Effectiveness of Glecaprevir/Pibrentasvir for Hepatitis C: Real-World Experience and Clinical Features of Retreatment Cases
Abstract
:1. Introduction
2. Methods
2.1. Patients and Methods
2.2. Laboratory Testing
2.3. Testing for RAS of the HCV-RNA Genome
2.4. Statistical Analysis
3. Results
3.1. Baseline Clinical Characteristics
3.2. G/P Outcomes
3.3. Comparisons between First Treatment and Retreatment Groups
3.4. RASs in HCV-RNA Genome in Retreatment Cases
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Kiyosawa, K.; Sodeyama, T.; Tanaka, E.; Gibo, Y.; Yoshizawa, K.; Nakano, Y.; Furuta, S.; Akahane, Y.; Nishioka, K.; Purcell, R.H.; et al. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: Analysis by detection of antibody to hepatitis C virus. Hepatology 1990, 12, 671–675. [Google Scholar] [CrossRef] [PubMed]
- Kiyosawa, K.; Tanaka, E.; Sodeyama, T.; Furuta, S. Natural History of Hepatitis C. Intervirology 1994, 37, 101–107. [Google Scholar] [CrossRef] [PubMed]
- Tanaka, E.; Kiyosawa, K. Natural history of acute hepatitis C. J. Gastroenterol. Hepatol. 2000, 15, E97–E104. [Google Scholar] [CrossRef] [PubMed]
- Kiyosawa, K.; Umemura, T.; Ichijo, T.; Matsumoto, A.; Yoshizawa, K.; Gad, A.; Tanaka, E. Hepatocellular carcinoma: Recent trends in Japan. Gastroenterology 2004, 127, S17–S26. [Google Scholar] [CrossRef]
- D’Ambrosio, R.; Pasulo, L.; Puoti, M.; Vinci, M.; Schiavini, M.; Lazzaroni, S.; Soria, A.; Gatti, F.; Menzaghi, B.; Aghemo, A.; et al. Real-world effectiveness and safety of glecaprevir/pibrentasvir in 723 patients with chronic hepatitis C. J. Hepatol. 2019, 70, 379–387. [Google Scholar] [CrossRef]
- Ogawa, E.; Furusyo, N.; Nakamuta, M.; Nomura, H.; Satoh, T.; Takahashi, K.; Koyanagi, T.; Kajiwara, E.; Dohmen, K.; Kawano, A.; et al. Glecaprevir and pibrentasvir for Japanese patients with chronic hepatitis C genotype 1 or 2 infection: Results from a multicenter, real-world cohort study. Hepatol. Res. 2019, 49, 617–626. [Google Scholar] [CrossRef]
- Sezaki, H.; Suzuki, F.; Hosaka, T.; Fujiyama, S.; Kawamura, Y.; Akuta, N.; Kobayashi, M.; Suzuki, Y.; Saitoh, S.; Arase, Y.; et al. Initial- and re-treatment effectiveness of glecaprevir and pibrentasvir for Japanese patients with chronic hepatitis C virus-genotype 1/2/3 infections. J. Gastroenterol. 2019, 54, 916–927. [Google Scholar] [CrossRef]
- Toyoda, H.; Atsukawa, M.; Uojima, H.; Nozaki, A.; Tamai, H.; Takaguchi, K.; Fujioka, S.; Nakamuta, M.; Tada, T.; Yasuda, S.; et al. Trends and Efficacy of Interferon-Free Anti-hepatitis C Virus Therapy in the Region of High Prevalence of Elderly Patients, Cirrhosis, and Hepatocellular Carcinoma: A Real-World, Nationwide, Multicenter Study of 10 688 Patients in Japan. Open Forum Infect. Dis. 2019, 6, ofz185. [Google Scholar] [CrossRef] [Green Version]
