RG7128 Alone or in Combination with Pegylated Interferon‐α2a and Ribavirin Prevents Hepatitis C Virus (HCV) Replication and Selection of Resistant Variants in HCV‐Infected Patients
| Autor: | Alan Kosaka, Hyunsoon Kang, Abel De La Rosa, Aren Ewing, M.M. Berrey, Nick Cammack, Isabel Najera, A. Seshaadri, J.M. Yan, Bill Symonds, Sophie Le Pogam |
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| Rok vydání: | 2010 |
| Předmět: |
Hepatitis C virus
Hepacivirus Viral quasispecies Interferon alpha-2 Viral Nonstructural Proteins Biology Virus Replication medicine.disease_cause Antiviral Agents Deoxycytidine Polyethylene Glycols chemistry.chemical_compound Pegylated interferon Drug Resistance Viral Ribavirin medicine Humans Immunology and Allergy Selection Genetic NS5B Interferon-alpha Hepatitis C Hepatitis C Chronic Viral Load medicine.disease Virology Recombinant Proteins United States Infectious Diseases Amino Acid Substitution chemistry Immunology Drug Therapy Combination Mericitabine Viral load New Zealand medicine.drug |
| Zdroj: | The Journal of Infectious Diseases. 202:1510-1519 |
| ISSN: | 1537-6613 0022-1899 |
| DOI: | 10.1086/656774 |
| Popis: | Introduction. RG7128 (prodrug of PSI-6130) shows potent antiviral efficacy in patients infected with hepatitis C virus (HCV) genotypes 1, 2, or 3, with mean viral load decreases of 2.7 and 5 log 10 IU/mL, respectively, associated with 1500-mg doses twice daily after monotherapy for 2 weeks and with 1000-mg and 1500-mg doses twice daily after treatment in combination with the standard of care (SOC) for 4 weeks.Results. From 32 patients treated with RG7128 monotherapy for 2 weeks, marginal viral load rebound was observed in 3 HCV genotype 1-infected patients, whereas partial response was observed in 2 genotype 1-infected patients. From 85 patients receiving RG7128 in combination with SOC, 1 HCV genotype 1-infected patient experienced a viral rebound, and 2 genotype 3-infected patients experienced a transient rebound. Five genotype 1-infected patients had an HCV load of >1000 IU/mL at the end of 4-week treatment. No viral resistance was observed, per NS5B sequencing and phenotypic studies. PSI-6130 resistance substitution S282T needs to be present at levels of ⩾90% within a patient's quasispecies to confer low-level resistance. No evidence of S282T was found by population or clonal sequence analyses.Conclusions. The requirement for a predominant S282T mutant quasispecies, its low replication capacity, and the low-level resistance it confers probably contribute to the lack of RG7128 resistance observed in HCV-infected patients. |
| Databáze: | OpenAIRE |
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