sofosbuvir with or without weight-based ribavirin for 12 or 24 weeks. The overall SVR rates were 90 percent among the null responders without advanced liver disease and 94 percent among patients with advanced liver disease. Among 28 patients from the two cohorts who received simeprevir plus sofosbuvir for 12 weeks, the SVR rate was 93 percent. There did not appear to be a benefit to the addition of ribavirin. In a pooled analysis, 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 [41]. A subsequent study reported high SVR rates with only 12 weeks of treatment among patients with compensated cirrhosis (95 and 92 percent in treatment-naïve and prior null responders). Nevertheless, the potential to improve on SVR rates with the 12 week regimen in cirrhotics has 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 [42,43].

Although the Q80K viral variant in patients with genotype 1a infection has been associated with decreased response rates to simeprevir plus peginterferon and ribavirin, it did not appear to dramatically affect SVR rates in the COSMOS trial. Although numerically lower than the SVR rates with genotype 1b infection, SVR rates with genotype 1a infection with a baseline Q80K mutation were 89 to 96 percent in the two cohorts [12]. These data suggest that the presence of a Q80K mutation should not argue against use of simeprevir plus sofosbuvir, but it may be an additional factor in deciding whether a patient who can defer antiviral therapy should await newer therapies. We do not routinely check for Q80K prior to initiating simeprevir plus sofosbuvir.

The regimen was well tolerated in this trial, 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 [41], 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 [44]. 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 'Second-generation protease inhibitors' and "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Nucleot(s)ide polymerase inhibitors (NPIs)'.)

Sofosbuvir plus ribavirin — The NS5B inhibitor sofosbuvir (400 mg orally once daily) and weight based ribavirin (1000 mg daily for patients ≤75 kg or 1200 mg daily for patients >75 kg) for 24 weeks has been evaluated in genotype 1 populations but generally results in lower SVR rates than would be expected with other interferon-free combinations or with sofosbuvir, peginterferon, and ribavirin [45,46]. We do not use this regimen in genotype 1 infected patients.

Interferon-containing regimens — In regions where interferon-free regimens are available, interferon-based regimens should not be used for the treatment of genotype 1 infection [2]. However, they may still be in use in regions that do not have access to newer regimens.

Sofosbuvir plus peginterferon and ribavirin — We do not use sofosbuvir plus peginterferon and ribavirin for genotype 1 infection given the high efficacy and safety of several interferon-free options, but this regimen may be in use in regions without access to newer regimens. It is effective for treatment-naïve patients and prior relapsers. It has reasonable but lower efficacy for treatment-experienced patients (including those who failed protease-inhibitor based treatment).

Sofosbuvir, peginterferon, and ribavirin are initiated together, without a lead-in period. Sofosbuvir is dosed at 400 mg orally once daily. It can be taken with or without food. The three drugs are given for 12 weeks duration. The choice and doses of peginterferon and ribavirin are discussed elsewhere. (See 'Choice of peginterferon' below and 'Doses of peginterferon and ribavirin' below.)

The efficacy of sofosbuvir plus peginterferon and ribavirin is greatest among treatment-naïve patients [6,10,11]. In an open label trial (NEUTRINO) that included 291 treatment-naïve genotype 1 HCV-infected patients, 89 percent of patients achieved SVR12 following 12 weeks of treatment [6]. The SVR12 rates for genotype 1a and 1b infected patients were 92 and 82 percent, respectively. Extending the sofosbuvir-containing regimen beyond 12 weeks does not appear to improve efficacy [11]. Patients with cirrhosis tend to have a lower, yet still high, likelihood of SVR; in the NEUTRINO trial above, 80 percent of the 54 participants with cirrhosis achieved SVR.