- Asahina, Y.; Izumi, N.; Hiromitsu, K.; Kurosaki, M.; Koike, K.; Suzuki, F.; Takikawa, H.; Tanaka, A.; Tanaka, E.; Tanaka, Y.; et al. JSH Guidelines for the Management of Hepatitis C Virus Infection: A 2016 update for genotype 1 and 2. Hepatol. Res. 2016, 46, 129–165. [Google Scholar] [CrossRef] [Green Version]
- Vallet-Pichard, A.; Mallet, V.; Nalpas, B.; Verkarre, V.; Nalpas, A.; Dhalluin-Venier, V.; Fontaine, H.; Pol, S. FIB-4: An inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and fibrotest. Hepatology 2007, 46, 32–36. [Google Scholar] [CrossRef]
- Castera, L.; Vergniol, J.; Foucher, J.; Le Bail, B.; Chanteloup, E.; Haaser, M.; Darriet, M.; Couzigou, P.; De Ledinghen, V. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005, 128, 343–350. [Google Scholar] [CrossRef] [PubMed]
- Suzuki, F.; Sezaki, H.; Akuta, N.; Suzuki, Y.; Seko, Y.; Kawamura, Y.; Hosaka, T.; Kobayashi, M.; Saito, S.; Arase, Y.; et al. Prevalence of hepatitis C virus variants resistant to NS3 protease inhibitors or the NS5A inhibitor (BMS-790052) in hepatitis patients with genotype 1b. J. Clin. Virol. 2012, 54, 352–354. [Google Scholar] [CrossRef] [PubMed]
- Kanda, T.; Yasui, S.; Nakamura, M.; Suzuki, E.; Arai, M.; Haga, Y.; Sasaki, R.; Wu, S.; Nakamoto, S.; Imazeki, F.; et al. Daclatasvir plus Asunaprevir Treatment for Real-World HCV Genotype 1-Infected Patients in Japan. Int. J. Med. Sci. 2016, 13, 418–423. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Miura, M.; Maekawa, S.; Sato, M.; Komatsu, N.; Tatsumi, A.; Takano, S.; Amemiya, F.; Nakayama, Y.; Inoue, T.; Sakamoto, M.; et al. Deep sequencing analysis of variants resistant to the non-structural 5A inhibitor daclatasvir in patients with genotype 1b hepatitis C virus infection. Hepatol. Res. 2014, 44, E360–E367. [Google Scholar] [CrossRef] [Green Version]
- Goossens, N.; Negro, F. Is genotype 3 of the hepatitis C virus the new villain? Hepatology 2014, 59, 2403–2412. [Google Scholar] [CrossRef] [Green Version]
- Zeuzem, S.; Foster, G.R.; Wang, S.; Asatryan, A.; Gane, E.; Feld, J.J.; Asselah, T.; Bourliere, M.; Ruane, P.J.; Wedemeyer, H.; et al. Glecaprevir-Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection. N. Engl. J. Med. 2018, 378, 354–369. [Google Scholar] [CrossRef] [PubMed]
- Kumada, H.; Watanabe, T.; Suzuki, F.; Ikeda, K.; Sato, K.; Toyoda, H.; Atsukawa, M.; Ido, A.; Takaki, A.; Enomoto, N.; et al. Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience, severe renal impairment, or genotype 3 infection. J. Gastroenterol. 2017, 53, 566–575. [Google Scholar] [CrossRef]
- Sugiura, A.; Joshita, S.; Umemura, T.; Yamazaki, T.; Fujimori, N.; Kimura, T.; Matsumoto, A.; Igarashi, K.; Usami, Y.; Wada, S.; et al. Past history of hepatocellular carcinoma is an independent risk factor of treatment failure in patients with chronic hepatitis C virus infection receiving direct-acting antivirals. J. Viral Hepat. 2018, 25, 1462–1471. [Google Scholar] [CrossRef]
