RETREATMENT OF PERSONS IN WHOM PRIOR THERAPY HAS FAILED

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Expansions and notes for abbreviations used in this section can be found in Methods Table 3.

A summary of recommendations for retreatment is found in the BOX.

This section provides guidance on the retreatment of a person with chronic HCV infection in whom prior therapy has failed.

The level of the evidence supporting the best treatment for each patient and the strength of the recommendation vary, and are  rated in the same manner as the other sections on initial treatment of treatment-naive patients (Methods Table 2). In addition, specific recommendations are given when treatment differs for a particular group (eg, those infected with various genotypes). A regimen is classified as "Recommended" when it is favored for most patients or "Alternative" when it might be optimal in a particular subset of patients in that category. When a treatment is clearly inferior or should not be used, it is classified as "Not Recommended." Unless otherwise indicated, such regimens should not be administered to patients with HCV infection. Specific considerations of persons with HIV/HCV coinfection, decompensated cirrhosis (moderate or severe hepatic impairment; Child Turcotte Pugh [CTP] class B or C), post–liver transplant HCV infection, and those with severe renal impairment or end-stage renal disease are addressed in other sections of the Guidance.

When several regimens are offered at the same recommendation level, choice of regimen should be based on patient-specific data, including potential drug interactions. As always, patients receiving direct-acting antiviral (DAA) therapy require careful pretreatment assessment for comorbidities that may influence treatment response. All patients should have careful monitoring during treatment, particularly for anemia if RBV is included in the regimen. (See Monitoring Section)

I. Genotype 1

Three highly potent DAA oral combination regimens are recommended for patients with HCV genotype 1 infection, although there are differences in the recommended regimens based on the viral subtype. With certain treatment regimens, patients infected with genotype 1a may have higher rates of virologic failure than those infected with genotype 1b. HCV genotype 1 infection that cannot be subtyped should be treated as genotype 1a infection.

The introduction of DAAs into HCV treatment regimens increased the risk of drug interactions with other concomitant medications used by patients, and now with combinations of DAAs, attention to drug interactions is all the more important (see Drug Interactions Table). The product prescribing information and other resources (eg, http://www.hep-druginteractions.org) should be referenced regularly to ensure safety when prescribing DAA regimens. In particular, the daily fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) (hereafter ledipasvir/sofosbuvir) has a potential interaction with acid-suppressing medications (eg, proton pump inhibitors) which may result in decreased absorption of ledipasvir and lower exposures. Because of over-the-counter access to acid-suppressing medications, a comprehensive assessment of all prescribed and over-the-counter medications is recommended prior to initiating treatment. If possible, acid-suppressing medications should be held prior to and during the HCV treatment period when ledipasvir is used to optimize ledipasvir exposure. For patients in whom interruption of acid suppression is not possible, use of another regimen or change in dosing of acid suppressants is recommended per the prescribing information.

Three options with similar efficacy in general are recommended for patients with HCV genotype 1a infection who do not have cirrhosis, in whom prior PEG-IFN and RBV treatment has failed (listed in alphabetic order; see text).

Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks is recommended for patients with HCV genotype 1a infection who do not have cirrhosis, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class I, Level A

Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dasabuvir (250 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks is recommended for patients with HCV genotype 1a infection who do not have cirrhosis, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class I, Level A

Daily sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 weeks is recommended for patients with HCV genotype 1a infection who do not have cirrhosis, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class IIa, Level B

Three options with similar efficacy in general are recommended for patients with HCV genotype 1b infection who do not have cirrhosis, in whom prior PEG-IFN and RBV treatment has failed (listed in alphabetic order; see text).

Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks is recommended for patients with HCV genotype 1b infection who do not have cirrhosis, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class I, Level A

Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) for 12 weeks is recommended for patients with HCV genotype 1b infection who do not have cirrhosis, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class I, Level A

Daily sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 weeks is recommended for patients with HCV genotype 1b infection who do not have cirrhosis, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class IIa, Level B

Recommended regimens for patients with HCV genotype 1a or 1b infection who have compensated cirrhosis, in whom prior PEG-IFN and RBV treatment has failed.

Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks is recommended for patients with HCV genotype 1a or 1b infection who have compensated cirrhosis, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class I, Level A

Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks is recommended for patients with HCV genotype 1a or 1b infection who have compensated cirrhosis, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class I, Level B

Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks is recommended for patients with HCV genotype 1a infection and for 12 weeks for patients with HCV genotype 1b infection who have compensated cirrhosis, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class I, Level A

Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks is recommended for patients with HCV genotype 1a infection who are negative for the Q80K variant by commercially available resistance assays and for patients with HCV genotype 1b infection, in whom prior PEG-IFN and RBV treatment has failed. Alternative regimens should be considered in patients with cirrhosis and HCV genotype 1a with the Q80K variant present.

