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. In general, treatment responses of patients achieving an undetectable level of virus during a prior treatment course who relapse following cessation of therapy (relapser) are similar to those of treatment-naive persons (see Initial Treatment). Treatment responses are generally lower in prior non-responders, which includes null responders (those in whom serum HCV RNA levels declined less than 2 log10 IU/mL by week 12 during a prior treatment course) and partial responders (those with a > 2 log10 IU/mL response whose virus remained detectable up to 24 weeks or the end of treatment). This section assumes that a decision to treat has been made and advises on the optimal treatment. In many instances, however, it may be advisable to delay treatment for some patients with documented early fibrosis stage (F 0-2), because waiting for future highly effective, pangenotypic, combinations in IFN-free regimens may be prudent. Potential advantages of waiting to begin to treatment will be provided in a future update to this guidance.
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 graded 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. Regimens are 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."
As always, patients receiving antiviral therapy require careful pretreatment assessment for comorbidities that may influence treatment response. All patients should have careful monitoring during treatment, particularly for anemia if ribavirin is included in the regimen.
I. Genotype 1
COSMOS is a phase 2a 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 to 1200 mg daily) for 12 or 24 weeks (Jacobson, 2013b). Of the 80 null responders with a Metavir fibrosis stage of 2 or less included in this trial, 79% to 96% achieved SVR (79%-96% in RBV-containing arms and 93% in both RBV-free arms). Among those null responders with a Metavir fibrosis stage of 3 or 4 (n=47) who received 12 weeks of sofosbuvir and simeprevir, SVR4 was observed in 14 (93%) of 15 patients in the ribavirin-containing arm and 100% (all 7 participants) in the RBV-free arm. Although benefit from RBV is not apparent from these preliminary results, it cannot be excluded before availability of SVR12 data. Post-treatment results are not yet available for the 24-week arms. Excluding nonvirologic failures, patients with HCV genotype 1a with Q80K mutations had slightly lower numeric response rates (fibrosis stage 0-2: SVR12=89% [n=27]; fibrosis stage 3 or 4: SVR4=91% [n=11]) than genotype 1a patients without Q80K and genotype 1b (fibrosis stage 2: SVR12 100%, n=47; fibrosis stage 3 or 4: SVR4=100% [n=29]). However, because the study was not powered to assess this comparison, insufficient evidence exists on the role of testing for the Q80K mutation at this time. These regimens were well tolerated, although adverse events (eg, anemia and hyperbilirubinemia) were seen more often in patients on RBV-containing regimens. (Jacobson, 2013b)
The safety and efficacy of simeprevir have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). The uncertain impact of cholestasis and the occasional association of SMV with elevated transaminases create potential for drug accumulation or impaired hepatic function during SMV use. Clinical trials with SMV have been limited to patients with compensated disease who have CTP class A, total bilirubin of 1.5 x ULN or lower, and transaminases 10 x ULN or lower. For these reasons, simeprevir use should be limited to patients with compensated liver disease. Use of simeprevir is not recommended in patients with moderate to severe hepatic impairment. The combination of PEG/RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C).
