Abstract
Background
This study sought to clarify the factors involved in virologic failure in patients with HCV receiving retreatment with glecaprevir/pibrentasvir (GLE/PIB) in real-world practice.
Methods
Forty-two patients who had previously received direct-acting antivirals (DAAs) therapies consisting of 35, 3, 3, and 1 patient(s) with genotype (GT)-1b, GT-2a, GT-2b, and GT-3b HCV, respectively, received GLE/PIB for 12 weeks. Resistance-associated substitutions (RASs) at baseline were evaluated, and the dynamics of NS5A-RASs were assessed by deep sequencing in patients showing virologic failure.
Results
Baseline NS5A-RASs were found in all the patients with GT-1b HCV including 16 patients with NS3-RASs. In contrast, both NS5A-RASs and NS3-RASs were absent in 3 and 2 patients with GT-2a and GT-2b HCV, respectively. Virologic failure occurred in 3 patients with GT-1b HCV with NS5A-P32del, while a sustained virologic response (SVR) was achieved in the remaining 39 patients including those with GT-1b HCV carrying NS5A-L31V + Y93H and NS5A-A92K. Virologic failure even occurred in a patient in whom the NS5A-P32del HCV strains had become undetectable by direct sequencing, and the percentage of such strains relative to the total HCV strains was 10%, as determined by deep sequencing. In the other patient with GT-1b HCV with NS5A-P32del, NS3-A156A/V/S were found at 4 weeks after GLE/PIB therapy, but had disappeared at 11 weeks, as determined by direct sequencing.
Conclusions
GLE/PIB was effective for patients with HCV who failed to achieve an SVR after prior DAA therapies except in those with GT-1b HCV carrying NS5A-P32del even when such strains became undetectable by direct sequencing.
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References
Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology. 2014;59:2083–91.
Uchida Y, Kouyama J, Naiki K, et al. A novel simple assay system to quantify the percent HCV-RNA levels of NS5A Y93H mutant strains and Y93 wild-type strains relative to the total HCV-RNA levels to determine the indication for antiviral therapy with NS5A inhibitors. PLoS ONE. 2014;9:e112647.
Uchida Y, Kouyama J, Naiki K, et al. Significance of variants associated with resistance to NS5A inhibitors in Japanese patients with genotype 1b hepatitis C virus infection as evaluated using cycling-probe real-time PCR combined with direct sequencing. J Gastroenterol. 2016;51:260–70.
Uchida Y, Kouyama J, Naiki K, et al. Development of rare RAVs that are extremely tolerant against NS5A inhibitors during daclatasvir/asunaprevir therapy via a two-hit mechanism. Hepatol Res. 2016;46:1234–46.
Uchida Y, Kouyama JI, Naiki K, et al. “Reversi-type virologic failure” involved in the development of non-structural protein 5A resistance-associated variants (RAVs) in patients with genotype 1b hepatitis C carrying no signature RAVs at baseline. Hepatol Res. 2017;47:1397–407.
Kurata H, Uchida Y, Kouyama J, et al. A case of chronic hepatitis caused by hepatitis C virus exhibiting a discrepancy between serogroup and genotype because of inter-genotypic 2b/1b recombination: a pitfall in antiviral therapy with direct-acting antivirals. Hepatol Res. 2018;48:E372–8.
Itakura J, Kurosaki M, Hasebe C, et al. Complex pattern of resistance-associated substitutions of hepatitis C virus after daclatasvir/asunaprevir treatment failure. PLoS ONE. 2016;10:e065339.
Uemura H, Uchida Y, Kouyama JI, et al. Retreatment with sofosbuvir/ledipasvir with or without lead-in interferon-β injections in patients infected with genotype 1b hepatitis C virus after unsuccessful daclatasvir/asunaprevir therapy. Hepatol Res. 2018;48:233–43.
Fridell RA, Qiu D, Wang C, et al. Resistance analysis of the hepatitis C virus NS5A inhibitor BMS-790052 in an in vitro replicon system. Antimicrob Agents Chemother. 2010;54:3641–50.
Wang C, Sun JH, O’Boyle DR 2nd, et al. Persistence of resistant variants in hepatitis C virus-infected patients treated with the NS5A replication complex inhibitor daclatasvir. Antimicrob Agents Chemother. 2013;57:2054–65.
Akuta N, Sezaki H, Suzuki F, et al. Ledipasvir plus sofosbuvir as salvage therapy for HCV genotype 1 failures to prior NS5A inhibitors regimens. J Med Virol. 2017;89:1248–54.
Chayama K, Suzuki F, Karino Y, et al. Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 1 hepatitis C virus infection with and without cirrhosis. J Gastroenterol. 2018;53:557–65.
