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 available to inform the best regimen for each patient and the strength of the recommendation vary, and are rated accordingly (see Methods Table 2). In addition, specific recommendations are given when treatment differs for a particular group (eg, those infected with various genotypes). Recommended regimens are those that are favored for most patients in that subgroup, based on optimal efficacy, favorable tolerability and toxicity profiles, duration, and pill burden. Alternative regimens are those that are effective but have, relative to Recommended regimens, potential disadvantages, limitations for use in certain patient populations, or less supporting data than Recommended regimens. In certain situations, an Alternative regimen may be an optimal regimen for a specific patient. Not Recommended regimens are clearly inferior compared to Recommended or Alternative regimens due to factors such as lower efficacy, unfavorable tolerability and toxicity, longer duration, and/or higher pill burden. 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.
Recommended and Alternative regimens are listed in order of level of evidence. When several regimens are offered at the same level of evidence, they are listed in alphabetic order. Choice of regimen should be determined based on patient-specific data, including drug interactions. 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 RBV is included in the regimen. (See Monitoring Section)
Five 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 and the presence or absence of baseline NS5A resistance-associated variants (RAVs), and the presence or absence of cirrhosis. With certain 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.
Approximately 10%-15% of HCV genotype 1-infected patients without prior exposure to NS5A inhibitors will have detectable HCV NS5A RAVs at the population level prior to treatment. While the clinical impact of NS5A RAVs remains to be fully elucidated, in patients with genotype 1a infection the presence of baseline NS5A RAVs that cause a large reduction in the activity of NS5A inhibitors (>5 fold) adversely impact response to NS5A-containing regimens. (Zeuzem, 2015b); (Jacobson, 2015b) These RAVs include variants at positions M28, Q30, L31, and Y93 in genotype 1a and are found by population sequencing in roughly 5%-10% of patients. Given that baseline NS5A RAVs are one of the strongest pre-treatment predictors of treatment outcome with certain regimens in patients with genotype 1a infection, testing for these RAVs prior to deciding on a therapeutic course is recommended in select situations. (Zeuzem, 2015c)
The introduction of DAAs into HCV treatment regimens increased the risk of drug interactions with concomitant medications 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. Important interactions with commonly used medications (eg, antacids, lipid lowering drugs, anti-epileptics, antiretrovirals, etc) exist for all of the regimens discussed below.
The fixed-dose, once-daily combination of elbasvir (50 mg) and grazoprevir (100 mg) (hereafter, elbasvir/grazoprevir) was evaluated in patients who had previously failed PEG-IFN/RBV in C-EDGE TE. In this phase III trial, patients were randomized to receive elbasvir/grazoprevir for 12 or 16 weeks with or without RBV. Genotype 1 patients treated for 12 weeks without RBV had an overall high SVR rate of 93.8% (90/96) which was similar to response rates in patients treated for 12 weeks with RBV (94.4%, 84/89). Response rates were similar in the 16-week arms without RBV (94.8%, 91/96) and with RBV (96.9%, 93/96). A subset analysis of patients with compensated cirrhosis revealed similar response rates to the noncirrhotic population when treated with elbasvir/grazoprevir without RBV for 12 weeks: SVR in cirrhosis 95% (19/20) vs no cirrhosis 94.9% (37/39).
