Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent

Forns, Xavier; Gordon, Stuart C.; Zuckerman, Eli; Lawitz, Eric; Calleja, José Luís; Hofer, Harald; Gilbert, Christopher L.; Palcza, John; Howe, Anita Y.M.; DiNubile, Mark J.; Robertson, Michael; Wahl, Janice; Barr, Eliav; Buti, Marı́a

doi:10.1016/j.jhep.2015.04.009

Cited by 130 publications

(116 citation statements)

References 26 publications

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“…Elbasvir plus grazoprevir (an investigational NS3/4A protease inhibitor) as a once-daily, oral, single fixed-dose combination tablet is currently being developed for treatment of chronic HCV infection (1,2,21,(24)(25)(26). Further analyses of the phase 3 trials of grazoprevir-elbasvir will soon provide more critical data concerning the safety and efficacy of this novel double direct-acting antiviral combination.…”

Section: Discussionmentioning

confidence: 99%

Susceptibilities of Genotype 1a, 1b, and 3 Hepatitis C Virus Variants to the NS5A Inhibitor Elbasvir

Liu

Curry

McMonagle

et al. 2015

Antimicrob Agents Chemother

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Elbasvir is an investigational NS5A inhibitor with in vitro activity against multiple HCV genotypes. Antiviral activity of elbasvir was measured in replicons derived from wild-type or resistant variants of genotypes 1a, 1b, and 3. The barrier to resistance was assessed by the number of resistant colonies selected by exposure to various elbasvir concentrations. In a phase 1b dose-escalating study, virologic responses were determined in 48 noncirrhotic adult men with chronic genotype 1 or 3 infections randomized to placebo or elbasvir from 5 to 50 mg (genotype 1) or 10 to 100 mg (genotype 3) once daily for 5 days. The NS5A gene was sequenced from plasma specimens obtained before, during, and after treatment. Elbasvir suppressed the emergence of resistanceassociated variants (RAVs) in vitro in a dose-dependent manner. Variants selected by exposure to high elbasvir concentrations typically encoded multiple amino acid substitutions (most commonly involving loci 30, 31, and 93), conferring high-level elbasvir resistance. In the monotherapy study, patients with genotype 1b had greater reductions in HCV RNA levels than patients with genotype 1a at all elbasvir doses; responses in patients with genotype 3 were generally less pronounced than for genotype 1, particularly at lower elbasvir doses. M28T, Q30R, L31V, and Y93H in genotype 1a, L31V and Y93H in genotype 1b, and A30K, L31F, and Y93H in genotype 3 were the predominant RAVs selected by elbasvir monotherapy. Virologic findings in patients were consistent with the preclinical observations. NS5A-RAVs emerged most often at amino acid positions 28, 30, 31, and 93 in both the laboratory and clinical trial. (The MK-8742 P002 trial has been registered at ClinicalTrials.gov under identifier NCT01532973.)

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Section: Discussionmentioning

confidence: 99%

Susceptibilities of Genotype 1a, 1b, and 3 Hepatitis C Virus Variants to the NS5A Inhibitor Elbasvir

Liu

Curry

McMonagle

et al. 2015

Antimicrob Agents Chemother

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“…Treatment-naïve and treatment-experienced patients infected with subtype 1b as well as treatment-naive patients infected by genotype 4 should receive this combination for 12 weeks without ribavirin; treatment should be prolonged to 16 weeks with the addition of ribavirin in genotype 1a patients with higher viral load (≥ 800,000 IU/mL) or with baseline NS5A RASs conferring resistance to elbasvir, as well as in genotype 4 treatment-experienced patients with higher viral load (≥ 800,000 IU/mL) [14,19,54,[68][69][70][71][72]. C-SALVAGE examined the use of elbasvir/grazoprevir plus R ribavirin BV in patient with chronic HCV genotype 1 infection (cirrhotic and non-cirrhotic patients) after failure of peg-IFN and ribavirin [69].…”

Section: Elbasvir/grazoprevirmentioning

confidence: 99%

“…C-SALVAGE examined the use of elbasvir/grazoprevir plus R ribavirin BV in patient with chronic HCV genotype 1 infection (cirrhotic and non-cirrhotic patients) after failure of peg-IFN and ribavirin [69]. The final results of that trial showed that SVR24 was achieved in 96.2% of patients; however, baseline resistance-associated variants reappeared at relapse in the three patients with virologic failure [68].…”

Section: Elbasvir/grazoprevirmentioning

confidence: 99%

Current and future challenges in HCV: insights from an Italian experts panel

et al. 2017

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“…ALT elevations were observed at a greater frequency (2%) in females, Asians, and older adults (65 years or older). 1,2,4,6,7,12,13,32 The warnings and precautions associated with ribavirin (eg, avoiding pregnancy) should be taken into account for patients who require concomitant therapy of elbasvir/grazoprevir with ribavirin. Refer to the ribavirin prescribing information for more information.…”

Section: Warnings and Precautionsmentioning

confidence: 99%

Elbasvir/Grazoprevir

2016

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Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433. The September 2016 monograph topics are barictinib, buprenorphine implants, sarilumab, sofosbuvir/velpatasvir, and cholera vaccine, live, oral. The Safey MUE is on sofosbuvir/velpatasvir.

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Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent

Cited by 130 publications

References 26 publications

Susceptibilities of Genotype 1a, 1b, and 3 Hepatitis C Virus Variants to the NS5A Inhibitor Elbasvir

Susceptibilities of Genotype 1a, 1b, and 3 Hepatitis C Virus Variants to the NS5A Inhibitor Elbasvir

Current and future challenges in HCV: insights from an Italian experts panel

Elbasvir/Grazoprevir

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