Treatment-Naive Genotype 4 Without Cirrhosis

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

Treatment-Naive Genotype 4 Patients Without Cirrhosis

RECOMMENDED DURATION RATING
Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg)a 8 weeks I, A
Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) 12 weeks I, A
Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) 12 weeks IIa, B
Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) 12 weeks IIa, B
ALTERNATIVE DURATION RATING
Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin 12 weeks I, A
a This is a 3-tablet coformulation. Please refer to the prescribing information.

 

Recommended Regimens

Glecaprevir/Pibrentasvir

Based on favorable data for 12 weeks of treatment for noncirrhotic patients in part 4 of the phase 2 SURVEYOR-2 study (100% SVR12 in 34 patients with genotype 4, 5, or 6) (Kwo, 2017b), ENDURANCE-4 enrolled 121 DAA-naive or -experienced (sofosbuvir plus ribavirin ± peginterferon) genotype 4, 5, or 6 patients without cirrhosis to receive 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 (Asselah, 2016). Of those enrolled, 86% were fibrosis stage F0 to F1 and 68% were treatment-naive. The genotype distribution was 63% genotype 4, 21% genotype 5, and 16% genotype 6. The overall SVR12 rate for the intention-to-treat population was 99% (120/121), including 99% (75/76) for genotype 4, 100% for genotype 5 (26/26), and 100% (19/19) for genotype 6.

Genotype 4, 5, and 6 patients were not included in the randomized study to compare an 8-week versus 12-week course of glecaprevir/pibrentasvir for DAA-naive, noncirrhotic patients. However, part 4 of the SURVEYOR-2 study investigated an 8-week course of glecaprevir/pibrentasvir in DAA-naive patients without cirrhosis (Hassanein, 2016). In the intention-to-treat analysis, 43/46 with genotype 4, 2/2 with genotype 5, and 9/10 with genotype 6 achieved SVR 12; there were no known virologic failures.

EXPEDITION-1 investigated use of glecaprevir/pibrentasvir in treatment-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, 99% (145/146) achieved SVR12, including 16/16 (100%) with genotype 4, 2/2 (100%) with genotype 5, and 7/7 (100%) with genotype 6 (Forns, 2017). Based on these studies, glecaprevir/pibrentasvir was approved for treatment of genotype 4-infected, DAA-naive, noncirrhotic patients for a duration of 8 weeks.

Sofosbuvir/Velpatasvir

The daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks was approved by the FDA for the treatment of genotype 4 infection in patients with or without cirrhosis. ASTRAL-1 included 64 genotype 4-infected, treatment-naive patients without cirrhosis or with compensated cirrhosis, all of whom achieved SVR12 (100%) (Feld, 2015).

The POLARIS-2 phase 3 study randomized DAA-naive patients to 8 weeks of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) versus 12 weeks of sofosbuvir/velpatasvir. Of 57 patients with genotype 4 in the sofosbuvir/velpatasvir arm, 98% achieved SVR and 1 patient experienced relapse (Jacobson, 2017).

Elbasvir/Grazoprevir

A phase 2/3 trial evaluated 66 treatment-naive, genotype 4 patients treated with daily elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks. Ten patients had weight-based ribavirin added to the regimen and 56 did not. Six participants (9.1%) were cirrhotic and 28 (42.4%) had HIV/HCV coinfection. Overall, 97% (64/66) achieved SVR12. There was 1 treatment failure and 1 subject was lost to follow-up. The impact of ribavirin could not be assessed, however the addition of ribavirin numerically increased the SVR12 rate in treatment-experienced participants. Baseline RASs and genotype subtype did not appear to impact SVR12 rates (Asselah, 2015).

Ledipasvir/Sofosbuvir

The SYNERGY trial was an open-label study evaluating 12 weeks of ledipasvir (90 mg)/sofosbuvir (400 mg) in 21 genotype 4-infected patients, of whom 60% were treatment-naive and 43% had advanced fibrosis (Metavir stage F3 or F4) (Kohli, 2015). One patient took the first dose and then withdrew consent. The 20 patients who completed treatment all achieved SVR12; thus, the SVR12 rate was 95% in the intention-to-treat analysis and 100% in the per-protocol analysis. Abergel and colleagues reported data from an open-label, single-arm study including 22 genotype 4-infected, treatment-naive patients (1 with cirrhosis) with an SVR12 rate of 95% (21/22) (Abergel, 2016). These pilot studies support the use of ledipasvir/sofosbuvir in patients with genotype 4 infection.

Alternative Regimen

Paritaprevir/Ritonavir/Ombitasvir + Ribavirin

PEARL-I was a randomized, open-label, phase 2b study that included a cohort of 86 treatment-naive patients with genotype 4 infection without cirrhosis who received 12 weeks of the daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg), with or without weight-based ribavirin. SVR12 rates were 100% (42/42) in the ribavirin arm and 90.9% (40/44) in the group not receiving ribavirin. Adverse effects were generally mild, with headache, asthenia, fatigue, and nausea most commonly reported. There were no discontinuations owing to adverse events (Hézode, 2015).

The AGATE-I trial randomized 120 treatment-naive and -experienced patients with genotype 4 infection and compensated cirrhosis to receive 12 weeks or 16 weeks of paritaprevir/ritonavir/ombitasvir 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 AGATE-II trial offered 100 treatment-naive and -experienced (interferon-based regimens) noncirrhotic patients with genotype 4 infection paritaprevir/ritonavir/ombitasvir plus weight-based ribavirin for 12 weeks. The SVR12 was 94%. These data support the use of a 12-week course of paritaprevir/ritonavir/ombitasvir plus ribavirin in treatment-experienced genotype 4 patients (Esmat, 2015).

Last update: 
September 21, 2017

Additional Reading:    HIV/HCV Coinfection    Renal Impairment    Acute Infection

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