Daclatasvir/Asunaprevir併用療法におけるウイルス学的治療効果とPCR-Invader法による薬剤耐性変異測定値との関連性

抄録

Daclatasvir and asunaprevir is the first all-oral therapy approved in Japan for treating chronic hepatitis C patients with HCV genotype 1b infection. In the phase 3 clinical trial, the dual combination therapy has demonstrated high sustained virologic response (SVR) rates across subgroups based on baseline characteristics (age, gender, IL28B genotype, HCV-RNA load and cirrhotic), however, resistance-associated variant (RAV) s at D168 in NS3 region and at L31/Y93 in NS5A region affected the efficacy. This study evaluated correlation between efficacy of the daclatasvir/asunaprevir combination therapy and HCV NS3/NS5A RAVs detected by PCR-Invader assay for 129 patients enrolled in the phase 2 and 3 trials. The RAVs were determined as negative (<1%), weak positive (1-20%) and positive (20%≤) by signal strength of invader reaction. The incidence rates of D168, L31 and Y93 RAVs by PCR-Invader assay were higher than those by direct sequencing. Especially, D168 RAVs were observed at much higher rate than direct sequencing (28.3% vs 1.6%). SVR rates were 84-95% and 75-88% for D168 or Y93H RAVs negative and weak positive groups, respectively. They were comparative to those in the phase 3 trial. Moreover, SVR rates for D168 RAVs negative and weak positive patients without NS5A L31/Y93 RAVs were 97% and 100%. In Y93H positive cases with direct sequencing or PCR-Invader assay, SVR rates were decreased down to SVR 46-48%. Minor RAVs detected at low level by PCR-Invader assay have less impact on the efficacy with the daclatasvir/asunaprevir treatment.