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 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), HCV infection post–liver transplant, 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 oral DAA 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.
The combination of daclatasvir and sofosbuvir has been studied in HCV genotype 1 treatment‒experienced patients who have previously been treated with PEG-IFN and RBV in 2 observational early access programs in the United Kingdom and France. (Foster, 2015); (Pol, 2015); (Foster, 2015b) In the French cohort, patients were treated with daclatasvir and sofosbuvir with or without RBV for 12 weeks or 24 weeks. In patients treated with daclatasvir and sofosbuvir alone, a numerically higher rate of sustained virologic response at 4 weeks (SVR4) was seen in those treated for 24 weeks (12 weeks, 15/18 or [82.6%] vs 24 weeks, 75/78 or [96.1%]). Patients treated with daclatasvir, sofosbuvir, and RBV had high response rates in the 12-week and the 24-week treatment groups (100% and 97.1%, respectively), but only 4 patients were treated for 12 weeks. In the United Kingdom cohort, 235 HCV genotype 1-infected patients with decompensated cirrhosis (45% had prior IFN-based HCV treatment failures) were treated with 12 weeks of sofosbuvir plus ledipasvir or daclatasvir with or without RBV as part of a compassionate access program. The selection of daclatasvir or ledipasvir and the use of RBV was at the discretion of the treating physician; most patients (94.4%) had RBV in their regimen. Among patients treated with sofosbuvir plus RBV for 12 weeks, the SVR rate was 86% for those who received ledipasvir (n=164) and 82% for those who received daclatasvir (n=82). Based on these limited data, consideration should be given to the addition of RBV when treating more difficult-to-treat patients, such as those with cirrhosis.
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 an 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) (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 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%). To address the need for RBV with this regimen in patients with HCV genotype 1b and cirrhosis, the TURQUOISE-III study evaluated the safety and efficacy of PrOD without RBV for 12 weeks in patients with HCV genotype 1b infection and compensated cirrhosis. Sixty patients (62% men, 55% treatment experienced, 83% with the IL28B non-CC genotype, 22% with platelet counts <90 x 109/L, and 17% with albumin levels <3.5 g/dL) were enrolled. All patients completed treatment, and all patients achieved an SVR12. On the basis of this study, treating patients with HCV genotype 1b with PrOD but without RBV is recommended, regardless of prior treatment experience or presence of cirrhosis. (Feld, 2015)
To address the need for RBV with this regimen in patients with HCV genotype 1b and cirrhosis, the TURQUOISE-III study evaluated the safety and efficacy of PrOD without RBV for 12 weeks in patients with HCV genotype 1b infection and compensated cirrhosis. Sixty patients (62% men, 55% treatment experienced, 83% with the IL28B non-CC genotype, 22% with platelet counts <90 x 109/L, and 17% with albumin levels <3.5 g/dL) were enrolled. All patients completed treatment, and all patients achieved an SVR12. On the basis of this study, treating patients with HCV genotype 1b with PrOD but without RBV is recommended, regardless of prior treatment experience or presence of cirrhosis. (Feld, 2015)
In the phase IIa COSMOS study, participants received simeprevir (150 mg once daily) plus sofosbuvir (400 mg once daily) with or without weight-based RBV for 12 weeks or 24 weeks. (Lawitz, 2014b) The OPTIMIST-1 and -2 studies subsequently 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, 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 simeprevir and sofosbuvir 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 used. (Janssen Therapeutics, 2013); (Lawitz, 2014b)
To date, clinical experience and trial data on the retreatment of such patients are 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 had prior protease inhibitor–based treatment 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.