- Reddy, K.R.; Lim, J.K.; Kuo, A.; Di Bisceglie, A.M.; Galati, J.S.; Morelli, G.; Everson, G.T.; Kwo, P.Y.; Brown, R.S.J.; Sulkowski, M.S.; et al. All-oral direct-acting antiviral therapy in HCV-advanced liver disease is effective in real-world practice: Observations through HCV-TARGET database. Aliment. Pharmacol. Ther. 2017, 45, 115–126. [Google Scholar] [CrossRef]
- Zeuzem, S.; Dusheiko, G.M.; Salupere, R.; Mangia, A.; Flisiak, R.; Hyland, R.H.; Illeperuma, A.; Svarovskaia, E.; Brainard, D.M.; Symonds, W.T.; et al. Sofosbuvir and Ribavirin in HCV Genotypes 2 and 3. N. Engl. J. Med. 2014, 370, 1993–2001. [Google Scholar] [CrossRef] [Green Version]
- Probst, A.; Dang, T.; Bochud, M.; Egger, M.; Negro, F.; Bochud, P.-Y. Role of Hepatitis C virus genotype 3 in liver fibrosis progression—A systematic review and meta-analysis. J. Viral Hepat. 2011, 18, 745–759. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lemm, J.A.; O’Boyle, D.; Liu, M.; Nower, P.T.; Colonno, R.; Deshpande, M.S.; Snyder, L.B.; Martin, S.W.; St Laurent, D.R.; Serrano-Wu, M.H.; et al. Identification of hepatitis C virus NS5A inhibitors. J. Virol. 2010, 84, 482–491. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Uemura, H.; Uchida, Y.; Kouyama, J.; Naiki, K.; Tsuji, S.; Sugawara, K.; Nakao, M.; Motoya, D.; Nakayama, N.; Imai, Y.; et al. NS5A-P32 deletion as a factor involved in virologic failure in patients receiving glecaprevir and pibrentasvir. J. Gastroenterol. 2019, 54, 459–470. [Google Scholar] [CrossRef] [PubMed]
- Osawa, M.; Imamura, M.; Teraoka, Y.; Uchida, T.; Morio, K.; Fujino, H.; Nakahara, T.; Ono, A.; Murakami, E.; Kawaoka, T.; et al. Real-world efficacy of glecaprevir plus pibrentasvir for chronic hepatitis C patient with previous direct-acting antiviral therapy failures. J. Gastroenterol. 2019, 54, 291–296. [Google Scholar] [CrossRef] [PubMed]
- Nitta, S.; Asahina, Y.; Kato, T.; Tsuchiya, J.; Inoue-Shinomiya, E.; Sato, A.; Tsunoda, T.; Miyoshi, M.; Kawai-Kitahata, F.; Murakawa, M.; et al. Impact of novel NS5A resistance-associated substitutions of hepatitis C virus detected in treatment-experienced patients. Sci. Rep. 2019, 9, 1–9. [Google Scholar] [CrossRef] [PubMed]
All Patients (n = 182) | ||
---|---|---|
Median | IQR | |
Age at entry (years) | 68 | (18–93) |
Gender (male/female) | 77/105 | |
HCV genotype | ||
1/2/3/1 + 2/ND | 86/66/4/1/25 | |
Chronic hepatitis/liver cirrhosis | 155/27 | |
Laboratory data | ||
White blood cells (μ/L) | 4910 | (1360–9010) |
Hemoglobin (g/dL) | 13.7 | (8.7–18.5) |
Platelet count (×109/L) | 176 | (12–369) |
Albumin (g/dL) | 4.1 | (2.7–4.8) |
AST (U/L) | 33 | (11–259) |
ALT (U/L) | 29 | (7–281) |
Total bilirubin (mg/dL) | 0.7 | (0.2–2.0) |
AFP (ng/mL) | 4.0 | (1.2–193.0) |
Cre (mg/dL) | 0.7 | (0.4–11.4) |
eGFR (mL/min/1.73 m2) | 68.1 | (3.0–118.1) |
Fibrosis markers | ||
FIB-4 index | 2.3 | (0.3–27.2) |
APRI | 0.5 | (0.1–17.5) |
Y93H mutation * | 50.0% | |
Complications | ||
Hypertension | 37.0% | |
Diabetes | 15.6% | |
Dyslipidemia | 8.7% | |
Hemodialysis | 5.0% | |
Experienced | ||
Prior IFN | 18.0% | |
Prior DAAs | 13.6% | |