The 12-week regimen of sofosbuvir, peginterferon, and ribavirin has not been directly studied in genotype 1 patients who had previously failed treatment with peginterferon and ribavirin. However, SVR rates might be extrapolated based on the assumption that SVR rates among treatment-experienced patients would be similar to those observed among patients with multiple negative predictors of SVR [47]. In an analysis of 52 patients who had several negative predictors (bridging fibrosis or cirrhosis, IL28B non-CC genotype, and HCV RNA >800,000 international units/ml), the SVR rate was 71 percent following 12 weeks of sofosbuvir, peginterferon, and ribavirin. However, the analysis cannot distinguish rates between relapsers (who generally have better responses to interferon-based therapy) and partial or null responders. Additionally, the regimen may have similar efficacy for patients who have previously failed a protease-inhibitor containing regimen. In a small trial of 50 patients who had previously failed treatment with peginterferon and ribavirin plus an investigational protease inhibitor with or without an additional direct-acting antiviral, the 12-week regimen of sofosbuvir plus peginterferon and ribavirin achieved SVR in 74 percent [48]. About half of the participants had been treated with more than one prior course of therapy, and the vast majority had at least one baseline mutation associated with antiviral resistance. Details on adverse effects and pharmacology of the components of this regimen are found elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection" and "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection".)

Simeprevir plus peginterferon and ribavirin — We do not use simeprevir plus peginterferon and ribavirin for genotype 1 infection given the high efficacy and safety of several interferon-free options, but this regimen may be in use in regions without access to newer regimens. It is effective for treatment-naïve patients and prior relapsers who do not have access to interferon-free regimens, although we prefer sofosbuvir plus peginterferon and ribavirin in such settings. The efficacy among treatment-experienced patients is considerably lower, even with a longer regimen. Simeprevir should not be used for patients with prior failure of first generation protease inhibitors. Additionally, genotype 1a patients who have a baseline Q80K mutation should not be treated with this regimen. In comparison to the first generation protease inhibitors (boceprevir and telaprevir), simeprevir has advantages of once daily dosing and lack of additional anemia.

Simeprevir, peginterferon, and ribavirin are initiated together, without a lead-in period. Simeprevir is given as 150 mg orally once daily. The choice and doses of peginterferon and ribavirin are discussed elsewhere. (See 'Choice of peginterferon' below and 'Doses of peginterferon and ribavirin' below.)

Patients should receive all three drugs for 12 weeks. The duration of additional therapy with peginterferon and ribavirin alone depends on the prior treatment response [49]:

Treatment-naïve patients and prior relapsers — an additional 12 weeks of peginterferon and ribavirin (thus, 24 weeks of total therapy).

Prior partial and null responders — an additional 36 weeks of peginterferon and ribavirin (thus, 48 weeks of total therapy).

The efficacy of simeprevir plus peginterferon and ribavirin is greatest among treatment-naïve patients and prior relapsers [7,8,50,51]. In two trials (QUEST 1 and 2), 785 treatment-naïve genotype 1 HCV-infected patients were randomly assigned to receive simeprevir or placebo in addition to peginterferon and ribavirin for 12 weeks [7,8]. Patients who received simeprevir subsequently received an additional 12 weeks of peginterferon and ribavirin if they achieved a HCV RNA level <25 international units/mL by week 4 and were undetectable by week 12 or an additional 36 weeks if they did not. Patients who received placebo received an additional 24 weeks of peginterferon and ribavirin. Overall, 85 to 91 percent of patients in the simeprevir group qualified for the shorter 24 week total course of therapy. SVR12 rates were substantially higher with simeprevir compared with placebo (80 to 81 versus 50 percent). A trial with a similar study design (PROMISE) among genotype 1 patients who had relapsed following prior peginterferon and ribavirin therapy demonstrated a similarly high SVR12 rate with simeprevir (79 versus 37 percent with placebo) [51].

However, treatment-experienced patients who had prior partial or null response have a lower likelihood of SVR. In a trial (ASPIRE) of 462 patients who had previously failed interferon and ribavirin therapy, patients were randomly assigned to simeprevir (100 or 150 mg dose) for 12, 24, or 48 weeks or placebo in addition to 48 weeks of peginterferon and ribavirin [52]. In patients with prior relapse to peginterferon and ribavirin, SVR rates were 82 to 89 percent. For partial and null responders, the outcomes varied according to subtype. In patients with a prior partial response, SVR rates were 56 percent (14 of 25 patients) for genotype 1a and 88 percent (38 of 43 patients) for genotypes 1b. In patients with prior null response, SVR rates were 42 percent (11 of 26 patients) for genotype 1a and 58 percent (14 of 24 patients) for genotype 1b. There was no significant change in efficacy with increased duration of simeprevir therapy.