The presence of certain baseline NS5A RAVs appears to be the single best predictor of relapse with the 12-week elbasvir/grazoprevir regimen. In genotype 1a patients treated with elbasvir/grazoprevir, decreased efficacy was seen among those with baseline NS5A resistance-associated varients (RAVs) when assessed by population sequencing (limit of detection 25%). These resistance-associated variants included mutations at positions M28, Q30, L31, H58, and Y93. Among 21 genotype 1a patients with baseline high fold-change NS5A RAVs (>5 fold), 11 patients achieved SVR (52.4%) due to higher relapse. (Kwo, 2015b) A subsequent integrated analysis of phase II and III trials confirmed a lower SVR in treatment-experienced genotype 1a patients with these specific baseline NS5A RAVs (90%, 167/185) vs patients without baseline RAVs (99%, 390/393). (Zeuzem, 2015b) In patients treated with 12 weeks of elbasvir/grazoprevir without ribavirin, 64% (9/14) of patients with baseline EBR NS5A RAVs achieved SVR, compared to 96% (52/54) of those without baseline RAVs. Extension of therapy to 16 weeks or 18 weeks with the addition of weight-based RBV increased response rates to 100% regardless of presence of baseline NS5A RAVs, suggesting this approach can overcome the negative impact of NS5A RAVs seen in the 12-week arms. (Jacobsen, 2015b) Based on the known inferior response in patients with specific NS5A RAVs, NS5A resistance testing is recommended in genotype 1a patients who are being considered for therapy with elbasvir/grazoprevir. If these RAVs are present, treatment extension to 16 weeks with the addition of weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) is recommended to decrease the risk of relapse.
Lack of RAV testing results or lack of access to RAV testing should not be used as a means to limit access to HCV therapy.
The fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) (hereafter, ledipasvir/sofosbuvir) has been evaluated in patients with and without cirrhosis in whom prior treatment with PEG-IFN/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/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/RBV, 33 of 35 (94%) achieved an SVR after treatment with ledipasvir/sofosbuvir for 12 weeks, and 38 of 38 (100%) patients achieved SVR after treatment with ledipasvir/sofosbuvir and RBV for 12 weeks. (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/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-naïve 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 two 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, 2015); (Reddy, 2015)
Baseline NS5A RAVs adversely impact responses to LDV/SOF therapy; though the magnitude of this impact varies based on a number of factors including virus (genotype subtype, specific RAV), regimen (companion drugs, use of RBV) and patient factors (treatment experience, presence of cirrhosis). In an analysis of over 350 HCV genotype 1 treatment-experienced patients with cirrhosis the presence of baseline LDV RAVs (defined as RAVs resulting in a >2.5 fold-shift in LDV EC50) detected at a 1% level resulted in lower SVR12 rates compared to those without baseline RAVs. (Zeuzem, 2015b) The SVR12 rates were 89% (RAVs) versus 96% (no RAVs) when ledipasvir/sofosbuvir plus RBV for 12 weeks was used and 87% versus 100%, respectively, with ledipasvir/sofosbuvir for 24 weeks. The impact is likely to be larger in a genotype 1a only population. Given the vulnerable nature of this population, baseline NS5A resistance testing should be considered in genotype 1a treatment-experienced patients with cirrhosis prior to use of ledipasvir/sofosbuvir. If ledipasvir associated RAVs are detected consideration should be given to adding RBV to the regimen and extending therapy to 24 weeks. This is based on a 100% SVR12 rate in 14 patients with cirrhosis and baseline LDV RAVs treated with 24 weeks of ledipasvir/sofosbuvir plus RBV. (Sarrazin, 2015)
Paritaprevir/ritonavir/ombitasvir + dasabuvir
In SAPPHIRE-2, the daily fixed-dose combination of paritaprevir (150 mg), ritonavir (100 mg), and ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) (PrOD) with weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) was investigated for treatment of patients with HCV genotype 1 infection, in whom previous PEG-IFN/RBV therapy failed. (Zeuzem, 2014) In this phase III trial, patients who did not have cirrhosis and who were treated for a total of 12 weeks had a high overall rate of response with 286 of 297 (96.3%). Response rates did not differ substantially when stratified by subtype (genotype 1a, 96.0% [166/173]; genotype 1b, 96.7% [119/123]) or kinetics of prior response to PEG-IFN/RBV (relapse, 95.3% [82/86]; partial response, 100% [65/65]; 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/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/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/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 and cirrhosis 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 without RBV is recommended, regardless of prior treatment experience or presence of cirrhosis. (Feld, 2015)
