Efficacy of an Interferon- and Ribavirin-Free Regimen of Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With HCV Genotype 1 Infection

Everson, Gregory T.; Sims, Karen; Rodrı́guez-Torres, Maribel; Hézode, Christophe; Lawitz, Eric; Bourlière, Marc; Loustaud‐Ratti, Véronique; Rustgi, Vinod K.; Schwartz, Howard; Tatum, H.; Marcellin, Patrick; Pol, Stanislas; Thuluvath, Paul J.; Eley, Timothy; Wang, Xiaodong; Huang, Shenlin; McPhee, Fiona; Wind‐Rotolo, Megan; Chung, Ellen; Pasquinelli, Claudio; Grasela, Dennis M.; Gardiner, David F.

doi:10.1053/j.gastro.2013.10.057

Cited by 193 publications

(169 citation statements)

References 31 publications

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“…A proof-of-concept clinical trial of triple-DAA treatment (10) also showed that SOF&DCV&SMV can achieve a high SVR rate, while reducing the treatment period from 12 wk to only 3 wk using a response-guided protocol. Our analysis clearly supports a clinical advantage for triple-DAA-based IFN-free treatments as discussed elsewhere (8,10,(20)(21)(22).…”

Section: Resultssupporting

confidence: 83%

“…Triple-DAA IFNfree combinations are being clinically evaluated to seek more rapid and efficacious elimination of HCV, including NI&N-S5AI&PI and NI&NS5AI&NNI (8,(20)(21)(22). However, it is not yet understood how much advantage triple-DAA treatment can provide over double-DAA treatment, and which triple-DAA combination will give the best treatment outcome (8,(20)(21)(22). Here, we quantified the anti-HCV activity of eight candidate combinations of triple-DAA treatment; SOF with NS5AI (DCV, LDV) plus PI (SMV, ASV) or NNI (VX, DAS) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

Koizumi

Ohashi

Nakajima

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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With the introduction of direct-acting antivirals (DAAs), treatment against hepatitis C virus (HCV) has significantly improved. To manage and control this worldwide infectious disease better, the “best” multidrug treatment is demanded based on scientific evidence. However, there is no method available that systematically quantifies and compares the antiviral efficacy and drug-resistance profiles of drug combinations. Based on experimental anti-HCV profiles in a cell culture system, we quantified the instantaneous inhibitory potential (IIP), which is the logarithm of the reduction in viral replication events, for both single drugs and multiple-drug combinations. From the calculated IIP of 15 anti-HCV drugs from different classes [telaprevir, danoprevir, asunaprevir, simeprevir, sofosbuvir (SOF), VX-222, dasabuvir, nesbuvir, tegobuvir, daclatasvir, ledipasvir, IFN-α, IFN-λ1, cyclosporin A, and SCY-635], we found that the nucleoside polymerase inhibitor SOF had one of the largest potentials to inhibit viral replication events. We also compared intrinsic antiviral activities of a panel of drug combinations. Our quantification analysis clearly indicated an advantage of triple-DAA treatments over double-DAA treatments, with triple-DAA treatments showing enhanced antiviral activity and a significantly lower probability for drug resistance to emerge at clinically relevant drug concentrations. Our framework provides quantitative information to consider in designing multidrug strategies before costly clinical trials.

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Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

Koizumi

Ohashi

Nakajima

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…GT-1a-and GT-1b-infected patients (23 of 26) treated with a combination of BMS-791325 (75 or 150 mg twice daily) plus pegylated interferon ␣ and ribavirin achieved sustained virologic response, a milestone strongly associated with the cure of HCV (8). In a more recent Phase 2 study, 63 of 66 HCV-infected GT-1 patients treated for 12 or 24 weeks with a combination of BMS-791325 (75 or 150 mg twice daily), daclatasvir (60 mg once daily), and asunaprevir (200 mg twice daily) achieved sustained virologic response (9). The preclinical profile of BMS-791325, including potent activity in GT-1a and -1b enzyme and replicon assays (IC 50 and EC 50 values of 0.7-4 nM), selection of significant resistance at a single substitution site, and a robust pharmacokinetic profile in animal models, anticipated the strong antiviral effect observed in patients (10,11).…”