Patients with cirrhosis also tend to have lower SVR rates. In the QUEST trials described above, approximately 60 percent of the 48 patients with cirrhosis achieved SVR12 [7,8]. Among treatment-experienced patients with cirrhosis, data have suggested SVR rates of approximately 75 to 80 for those with prior relapse or partial response and 31 percent in those with null response. However, it is important to note that these rates are reported from small numbers of patients.

Details on adverse effects and pharmacology of the components of this regimen are found elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection" and "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection".)

Additional adverse effects and drug information, including pharmacokinetics and potential drug interactions, for simeprevir are discussed elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Second-generation protease inhibitors'.)

Telaprevir or boceprevir plus peginterferon and ribavirin — Telaprevir and boceprevir were the first HCV protease inhibitors available and resulted in significantly better efficacy against genotype 1 infection compared with peginterferon and ribavirin alone. However, with the availability of substantially better tolerated and more effective direct-acting antivirals, their use is limited to locations where newer agents are not available. We do not use telaprevir or boceprevir.

Telaprevir is given as 1125 mg (three 375 mg tablets) twice per day with food (not low-fat) and is initiated with peginterferon and ribavirin, without a lead-in period. The choice and doses of peginterferon and ribavirin are discussed elsewhere (see 'Choice of peginterferon' below and 'Doses of peginterferon and ribavirin' below). All three agents are given for 12 weeks, followed by peginterferon and ribavirin only for the remainder of the treatment course. The duration of treatment depends on the history of prior treatment, the presence of cirrhosis, and the on treatment virological response. Viral loads are checked at weeks 4, 12, and 24 to assess for a treatment response and to make decisions about treatment duration. Treatment discontinuation is recommended with HCV RNA >1000 IU/mL at week 4 or 12 because of the unlikelihood of SVR in those settings. Details can be found in the Lexicomp drug entry for telaprevir.

Boceprevir is given as 800 mg (four 200 mg capsules) three times per day with food and is initiated at week 4 of treatment, following a four-week lead-in period of treatment with peginterferon and ribavirin. The choice and doses of peginterferon and ribavirin are discussed elsewhere (see 'Choice of peginterferon' below and 'Doses of peginterferon and ribavirin' below). All three agents are then continued for the remainder of the treatment course; in certain cases, peginterferon and ribavirin are continued for several weeks following the course of triple therapy. The duration of treatment depends on the history of prior treatment, the presence of cirrhosis, and the on treatment virological response. Viral loads are checked at weeks 4, 8, 12, and 24 to assess for a treatment response and to make decisions about treatment duration. Treatment discontinuation is recommended with HCV RNA ≥100 IU/mL at week 12 or detectable at week 24 because of the unlikelihood of SVR in those settings. Details can be found in the Lexicomp drug entry for boceprevir.

In addition to the discontinuation recommendations above, 2011 guidelines from the American Association for the Study of Liver Diseases (AASLD) and 2012 UK consensus guidelines suggest that patients who have virologic breakthrough during treatment (>1 log10 increase in HCV RNA above the nadir) should have their telaprevir or boceprevir discontinued while continuing the peginterferon and ribavirin [53,54]. The AASLD recommends against switching from one protease to another in patients who experience virologic breakthrough or who relapse on one protease inhibitor.

Response rates to protease inhibitor-containing regimens vary depending upon the patient's prior treatment:

Treatment-naïve patients: response rates between 67 and 75 percent [55-61]

Prior relapsers: response rates between 69 and 88 percent [59,62-65]

Prior partial responders: response rates between 40 and 59 percent [62-65]

Prior null responders: response rates between 23 and 38 percent [59,63,64]

No trials have directly compared telaprevir and boceprevir-based regimens, but they appear generally comparable [66]. Other factors, such as the presence of cirrhosis and African American race, unfavorably affect response rates [56,59,61,63].