Rating: Class IIa, Level B

Ledipasvir/sofosbuvir has been evaluated in patients with and without cirrhosis in whom prior treatment with PEG-IFN and RBV, with or without HCV protease inhibitors (telaprevir or boceprevir), failed. In the ION-2 study, patients who had not responded to prior PEG-IFN and RBV were treated with ledipasvir/sofosbuvir. This regimen was given for 12 weeks or 24 weeks, with or without RBV. In the population without cirrhosis, the overall response rate was 98% (95% confidence interval [CI], 96%-99%). Specifically, in patients without cirrhosis who did not respond to PEG-IFN and RBV, 33 of 35 (94%) achieved a sustained virologic response (SVR) after treatment with ledipasvir/sofosbuvir alone, and 38 of 38 (100%) patients achieved SVR after treatment with ledipasvir/sofosbuvir and RBV. (Afdhal, 2014b) This regimen was well tolerated in all groups, with no serious adverse events reported in the 12-week regimen with or without RBV. In the population with cirrhosis, patients treated for 24 weeks had higher SVR rates than those treated for 12 weeks, supporting the recommendation that HCV treatment–experienced patients with cirrhosis receive 24 weeks of treatment without RBV.

In SIRIUS, a double-blind placebo-controlled French study, patients with cirrhosis who did not respond to PEG-IFN and RBV plus telaprevir or boceprevir, were randomized to receive placebo for 12 weeks followed by ledipasvir/sofosbuvir plus RBV for 12 weeks or ledipasvir/sofosbuvir plus placebo for 24 weeks. The SVR rate was similar in each group, 74 of 77 (96%) in the group that received ledipasvir/sofosbuvir plus RBV for 12 weeks (3 patients with relapse) and 75 of 77 (97%) in the group that received ledipasvir/sofosbuvir for 24 weeks (2 patients with relapse). This observation was further supported by a meta-analysis of treatment-naive and -experienced patients with cirrhosis who were treated with ledipasvir/sofosbuvir in phase II and III studies (including the SIRIUS study). In this analysis, ledipasvir/sofosbuvir for 12 weeks was inferior to ledipasvir/sofosbuvir for 24 weeks and ledipasvir/sofosbuvir plus RBV for 12 weeks; no difference in SVR was detected between the latter 2 groups. Safety and tolerability were similar in each group, and with the exception of anemia, reported adverse events did not differ substantially between patients treated with or without RBV. (Bourliere, 2014a); (Bourliere, 2014b)

The daily fixed-dose combination of paritaprevir (150 mg), ritonavir (100 mg), and ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) (hereafter PrOD) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 mg]) has been investigated for treatment of patients with HCV genotype 1 infection in whom previous PEG-IFN and RBV therapy failed. (Zeuzem, 2014) In this phase III trial, patients who did not have cirrhosis who were treated for a total of 12 weeks had a high overall rate of response with 286 of 297 (96.3%) patients achieving SVR at 12 weeks (SVR12). Response rates did not differ substantially when stratified by genotype subtype (genotype 1a, 96.0% [166/173]; genotype 1b, 96.7% [119/123]) or kinetics of prior response to PEG-IFN and RBV (relapse, 95.3% [82/86]; partial response, 100% [139/146]; null response, 95.2% [139/146]). In the PEARL-II study, 179 patients without cirrhosis and HCV genotype 1b infection, in whom previous therapy with PEG-IFN and RBV failed, were treated with PrOD with or without weight-based RBV for 12 weeks. (Andreone, 2014) SVR rates were high in both arms: 100% (91/91) in the RBV-free arm and 96.6% (85/88) in the RBV-containing arm, supporting the recommendation that this regimen may be used without RBV for patients with HCV genotype 1b infection.

In the TURQUOISE-II study, patients with CTP class A cirrhosis were treated with PrOD and RBV for 12 weeks or 24 weeks. (Poordad, 2014) Of the 380 patients enrolled in this study, 220 had received prior PEG-IFN and RBV therapy that failed. Among the treatment-experienced patients, SVR12 was achieved in 90.2% (110/122) of patients in the 12-week arm and 96.9% (95/98) of patients in the 24-week arm. In multivariate logistic regression analysis, both prior null response to PEG-IFN and RBV therapy and genotype 1a subtype were associated with lower likelihood of SVR in patients who received 12 weeks of therapy. Therefore patients with HCV genotype 1a infection should be treated for 24 weeks. Hemoglobin decline to less than 10 g/dL occurred in 7.2% of the 12-week arm and 11.0% of the 24-week arm; however, treatment discontinuation for adverse events was rare overall (2.1%).

