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Triple-DAA Combo (a Possible 3-in-1 Pill) Yields SVRs Over 90% After 12 Weeks
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CROI 2014, March 3-6, 2014, Boston
CROI: All-Oral Combination of Daclatasvir, Asunaprevir, and BMS-791325 for HCV Genotype 1 Infection - (03/04/14)
Mark Mascolini
Twelve weeks of a regimen containing three direct-acting antivirals (DAAs) that may become the first anti-HCV triple coformulation produced sustained virologic response rates above 90% through 12 weeks after treatment ended (SVR12) [1]. The 166-person study had 11 virologic failures (6.6%), all in people with HCV genotype 1a.
The combination includes daclatasvir (an NS5A replication complex inhibitor), asunaprevir (an NS3 protease inhibitor), and BMS-791325 (a nonnucleoside NS5B polymerase inhibitor). Because the three-drug regimen produced high SVR12s in HCV-infected people without cirrhosis, researchers extended that study to include patients with cirrhosis. Although daclatasvir can be dosed once daily, all three drugs were given twice daily in this trial, with an eye toward a developing a twice-daily fixed-dose triple combination. The primary endpoint was SVR12 with response determined by an assay that has a lower limit of 25 IU/mL.
The only difference between the two study arms was the dose of BMS-791325, 75 or 150 mg. Eighty people got randomized to 75 mg and 86 to 150 mg. All 166 study participants were treatment naive and had genotype 1 infection. Most participants were white (83%), men (67%), and had the GT1a genotype (82%) and an IL28B non-CC genotype (67%). Only 9% of participants had cirrhosis, 10% in the 75-mg arm and 8% in the 150-mg arm. Age averaged about 55.
At the end of treatment, 97.5% in the 75-mg arm and 94.2% in the 150-mg arm had an undetectable HCV load. Overall SVR12 (an undetectable load 12 weeks after treatment stopped) stood at 92.2% in the 75-mg group and 91.7% in the 150-mg group. The investigators counted 11 virologic failures, 6 in the 75-mg arm and 5 in the 150-mg arm. Failures included 2 on-treatment breakthroughs and 4 relapses before week 4 in the 75-mg group and 3 breakthroughs and 2 relapses in the 150-mg group.
Everyone with virologic failure had genotype 1a. But SVR12s were 91% for 1a-infected people in both treatment arms. SVR12s were 100% for genotype 1b patients taking the lower dose of BMS-791325 and 94% in those taking the higher dose. Among people with cirrhosis, SVR12s were 100% in the 75-mg arm and 71% in the 150-mg arm, but the study included few cirrhotics. SVR12 varied little by study arm in people with an IL28B CC genotype or a non-CC genotype.
While 2 people in the 75-mg group discontinued treatment, 6 in the 150-mg group discontinued. But only 1 person in each group discontinued because of adverse events. No one taking 75 mg of BMS-791325 stopped treatment for lack of efficacy, compared with 3 people taking 150 mg. Poor adherence explained 1 discontinuation in the 150-mg arm and none in the 75-mg arm.
Serious adverse event rates were 1.3% with 75 mg of BMS-791325 and 2.3% with 150 mg. Respective discontinuations for adverse events were 1.3% and 1.2%. No one in the 75-mg arm and 1 in the 150-mg arm had a grade 3 or 4 adverse event. Headache was the most frequent adverse event, affecting about 25% of participants.
Two phase 3 trials of the triple fixed-dose combination, UNITY 1 and UNITY 2, are fully enrolled (clinicaltrials.gov identifiers NCT01979939 and NCT01973049). UNITY 1 excludes people with cirrhosis and UNITY 2 includes people with compensated cirrhosis who may be randomized to add ribavirin to the triple pill.
Reference
1. Everson GT, Thuluvath PJ, Lawitz E, et al. All-oral combination of daclatasvir, asunaprevir, and BMS-791325 for HCV genotype 1 infection. CROI 2014. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 25.
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