Implications of baseline polymorphisms for potential resistance to NS3 protease inhibitors in Hepatitis C virus genotypes 1a, 2b and 3a

Palanisamy, Navaneethan; Danielsson, Axel; Kokkula, Chakradhar; Yin, Huan; Bondeson, Kåre; Wesslén, Lars; Duberg, Ann‐Sofi; Lennerstrand, Johan

doi:10.1016/j.antiviral.2013.04.018

Cited by 61 publications

(57 citation statements)

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“…Second, the striking differences between subtypes 1a and 1b in genetic barriers to resistance to most DAAs (4,12,35), and the presence of naturally occurring resistance mutations in other HCV-1 subtypes (11), strongly suggest that a similar phenomenon is likely to occur with other genotypes, especially for genotypes 2, 4, and 6 because of their high subtype diversity (11 subtypes for G2, 17 for G4, and 24 for G6). Unfortunately, subtype-specific resistance data for other genotypes remain scarce (36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

High-Resolution Hepatitis C Virus Subtyping Using NS5B Deep Sequencing and Phylogeny, an Alternative to Current Methods

et al. 2015

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There are seven confirmed hepatitis C virus (HCV) genotypes, with whole-genome nucleotide sequences differing by Ͼ30%, and each can be further subdivided into related subtypes (67 confirmed), with nucleotide sequence divergence of between 15% and 30% (1).Genotype identification has long been used in clinical practice, because major genotypes have different response rates and require different doses and durations of pegylated interferon and ribavirin (PR) treatment. In contrast, until recently, subtype identification was mainly used in epidemiological studies. However, both in vitro studies and clinical trials with different classes of direct-acting antiviral (DAA) agents (NS3 protease, NS5A-, and nucleos[t]ide and nonnucleos[t]ide NS5B-polymerase inhibitors), given with PR or in interferon-free combinations, have shown lower response rates for HCV genotype 1a than for HCV genotype 1b (2-8). Moreover, at least for HCV genotype 1, both the frequency and the pattern of resistance to different DAA classes are subtype specific (9). A striking example is the NS3-Q80K polymorphism, naturally found in Ͼ30% of naive subtype 1a patients but in Ͻ1% of subtype 1b patients (10), which conveys 30%-to-40%-lower sustained-virologic-response (SVR) rates to the macrocyclic protease inhibitor simeprevir (2). Similarly, all subtype 1g sequences identified naturally carry a mutation conferring resistance to linear NS3 protease inhibitors (11).Subtype-specific differences in the genetic barrier to resistance appear to correlate to the RNA-dependent RNA polymerase mu-

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Section: Discussionmentioning

confidence: 99%

High-Resolution Hepatitis C Virus Subtyping Using NS5B Deep Sequencing and Phylogeny, an Alternative to Current Methods

et al. 2015

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“…These therapy although more promising have complicated dosing regimens limiting patient compliance [4e7]. Further, the selection of HCV drug resistant variants continues to remain a concern [8,9]. On the other hand, acute and chronic liver diseases that are caused by an infection with hepatitis-C virus (HCV), such as hepatocellular carcinoma and liver cirrhosis have received much attention over the past decade.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel diflunisal hydrazide–hydrazones as anti-hepatitis C virus agents and hepatocellular carcinoma inhibitors

