Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1

Department of Internal Medicine, Division of Gastroenterology, 3912 Taubman Center, SPC 5362, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
New England Journal of Medicine (Impact Factor: 55.87). 01/2012; 366(3):216-24. DOI: 10.1056/NEJMoa1104430
Source: PubMed


Patients with chronic hepatitis C virus (HCV) infection who have not had a response to therapy with peginterferon and ribavirin may benefit from the addition of multiple direct-acting antiviral agents to their treatment regimen.
This open-label, phase 2a study included an exploratory cohort of 21 patients with chronic HCV genotype 1 infection who had not had a response to previous therapy (i.e., had not had ≥2 log(10) decline in HCV RNA after ≥12 weeks of treatment with peginterferon and ribavirin). We randomly assigned patients to receive the NS5A replication complex inhibitor daclatasvir (60 mg once daily) and the NS3 protease inhibitor asunaprevir (600 mg twice daily) alone (group A, 11 patients) or in combination with peginterferon alfa-2a and ribavirin (group B, 10 patients) for 24 weeks. The primary end point was the percentage of patients with a sustained virologic response 12 weeks after the end of the treatment period.
A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a sustained virologic response at 12 weeks after treatment and also at 24 weeks after treatment.. Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases; 1 patient had a viral response at the end of treatment but had a relapse after the treatment period. All 10 patients in group B had a sustained virologic response at 12 weeks after treatment, and 9 had a sustained virologic response at 24 weeks after treatment. Diarrhea was the most common adverse event in both groups. Six patients had transient elevations of alanine aminotransferase levels to more than 3 times the upper limit of the normal range.
This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents only. In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with peginterferon alfa-2a and ribavirin. (Funded by Bristol-Myers Squibb; number, NCT01012895.).

