Effect of Ribavirin in Genotype 1 Patients With Hepatitis C Responding to Pegylated Interferon Alfa-2a Plus Ribavirin

Bronowicki, Jean–Pierre; Ouzan, Denis; Asselah, Tarik; Desmorat, Hervé; Zarski, Jean–Pierre; Foucher, Juliette; Bourlière, Marc; Renou, Christophe; Tran, Albert; Melin, P.; Hézode, Christophe; Chevalier, Michelle; Bouvier‐Alias, Magali; Chevaliez, Stéphane; Montestruc, François; Lonjon–Domanec, Isabelle; Pawlotsky, Jean‐Michel

doi:10.1053/j.gastro.2006.07.022

Cited by 170 publications

(135 citation statements)

References 27 publications

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“…Furthermore, in the present study, the inhibitory effect of HCV RNA replication was increased when 2′-C-MeC was used in combination with IFN-a2b, which is in agreement with a recent Phase IIb human trial of the anti-HCV activity of a prodrug of 2′-CMeC (NM-283) shown to produce profound synergistic effects when combined with pegylated IFN [6,30,31]. As mentioned previously, combinations of pegylated IFN-a and RBV have a relatively low sustained viral response especially in individuals infected with HCV genotype 1 [2]. Because of the high genetic heterogeneity, increased efficiency of replication of HCV and expected emergence of resistance mutations, it is likely that the future therapy for HCV will include orally bioavailable drug combinations in addition to RBV and IFN.…”

supporting

confidence: 86%

“…The combination of RBV to the IFN treatment of chronic hepatitis C infection greatly improved responses [22], but unfortunately half of the infected individuals still do not achieve sustained clearance of HCV [2]. For this reason, newer potent antiviral agents are likely to be used in combination with these agents.…”

Section: Discussionmentioning

confidence: 99%

“…Drug interaction analyses were performed using the CalcuSyn program. The current standard of care for chronic hepatitis C virus (HCV) infection is a combination of pegylated interferon (IFN)-a and ribavirin (RBV), which results in a sustained virological response in about a half of infected individuals; however, this combined modality is associated with considerable side effects [1,2]. Several new HCV inhibitors have been identified and some are being evaluated in controlled clinical trials [3].…”

mentioning

confidence: 99%

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Combinations of 2'-C-Methylcytidine Analogues with Interferon-α2b and Triple Combination with Ribavirin in the Hepatitis C Virus Replicon System

Bassit

Grier

Bennett

et al. 2008

Antivir Chem Chemother

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Background: Hepatitis C virus (HCV) polymerase is an essential enzyme for HCV replication and has multiple inhibitor binding sites making it a major target for antiviral intervention. It is apparent that no single drug can inhibit HCV replication in humans. Hence, combinations of nucleoside analogues β-d-2'-C-methylcytidine (2'-C-MeC; NM-107) or β-d-2'-deoxy-2'-fluoro-2'-C-methylcytidine (2'-F-C-MeC; PSI-6130) with interferon-a2b (IFN-a2b) or triple combination with ribavirin (RBV) were evaluated. Methods: Huh-7 cells containing the self-replicating subgenomic HCV replicon (Clone B) were used for drug combination studies. After drug treatment for 5 days, total cellular RNA was then extracted and both ribosomal RNA and HCV replicon RNA were amplified in a singlestep multiplex real-time PCR assay. Drug interaction analyses were performed using the CalcuSyn program. The current standard of care for chronic hepatitis C virus (HCV) infection is a combination of pegylated interferon (IFN)-a and ribavirin (RBV), which results in a sustained virological response in about a half of infected individuals; however, this combined modality is associated with considerable side effects [1,2]. Several new HCV inhibitors have been identified and some are being evaluated in controlled clinical trials [3]. Recently, promising 2′-modified nucleoside analogues with activity against HCV have been reported; for instance, valopicitabine (NM-283), the 3′-valine ester of β-d-2′-Cmethylcytidine (2′-C-MeC; NM-107), is a prodrug nucleoside that after intracellular phosphorylation to its 5′-triphosphate metabolite, selectively inhibits HCV RNA-dependent RNA polymerase [4,5]. Although valopicitabine was recently evaluated in clinical trials and the combination of valopicitabine with IFN-a (plus RBV) has led to successful viral RNA suppression in a number of HCV-infected individuals, this drug was found to have gastrointestinal toxicity leading to its discontinuation in its present form [6]. Another novel cytidine analogue, β-d-2′-deoxy-2′-fluoro-2′-C-methylcytidine (PSI-6130, 2′-F-C-MeC has demonstrated potent and specific in vitro anti-HCV activity with no apparent cytotoxicity [7,8]. Recently, in a 14 day Phase I monotherapy study, a new prodrug of 2′-F-C-MeC named R7128 was shown to be highly potent at lowering levels of HCV RNA, with a 2.7-log reduction in the viral load of individuals infected with HCV genotype 1 who had failed prior IFN therapy [9,10]. These nucleoside analogues have demonstrated excellent anti-HCV activity in vitro in both antireplicon and infectious HCV systems [11]. Furthermore, nucleoside analogue prodrugs can be administered in combination with IFN, with or without Results: Double combinations of 2'-C-MeC or 2'-F-C-

