scholarly journals Improving the Resistance Profile of Hepatitis C NS3/4A Inhibitors: Dynamic Substrate Envelope Guided Design

2013 ◽  
Vol 9 (12) ◽  
pp. 5693-5705 ◽  
Author(s):  
Ayşegül Özen ◽  
Woody Sherman ◽  
Celia A. Schiffer
Keyword(s):  
Hepatitis C ◽  
Resistance Profile ◽  
Substrate Envelope

scholarly journals Drug Resistance Profile and Clinical Features for Hepatitis C Patients Experiencing DAA Failure in Taiwan

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2294
Author(s):  
Chun-Ming Hong ◽  
You-Yu Lin ◽  
Chun-Jen Liu ◽  
Ya-Yun Lai ◽  
Shiou-Hwei Yeh ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Hcv Rna ◽  
Whole Genome ◽  
Svr12 Rate ◽  
Resistance Profile ◽  
Drug Resistance Profile ◽  
Taiwan National Health Insurance ◽  
Cause Of Failure

About 4% of the population in Taiwan are seropositive for anti-HCV Ab and 70% with HCV RNA. To address this high chronic hepatitis C disease load, Taiwan National Health Insurance started reimbursing genotype-specific DAAs in 2017 and pangenotype DAAs in mid-2018. With a 97% SVR12 rate, there were still 2–3% of patients that failed to clear HCV. To understand the causes of DAA failure in Taiwan, we conducted a multi-center, clinical, and virologic study. A total of 147 DAA-failure patients were recruited, and we searched HCV NS3/4A, NS5A and NS5B for known resistance-associated substitutions (RASs) by population sequencing, and conducted whole genome sequencing (WGS) for those without known RASs. A total of 107 patients received genotype-specific DAAs while 40 had pangenotype DAAs. Clinically, the important cause of failure is poor adherence. Virologically, common RASs in genotype-specific DAAs were NS5A-L31, NS5A-Y93, and NS5B-C316, while common RASs in pangenotype DAAs were NS5A-L31, NS5A-A/Q/R30, and NS5A-Y93. Additionally, new amino acid changes were found by WGS. Finally, we identified 12 cases with inconsistent baseline and post-treatment HCV genotypes, which is suggestive of re-infection rather than treatment failure. Our study described the drug resistance profile for DAA failure in Taiwan, showing differences from other countries.

In vitro resistance profile of hepatitis C virus NS5A inhibitor velpatasvir in genotypes 1 to 6

2019 ◽  
Author(s):  
Hadas Dvory‐Sobol ◽  
Bin Han ◽  
Julia Lu ◽  
Mei Yu ◽  
Rudolf K. Beran ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Resistance Profile ◽  
Ns5a Inhibitor

scholarly journals In VitroAntiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir

2016 ◽  
Vol 60 (3) ◽  
pp. 1847-1853 ◽  
Author(s):  
Guofeng Cheng ◽  
Yang Tian ◽  
Brian Doehle ◽  
Betty Peng ◽  
Amoreena Corsa ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Fixed Dose ◽  
Resistance Profile ◽  
Direct Acting Antiviral ◽  
Ns5b Polymerase Inhibitor ◽  
Polymerase Inhibitor ◽  
Ns5b Polymerase

Ledipasvir (LDV; GS-5885), a component of Harvoni (a fixed-dose combination of LDV with sofosbuvir [SOF]), is approved to treat chronic hepatitis C virus (HCV) infection. Here, we report key preclinical antiviral properties of LDV, includingin vitropotency,in vitroresistance profile, and activity in combination with other anti-HCV agents. LDV has picomolar antiviral activity against genotype 1a and genotype 1b replicons with 50% effective concentration (EC50) values of 0.031 nM and 0.004 nM, respectively. LDV is also active against HCV genotypes 4a, 4d, 5a, and 6a with EC50values of 0.11 to 1.1 nM. LDV has relatively lessin vitroantiviral activity against genotypes 2a, 2b, 3a, and 6e, with EC50values of 16 to 530 nM.In vitroresistance selection with LDV identified the single Y93H and Q30E resistance-associated variants (RAVs) in the NS5A gene; these RAVs were also observed in patients after a 3-day monotherapy treatment.In vitroantiviral combination studies indicate that LDV has additive to moderately synergistic antiviral activity when combined with other classes of HCV direct-acting antiviral (DAA) agents, including NS3/4A protease inhibitors and the nucleotide NS5B polymerase inhibitor SOF. Furthermore, LDV is active against known NS3 protease and NS5B polymerase inhibitor RAVs with EC50values equivalent to those for the wild type.

scholarly journals In Vitro Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor TMC435

2010 ◽  
Vol 54 (5) ◽  
pp. 1878-1887 ◽  
Author(s):  
O. Lenz ◽  
T. Verbinnen ◽  
T. I. Lin ◽  
L. Vijgen ◽  
M. D. Cummings ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Resistance Profile

Combatting Drug Resistance: Lessons from the viral proteases of HIV and HCV

2014 ◽  
Vol 70 (a1) ◽  
pp. C116-C116
Author(s):  
Celia Schiffer
Keyword(s):  
Drug Resistance ◽  
Hepatitis C ◽  
Biological Function ◽  
Substrate Recognition ◽  
Atomic Resolution ◽  
Inhibitor Binding ◽  
Detailed Understanding ◽  
Viral Proteases ◽  
Hiv 1 ◽  
Substrate Envelope

