1192 Vast Majority of Detected Ns5a Resistant Variants Are Not Amplified in HCV Patients During 3-Day Monotherapy With the Optimized Ns5a Inhibitor Ppi-668

Huang, Qi; Huang, Ningwu; Huq, A.; Lau, Meiyen; Peng, E.; Lalezari, J.; Farrell, Geoffrey C.; Shah, Pratish; Lawitz, Eric; Brown, Nathaniel; Colonno, Richard J.

doi:10.1016/s0168-8278(13)61193-9

Cited by 5 publications

(4 citation statements)

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“…Different from the NS5A inhibitors aforementioned, RDV is a pangenotypic HCV NS5A inhibitor with high resistance barrier and more potent antiviral activity in accordance with a higher administration dose at 200 mg per day boosting to garner greater exposure 4. Besides, the wild-type HCV virus, conversely, in a previous study of RDV also demonstrated its potency to fully inhibit single NS5A substitution variants 13. In this study, GT1 NS5A resistance-associated species were detected in 76 of the participating subjects (24.6%, 76/309) in the treatment arm and 29 in the control arm (29%, 29/101, per protocol set) at baseline (Fig.…”

Section: Discussionsupporting

confidence: 61%

Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China

Xu¹,

Feng²,

Guan³

et al. 2019

Journal of Clinical and Translational Hepatology

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Background and Aims: Ravidasvir (RDV) is a new generation pangenotypic hepatitis C virus (HCV) NS5A inhibitor, with high barrier to baseline resistance-associated species. This is the first phase 2/3 study conducted in Mainland China confirming the efficacy and safety of RDV + ritonavir-boosted danoprevir + ribavirin for 12 weeks in treatment-naïve noncirrhotic patients with genotype 1 infection in a large population.Methods: In this multicenter, randomized, double-blinded, placebo-controlled phase 2/3 trial (NCT03362814), we enrolled 424 treatment-naïve, noncirrhotic adult HCV genotype 1 patients. All patients were randomized at 3:1 ratio to receive a combination of RDV 200mg once daily plus ritonavir-boosted danoprevir 100mg/100mg twice daily and oral ribavirin 1000/1200mg/day (body weight <75/≥75 kg) (n = 318) or placebo (n = 106) for 12 weeks. The primary end-point was the rate of sustained virologic response 12 weeks after the end of treatment, and the safety was evaluated and compared between treatment and placebo groups.Results: The overall rate of sustained virological response at 12 weeks after treatment is 99% (306/309, 95%, CI: 97%–100%) under per protocol set analysis. All patients harboring baseline NS5A resistance-associated species in the treatment group (76/76, per protocol set) achieved sustained virological response at 12 weeks after treatment. No treatment-related serious adverse events were reported. Laboratory abnormalities showed mild or moderate severity (grade 1 and grade 2) in liver function tests.Conclusions: In treatment-naïve, noncirrhotic HCV Chinese patients infected with HCV genotype 1, all-oral regimen of RDV + ritonavir-boosted danoprevir + ribavirin for 12 weeks was highly efficacious, safe, and well tolerated.

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Section: Discussionsupporting

confidence: 61%

Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China

Xu¹,

Feng²,

Guan³

et al. 2019

Journal of Clinical and Translational Hepatology

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“…A similar resistance pattern was seen with ledipasvir monotherapy: M28T, Q30R/H, L31M and Y93H/C in patients with genotype 1a, and only Y93H in patients with genotype 1b . In a study of PPI‐668 monotherapy, resistant variants at positions 28, 30, 31 and 93 were detected early after starting therapy, and eight of 40 patients had NS5A resistant variants at baseline . However, the lack of further amplification of resistant variants during PPI‐668 monotherapy indicates that the pharmacokinetic profile of PPI‐668 suppresses single variants .…”

Section: Ns5a and Ns5b Inhibitorsmentioning

confidence: 99%

“…In a study of PPI‐668 monotherapy, resistant variants at positions 28, 30, 31 and 93 were detected early after starting therapy, and eight of 40 patients had NS5A resistant variants at baseline . However, the lack of further amplification of resistant variants during PPI‐668 monotherapy indicates that the pharmacokinetic profile of PPI‐668 suppresses single variants . PPI‐668 is now entering a phase 2 study with faldaprevir and deleobuvir with or without RBV (ClinicalTrials.gov Identifier: NCT01859962).…”

Section: Ns5a and Ns5b Inhibitorsmentioning

confidence: 99%

Importance of HCV genotype 1 subtypes for drug resistance and response to therapy

Wyles

Gutiérrez

2014

Journal of Viral Hepatitis

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The treatment for patients infected with hepatitis C virus (HCV) genotype 1 has undergone major changes with the availability of direct-acting antivirals. Triple therapy, containing telaprevir or boceprevir, first-wave NS3 protease inhibitors, in combination with peginterferon and ribavirin, improved rates of sustained virologic response compared with peginterferon and ribavirin alone in patients with HCV genotype 1. However, the development of drug-resistant variants is a concern. In patients treated with telaprevir or boceprevir, different patterns of resistance are observed for the two major HCV genotype 1 subtypes, 1a and 1b. Genotype 1b is associated with a lower rate of resistant variant selection and better response to triple therapy compared with genotype 1a. Similar subtype-specific patterns have been observed for investigational direct-acting antivirals, including second-wave NS3 protease inhibitors, NS5A inhibitors and non-nucleoside NS5B inhibitors. This review explores resistance to approved and investigational direct-acting antivirals for the treatment of HCV, focusing on the differences between genotype 1a and genotype 1b. Finally, given the importance of HCV genotype 1 subtype on resistance and treatment outcomes, clinicians must also be aware of the tests currently available for genotype subtyping and their limitations.

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“…The finding that RAMs present at baseline can impact the antiviral response to monotherapy is not unique to EDP-239. Several other studies of NS5A inhibitors, including daclatasvir, ledipasvir, and PPI-668 (16)(17)(18), reported patient isolates harboring NS5A RAMs prior to dosing, all of which limited the antiviral response.…”

Section: Discussionmentioning

confidence: 99%

Preclinical and Clinical Resistance Profile of EDP-239, a Novel Hepatitis C Virus NS5A Inhibitor

Owens

Brasher

Polemeropoulos

et al. 2016

Antimicrob Agents Chemother

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1192 Vast Majority of Detected Ns5a Resistant Variants Are Not Amplified in HCV Patients During 3-Day Monotherapy With the Optimized Ns5a Inhibitor Ppi-668

Cited by 5 publications

References 0 publications

Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China

Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China

Importance of HCV genotype 1 subtypes for drug resistance and response to therapy

Preclinical and Clinical Resistance Profile of EDP-239, a Novel Hepatitis C Virus NS5A Inhibitor

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