Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study

Hézode, Christophe; Hirschfield, Gideon M.; Ghesquière, Wayne; Sievert, William; Rodrı́guez-Torres, Maribel; Shafran, Stephen D.; Thuluvath, Paul J.; Tatum, H.; Waked, Imam; Esmat, Gamal; Lawitz, Eric; Rustgi, Vinod K.; Pol, Stanislas; Weis, Nina; Pockros, Paul J.; Bourlière, Marc; Serfaty, Lawrence; Vierling, John M.; Fried, Michael; Weiland, Ola; Brunetto, Maurizia Rossana; Everson, Gregory T.; Zeuzem, Stefan; Kwo, Paul Y.; Sulkowski, Mark S.; Bräu, Norbert; Hernandez, Dennis; McPhee, Fiona; Wind‐Rotolo, Megan; Liu, Zhaohui; Noviello, Stephanie; Hughes, Eric; Yin, Philip D.; Schnittman, Steven M.

doi:10.1136/gutjnl-2014-307498

Cited by 106 publications

(89 citation statements)

References 29 publications

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“…In the COMMAND-1 trial, 55 treatment-naive HCV GT-1 and 4 patients were treated with DCV (or placebo) plus Peg-IFNa/RBV. The study design consisted of three arms: Peg-IFNa/RBV plus DCV 20 mg, DCV 60 mg, or placebo.…”

Section: Genotypementioning

confidence: 99%

Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection: Update 2016

Puri

Saraswat

Dhiman

et al. 2016

Journal of Clinical and Experimental Hepatology

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India contributes significantly to the global burden of HCV. While the nucleoside NS5B inhibitor sofosbuvir became available in the Indian market in March 2015, the other directly acting agents (DAAs), Ledipasvir and Daclatasvir, have only recently become available in the India. The introduction of these DAA in India at a relatively affordable price has led to great optimism about prospects of cure for these patients as not only will they provide higher efficacy, but combination DAAs as all-oral regimen will result in lower side effects than were seen with pegylated interferon alfa and ribavirin therapy. Availability of these newer DAAs has necessitated revision of INASL guidelines for the treatment of HCV published in 2015. Current considerations for the treatment of HCV in India include the poorer response of genotype 3, nonavailability of many of the DAAs recommended by other guidelines and the cost of therapy. The availability of combination DAA therapy has simplified therapy of HCV with decreased reliance of evaluation for monitoring viral kinetics or drug related side effects. ( J CLIN EXP HEPATOL 2016;6:119-145) T here have been revolutionary changes in the management of chronic hepatitis C (CH-C) over the last few years. Pegylated interferon alfa (Peg-IFNa) plus ribavirin (RBV) therapy, which till the recent past was the standard of care, has been eclipsed by the arrival of newer directly acting antiviral agents (DAAs). Not only do the DAAs have better efficacy, they are also associated with lower side effects, have better tolerability, a shorter duration of therapy, and have simpler administration.In the recent guidelines issued by the American Association for the study of Liver Diseases (AASLD), in collaboration with the Infectious Diseases Society of America 1 and the European Association for Study of the Liver z (EASL), 2 the role of Peg-IFNa/RBV therapy in the management of HCV has been relegated to second-line, backup status. These newer guidelines, however, cannot be implemented in India as many of the recommended drugs are yet to be marketed in India. Other considerations for the treatment of HCV in India are a predominance of

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Section: Genotypementioning

confidence: 99%

Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection: Update 2016

Puri

Saraswat

Dhiman

et al. 2016

Journal of Clinical and Experimental Hepatology

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“…Recently, LDV was shown to inhibit NS5A through direct binding to the NS5A protein, and resistance to LDV was shown to be the result of lower binding affinity to NS5A mutants (12). Targeting NS5A has been validated clinically, as treatment with NS5A inhibitors elicits a rapid decline of HCV viral load (13,14) and enhanced SVR rates when combined with Peg-IFN and RBV (15) or other DAAs, including SOF (7,8,16).…”

