Elimination of hepatitis C virus by short term NS3-4A and NS5B inhibitor combination therapy in human hepatocyte chimeric mice

Ohara, Eiji; Hiraga, Nobuhiko; Imamura, Michio; Iwao, Eiji; Kamiya, Naohiro; Yamada, Itsunari; Kono, Tomohiko; Onishi, Mai; Hirata, Daizaburo; Mitsui, Fukiko; Kawaoka, Tomokazu; Tsuge, Masataka; Takahashi, Shoichi; Abe, Hiromi; Hayes, C. Nelson; Ochi, Hidenori; Tateno, Chise; Yoshizato, Katsutoshi; Tanaka, Shinji; Chayama, Kazuaki

doi:10.1016/j.jhep.2010.08.033

Cited by 45 publications

(33 citation statements)

References 31 publications

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“…16 In HCV-infected human hepatocyte chimeric mice, dual DAA treatment eradicated HCV without resistance, whereas resistance emerged rapidly with single DAA treatment. 17 In a clinical study that included null responders, marked antiviral effects were observed after 13 days of dual DAA treatment, supporting the evaluation of longer term dual DAA therapy reported in this study. 18 Daclatasvir (BMS-790052) is a first-in-class, highly selective nonstructural protein 5A (NS5A) replication complex inhibitor with picomolar potency and broad genotypic coverage; asunaprevir (BMS-650032) is a nonstructural protein 3 (NS3) protease inhibitor active against HCV genotypes 1a and 1b.…”

supporting

confidence: 81%

Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b–infected null responders

Chayama¹,

Takahashi²,

et al. 2012

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Patients with chronic hepatitis C virus (HCV) infection and previous null response to pegylated interferon (Peg-IFN) and ribavirin (RBV) have limited therapeutic options. HCV genotype 1 is the most common worldwide and the most difficult to treat; genotype 1b is the most common subtype of genotype 1 outside North America. The enhanced antiviral activity achieved by combining two direct-acting antiviral (DAA) agents may improve clinical outcomes. This open-label, phase IIa study included 10 patients with chronic HCV genotype 1b infection and previous null response (<2 log10 reduction in HCV RNA after 12 weeks) to Peg-IFN and RBV. Patients received dual DAA treatment for 24 weeks with the nonstructural protein 5A replication complex inhibitor, daclatasvir (60 mg once-daily), and the nonstructural protein 3 protease inhibitor, asunaprevir (initially 600 mg twice-daily, then subsequently reduced to 200 mg twice-daily). The primary efficacy endpoint was the proportion of patients with sustained virologic response (SVR) at 12 weeks post-treatment (SVR12). Nine patients completed 24 weeks of treatment; 1 patient discontinued treatment after 2 weeks. In the 9 patients who completed the full course of treatment, HCV RNA was undetectable at week 8 and remained undetectable through the end of treatment; all 9 patients achieved SVR12 and SVR24. HCV RNA also remained undetectable post-treatment in the patient who discontinued after 2 weeks. There was no viral breakthrough. Diarrhea and headache, generally mild, were the most common adverse events; transaminase elevations were reported in 3 patients, but did not result in discontinuation. Conclusions : Dual therapy with daclatasvir and asunaprevir, without Peg-IFN and RBV, can achieve high SVR rates in difficult-to-treat patients with HCV genotype 1b infection and previous null response to Peg-IFN and RBV.

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supporting

confidence: 81%

Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b–infected null responders

Chayama¹,

Takahashi²,

et al. 2012

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“…RNA extraction, nested PCR and quantitation of HCV by real-time PCR were performed as described previously 11 12. Briefly, RNA was extracted from serum samples and extracted livers using SepaGene RVR (Sankojunyaku, Tokyo, Japan) and reverse transcribed with a random hexamer and a reverse transcriptase (ReverTraAce; TOYOBO, Osaka, Japan) according to the instructions provided by the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

“…This animal model is useful for evaluating anti-HCV drugs such as Peg-alfa and NS3 PI 10 11. Using this animal model, we recently described the successful elimination of HCV genotype 1b by treatment with a combination of NS3 protease and NS5B inhibitors 12. In this study, we investigated whether short-term combination treatments with NS5A RCI and either NS3 protease or NS5B site I inhibitors could eliminate HCV in vivo in human hepatocyte chimeric mice, and we compared the efficacy of the drugs against HCV genotype 1 versus genotype 2.…”

