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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 Support and/or Advisory Boards: Genentech [Novel agents for hepatitis C, treatment of liver cancer (pegylated interferon)]; Gilead Sciences (Novel agents for hepatitis C, treatment of hepatitis B); Idenix (novel agents to treat hepatitis C); Vertex [Novel agents for hepatitis C (telaprevir)]; Bristol-Myers-Squibb (novel agents for hepatitis C, treatment of liver cancer); GlobeImmune (treatment of viral hepatitis); Transgene (novel agents for hepatitis C); Janssen (novel agents for hepatitis C); AbbVie (treatment of viral hepatitis, treatment of liver cancer); Bayer (treatment of liver cancer). Allyson Bloom, MD Employee of UpToDate, Inc.

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Literature review current through: Nov 2014. | This topic last updated: Nov 26, 2014.

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 'Prior peginterferon and ribavirin failure' below and 'Prior protease inhibitor failures' 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 regimen, as it avoids the substantial toxicity associated with interferon use. If such a regimen is not an option for the patient and the patient cannot or does not wish to defer treatment to await interferon-free regimens, then a combination regimen of a DAA with peginterferon plus ribavirin can be used. In such cases, the DAAs sofosbuvir and simeprevir, if available, are preferable to telaprevir or boceprevir because of fewer adverse effects and greater ease of administration. In fact, we rarely use telaprevir and boceprevir-based regimens, only in patients for whom imminent treatment is warranted and who do not have access to other DAAs.

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 'Regimen options' 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, we favor the regimen of ledipasvir-sofosbuvir because of its efficacy, its favorable adverse effect profile, its extreme ease of administration (a single pill once daily), and extensive data to support its use. The regimen of simeprevir plus sofosbuvir is also likely highly effective for this population, but the data are more limited than with ledipasvir-sofosbuvir (algorithm 1).

For treatment-naïve patients, the duration of ledipasvir-sofosbuvir 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]. They are discussed in greater detail elsewhere. (See 'Ledipasvir-sofosbuvir' below.)

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]. It 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. This regimen is discussed in greater detail elsewhere. (See 'Simeprevir plus sofosbuvir' below.)

If these regimens are not available to the patient, then sofosbuvir or simeprevir plus peginterferon and ribavirin are also effective options (SVR rates 80 to 90 percent). Between the two, we favor the regimen of sofosbuvir, peginterferon, and ribavirin in treatment-naïve genotype 1 infected patients because of its relatively short (12 weeks versus 24 weeks with simeprevir) duration, fewer expected drug interactions with sofosbuvir, the greater simplicity of administration (ie, no need for decisions about response guided therapy), and the absence of clinically relevant resistance mutations. (See 'Sofosbuvir plus peginterferon and ribavirin' below.)

Of note, if the regimen of simeprevir plus peginterferon and ribavirin is being considered in a patient with genotype 1a infection, testing to evaluate for the presence of a Q80K variant should be performed. This variant is associated with a lower response rate to this regimen, and if present, should prompt selection of a different regimen. (See 'Simeprevir plus peginterferon and ribavirin' below.)

In general, 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. An exception is for patients with compensated cirrhosis awaiting liver transplantation to prevent graft reinfection. (See 'Patients awaiting liver transplant' 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, we favor the regimen of ledipasvir-sofosbuvir because of its efficacy, its favorable adverse effect profile, its extreme ease of administration (a single pill once daily), and extensive data to support its use (algorithm 1). The regimen of simeprevir plus sofosbuvir is also highly effective for this population, but the data are more limited than with 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 ribavirin given for 12 weeks has comparable efficacy to ledipasvir-sofosbuvir for 24 weeks in patients with cirrhosis. This regimen is discussed in greater detail elsewhere. (See 'Ledipasvir-sofosbuvir' below.)

The regimen of simeprevir plus sofosbuvir 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]. 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. This regimen is discussed in greater detail elsewhere. (See 'Simeprevir plus sofosbuvir' below.)

If these regimens are not available to the patient, management depends on the type of prior treatment failure. Patients who are prior relapsers to peginterferon and ribavirin generally have similar response rates to interferon-DAA combination regimens. Thus, alternative options for prior relapsers are sofosbuvir or simeprevir plus peginterferon and ribavirin, as discussed for treatment-naïve patients. (See 'Treatment-naïve patients' above.)