mentioning

confidence: 99%

In Vitro Antiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir

Cheng

Yang

Doehle

et al. 2016

Antimicrob Agents Chemother

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Ledipasvir (LDV; GS-5885), a component of Harvoni (a fixed-dose combination of LDV with sofosbuvir [SOF]), is approved to treat chronic hepatitis C virus (HCV) infection. Here, we report key preclinical antiviral properties of LDV, including in vitro potency, in vitro resistance profile, and activity in combination with other anti-HCV agents. LDV has picomolar antiviral activity against genotype 1a and genotype 1b replicons with 50% effective concentration (EC 50 ) values of 0.031 nM and 0.004 nM, respectively. LDV is also active against HCV genotypes 4a, 4d, 5a, and 6a with EC 50 values of 0.11 to 1.1 nM. LDV has relatively less in vitro antiviral activity against genotypes 2a, 2b, 3a, and 6e, with EC 50 values of 16 to 530 nM. In vitro resistance selection with LDV identified the single Y93H and Q30E resistance-associated variants (RAVs) in the NS5A gene; these RAVs were also observed in patients after a 3-day monotherapy treatment. In vitro antiviral combination studies indicate that LDV has additive to moderately synergistic antiviral activity when combined with other classes of HCV direct-acting antiviral (DAA) agents, including NS3/4A protease inhibitors and the nucleotide NS5B polymerase inhibitor SOF. Furthermore, LDV is active against known NS3 protease and NS5B polymerase inhibitor RAVs with EC 50 values equivalent to those for the wild type.

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“…An in vitro study revealed that replicons containing multiple NS5A mutations (L28S, M31I, and Y93H) conferred high resistance to DCV [24]. Hézode et al [25] reported treatment failure to DCV in patients infected with genotype 4a mutants harboring double substitutions at positions 28 and 30. In a parallel in vitro study, double substitutions at L28M-R30H and L28M-L30S positions conferred >10,000-fold resistance against the NS5A inhibitors DCV and LDV [25].…”

Section: Ns5a Inhibitorsmentioning

confidence: 99%

“…Hézode et al [25] reported treatment failure to DCV in patients infected with genotype 4a mutants harboring double substitutions at positions 28 and 30. In a parallel in vitro study, double substitutions at L28M-R30H and L28M-L30S positions conferred >10,000-fold resistance against the NS5A inhibitors DCV and LDV [25]. The influence of baseline NS5A single or multiple mutations in genotype 4-infected patients was investigated in 186 patients receiving DCV.…”

Section: Ns5a Inhibitorsmentioning

confidence: 99%

Resistance to Direct-Acting Antiviral Agents in Treatment of Hepatitis C Virus Infections

Awady¹,

Dawood²

2017

Update on Hepatitis C

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Compounds targeting nonstructural (NS) proteins of hepatitis C virus (HCV) demonstrate clinical promise, suggesting that NS3/NS4a, NS5A, or NS5B inhibitors are potential components in direct-acting antiviral (DAA) combination therapies. In vitro studies revealed dramatic inhibition of viral replication or alteration in subcellular localization of NS proteins. DAAs bind either to catalytic sites (NS3 and NS5B) or to domain-1 of NS5A. Although >90% of the patients clear HCV RNA from their sera, a significant portion of cirrhotic patients suffer from resistance or virological relapse. Mutations in specific residues (Q80K) in NS3 (M28, A30, L31, and Y93 in genotypes 1a and 1b or L28, L30, M31, and Y93 in genotype 4) in NS5A and A282T in NS5B are associated with resistance to DAA [resistance-associated variants (RAVs)]. Current knowledge on the NS functions, mode of action of DAAs, and impacts of RAVs on treatment response are discussed. Not only mutations affecting the binding of DAAs to target proteins but also substitutions affecting the replication fitness of mutant quasispecies are major determinants of treatment failures. These resistance-associated substitutions (RASs) are now considered the major viral mutants that influence the virological outcome after DAA treatment.

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Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study

Abstract: NCT01125189.

Cited by 106 publications

References 29 publications

Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection: Update 2016

Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection: Update 2016

In Vitro Antiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir

Resistance to Direct-Acting Antiviral Agents in Treatment of Hepatitis C Virus Infections

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