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    • "In vitro, the resistance profile of DCV has been established in authentic and hybrid HCV replicons representing GT1 through GT6 [10] while in proof-of-concept clinical studies, efforts have mostly focused on HCV GT1 [11]. The most frequently observed NS5A substitutions emerge at positions 28, 30, 31, and 93, although substitutions at 32, 58, 62 and 92 have been reported [11] [12] [13] [14] [15]. Limited data is available for GT4, and most available data are on subgenotype 4a [13] [16], that is the most frequent subgenotype in Egypt [2] [3]. "
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    ABSTRACT: Daclatasvir (DCV) is an approved NS5A inhibitor with potent anti-HCV activity and broad genotype coverage. DCV resistance-associated variants (RAVs) have been described for patients infected with genotype (GT) 1, but increased GT4 prevalence in European countries as a result of immigration has boosted interest in this genotype. Establishment of NS5A variability in treatment-naive patients with HCV genotype 4 infection and a case study of the dynamics of resistance-associated variants in a virologic failure receiving pIFN/RBV+DCV, as assessed by ultra-deep sequencing. Five treatment-naïve GT4 patients (GT4a [n=1], GT4d [n=3], GT4o [n=1]) were evaluated for inclusion in the COMMAND-4 study and treatment with pIFN/RBV±DCV. Patient (Pt) 1 received pIFN/RBV; Pts2-4 received pIFN/RBV + DCV; Pt5 was a screening failure. Pt1 relapsed; Pt2 experienced breakthrough at Wk4; Pts3 and 4 achieved a sustained virologic response. No substitutions associated with DCV-resistance were detected at baseline. In terms of viremic time points for Pts1 and 2, the extent of NS5A diversity pre-treatment was not significantly related to viral load (r = -0568; p = 0.035). In Pt2, multiple substitutions associated with DCV-resistance were observed after breakthrough at NS5A amino acid positions 28, 31 and 93. These substitutions were frequently observed on the same haplotype (L28S + M31I = 55.52, 82.50, and 99.36% at Wk4, 8 and 9; L28S + M31I + Y93H = 11.77, 5.01 and <0.6% at Wk4, 8 and 9). This is the first report to describe DCV-resistance in patients infected with GT4d, supporting a possible role for a recently described RAV (L28S), and presenting the dynamics of HCV quasispecies during therapy failure, with indications of changes of diversity and association of mutations. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Clinical Virology 02/2015; 66. DOI:10.1016/j.jcv.2015.02.001 · 3.02 Impact Factor
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    • "In the current study, most events of diarrhoea were grade 1/2, and none led to treatment discontinuation. Asunaprevir at doses >200 mg has been associated with grade 3/4 aminotransferase elevations [13] [18]. In the current study, incidences of grade 3/4 aminotransferase elevations were higher with asunaprevir, but there were no associated signs or symptoms of liver decompensation and no patients met the criteria for possible drug-induced liver injury (pDILI). "
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    ABSTRACT: Beclabuvir is a potent, non-nucleoside inhibitor of the HCV NS5B RNA polymerase, with nanomolar activity against HCV genotypes 1, 3, 4, 5 and 6 in vitro. This study evaluated the efficacy and safety of beclabuvir, in combination with peginterferon alfa-2a (pegIFN) and ribavirin (RBV), in HCV genotype 1. In this randomized (1:1:1), double-blinded, placebo-controlled, dose-ranging phase 2a study, 39 treatment-naive patients chronically infected with HCV genotype 1 were treated for 48 weeks with beclabuvir (75 mg or 150 mg) plus pegIFN (180 μg) and RBV (1000 mg/day [<75 kg] or 1200 mg/day [≥75 kg]) vs pegIFN/RBV alone. The primary efficacy endpoint of extended rapid virologic response (undetectable HCV RNA at treatment weeks 4 and 12) was achieved by 76.9% (10/13) of patients receiving beclabuvir 75 mg and 38.5% (5/13) receiving beclabuvir 150 mg vs 0% receiving pegIFN/RBV alone. Higher response rates were observed among patients receiving beclabuvir 75 mg for all secondary efficacy endpoints, including sustained virologic response at follow-up weeks 12 or 24. Three patients experienced virologic breakthrough on treatment, all in the beclabuvir 150-mg treatment group. Beclabuvir was well tolerated at both doses, with the most commonly observed adverse events (headache, fatigue, nausea, decreased appetite, irritability, depression and insomnia) consistent with those observed with pegIFN/RBV. In conclusion, beclabuvir was both effective and well tolerated when administered in combination with pegIFN/RBV for the treatment of chronic HCV GT 1, supporting the study of beclabuvir as part of an all-oral regimen for HCV GT1.
    Journal of Viral Hepatitis 12/2014; 22(8). DOI:10.1111/jvh.12372 · 3.91 Impact Factor
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    • "The first agent reported in this class, daclatasvir, demonstrated rapid and profound HCV RNA suppression after a single dose administered as monotherapy [51]. Importantly, Lok and co-workers evaluated the interferon-free combination of daclatasvir plus asunaprevir (NS3 protease inhibitor) in patients with HCV genotype 1 who had failed prior peginterferon/ribavirin therapy, providing the first evidence that chronic HCV infection could be eradicated without interferon [52]. Subsequently, NS5A inhibitors have emerged as critical components of several oral HCV DAA regimens which have completed phase 3 clinical development and are expected to be approved for clinical use [53] [54] [55] [56] [57] [58] [59] [60]. "
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    ABSTRACT: Due to shared routes of transmission, acute and chronic infection with hepatitis C virus is common among persons living with HIV infection in many regions of the world. In the era of effective antiretroviral therapy, acute HCV infection has been increasingly recognized in HIV-infected persons, particularly men who have sex with men, and liver disease, including hepatocellular carcinoma, has emerged as a leading cause of morbidity and mortality in those with chronic HCV infection, particularly older adults with long-standing coinfection. Over the past decade, the foundation for the management of acute and chronic HCV infection has been interferon alfa. However, due the high burden of treatment-related side effects and low likelihood of sustained virologic response, the impact of treatment with peginterferon/ribavirin on the burden of HCV disease in has been limited. However, the anticipated availability of safe, tolerable and highly efficacious interferon-free, oral HCV direct-acting antiviral combination therapies promise to dramatically change the management of acute and chronic HCV infection in HIV-infected persons. Preliminary data from studies of such oral DAA regimens in HIV/HCV coinfected patients suggest that coinfection with HIV will not impair HCV cure with these regimens. Indeed, in the coming era of high effective oral HCV DAA treatments, the only special feature concerning treatment of acute and chronic HCV infection in HIV-infected patients may be drug interactions between the antiretroviral drugs for HIV infection and direct-acting antiviral drugs for HCV infection.
    Journal of Hepatology 11/2014; 61(1). DOI:10.1016/j.jhep.2014.08.006 · 11.34 Impact Factor
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