For patients who are partial and null responders to prior peginterferon and ribavirin, alternative options have suboptimal response rates. Thus, we generally reserve treatment with such alternative options for those who cannot defer therapy:

The 12-week regimen of sofosbuvir, peginterferon, and ribavirin has not been directly studied in treatment-experienced genotype 1 patients, but an SVR rate of approximately 70 to 75 percent is expected based on indirect data from other populations. Although the United States Food and Drug Administration (FDA) allows discretion to clinicians who are considering this sofosbuvir plus peginterferon and ribavirin regimen for treatment experienced patients based on such indirect information, we cannot routinely recommend this approach without more direct prospective data. (See 'Sofosbuvir plus peginterferon and ribavirin' below.)

The regimen of simeprevir plus peginterferon and ribavirin has been directly studied in prior partial and null responders, however a 48-week course of therapy is recommended for this population and SVR rates remain suboptimal, especially for subtype 1a [18]. Of note, patients with genotype 1a infection who are being considered for this simeprevir-based regimen should undergo testing to evaluate for the presence of a Q80K variant. This variant is associated with a lower response rate to simeprevir plus peginterferon and ribavirin, and if present, should prompt selection of an alternative regimen. (See 'Simeprevir plus peginterferon and ribavirin' below.)

In general, 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. An exception is for patients with compensated cirrhosis awaiting liver transplantation to prevent graft reinfection. (See 'Patients awaiting liver transplant' 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 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 [15,19]. They are discussed in greater detail elsewhere. (See 'Ledipasvir-sofosbuvir' below.)

The alternative regimen is sofosbuvir plus peginterferon and ribavirin for 12 weeks. Such patients could reasonably be expected to achieve an SVR rate of at least 74 percent with this regimen, based on results of a small study in patients who had failed treatment with investigational protease inhibitor-based therapy [20]. This is lower than would be expected with ledipasvir-sofosbuvir and has the added toxicity of peginterferon and ribavirin. (See 'Sofosbuvir plus peginterferon and ribavirin' below.)

There are no other currently available options for these patients. If a patient has failed one protease inhibitor, treatment with another protease inhibitor (boceprevir, telaprevir, or simeprevir) is not recommended due to likely resistance development and thus subsequent treatment failure. Thus, the combination of simeprevir plus sofosbuvir is not an option 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 [21,22]. For patients who have failed prior sofosbuvir plus ribavirin with or without peginterferon, we attempt retreatment with ledipasvir-sofosbuvir plus ribavirin for 12 weeks. Ledipasvir-sofosbuvir alone for 12 weeks also appears effective, but the efficacy is based on fewer individuals. (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 await non-sofosbuvir-containing interferon free regimens that are expected imminently.

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.)

If 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. For treatment-naïve patients with compensated cirrhosis who cannot wait for additional interferon-free DAA regimens and do not have any contraindications to interferon (including platelets <90,000/microL or albumin <3.5 g/dL), we cautiously use sofosbuvir with peginterferon and ribavirin for 12 weeks. Among the small numbers of patients with compensated cirrhosis in trials of sofosbuvir or simeprevir combined with peginterferon and ribavirin, SVR rates are moderately high (60 to 80 percent), but generally lower than in those without cirrhosis [6-8]. These agents also appear relatively well tolerated. Our rationale for preferring a sofosbuvir over simeprevir-based regimen is discussed elsewhere. (See 'Selection of treatment regimens' above and 'Sofosbuvir plus peginterferon and ribavirin' below.)

However, 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 [23,24]. 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 [23]. Predictors of serious adverse events included platelet count ≤100,000/microL and albumin <3.5 g/dL. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Bridging fibrosis and compensated cirrhosis'.)

Although the limited data thus far do not suggest that a similarly high adverse effect rate would be observed among cirrhotics treated with peginterferon and ribavirin in combination with sofosbuvir or simeprevir, in light of this concern, we favor not using an interferon-based regimen for cirrhotic patients who have platelet counts <90,000/microL or albumin <3.5 g/dL. 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'.)

Regimen selection for patients with cirrhosis who are awaiting liver transplant is discussed elsewhere. (See 'Patients awaiting liver transplant' below.)

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. These patients will ultimately benefit from interferon-free regimens. 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 [25]. 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.

