65 Clonal Analysis of Mutations Selected in the HCV Ns3 Protease Domain of Genotype 1 Non-Responders Treated With Boceprevir (Sch503034)

Susser, S.; Welker, Martin; Zettler, Markus; Wohnsland, A.; Hughes, E.; Ralston, Robert; Zeuzem, Stefan; Sarrazin, C.

doi:10.1016/s0168-8278(08)60067-7

Cited by 15 publications

(14 citation statements)

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“…Moreover, other resistant variants have been identified in vitro (T54A, A156S/T, V170A) and in vivo (V36A/L/M, F43C/S, T54A/S, R155K/Q/T/M, A156S, V170A/T) (Tong et al 2006, Susser et al 2008, Qiu et al 2009.…”

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confidence: 99%

Variability and resistance mutations in the hepatitis C virus NS3 protease in patients not treated with protease inhibitors

Zeminian

Padovani

Corvino

et al. 2013

Mem. Inst. Oswaldo Cruz

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The goal of treatment of chronic hepatitis C is to achieve a sustained virological response, which is defined as exhibiting undetectable hepatitis C virus (HCV) RNA levels in serum following therapy for at least six months. However, the current treatment is only effective in 50% of patients infected with HCV genotype 1, the most prevalent genotype in Brazil. Inhibitors of the serine protease non-structural protein 3 (NS3) have therefore been developed to improve the responses of HCV-infected patients. However, the emergence of drug-resistant variants has been the major obstacle to therapeutic success. The goal of this study was to evaluate the presence of resistance mutations and genetic polymorphisms in the NS3 genomic region of HCV from 37 patients infected with HCV genotype 1 had not been treated with protease inhibitors. Plasma viral RNA was used to amplify and sequence the HCV NS3 gene. The results indicate that the catalytic triad is conserved. A large number of substitutions were observed in codons 153, 40 and 91; the resistant variants T54A, T54S, V55A, R155K and A156T were also detected. This study shows that resistance mutations and genetic polymorphisms are present in the NS3 region of HCV in patients who have not been treated with protease inhibitors, data that are important in determining the efficiency of this new class of drugs in Brazil.

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confidence: 99%

Variability and resistance mutations in the hepatitis C virus NS3 protease in patients not treated with protease inhibitors

Zeminian

Padovani

Corvino

et al. 2013

Mem. Inst. Oswaldo Cruz

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“…However, given the available experience with human immunodeficiency virus, the selection of double or triple HCV mutants resistant to different drugs targeting different viral genes (i.e., protease and polymerase) seems unlikely. Selected resistant variants in the protease have been implicated in late relapse after cessation of treatment, and may decline or remain detectable for years after treatment failure [44][45][46] . These resistance mutations may also revert to wild-type virus with time, but still some resistant viruses revert very slowly [47] .…”

Section: Hcv Resistance To Ns3/4a Pismentioning

confidence: 99%

Hepatitis C virus resistance to new specifically-targeted antiviral therapy: A public health perspective

Salvatierra

Fareleski²,

Forcada³

et al. 2013

WJV

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Until very recently, treatment for chronic hepatitis C virus (HCV) infection has been based on the combination of two non-viral specific drugs: pegylated interferon-α and ribavirin, which is effective in, overall, about 40%-50% of cases. To improve the response to treatment, novel drugs have been designed to specifically block viral proteins. Multiple compounds are under development, and the approval for clinical use of the first of such direct-acting antivirals in 2011 (Telaprevir and Boceprevir), represents a milestone in HCV treatment. HCV therapeutics is entering a new expanding era, and a highly-effective cure is envisioned for the first time since the discovery of the virus in 1989. However, any antiviral treatment may be limited by the capacity of the virus to overcome the selective pressure of new drugs, generating antiviral resistance. Here, we try to provide a basic overview of new treatments, HCV resistance to new antivirals and some considerations derived from a Public Health perspective, using HCV resistance to protease and polymerase inhibitors as examples.

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“…The substance exhibited appropriate nanomolar potency in enzyme-and replicon-based assays as well as a favourable selectivity profile compared to inhibition of human neutrophil elastase. Similarly to telaprevir, the monotherapeutic application leads to the development of mutations associated with resistance [87]. However, the recently presented SPRINT1 study clearly exhibited the benefit in response of a triple-regimen including boceprevir, peginterferon, and ribavirin [88].…”

Section: The Hcv Ns3-4a Proteasementioning

confidence: 99%

Recent Advances in Targeting Viral Proteases for the Discovery of Novel Antivirals

Steuber¹,

Hilgenfeld²

2010

CTMC

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The occurrence of life-threatening viral infections and the establishment of appropriate defense strategies exhibit major challenges to the disease management in our society. The unpredictable character of viral outbreaks will even be enhanced in the future due to human activities such as increasing international travel, deforestation, changes in social conditions, or influences induced by the climate change. The defense against these pathogenic agents requires preparedness, including successful drug design strategies. Viral proteases represent attractive targets for the design of anti-infective lead compounds, as in case that a viral mRNA encoding several types of proteins is recognized as a monocistronic template by the host-cell translation machinery, the presence of protease activities is required for processing the viral polyprotein precursor into structural or non-structural components essential for the formation of new virion particles. In addition, viral proteases can be involved in further processes relevant for viral replication. Numerous efforts have been made to develop potent small-molecule inhibitors of viral proteases, however, until now only a limited number reached the market. In the present contribution, functional aspects of the target proteases, their structural properties, drug design strategies, resulting inhibitors, and resistance management are reviewed and discussed by means of the four essential representative cases of HIV, HCV, SARS coronavirus, and the flaviviruses Dengue and West Nile virus.

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65 Clonal Analysis of Mutations Selected in the HCV Ns3 Protease Domain of Genotype 1 Non-Responders Treated With Boceprevir (Sch503034)

Cited by 15 publications

References 0 publications

Variability and resistance mutations in the hepatitis C virus NS3 protease in patients not treated with protease inhibitors

Variability and resistance mutations in the hepatitis C virus NS3 protease in patients not treated with protease inhibitors

Hepatitis C virus resistance to new specifically-targeted antiviral therapy: A public health perspective

Recent Advances in Targeting Viral Proteases for the Discovery of Novel Antivirals

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