Analysis Of The Effect Of HCV Resistance-associated Substitutions On Viral Load Reduction After Single Administration Of DAA In Three Phase Ib Clinical Trials

Objective:Resistance-associated substitutions?RASs?are factors in Hepatitis C virus?HCV?management and are associated with the treatment outcome of some direct-acting antivirals?DAAs?-based regimens.In this study,we mainly analyzed the effect of Y93H or Y93Y/H at baseline on viral load reduction after single administration of NS5A inhibitors in three phase Ib clinical trials respectively,and analyzed the prevalence of baseline RASs and treatment-emergent RASs.Method:A total of 94 treatment-na?ve HCV genotype?GT?-1b?n=63?and GT-2a?n=31?Chinese naive Chronic hepatitis c?CHC?patients were enrolled in three phase Ib clinical trials with NS5A inhibitors?drug A,drug B,and drug c,respectively?.In this study,we used Sanger sequencing and Next generation sequencing?NGS?to detect RASs in 77 patients?including 63 GT-1b patients and 14 GT-2a patients?.Result:In the 7-day single dose trial of drug A?30 mg/100 mg/200 mg?,the mean maximum HCV RNA decrease of patients with baseline Y93H or Y93Y/H mutation was lower than that of patients without the mutation in the 30 mg and 200 mg cohorts,(0.83 vs 2.45 log₁₀IU/ml and1.92 vs 2.63 log₁₀0 IU/ml,respectively).In this study,the drug exposure?AUC?in vivo increased with the increase of drug dose,but the efficacy of 100mg dose group was significantly better than 200mg dose group,and there was no Y93H or Y93Y/H mutation at baseline in 100mg dose group.In the 3-day single dose trial of drug B?30 mg/60 mg/90 mg/120 mg?,the mean maximum HCV RNA decrease in patients with baseline Y93H or Y93Y/H mutation was lower than that of patients without the mutation in the 30 mg,60 mg and 120 mg cohorts,which were 1.58 vs 2.89 log₁₀0 IU/ml,3.16 vs 4.09 log₁₀0 IU/ml and 3.00 vs 5.04 log₁₀0 IU/ml,respectively.In this study,the drug exposure?AUC?in vivo increased with the increase of drug dose,but the efficacy of 60 mg group was similar to that of 90 mg group and 120 mg group,and the mutation rate of Y93H or Y93Y/H in 120 mg group was higher than that in 90mg and 60 mg group.In the 3-day single dose trial of drug C?30 mg/60 mg/90 mg?,only 30mg dose group had baseline Y93H or Y93Y/H mutation,and the average maximum HCV RNA decrease of patients with Y93H or Y93Y/H mutation at baseline was lower than that of patients without the mutation,which was 1.45 vs 3.59 log₁₀IU/ml.In the three trials,baseline RASs in the NS5A region were observed in 54 patients?70.1%;54/77?.In patients with HCV GT-1b infection,the prevalence of baseline RASs was65.1%?41/63?,while in patients with HCV GT-2a infection,the prevalence of baseline RASs was 92.9%?13/14?,and the baseline mutation sites of the two genotypes are different.The most common baseline RASs in GT-1b patients were Y93H and Y93Y/H?22.2%;14/63?,and in GT-2a was L31M?92.9%;13/14?.In the study,24 cases?31.2%;24/77?of multiple amino acid site mutations were found.The rate of combined RASs at baseline in GT-1b patients was 33.3%?21/63?,and in GT-2a patients was 21.4%?3/14?.The most common RASs after single drug administration of NS5A inhibitors were Y93H and Y93Y/H.Conclusion:Baseline Y93H or Y93Y/H mutations in na?ve chronic hepatitis c patients with HCV GT-1b may affect the viral load reduction and dose-effect relationship of DAA after single drug administration of DAA in early clinical trials,and the effect of baseline RASs on the efficacy should be considered in the early clinical study of DAA to carry out objective analysis of the results of the dose-effect relationship.In the study,the prevalence of baseline RASs in na?ve chronic hepatitis c patients infected with GT-1b and 2a was relatively high?higher than previous literature reports?.