Patients awaiting liver transplant — Apart from cure of HCV infection through SVR, an alternative goal for patients awaiting liver transplant is avoidance of infection of the new liver by obtaining an undetectable HCV RNA at the time of transplant. Based on preliminary data, the use of sofosbuvir and ribavirin until the time of transplant appears to be a relatively safe and effective strategy to prevent graft reinfection for patients with compensated cirrhosis awaiting liver transplantation when the timing of transplantation can be reasonably predicted.

This strategy was evaluated in a study of patients with hepatocellular carcinoma awaiting liver transplantation [26]. This population was selected due to the ability to predict timing of transplantation. Although they were awaiting transplantation with high MELD scores earned through hepatocellular carcinoma exception points, the patients also had compensated cirrhosis with Child-Pugh scores ≤7. Patients were treated with sofosbuvir and weight-based ribavirin (1000 or 1200 mg daily dose) for up to 48 weeks or the time of the liver transplant. Of the 61 patients enrolled in this ongoing study, 39 received a transplant with undetectable HCV RNA and had been followed for 12 weeks post-transplant. Treatment was well tolerated, and prevention of recurrent infection at 12 weeks post-transplantation occurred in 25/39 (64 percent). Recurrence was associated with shorter duration of undetectable HCV RNA; infection recurred more commonly if HCV RNA was not detectable for less than four weeks duration (9/13) compared with greater than four weeks duration (1/25).


This approach cannot be recommended for patients with decompensated cirrhosis; studies are in progress to evaluate treatment in this group prior to liver transplantation.

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 [27,28], but studies with the first generation protease inhibitors demonstrated similar SVR rates among both groups [29,30]. However, drug-drug interactions between HIV 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 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.

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) [19]. 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 [31].

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) [22]. 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 [21]. 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.

Monitoring of on-treatment viral levels does not affect management decisions with this regimen as all patients who had virologic failure had achieved viral suppression during treatment and subsequently relapsed. 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 (and 24, depending on treatment duration) in clinical practice. 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, and then monthly, with more frequent monitoring for concerning results or trends.

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'.)

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. 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 [32]. The potential to improve on SVR rates with the 12 week regimen in cirrhotics was also 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 [33,34].

Monitoring of on-treatment viral levels does not affect management decisions with this regimen as all patients who had virologic failure had achieved viral suppression during treatment and subsequently relapsed. 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 (end of treatment) in clinical practice. 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.

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 [32], 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 [35]. 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. Sofosbuvir and ribavirin may have greater utility among genotype 1 infected patients who are awaiting liver transplant, among whom the regimen may be effective in decreasing the risk of reinfection of the graft [26]. (See 'Patients awaiting liver transplant' above.)

In the SPARE trial of genotype 1 infected patients from an urban Washington, DC population who had a number of negative predictors of response to peginterferon and ribavirin therapy (83 percent black race, 81 percent unfavorable IL28B genotype, 62 percent baseline HCV RNA levels >800,000 international units/mL), SVR rates with 24 weeks of sofosbuvir and weight based ribavirin (1000 or 1200 mg daily dose) were 68 percent (17 of 25 patients) [36]. This regimen was also studied in the PHOTON study of 182 HIV/HCV coinfected patients, in which the overall SVR rate was 76 percent [37].

Adverse effects and additional drug information for sofosbuvir and ribavirin are discussed elsewhere. (See "Direct acting antivirals for the treatment of hepatitis C virus infection", section on 'Nucleot(s)ide polymerase inhibitors (NPIs)' and "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection".)

Interferon-containing regimens — Interferon-based regimens that contain a direct-acting antiviral (such as sofosbuvir or simeprevir) with peginterferon and ribavirin are generally reserved for those who do not have access to interferon-free regimens yet warrant prompt therapy.

Sofosbuvir plus peginterferon and ribavirin — The regimen of the NS5B inhibitor sofosbuvir, peginterferon, and ribavirin is an effective option for treatment-naïve patients and prior relapsers who do not have access to interferon-free regimens. It has reasonable but lower for treatment experienced patients (including those who failed protease-inhibitor based treatment), and we only use it in treatment-experienced patients who have no alternative and who cannot defer therapy.

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 [38]. 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 [20]. 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.

