Treatment-Naive Genotype 3 Without Cirrhosis

Recommended and alternative regimens listed alphabetically for:

Treatment-Naive Genotype 3 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
ALTERNATIVE DURATION RATING
Daily daclatasvir (60 mg)b plus sofosbuvir (400 mg) 12 weeks I, A
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.

 

Recommended Regimens

Glecaprevir/Pibrentasvir

ENDURANCE-3 was a randomized (2:1) trial comparing 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, to 12 weeks of sofosbuvir (400 mg) and daclatasvir (60 mg) among 348 treatment-naive participants with genotype 3 infection without cirrhosis. The trial was later amended to include an open-label arm that evaluated glecaprevir/pibrentasvir for an 8-week duration among 157 treatment-naive participants with genotype 3 infection without cirrhosis. Participants receiving glecaprevir/pibrentasvir for 8 or 12 weeks achieved an SVR12 rate of 95% in an intention-to-treat analysis (222/233 participants receiving the 12-week regimen; 149/157 participants receiving the 8-week regimen). Virologic failure was observed in 6 participants receiving the 8-week regimen (1 virologic breakthrough; 5 relapses) and in 4 participants in the 12-week arm (1 virologic breakthrough; 3 relapses). Both the 8- and 12-week glecaprevir/pibrentasvir regimens met noninferiority criteria for SVR12 compared to the standard of care arm of sofosbuvir/daclatasvir, which reported an SVR12 rate of 97%. Baseline RASs did not influence SVR12 rates. These data support an 8-week regimen of glecaprevir/pibrentasvir for the treatment of genotype 3-infected patients who are treatment-naive without cirrhosis.

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 3 infection in patients without cirrhosis or with compensated cirrhosis. ASTRAL-3 demonstrated superiority of 12 weeks of sofosbuvir/velpatasvir to 24 weeks sofosbuvir plus ribavirin in 552 treatment-naive and -experienced patients without cirrhosis or with compensated cirrhosis (Foster, 2015a). Among treatment-naive, noncirrhotic patients, SVR12 rates were 98% (160/163) for sofosbuvir/velpatasvir compared to 90% (141/156) for sofosbuvir plus ribavirin. Among patients with compensated cirrhosis, SVR12 was 93% (40/43) for sofosbuvir/velpatasvir compared to 73% (33/45) for sofosbuvir plus ribavirin. Of the 250 participants who received sofosbuvir/velpatasvir, 43 (16%) had baseline NS5A RASs, of which 88% achieved SVR12 compared to 97% without baseline RASs. Eighty-four percent (21/25) with Y93H achieved SVR12. Pending further data on optimal therapy in the setting of a baseline Y93 substitution, the addition of ribavirin is recommended for patients with cirrhosis.

The phase 3 POLARIS-2 study evaluated 12 weeks of sofosbuvir/velpatasvir in genotype 3-infected, noncirrhotic patients who were either treatment-naive or interferon-experienced. Eighty-nine genotype 3 patients received the sofosbuvir/velpatasvir regimen and 97% achieved SVR12 (86/89). There were no virologic failures. This confirms the efficacy of sofosbuvir/velpatasvir in genotype 3-infected patients without cirrhosis.
 

Alternative Regimen

Daclatasvir + Sofosbuvir

Daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks was approved by the FDA for the treatment of genotype 3 infection. The recommendation is based on ALLY-3, a phase 3 study of the once-daily NS5A inhibitor daclatasvir plus sofosbuvir for 12 weeks among genotype 3-infected, treatment-naive or -experienced (interferon ± ribavirin, sofosbuvir plus ribavirin, or other anti-HCV agents) patients. The study included 101 treatment-naive patients and demonstrated an SVR12 rate of 90%. Among treatment-naive patients without cirrhosis (Metavir F0-F3), 97% achieved SVR12; in treatment-naive patients with compensated cirrhosis (Metavir F4), 58% achieved SVR12 (Nelson, 2015). This suggests that patients with genotype 3 infection and compensated cirrhosis are likely to benefit from an extension of therapy. 

Baseline NS5A RASs significantly reduce SVR12 rates with a 12-week course of daclatasvir/sofosbuvir in genotype 3-infected patients. In an analysis of 175 genotype 3-infected patients with nucleotide sequence data from the ALLY-3 trial, the presence of a NS5A Y93H was associated with a reduced SVR12 rate; 54% (7/13) in those with the substitution compared to 92% (149/162) in those without it. Although the small numbers make interpretation difficult, only 7% of participants (13/175) had NS5A Y93H, all of which were subtype 3a. SVR rates were numerically lower among those with both cirrhosis and Y93H. In noncirrhotic patients with Y93H, 67% (6/9) achieved SVR12 compared to 98% (125/128) among noncirrhotics without Y93H. In those with both cirrhosis and Y93H, 25% (1/4) achieved SVR12 compared to 71% (24/34) in those with cirrhosis but without the Y93H substitution (Daklinza PI).

Substitutions A30K, L31F, L31I in the genotype 3a replicon are associated with reduced daclatasvir susceptibility (Daklinza PI). In the ALLY-3 trial, participants with A30K and without cirrhosis achieved 100% SVR12 (9/9); those with compensated cirrhosis had lower SVR12 rates (1/5); (Nelson, 2015). The impact of this single substitution is difficult to discern as 2/5 patients had compound substitutions with Y93H. Pending further data on optimal therapy, the addition of ribavirin for patients with cirrhosis is recommended in the setting of a baseline Y93 substitution.

ENDURANCE-3 was a randomized (2:1) trial comparing 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, to 12 weeks of daclatasvir/sofosbuvir among 348 treatment-naive participants with genotype 3 infection without cirrhosis. In the 115 patients randomized to daclatasvir/sofosbuvir, 97% achieved SVR12, and 20 of 21 participants (95%) with baseline NS5A RAS achieved SVR.​

Last update: 
September 21, 2017

Additional Reading:    HIV/HCV Coinfection    Renal Impairment    Acute Infection

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