Şenkardeş

Kaushik‐Basu

Durmaz

et al. 2016

European Journal of Medicinal Chemistry

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a b s t r a c tHepatitis C virus (HCV) infection is a main cause of chronic liver disease, leading to liver cirrhosis and hepatocellular carcinoma (HCC). The objective of our research was to develop effective agents against viral replication. We have previously identified the hydrazideehydrazone scaffold as a promising hepatitis C virus (HCV) and hepatocelluler inhibitor. Herein we describe the design a number of 2 0 ,4 0 -difluoro-4-hydroxy-N'-(arylmethylidene) biphenyl-3-carbohydrazide (3a-t) as anti-HCV and anticancer agents. Results from evaluation of anti-HCV activity indicated that most of the synthesized hydrazone derivatives inhibited viral replication in the Huh7/Rep-Feo1b and Huh 7.5-FGR-JCI-Rluc2A reporter systems. Antiproliferative activities of increasing concentrations of 2 0 ,4 0 -difluoro-4-hydroxy-N'-(2-pyridyl methylidene)biphenyl-3-carbohydrazide 3b and diflunisal (2.5e40 mM) were assessed in liver cancer cell lines (Huh7, HepG2, Hep3B, Mahlavu, FOCUS and SNU-475) with sulforhodamine B assay for 72 h. Compound 3b with 2-pyridinyl group in the hydrazone part exhibited promising cytotoxic activity against all cell lines with IC 50 values of 10, 10.34 16.21 4.74, 9.29 and 8.33 mM for Huh7, HepG2, Hep3B, Mahlavu, FOCUS and SNU-475 cells, respectively, and produced dramatic cell cycle arrest at SubG1/G0 phase as an indicator of apoptotic cell death induction.

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“…Using population sequence analysis (i.e., direct sequencing), baseline RAVs against NS3/4A protease inhibitors (PIs) telaprevir and boceprevir have been detected in 2 to 28% of treatment-naive patients in previous studies (1,(5)(6)(7)(8)(9)(10)(11). During triple therapies combining pegIFN and ribavirin with telaprevir or boceprevir, the presence of preexisting RAVs at baseline did not decrease the sustained virological response (SVR) rates (rates of infection cure) in patients who naturally responded to pegIFN-ribavirin; however, lower SVR rates have been observed in patients with baseline RAVs who were also poor pegIFN-ribavirin responders.…”

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confidence: 99%

Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin

et al. 2015

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The pretherapeutic presence of protease inhibitor (PI) resistance-associated variants (RAVs) has not been shown to be predictive of triple-therapy outcomes in treatment-naive patients. However, they may influence the outcome in patients with less effective pegylated interferon (pegIFN)-ribavirin (RBV) backbones. Using hepatitis C virus (HCV) population sequence analysis, we retrospectively investigated the prevalence of baseline nonstructural 3 (NS3) RAVs in a multicenter cohort of poor IFN-RBV responders (i.e., prior null responders or patients with a viral load decrease of <1 log IU/ml during the pegIFN-RBV lead-in phase). The impact of the presence of these RAVs on the outcome of triple therapy was studied. Among 282 patients, the prevalances (95% confidence intervals) of baseline RAVs ranged from 5.7% (3.3% to 9.0%) to 22.0% (17.3% to 27.3%), depending to the algorithm used. Among mutations conferring a >3-fold shift in 50% inhibitory concentration (IC 50 ) for telaprevir or boceprevir, T54S was the most frequently detected mutation (3.9%), followed by A156T, R155K (0.7%), V36M, and V55A (0.35%). Mutations were more frequently found in patients infected with genotype 1a (7.5 to 23.6%) than 1b (3.3 to 19.8%) (P ‫؍‬ 0.03). No other sociodemographic or viroclinical characteristic was significantly associated with a higher prevalence of RAVs. No obvious effect of baseline RAVs on viral load was observed. In this cohort of poor responders to IFN-RBV, no link was found with a sustained virological response to triple therapy, regardless of the algorithm used for the detection of mutations. Based on a cross-study comparison, baseline RAVs are not more frequent in poor IFN-RBV responders than in treatment-naive patients and, even in these difficult-to-treat patients, this study demonstrates no impact on treatment outcome, arguing against resistance analysis prior to treatment.

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Implications of baseline polymorphisms for potential resistance to NS3 protease inhibitors in Hepatitis C virus genotypes 1a, 2b and 3a

Cited by 61 publications

References 36 publications

High-Resolution Hepatitis C Virus Subtyping Using NS5B Deep Sequencing and Phylogeny, an Alternative to Current Methods

High-Resolution Hepatitis C Virus Subtyping Using NS5B Deep Sequencing and Phylogeny, an Alternative to Current Methods

Synthesis of novel diflunisal hydrazide–hydrazones as anti-hepatitis C virus agents and hepatocellular carcinoma inhibitors

Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin

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