Following the phase IIa COSMOS study in which participants received sofosbuvir (400 mg once daily) plus simeprevir (150 mg once daily) with or without weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) for 12 weeks or 24 weeks, the OPTIMIST-1 and -2 studies evaluated the combination of sofosbuvir plus simeprevir for 12 weeks in patients with HCV genotype 1 infection who were HCV treatment-naive and -experienced.(Lawitz, 2014b); (Lawitz, 2015); (Kwo, 2015) In OPTIMIST-1, patients with HCV genotype 1 infection and no evidence of cirrhosis were randomized to 8 weeks or 12 weeks of treatment. Overall, 8 weeks (SVR 83%) was less effective than 12 weeks (SVR 97%) of treatment. Among those treated for 12 weeks, the SVR rate in PEG-IFN plus RBV treatment-experienced patients was 95% (38 of 40) and the SVR rate in patients with genotype 1a infection with the Q80K polymorphism (96%; 44 of 46) was similar to that observed in patients without the Q80K variant (97%; 69 of 70). In contrast, in the OPTIMIST-2 study, 79% (42 of 53) of treatment-experienced patients with HCV genotype 1 infection and cirrhosis who were treated with 12 weeks of sofosbuvir and simeprevir achieved SVR. Overall, in this population of patients with cirrhosis, the SVR rate was lower in patients with HCV genotype 1a with the Q80K variant (74%; 25 of 34) than in patients with HCV genotype 1a without the Q80K variant (92%, 35 of 38). Taken together, these studies support the evaluation of treatment-experienced patients with cirrhosis and HCV genotype 1a for the presence of the Q80K polymorphism. If the Q80K polymorphism is detected, alternative treatment regimens should be considered. (Janssen Therapeutics, 2013); (Lawitz, 2014b)

Recommended regimen for patients in whom a previous sofosbuvir plus RBV or sofosbuvir plus RBV with PEG-IFN treatment has failed.

No Cirrhosis

Daily fixed-dose combination of ledispavir (90 mg)/sofosbuvir (400 mg) with weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks is recommended for patients without cirrhosis, in whom a previous sofosbuvir plus RBVcontaining regimen with or without PEG-IFN has failed.

Rating: Class IIb, Level C

Cirrhosis

Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks is recommended for patients who have cirrhosis, in whom a previous sofosbuvir-containing regimen has failed.

Rating : Class IIa, Level C

To date, clinical experience and trial data on the retreatment of such patients is very limited. However, retreatment after a sofosbuvir-containing treatment failure with a second course of treatment using sofosbuvir plus new agents, or retreatment with the same sofosbuvir-based regimen has been reported.

Retreatment with ledipasvir/sofosbuvir in subjects with HCV genotype 1 infection, with or without cirrhosis, in whom a sofosbuvir-containing regimen failed has been evaluated in 2 small pilot studies utilizing ledipasvir/sofosbuvir for 12 weeks. With prior failures of 24 weeks of sofosbuvir plus RBV, high SVR rates were noted when patients were retreated with ledipasvir/sofosbuvir for 12 weeks. (Osinusi, 2014a) Ledipasvir/sofosbuvir plus RBV has also been evaluated in subjects in whom prior treatment with sofosbuvir plus PEG-IFN and RBV or sofosbuvir and RBV failed. In this study of 51 patients, retreatment with ledipasvir/sofosbuvir plus RBV for 12 weeks led to SVR12 in 100% of 50 patients with HCV genotype 1 infection; 1 virologic failure was observed in a patient determined to have HCV genotype 3 infection prior to retreatment. (Wyles, 2015b) There are exceedingly limited data on the retreatment of such patients with cirrhosis. However, a post hoc analysis of 352 previously treated patients with cirrhosis (240 of whom were PI failures) who were retreated with 12 weeks or 24 weeks of ledipasvir/sofosbuvir with or without RBV found that SVR12 was achieved in 95% to 98%. (Reddy, 2015) Thus, for previously treated HCV genotype 1–infected patients with compensated cirrhosis, retreatment with 24 weeks of ledipasvir/sofosbuvir plus RBV is recommended.

Recommended regimen for patients without cirrhosis who have HCV genotype 1 infection, regardless of subtype, in whom a prior treatment with an HCV NS3 protease inhibitor plus PEG-IFN and RBV or plus sofosbuvir has failed (no prior NS5A treatment).

Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks is recommended for retreatment of patients without cirrhosis who have HCV genotype 1 infection, regardless of subtype, in whom a prior PEG-IFN, RBV, and an HCV protease inhibitor regimen has failed. Based on limited data, the addition of weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) to ledipasvir/sofosbuvir is recommended for patients without cirrhosis in whom prior treatment with the HCV protease inhibitor simeprevir plus sofosbuvir has failed.

