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Resistance associated substitutions for hepatitis C virus (HCV) NS5A inhibitors

Resistance associated substitutions for hepatitis C virus (HCV) NS5A inhibitors
NS5A inhibitor Genotype 1a Genotype 3
Pibrentasvir Y93* No single position variants
Velpatasvir Y93 Y93H
Ledipasvir K24, M28, Q30, L31, Y93 N/A
Elbasvir M28, Q30, L31, Y93 N/A
Daclatasvir M28, Q30, L31, Y93 A30K, Y93H
EC50: Half maximal effective concentration

* Results in low level resistance in vitro (<10x shift in EC50).
¶ In vitro, no single position variant results in >3x shift in EC50. Dual A30K and Y93H results in 70x shift in EC50.

Data from:
  1. Jacobson IM, Asante-Appiah E, Wong P, et al. Prevalence and impact of baseline NSA resistance associated variants (RAVs) on the efficacy of elbasvir/grazoprevir (EBR/GZR) against GT1a infection. Presented at the American Association for the Study of Liver Diseases Liver Meeting, San Francisco CA, November 13-17, 2015. Abstract #LB-22.
  2. Sarrazin C, Dvory-Sobol H, Svarovskaia ES, et al. Prevalence of Resistance-Associated Substitutions in HCV NS5A, NS5B, or NS3 and Outcomes of Treatment With Ledipasvir and Sofosbuvir. Gastroenterology 2016; 151:501.
  3. Lawitz EJ, Dvory-Sobol H, Doehle BP, et al. Clinical Resistance to Velpatasvir (GS-5816), a Novel Pan-Genotypic Inhibitor of the Hepatitis C Virus NS5A Protein. Antimicrob Agents Chemother 2016; 60:5368.
  4. Krishnan P, Tripathi R, Schnell G, et al. Pooled analysis of resistance in patients treated with ombitasvir/ABT-450/r and dasabuvir with or without ribavirin in Phase 2 and Phase 3 clinical trials. Hepatology 2014; 60:1134A.
  5. Daklinza [package insert]. Princeton, NJ USA. Bristol Myers Squibb. April 2016.
Graphic 109921 Version 3.0

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