The combination of daclatasvir and sofosbuvir was studied in 41 patients without cirrhosis in whom previous therapy with PEG-IFN, RBV, and an HCV protease inhibitor had failed. Of these patients, 21 were treated with daclatasvir and sofosbuvir for 24 weeks and 20 were treated with daclatasvir and sofosbuvir plus RBV for 24 weeks. Both groups had high cure rates and no additional benefit was seen with the inclusion of RBV (98% SVR12 overall). (Sulkowski, 2014b) Although data are limited, the addition of RBV can be considered in difficult-to-treat situations, such as in patients with cirrhosis. (Pol, 2015)
The safety and efficacy of ledipasvir/sofosbuvir was evaluated in subjects in whom prior treatment with an HCV protease inhibitor (telaprevir or boceprevir) plus PEG-IFN and RBV has 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 has 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.
In the phase IIb ASPIRE trial, simeprevir was combined with PEG-IFN and RBV to treat patients in whom previous PEG-IFN and RBV 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.
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 prior to selecting the next HCV treatment regimen. For patients with no NS5A inhibitor RAVs detected, retreatment with ledipasvir/sofosbuvir and RBV for 24 weeks is recommended. For patients who have NS5A inhibitor RAVs detected and who do not have NS3 inhibitor RAVs detected, treatment with simeprevir, sofosbuvir, and RBV for 24 weeks is recommended. For patients who have both NS3 and NS5A inhibitor RAVs detected, retreatment should be conducted in a clinical trial setting, as an appropriate treatment regimen cannot be recommended at this time.
No data are yet available on the retreatment of patients for whom prior treatment with PrOD has failed. However, studies that have evaluated patients whose virus did not respond to PrOD have reported the presence of RAVs that confer decreased susceptibly to NS3 protease inhibitors (eg, paritaprevir), NS5A inhibitors (eg, daclatasvir, ledipasvir, ombitasvir), and nonnucleoside polymerase inhibitors (eg, dasabuvir). Based on these observations, patients for whom treatment with PrOD did not result in an SVR should have HCV treatment deferred in the setting of mild liver disease, and for those with advanced fibrosis, testing for RAVs should be performed.
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 inhibitor RAVs. Among 11 patients for whom NS5A inhibitor RAVs were not detected, SVR occurred in 11 of 11 (100%); in contrast, among 30 patients for whom NS5A inhibitor RAVs were detected, SVR occurred in 18 of 30 (60%). Importantly, NS5B inhibitor 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 simeprevir and sofosbuvir, the presence of NS3 RAVs, namely the Q80K polymorphism, led to a decreased SVR rate in patients with HCV genotype 1a infection. SVR occurred in 25 of 34 (74%) patients with HCV genotype 1a and the Q80K RAV and in 35 of 38 (92%) patients with HCV genotype 1a without the Q80K RAV. Based on these data, retreatment for patients for whom an NS5A inhibitor-containing regimen 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 the RAVs present.
II. Genotype 2
High SVR12 rates were demonstrated in patients with HCV genotype 2 infection 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) Further, in the BOSON study, 48 patients with HCV genotype 2 infection who did not respond to prior treatment with PEG-IFN plus RBV were treated with sofosbuvir plus RBV for 16 weeks (n=15) or 24 weeks (n=17) or in combination with PEG-IFN for 12 weeks (n=16). (Foster, 2015) SVR was achieved in 13 of 15 (87%) and 17 of 17 (100%) patients treated with sofosbuvir plus RBV for 16 weeks and 24 weeks, respectively. Among those who received sofosbuvir, PEG-IFN, and RBV for 12 weeks, SVR occurred in 15 of 16 (94%). 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 with sofosbuvir plus RBV to 16 weeks or 24 weeks or to add PEG-IFN for 12 weeks should be made on an individual patient basis.
In recognition of the potential limitations of sofosbuvir plus RBV in harder-to-treat, HCV genotype 2–infected patients in whom a prior treatment had failed, particularly those with cirrhosis, treatment that included 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 (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 patients (93%) and 9 of 9 patients (100%), respectively. Despite the limitations of the data from this small study and accounting for the potential challenges inherent with IFN-based therapy, sofosbuvir plus PEG-IFN and RBV is an alternative 12-week regimen for HCV genotype 2–infected patients with cirrhosis.