In October 2015, the FDA released a warning regarding the use of the PrOD or PrO (without dasabuvir) in patients with cirrhosis. (This statement is based on our review of the limited data available from the FDA and will be updated if and when more data become available.) PrOD and PrO are contraindicated in patients with Child Turcotte Pugh (CTP) class B or C hepatic impairment (decompensated liver disease). The manufacturer’s pharmacovigilance program reported rapid onset of liver injury and in some cases hepatic decompensation in patients with cirrhosis, including CTP class A compensated cirrhosis and decompensated cirrhosis, who were receiving PrOD or PrO. The liver injury and decompensating events occurred largely during the first 4 weeks of therapy and primarily involved a rapid increase in total and direct bilirubin, often associated with a concomitant increase in liver enzyme levels. In most cases, early recognition and prompt discontinuation of PrOD or PrO resulted in resolution of injury, although some patients, including at least 2 patients with CTP class A compensated cirrhosis, died or required liver transplantation. Although cirrhosis carries a 2% to 4% annual risk of hepatic decompensation, the rapid onset of hepatic decompensation and in many cases its resolution with discontinuation of treatment with PrOD or PrO is suggestive of drug-induced liver injury. Although PrOD and PrO are contraindicated in patients with CTP class B or C cirrhosis and decompensated liver disease, predictors of these events in patients with CTP class A cirrhosis are currently unclear.
For patients with CTP class A cirrhosis, the unlikely but real possibility of drug-induced liver injury should be discussed with the patient. If the decision is made to initiate treatment with PrOD or PrO, close monitoring of total and direct bilirubin and transaminase levels every 1 week or 2 weeks for the first 4 weeks is recommended to ensure early detection of drug-induced liver injury. Also, educating patients about the importance of reporting systemic symptoms such as jaundice, weakness, and fatigue is strongly recommended. The regimen should be discontinued immediately if drug-induced liver injury is suspected. If a patient is already taking PrOD or PrO and is tolerating the regimen, laboratory monitoring as above without discontinuation is recommended unless there are signs or symptoms of liver injury. If heightened monitoring cannot be provided in the first 4 weeks of therapy with PrOD or PrO in patients with cirrhosis, the use of these regimens is not recommended.
Simeprevir + sofosbuvir
In the phase IIa COSMOS study, 167 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. Overall SVR12 was 92% (90% among 80 patients with prior PEG-IFN/RBV nonresponse and limited (Metavir F0-F2) fibrosis, and 94% among 87 patients with Metavir F3-F4 fibrosis), and the regimens were well tolerated confirming high efficacy and safety. (Lawitz, 2014b) The OPTIMIST-1 and -2 phase III studies subsequently evaluated the combination of sofosbuvir plus simeprevir for 12 weeks in patients with HCV genotype 1 infection who were HCV treatment-naïve and -experienced and without or with cirrhosis, respectively. (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. Superiority in SVR12 was assessed for simeprevir plus sofosbuvir at 12 and 8 weeks versus a composite historical control SVR rate. The SVR12 in the 12-week arm was 97%, meeting superiority versus the historical control (87%); however, the 8-week arm only achieved an SVR12 of 83%, which did not meet superiority versus the historical control. Among those treated for 12 weeks, the SVR rate in PEG-IFN plus RBV treatment-experienced patients was 95% (38/40) and the SVR rate in patients with genotype 1a infection with the baseline Q80K polymorphism (96%; 44/46) was similar to that observed in patients without the Q80K variant (97%; 69/70). In contrast, in the OPTIMIST-2 study (a single-arm 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, a different treatment regimen should be used. If Q80K polymorphisms are not detected then a 24-week regimen should be used. (Janssen Therapeutics, 2013); (Lawitz, 2014b)
Daclatasvir + sofosbuvir
The combination of daclatasvir and sofosbuvir has been studied in HCV genotype 1 treatment-experienced patients who have previously been treated with PEG-IFN/RBV in two 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.