Prior HCC | 6.2% | |
Outcome | ||
SVR (ITT) | 178/182 (97.8%) | |
SVR (PP) | 178/179 (99.4%) | |
Discontinuation | 3/182 (0.16%) |
First Treatment (n = 159) | Retreatment (n = 23) | p-Value | |
---|---|---|---|
Median (IQR) | Median (IQR) | ||
Age at entry (years) | 68 | 68 | 0.362 |
Gender (male/female) | 68/91 | 9/14 | 0.705 |
HCV genotype | |||
1/2/3/1 + 2/ND | 66/63/4/1/25 | 19/4/0/0/0 | |
Chronic hepatitis/liver cirrhosis | 135/24 | 20/3 | 0.357 |
Laboratory data | |||
White blood cells (μ/L) | 4900 (1360–9010) | 4920 (2310–8670) | 0.937 |
Hemoglobin (g/dL) | 13.5 (8.7–17.6) | 14.3 (8.7–18.5) | 0.111 |
Platelet count (×109/L) | 176 (12–369) | 174 (34–343) | 0.249 |
Albumin (g/dL) | 4.1 (2.7–4.8) | 4.1 (2.8–4.7) | 0.653 |
AST (U/L) | 33 (11–259) | 33 (19–90) | 0.580 |
ALT (U/L) | 30 (7–281) | 27 (15–141) | 0.458 |
Total bilirubin (mg/dL) | 0.6 (0.2–2.0) | 0.7 (0.4–1.5) | 0.399 |
AFP (ng/mL) | 4.0 (1.2–193.0) | 5.0 (1.7–24.6) | 0.455 |
Cre (mg/dL) | 0.8 (0.5–11.1) | 0.7 (0.5–3.0) | 0.180 |
eGFR (mL/min/1.73 m2) | 66.9 (3.0–115.7) | 78.3 (17.8–118.1) | 0.061 |
Fibrosis markers | |||
FIB-4 index | 2.2 (0.3–27.3) | 2.6 (0.8–9.7) | 0.592 |
APRI | 0.5 (0.1–17.5) | 0.5 (0.1–3.8) | 0.805 |
Y93H mutation * | 25.0% | 75.0% | <0.001 |
Complications | |||
Hypertension | 37.0% | 36.8% | 0.991 |
Diabetes | 17.4% | 5.0% | 0.158 |
Dyslipidemia | 9.2% | 5.3% | 0.567 |
Hemodialysis | 5.8% | 0% | 0.236 |
Experienced | |||
Prior IFN | 12.3% | 52.2% | <0.001 |
Prior HCC | 5.8% | 8.7% | 0.593 |
Case | Age | Gender | Prior DAA Treatment | NS5A | NS3 | |||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Genotype 1 | L23 | Q24 | L28 | R30 | L31 | P32 | F37 | Q54 | P58 | Q62 | A92 | Y93 | V36 | F43 | T54 | V55 | N77 | Q80 | S122 | R155 | A156 | D168 | V170 | |||
1 | 55 | F | DCV/ASV | - | - | - | - | M | - | - | - | S | - | - | H | - | - | - | - | - | - | - | - | - | - | - |
2 | 69 | M | DCV/ASV | - | K | M | R/A/G/T | - | - | - | - | - | - | - | - | - | - | - | - | - | L | G | - | - | - | - |
3 | 74 | F | DCV/ASV | - | - | - | - | F | - | - | H | - | - | V | H | - | - | - | - | - | - | G | - | - | - | - |
4 | 75 | F | DCV/ASV | - | K | T | H | - | - | - | - | - | - | - | - | - | - | - | - | - | - | G | - | - | - | I |
5 | 34 | F | DCV/ASV | - | - | - | - | V | - | L | G | - | - | - | H | - | - | - | - | - | L | - | - | - | E | I |
6 | 68 | F | DCV/ASV | - | K | M/V | H/Q | - | - | - | - | - | - | - | Y/H | - | - | - | - | - | Q/R | - | - | - | E | I |
7 | 70 | F | DCV/ASV | - | - | - | - | - | - | - | Y | - | - | - | H | - | - | - | - | - | - | G | - | - | - | - |
8 | 76 | F | LDV/SOF | - | - | - | - | L/M | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | I |
9 | 37 | M | LDV/SOF | - | K | M | Q | - | - | L | N | - | - | - | H/N | - | - | - | - | - | - | S/N | - | - | - | I |
10 | 70 | F | LDV/SOF | - | - | - | - | - | - | F/L | - | - | - | - | H | - | - | - | - | - | - | N | - | - | - | - |
