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
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima (Japan)
Highlights: • NS5A-P32 deletions were detected in 4.3% of genotype 1 HCV-infected patients with prior NS5A inhibitors treatment failure. • Efficacy of glecaprevir and pibrentasvir treatment for NS5A-P32 deleted HCV is lower compared to the wild-type strain. • Sofosbuvir plus glecaprevir and pibrentasvir combination treatment was effective for NS5A-P32del in humanized mice. Patients with chronic hepatitis C virus (HCV) infection who have failed to respond to direct-acting antiviral (DAA) treatment often acquire drug resistance-associated variants (RAVs). The NS5A-P32 deletion (P32del) RAV confers potent resistance to NS5A inhibitors; therefore, patients who acquire this deletion are likely to fail to respond to DAA re-treatment. We investigated the prevalence of N55A-P32del in patients who failed to respond to prior NS5A inhibitor treatment using direct sequencing and analyzed the efficacy of DAA combination treatment in the presence of NS5A-P32del RAVs using human hepatocyte transplanted mice. NS5A-P32del was detected in one of 23 (4.3%) patients who had failed to respond to prior NS5A inhibitor treatment. Although four weeks of NS3/4A protease inhibitor glecaprevir plus NS5A inhibitor pibrentasvir treatment effectively suppressed HCV replication in wild-type HCV-infected mice, serum HCV RNA never became negative in P32del HCV-infected mice. When P32del HCV-infected mice were treated with four weeks of glecaprevir plus pibrentasvir combined with the NS5B polymerase inhibitor sofosbuvir, serum HCV RNA became negative, and the virus was eliminated from the liver in three out of four mice. We conclude that the combination of sofosbuvir and glecaprevir plus pibrentasvir may be an effective new treatment option for patients with NS5A-P32del.
- OSTI ID:
- 23137119
- Journal Information:
- Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 2 Vol. 500; ISSN BBRCA9; ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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