Rating: Class I, Level A

Two options with similar efficacy in general are recommended for patients with cirrhosis who have HCV genotype 1 infection, regardless of subtype, in whom prior PEG-IFN, RBV, and an HCV protease inhibitor regimen has failed.

Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks is recommended for retreatment of patients with cirrhosis who have HCV genotype 1 infection, regardless of subtype, in whom a prior regimen of PEG-IFN, RBV, and an HCV protease inhibitor failed. Based on limited data, the addition of weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) to ledipasvir/sofosbuvir is recommended for patients with cirrhosis in whom prior treatment with the HCV protease inhibitor simeprevir plus sofosbuvir has failed.

Rating: Class I, Level A

Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks is recommended for retreatment of patients with cirrhosis who have HCV genotype 1 infection, regardless of subtype, in whom a prior regimen of PEG-IFN, RBV, and an HCV protease inhibitor failed. Patients with cirrhosis who have HCV genotype 1 infection in whom prior treatment with the HCV protease inhibitor simeprevir plus sofosbuvir has failed should not be treated with this 12-week regimen.

Rating: Class IIa, Level B

The safety and efficacy of ledipasvir/sofosbuvir were evaluated in subjects in whom prior treatment with an HCV protease inhibitor (telaprevir or boceprevir) plus PEG-IFN and RBV failed. (Afdhal, 2014b) SVR12 rates with 12- and 24-week regimens were high during both treatment durations (94% and 98%, respectively). Relapse rates in the ION-2 retreatment trial were numerically higher in the 12-week arms than in the 24-week arms. The pretreatment presence of cirrhosis or nonstructural protein 5A (NS5A) resistance–associated variants (RAV) were the major reasons for the higher relapse rate in the 12-week arm. Thus, patients with cirrhosis in whom a prior regimen of PEG-IFN, RBV, and an HCV protease inhibitor failed should receive 24 weeks of ledipasvir/sofosbuvir, and patients without cirrhosis should receive 12 weeks of ledipasvir/sofosbuvir. Based on data from the SIRIUS study, patients with cirrhosis in whom a prior protease inhibitor–containing regimen failed may also receive ledipasvir/sofosbuvir plus weight-based RBV for 12 weeks.

Emerging data suggest that approximately 10% to 15% of patients with HCV genotype 1 infection treated for 12 weeks with simeprevir plus sofosbuvir will experience treatment failure, typically due to viral relapse after discontinuing therapy. Treatment failure appears to be more common in persons infected with HCV genotype 1a and those with cirrhosis. Data from the COSMOS study indicate that treatment failure following a regimen of simeprevir plus sofosbuvir is associated with resistance to simeprevir and cross-resistance to other HCV NS3 and NS4A  protease inhibitors such as paritaprevir, telaprevir, and boceprevir. On the other hand, sofosbuvir RAVs were not observed in the COSMOS trial and are likely to be rare in clinical practice. 

The following regimens are NOT recommended for patients with HCV genotype 1 infection in whom prior treatment that included an HCV protease inhibitor has failed.

  • Any regimen containing PEG-IFN, including

    • Simeprevir, PEG-IFN, and RBV

    • Sofosbuvir, PEG-IFN, and RBV

    • Telaprevir or boceprevir, PEG-IFN, and RBV

    • PEG-IFN and RBV alone

    Rating: Class IIb Level A

  • Monotherapy with PEG-IFN, RBV, or a direct-acting antiviral

    Rating: Class III, Level A

  • Any interferon-free regimen containing an HCV protease inhibitor

    • Simeprevir 

    • Paritaprevir

    Rating: Class IIb, Level A

In the phase IIb ASPIRE trial, simeprevir was combined with PEG-IFN and RBV to treat patients in whom previous PEG-IFN and RBV dual therapy failed. (Zeuzem, 2013a); (Janssen Therapeutics, 2013); (www.fda.gov; package insert) The SVR24 rate after 48 total weeks of therapy in the simeprevir 150 mg per day arm was 65% in patients with a previous partial response (n=23) and 53% in patients with a prior null response (n=17). Based on a relatively poor response to treatment, a need for prolonged therapy, and poor tolerability, this treatment is no longer recommended.

Sofosbuvir combined with PEG-IFN and RBV has high efficacy in treatment-naive patients but has not been studied prospectively in the treatment-experienced population. Based on limited prospective data and poor tolerability to PEG-IFN–based regimens, this treatment is no longer recommended.

