Seiichi Mawatari1, Kohei Oda2, Kazuaki Tabu2, Sho Ijuin2, Kotaro Kumagai2, Yukiko Inada3, Hirofumi Uto2,3, Yasunari Hiramine4, Takeshi Kure2,4, Kunio Fujisaki5, Masafumi Hashiguchi2,5, Takeshi Hori6, Akihiko Oshige2,6, Dai Imanaka2,7, Akiko Saishoji2,8, Oki Taniyama2, Haruka Sakae2, Tsutomu Tamai2, Akihiro Moriuchi2, Akio Ido2. 1. Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan. mawatari@m2.kufm.kagoshima-u.ac.jp. 2. Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan. 3. Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, 2-16 Takamatsu-cho, Miyazaki, 880-0003, Japan. 4. Department of Internal Medicine, Kagoshima Kouseiren Hospital, 22-25 Tenpozan-cho, Kagoshima, 890-0061, Japan. 5. Department of Hepatology, Kirishima Medical Center, 3320 Hayato-cho, Kirishima, Kagoshima, 899-5112, Japan. 6. Department of Gastroenterology and Hepatology, Kagoshima City Hospital, 37-1 Uearata-cho, Kagoshima, 890-8760, Japan. 7. Department of Gastroenteroloby, Ikeda Hospital, 1830 Shimoharaigawa-cho, Kanoya, Kagoshima, 893-0024, Japan. 8. Department of Hepatology, Kagoshima Teishin Hospital, 1-12-1 Shimoishiki, Kagoshima, 890-8798, Japan.
Abstract
BACKGROUND: Daclatasvir (DCV) and asunaprevir (ASV) combination therapy has been primarily used in patients without NS5A L31 or Y93 resistance-associated substitutions (RASs) before treatment. We examined the characteristics of patients without these baseline RASs who did not achieve hepatitis C virus eradication with DCV and ASV combination therapy and identified new baseline NS5A RASs that are closely associated with failure of combination therapy. METHODS: Three hundred thirty-five patients with hepatitis C virus genotype 1 infection with no NS5A L31, NS5A Y93, and NS3 D168 RASs before DCV and ASV combination therapy and no history of protease inhibitor therapy were enrolled. All RASs were evaluated by direct sequencing. RESULTS: Sustained virologic response at 12 weeks (SVR12) was achieved in 297 patients (89%). Patients with NS5A Q24, L28, and/or R30 RASs or concomitant NS5A F37 and Q54 RASs had a significantly lower SVR12 rate than patients without these RASs (70% vs 92%, p < 0.001 and 79% vs 92%, p = 0.002 respectively). Multivariate analysis showed that NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs were significantly associated with virologic failure. The SVR12 rate in patients without NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs was 96.2% (202/210). CONCLUSIONS: In patients without NS5A L31 or Y93 RASs, the presence of NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs at the baseline was associated with failure of DCV and ASV combination therapy. The coexistence of baseline RASs other than NS5A L31 and Y93 may affect the therapeutic effectiveness of DCV and ASV combination therapy.
BACKGROUND: Daclatasvir (DCV) and asunaprevir (ASV) combination therapy has been primarily used in patients without NS5A L31 or Y93 resistance-associated substitutions (RASs) before treatment. We examined the characteristics of patients without these baseline RASs who did not achieve hepatitis C virus eradication with DCV and ASV combination therapy and identified new baseline NS5A RASs that are closely associated with failure of combination therapy. METHODS: Three hundred thirty-five patients with hepatitis C virus genotype 1 infection with no NS5A L31, NS5A Y93, and NS3 D168 RASs before DCV and ASV combination therapy and no history of protease inhibitor therapy were enrolled. All RASs were evaluated by direct sequencing. RESULTS: Sustained virologic response at 12 weeks (SVR12) was achieved in 297 patients (89%). Patients with NS5A Q24, L28, and/or R30 RASs or concomitant NS5A F37 and Q54 RASs had a significantly lower SVR12 rate than patients without these RASs (70% vs 92%, p < 0.001 and 79% vs 92%, p = 0.002 respectively). Multivariate analysis showed that NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs were significantly associated with virologic failure. The SVR12 rate in patients without NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs was 96.2% (202/210). CONCLUSIONS: In patients without NS5A L31 or Y93 RASs, the presence of NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs at the baseline was associated with failure of DCV and ASV combination therapy. The coexistence of baseline RASs other than NS5A L31 and Y93 may affect the therapeutic effectiveness of DCV and ASV combination therapy.
Entities:
Keywords:
Asunaprevir; Daclatasvir; Hepatitis C virus; NS5A resistance-associated substitutions
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