Drug resistance negatively impacts the lives of millions of patients and costs our society billions of dollars by limiting the longevity of many of our most potent drugs. Drug resistance can be caused by a change in the balance of molecular recognition events that selectively weakens inhibitor binding but maintains the biological function of the target. To reduce the likelihood of drug resistance, a detailed understanding of the target's function is necessary. Both structure at atomic resolution and evolutionarily constraints on its variation is required. "Resilient" targets are less susceptible to drug resistance due to their key location in a particular pathway. This rationale was derived through crystallographic studies elucidating substrate recognition and drug resistance in HIV-1 protease and Hepatitis C (HCV) NS3/4A protease. Both are key therapeutic targets and are potentially "resilient" targets where resistant mutations occur outside of the substrate binding site. To reduce the probability of drug resistance inhibitors should be designed to fit within what we define as the "substrate envelope". These principals are likely more generally applicable to other quickly evolving diseases where drug resistance is quickly evolving. http://www.umassmed.edu/schifferlab/index.aspx

In vitro Anti-hepatitis C Virus (HCV) Activities and Resistance Profile of Debio 025, A Non-immunosuppressive Cyclophilin Binding Molecule

2009 ◽  
Vol 82 (2) ◽  
pp. A20 ◽  
Author(s):  
Lotte Coelmont ◽  
Philippe Gallay ◽  
Michael Bobardt ◽  
Suzanne Kaptein ◽  
Jan Paeshuyse ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Resistance Profile

scholarly journals In VitroCharacterization of GSK2485852, a Novel Hepatitis C Virus Polymerase Inhibitor

2013 ◽  
Vol 57 (11) ◽  
pp. 5216-5224 ◽  
Author(s):  
Christian Voitenleitner ◽  
Renae Crosby ◽  
Jill Walker ◽  
Katja Remlinger ◽  
Jessica Vamathevan ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cross Resistance ◽  
Hcv Rna ◽  
Resistance Mutations ◽  
Subgenomic Replicon ◽  
Resistance Profile ◽  
Long Term Treatment ◽  
Ns5b Polymerase Inhibitor ◽  
Polymerase Inhibitor

ABSTRACTGSK2485852 (referred to here as GSK5852) is a hepatitis C virus (HCV) NS5B polymerase inhibitor with 50% effective concentrations (EC50s) in the low nanomolar range in the genotype 1 and 2 subgenomic replicon system as well as the infectious HCV cell culture system. We have characterized the antiviral activity of GSK5852 using chimeric replicon systems with NS5B genes from additional genotypes as well as NS5B sequences from clinical isolates of patients infected with HCV of genotypes 1a and 1b. The inhibitory activity of GSK5852 remained unchanged in these intergenotypic and intragenotypic replicon systems. GSK5852 furthermore displays an excellent resistance profile and shows a <5-fold potency loss across the clinically important NS5B resistance mutations P495L, M423T, C316Y, and Y448H. Testing of a diverse mutant panel also revealed a lack of cross-resistance against known resistance mutations in other viral proteins. Data from both the newer 454 sequencing method and traditional population sequencing showed a pattern of mutations arising in the NS5B RNA-dependent RNA polymerase in replicon cells exposed to GSK5852. GSK5852 was more potent than HCV-796, an earlier inhibitor in this class, and showed greater reductions in HCV RNA during long-term treatment of replicons. GSK5852 is similar to HCV-796 in its activity against multiple genotypes, but its superior resistance profile suggests that it could be an attractive component of an all-oral regimen for treating HCV.

scholarly journals In VitroActivity and Resistance Profile of Samatasvir, a Novel NS5A Replication Inhibitor of Hepatitis C Virus

2014 ◽  
Vol 58 (8) ◽  
pp. 4431-4442 ◽  
Author(s):  
J. P. Bilello ◽  
L. B. Lallos ◽  
J. F. McCarville ◽  
M. La Colla ◽  
I. Serra ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Resistance Profile ◽  
Direct Acting Antiviral ◽  
Genotype 1A ◽  
Hcv Protease ◽  
Chronic Hcv ◽  
Direct Acting

ABSTRACTThe hepatitis C virus (HCV) nonstructural 5A (NS5A) protein is a clinically validated target for drugs designed to treat chronic HCV infection. This study evaluated thein vitroactivity, selectivity, and resistance profile of a novel anti-HCV compound, samatasvir (IDX719), alone and in combination with other antiviral agents. Samatasvir was effective and selective against infectious HCV and replicons, with 50% effective concentrations (EC50s) falling within a tight range of 2 to 24 pM in genotype 1 through 5 replicons and with a 10-fold EC50shift in the presence of 40% human serum in the genotype 1b replicon. The EC90/EC50ratio was low (2.6). A 50% cytotoxic concentration (CC50) of >100 μM provided a selectivity index of >5 × 107. Resistance selection experiments (with genotype 1a replicons) and testing against replicons bearing site-directed mutations (with genotype 1a and 1b replicons) identified NS5A amino acids 28, 30, 31, 32, and 93 as potential resistance loci, suggesting that samatasvir affects NS5A function. Samatasvir demonstrated an overall additive effect when combined with interferon alfa (IFN-α), ribavirin, representative HCV protease, and nonnucleoside polymerase inhibitors or the nucleotide prodrug IDX184. Samatasvir retained full activity in the presence of HIV and hepatitis B virus (HBV) antivirals and was not cross-resistant with HCV protease, nucleotide, and nonnucleoside polymerase inhibitor classes. Thus, samatasvir is a selective low-picomolar inhibitor of HCV replicationin vitroand is a promising candidate for future combination therapies with other direct-acting antiviral drugs in HCV-infected patients.

Sign in / Sign up

Export Citation Format

Share Document