1096 Asunaprevir (Asv; BMS-650032), an Ns3 Protease Inhibitor, in Combination With Peginterferon and Ribavirin in Treatment-Naive Patients With Genotype 1 Chronic Hepatitis C Infection

Bronowicki, J.-P.; Pol, S.; Thuluvath, Paul J.; Larrey, Dominique; Martorell, Claudia; Rustgi, Vinod K.; Morris, Danny; Younes, Ziad; Fried, M.W.; Bourlière, Marc; Hézode, Christophe; Reddy, RK; Massoud, Omar; Abrams, Gary A.; Ratziu, Vlad; He, Bing; Eley, Timothy; Ahmad, Asad Maqbool; Thiry, Alexandra; Llamoso, Cyril; Hughes, Eric

doi:10.1016/s0168-8278(12)61108-8

Cited by 10 publications

(13 citation statements)

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“…Asunaprevir is a selective NS3 protease inhibitor with antiviral activity in vitro against HCV genotype (GT) 1 and GT4 . These direct‐acting antivirals have demonstrated efficacy when individually combined with peginterferon alfa‐2a and ribavirin to treatment‐naive GT1 patients . These regimens were well tolerated.…”

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confidence: 99%

Resistance Analysis of Hepatitis C Virus Genotype 1 Prior Treatment Null Responders Receiving Daclatasvir And Asunaprevir

et al. 2013

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In a sentinel cohort, hepatitis C virus (HCV) patients (primarily genotype [GT] 1a) were treated with daclatasvir (NS5A inhibitor) and asunaprevir (NS3 protease inhibitor). Preexistence, emergence, and persistence of resistance variants in patients who failed this treatment are described. HCV-infected null responders received daclatasvir (60 mg once daily) and asunaprevir (600 mg twice daily) alone (Group A, 11 patients) or with peginterferon alfa-2a and ribavirin (Group B, 10 patients) for 24 weeks. Resistance testing was performed on baseline samples and samples with HCV RNA 1,000 IU/mL at Week 1 through posttreatment Week 48. Resistance substitution susceptibility to inhibition by asunaprevir and daclatasvir was assessed using HCV replicon assays. In Group A, six GT1a patients experiencing viral breakthrough and one GT1a patient who relapsed had detectable NS5A (Q30E/R, L31V/M, Y93C/N) and NS3 (R155K, D168A/ E/V/Y) resistance-associated variants at failure. Two of six viral breakthrough patients achieved SVR48 after treatment intensification with peginterferon alfa-2a and ribavirin. For 2/4 viral breakthrough patients not responding to treatment intensification, NS3 resistance variants changed (D168Y to D168T; R155K to V36M-R155K). At posttreatment Week 48, daclatasvir-resistant variants persisted while asunaprevir-resistant variants were generally replaced by wild-type sequences. The NS3 sequence remained unchanged in the one patient with NS3-R155K at baseline, relapse, and posttreatment Week 48. In Group B, no viral breakthrough was observed. Conclusion: The treatment failure of daclatasvir and asunaprevir in HCV GT1a patients was associated with both NS5A and NS3 resistance variants in prior null responders. NS5A resistance variants persisted while NS3 resistance variants generally decayed, suggesting a higher relative fitness of NS5A variants. (HEPATOLOGY 2013;58:902-911) T he investigational direct-acting antivirals, daclatasvir and asunaprevir, are currently in clinical development for treating hepatitis C virus (HCV). Daclatasvir is a first-in-class, highly selective NS5A replication complex inhibitor with picomolar potency and broad HCV genotypic coverage. 1 Asunaprevir is a selective NS3 protease inhibitor with antiviral activity in vitro against HCV genotype (GT) 1 and GT4. 2 These direct-acting antivirals have demonstrated efficacy when individually combined with peginterferon alfa-2a and ribavirin to treatmentnaive GT1 patients. [3][4][5][6] These regimens were well tolerated.When peginterferon alfa-2a and ribavirin were added to the dual combination of daclatasvir and asunaprevir, all patients experienced sustained virologic response (SVR) at 48 weeks posttreatment. 7 The combination of daclatasvir and asunaprevir alone resulted in rapid suppression of HCV RNA levels in GT1 null responder patients. 7 This proof-of-concept study was the first to show that null responder HCV-infected patients could be cured with 24 weeks of an Abbreviations: HCV, hepatitis C virus; GT, genotype; LLOQ, lower lim...