NEUTRINO is an open-label, single-arm trial that evaluated 12 weeks of sofosbuvir plus PEG/RBV in treatment-naive subjects with HCV genotypes 1, 4, 5, or 6; 89% had HCV genotype 1, and 17% had cirrhosis. The SVR was 89% (261 of 292) and was somewhat lower in patients with genotype 1b than 1a (82% and 92%, respectively) and those with cirrhosis versus those without (80% versus 92%, respectively). (Lawitz, 2013a) Treatment-experienced subjects who did not respond to PEG/RBV with or without an HCV protease inhibitor were not included in this study. There are no data available to estimate the response in patients who have been previously treated with a protease inhibitor. However, among patients who were previously treated with PEG/RBV, the FDA estimates that the response rate in such patients would approximate the observed response rate in those NEUTRINO subjects with baseline factors traditionally associated with a lower response to IFN-based treatment. (US FDA, 2013a) In the NEUTRINO trial, SVR rate was 71% among participants with HCV genotype 1 with IL28B non-C/C alleles, high HCV RNA levels, and METAVIR 1 fibrosis stage F3 or F4 (37 of 52 patients). (Gilead Sciences, 2013; Sovaldi package insert)
In a prospective, multicenter trial of sofosbuvir (400 mg/day) plus RBV (ascending dose of 400 mg/day, escalating based on hemoglobin level) including treatment-experienced patients with recurrent HCV infection after liver transplantation, SVR12 was 70% in this population. (Charlton, 2013a)
Simeprevir was combined with PEG/RBV in patients who had previously failed to respond to PEG/RBV dual therapy in the Phase 2b ASPIRE trial. (Zeuzem, 2013a); (Janssen Therapeutics, 2013) (www.fda.gov; package insert). SVR24 after 48 weeks of triple therapy in the simeprevir 150 mg/day arm was 65% in patients with a previous partial response (n=23) and 53% in patients with a prior null response (n=17). Patients with HCV genotype 1a infection had inferior response rates compared with those with genotype 1b (SVR24: 47% vs 77% in patients with a partial response and 41% vs 47% in patients with a null response, respectively). Despite lower SVR in patients with HCV genotype 1a infection, SVR rates were similar with and without the presence of the Q80K mutations at baseline. SVR rates in patients with advanced fibrosis (METAVIR stage F3 or F4) treated with simeprevir (150 mg daily) plus PEG/RBV for 48 weeks were 59% in patients with a partial response (n=33) and 35% in patients with a null response (n=34). Safety in patients exposed to simeprevir was similar to that of persons in the placebo arms; however, there was a higher incidence of hyperbilirubinemia (8%) and photosensitivity/rash (5%). (Zeuzem, 2013a)
The safety and efficacy of simeprevir have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). The uncertain impact of cholestasis and the occasional association of simeprevir with elevated transaminases pose potential for impaired hepatic function during simeprevir use. Clinical trials with simeprevir have been limited to patients with compensated disease who have CTP class A, total bilirubin level of 1.5 x ULN or lower, and transaminase level of 10 x ULN or lower. For these reasons, simeprevir use should be limited to patients with compensated liver disease. Use of simeprevir is not recommended in patients with moderate to severe hepatic impairment. Use of the drug in this population is not recommended at this time. The combination of PEG/RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C).
Triple therapy with boceprevir plus PEG/RBV for 48 weeks may result in SVR for up to 52% of PEG/RBV partial responders (RESPOND 2; (Bacon, 2011)) and 38% of null responders (PROVIDE; (Di Bisceglie, 2013)). Similarly, telaprevir plus PEG/RBV resulted in SVR24 of 54% to 59% among partial responders and an SVR24 of 29% to 33% among null responders (REALIZE; (Zeuzem, 2011)). Due to the relatively poor efficacy, prolonged duration of therapy (48 weeks), and poor tolerability, these regimens are no longer recommended.
Monotherapy with PEG, RBV, or any of the available DAAs is ineffective; further, DAA monotherapy leads to rapid selection of resistant variants.
Patients with advanced liver disease are at increased risk for sepsis, worsening decompensation, and death when treated with dual or triple IFN-based therapy. (Crippin, 2002); (Coilly, 2014) Simeprevir is primarily metabolized by the liver and should not be used in patients with advanced cirrhosis (CTP B or C), as the AUC is increased 2.4- to 5.2-fold. (Janssen Therapeutics, 2013) (Olysio package insert, Janssen).
II. Genotype 2
High SVR12 rates have been demonstrated in non-cirrhotic genotype 2 treatment-experienced patients who received 12 weeks of sofosbuvir plus RBV. Limited data are available in cirrhotic genotype 2 treatment experienced patients; 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, at this time definitive recommendations on the appropriate duration of sofosbuvir and RBV for treatment-experienced, HCV genotype 2-infected persons with cirrhosis cannot be made. The decision to extend therapy to 16 weeks should be made on a case-by-case basis.
