Etsuko Iio1, Noritomo Shimada2, Hiroshi Abe3, Masanori Atsukawa4, Kai Yoshizawa5, Koichi Takaguchi6, Yuichiro Eguchi7, Hideyuki Nomura8, Tomoyuki Kuramitsu9, Jong-Hon Kang10, Takeshi Matsui10, Noboru Hirashima11, Akihito Tsubota12, Atsunori Kusakabe13, Izumi Hasegawa14, Tomokatsu Miyaki15, Noboru Shinkai1, Kei Fujiwara1, Shunsuke Nojiri1, Yasuhito Tanaka16. 1. Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan. 2. Ootakanomori Hospital, Kashiwa, Japan. 3. Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan. 4. Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan. 5. Machida Municipal Hospital, Tokyo, Japan. 6. Kagawa Prefectural Central Hospital, Takamatsu, Japan. 7. Saga University Hospital, Saga, Japan. 8. Shin-Kokura Hospital, Kitakyushu, Japan. 9. Kuramitsu Clinic, Akita, Japan. 10. Teine Keijinkai Hospital, Sapporo, Japan. 11. National Hospital Organization Nagoya Medical Center, Nagoya, Japan. 12. Jikei University School of Medicine, Tokyo, Japan. 13. Nagoya Red Cross Hospital, Nagoya, Japan. 14. Japan Community Health Care Organization, Chukyo Hospital, Nagoya, Japan. 15. Toyokawa City Hospital, Toyokawa, Japan. 16. Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan. ytanaka@med.nagoya-cu.ac.jp.
Abstract
BACKGROUND: The present study explored the treatment outcome of daclatasvir (DCV) and asunaprevir (ASV) therapy combining oral direct-acting antiviral agents (DAAs) for chronic hepatitis C (HCV) including liver cirrhosis according to resistance-associated variants (RAVs) in NS3/NS5A region. METHODS: Overall, 641 patients enrolled in Japan with HCV-1b received DCV and ASV for 24 weeks. Baseline drug-resistant mutations L31F/I/M/V, Q54H, P58S, A92K, and Y93H in the HCV NS5A region and V36A, T54A/S, Q80K/L/R, R155K/T/Q, A156S/V/T, and D168A/E/H/T/V in the HCV NS3/4A region were assessed by direct sequencing. RESULTS: Overall, 86.9 % (543/625) of patients had SVR12, which was significantly higher in NS5A 93Y (wild) (88.3 %) compared with NS5A 93H at baseline (48.0 %), indicating the SVR12 rate was significantly lower in patients with 93H mutations. Additionally, 66.7 % (18/27) of patients with prior triple therapy including simeprevir (SMV) failure had virological failure. The virological failure rate of DCV/ASV therapy after SMV failure was significantly higher in those with preexisting NS3/4A 168 substitutions compared with without substitutions at baseline [84.2 % (16/19) vs. 28.6 % (2/7), p = 0.014]. The number of patients with multiple RAVs or deletions in NS5A increased from 0 to 85 % in failed patients. Alanine aminotransferase elevation was a frequent adverse event causing discontinuation of DCV/ASV therapy, although 87.5 % (14/16) patients achieved SVR12, subsequently. CONCLUSIONS: History of SMV therapy and pre-existing NS5A Y93H were associated with virological failure of DCV/ASV therapy, resulting in the emergence of multiple RAVs. Patients with RAVs at baseline should be assessed to optimize future DAA therapies.
BACKGROUND: The present study explored the treatment outcome of daclatasvir (DCV) and asunaprevir (ASV) therapy combining oral direct-acting antiviral agents (DAAs) for chronic hepatitis C (HCV) including liver cirrhosis according to resistance-associated variants (RAVs) in NS3/NS5A region. METHODS: Overall, 641 patients enrolled in Japan with HCV-1b received DCV and ASV for 24 weeks. Baseline drug-resistant mutations L31F/I/M/V, Q54H, P58S, A92K, and Y93H in the HCV NS5A region and V36A, T54A/S, Q80K/L/R, R155K/T/Q, A156S/V/T, and D168A/E/H/T/V in the HCV NS3/4A region were assessed by direct sequencing. RESULTS: Overall, 86.9 % (543/625) of patients had SVR12, which was significantly higher in NS5A 93Y (wild) (88.3 %) compared with NS5A 93H at baseline (48.0 %), indicating the SVR12 rate was significantly lower in patients with 93H mutations. Additionally, 66.7 % (18/27) of patients with prior triple therapy including simeprevir (SMV) failure had virological failure. The virological failure rate of DCV/ASV therapy after SMV failure was significantly higher in those with preexisting NS3/4A 168 substitutions compared with without substitutions at baseline [84.2 % (16/19) vs. 28.6 % (2/7), p = 0.014]. The number of patients with multiple RAVs or deletions in NS5A increased from 0 to 85 % in failed patients. Alanine aminotransferase elevation was a frequent adverse event causing discontinuation of DCV/ASV therapy, although 87.5 % (14/16) patients achieved SVR12, subsequently. CONCLUSIONS: History of SMV therapy and pre-existing NS5A Y93H were associated with virological failure of DCV/ASV therapy, resulting in the emergence of multiple RAVs. Patients with RAVs at baseline should be assessed to optimize future DAA therapies.
Entities:
Keywords:
DCV/ASV; Direct acting antivirals; HCV; Resistance-associated variants; Simeprevir failure
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