To date, clinical experience and trial data on the retreatment of sofosbuvir-experienced 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 for a longer duration, have 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 two 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/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.
There are no published data on retreatment of sofosbuvir-containing treatment failures with non-sofosbuvir based DAA regimens. In theory the lack of cross resistance between SOF and all other currently available DAAs suggests that such regimens may be efficacious in retreatment settings. However, given the lack of available data recommendations cannot be made. If use of non-sofosbuvir based DAA regimens is being considered, those patients should be treated in line with the recommendations for pegylated interferon-experienced patients according to genotype subtype and cirrhosis status.
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/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. (Bourliere, 2015)
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)
Grazoprevir is a next-generation protease inhibitor that retains activity in vitro against many common protease inhibitor resistant variants. (Summa, 2012); (Howe, 2014) The combination of grazoprevir (100 mg) plus elbasvir (50 mg) with expanded weight-based RBV (800-1400 mg) was evaluated in an open-label phase II study of 79 patients who had failed prior interferon-based HCV therapy including a protease inhibitor. (Forns, 2015a) The majority of enrolled subjects had failed prior PEG-IFN/RBV plus either boceprevir (35%, n=28) or telaprevir (54%, n=43); importantly 83% experienced virologic failure with their prior PI-containing regimen and 44% had detectable NS3 RAVs to early generation PIs at study entry. Sustained virologic response 12 weeks after completion of therapy was attained in 96% of patients including in 93% (28/30) of genotype 1a patient and 94% (32/34) of those with cirrhosis. Baseline NS3 RAVs did not appear to have a large impact on responses with a SVR12 rate of 91% (31/34). Presence of NS5A or dual NS3/NS5A variants was associated with lower SVR12 rates of 75% and 66%, respectively, but with only 3 failures in the entire study firm conclusions cannot be drawn. Consistent with the recommendations for other populations, extension of therapy to 16 weeks with RBV is recommended in patients with baseline NS5A RAVs resulting in a >5-fold shift in elbasvir potency.
Simeprevir + sofosbuvir failures
Data suggest that approximately 5% to 10% of patients without cirrhosis and with HCV genotype 1 infection treated for 12 weeks with simeprevir plus sofosbuvir will experience treatment failure, typically due to viral relapse. (Kwo, 2015b) Failure rates in patients with cirrhosis treated for 24 weeks with this regimen are limited; however, treatment failure appears to be more common in persons infected with HCV genotype 1a and those with cirrhosis. Data from the OPTIMIST-1 and -2 studies indicate that treatment failure following a regimen of simeprevir plus sofosbuvir is associated with resistance to simeprevir and cross-resistance to other HCV NS3 protease inhibitors such as paritaprevir, telaprevir, and boceprevir; grazoprevir cross-resistance may also occur in the setting of D168 or A156 variants. (Kwo, 2015b); (Lawitz, 2015d) On the other hand, only a single patient developed the signature sofosbuvir RAV S282T in the OPTIMIST trials supporting the rare occurrence of this variant in clinical practice.
Data on retreatment of simeprevir plus sofosbuvir failures is extremely limited. Interim data from a cohort of 31 patients who had failed simeprevir plus sofosbuvir therapy indicated reasonable response rates to 12-24 weeks of ledipasvir/sofosbuvir therapy with or without RBV. (Gonzales, 2015) In the subset of pateints with SVR12 data available, 85% SVR12 was achieved in non-cirrhotic patients and 91% in cirrhotic patients. Given the lack of a standardized treatment approach and heterogeneous nature of the population, conclusions on the optimal retreatment regimen cannot be drawn.
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. (Lawitz, 2015b) 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. (Lawitz, 2015b) 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. (Lawitz, 2015) 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.