Recognizing the potential limitations of sofosbuvir plus RBV in harder-to-treat genotype 2 nonresponders, particularly those with cirrhosis, combination therapy with PEG has been studied. The LONESTAR-2 trial (an open-label, single site, single-arm phase 2 trial) evaluated PEG (180 μg weekly), sofosbuvir (400 mg daily), and weight-based RBV (1000 mg to 1200 mg daily in 2 divided doses for 12 weeks) in treatment-experienced patients with HCV genotype 2 or 3. Cirrhosis was present at baseline in 61% of patients. SVR12 was achieved in 22 (96%) of 23 persons with genotype 2 HCV infection. For patients with and without cirrhosis, SVR occurred in 13 (93%) of 14 and 9 (100%) of 9, respectively. Despite the limitations of this small study (and accounting for the potential challenges inherent with IFN therapy), combination PEG plus sofosbuvir and RBV is an alternative 12-week regimen for genotype 2-infected patients with cirrhosis.
No HCV protease inhibitors have been approved or are indicated for the treatment of genotype 2 infection. Although PEG/RBV has been the mainstay of treatment of 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 3 FUSION trial compared 12 weeks (n=103) with 16 weeks (n=98) of daily sofosbuvir (400 mg) and weight-based RBV (1000 mg to 1200 mg) in genotype 2 or 3 HCV-infected patients in whom previous PEG/RBV therapy had failed. Of patients, 63% had genotype 3; 34% of all patients 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 genotype 3 patients in the 12-week arm was 30% (19% among patients with cirrhosis and 37% among those without cirrhosis). Extending therapy to 16 weeks increased the SVR rate among genotype 3 patients to 62% (61% among patients with and 63% in those without cirrhosis).
Based on results from FUSION, the phase 3 multicenter, randomized placebo-controlled VALENCE trial was amended to evaluate the effect 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 relapsed. The SVR12 rates after 24 weeks of therapy for treatment-experienced patients with genotype 3 was 79% (60% among patients with 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 in all genotype 3 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%). Although longer treatment duration with a well-tolerated regimen may potentially be more successful in these more difficult-to-treat patients, data remain limited. Either duration of treatment is considered acceptable at this time (see below).
Choice of specific regimen may be influenced by previous or anticipated tolerance to PEG or 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. 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 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 for 24 weeks. Of HCV genotype 3-infected patients with and without cirrhosis, 10 (83%) of 12 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 genotype 3 HCV infection. Although PEG/RBV has been the mainstay of treatment of genotype 3 HCV, it is less efficacious and has more adverse effects than the recommended regimens.
IV. Genotypes 4, 5, and 6
In the NEUTRINO trial, high SVR rates were seen in small numbers of treatment-naive patients with HCV genotypes 4, 5, and 6 treated with sofosbuvir plus PEG/RBV for 12 weeks (genotype 4: n=28, SVR=96%; genotype 5: n=1, SVR=100%; and genotype 6: n=6, SVR=100%). (Lawitz, 2013a) In a pilot study of treatment-experienced HCV genotype 4 patients of Egyptian ancestry, SVR12 was 59% in patients treated with sofosbuvir plus RBV for 12 weeks; SVR4 was 93% in patients treated for 24 weeks. In this cohort, 24% to 27% of patients had cirrhosis. (Ruane, 2013) The only available data with simeprevir for treatment-experienced patients with genotype 4 come from the ongoing RESTORE trial, in which patients (n=50) are receiving treatment with daily simeprevir 150 mg for 12 weeks plus PEG/RBV for a total of 48 weeks (10 prior partial responders, 40 prior null responders). Interim analysis revealed a 40% to 49% RVR rate using this regimen. Final SVR results are pending. (Moreno, 2013) Given the relative paucity of data, expert consultation is needed to determine optimal duration of therapy in patients with genotype 4, 5, or 6 treated with sofosbuvir.
Explanations of highlighted changes made on March 21, 2014 are available here.