Monitoring of on-treatment viral levels does not affect management decisions with a sofosbuvir-based regimen. In the clinical studies of sofosbuvir, treatment failure was almost exclusively due to relapse. With 99 percent of patients in the NEUTRINO trial above achieving HCV RNA <25 international units/mL at weeks 4 and 12, one could argue that monitoring on treatment is not necessary except to document compliance with the regimen. However, given the expense of the medicines and the potential risk of viral resistance with inappropriate use, we recommend HCV RNA quantitative testing at weeks 4 and 12 (end of treatment) in clinical practice.

Sofosbuvir is well tolerated with no significant side effects beyond what is seen with peginterferon and ribavirin. In clinical trials, the most commonly reported adverse effects of sofosbuvir, peginterferon, and ribavirin are likely attributable to the last two agents, namely fatigue, headache, nausea, insomnia, and anemia [6,10,11]. Treatment discontinuation for adverse effects in trials was infrequent. (See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection".)

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 are discussed elsewhere. (See "Direct acting antivirals for the treatment of hepatitis C virus infection", section on 'Nucleot(s)ide polymerase inhibitors (NPIs)'.)

Simeprevir plus peginterferon and ribavirin — The regimen of the HCV protease inhibitor simeprevir plus peginterferon, and ribavirin is an effective option 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, and so we only use it in such patients who have no other options and cannot defer therapy. It should be emphasized that simeprevir is only recommended for patients with genotype 1 infection and not 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 [39]:

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 [7,8,40,41]. 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) [41].

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 [18]. 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, and further data are warranted to more accurately assess efficacy among patients with cirrhosis.

On treatment viral load monitoring should be performed at weeks 4, 12, 24, and 48 to assess for a treatment response and assess for stopping rules. Discontinuation is warranted for patients who are unlikely to achieve SVR based on the on-treatment virological response. If the HCV RNA is >25 international units/mL at week 4, the entire regimen of simeprevir, peginterferon, and ribavirin should be discontinued. If the HCV RNA is >25 international units/ml at week 12 or 24 after the simeprevir has been completed, peginterferon and ribavirin should be discontinued.

In general, simeprevir is well tolerated. Photosensitivity and rash were reported in the simeprevir trials with some serious reactions requiring hospitalization. Patients should be cautioned about this risk and instructed to use sun protective measures and limit sun exposure. Simeprevir use has also been associated with transient, mild elevations in the bilirubin levels that are not accompanied by increases in liver enzymes. Treatment discontinuation for adverse effects was infrequent [7,8]. Other side effects are likely attributable to the peginterferon and ribavirin component. (See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection".)

Pharmacologic issues with simeprevir may limit the use of this regimen. The elimination of simeprevir is by the liver [32], 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 [35]. Therefore, coadministered drugs that are significant inducers or inhibitors of CYP3A4 are expected to alter concentrations of simeprevir (table 1).

Several mutations in the NS3/4A protease are associated with reduced susceptibility to simeprevir. One of the most prevalent and clinically relevant mutations is the substitution Q80K. Among patients in clinical trials of simeprevir, this polymorphism was present at baseline in 30 percent of patients with genotype 1a and was associated with a lower SVR rate (58 versus 84 percent if the Q80K was not present) [42]. For patients with genotype 1a, baseline Q80K testing is therefore recommended, and patients with this variant should consider other treatment options. In the United States, testing for this variant is available at LabCorp.

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 direct acting antivirals, their use is limited to patients for whom imminent treatment is warranted and who do not have access to newer agents. In the United States, telaprevir is no longer being produced.

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 [43,44]. 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 [45-51]

Prior relapsers: response rates between 69 and 88 percent [49,52-55]

Prior partial responders: response rates between 40 and 59 percent [52-55]

Prior null responders: response rates between 23 and 38 percent [49,53,54]

No trials have directly compared telaprevir and boceprevir-based regimens, but they appear generally comparable [56]. Other factors, such as the presence of cirrhosis and African American race, unfavorably affect response rates [46,49,51,53].

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 [57,58]. 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 [59].

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 [59,60]. 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 [61-63]. 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 [64].

Studies comparing the two peginterferons in combination with ribavirin without a DAA have also had variable results [65-71]. 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 [66], results from meta-analyses and a systematic review suggest a slight advantage for peginterferon alfa-2a [9,72,73].

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 [72]. 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.

MAINTENANCE THERAPY IN NONRESPONDERS — Long term maintenance therapy with peginterferon does not halt liver disease progression [74], and maintenance therapy is not recommended for nonresponders.