11 | 68 | F | EBR + GRZ | - | - | - | - | V | - | L | H | - | - | - | H | - | - | - | - | - | - | - | - | - | - | - |
12 | 65 | F | OBV/PTV/r | - | - | - | - | - | - | - | H | - | D | - | Y/H | - | - | - | - | - | - | T | - | - | - | I |
13 | 76 | M | DCV/ASV followed by LDV/SOF | - | K | M | Q | - | - | L | R | - | E | - | H | - | - | - | - | - | - | - | - | - | - | I |
14 | 58 | M | DCV/ASV followed by LDV/SOF | - | - | - | - | V | - | L | - | - | - | - | H | - | - | - | - | - | L | C | - | - | E | I |
15 | 82 | M | DCV/ASV followed by EBR + GRZ | - | K | M | Q | V | - | - | - | - | - | - | F | - | - | - | - | - | - | - | - | - | - | - |
16 | 63 | M | SMV followed by DCV/ASV followed by LDV/SOF | - | - | - | - | I/M | - | L | H | - | - | - | Y/H | - | - | - | - | - | L | - | - | - | D/E | I |
17 * | 28 | M | VPV | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT |
18 * | 70 | F | SMV | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT |
19 * | 57 | F | SMV | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT |
Major RAS | L23 | Q24K | L28M | R30Q | L31M | P32 | F37L | Q54H | P58S | Q62 | A92V | Y93H | V36 | F43 | T54 | V55 | N77 | Q80L | S122G | R155 | A156 | D168E | V170I | |||
Frequency | 0 | 37.5% | 31.2% | 25.0% | 18.7% | 0 | 43.7% | 25.0% | 6.2% | 0 | 6.2% | 75.0% | 0 | 0 | 0 | 0 | 0 | 25.0% | 25.0% | 0 | 0 | 25.0% | 56.2% |
Case | Age | Gender | Prior DAA Treatment | NS5B | ||||
---|---|---|---|---|---|---|---|---|
Genotype 2 | L159 | S282 | C316 | L320 | V321 | |||
20 | 59 | M | SOF + RBV | - | - | - | - | - |
21 | 50 | M | SOF + RBV | - | - | - | - | - |
22 | 77 | F | SOF + RBV | - | - | - | - | - |
23 | 53 | M | SOF + RBV | - | - | - | - | - |
Major RAS | L159 | S282 | C316N | L320 | V321 | |||
Frequency | 0 | 0 | 0 | 0 | 0 | |||
G/P failure case | 75 | M | Before G/P | NT | NT | NT | NT | NT |
After G/P | - | - | - | - | - |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Sugiura, A.; Joshita, S.; Yamashita, Y.; Yamazaki, T.; Fujimori, N.; Kimura, T.; Matsumoto, A.; Wada, S.; Mori, H.; Shibata, S.; et al. Effectiveness of Glecaprevir/Pibrentasvir for Hepatitis C: Real-World Experience and Clinical Features of Retreatment Cases. Biomedicines 2020, 8, 74. https://doi.org/10.3390/biomedicines8040074
Sugiura A, Joshita S, Yamashita Y, Yamazaki T, Fujimori N, Kimura T, Matsumoto A, Wada S, Mori H, Shibata S, et al. Effectiveness of Glecaprevir/Pibrentasvir for Hepatitis C: Real-World Experience and Clinical Features of Retreatment Cases. Biomedicines. 2020; 8(4):74. https://doi.org/10.3390/biomedicines8040074
Chicago/Turabian StyleSugiura, Ayumi, Satoru Joshita, Yuki Yamashita, Tomoo Yamazaki, Naoyuki Fujimori, Takefumi Kimura, Akihiro Matsumoto, Shuichi Wada, Hiromitsu Mori, Soichiro Shibata, and et al. 2020. "Effectiveness of Glecaprevir/Pibrentasvir for Hepatitis C: Real-World Experience and Clinical Features of Retreatment Cases" Biomedicines 8, no. 4: 74. https://doi.org/10.3390/biomedicines8040074