Treatment-Naive Genotype 1b Without Cirrhosis

Recommended and alternative regimens listed by evidence level and alphabetically for:

Treatment-Naive Patients Genotype 1b Without Cirrhosis

RECOMMENDED DURATION RATING
Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) 12 weeks I, A
Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg)a 8 weeks I, A
Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) 12 weeks I, A

Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for patients who are non-black, HIV-uninfected, and whose HCV RNA level is <6 million IU/mL 8 weeks I, B
Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) 12 weeks I, A
ALTERNATIVE DURATION RATING
Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) with dasabuvir (600 mg) as part of an extended-release regimen or plus twice-daily dosed dasabuvir (250 mg) 12 weeks I, A
Daily simeprevir (150 mg) plus sofosbuvir (400 mg) 12 weeks I, A
Daily daclatasvir (60 mg)b plus sofosbuvir (400 mg) 12 weeks I, B
a This is a 3-tablet coformulation. Please refer to the prescribing information.
b The dose of daclatasvir may need to be increased or decreased when used concomitantly with cytochrome P450 3A/4 inducers and inhibitors, respectively. Please refer to the prescribing information and the section on HIV/HCV coinfection for patients on antiretroviral therapy.

For genotype 1b-infected, treatment-naive patients without cirrhosis, there are 4 regimens of comparable efficacy. Three additional regimens are classified as alternative because, compared to the recommended regimens, they require a longer duration of treatment, involve greater prescribing complexity, are potentially less efficacious, and/or there are limited supporting data.

Recommended Regimens

Elbasvir/Grazoprevir

The fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) is recommended based on data from the phase 3 C-EDGE trial, which assessed the efficacy and safety of this regimen for 12 weeks in treatment-naive adults (genotypes 1, 4, and 6) (Zeuzem, 2015f). Patients were enrolled from 60 centers in 9 countries on 4 continents. Three hundred eighty-two patients (91% of the study cohort) were infected with genotype 1 (50% genotype 1a, 41% genotype 1b). The SVR12 was 92% (144/157) in treatment-naive patients with genotype 1a and 99% (129/131) in those with genotype 1b. Findings from this phase 3 study support earlier phase 2 findings from the C-WORTHY trial in which SVR12 rates of 92% (48/52) and 95% (21/22) were demonstrated among genotype 1a and genotype 1b treatment-naive noncirrhotic patients, respectively, who received 12 weeks of elbasvir/grazoprevir without ribavirin (Sulkowski, 2015b). The C-WORTHY trial enrolled both HCV-monoinfected and HIV/HCV-coinfected patients. 

In contrast to genotype 1a, the presence of baseline substitutions associated with NS5A resistance did not appear to affect genotype 1b response to elbasvir/grazoprevir. Thus, current data do not support extending the treatment duration or adding ribavirin in genotype 1b patients with NS5A RASs.

Glecaprevir/Pibrentasvir

Based on favorable data for 8 weeks of treatment for noncirrhotic patients in the phase 2 SURVEYOR-1 study (33/34 patients with SVR and no virologic failures) (Kwo, 2017b), ENDURANCE-1 enrolled 703 noncirrhotic, genotype 1 patients who were DAA-naive or in whom a previous interferon-based regimen failed. Participants were randomized to receive 8 weeks or 12 weeks of the daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) administered as three 100 mg/40 mg fixed-dose combination pills (Zeuzem, 2016). Of those enrolled, 43% had genotype 1a, 85% had fibrosis stage 0 or 1, and 62% were treatment naive. Overall SVR12 rates for the intention-to-treat population were 99% (348/351) in the 8-week arm and 99.7% (351/352) in the 12-week arm. The 8-week arm met the predefined study criteria for noninferiority to the 12-week arm. A single patient experienced on-treatment virologic failure in this study (genotype 1a, day 29). Notably, there were no documented relapses in either arm. 

EXPEDITION-1 investigated the use of glecaprevir/pibrentasvir in DAA-naive (75%) or -experienced (interferon or peginterferon ± ribavirin, or sofosbuvir plus ribavirin ± peginterferon) patients with compensated cirrhosis. Of 146 patients with genotype 1, 2, 4, 5, or 6 given 12 weeks of glecaprevir/pibrentasvir, 145 (99%) achieved SVR12. All genotype 1b patients achieved SVR (Forns, 2017).