Triple therapy with boceprevir plus PEG-IFN and RBV for 48 weeks may result in SVR for up to 52% of patients who had a partial response to previous PEG-IFN and RBV treatment (RESPOND 2;  [Bacon, 2011]), and up to 38% of patients with a prior null response (PROVIDE; [Di Bisceglie, 2013]). Similarly, telaprevir plus PEG-IFN and RBV resulted in an SVR24 rate of 54% to 59% among patients who had a partial response to previous treatment and an SVR24 rate of 29% to 33% among those who had a prior null response (REALIZE; [Zeuzem, 2011]). Because of relatively poor efficacy, need for prolonged therapy (48 weeks), and poor tolerability, these regimens are no longer recommended.

Monotherapy with PEG-IFN, RBV, or any of the available DAAs is ineffective; further, DAA monotherapy leads to rapid selection of resistant variants.

Recommended regimen for patients in whom previous treatment with any HCV NS5A inhibitors has failed (including ledipasvir/sofosbuvir and PrOD).

For patients with minimal liver disease, deferral of treatment is recommended, pending availability of data.

Rating: Class IIb, Level C

For patients with cirrhosis or other patients who require retreatment urgently, testing for RAVs that confer decreased susceptibility to NS3 protease inhibitors (eg, Q80K) and to NS5A inhibitors should be performed using commercially available assays. For patients with no NS5A RAVs detected, retreatment with ledipasvir/sofosbuvir and RBV for 24 weeks is recommended. For patients who have NS5A RAVs detected and who do not have NS3 RAVs detected, treatment with sofosbuvir, simeprevir, and RBV for 24 weeks is recommended. For patients who have both NS3 and NS5A RAVs detected, retreatment should be conducted in clinical trials settings.

No data have been presented on the retreatment of patients for whom prior treatment with PrOD has failed.

Data on the retreatment of patients for whom prior treatment with ledipasvir/sofosbuvir has failed are very limited. In a pilot study, 41 patients with and without cirrhosis who did not achieve an SVR with 8 weeks or 12 weeks of ledipasvir/sofosbuvir were retreated with 24 weeks of ledipasvir/sofosbuvir. SVR12 rates varied according to the presence or absence of NS5A RAVs. Among 11 patients for whom NS5A RAVs were not detected, the SVR rate was 100% (11 of 11); in contrast, among 30 patients for whom NS5A RAVs were detected, the SVR rate was 60% (18 of 30). Importantly, NS5B RAVs (eg, S282T) known to confer decreased activity of sofosbuvir were observed in 3 of 12 (25%) patients for whom the retreatment regimen was not successful. Similarly, in the OPTIMIST-2 study in which patients with cirrhosis were treated with sofosbuvir and simeprevir, the presence of NS3 RAVs, namely the Q80K polymorphism, led to a decreased SVR rate in patients with HCV genotype 1a infection. The SVR rate in patients with HCV genotype 1a and the Q80K RAV was 74% (25 of 34) and was 92% (35 of 38) in patients with HCV genotype 1a without the Q80K RAV. Based on these data, retreatment for patients for whom NS5A-containing regimens has failed should be considered in the context of retreatment urgency and the presence or absence of RAVs to inhibitors of NS3 and NS5A. Further, based on limited data, RBV is recommended as part of all retreatment regimens for patients in whom prior treatment with NS5A inhibitors has failed. Although no data exist, consideration may also be given to the addition of PEG-IFN to the retreatment regimen in patients who are eligible for this agent; PEG-IFN will have antiviral activity regardless of RAVs present.

II. Genotype 2

Recommended regimen for patients with HCV genotype 2 infection in whom prior PEG-IFN and RBV treatment has failed.

Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks to 16 weeks is recommended for patients with HCV genotype 2 infection, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class I, Level A

High SVR12 rates were demonstrated in patients with HCV genotype 2 in whom prior treatment with PEG-IFN and RBV had failed who were retreated with 12 weeks of sofosbuvir plus RBV. Limited data are available for treatment-experienced patients with HCV genotype 2 infection and cirrhosis; however, in the FUSION study, numerically higher SVR12 rates were seen with extension of therapy from 12 weeks (60%) to 16 weeks (78%). (Jacobson, 2013b) In contrast, the VALENCE trial found high SVR12 rates among HCV genotype 2–infected persons with cirrhosis after only 12 weeks of sofosbuvir plus RBV (88%). (Zeuzem, 2013b) Thus, definitive recommendations on the appropriate duration of sofosbuvir and RBV for treatment-experienced, HCV genotype 2–infected persons with cirrhosis cannot be made at this time. The decision to extend therapy to 16 weeks should be made on a case-by-case basis.

Alternative regimen for patients who have HCV genotype 2 infection and are eligible to receive IFN and in whom previous PEG-IFN and RBV treatment failed.

Retreatment with daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) plus weekly PEG-IFN for 12 weeks is an alternative for patients who have HCV genotype 2 infection, are eligible to receive IFN, and in whom previous PEG-IFN and RBV treatment failed.

