Sequence and Phenotypic Analysis for Resistance Monitoring in Hepatitis C Virus Drug Development: Recommendations From the HCV DRAG

Kwong, Ann D.; Nájera, Isabel; Bechtel, Jill; Bowden, Scott; Fitzgibbon, Joseph E.; Harrington, Patrick R.; Kempf, Dale J.; Kieffer, Tara L.; Koletzki, Diana; Kukolj, George; Lim, Soo Yeon; Pilot‐Matias, Tami; Lin, Kai; Mani, Nina; Mo, Hongmei; O’Rear, Jules; Otto, Michael; Parkin, Neil; Pawlotsky, Jean‐Michel; Petropoulos, C; Picchio, Gastón; Ralston, Robert; Reeves, Jacqueline D.; Schooley, Robert T.; Seiwert, Scott D.; Standring, David N.; Stuyver, Lieven; Sullivan, James C.; Miller, Veronica

doi:10.1053/j.gastro.2011.01.029

Cited by 34 publications

(27 citation statements)

References 37 publications

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“…However, HCV populations are inherently heterogeneous due to the poor fidelity of the HCV RNA-dependent polymerase and the high replication rate of HCV (20). Within this diverse quasispecies population, variants with reduced drug susceptibility may be present prior to therapy, which allows for their rapid emergence.…”

Section: Discussionmentioning

confidence: 99%

“…Fourteen-day danoprevir monotherapy resulted in robust antiviral responses in treatment-naïve patients and patients who failed prior pegylated interferon therapy (4). This compound is currently in development as a twice-daily, ritonavirboosted agent, where it has demonstrated a favorable side effect profile when administered with SOC for 12 weeks (7,9,43).The high replication rate of HCV and the poor fidelity of the HCV RNA-dependent RNA polymerase result in the selection of drug-resistant HCV variants during treatment (20). In vitro and in vivo studies indicate that overlapping but distinct sets of NS3/4A variants are associated with reduced susceptibility to PIs (18,23,30,38,44,49).…”

mentioning

confidence: 99%

“…The high replication rate of HCV and the poor fidelity of the HCV RNA-dependent RNA polymerase result in the selection of drug-resistant HCV variants during treatment (20). In vitro and in vivo studies indicate that overlapping but distinct sets of NS3/4A variants are associated with reduced susceptibility to PIs (18,23,30,38,44,49).…”

mentioning

confidence: 99%

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Virologic Escape during Danoprevir (ITMN-191/RG7227) Monotherapy Is Hepatitis C Virus Subtype Dependent and Associated with R155K Substitution

Lim¹,

Qin²,

Susser

et al. 2012

Antimicrob Agents Chemother

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Danoprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor that promotes multi-log 10 reductions in HCV RNA when administered as a 14-day monotherapy to patients with genotype 1 chronic HCV. Of these patients, 14/37 experienced a continuous decline in HCV RNA, 13/37 a plateau, and 10/37 a rebound. The rebound and continuous-decline groups experienced similar median declines in HCV RNA through day 7, but their results diverged notably at day 14. Plateau group patients experienced a lesser, but sustained, median HCV RNA decline. Baseline danoprevir susceptibility was similar across response groups but was reduced significantly at day 14 in the rebound group. Viral rebound in genotype 1b was uncommon (found in 2/23 patients). Population-based sequence analysis of NS3 and NS4A identified treatment-emergent substitutions at four amino acid positions in the protease domain of NS3 (positions 71, 155, 168, and 170), but only two (155 and 168) were in close proximity to the danoprevir binding site and carried substitutions that impacted danoprevir potency. R155K was the predominant route to reduced danoprevir susceptibility and was observed in virus isolated from all 10 rebound, 2/13 plateau, and 1/14 continuous-decline patients. Virus in one rebound patient additionally carried partial R155Q and D168E substitutions. Treatment-emergent substitutions in plateau patients were less frequently observed and more variable. Single-rebound patients carried virus with R155Q, D168V, or D168T. Clonal sequence analysis and drug susceptibility testing indicated that only a single patient displayed multiple resistance pathways. These data indicate the ascendant importance of R155K for viral escape during danoprevir treatment and may have implications for the clinical use of this agent.H epatitis C virus (HCV) is a positive-strand RNA virus that infects approximately 170 million people worldwide (39). It is a major cause of chronic liver disease, cirrhosis, and primary hepatocellular carcinoma. Therapy for chronic HCV infection is based on weekly injections of pegylated alpha interferon (PEG-IFN-␣) and twice-daily orally administered ribavirin (RBV). This standard of care (SOC) is associated with significant side effects and achieves a sustained virologic response (SVR) in approximately half of treated patients (5, 28). Thus, novel therapeutic modalities are clearly needed.The addition of one or more direct-acting antiviral agents (DAA) to the SOC has become a favored strategy to improve the treatment outcome of chronic HCV therapy. The two most clinically advanced DAAs, telaprevir (Incivek) and boceprevir (Victrelis), are linear peptidomimetic inhibitors of NS3/4A protease. These two NS3/4A protease inhibitors (PIs) have demonstrated significant improvements in SVR rates in genotype 1 patients when added to SOC (1,14,32,46) and have recently been licensed for use in the treatment of chronic HCV infection in the United States and in Europe. While clearly a dramatic advance in the treatment of chronic HCV, both of these compounds...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Virologic Escape during Danoprevir (ITMN-191/RG7227) Monotherapy Is Hepatitis C Virus Subtype Dependent and Associated with R155K Substitution

