[14] Clearance of Hcvrna With Valopicitabine (Nm) Plus Peg-Interferon in Treatment-Naive Patients With HCV-1 Infection: Results at 24 and 48 Weeks

Läwitz, E.; Nguyen, Thanh Van; Younes, Ziad; Santoro, John J.; Gitlin, Norman; McEniry, D.; Chasen, Richard; Goff, John S.; Dieterich, Doug; Knox, Steven J.; Kleber, K.; Belanger, Bruce; Brown, NA

doi:10.1016/s0168-8278(07)61612-2

Cited by 32 publications

(22 citation statements)

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“…The variant NS5B S282T conveys decreased susceptibility to the 2=-methyl-cytidine inhibitor mericitabine (RG7128) and sofosbuvir (GS-7977) in the replicon system. NS5B S282T has been observed in a very small number of patients either receiving NM283 monotherapy (37) or after failing treatment with mericitabine in combination with danoprevir (38). In addition, variants NS5B S96T and N142T appear to be compensatory mutations for S282T in the replicon (39).…”

Section: Baselinementioning

confidence: 99%

Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

Bartels

Sullivan

Zhang

et al. 2013

J Virol

135

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The prevalence of naturally occurring hepatitis C virus (HCV) variants that are less sensitive to direct-acting antiviral (DAA) inhibitors has not been fully characterized. We used population sequence analysis to assess the frequency of such variants in plasma samples from 3,447 DAA-naive patients with genotype 1 HCV. In general, HCV variants with lower-level resistance (3-to 25-fold increased 50% inhibitor concentration [IC 50 ]) to telaprevir were observed as the dominant species in 0 to 3% of patients, depending on the specific variant, whereas higher-level resistant variants (>25-fold-increased IC 50 ) were not observed. Specific variants resistant to NS5A inhibitors were predominant in up to 6% of patients. Most variants resistant to nucleo(s/t)ide activesite NS5B polymerase inhibitors were not observed, whereas variants resistant to non-nucleoside allosteric inhibitors were observed in up to 18% of patients. The presence of DAA-resistant variants in NS5A, NS5B, or NS3 (including telaprevir-resistant variants), in baseline samples of treatment-naive patients receiving a telaprevir-based regimen in phase 3 studies did not affect the sustained viral response (SVR). Treatment-naive patients with viral populations containing the telaprevir-resistant variants NS3 V36M, T54S, or R155K at baseline achieved a 74% SVR rate, whereas patients with no resistant variants detected prior to treatment achieved a 76% SVR rate. The effect of specific resistant variant frequency on response to various DAA treatments in different patient populations, including interferon nonresponders, should be further studied.

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Section: Baselinementioning

confidence: 99%

Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

Bartels

Sullivan

Zhang

et al. 2013

J Virol

135

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“…NM283 has demonstrated antiviral efficacy upon oral administration in HCV-infected patients (1,2,14,20). However, gastrointestinal side effects have limited the dose levels and resulted in the discontinuation of development of the compound.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Efficacy upon Administration of a HepDirect Prodrug of 2′- C -Methylcytidine to Hepatitis C Virus-Infected Chimpanzees

Carroll

Koeplinger

Vavrek

et al. 2011

Antimicrob Agents Chemother

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. One approach to increase the antiviral efficacy of 2-C-methylcytidine is to increase the concentration of the active inhibitory species, the 5-triphosphate, in infected hepatocytes. HepDirect prodrug technology can increase intracellular concentrations of a nucleoside triphosphate in hepatocytes by introducing the nucleoside monophosphate into the cell, bypassing the initial kinase step that is often rate limiting. Screening for 2-C-methylcytidine triphosphate levels in rat liver after oral dosing identified 1-[3,5-difluorophenyl]-1,3-propandiol as an efficient prodrug modification. To determine antiviral efficacy in vivo, the prodrug was administered separately via oral and intravenous dosing to two HCV-infected chimpanzees. Circulating viral loads declined by ϳ1.4 log 10 IU/ml and by >3.6 log 10 IU/ml after oral and intravenous dosing, respectively. The viral loads rebounded after the end of dosing to predose levels. The results indicate that a robust antiviral response can be achieved upon administration of the prodrug.Chronic hepatitis C virus (HCV) infection is associated with increased incidence of liver fibrosis, cirrhosis, and hepatocellular carcinoma and is the leading cause of liver transplantation in the United States (13). The current standard for treatment is a combination of pegylated interferon alpha and ribavirin, which results in sustained viral response (SVR) (undetectable virus 6 months after the end of treatment) in 50% or 80% of treated patients harboring a genotype 1 or a genotype 2 or 3 infection, respectively (25). Thus, novel therapies resulting in higher SVR rates, particularly in the treatment of genotype 1 infections, are needed.Nucleoside analogs inhibiting the HCV RNA polymerase have been investigated as potential therapeutics to treat HCV infections. 2Ј-C-Methylcytidine inhibits HCV RNA replication in the replicon assay (consensus 1 50% effective concentration [EC 50 ], ϳ1 M) via inhibition of the HCV RNA polymerase, which is inhibited by the 2Ј-C-methylcytidine triphosphate in vitro in cell-free biochemical assays (50% inhibitory concentration [IC 50 ], ϳ0.2 M) (15). NM283, the 3Ј-O-valinyl ester prodrug of 2Ј-C-methylcytidine, has improved oral bioavailability compared to 2Ј-C-methylcytidine (21) and has been investigated in HCV-infected patients in clinical studies. In a phase IIb study, patients receiving NM283 in combination with pegylated interferon alpha and ribavirin at 24 weeks of therapy experienced mean viral load reductions of up to 3.3 log 10 IU/ml compared to 2.3 log 10 IU/ml reductions for patients receiving pegylated interferon-ribavirin alone (2). Due to the high incidence of gastrointestinal side effects, which required reduction of the highest daily dose of 800 mg to 200 or 400 mg, further development of NM283 was placed on hold.The HepDirect prodrug modifications of nucleoside 5Ј-monophosphates (NMP) are substituted cyclic 1,3-propanyl esters that offer an opportunity to bypass the initial phosphorylation step that is often rate limiting for the formation of...

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“…62,68 , Valopicitabine, [69][70][71][72] R-1479 and its prodrug Balapiravir R-1626 [73][74][75][76][77][78][79] as shown in Figure 9.…”

Section: Idx184mentioning

confidence: 99%

Antiviral Nucleoside and Nucleotide Analogs: A Review

Mahmoud

Hasabelnaby

Hammad

et al. 2018

Journal of Advanced Pharmacy Research

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Virus infections are an increasing and probably lasting global risk. Nucleoside and nucleotide analogs represent the largest class of antiviral drugs. Early success in the treatment of human immunodeficiency virus infection and the recent approval of sofosbuvir as phosphoramidate nucleoside prodrug for chronic hepatitis C have provided proof of concept for important this class of compounds as an antiviral agent. This review summarizes the antiviral activity of nucleoside and nucleotide analogs and their recent application.

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[14] Clearance of Hcvrna With Valopicitabine (Nm) Plus Peg-Interferon in Treatment-Naive Patients With HCV-1 Infection: Results at 24 and 48 Weeks

Cited by 32 publications

References 0 publications

Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

Antiviral Efficacy upon Administration of a HepDirect Prodrug of 2′- C -Methylcytidine to Hepatitis C Virus-Infected Chimpanzees

Antiviral Nucleoside and Nucleotide Analogs: A Review

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