Rating: Class IIa Level B

In recognition of the potential limitations of sofosbuvir plus RBV in harder-to-treat, HCV genotype 2–infected patients with a prior treatment failure, particularly those with cirrhosis, combination therapy with PEG-IFN has been studied. The LONESTAR-2 trial (an open-label, single-site, single-arm, phase II trial) evaluated PEG-IFN (180 μg weekly), sofosbuvir (400 mg daily), and weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg] daily in 2 divided doses for 12 weeks) in treatment-experienced patients with HCV genotype 2 or 3. (Lawitz, 2014a) Cirrhosis was present at baseline in 61% of patients. SVR12 was achieved in 22 of 23 (96%) persons with HCV genotype 2 infection. For patients with and without cirrhosis, SVR rates were 93% (13 of 14) and 100% (9 of 9), respectively. Despite the limitations of this small study and accounting for the potential challenges inherent with IFN therapy, sofosbuvir plus PEG-IFN and RBV is an alternative 12-week regimen for HCV genotype 2–infected patients with cirrhosis.

The following regimens are NOT recommended for patients with HCV genotype 2 infection in whom prior HCV therapy with PEG-IFN and RBV has failed.

  • PEG-IFN and RBV with or without telaprevir or boceprevir

    Rating: Class IIb, Level A

  • Fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg)

    Rating: Class III, Level A

  • Monotherapy with PEG-IFN, RBV, or a direct-acting antiviral

    Rating: Class III, Level A

No HCV protease inhibitors have been approved or are indicated for the treatment of HCV genotype 2 infection. However, there is in vitro and in vivo evidence that simeprevir has activity against HCV genotype 2. Although PEG-IFN plus RBV has been the mainstay of treatment for HCV genotype 2, it requires a longer duration of therapy, is less efficacious, and has more adverse effects than the regimen recommended above.

III. Genotype 3

Recommended regimen for patients with HCV genotype 3 infection in whom prior PEG-IFN and RBV treatment has failed who are IFN eligible.

Retreatment with daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG-IFN for 12 weeks is recommended for patients with HCV genotype 3 infection who are IFN eligible, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class I Level A

Recommended regimen for patients with HCV genotype 3 infection in whom prior PEG-IFN and RBV treatment has failed who are not eligible to receive IFN.

Retreatment with daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks is recommended for treatment of HCV genotype 3 infection in patients in whom prior PEG-IFN and RBV treatment has failed who are not eligible to receive IFN.

Rating: Class I, Level B

The phase III FUSION trial compared 12 weeks (n=103) with 16 weeks (n=98) of daily sofosbuvir (400 mg) and weight-based RBV in patients with HCV genotype 2 or 3 in whom previous PEG-IFN and RBV therapy failed. Of all patients, 63% had HCV genotype 3 and 34% had cirrhosis. Because persons who had prior relapses to IFN-based therapy accounted for 75% of patients, the number of patients with a prior nonresponse in the study was limited. The SVR rate for patients with HCV genotype 3 in the 12-week arm was 30% (19% among patients with cirrhosis and 37% among patients without cirrhosis). Extending therapy to 16 weeks increased the SVR rate to 62%.

Based on results from the FUSION study, the phase III multicenter, randomized, placebo-controlled VALENCE trial was amended to evaluate the effects of extending sofosbuvir plus RBV therapy to 24 weeks in all patients with HCV genotype 3 infection. As with the FUSION study, most (65%) treatment-experienced patients had a relapse. The SVR12 rate after 24 weeks of therapy for treatment-experienced patients with HCV genotype 3 was 79% (60% among patients with cirrhosis and 87% in those without cirrhosis). The increased efficacy with 24 weeks of sofosbuvir plus RBV therapy across all fibrosis stages combined with a favorable safety and tolerability profile supports the recommendation to use 24 weeks of sofosbuvir plus RBV for all HCV genotype 3–infected patients, despite the minimal number of patients studied to date. The SVR rate for HCV genotype 3–infected patients with cirrhosis who were treated for 24 weeks in the VALENCE trial (60%) was similar to that observed after 16 weeks of treatment in the FUSION trial (61%).

Choice of specific regimen may be influenced by previous or anticipated tolerance to PEG-IFN or by the presence of advanced fibrosis or cirrhosis. For most patients, the ease of administration and tolerability of sofosbuvir plus RBV will outweigh any potential benefit associated with the addition of PEG-IFN. However, for HCV genotype 3–infected patients who have cirrhosis, responses to a regimen of sofosbuvir and RBV alone for 24 weeks was suboptimal.