Lim¹,

Qin²,

Susser

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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“…D168 polymorphism G, N, or E was observed in 27% (14/52) of GT1a baseline samples (23%, 2%, and 2%, respectively) and G and N in 32% (14/44) of GT1b baselines (27% and 5%, respectively). The theoretical lower limit of NS3 variant detection is 4% (95% confidence interval) for sequencing of 80 clones (22). Only two baseline samples contained clones that carried R155 or D168 substitutions above this limit of detection: one baseline sample with 5% of clones carrying GT1b D168G (TE, 240-mg QD dose group) and one GT1a baseline sample with 53% of clones carrying D168E (TN, placebo).…”

Section: Viral Load Responsementioning

confidence: 99%

Viral Resistance in Hepatitis C Virus Genotype 1-Infected Patients Receiving the NS3 Protease Inhibitor Faldaprevir (BI 201335) in a Phase 1b Multiple-Rising-Dose Study

Berger

Lagacé

Triki

et al. 2013

Antimicrob Agents Chemother

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“…The molecular and physiological bases of the therapeutic activity of the current combination treatment with IFN-␣ plus ribavirin are poorly understood. It might be possible to establish new treatment protocols based on recently developed directly acting antiviral agents (DAAs), with or without IFN-␣ and ribavirin (22)(23)(24)(25)(26)(27).…”

mentioning

confidence: 99%

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

Perales

Beach

Gallego

et al. 2013

J Virol

172

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H epatitis C virus (HCV) infects an estimated 180 million people worldwide, and about 75% of newly infected patients progress toward a chronic infection, which constitutes a risk for severe liver diseases such as cirrhosis and hepatocarcinoma (1-4). HCV is a hepacivirus in the Flaviviridae family characterized by the error-prone replication and quasispecies dynamics typical of RNA viruses (2,(5)(6)(7). No vaccine is available to prevent HCV infections or disease, and the current standard of care treatment consists of the combination of pegylated alpha interferon (IFN-␣) and the purine nucleoside analogue ribavirin (1-␤-D-ribofuranosyl-1-H-1,2,4-triazole-3-carboxamide) (8-10). Type I interferons (IFNs) such as IFN-␣ are members of a family of cytokines that constitute key components of the innate immune response to viruses, and their induction results in an antiviral state of the cell and suppression of viral replication (11)(12)(13)(14). Ribavirin is currently used to treat a number of human viral infections, and it can display multiple mechanisms of action, including enhancement of Th1 antiviral immune responses, upregulation of IFN-stimulated genes (ISGs), depletion of GTP pools, or viral RNA mutagenesis (see reviews in references 15, 16 and 17). However, on average only about 60% of the chronically infected patients show a sustained virological response to treatment with IFN-␣ plus ribavirin that results in virus clearance (18-21). The molecular and physiological bases of the therapeutic activity of the current combination treatment with IFN-␣ plus ribavirin are poorly understood. It might be possible to establish new treatment protocols based on recently developed directly acting antiviral agents (DAAs), with or without .Highly variable viruses exploit a number of strategies to counteract selective constraints intended to prevent their replication (reviewed in reference 7). Mutations that confer resistance to DAAs generally map in the target protein or in a protein that interacts with the target (28-30). However, the complexity of the cellular IFN response pathway is expected to require greater diversity of viral resistance mutations. Current evidence suggests that the response of HCV to IFN-␣-based therapy is influenced by several host (i.e., interleukin-28B [IL-28B] gene polymorphisms) and viral genetic (i.e., viral genotype and population complexity) factors (31-37).The advent of cell culture systems for sustained replication of HCV offers new prospects to approach the evolutionary dynamics of HCV and the host cell-virus relationship, including the anti-HCV activity of IFN-␣. Using these systems, Garaigorta and Chisari documented that HCV-induced protein kinase R (PKR) phosphorylation inhibited translation of IFN-stimulated genes (ISGs) in infected hepatocytes (38). Here we describe the adaptation of the HCV replication system of genotype 2a (39-41) to perform serial passages of HCV in the Huh-7.5 hepatocyte cell line with sustained, efficient viral replication for at least 100 serial passages. This cell ...

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Sequence and Phenotypic Analysis for Resistance Monitoring in Hepatitis C Virus Drug Development: Recommendations From the HCV DRAG

Cited by 34 publications

References 37 publications

Virologic Escape during Danoprevir (ITMN-191/RG7227) Monotherapy Is Hepatitis C Virus Subtype Dependent and Associated with R155K Substitution

Virologic Escape during Danoprevir (ITMN-191/RG7227) Monotherapy Is Hepatitis C Virus Subtype Dependent and Associated with R155K Substitution

Viral Resistance in Hepatitis C Virus Genotype 1-Infected Patients Receiving the NS3 Protease Inhibitor Faldaprevir (BI 201335) in a Phase 1b Multiple-Rising-Dose Study

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

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