Both telaprevir and boceprevir-based regimens are associated with substantial side effects. For severe adverse effects, discontinuation of telaprevir or boceprevir may be warranted. Additionally, decreasing the dose of ribavirin or peginterferon is another approach (particularly with hematologic toxicity). However, the dose of telaprevir or boceprevir should not be decreased because of the risk of selecting for resistance mutations. Currently there are no data to support switching between the protease inhibitors if significant side effects develop. However, in the case of anal pruritus associated with telaprevir, switching to boceprevir may lead to resolution of the pruritus.

The most common side effects associated with telaprevir are rash, pruritus, anemia, nausea, hemorrhoids, diarrhea, anorectal discomfort, dysgeusia, fatigue, vomiting, and anal pruritus. Rashes (typically a pruritic eczematous pruritus) occur in approximately half of patients but are usually mild to moderate [67,68]. However, fatalities have been seen in patients who developed severe rashes while receiving telaprevir, peginterferon, and ribavirin. Patients with rashes with systemic symptoms or with severe rashes that are progressive should have all three drugs discontinued immediately. In most cases otherwise, provided the side effects are not severe, our approach is to try to provide supportive care (eg, with topical corticosteroids) while maintaining the patient on the protease inhibitor if possible. The US FDA recommends that telaprevir should be discontinued in patients with progression of mild to moderate rashes and that peginterferon and ribavirin should also be discontinued if there is no improvement [69].

The most common side effects of boceprevir include fatigue, anemia, nausea, headache, and dysgeusia. Other side effects include dry mouth, vomiting, and diarrhea. In most cases, provided the side effects are not severe, the approach is to try to provide supportive care while maintaining the patient on the protease inhibitor if possible.

Both telaprevir and boceprevir have been associated with anemia beyond that seen with peginterferon and ribavirin alone [69,70]. A complete blood count should be monitored routinely throughout therapy. For patients with significant anemia, discontinuation or dose reductions of ribavirin or the use of erythropoietic growth factors may be indicated. (See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection", section on 'Anemia'.)

Telaprevir and boceprevir are cleared by CYP3A4/5 and numerous drug interactions have been noted [71-73]. The drugs should not be given in conjunction with medications that are CYP3A4/5 inducers or with drugs that are highly dependent on CYP3A4/5 for clearance and that are associated with serious and/or life-threatening events when plasma concentrations are high. When possible, such drugs should be discontinued prior to starting treatment with a protease inhibitor. Details can be found in the Lexicomp drug entries for telaprevir and boceprevir. (See "Drugs and the liver: Metabolism and mechanisms of injury", section on 'Phase I reactions'.)

Peginterferon and ribavirin alone — Patients who are unable to receive a direct-acting antiviral and warrant imminent treatment can be treated with peginterferon and ribavirin for a total of 48 weeks, although response rates are generally only 40 to 50 percent. This regimen should generally only be used in resource-limited settings. For patients in whom HCV RNA does not become undetectable until after week 12 (late responders), treatment for a total of 72 weeks can be considered in an attempt to increase the sustained virologic response rate. We offer a prolonged course of treatment to those patients with significant liver disease who have been tolerating therapy well. For all patients, treatment should be discontinued if HCV RNA is detectable after 24 weeks of treatment.

Choice of peginterferon — Peginterferon alfa-2a (Pegasys) and peginterferon alfa-2b (Peg-Intron) differ in their pharmacokinetics. There are no clear data to suggest that one is associated with better efficacy in a regimen that contains a direct-acting antiviral (DAA). We favor peginterferon alfa-2a for ease of administration.

Studies that have compared the two peginterferons in combination with ribavirin in the setting of direct-acting antiviral use have been mixed. In the QUEST 2 trial, among patients who received simeprevir in combination with peginterferon and ribavirin, there was a trend towards better SVR12 rates among those who had been randomly assigned to receive peginterferon alfa-2a compared with alfa-2b (88 versus 78 percent) [8]. In contrast, in a randomized trial with 161 patients who received telaprevir with either peginterferon alfa-2a or peginterferon alfa-2b, there was no significant difference in SVR rates between the two groups [74].