EXPEDITION-2, a study of glecaprevir/pibrentasvir in 153 HIV/HCV-coinfected persons with genotype 1, 2, 3, 4, 5, or 6, utilized 8 weeks of treatment for noncirrhotic patients and 12 weeks for cirrhotic patients (the recommended durations approved by the FDA). The overall SVR12 rate was 98% and there were no observed virologic failures among the 94 patients with genotype 1 infection (Rockstroh, 2017). In EXPEDITION-1 and EXPEDITION-2, neither subtype (1a vs 1b) nor the presence of baseline RASs impacted SVR12 results in DAA-naive genotype 1 patients.

Ledipasvir/Sofosbuvir

The fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) was approved by the FDA for the treatment of genotype 1 infection in treatment-naive patients based on a pair of registration trials: ION-1 (865 treatment-naive patients; those with cirrhosis were included) and ION-3 (647 treatment-naive patients; those with cirrhosis were excluded). ION-1 investigated length of treatment (12 weeks vs 24 weeks) and the need for ribavirin (Afdhal, 2014a). SVR12 rates were 97% to 99% across all study arms with no difference in SVR based on length of treatment, use of ribavirin, or genotype 1 subtype. Sixteen percent of participants enrolled were classified as having cirrhosis. There was no difference in SVR12 rate in those with cirrhosis (97%) versus those without cirrhosis (98%).

ION-3 excluded patients with cirrhosis and investigated shortening ledipasvir/sofosbuvir therapy from 12 weeks to 8 weeks (with or without ribavirin) (Kowdley, 2014). SVR12 rates were 93% to 95% across all study arms, with no difference in SVR in the intention-to-treat analysis. However, relapse rates were higher in the 8-week arms (20/431)—regardless of ribavirin use—compared with the 12-week arm (3/216). Post hoc analyses of the ribavirin-free arms assessed baseline predictors of relapse and identified lower relapse rates in patients receiving 8 weeks of ledipasvir/sofosbuvir who had baseline HCV RNA levels <6 million IU/mL (2/123; 2%). The same held true for patients with similar baseline HCV RNA levels who received 12 weeks of treatment (2/131; 2%). This analysis was not controlled, which limits the generalizability of this approach to clinical practice.

Published, real-world cohort data generally show comparable effectiveness of 8 and 12 weeks of ledipasvir/sofosbuvir in treatment-naive patients without cirrhosis (Backus, 2016); (Ingiliz, 2016); (Ioannou, 2016); (Kowdley, 2016); (Terrault, 2016). However, only about half of patients eligible for 8 weeks received it, assignment of duration was not randomized, and baseline characteristics may have varied between 8- and 12-week groups.

Based on available data, shortening treatment to less than 12 weeks is not recommended for HIV-infected patients (see HIV/HCV Coinfection section) and black patients (Su, 2016); (Wilder, 2016); (O'Brien, 2014); (Ioannou, 2016). For others, it should be done at the discretion of the practitioner with consideration of other potential negative prognostic factors.

Sofosbuvir/Velpatasvir

The fixed-dose combination of 12 weeks of sofosbuvir (400 mg)/velpatasvir (100 mg) was approved by the FDA for the treatment of genotype 1 infection in treatment-naive patients based on ASTRAL-1. This placebo-controlled trial involved a 12-week course of sofosbuvir/velpatasvir administered to 624 participants with genotype 1, 2, 4, 5, or 6 who were treatment-naive (n=423) or previously treated with interferon-based therapy, with or without ribavirin or a protease inhibitor (n=201); (Feld, 2015). Of the 328 genotype 1 patients included, 323 achieved SVR with no difference observed by subtype (98% 1a, 99% 1b). Of 121 participants (all genotypes) classified as having cirrhosis, 120 achieved SVR (99%). The presence of baseline NS5A RASs (at 15% cutoff)—reported in 11% of genotype 1a and 18% of genotype 1b participant samples tested—did not influence SVR rate for genotype 1 (Hézode, 2016). Of the 2 virologic failures in ASTRAL-1 (<1% of treated participants), both were genotype 1 and had baseline RASs. There was no significant difference in the rates of adverse events in the sofosbuvir/velpatasvir vs placebo groups.