Retreatment approach and potential regimens (including other NS5A regimen containing failures)
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, limited data suggest a retreatment approach based on sofosbuvir combined with either elbasvir/grazoprevir or PrOD may be efficacious. (Lawitz, 2015e); (Poordad, 2015a) In a retreatment arm of the C-SWIFT study, 23 patients who had failed shorter courses of elbasvir/grazoprevir plus sofosbuvir were retreated with 12 weeks of this combination plus weight-based RBV. In a per protocol analysis a 100% SVR12 rate was achieved (23/23), including SVR in 9/9 patients with dual NS3 and NS5A RAVs. (Lawitz, 2015e) A second phase II study of 22 patients, including 14 PrOD failures, evaluated retreatment with 12-24 weeks of PrOD plus sofosbuvir. Treatment duration and RBV usage were determined by cirrhosis status, HCV RNA response on therapy, and genotype subtype. SVR12 data was available on 15 patients with 14/15 (93%) attaining SVR12. Based on these limited data, patients with dual NS3 and NS5A class RAVs may be retreated with elbasvir/grazoprevir plus sofosbuvir with weight-based RBV for 12 weeks or PrOD plus sofosbuvir for 12 weeks in genotype 1b and 24 weeks with weight-based RBV in those with genotype 1a. If these regimens are unavailable, retreatment should be conducted in a clinical trial setting, as an appropriate treatment regimen cannot be recommended at this time.
In the phase IIb ASPIRE trial, simeprevir was combined with PEG-IFN/RBV to treat patients in whom previous PEG-IFN/RBV failed. (Zeuzem, 2014c); (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/RBV has high efficacy in treatment-naïve 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/RBV for 48 weeks may result in SVR for up to 52% of patients who had a partial response to previous PEG-IFN/RBV treatment (RESPOND 2), (Bacon, 2011) and up to 38% of patients with a prior null response. (PROVIDE); (Sterling, 2015) Similarly, telaprevir plus PEG-IFN/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.
II. Genotype 2
High SVR12 rates were demonstrated in patients with HCV genotype 2 infection in whom prior treatment with PEG-IFN/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%). (Lawitz, 2014b) 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.
The once-daily combination of daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 to 24 weeks has been shown to have efficacy in HCV genotype 2 infection, however available data in patients previously treated with PEG-IFN/RBV is very limited. (Wyles, 2015a); Sulkowski, 2014a) For patients who require treatment and are ineligible to receive RBV, treatment with dacalatasvir/sofosbuvir for 12 weeks is recommended with consideration of extension of therapy to 24 weeks in more difficult patients to treat such as those with cirrhosis.
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/RBV for 12 weeks is an Alternative 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/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. (Foster, 2015)
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. (Lawitz, 2014a) 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 one of three 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. (Foster, 2015) 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.
Data are limited for treatment-experienced HCV genotype 3-infected patients with cirrhosis, especially those who are ineligible for IFN. In the ALLY-3 study, a suboptimal response to 12 weeks of daclatasvir plus sofosbuvir (SVR12 69% [9/13]) was seen. (Nelson, 2015) In contrast, treatment-experienced patients without cirrhosis did well in the ALLY-3 study with an SVR12 rate of 94% (32/34). In a follow-up study (ALLY-3+), 36 genotype 3 cirrhotic patients were randomized to daclatasvir plus sofosbuvir with RBV for 12 or 16 weeks. An on-treatment analysis showed similar SVR12 rates of 88% (15/17) and 89% (16/18), respectively, in the 12-week and 16-week treatment arms. (Leroy, 2016) These data suggest at a minimum RBV should be included, if possible, for all cirrhotic patients treated with this regimen. Given the vulnerable nature of this population, treatment with daclatasvir and sofosbuvir plus RBV for 24 weeks is recommended pending additional data; however, omission of RBV can be considered for patients in whom RBV-containing therapy is contraindicated.