In the LONESTAR-2 study, adding 12 weeks of PEG-IFN to the sofosbuvir and RBV regimen resulted in numerically higher response rates among persons with HCV genotype 3 infection than those obtained with sofosbuvir and RBV alone for 24 weeks. Of HCV genotype 3–infected patients with and without cirrhosis, 10 of 12 (83%) achieved SVR. These preliminary findings were confirmed in the BOSON study in which patients with HCV genotype 3 infection were randomly assigned to receive treatment with 1 of 3 regimens: sofosbuvir and RBV for 16 weeks; sofosbuvir and RBV for 24 weeks; or PEG-IFN (alfa-2a 180 mcg SC weekly), sofosbuvir, and RBV for 12 weeks. Among patients with HCV genotype 3 infection, SVR12 was achieved in 92.8% of patients (168 of 181) treated with 12 weeks of PEG-IFN, sofosbuvir, and RBV and 84.1% of patients (153/182) treated with 24 weeks of sofosbuvir and RBV, whereas only 70.7% of patients (128 of 181) treated with 16 weeks of sofosbuvir and RBV achieved SVR12. Treatment with PEG-IFN, sofosbuvir, and RBV for 12 weeks led to higher SVR rates than sofosbuvir and RBV in treatment-experienced patients with HCV genotype 3 infection with (85.7% and 76.5%, respectively) and without cirrhosis (94.2% and 81.5%, respectively). No difference was observed with respect to safety and tolerability of the studied regimens. Accordingly, data from this randomized controlled trials strongly support the use of PEG-IFN in all treatment-experienced patients with HCV genotype 3 infection, including those without cirrhosis. Treatment with sofosbuvir and RBV for 24 weeks should be limited to those treatment-experienced patients with HCV genotype 3 infection with strong contraindications to retreatment with PEG-IFN.
 

Recommended regimen for patients with HCV genotype 3 infection in whom prior sofosbuvir and RBV treatment has failed who are IFN eligible.

Retreatment with daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG-IFN for 12 weeks is recommended for patients with HCV genotype 3 infection who are IFN eligible, in whom prior sofosbuvir and RBV treatment has failed.

Rating: Class IIa Level C

The following regimens are NOT recommended for patients with HCV genotype 3 infection in whom prior PEG-IFN and RBV treatment has failed.

  • PEG-IFN and RBV for 24 weeks to 48 weeks

    Rating: Class IIb, Level A

  • Monotherapy with PEG-IFN, RBV, or a direct-acting antiviral

    Rating: Class III, Level A

  • Telaprevir-, boceprevir-, or simeprevir-based regimens should not be used for patients with HCV genotype 3 infection.

    Rating: Class III, Level A

No HCV protease inhibitors have been approved or are indicated for the treatment of HCV genotype 3 infection. Although PEG-IFN plus RBV has been the mainstay of treatment of HCV genotype 3 infection, it is less efficacious and has more adverse effects than the recommended regimens.

IV. Genotype 4

Data to guide decision making in patients infected with HCV genotype 4 infection are limited. Nonetheless, for patients in whom treatment is required, the following recommendations can be made.

Four options with similar efficacy in general are recommended for patients with HCV genotype 4 infection, in whom prior PEG-IFN and RBV treatment has failed (listed in alphabetic order; see text).

Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks is recommended for patients with HCV genotype 4 infection, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class IIa, Level B

Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks is recommended for patients with HCV genotype 4 infection, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class IIa, Level B

Daily sofosbuvir (400 mg) for 12 weeks and daily weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG-IFN for 12 weeks is recommended for retreatment of IFN-eligible patients with HCV genotype 4 infection, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class IIa, Level B

Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks is recommended for retreatment of patients with HCV genotype 4 infection, in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class IIa, Level B

PEARL-I was an open-label phase IIb study that included a cohort of 49 treatment-experienced patients with HCV genoype 4 infection without cirrhosis who received 12 weeks of paritaprevir/ritonavir/ombitasvir (PrO) with or without weight-based RBV. In intention-to-treat analysis, SVR12 was achieved in 100% (41/41) of patients. This regimen was well tolerated with no serious adverse events reported. (Hezode, 2015)

Sofosbuvir-based regimens have also shown efficacy in patients infected with HCV genotype 4. Sofosbuvir administered with PEG-IFN and RBV for 12 weeks was investigated in the phase III NEUTRINO trial. (Lawitz, 2013a) Of the 28 treatment-naive patients with HCV genotype 4 infection, 27 (96%) achieved SVR12. In a pilot study of treatment-experienced patients of Egyptian ancestry with HCV genotype 4 infection, patients were randomized to receive sofosbuvir and RBV for 12 weeks or 24 weeks. SVR12 rate was numerically higher in the 24-week arm (89% [24/27] in the 24-week arm vs 70% [19/27] in the 12-week arm), supporting the recommendation for longer treatment duration with a sofosbuvir and RBV regimen. (Esmat, 2014) In the SYNERGY trial, 20 patients with HCV genotype 4 infection were treated with ledipasvir/sofosbuvir for 12 weeks. Of these patients, 40% were treatment experienced and 40% had advanced fibrosis. Preliminary data demonstrate efficacy, with 95% achieving SVR12 based on an intention-to-treat analysis. (Kapoor, 2014)

The following regimens are NOT recommended for patients with HCV genotype 4 infection in whom prior PEG-IFN and RBV treatment has failed.