Toyoda H, Chayama K, Suzuki F, et al. Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 2 hepatitis C virus infection. Hepatology. 2018. https://doi.org/10.1002/hep.29510.
Kumada H, Watanabe T, Suzuki F, 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. 2018;53:566–75.
Ng TI, Tripathi R, Reisch T, et al. In vitro antiviral activity and resistance profile of the next-generation hepatitis C virus NS3/4A protease inhibitor glecaprevir. Antimicrob Agents Chemother. 2017;21:62.
Ng TI, Krishnan P, Pilot-Matias T, et al. In vitro antiviral activity and resistance profile of the next-generation hepatitis C virus NS5A inhibitor pibrentasvir. Antimicrob Agents Chemother. 2017;24:61.
Gilead Sciences HARVONI combination tablets® (sofosbuvir + ledipasvir), for oral use: PRESCRIBING INFORMATION. 2015.
Akuta N, Sezaki H, Suzuki F, et al. Favorable efficacy of glecaprevir plus pibrentasvir as salvage therapy for HCV failures to prior direct-acting antivirals regimens. J Med Virol. 2019;91:102–6.
Osawa M, Imamura M, Teraoka Y, et al. Real-world efficacy of glecaprevir plus pibrentasvir for chronic hepatitis C patient with previous direct-acting antiviral therapy failures. J Gastroenterol. 2018. https://doi.org/10.1007/s00535-018-1520-9.
Wong KA, Worth A, Martin R, et al. Characterization of hepatitis C virus resistance from a multiple-dose clinical trial of the novel NS5A inhibitor GS-5885. Antimicrob Agents Chemother. 2013;57:6333–40.
Krishnan P, Beyer J, Mistry N, et al. In vitro and in vivo antiviral activity and resistance profile of ombitasvir, an inhibitor of hepatitis C virus NS5A. Antimicrob Agents Chemother. 2015;59:979–87.
Suda G, Ogawa K, Yamamoto Y, et al. Retreatment with sofosbuvir, ledipasvir, and add-on ribavirin for patients who failed daclatasvir and asunaprevir combination therapy. J Gastroenterol. 2017;52:1122–9.
Krishnan P, Schnell G, Tripathi R, et al. Integrated resistance analysis of CERTAIN-1 and CERTAIN-2 studies in hepatitis C virus-infected patients receiving glecaprevir and pibrentasvir in Japan. Antimicrob Agents Chemother. 2018;25:62.
Doi A, Hikita H, Sakamori R, et al. Nonstructural protein 5A/P32 deletion after failure of ledipasvir/sofosbuvir in hepatitis C virus genotype 1b infection. Hepatology. 2018;68:380–3.
Teraoka Y, Uchida T, Imamura M, et al. Prevalence of NS5A resistance associated variants in NS5A inhibitor treatment failures and an effective treatment for NS5A-P32 deleted hepatitis C virus in humanized mice. Biochem Biophys Res Commun. 2018. https://doi.org/10.1016/j.bbrc.2018.04.005.
Bourlière M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med. 2017;376:2134–46.
Gane EJ, Shiffman ML, Etzkorn K, et al. Sofosbuvir-velpatasvir with ribavirin for 24 weeks in hepatitis C virus patients previously treated with a direct-acting antiviral regimen. Hepatology. 2017;66:1083–9.
Acknowledgements
Satoshi MOCHIDA has received patent royalties from SRL Inc., has received speaking fees or honoraria from AbbVie GK, Ajinomoto Pharmaceuticals Co. Ltd., Bristol Myers Squibb Co., Gilead Sciences Inc., MSD K.K., Sumitomo Dainippon Pharma Co., Toray Medical Co. Ltd., has received research Grants from A2 Healthcare Co., AbbVie GK, Bristol Myers Squibb Co., Chugai Pharmaceutical Co. Ltd., EA Pharma Co. Ltd., Mitsubishi Tanabe Pharma Co., MSD K.K., Sumitomo Dainippon Pharma Co., Toray Medical Co. Ltd.
Yoshihito UCHIDA has received research Grant from AbbVie GK.
Funding
This study was supported by Research Program on Hepatitis from Japan Agency for Medical Research and Development (AMED): (Grant Number 18fk0210002h0003).
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Uemura, H., Uchida, Y., Kouyama, Ji. et al. NS5A-P32 deletion as a factor involved in virologic failure in patients receiving glecaprevir and pibrentasvir. J Gastroenterol 54, 459–470 (2019). https://doi.org/10.1007/s00535-018-01543-9
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DOI: https://doi.org/10.1007/s00535-018-01543-9