Baseline NS5A polymorphisms in genotype 3 also impact DAA treatment response with the Y93H variant being most problematic. In the ALLY-3 study the Y93H was detected in 13 (9%) of patients with an SVR12 of 54% (7/13); including a 67% SVR12 in patients without cirrhosis. Given that cirrhotic patients are already recommended to have RBV added and extend therapy, baseline testing for NS5A RAVs in GT 3 would only impact treatment approaches for patients without cirrhosis. Pending additional data, baseline NS5A RAV testing should be considered in all treatment-experienced genotype 3 patients without cirrhosis. If the Y93H variant is identified, weight-based RBV should be added to the treatment course.
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 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
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) The AGATE-I trial, in its first phase, randomized 120 treatment-naïve and -experienced patients with genotype 4 HCV and compensated cirrhosis to receive 12 weeks or 16 weeks of paritaprevir/ritonavir/ombitasvir (PrO) plus weight-based ribavirin. The SVR12 rates in the 12-week and 16-week arms were 96% and 100%, respectively. The regimens were well tolerated (Asselah, 2015a). Similarly, the ongoing AGATE-II trial offered 100 treatment-naïve and -experienced noncirrhotic patients with genotype 4 PrO plus weight-based RBV for 12 weeks. The SVR12 was 94%. Additionally, AGATE-II randomized 60 treatment-naïve and -experienced genotype 4-infected patients with compensated cirrhosis to receive either 12 or 24 weeks of PrO plus weight-based RBV. The SVR12 rate from the 12-week arm, reported recently, was 97%. These data continue to support the use of PrO plus RBV for 12 weeks in treatment-experienced genotype 4 patients, including those with cirrhosis. (Esmat, 2015)
Sofosbuvir-based regimens have also shown efficacy in patients infected with HCV genotype 4. Sofosbuvir administered with PEG-IFN/RBV for 12 weeks was investigated in the phase III NEUTRINO trial. (Lawitz, 2013a) Of the 28 treatment-naïve 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)
An integrated analysis of all phase 2/3 elbasvir/grazoprevir studies demonstrated efficacy of this regimen for both treatment-naïve (n=66) and -experienced (n=37) patients with genotype 4 HCV infection. (Asselah, 2015b) The overall SVR12 rate among treatment-experienced genotype 4 infected patients was 87% (32/37) with numerical response differences based on prior interferon treatment response (relapse vs. on-treatment viral failure) and elbasvir/grazoprevir duration (12 vs 16 weeks) and/or RBV usage (no RBV vs RBV). Numbers within any specific subgroup are too small to make definitive recommendation; however, trends emerged which were used to guide the current recommendations pending additional data. No treatment failures were seen in patients who relapsed after prior PEG-IFN/RBV therapy, regardless of elbasvir/grazoprevir treatment duration or RBV usage. In contrast, response rates were numerically lower in patients with prior on-treatment virologic failure in the non-RBV-containing arms (12 weeks: 78%, 16 weeks: 60%) compared to RBV-containing treatment (12 weeks + RBV: 91%, 16 weeks + RBV: 100%). Given the lack of sufficient numbers to differentiate response between 12 weeks with RBV and 16 weeks with RBV, the use of 16 weeks plus RBV in genotype 4-infected patients with prior on-treatment virologic failure represents the most conservative approach.
PEG-IFN/RBV for 48 weeks was previously recommended for patients with HCV genotype 4 infection. (AASLD-IDSA, 2015) Adding sofosbuvir (400 mg daily) to PEG-IFN/RBV increases SVR rates and markedly shortens therapy with no apparent additional adverse effects. The addition of simeprevir to PEG-IFN/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/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-naïve 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 six patients with HCV genotype 6 and the one 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/RBV therapy.
Ledipasvir has in vitro activity against most HCV genotype 6 subtypes (exception 6e). (Wong, 2013); (Kohler, 2014) A small, two-center, open-label study (NCT01826981) investigated the safety and in vivo efficacy of ledipasvir/sofosbuvir for 12 weeks in treatment-naïve and -experienced patients with HCV genotype 6 infection. Twenty-five patients (92% treatment-naïve) 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.
Changes made on April 25, 2016.