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 [75]. 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'.)

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, 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. Of interferon-free regimens, we suggest ledipasvir-sofosbuvir rather than simeprevir plus sofosbuvir (Grade 2B). (See 'Selection of treatment regimens' above.)

Expected SVR rates with ledipasvir-sofosbuvir exceed 90 percent 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.)

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. 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. For patients with compensated cirrhosis who are awaiting liver transplant, sofosbuvir plus ribavirin until the time of transplant appears to be a relatively safe and effective strategy to prevent graft reinfection. Otherwise, sofosbuvir plus ribavirin results in lower SVR rates for genotype 1 infection compared with other genotypes. (See 'Additional treatment considerations' above and 'Sofosbuvir plus ribavirin' above.)

Interferon-based regimens that contain a direct-acting antiviral (such as sofosbuvir or simeprevir) with peginterferon and ribavirin are generally reserved for those who do not have access to interferon-free regimens yet warrant prompt therapy. These regimens have high efficacy for treatment-naïve patients but are less effective in patients who had prior partial or null response to peginterferon and ribavirin. (See 'Sofosbuvir plus peginterferon and ribavirin' above and 'Simeprevir plus peginterferon and ribavirin' 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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REFERENCES

  1. Swain MG, Lai MY, Shiffman ML, et al. A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology 2010; 139:1593.
  2. Recommendations for Testing, Managing, and Treating Hepatitis C. Joint panel from the American Association of the Study of Liver Diseases and the Infectious Diseases Society of America. January 2014 http://www.hcvguidelines.org/ (Accessed on January 30, 2014).
  3. European Association for the Study of the Liver. Recommendations on treatment of hepatitis C. 2014 http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C.pdf (Accessed on April 14, 2014).
  4. Miller MH, Agarwal K, Austin A, et al. Review article: 2014 UK consensus guidelines - hepatitis C management and direct-acting anti-viral therapy. Aliment Pharmacol Ther 2014; 39:1363.
  5. World Health Organization. Guidelines for the screening, care, adn treatment of persons with hepatitis C infection. April 2014. http://apps.who.int/iris/bitstream/10665/111747/1/9789241548755_eng.pdf?ua=1 (Accessed on April 14, 2014).
  6. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878.
  7. Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2014; 384:403.
  8. Manns M, Marcellin P, Poordad F, et al. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2014; 384:414.
  9. Chou R, Hartung D, Rahman B, et al. Comparative effectiveness of antiviral treatment for hepatitis C virus infection in adults: a systematic review. Ann Intern Med 2013; 158:114.
  10. Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013; 13:401.
  11. Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 2013; 381:2100.
  12. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014; 384:1756.
  13. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014; 370:1889.
  14. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370:1879.
  15. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014; 370:1483.
  16. Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet 2014; 383:515.
  17. Gane EJ, Stedman CA, Hyland RH, et al. Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection. Gastroenterology 2014; 146:736.
  18. Zeuzem S, Berg T, Gane E, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology 2014; 146:430.
  19. Bourliere M, Bronowicki J, de Ledinghen V, et al. Ledipasvir/sofosbuvir fixed dose combination is safe and efficacious in cirrhotic patients who have previously failed protease-inhibitor based triple therapy. Presented at the American Association for the Study of Liver Diseases Liver Meeting, Boston MA, November 7-11, 2014. Abstract #LB-6.
  20. Pol S, Sulkowski M, Hassanein T, et al. Successful retreatment of HCV genotype-1 infected patients who failed prior therapy with peginterferon plus ribavirin plus 1 or 2 other direct-acting antiviral agents with sofosbuvir. Presented at the 49th Annual Meeting of the European Association for the Study of the Liver (EASL), London UK, April 9-13, 2014.
  21. Osinusi A, Kohli A, Marti MM, et al. Re-treatment of Chronic Hepatitis C Virus Genotype 1 Infection After Relapse: An Open-Label Pilot Study. Ann Intern Med 2014; 161:634.