  • PEG-IFN and RBV with or without telaprevir or boceprevir

    Rating: Class IIb, Level A

  • Monotherapy with PEG-IFN, RBV, or a direct-acting antiviral

    Rating: Class III, Level A

PEG-IFN and RBV for 48 weeks was previously recommended for patients with HCV genotype 4 infection. (AASLD/IDSA/IAS-USA, 2014) Adding sofosbuvir (400 mg daily) to PEG-IFN and RBV increases SVR rates and markedly shortens therapy with no apparent additional adverse effects. The addition of simeprevir to PEG-IFN and RBV increases response rates but has inferior SVR rates compared with SVR rates of other available regimens and requires a longer duration of PEG-IFN and RBV therapy, which increases the risk of adverse events. Therefore, this treatment is no longer recommended. (Moreno, 2013b)

Because of their limited activity against HCV genotype 4 in vitro and in vivo, boceprevir and telaprevir should not be used to treat patients with HCV genotype 4 infection.

V. Genotype 5 and 6

Few data are available to help guide decision making for patients infected with HCV genotype 5 or 6. Thus, for those patients for whom immediate treatment is required, the following recommendations have been drawn from available data.

Recommended regimen for patients with HCV genotype 5 or 6 infection in whom prior treatment has failed.

Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks is recommended for patients with HCV genotype 5 or 6 infection in whom prior PEG-IFN and RBV treatment has failed.

Rating: Class IIa, Level C

Recommended regimen for patients with HCV genotype 5 or 6 infection in whom prior treatment has failed who are IFN eligible.

Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG-IFN for 12 weeks is an alternative regimen for IFN-eligible patients with HCV genotype 5 or 6 infection in whom prior treatment has failed.

Rating: Class IIa, Level C

In the phase III NEUTRINO trial, (Lawitz, 2013a) treatment-naive patients with HCV genotypes 1 (n=291), 4 (n=28), 5 (n=1), and 6 (n=6) were treated with sofosbuvir (400 mg daily) plus PEG-IFN (2a 180 µg weekly) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) for 12 weeks. All 6 patients with HCV genotype 6 and the 1 patient with HCV genotype 5 achieved SVR12. The adverse event profile in these patients and in the larger study population was similar to that seen with PEG-IFN and RBV therapy.

Ledipasvir has in vitro activity against most HCV genotype 6 subtypes (exception 6e). (Wong, 2013); (Kohler, 2014) A small, 2-center, open-label study (NCT01826981) investigated the safety and in vivo efficacy of ledipasvir/sofosbuvir for 12 weeks in treatment-naive and -experienced patients with HCV genotype 6 infection. Twenty-five patients (92% treatment naive) who were primarily of Asian descent (88%) were infected with different subtypes of HCV genotype 6 (32%, 6a; 24%, 6e; 12%, 6l; 8%, 6m; 12%, 6p; 8%, 6q; 4%, 6r). Two patients (8%) had cirrhosis. The SVR12 rate was 96% (24/25). The 1 patient who experienced relapse had discontinued therapy at week 8 because of drug use. No patient discontinued treatment owing to adverse events.

The following regimens are NOT recommended for patients with HCV genotype 5 or 6 infection in whom prior treatment has failed.

  • Monotherapy with PEG-IFN, RBV, or a direct-acting antiviral

    Rating: Class III, Level A

  • Telaprevir- or boceprevir-based regimens

    Rating: Class III, Level A

Because of their limited activity against HCV genotypes 5 and 6 in vitro and in vivo, boceprevir and telaprevir should not be used as therapy for patients with HCV genotype 5 or 6 infection.

Mixed Genotypes

Rarely, genotyping assays may indicate the presence of a mixed infection (eg, genotypes 1a and 2). Treatment data for mixed genotypes with DAA are sparse, and awaiting availability of a pangenotypic regimen may be considered. Until then, when treatment is necessary, the choice of antiviral combination and duration of treatment should maximize efficacy against each genotype represented in the assay. When the correct combination or duration is unclear, expert consultation should be sought.

 

Complete revision made to this section on December 19, 2014. Additional changes made on June 28, 2015.