Efficacy of glecaprevir and pibrentasvir treatment for genotype 1b hepatitis C virus drug resistance-associated variants in humanized mice
| Autor: | C. Nelson Hayes, Takuro Uchida, Yohei Miyayama, Masataka Tsuge, Hiromi Abe-Chayama, Mitsutaka Osawa, Yuji Teraoka, Eisuke Murakami, Hatsue Fujino, Daiki Miki, Kazuaki Chayama, Yuji Ishida, Tomokazu Kawaoka, Grace Naswa Makokha, Makoto Hijikata, Michio Imamura, Takashi Nakahara, Hiroshi Aikata, Atsushi Ono, Akira Hiramatsu, Chise Tateno |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Pyrrolidines Daclatasvir Genotype Combination therapy viruses Hepatitis C virus 030106 microbiology Hepacivirus Mice SCID Drug resistance Viral Nonstructural Proteins Biology medicine.disease_cause Antiviral Agents Mice 03 medical and health sciences chemistry.chemical_compound Quinoxalines Virology Drug Resistance Viral medicine Animals Humans NS5A Phylogeny Aged Sulfonamides virus diseases Glecaprevir Middle Aged biochemical phenomena metabolism and nutrition Phosphoproteins Hepatitis C digestive system diseases Pibrentasvir Drug Combinations 030104 developmental biology chemistry Mutation Asunaprevir Benzimidazoles Drug Therapy Combination Female medicine.drug |
| Zdroj: | Journal of General Virology. 100:1123-1131 |
| ISSN: | 1465-2099 0022-1317 |
| DOI: | 10.1099/jgv.0.001268 |
| Popis: | Combination therapy with glecaprevir (GLE) and pibrentasvir (PIB) has high efficacy for pan-genotypic hepatitis C virus (HCV)-infected patients. However, the efficacy for patients who acquired potent NS5A inhibitor resistance-associated variants (RAVs) as a result of failure to respond to previous direct-acting antiviral (DAA) therapies is unclear. We investigated the efficacy of GLE/PIB treatment for genotype 1b HCV strains containing RAVs using subgenomic replicon systems and human hepatocyte transplanted mice. Mice were injected with serum samples obtained from a DAA-naïve patient or daclatasvir plus asunaprevir (DCV/ASV) treatment failures including NS5A-L31M/Y93H, -P58S/A92K or -P32 deletion (P32del) RAVs, then treated with GLE/PIB. HCV was eliminated by GLE/PIB treatment in mice with wild-type and NS5A-L31M/Y93H but relapsed in mice with NS5A-P58S/A92K, followed by emergence of additional NS5A mutations after cessation of the treatment. In NS5A-P32del-infected mice, serum HCV RNA remained positive during the GLE/PIB treatment. NS5A-P58S/A92K showed 1.5-fold resistance to PIB relative to wild-type based on analysis using HCV subgenomic replicon systems. When mice were administered various proportions of HCV wild-type and P32del strains and treated with GLE/PIB, serum HCV RNA remained positive in mice with high frequencies of P32del. In these mice, the P32del was undetectable by deep sequencing before GLE/PIB treatment, but P32del strains relapsed after cessation of the GLE/PIB treatment. GLE/PIB is effective for wild-type and NS5A-L31M/Y93H HCV strains, but the effect seems to be low for P58S/A92K and NS5A-P32del RAVs. Although NS5A-P32del was not detected, the mutation may be present at low frequency in DCV/ASV treatment failures. |
| Databáze: | OpenAIRE |
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