Studies comparing the two peginterferons in combination with ribavirin without a DAA have also had variable results [75-81]. While the largest randomized trial (IDEAL) showed that peginterferon alfa-2a and peginterferon alfa-2b appeared to have comparable efficacies in the treatment of chronic hepatitis C [76], results from meta-analyses and a systematic review suggest a slight advantage for peginterferon alfa-2a [9,82,83].

One meta-analysis of eight randomized controlled trials including 4335 patients compared sustained virologic response (SVR) rates and adverse event rates between patients treated with peginterferon alfa-2a and alfa-2b [82]. The analysis found that peginterferon alfa-2a was superior to peginterferon alfa-2b (SVR rates of 47 versus 41 percent; relative risk [RR] 1.11, 95% confidence interval [CI] 1.04-1.19). When patients with genotypes 1 and 4 were examined, the results continued to favor peginterferon alfa-2a (RR 1.21, 95% CI 1.03-1.24). There was no difference between the treatments with regard to adverse events, though the number of patients included in the meta-analysis was too small to draw definitive conclusions.

Doses of peginterferon and ribavirin — There are two peginterferon preparations used in the treatment of HCV (peginterferon alfa-2a and peginterferon alfa-2b). The doses of peginterferon differ for the two preparations:

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

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

For patients with genotype 1, ribavirin dosing is weight-based. Ribavirin is given in divided daily doses (typically twice per day):

For patients receiving peginterferon alfa-2a, the ribavirin dose is 1000 mg for patients who weigh ≤75 kg or 1200 mg for those who weigh >75 kg.

For patients receiving peginterferon alfa-2b, the ribavirin dose is 800 mg for patients weighing <65 kg, 1000 mg for 65 to 85 kg, 1200 mg for >85 to 105 kg, and 1400 mg for >105 kg.

MONITORING DURING INTERFERON-FREE REGIMENS — Clinical assessment during treatment with an interferon-free regimen focuses on adherence to the regimen and emergence of adverse effects.

Monitoring viral levels during treatment with interferon-free regimens has minimal prognostic value, as almost all patients without cirrhosis in the large clinical trials of interferon-free regimens achieve an undetectable HCV viral level by four weeks of treatment. Thus, the main reason to check viral levels during therapy is to assess adherence to the regimen. Given the expense of the medicines and the potential risk of viral resistance with inappropriate use, we check HCV RNA quantitative testing at weeks 4 and 12 (or end of treatment) in clinical practice. The joint guidelines from the AASLD and IDSA recommend rechecking HCV RNA quantitative testing at week 6 if the week 4 level is detectable and discontinuing therapy if the level has increased by >1 log [2]. Although there are no direct clinical data to support this practice, we agree that this is an appropriate approach. Although a week 12 (or end of treatment) viral level is undetectable in the vast majority of treated patients and many providers choose not to check this, documentation of a detectable level at this time point may reflect incomplete adherence to the regimen and can help distinguish between viral breakthrough and relapse.

To monitor for potential drug toxicity, we check basic laboratory tests (eg, complete blood count, basic chemistry panel, and liver enzyme and bilirubin levels) at weeks 1 to 2, 4, 8, and 12, with more frequent monitoring for concerning results or trends. If an increase in the alanine aminotransferase exceeds 10-fold the baseline level or is accompanied by symptoms or hyperbilirubinemia, treatment discontinuation is recommended [2].

FOLLOW-UP AFTER TREATMENT — Virologic response to treatment should be assessed by checking the viral load at 12 to 24 weeks following the cessation of therapy. SVR is defined by an undetectable viral level at this time point. An undetectable level at week 12 after treatment is generally maintained through week 24. However, a small proportion of patients (approximately two percent) experience virologic relapse between weeks 12 and 24 [84-86]. Thus, some practitioners also check the viral load at 24 weeks if SVR was determined at 12 weeks.

