762 Resistance Profile of Abt-333 and Relationship to Viral Load Decrease in Patients Treated in Combination With Peg-Interferon and Ribavirin for 28 Days

Middleton, Tim; He, Yukai; Beyer, Jill; Menon, Rani; Klein, C.; Cohen, Daniel E.; Collins, Christine A.

doi:10.1016/s0168-8278(10)60764-7

Cited by 17 publications

(21 citation statements)

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“…In particular, the 316Y variant, located near the polymerase active site, was described to confer resistance to NNI-4 and NNI-3 compounds, such as ABT-333 (12,41,80) and tegobuvir, along with substitutions at positions 448, 452, and 445 (44). The 448H variant also was found to be the first resistance substitution to emerge in HCV-1 patients failing tegobuvir in combination with PEG-IFN plus ribavirin (45).…”

Section: Discussionmentioning

confidence: 99%

“…1). According to the level of resistance, NI/NNI resistance-associated variants have been divided into major (high-intermediate level of resistance) and minor (low level of resistance) variants (7,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). Only variants with prevalences of Ͼ1% and found in Ն2 patients were considered.…”

Section: Methodsmentioning

confidence: 99%

“…The obtained models were adopted for quantum mechanics polarized ligand docking (QPLD) (54) molecular docking studies. For each NS5B structure, a grid box of 27,000 Å (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). The number in the bar represents the amino acid position.…”

Section: Methodsmentioning

confidence: 99%

“…The letter above the number refers to the wild-type amino acid (HCV-1b reference sequence, GenBank accession number AJ238799), and the letter(s) below the bars represents the resistance substitutions. Bold type represents the key major substitutions associated with the resistance phenotype (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). For the drug with an asterisk, reported substitutions are associated with resistance only in vitro.…”

Section: Methodsmentioning

confidence: 99%

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Hepatitis C Virus Genetic Variability and the Presence of NS5B Resistance-Associated Mutations as Natural Polymorphisms in Selected Genotypes Could Affect the Response to NS5B Inhibitors

Maio

Cento

Mirabelli

et al. 2014

Antimicrob Agents Chemother

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Because of the extreme genetic variability of hepatitis C virus (HCV), we analyzed the NS5B polymerase genetic variability in circulating HCV genotypes/subtypes and its impact on the genetic barrier for the development of resistance to clinically relevant nucleoside inhibitors (NIs)/nonnucleoside inhibitors (NNIs). The study included 1,145 NS5B polymerase sequences retrieved from the Los Alamos HCV database and GenBank. The genetic barrier was calculated for drug resistance emergence. Prevalence and genetic barrier were calculated for 1 major NI and 32 NNI resistance variants (13 major and 19 minor) at 21 total NS5B positions. Docking calculations were used to analyze sofosbuvir affinity toward the diverse HCV genotypes. Overall, NS5B polymerase was moderately conserved among all HCV genotypes, with 313/591 amino acid residues (53.0%) showing <1% variability and 83/591 residues (14.0%) showing high variability (>25.1%). Nine NNI resistance variants (2 major variants, 414L and 423I; 7 minor variants, 316N, 421V, 445F, 482L, 494A, 499A, and 556G) were found as natural polymorphisms in selected genotypes. In particular, 414L and 423I were found in HCV genotype 4 (HCV-4) (n ‫؍‬ 14/38, 36.8%) and in all HCV-5 sequences (n ‫؍‬ 17, 100%), respectively. Regardless of HCV genotype, the 282T major NI resistance variant and 10 major NNI resistance variants (316Y, 414L, 423I/T/V, 448H, 486V, 495L, 554D, and 559G) always required a single nucleotide substitution to be generated. Conversely, the other 3 major NNI resistance variants (414T, 419S, and 422K) were associated with a different genetic barrier score development among the six HCV genotypes. Sofosbuvir docking analysis highlighted a better ligand affinity toward HCV-2 than toward HCV-3, in agreement with the experimental observations. The genetic variability among HCV genotypes, particularly with the presence of polymorphisms at NNI resistance positions, could affect their responsiveness to NS5B inhibitors. A pretherapy HCV NS5B sequencing could help to provide patients with the full efficacy of NNI-containing regimens.T he advent of direct antiviral agents (DAAs) has opened a new era for the treatment of hepatitis C virus (HCV) infection. Since 2011, telaprevir and boceprevir, two linear protease inhibitors, have been approved by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a new standard of care for first-line treatment of HCV genotype 1 (HCV-1), in association with pegylated alpha interferon (PEG-IFN) and ribavirin. Both of these combination treatments have shown improved sustained virological response (SVR) rates along with reduced treatment duration (1-4). Despite the increase in SVR and their high potency, these two first approved protease inhibitors are still "fragile" drugs because of their low genetic barrier, extensive cross-resistance profile, and significant side effects. Therefore, additional DAAs that target different HCV proteins as well are currently in development (5-8) (http://www.pipelinereport.org; htt...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Hepatitis C Virus Genetic Variability and the Presence of NS5B Resistance-Associated Mutations as Natural Polymorphisms in Selected Genotypes Could Affect the Response to NS5B Inhibitors