The phase 3 POLARIS-2 study randomized 941 DAA-naive patients with genotypes 1, 2, 3, 4, 5, or 6—with or without compensated cirrhosis—to receive either 8 weeks of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100mg) or 12 weeks of sofosbuvir/velpatasvir (Jacobson, 2017). Of participants treated with sofosbuvir/velpatasvir, 170/172 (99%) with genotype 1a and 57/59 (97%) with genotype 1b achieved SVR with a single relapse observed in each subtype.
 

Alternative Regimens

Paritaprevir/Ritonavir/Ombitasvir + Dasabuvir

The daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) was approved by the FDA for the treatment of genotype 1b infection in treatment-naive patients based on 3 registration trials; 2 focused specifically on those without cirrhosis. SAPPHIRE-I, which included 151 treatment-naive, genotype 1b-infected patients without cirrhosis, reported an SVR12 rate of 98% with 12 weeks of paritaprevir/ritonavir/ombitasvir + dasabuvir in these patients (Feld, 2014).

Given the high SVR12 rates seen in SAPPHIRE-I, PEARL-III was specifically designed to determine the role of weight-based ribavirin with paritaprevir/ritonavir/ombitasvir + dasabuvir in treatment-naive, genotype 1b-infected patients without cirrhosis (Ferenci, 2014). The SVR12 rate among the 419 study participants was 99% in both treatment arms, confirming there is no added benefit from use of weight-based ribavirin for patients without cirrhosis who have genotype 1b infection.

GARNET, a phase 3b single-arm study of 163 genotype 1b patients without cirrhosis, demonstrated a 98% SVR rate with an 8-week course of paritaprevir/ritonavir/ombitasvir + dasabuvir. When considering the generalizability of these results, it is important to note that 91% of the GARNET participants had fibrosis stage 0 to 2, 93% had HCV RNA levels <6 million IU/mL, and 96% were white. In addition, 2 of the 15 patients with fibrosis stage 3 experienced virologic relapse, suggesting that if used, an 8-week strategy should be reserved for those with early-stage fibrosis (Welzel, 2016b).

 

Simeprevir + Sofosbuvir

The OPTIMIST-1 trial investigated the safety and efficacy of simeprevir (150 mg) plus sofosbuvir (400 mg) in patients with genotype 1 without cirrhosis. In this study, 310 treatment-naive and -experienced patients without cirrhosis were randomly assigned to 12 weeks or 8 weeks of the simeprevir plus sofosbuvir regimen (Kwo, 2016). Overall SVR12 rates were 97% (150/155) in the 12-week arm and 83% (128/155) in the 8-week arm, with a statistically significantly greater relapse rate in the 8-week arm. In the 12-week arm, there was no difference in SVR12 based on past treatment experience; treatment-naive and -experienced patients achieved SVR12 rates of 97% and 95%, respectively. There was also no difference in SVR12 based on genotype 1 subtype or the presence of the baseline Q80K resistance substitution.

Daclatasvir + Sofosbuvir

Daclatasvir (60 mg) plus sofosbuvir (400 mg) for the treatment of genotype 1 infection is recommended based on data from the phase 3 ALLY-2 trial, which assessed the efficacy and safety of daclatasvir/sofosbuvir for 12 weeks in patients coinfected with HIV and HCV (genotype 1, 2, 3, or 4) (Wyles, 2015). One hundred twenty-three (83%) patients receiving 12 weeks of therapy in the trial were infected with genotype 1. Eighty-three (54%) of these patients were treatment naive. Only 12 had genotype 1b and all achieved SVR12 (Wyles, 2015). Furthermore, in the ALLY-1 study, all 11 genotype 1b-infected patients with advanced cirrhosis achieved SVR12. Due to the limited numbers of genotype 1b patients represented in the phase 3 trials of this regimen, there is not enough evidence to support a different approach by subtype at this time.

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Last update: 
September 21, 2017
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