Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1-7 and Escape Variants

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Validation and update of the Lémann index to measure cumulative structural bowel damage in Crohn's disease

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Challenges and Opportunities in IBD Clinical Trial Design

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Selecting End Points for Disease-Modification Trials in Inflammatory Bowel Disease: the SPIRIT Consensus From the IOIBD

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Cancer Risk in Pediatric-Onset Inflammatory Bowel Disease: A Population-Based Danish Cohort Study

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Inferior cure rate in pilot study of 4-week glecaprevir/pibrentasvir treatment with or without ribavirin of chronic hepatitis C

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Efficacy of Ion-Channel Inhibitors Amantadine, Memantine and Rimantadine for the Treatment of SARS-CoV-2 In Vitro

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Hepatitis C virus envelope protein dynamics and the link to hypervariable region 1

    Publikation: Bidrag til tidsskriftReviewForskningpeer review

Vis graf over relationer

BACKGROUND & AIMS: Inhibitors of the hepatitis C virus (HCV) NS5A protein are a key component of effective treatment regimens, but the genetic heterogeneity of HCV has limited the efficacy of these agents and mutations lead to resistance. We directly compared the efficacy of all clinically relevant NS5A inhibitors against HCV genotype 1-7 prototype isolates and resistant escape variants, and investigated the effects of pre-existing resistance-associated substitutions (RAS) on HCV escape from treatment.

METHODS: We measured the efficacy of different concentrations of daclatasvir, ledipasvir, ombitasvir, elbasvir, ruzasvir, velpatasvir, and pibrentasvir in cultured cells infected with HCV recombinants expressing genotype 1-7 NS5A proteins with or without RAS. We engineered HCV variants that included RAS identified in escape experiments, using recombinants with or without T/Y93H and daclatasvir, or that contained RAS previously reported from patients.

RESULTS: NS5A inhibitors had varying levels of efficacy against original and resistant viruses. Only velpatasvir and pibrentasvir had uniform high activity against all HCV genotypes tested. RAS hotspots in NS5A were found at amino acids 28, 30, 31, and 93. Engineered escape variants had high levels of fitness. Pibrentasvir had the highest level of efficacy against variants; viruses with RAS at amino acids 28, 30, or 31 had no apparent resistance to pibrentasvir, and HCV with RAS at amino acid 93 had a low level of resistance to this drug. However, specific combinations of RAS and deletion of amino acid 32 led to significant resistance to pibrentasvir. For the remaining NS5A inhibitors tested, RAS at amino acids 28 and 93 led to high levels of resistance. Among these inhibitors, velpatasvir was more effective against variants with RAS at amino acid 30 and some variants with RAS at amino acid 31 than the other agents. Variants with the pre-existing RAS T/Y93H acquired additional NS5A changes during escape experiments, resulting in HCV variants with specific combinations of RAS, showing high fitness and high resistance.

CONCLUSIONS: We performed a comprehensive comparison of the efficacy of the 7 clinically relevant inhibitors of HCV NS5A and identified variants associated with resistance to each agent. These findings could improve treatment of patients with HCV infection.

OriginalsprogEngelsk
TidsskriftGastroenterology
Vol/bind154
Udgave nummer5
Sider (fra-til)1435-1448
ISSN0016-5085
DOI
StatusUdgivet - apr. 2018

ID: 52363684