WASHINGTON — A fixed-dose combination of grazoprevir/elbasvir (Merck) given for 12 to 16 weeks with or without ribavirin yielded sustained virologic response rates ranging from 89% to 100% in a cohort of patients with cirrhosis and genotypes 1, 4 and 6, according to findings presented here.
Paul Y. Kwo, MD, of Indiana University in Indianapolis, Indiana, and colleagues evaluated the efficacy and safety of grazoprevir 100 mg and elbasvir 50 mg in a fixed-dose combination with or without twice-daily ribavirin in cirrhotic or non-cirrhotic patients with genotype 1, 4 or 6 disease. Prior non-responders, including partial and null responders as well as relapsers, were included in the study along with those coinfected with HIV.
Paul Y. Kwo
The analysis included 105 patients treated for 12 weeks without ribavirin; 104 patients treated for 12 weeks with ribavirin; 105 patients treated for 16 weeks without ribavirin; and 106 patients treated for 16 weeks with ribavirin.
“Patients were stratified according to cirrhosis status and prior experience with peginterferon and ribavirin,” Kwo said. He added that all races were well represented in the trial.
Overall SVR12 rates were 92% in the 12-week arm without ribavirin, 94% in the 12-week arm with ribavirin, 92% for the 16-week arm without ribavirin and 97% for the 16-week arm with ribavirin.
For genotype 1a disease, SVR12 rates were 90% without ribavirin for 12 weeks, 93% for 12 weeks with ribavirin, 94% for the non-ribavirin 16-week arm and 95% for the ribavirin 16-week arm. One hundred percent SVR12 rates were reported for two groups of genotype 1b patients (12 weeks without ribavirin, 16 weeks with ribavirin) and greater than 94% for the other two groups.
Responses in genotype 4 disease were slightly lower, with 78% of those in the 12-week, non-ribavirin arm responding; 93% of those in the 12-week ribavirin arm responding; 80% of 16-week non-ribavirin patients but 100% of those treated for 16 weeks with ribavirin.
Responses ranged from 87% to 98% for prior null responders and from 95% to 100% for partial responders and previous treatment relapsers.
In a subgroup analysis, the lowest sustained response rate in cirrhotics was 89% (12 weeks with ribavirin) with the 16 week arm with ribavirin achieving a 100% sustained response rate in cirrhotic patients. All other responses in patients with cirrhosis were higher than 90%.
“The SVR rates are outstanding across all treatment arms, with or without cirrhosis for relapsers , regardless of genotype or severity of fibrosis,” Kwo said. “SVR rates also were no different for white patients compared with African Americans.”
Fatigue was reported in 23% of patients, while headache occurred in 20% and nausea occurred in 11%. “The regimen was well tolerated,” Kwo said. “The SAE rate was very low. Discontinuation was uncommon and not related to therapy.”
In an analysis of resistance associated variants (RAVs) present prior to initiation of therapy, 50% of patients with genotype 1a disease had low level natural RAVs to grazoprevir that conferred a less than five-fold reduction in potency to grazoprevir and the presence of these RAVs did not affect SVR rates, according to Kwo.
For the NS5a domain, the findings were different. There was a much lower prevalence of naturally occurring RAVs to the NS5A domain with 4% of the genotype 1a cohort having low level RAVs to elbasvir that conferred a less than five-fold reduction in potency to elbasvir and 9% of the genotype 1a cohort having RAVS that conferred a greater than 5 fold reduction in potency to elbasvir.
“SVR12 rates were 99% or 100% in patients with no NS5A RAVs or low-level RAVs,” he said. But with high level NS5A RAVs, the SVR rate was 52%,” he said. “When the treatment arms were examined, the 16 week treatment arm with ribavirin achieved a 100% SVR rate in those with high level NS5A RAVs implying that if these high level NS5A RAVs are present, it will be the 16 week duration with ribavirin that will allow successful completion of therapy with no reduction in sustained response rates. This is important because if you relapse, you generally produce new RAVs with higher level of variants in either the NS3 or NS5A domains.”
For more information:
Kwo P, et al. Abstract 901f. Presented at: Digestive Disease Week, May 16-19, 2015; Washington, D.C.
Disclosure: Kwo reports associations with a number of device and pharmaceutical companies. Please see the DDW faculty disclosure index for all other researchers’ relevant financial disclosures.
Editor's note: This article has been updated on May 26, 2015, with clarifications from the presenter.