Section: Introductionmentioning

confidence: 99%

Combination therapies with NS5A, NS3 and NS5B inhibitors on different genotypes of hepatitis C virus in human hepatocyte chimeric mice

Shi

Hiraga

Imamura

et al. 2013

Gut

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“…Recent literature indicates that treatment with combinations of non-cross-resistant inhibitors not only improves antiviral activity during treatment but also suppresses the posttreatment viral rebound often associated with monotherapy (19,21,26). To achieve a sustained viral response (SVR), it would be essential to use combination therapies similar to those that have recently been explored in replicon studies (5,10,29), animal models (44), and patient studies (14,51) as a viable approach to improving the efficacy, tolerability, and compliance issues associated with current therapies. For this report, the effects of a combination approach to HCV therapy have been studied in the HCV replicon system using two-and three-drug combinations that include an NS5A replication complex inhibitor (DCV), the NS3 protease inhibitor asunaprevir (ASV), and the nonnucleoside NS5B RNA polymerase inhibitor BMS-791325.…”

mentioning

confidence: 99%

Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir

Pelosi

Voss

Liu

et al. 2012

Antimicrob Agents Chemother

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Three hepatitis C virus (HCV) inhibitors, asunaprevir (ASV; BMS-650032), daclatasvir (DCV; BMS-790052), and BMS-791325, each targeting a different nonstructural protein of the virus (NS3, NS5A, and NS5B, respectively), have independently demonstrated encouraging preclinical profiles and are currently undergoing clinical evaluation. Since drug-resistant variants have rapidly developed in response to monotherapy with almost all direct-acting antiviral agents (DAAs) for HCV, the need for combination therapies to effectively eradicate the virus from infected patients is clear. These studies demonstrated the additivesynergistic effects on replicon inhibition and clearance of combining NS3 protease or NS5B RNA polymerase inhibitors with the first-in-class, NS5A replication complex inhibitor daclatasvir (DCV) and reveal new resistance pathways for combinations of two small-molecule inhibitors that differ from those that develop during monotherapy. The results suggest that under a specific selective pressure, a balance must be reached in the fitness costs of substitutions in one target gene when substitutions are also present in another target gene. Further synergies and additional novel resistance substitutions were observed during triple-combination treatment relative to dual-drug therapy, indicating that, in combination, HCV inhibitors can exert cross-target influences on resistance development. Enhanced synergies in replicon inhibition and a reduced frequency of resistance together lend strong support to the utility of combinations of DAAs for the treatment of HCV, and the identification of altered resistance profiles during combination treatment provides useful information for monitoring resistance in the clinic. H epatitis C virus (HCV) is a positive-stranded RNA virus in theFlaviviridae family of enveloped virions which affects an estimated 170 million people worldwide and is the major cause of chronic hepatitis. Currently, approximately 50% of patients infected with genotype 1 (gt 1), the most prevalent form of the virus, fail to achieve a sustained reduction in viral load with therapy employing pegylated alpha interferon (IFN-␣) plus ribavirin (alfa/RBV) (52,54,56). A substantial fraction (20%) of chronically infected patients develop serious progressive liver disease, including cirrhosis or hepatocellular carcinoma. alfa/RBV treatment is associated with a high incidence (Ͼ30%) of adverse effects, some of which are of sufficient severity to cause patients to discontinue therapy (56). Despite the recent approval of two new direct-acting antiviral agents (DAAs), boceprevir and telaprevir, for use in combination with alfa/RBV (18, 47), their use may be limited by poor efficacy in some patient populations, inconvenient 3-times-daily dosing of the DAA, and association with side effects, including anemia, rash, and gastrointestinal effects, in addition to the well-documented spectrum of adverse effects associated with alfa/RBV. Although addition of these DAAs to the standard of care for HCV represents a significant i...

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Elimination of hepatitis C virus by short term NS3-4A and NS5B inhibitor combination therapy in human hepatocyte chimeric mice

Cited by 45 publications

References 31 publications

Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b–infected null responders

Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b–infected null responders

Combination therapies with NS5A, NS3 and NS5B inhibitors on different genotypes of hepatitis C virus in human hepatocyte chimeric mice

Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir

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