  22. Wyles DL, Pockros PJ, Yang JC, et al. Retreatment of patients who failed prior sofosbuvir-based regimens with all oral fixed-dose combination ledipasvir-sofosbuvir plus ribavirin for 12 weeks. Presented at the American Association for the Study of Liver Diseases Liver Meeting, Boston MA, November 7-11, 2014. Abstract #235
  23. Hézode C, Fontaine H, Dorival C, et al. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol 2013; 59:434.
  24. Afdhal NH, Reau N, Everson GT, et al. Safety and efficacy of telaprevir (TVR) or boceprevir (BOC) in patientns with cirrhosis: Interim results of a longitudinal, observational study. Presented at the 64th annual meeting of the American Association for the Study of Liver Diseases, Washington, DC, November 1-5, 2013.
  25. Flamm SL, Everson GT, Charlton M, et al. Ledipasvir/sofosbuvir with ribavirin for the treatment of HCVin patients with decompensated cirrhosis: Preliminary results of a prospective, multicenter study. Presented at the American Association for the Study of Liver Diseases Liver Meeting, Boston MA, November 7-11, 2014. Abstract #239.
  26. Curry MP, Forns X, Chung RT, et al. Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence of HCV Infection after Liver Transplantation. Presented at the 64th annual meeting of the American Association for the Study of Liver Diseases, Washington, DC, November 1-5, 2013. Abstract #213.
  27. Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004; 351:451.
  28. Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 2004; 292:2839.
  29. Sulkowski M, Pol S, Mallolas J, et al. Boceprevir versus placebo with pegylated interferon alfa-2b and ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a randomised, double-blind, controlled phase 2 trial. Lancet Infect Dis 2013; 13:597.
  30. Sulkowski MS, Sherman KE, Dieterich DT, et al. Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial. Ann Intern Med 2013; 159:86.
  31. Bourliere M, Sulkowski M, Omata M, et al. An integrated safety and efficacy analysis of >500 patients with compensated cirrhosis treated with ledipasvir/sofosbuvir with or without ribavirin. Presented at the American Association for the Study of Liver Diseases Liver Meeting, Boston MA, November 7-11, 2014. Abstract #82.
  32. Olysio (simeprevir). US FDA approved product information. National Library of Medicine. Available online at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=1816fd68-0ed7-4a37-84bb-e298c5ab6e28 (Accessed on November 17, 2014).
  33. Jesnsen DM, O'Leary J, Pockros, P, et al. Safety and efficacy of sofosbuvir-containing regimens for hepatitis C: Real world experience in a diverse, longitudinal observational cohort. Presented at the American Association for the Study of Liver Diseases Liver Meeting, Boston MA, November 7-11, 2014.
  34. Dieterich D, Bacon B, FlammS, et al. Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network: Academic and community treatment of a real-world, heterogenous population. Presented at the American Association for the Study of Liver Diseases Liver Meeting, Boston MA, November 7-11, 2014.
  35. Williams JA, Ring BJ, Cantrell VE, et al. Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos 2002; 30:883.
  36. Osinusi A, Meissner EG, Lee YJ, et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA 2013; 310:804.
  37. Sulkowski M, Rodriguez-Torres M, Lalezari J, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1). Presented at the 64th annual meeting of the American Association for the Study of Liver Diseases, Washington, DC, November 1-5, 2013. Abstract #212.
  38. Sovaldi (sofosbuvir). US FDA approved product information; Foster City, CA: Gilead Sciences; December 2013.
  39. FDA. Olysio U.S. prescribing information http://www.accessdata.fda.gov/drugsatfda (Accessed on October 15, 2014).
  40. Hayashi N, Izumi N, Kumada H, et al. Simeprevir with peginterferon/ribavirin for treatment-naïve hepatitis C genotype 1 patients in Japan: CONCERTO-1, a phase III trial. J Hepatol 2014; 61:219.
  41. Forns X, Lawitz E, Zeuzem S, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial. Gastroenterology 2014; 146:1669.
  42. Lenz O, Fevery B, Verbinnen T, et al. Resistance analyses of HCV isolates from patients treated with simeprevir in phase 2b/3 studies. Presented at the 64th annual meeting of the American Association for the Study of Liver Diseases, Washington, DC, November 1-5, 2013. Abstract #1101.
  43. Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54:1433.
  44. Ramachandran P, Fraser A, Agarwal K, et al. UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients. Aliment Pharmacol Ther 2012; 35:647.
