AT DDW 2015
WASHINGTON (FRONTLINE MEDICAL NEWS) – An investigational once-daily antiviral drug combination produced high rates of sustained viral responses after 12 or 16 weeks of therapy – with or without ribavirin – in patients with chronic hepatitis viral infections for whom prior therapy with peg-interferon and ribavirin had failed, investigators reported.
The rate of sustained viral responses at 12 weeks after the end of treatment (SVR12) was 92% for patients who received the combination of grazoprevir and elbasvir (GZR/EBR, Merck) alone, compared with 94% for patients who received the antivirals plus ribavirin, reported Dr. Paul Kwo of Indiana University Hospital in Indianapolis.
Among patients who received 16 weeks of therapy, the SVR12 rates were 92% without ribavirin, and 97% with ribavirin, Dr. Kwo said at the annual Digestive Disease Week.
“In patients who have failed peg-interferon and ribavirin therapy, 12 weeks of grazoprevir and elbasvir without ribavirin gives outstanding SVR rates in genotype 1b-infected individuals, regardless of treatment response, including those with cirrhosis. If you’re a relapser with genotype 1a or genotype 4 infection, 12 weeks of grazoprevir and elbasvir gives outstanding SVR rates. For genotype 1a, 4 and 6 prior null and partial responders, including those with cirrhosis, 16 weeks of grazoprevir and elbasvir with ribavirin gives outstanding SVR rates with no virologic failures,” he said.
Dr. Kwo presented updated results from the C-EDGE (Study of Efficacy and Safety of Grazoprevir (MK-5172)/Elbasvir (MK-8742) Combination Regimen for Treatment-Naive Participants With Chronic Hepatitis C Virus Genotypes 1, 4, and 6) treatment-experienced trial.
The 12-week C-EDGE results in 316 treatment-naive patients were presented earlier this year in Vienna at the International Liver Congress.
The fixed-dose, once-daily combination is composed of grazoprevir, an inhibitor of the HCV NS3/4a protease, at a dose of 100 mg, and elbasvir, a potent inhibitor of the NS5a protein, at a dose of 50 mg. This combination was shown to have broad activity against most HCV genotypes in vitro, and was efficacious in both treatment-naive and treatment-experienced patients with and without cirrhosis, including those with HIV/HCV coinfections, in the C-WORTHY trial .
The C-EDGE study was a phase III trial of GZR/EBR with or without ribavirin for 12 or 16 weeks for patients for whom prior therapy with peg-interferon and ribavirin had failed because of either null or partial response or viral relapse. The trial included patients with and without cirrhosis, those with HCV genotypes 1, 4, or 6, and those with either HCV mono-infections or HIV coinfections.
A total of 420 patients were enrolled.
As noted before, 97 of 105 patients (92%) on 12 weeks of therapy without ribavirin had an SVR12, although two patients in this group were lost to follow-up or discontinued therapy for reasons other than virologic failure (included as nonresponders). Among patients who received 12 weeks of GZR/EBR plus ribavirin, 98 of 104 (94%) had an SVR12, with no losses to follow-up.
For those patients treated for 16 weeks, 97 of 105 (92%) without ribavirin had an SVR12, compared with 103 of 106 (97%) who received ribavirin in addition to the combination antivirals. In these groups, one and three patients, respectively, were lost to follow-up.
In a subanalysis by HCV genotype or subtype, the combination alone was least effective among patients with genotype 4 treated for 16 weeks, with 3 of 5 patients (60%) having an SVR12, compared with 7 of 9 patients (79%) with genotype 4 treated with no ribavirin for 12 weeks, 14 of 15 (93%) with ribavirin for 12 weeks, and 8 of 8 (100%) treated with ribavirin for 16 weeks. The overall numbers of patients in each subgroup was too small for statistical significance analysis, however.
Among patients with HCV coinfection, the SVR12 rate was 100% in all treatment arms except 16 weeks GZR/EBR without ribavirin (5 of 6; 83%).
A subanalysis by prior response, excluding the 12 total patients who did not complete treatment, showed excellent SVR12 rates in all four treatment arms among patients with a prior relapse, and slightly less robust but still high rates among prior partial or null responders, Dr. Kwo said.
Patients tolerated the regimen well, with the rates of serious adverse events ranging from 2.9% to 3.8%. There were no deaths, and seven discontinuations due to adverse events (one in each in the 12-week arms, and five in the 16-week with ribavirin arm). A total of 31 patients who received ribavirin had hemoglobin reductions below 10 g/dL, and 60 reported fatigue, both common with ribavirin. The majority of adverse events in all arms were fatigue, headache, and nausea.
The combination has received two Breakthrough Therapy designations from the Food and Drug Administration for patients with HCV genotype 4, and for patients with genotype 1 infections who are on hemodialysis for end stage renal disease. The breakthrough designation makes the drug eligible for expedited review.
Dr. Kwo disclosed ties with Merck, which supported the C-EDGE study.