Maio

Cento

Mirabelli

et al. 2014

Antimicrob Agents Chemother

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“…The resistance profile of inhibitors that bind allosterically in the palm domain of NS5B, near the elongation pocket of the polymerase, has been thoroughly characterized using the replicon system (41,42) and the clinical resistance pattern from early studies for some of the compounds in development has been reported (2). In early clinical trials with ABT-333, NS5B variants C316Y, M414T, Y448H, S556G, and D559G/N were observed (43). A partially overlapping resistance profile of NS5B C316N, C445F, Y448H, and Y452H was reported for tegobuvir (GS-9190) in patients that failed in the combination of tegobuvir, and the protease inhibitor GS-9256 and ribavirin (44,45).…”

Section: Baselinementioning

confidence: 99%

Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

Bartels

Sullivan

Zhang

et al. 2013

J Virol

135

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The prevalence of naturally occurring hepatitis C virus (HCV) variants that are less sensitive to direct-acting antiviral (DAA) inhibitors has not been fully characterized. We used population sequence analysis to assess the frequency of such variants in plasma samples from 3,447 DAA-naive patients with genotype 1 HCV. In general, HCV variants with lower-level resistance (3-to 25-fold increased 50% inhibitor concentration [IC 50 ]) to telaprevir were observed as the dominant species in 0 to 3% of patients, depending on the specific variant, whereas higher-level resistant variants (>25-fold-increased IC 50 ) were not observed. Specific variants resistant to NS5A inhibitors were predominant in up to 6% of patients. Most variants resistant to nucleo(s/t)ide activesite NS5B polymerase inhibitors were not observed, whereas variants resistant to non-nucleoside allosteric inhibitors were observed in up to 18% of patients. The presence of DAA-resistant variants in NS5A, NS5B, or NS3 (including telaprevir-resistant variants), in baseline samples of treatment-naive patients receiving a telaprevir-based regimen in phase 3 studies did not affect the sustained viral response (SVR). Treatment-naive patients with viral populations containing the telaprevir-resistant variants NS3 V36M, T54S, or R155K at baseline achieved a 74% SVR rate, whereas patients with no resistant variants detected prior to treatment achieved a 76% SVR rate. The effect of specific resistant variant frequency on response to various DAA treatments in different patient populations, including interferon nonresponders, should be further studied.

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Hepatitis C virus drug resistance–associated substitutions: State of the art summary

et al. 2015

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Hepatitis C virus (HCV) drug development has resulted in treatment regimens composed of interferon‐free, all‐oral combinations of direct‐acting antivirals. While the new regimens are potent and highly efficacious, the full clinical impact of HCV drug resistance, its implications for retreatment, and the potential role of baseline resistance testing remain critical research and clinical questions. In this report, we discuss the viral proteins targeted by HCV direct‐acting antivirals and summarize clinically relevant resistance data for compounds that have been approved or are currently in phase 3 clinical trials. Conclusion: This report provides a comprehensive, systematic review of all resistance information available from sponsors’ trials as a tool to inform the HCV drug development field. (Hepatology 2015;62:1623–1632)

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762 Resistance Profile of Abt-333 and Relationship to Viral Load Decrease in Patients Treated in Combination With Peg-Interferon and Ribavirin for 28 Days

Cited by 17 publications

References 0 publications

Hepatitis C Virus Genetic Variability and the Presence of NS5B Resistance-Associated Mutations as Natural Polymorphisms in Selected Genotypes Could Affect the Response to NS5B Inhibitors

Hepatitis C Virus Genetic Variability and the Presence of NS5B Resistance-Associated Mutations as Natural Polymorphisms in Selected Genotypes Could Affect the Response to NS5B Inhibitors

Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

Hepatitis C virus drug resistance–associated substitutions: State of the art summary

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