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supporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Combinations of 2'-C-Methylcytidine Analogues with Interferon-α2b and Triple Combination with Ribavirin in the Hepatitis C Virus Replicon System

Bassit

Grier

Bennett

et al. 2008

Antivir Chem Chemother

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“…The standard of care therapy (SOC) for HCV-4 consists of a 48-week combination therapy of pegylated interferon (PEG-IFN) α and ribavirin. However, only 50% of treated patients achieve a sustained virological response (SVR) [3][4][5] . The response to therapy and the progression of the disease to more severe liver injury are determined by many factors, including host (immunologic and genetic) and viral factors 6 .…”

Section: Introductionmentioning

confidence: 99%

Impact of the IL-18 gene polymorphism in response to antiviral therapy in chronic HCV genotype 4 patients

Mandour

Nemr

Kishk

et al. 2014

Rev. Soc. Bras. Med. Trop.

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Introduction: Interleukin (IL)-18 is a well-known major proinfl ammatory cytokine with broad biological effects. The major immunomodulatory functions of IL-18 include enhancing T cell and natural killer cell cytotoxicity. Serum levels of this cytokine were shown to increase in chronic hepatitis C patients compared to non-infected healthy people. An association between IL-18 gene promoter polymorphisms and pegylated interferon (PEG-IFN) and ribavirin treatment outcomes has been reported for individuals with chronic hepatitis C virus genotype 1 (HCV-1). In this study, HCV genotype 4 (HCV-4) patients were assessed for IL-18 gene polymorphisms and treatment outcomes or severity of liver disease because data concerning the impact of IL-18 gene polymorphisms on patients with HCV-4 infections are limited. Methods: This study included 123 chronic HCV-4 Egyptian patients and 123 apparently healthy volunteer blood donors who served as a control group. HCV genotyping was performed using the line probe assay. IL-18 genotyping was performed using the TaqMan Real-Time PCR method in all 246 patient and control samples. Results: In our study, all patients had HCV-4. IL-18 gene single nucleotide polymorphism (SNP) (-607C/A) genotype distributions and allele frequencies did not differ between HCV patients and normal healthy subjects or between patient groups when compared according to the therapeutic response. Moreover, the presence of an IL-18 SNP was not associated with histological disease severity. We conclude that the presence of the IL-18 SNP rs1946518 does not affect the outcome of chronic HCV-4 treatment in Egyptian patients. Conclusions: The IL-18 SNP rs1946518 does not affect response to treatment in chronic HCV-4 patients.

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“…The importance of RBV for preventing relapse was illustrated by a recent study by Bronowicki et al 35 They studied 516 patients with HCV genotype 1 who were treated with PEG-IFN alfa-2a 180μg/week and RBV 800 mg/d. At week 24, 69% were HCV-RNA negative and were randomized to either continue PEG-IFN and RBV or to discontinue RBV and remain on PEG-IFN monotherapy through treatment week 48.…”

Section: Effect Of Rbv Dose Reductions On Svrmentioning

confidence: 99%

Optimizing the Dose and Duration of Therapy for ChronicHepatitis C

Pichetshote¹,

Groessl²,

Yee³

et al. 2009

Gut Liver

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Effect of Ribavirin in Genotype 1 Patients With Hepatitis C Responding to Pegylated Interferon Alfa-2a Plus Ribavirin

Cited by 170 publications

References 27 publications

Combinations of 2'-C-Methylcytidine Analogues with Interferon-α2b and Triple Combination with Ribavirin in the Hepatitis C Virus Replicon System

Combinations of 2'-C-Methylcytidine Analogues with Interferon-α2b and Triple Combination with Ribavirin in the Hepatitis C Virus Replicon System

Impact of the IL-18 gene polymorphism in response to antiviral therapy in chronic HCV genotype 4 patients

Optimizing the Dose and Duration of Therapy for ChronicHepatitis C

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