Alone or in Combination with Pegylated Interferon-a 2 a and Ribavirin Prevents Hepatitis C Virus ( HCV ) Replication and Selection of Resistant Variants in HCV-Infected Patients

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 log10 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 11000 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.