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Resistance Analysis of Hepatitis C Virus Genotype 1 Prior Treatment Null Responders Receiving Daclatasvir And Asunaprevir

et al. 2013

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“…Besides, the safety profile seems to be good. The pan-genotypic activity of this new treatment provides new therapeutic options for a greater number of patients, in particular for those infected with GT-4 25,27–29…”

Section: Treatment Of Gt-1 Patients Beyond Boceprevir and Telaprevirmentioning

confidence: 99%

Chronic hepatitis C: future treatment

Wendt¹,

Adhoute²,

Castellani³

et al. 2014

CPAA

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The launch of first-generation protease inhibitors (PIs) is a major step forward in HCV treatment. However, the major advance is up to now restricted to genotype 1 (GT-1) patients. The development of second-wave and second-generation PIs yields higher antiviral potency through plurigenotypic activity, more convenient daily administration, fewer side effects and, for the second-generation PIs, potential activity against resistance-associated variants. NS5B inhibitors include nucleoside/nucleotide inhibitors (NIs) and non-nucleotide inhibitors (NNIs). NIs have high efficacy across all genotypes. Sofosbuvir has highly potent antiviral activity across all genotypes in association with pegylated interferon and ribavirin (PR), thus allowing shortened treatment duration. NS5A inhibitors (NS5A.I) have highly potent antiviral activity. It has recently been shown for the first time that NS5A.I in combination with protease inhibitors can cure GT-1b null responders in an interferon-free regimen. Besides, several studies demonstrate that interferon (IFN)-free regimens with direct-acting antiviral agent combinations are able to cure a large number of either naïve or treatment-experienced GT-1 patients. Moreover, quadruple regimen with PR is able to cure almost all GT-1 null responders. The development of pan-genotypic direct-acting antiviral agents (NIs or NS5A.I) allows new combinations with or without PR that increase the rate of sustained virological response for all patients, even for those with cirrhosis and independently of the genotype. Therefore, the near future of HCV treatment looks promising. The purpose of this article is to provide an overview of the clinical results recently reported for HCV treatment.

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“…Second-wave PIs have a higher barrier to resistance, better activity against multiple genotypes except GT-3, more convenient dosing schedules and improved safety and tolerance [Ciesek et al 2011;Fusco et al 2011;Asselah et al 2011]. Second-generation PIs are compounds that are broadly active against all genotypes and against viral isolates that carry resistance mutations for first-generation PIs [Jacobson et al 2013;Manns et al 2013a;Zeuzem et al 2012a;Ferenci et al 2013;Sulkowski et al 2013aSulkowski et al , 2013bEverson et al 2012a;Feld et al 2012;Manns et al 2012;Lawitz et al 2011bLawitz et al , 2012bPoordad et al 2012a;Bronowicki et al 2012;Lok et al 2012b]. In combination with PR, the new PIs appear to achieve greater SVR rates than the first-generation PIs.…”

Section: Treatment Of Gt-1 Patients Beyond Boceprevir or Telaprevirmentioning

confidence: 99%

“…In addition, the safety profile seems to be good. The pan-genotypic activity of these new treatments provides new therapeutic options for a greater number of patients, in particular for those infected with GT-4 [Moreno et al 2010;Bronowicki et al 2012;Hezode et al 2012b]. Table 1 gives an overview of the efficacy and tolerance of the second-wave PIs that are currently developed.…”

Section: Treatment Of Gt-1 Patients Beyond Boceprevir or Telaprevirmentioning

confidence: 99%

An update on the treatment of genotype-1 chronic hepatitis C infection: lessons from recent clinical trials

Wendt

Bourlière

2013

Therapeutic Advances in Infection

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The launch of first-generation protease inhibitors (PIs) was a major step forward in hepatitis C virus (HCV) treatment. However, this major advance is, up to now, restricted to genotype-1 (GT-1) patients. However, the ongoing development of new direct-acting antiviral agents (DAAs) allows new hope for the future. The development of second-wave and second-generation PIs yields higher antiviral potency through plurigenotypic activity, more convenient daily administration, fewer side effects and, for the second-generation PIs, potential activity against resistance-associated variants. NS5B inhibitors (NS5B.I) include nucleoside/nucleotide inhibitors (NIs) and nonnucleotide inhibitors (NNIs). NIs have high efficacy across all genotypes. Sofosbuvir has highly potent antiviral activity across all genotypes in association with pegylated interferon (IFN) and ribavirin (PR), thus allowing shortened treatment duration. NS5A inhibitors (NS5A.I) have highly potent antiviral activity. It has recently been shown for the first time that NS5A.I in combination with PI can cure GT-1b null-responder patients in an IFN-free regimen. In addition, several studies demonstrate that IFN-free regimens with DAA combinations are able to cure a large number of either naïve or treatment-experienced GT-1 patients. Moreover, a quadruple regimen with PR is able to cure almost all GT-1 null-responders. The development of pan-genotypic DAAs (NIs or NS5A.I) allows new combinations with or without PR that increase the rate of sustained virological response (SVR) for all patients, even for those with cirrhosis and independently of the genotype. Therefore, the near future of HCV treatment looks promising. The purpose of this article is to provide an overview of the clinical results recently reported for HCV treatment in GT-1 patients.

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1096 Asunaprevir (Asv; BMS-650032), an Ns3 Protease Inhibitor, in Combination With Peginterferon and Ribavirin in Treatment-Naive Patients With Genotype 1 Chronic Hepatitis C Infection

Cited by 10 publications

References 0 publications

Resistance Analysis of Hepatitis C Virus Genotype 1 Prior Treatment Null Responders Receiving Daclatasvir And Asunaprevir

Resistance Analysis of Hepatitis C Virus Genotype 1 Prior Treatment Null Responders Receiving Daclatasvir And Asunaprevir

Chronic hepatitis C: future treatment

An update on the treatment of genotype-1 chronic hepatitis C infection: lessons from recent clinical trials

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