RETREATMENT OF PERSONS IN WHOM PRIOR THERAPY HAS FAILED
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 corresponding confidence in the recommendation varies as does the strength of the recommendation, and is rated in the same manner as the section on initial treatment of treatment-naive patients (Methods Table 2). In addition, when treatment differs for a particular group (eg, those infected with various genotypes) specific recommendations are given. 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)
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. Genotype 1 HCV 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, for example 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 to optimize ledipasvir exposure. For patients in whom interruption of acid suppression is not possible, dosing of acid suppressants is recommended per the prescribing information.
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) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 mg]) (hereafter paritaprevir/ritonavir/ombitasvir plus dasabuvir and RBV) has been investigated for treatment of patients with HCV genotype 1 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 paritaprevir/ritonavir/ombitasvir plus dasabuvir 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.
In the TURQUOISE-II study, patients with CTP class A cirrhosis were treated with paritaprevir/ritonavir/ombitasvir plus dasabuvir and RBV for 12 weeks or 24 weeks. (Poordad, 2014) Of the 380 patients enrolled in this study, prior PEG-IFN and RBV therapy had failed in 220. 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%).
COSMOS is a phase IIa randomized trial 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. (Lawitz, 2013a); (Jacobson, 2013b) Of the 80 patients with a null response to PEG-IFN and RBV treatment who had fibrosis (Metavir stage ≤F2) included in this trial, 79% to 96% achieved SVR (79%-96% in the RBV-containing arms and 93% in both RBV-free arms). Although benefit from RBV is not apparent from these results, this study was not powered to show noninferiority of RBV-free regimens. Preliminary data from large prospective observational cohort studies confirm high SVR rates (>80%) in patients treated with sofosbuvir plus simeprevir in clinical practice. (Jensen, 2014); (Dieterich, 2014a) These studies also demonstrate higher rates of virologic failure in patients with HCV genotype 1a infection than patients with HCV genotype 1b infection, but additional data have not been provided regarding the contribution of treatment duration (12 weeks vs 24 weeks), use of RBV, and presence of the Q80K polymorphism to observed rates of HCV treatment failure in genotype 1a infection. In patients with cirrhosis, high SVR rates (96%) occurred in patients treated for a longer duration, supporting the recommendation that these patients be treated for 24 weeks. (Janssen Therapeutics, 2013); (Lawitz, 2014b)
Emerging data suggest that approximately 10% to 15% of patients with HCV genotype 1 infection treated for 12 weeks with the combination of simeprevir plus sofosbuvir will experience treatment failure, typically owing 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 simeprevir plus sofosbuvir is associated with resistance to simeprevir with cross-resistance to other HCV nonstructural protein 3/4A (NS3/4A) protease inhibitors such as paritaprevir, telaprevir, and boceprevir. On the other hand, sofosbuvir resistance–associated variants were not observed in the COSMOS trial and are likely to be rare in clinical practice.
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, 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 pilot study, viral response at the end of treatment is promising, however, SVR12 data are pending. (Wyles, 2014a)
In the absence of data, for patients in whom prior treatment with simeprevir plus sofosbuvir failed, strong consideration should be given to enrolling them in clinical trials. For patients with minimal liver disease, consideration should be given to deferral of retreatment pending the availability of data. In patients who require retreatment more urgently, based on emerging data and the expected pattern of HCV drug resistance, patients in whom simeprevir plus sofosbuvir does not result in a cure may be treated with ledipasvir/sofosbuvir with or without RBV for 24 weeks.
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 presence of cirrhosis or NS5A resistance–associated variants at baseline were the major reasons for the higher relapse rate in the 12-week arm. Thus, patients with cirrhosis in whom a prior PEG-IFN, RBV, and HCV protease inhibitor regimen 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.
Simeprevir was combined with PEG-IFN and RBV in patients in whom previous PEG-IFN and RBV dual therapy failed, in the phase IIb ASPIRE trial. (Zeuzem, 2013a); (Janssen Therapeutics, 2013); (www.fda.gov; package insert) SVR24 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 relatively poor response, 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 of 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 with 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 with a partial response to previous treatment and an SVR24 rate of 29% to 33% among those with a prior null response (REALIZE; [Zeuzem, 2011]). Because of the 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.
II. Genotype 2
High SVR12 rates were demonstrated in patients with HCV genotype 2 in whom prior treatment with PEG-IFN and RBV 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.
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 occurred in 13 of 14 (93%) and 9 of 9 (100%), 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.
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
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 experienced 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. 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 response rate for HCV genotype 3–infected patients with cirrhosis 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 sofosbuvir and RBV alone for 24 weeks were 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 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. Given the limited number of patients in this demographic in both the VALENCE and LONESTAR-2 studies, these differences in response rates should be interpreted with caution.
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 are limited to help guide decision making for patients infected with HCV genotype 4. Nonetheless, for patients in whom treatment is required, the following recommendations can be made.
PEARL-I was an open-label phase IIb study that included a cohort of 49 treatment-experienced patients without cirrhosis with HCV genotype 4 infection who received 12 weeks of paritaprevir/ritonavir/ombitasvir with or without weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]). 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. (Pol, 2014)
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 were treated with ledipasvir/sofosbuvir for 12 weeks. Of these patients, 40% were treatment experienced and 40% had advanced fibrosis. Preliminary data support efficacy, with 95% achieving SVR12 in an intention-to-treat analysis. (Kapoor, 2014)
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 response 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 to the other available regimens and requires a longer duration of PEG-IFN and RBV, which increases the risk of adverse events and thus 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 as therapy for patients with HCV genotype 4 infection.
Few data are available to help guide decision making for patients infected with HCV genotype 5 or 6. Nonetheless, for those patients for whom immediate treatment is required, the following recommendations have been drawn from available data.
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.
PEG-IFN and RBV for 48 weeks was the previously recommended regimen for patients infected with HCV genotype 5, but the availability of recommended regimens that substantially reduce exposure to IFN and RBV make this regimen less appealing.
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 Asian (88%) had infection from 7 different subtypes (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), and the 1 patient who experienced relapse had discontinued therapy at week 8 because of drug use. No patient discontinued treatment owing to adverse events.
In the phase III NEUTRINO trial, this regimen has been shown to have efficacy in a small number of patients with HCV genotype 6 infection (6 of 6 patients with SVR12). (Lawitz, 2013a)
Because of their limited activity against genotypes 5 and 6 HCV in vitro and in vivo, boceprevir and telaprevir should not be used as therapy for patients with HCV genotype 5 or 6 infection.
Rarely, genotyping assays may indicate the presence of a mixed infection (eg, genotypes 1a and 2). Treatment data for mixed genotypes with direct-acting antivirals 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 January 26, 2015.