Section: Hepatitis C Virus (Hcv)mentioning

confidence: 99%

Mechanism of Inhibition for BMS-791325, a Novel Non-nucleoside Inhibitor of Hepatitis C Virus NS5B Polymerase

Rigat

Lü

Wang

et al. 2014

Journal of Biological Chemistry

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Background: BMS-791325, a non-nucleoside inhibitor of HCV NS5B, has robust clinical efficacy. Results: Biochemical and biophysical methods revealed a non-competitive time-dependent inhibition mechanism and permitted complete parameterization of inhibitor binding kinetics. Conclusion: Thumb and finger variants affect BMS-791325 association rates. Significance: The impact of NS5B variants on BMS-791325 binding provides insight into the basis of inhibitor resistance and the process of replication complex formation.

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“…51 Based on a modified intent-to-treat analysis, 92% of the patients achieved an SVR12. Results of an expansion cohort evaluating this triple DAA regimen in a larger number (n ¼ 166) of therapy-naïve patients including cirrhotic patients were presented at AASLD 2013.…”

Section: Clinical Trials Investigating Triple Daa Combination Therapiesmentioning

confidence: 99%

Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

Welzel

Zeuzem

2014

Semin Liver Dis

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The establishment of a robust hepatitis C virus (HCV) cell culture system and subsequent detailed characterization of the HCV life cycle was a key step toward the identification of putative antiviral targets and respective antiviral drugs. 1,2 These include direct-acting antiviral agents (DAAs) such as NS3/4A protease inhibitors, NS5A inhibitors, nucleos(t)ide and non-nucleoside polymerase inhibitors, as well as hosttargeting agents (HTAs) directed against cellular factors involved in viral entry or replication. 3 Trials investigating different drug classes with and without pegylated interferon (PegIFN) and/or ribavirin have rapidly evolved, yielding highly promising sustained virologic response (SVR) rates. 4,5 In regard to the enormous public health impact of HCV infection with an estimated 184 million anti-HCV positive persons worldwide, the recent advances in HCV drug development, together with implementation of improved HCV screening programs, have the potential to substantially reduce the burden of HCV-associated advanced liver disease including hepatocellular carcinoma. 6-9The first-in-class NS3/4A inhibitors telaprevir and boceprevir were approved in 2011. Addition of these drugs to the PegIFN/ribavirin backbone has considerably improved response rates in HCV therapy naïve and experienced patients compared with PegIFN/ribavirin alone. [10][11][12][13] The poor side-effect profile of these IFN-based therapies, however, limits the wide clinical applicability. Proof of the principle that viral clearance can be achieved with an IFN-free DAA combination has fast-tracked design and the conduct of clinical trials investigating IFN-free DAA combinations. 14 Different HCV genotypes and multiple subtypes result in a genotype and subtype-dependent efficacy of many available DAAs. 15,16 Furthermore, viral clearance is challenged by the presence and selection of resistance-associated variants (RAVs). 17,18 Thus, essential prerequisites for DAAs in clinical development comprise a high antiviral efficacy, a broad and at best pan-genotypic activity, as well as a high barrier to resistance. In this respect, nucleos(t)ide polymerase inhibitors display very favorable characteristics. [19][20][21] In addition to a high antiviral efficacy, binding to the highly conserved active site of the RNA-dependent RNA-polymerase (RdRp) and incorporation as active triphosphates into the growing HCV RNA chain terminating its elongation, confers a pan-genotypic activity. Also, the low replication fitness of emergent Keywords ► interferon-free HCV treatment ► direct-acting antiviral agents ► NS3/4A protease inhibitors ► NS5A inhibitors ► non-nucleoside polymerase inhibitors ► host-targeting agents AbstractThe identification of viral and host factors involved in hepatitis C virus (HCV) replication was a key prerequisite for the discovery and further exploration of antiviral drug targets. As of today, numerous direct-acting antiviral agents (DAAs), as well as host-targeting agents (HTAs), have been developed and entered clinical testing. The...

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Efficacy of an Interferon- and Ribavirin-Free Regimen of Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With HCV Genotype 1 Infection

Cited by 193 publications

References 31 publications

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

Mechanism of Inhibition for BMS-791325, a Novel Non-nucleoside Inhibitor of Hepatitis C Virus NS5B Polymerase

Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

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