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 increase or decrease 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, 2017). 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 supported 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 had 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 durations since approved by the FDA and recommended in the package insert). 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 was 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 rate was 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 genotype.

The safety profiles of all the recommended regimens above appear favorable. Across numerous phase 3 programs, <1% of patients without cirrhosis discontinued treatment early and adverse events were mild. Most adverse events occurred in ribavirin-containing arms.
 

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, 2016).

 

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 (genotypes 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.

Last update: 
September 21, 2017

Additional Reading:    HIV/HCV Coinfection    Renal Impairment    Acute Infection

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