To date, there are little data available to guide therapy in patients with HCV genotype 2 infection in whom prior treatment with sofosbuvir and RBV has failed. In the BOSON study, patients who had prior treatment with PEG-IFN and RBV had high response rates (SVR12 in 15 of 16 patients) when retreated with sofosbuvir, PEG-IFN, and RBV for 12 weeks. Although patients who were previously treated with sofosbuvir plus RBV were not specifically studied, retreatment with the addition of PEG-IFN will likely improve response rates and may be considered in an IFN-eligible patient in need of more-immediate therapy.
The combination of daclatasvir and sofosbuvir is effective in patients with HCV genotype 2 infection, but there are limited data about this therapy in treatment-experienced patients with HCV genotype 2 infection. (Sulkowski, 2014b); (Wyles, 2015) For patients in whom prior treatment with sofosbuvir and RBV failed who are IFN ineligible, the decision to treat with daclatasvir and sofosbuvir should be made on an individual patient basis with consideration of extension of therapy to 24 weeks with the addition of RBV, especially in difficult-to-treat patients such as those with cirrhosis.
No HCV protease inhibitors have been approved by the US Food and Drug Administration (FDA) 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 recommended regimens.
III. Genotype 3
In the LONESTAR-2 study, adding 12 weeks of PEG-IFN to the sofosbuvir and RBV regimen resulted in a numerically higher response rate among persons with HCV genotype 3 infection than that achieved with sofosbuvir and RBV alone for 24 weeks. Of HCV genotype 3–infected patients with and without cirrhosis, 10 of 12 (83%) achieved an 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 168 of 181 patients (92.8%) treated with 12 weeks of PEG-IFN, sofosbuvir, and RBV and 153 of 182 patients (84.1%) treated with 24 weeks of sofosbuvir and RBV; only 128 of 181 patients (70.7%) treated with 16 weeks of sofosbuvir and RBV achieved an SVR12. Treatment with PEG-IFN, sofosbuvir, and RBV for 12 weeks led to a higher SVR rate 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 these randomized controlled trials strongly support the addition of PEG-IFN to sofosbuvir and RBV in all treatment-experienced patients with HCV genotype 3 infection, including those without cirrhosis when compared with sofosbuvir and RBV alone.
In the ALLY-3 study, the safety and efficacy of treatment with daclatasvir plus sofosbuvir for 12 weeks was evaluated in 51 treatment-experienced patients. (Nelson, 2015b) The majority of these patients were previously treated with IFN-based regimens. Among patients without cirrhosis, 32 of 34 (94%) achieved SVR12. Patients with cirrhosis had lower response rates, with 9 of 13 (69%) achieving SVR12. These data support the use of daclatasvir and sofosbuvir for 12 weeks in patients without cirrhosis, but this is likely a suboptimal regimen for patients with cirrhosis. Although data are very limited, treatment with daclatasvir and sofosbuvir for 24 weeks with or without RBV should be considered in treatment-experienced HCV genotype 3-infected patients with cirrhosis, especially in those who are ineligible for IFN.
In the ALLY-3 study, 7 patients previously treated with sofosbuvir-containing regimens were retreated with daclatasvir and sofosbuvir for 12 weeks. Of these patients, 5 (71%) achieved an SVR12. (Nelson, 2015) Based on these limited data, 12 weeks of daclatasvir and sofosbuvir may be insufficient, and extending the duration to 24 weeks of therapy and adding weight-based RBV is recommended.
No HCV protease inhibitors have been FDA 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 retreatment 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 with HCV genotype 4 infection without cirrhosis who received 12 weeks of paritaprevir, ritonavir, and ombitasvir (PrO) with or without weight-based RBV. In intention-to-treat analysis, SVR12 was achieved in 41 of 41 (100%) 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 randomly assigned 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)
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, neither boceprevir nor telaprevir should not be used to treat patients with HCV genotype 4 infection.
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.
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.
Because of their limited activity against HCV genotypes 5 and 6 in vitro and in vivo, neither boceprevir nor 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 DAAs are sparse, and awaiting the 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 August 7, 2015.