Peginterferon/Ribavirin-Experienced, Genotype 1b Patients Without Cirrhosis

Recommended regimens listed by evidence level and alphabetically for:

Peginterferon/Ribavirin-Experienced, Genotype 1b Patients 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 sofosbuvir (400 mg)/velpatasvir (100 mg) 12 weeks I, A
a Dosing is 3 coformulated tablets (glecaprevir [100 mg]/pibrentasvir [40 mg]) taken once daily. Please refer to the prescribing information.

 

Elbasvir/Grazoprevir

The phase 3 C-EDGE TE trial evaluated the daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) in patients with a prior peginterferon/ribavirin treatment failure. Patients were randomized to elbasvir/grazoprevir for 12 weeks or 16 weeks, with or without ribavirin. Genotype 1 patients treated for 12 weeks without ribavirin had an overall SVR12 of 93.8% (90/96), which was nearly identical to the response rate in patients treated for 12 weeks with added ribavirin (94.4%, 84/89) (Kwo, 2017). SVR rates were similar in the 16-week arms without ribavirin (94.8%, 91/96) and with ribavirin (96.9%, 93/96).

The presence of certain baseline NS5A RASs 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 RASs when assessed by population sequencing (25% limit of detection). These RASs included substitutions at positions M28, Q30, L31, H58, and Y93. Among 21 genotype 1a patients with baseline NS5A RASs (>5 fold), only 52% (11/21) achieved SVR due to a higher relapse rate (Kwo, 2015).

A subsequent integrated analysis of phase 2 and phase 3 trials confirmed a lower SVR in treatment-experienced genotype 1a patients with these specific baseline NS5A RASs (90%, 167/185) versus patients without baseline RASs (99%, 390/393) (Zeuzem, 2017). In patients treated with 12 weeks of elbasvir/grazoprevir without ribavirin, 64% (9/14) with baseline elbasvir NS5A RASs achieved SVR, compared to 96% (52/54) among those without these baseline RASs. Extension of therapy to 16 weeks or 18 weeks with the addition of weight-based ribavirin increased the response rate to 100% regardless of the presence of baseline NS5A RASs, suggesting this approach can overcome the negative impact of NS5A RASs seen with the 12-week regimen (Jacobson, 2015b).

Based on the known inferior response in patients with specific NS5A RASs, NS5A resistance testing is recommended for genotype 1a patients being considered for elbasvir/grazoprevir therapy. If these RASs are present, treatment extension to 16 weeks with the addition of weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [≥75 kg]) is recommended to decrease relapse risk. Lack of access to RAS testing or results should not be used as a means to limit access to HCV therapy.

Glecaprevir/Pibrentasvir

The phase 3 ENDURANCE-1 trial enrolled 703 treatment-naive or -experienced patients (interferon or peginterferon ± ribavirin, or sofosbuvir plus ribavirin ± peginterferon) with genotype 1 and no cirrhosis. Participants were randomized to 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 F0 or F1, and 38% were treatment experienced. Ninety-nine percent of the treatment-experienced patients had previously received interferon-based therapy and 1% had received sofosbuvir-based treatment. 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. A single patient experienced on-treatment virologic failure (genotype 1a, day 29). There were no documented relapses in either study arm. This regimen was well tolerated with rare adverse events leading to discontinuation (0.1%); no significant laboratory abnormalities were noted.

Ledipasvir/Sofosbuvir

The daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) has been evaluated in patients without cirrhosis and a history of treatment failure with peginterferon/ribavirin, with or without HCV protease inhibitors (telaprevir or boceprevir). In the ION-2 study, patients who had not responded to prior peginterferon/ribavirin therapy were treated with ledipasvir/sofosbuvir, with or without ribavirin, for 12 weeks or 24 weeks. In the population without cirrhosis, the overall SVR was 98%. Specifically, in patients without cirrhosis and a history of peginterferon/ribavirin failure, 94% (33/35) achieved SVR12 after 12 weeks of ledipasvir/sofosbuvir treatment, and 100% (38/38) achieved SVR in the ledipasvir/sofosbuvir plus ribavirin study arm (Afdhal, 2014b). This regimen was well tolerated in all groups with no serious adverse events reported for the 12-week regimen, with or without ribavirin.

Sofosbuvir/Velpatasvir

The double-blind, placebo-controlled ASTRAL-1 trial evaluated treatment-naive or -experienced patients with genotype 1, 2, 4, 5, or 6 who were treated with sofosbuvir (400 mg)/velpatasvir (100 mg) as a daily fixed-dose combination for 12 weeks (Feld, 2015). Patients in the placebo arm were eligible to roll over into a deferred therapy arm with the same regimen. The overall response rate among genotype 1 treatment-experienced patients was 99% (109/110), with 100% (78/78) in participants with genotype 1a and 97% (31/32) in those with genotype 1b. Among patients previously treated with peginterferon/ribavirin, 98% (50/51) achieved SVR12; 100% (48/48) of those previously treated with a DAA plus peginterferon/ribavirin achieved SVR12. The single treatment-experienced patient who did not respond to this regimen was a genotype 1b, black adult with cirrhosis and IL28 TT genotype. This individual had a persistently detectable HCV viral load during previous peginterferon/ribavirin therapy. The regimen was well tolerated and there was no significant difference in the rate of adverse events in the sofosbuvir/velpatasvir group (78%) vs the placebo group (77%).

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Last update: 
November 6, 2019
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