Akito Nozaki1, Masanori Atsukawa2, Chisa Kondo2, Hidenori Toyoda3, Makoto Chuma4, Makoto Nakamuta5, Haruki Uojima6, Koichi Takaguchi7, Hiroki Ikeda8, Tsunamasa Watanabe8, Shintaro Ogawa9, Norio Itokawa10, Taeang Arai11, Atsushi Hiraoka12, Toru Asano13, Shinichi Fujioka14, Tadashi Ikegami15, Toshihide Shima16, Chikara Ogawa17, Takehiro Akahane18, Noritomo Shimada19, Shinya Fukunishi20, Hiroshi Abe21, Akihito Tsubota22, Takuya Genda23, Hironao Okubo24, Shigeru Mikami25, Asahiro Morishita26, Akio Moriya27, Joji Tani28, Yoshihiko Tachi29, Naoki Hotta30, Toru Ishikawa31, Takeshi Okanoue16, Yasuhito Tanaka9, Takashi Kumada3, Katsuhiko Iwakiri2, Shin Maeda4,32. 1. Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024, Japan. akino@yokohama-cu.ac.jp. 2. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan. 3. Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan. 4. Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024, Japan. 5. National Hospital Organization Kyushu Medical Center, Fukuoka, Japan. 6. Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan. 7. Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan. 8. Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan. 9. Department of Virology and Liver Unit, Nagoya City University, Graduate School of Medical Sciences, Aichi, Japan. 10. Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan. 11. Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Musashikosugi Hospital, Kawasaki, Japan. 12. Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan. 13. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan. 14. Department of Gastroenterology, Okayama Saiseikai General Hospital, Okayama, Japan. 15. Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan. 16. Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita, Japan. 17. Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Japan. 18. Department of Gastroenterology, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Japan. 19. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Otakanomori Hospital, Kashiwa, Japan. 20. Second Department of Internal Medicine, Osaka Medical College, Osaka, Japan. 21. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shinmatsudo Central General Hospital, Matsudo, Japan. 22. Core Research Facilities for Basic Science, The Jikei University School of Medicine, Tokyo, Japan. 23. Department of Gastroenterology, Juntendo Shizuoka University Hospital, Shizuoka, Japan. 24. Department of Gastroenterology, Juntendo Nerima University Hospital, Tokyo, Japan. 25. Division of Gastroenterology, Department of Internal Medicine, Kikkoman General Hospital, Noda, Japan. 26. Department of Gastroenterology, Kagawa University Graduate School of Medicine, Kagawa, Japan. 27. Department of Gastroenterology, Mitoyo General Hospital, Kannonji, Japan. 28. Department of Internal Medicine, Yashima General Hospital, Takamatsu, Japan. 29. Bantane Hospital, Fujita Health University School of Medicine, Nagoya, Japan. 30. Division of Hepatology, Department of Internal Medicine, Masuko Memorial Hospital, Nagoya, Japan. 31. Department of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Japan. 32. Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Abstract
BACKGROUND: Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment. METHODS: In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed. RESULTS: Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naïve patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 × 10-5; genotype 2 vs. 3, p = 3.28 × 10-5) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1-3 (99.1% [1209/1220]) and chronic kidney disease (CKD) stage 4-5 (98.9% [188/190]) patients, or between cirrhotic (99.0% [398/402]) and non-cirrhotic (99.1% [999/1008]) patients. Multiple logistic regression analysis revealed that genotype 3 [OR 33.404, 95% CI (7.512-148.550), p value (p = 4.06 × 10-5)] and past experience of IFN-free DAAs [OR 3.977, 95% CI (1.153-13.725), p value (p = 0.029)] were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4-5 (41.6% [79/190]) than CKD stage 1-3 (26.1% [319/1220]) patients (p = 2.00 × 10-5). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 × 10-18) patients. CONCLUSIONS: G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.
BACKGROUND: Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment. METHODS: In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed. RESULTS: Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naïve patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 × 10-5; genotype 2 vs. 3, p = 3.28 × 10-5) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1-3 (99.1% [1209/1220]) and chronic kidney disease (CKD) stage 4-5 (98.9% [188/190]) patients, or between cirrhotic (99.0% [398/402]) and non-cirrhotic (99.1% [999/1008]) patients. Multiple logistic regression analysis revealed that genotype 3 [OR 33.404, 95% CI (7.512-148.550), p value (p = 4.06 × 10-5)] and past experience of IFN-free DAAs [OR 3.977, 95% CI (1.153-13.725), p value (p = 0.029)] were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4-5 (41.6% [79/190]) than CKD stage 1-3 (26.1% [319/1220]) patients (p = 2.00 × 10-5). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 × 10-18) patients. CONCLUSIONS: G/P regimen is highly effective and safe to treat CHCpatients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.
Authors: O Ohno; M Mizokami; R R Wu; M G Saleh; K Ohba; E Orito; M Mukaide; R Williams; J Y Lau Journal: J Clin Microbiol Date: 1997-01 Impact factor: 5.948
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Authors: Cas J Isfordink; Thijs J W van de Laar; Sjoerd P H Rebers; Els Wessels; Richard Molenkamp; Marjolein Knoester; Bert C Baak; Cees van Nieuwkoop; Bart van Hoek; Sylvia M Brakenhoff; Hans Blokzijl; Joop E Arends; Marc van der Valk; Janke Schinkel Journal: Open Forum Infect Dis Date: 2021-01-06 Impact factor: 3.835