Patients who achieve a sustained virologic response (SVR) who do not have bridging fibrosis or cirrhosis do not require any specific follow-up for their HCV, though some will check an HCV viral load one year after the completion of treatment to confirm that the patient has achieved an SVR. Patients who fail to achieve an SVR should be followed for signs of progression of their liver disease. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection" and "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Overview of the management of chronic hepatitis C virus infection", section on 'General management'.)

Patients with bridging fibrosis and cirrhosis, regardless of whether they attain an SVR, warrant ongoing monitoring because they continue to be at risk of hepatocellular carcinoma or other complications of advanced liver disease, which require ongoing surveillance. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Preventing and identifying complications'.)

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.

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 topics (see "Patient information: 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 six months 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 is 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 whom and 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). Most interferon-free regimens are highly effective for all patient populations and are well tolerated, without the well-known toxicity associated with interferon.

For treatment-naïve patients and those who have failed treatment with peginterferon and ribavirin, ledipasvir-sofosbuvir, ombitasvir-paritaprevir-ritonavir plus dasabuvir with or without ribavirin, and simeprevir plus sofosbuvir have comparably high expected efficacy and safety. The choice between them 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(Grade 2B). (See 'Selection of treatment regimens' above.)

Ledipasvir-sofosbuvir regimens achieve SVR rates of approximately 95 percent or higher with only mild to moderate side effects, most commonly fatigue or headache. Duration of ledipasvir-sofosbuvir depends on treatment history and the presence of cirrhosis (algorithm 1). Among treatment-naïve patients, treatment duration can be 8 weeks for those without cirrhosis and a viral level <6 million international units/mL and 12 weeks for those with cirrhosis or a higher viral level. Among treatment-experienced patients, treatment duration is 12 weeks for those without cirrhosis and 24 weeks for those with cirrhosis. Both sofosbuvir and ledipasvir are substrates of P-glycoprotein so review of potential drug interactions is important prior to use. (See 'Selection of treatment regimens' above and 'Ledipasvir-sofosbuvir' above.)

Ombitasvir-paritaprevir-ritonavir plus dasabuvir with or without weight based ribavirin achieve SVR rates of 95 percent of higher. It is especially effective for subtype 1b infection. For subtype 1a infection, the regimen is given with ribavirin for 12 weeks to those without cirrhosis and 24 weeks to those with cirrhosis. For subtype 1b infection, the regimen is given for 12 weeks without ribavirin to those without cirrhosis and for 12 weeks with ribavirin to those with cirrhosis (algorithm 1). Because of potential cross resistance with HCV protease inhibitors, this regimen should not be used in patients with prior protease inhibitor (simeprevir, telaprevir, or boceprevir) based regimen failure. Adverse effects are common but typically mild in severity. Potential drug interactions are considerable with this regimen. (See 'Ombitasvir-paritaprevir-ritonavir and dasabuvir' above.)

Simeprevir plus sofosbuvir is also highly effective for treatment-naïve patients and those who have failed prior peginterferon and ribavirin therapy, but the data supporting its use are more limited than for ledipasvir-sofosbuvir or ombitasvir-paritaprevir-ritonavir plus dasabuvir. Furthermore, drug interactions with simeprevir may limit the use of this regimen. Because of potential cross resistance with HCV protease inhibitors, this regimen should not be used in patients with prior protease inhibitor (simeprevir, telaprevir, or boceprevir) based regimen failure. Simeprevir plus sofosbuvir is given for 12 weeks to those without cirrhosis and for 24 weeks to those with cirrhosis (algorithm 1). (See 'Selection of treatment regimens' above and 'Simeprevir plus sofosbuvir' 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. (See 'Additional treatment considerations' above.)

Peginterferon and ribavirin are associated with a number of side effects, that are discussed elsewhere. Ribavirin is teratogenic, so two effective forms of contraception should be used by both men and women of child-conceiving potential during treatment and six months after treatment with ribavirin-containing regimens. (See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection".)

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