Treatment-Naive Genotype 1a With Compensated Cirrhosis

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

Treatment-Naive Genotype 1a Patients With Compensated Cirrhosis

RECOMMENDED DURATION RATING
Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for patients without baseline NS5A RASsb for elbasvir 12 weeks I, A
Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg)c 12 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
ALTERNATIVE DURATION RATING
Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based ribavirin for patients with baseline NS5A RASsb for elbasvir 16 weeks IIa, B
a For decompensated cirrhosis, please refer to the appropriate section.
b Includes genotype 1a resistance-associated substitutions at amino acid positions 28, 30, 31, or 93 known to confer antiviral resistance.
c This is a 3-tablet coformulation. Please refer to the prescribing information.

 

For genotype 1a-infected, treatment-naive patients with compensated cirrhosis, there are 4 recommended regimens with comparable efficacy. The alternative regimen is classified as such because, compared to the recommended regimens, it requires a longer duration of treatment, involves greater prescribing complexity, is potentially less efficacious, and/or there are limited supporting data.

Recommended Regimens

Elbasvir/Grazoprevir

The recommendation for use of daily fixed-dose elbasvir (50 mg)/grazoprevir (100 mg) in cirrhotic patients with genotype 1 infection is based on 92 patients (22% of the study cohort) in the phase 3 C-EDGE trial who had Metavir F4 disease (Zeuzem, 2015f). SVR12 was 97% in this subgroup of cirrhotic patients. A similar 97% (28/29) SVR12 rate had previously been demonstrated in genotype 1 cirrhotic treatment-naive patients treated with 12 weeks of elbasvir/grazoprevir without ribavirin in the open-label phase 2 C-WORTHY trial, which enrolled both HCV-monoinfected and HIV/HCV-coinfected patients (Lawitz, 2015c). Presence or absence of cirrhosis does not appear to alter the efficacy of the elbasvir/grazoprevir regimen (Lawitz, 2015c); (Zeuzem, 2017).

Presence of certain baseline NS5A RASs significantly reduces SVR12 rates with a 12-week course of the elbasvir/grazoprevir regimen in genotype 1a-infected patients (Zeuzem, 2017). Baseline NS5A RASs were identified in 12% (19/154) of genotype 1a-infected patients enrolled in the C-EDGE study, of which 58% (11/19) achieved SVR12 compared to 99% (133/135) in patients without these RASs (Zeuzem, 2017). Among treatment-naive patients, the presence of baseline NS5A RASs with a greater than 5-fold reduced sensitivity to elbasvir was associated with the most significant reduction in SVR12 with only 22% (2/9) of genotype 1a patients with these RASs achieving SVR12.

Recommendations for prolonging duration of treatment to 16 weeks with inclusion of ribavirin for treatment-naive genotype 1a patients with baseline NS5A RASs is based on extrapolation of data from the C-EDGE TE trial. In this phase 3 open-label trial of elbasvir/grazoprevir that enrolled treatment-experienced patients, among 58 genotype 1a patients who received 16 weeks of therapy with elbasvir/grazoprevir plus ribavirin, there were no virologic failures (Kwo, 2017).​ Subsequent integrated analysis of elbasvir/grazoprevir phase 2 and 3 trials demonstrated an SVR12 rate of 100% (6/6 patients) in genotype 1 patients with pretreatment NS5A RASs treated with elbasvir/grazoprevir for 16 or 18 weeks plus ribavirin (Jacobson, 2015b); (Thompson, 2015).

Based on known inferior response in patients with baseline NS5A RASs, NS5A resistance testing is recommended in genotype 1a patients who are being considered for elbasvir/grazoprevir therapy. If baseline RASs are present (ie, substitutions at amino acid positions 28, 30, 31, or 93), 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

EXPEDITION-1 investigated the use of the daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) administered as three 100 mg/40 mg fixed-dose combination pills 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. The single relapse occurred in a genotype 1a patient; SVR among these patients was 98% (47/48) (Forns, 2017).

EXPEDITION-2, a study of glecaprevir/pibrentasvir in 153 HIV/HCV-coinfected adults 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 2 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%).

Sofosbuvir/Velpatasvir

The daily fixed-dose combination sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks 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 in SVR 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, 2018).​​ 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 genotype 1, 2, 3, 4, 5, or 6—19% with cirrhosis—to receive 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 with each subtype.

 

  • Related References
  • Additional Reading
Last update: 
September 21, 2017
Top