  45. Sherman KE, Flamm SL, Afdhal NH, et, al. Telaprevir in combination wtih peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients who achieved an extended rapid viral response: Final results of phase 3 ILLUMINATE study. Hepatology 2010; 52:401A.
  46. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1195.
  47. Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010; 376:705.
  48. Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360:1839.
  49. Akuta N, Suzuki F, Hirakawa M, et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology 2010; 52:421.
  50. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364:2405.
  51. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360:1827.
  52. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1207.
  53. McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010; 362:1292.
  54. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364:2417.
  55. Flamm SL, Lawitz E, Jacobson I, et al. Boceprevir with peginterferon alfa-2a-ribavirin is effective for previously treated chronic hepatitis C genotype 1 infection. Clin Gastroenterol Hepatol 2013; 11:81.
  56. Kieran J, Schmitz S, O'Leary A, et al. The relative efficacy of boceprevir and telaprevir in the treatment of hepatitis C virus genotype 1. Clin Infect Dis 2013; 56:228.
  57. Jacobson IM, McHutchison JG, Dusheiko GM. Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naive patients: Final results of phase 3 ADVANCE study. Hepatology 2010; 52:427A.
  58. Roujeau JC, Mockenhaupt M, Tahan SR, et al. Telaprevir-related dermatitis. JAMA Dermatol 2013; 149:152.
  59. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201917lbl.pdf (Accessed on May 24, 2011).
  60. Sulkowski MS, Poordad F, Manns MP, et al. Anemia during treatment with peginterferon Alfa-2b/ribavirin and boceprevir: Analysis from the serine protease inhibitor therapy 2 (SPRINT-2) trial. Hepatology 2013; 57:974.
  61. Kiser JJ, Burton JR, Anderson PL, Everson GT. Review and management of drug interactions with boceprevir and telaprevir. Hepatology 2012; 55:1620.
  62. Kiser JJ, Burton JR Jr, Everson GT. Drug-drug interactions during antiviral therapy for chronic hepatitis C. Nat Rev Gastroenterol Hepatol 2013; 10:596.
  63. University of Liverpool hep drug interactions website http://www.hep-druginteractions.org/.
  64. Marcellin P, Forns X, Goeser T, et al. Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon alfa-2a or -2b to patients with chronic hepatitis C. Gastroenterology 2011; 140:459.
  65. Silva M, Poo J, Wagner F, et al. A randomised trial to compare the pharmacokinetic, pharmacodynamic, and antiviral effects of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C (COMPARE). J Hepatol 2006; 45:204.
  66. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361:580.
  67. Di Bisceglie AM, Ghalib RH, Hamzeh FM, Rustgi VK. Early virologic response after peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin treatment in patients with chronic hepatitis C. J Viral Hepat 2007; 14:721.
  68. Laguno M, Cifuentes C, Murillas J, et al. Randomized trial comparing pegylated interferon alpha-2b versus pegylated interferon alpha-2a, both plus ribavirin, to treat chronic hepatitis C in human immunodeficiency virus patients. Hepatology 2009; 49:22.
  69. Rumi MG, Aghemo A, Prati GM, et al. Randomized study of peginterferon-alpha2a plus ribavirin vs peginterferon-alpha2b plus ribavirin in chronic hepatitis C. Gastroenterology 2010; 138:108.
  70. Ascione A, De Luca M, Tartaglione MT, et al. Peginterferon alfa-2a plus ribavirin is more effective than peginterferon alfa-2b plus ribavirin for treating chronic hepatitis C virus infection. Gastroenterology 2010; 138:116.
  71. Awad T, Thorlund K, Hauser G, et al; Cochrane Hepato-Biliary Group. Peginterferon alpha-2a may achieve higher sustained virological response than peginteferon alpha-2b in chronic hepatitis C: a Cochrane systematic review of randomized clinical trials. Hepatology 2009; 50(Suppl):707A.
  72. Awad T, Thorlund K, Hauser G, et al. Peginterferon alpha-2a is associated with higher sustained virological response than peginterferon alfa-2b in chronic hepatitis C: systematic review of randomized trials. Hepatology 2010; 51:1176.
  73. Flori N, Funakoshi N, Duny Y, et al. Pegylated interferon-α2a and ribavirin versus pegylated interferon-α2b and ribavirin in chronic hepatitis C : a meta-analysis. Drugs 2013; 73:263.
  74. Di Bisceglie AM, Shiffman ML, Everson GT, et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008; 359:2429.
  75. Chen J, Florian J, Carter W, et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology 2013; 144:1450.
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