BACKGROUND: Resistance to mericitabine (prodrug of HCV NS5B polymerase inhibitor 
PSI-6130) is rare and conferred by the NS5B S282T mutation.
METHODS: Serum HCV RNA from patients who experienced viral breakthrough, partial 
response, or nonresponse in 2 clinical trials in which patients received 
mericitabine plus peginterferon alfa-2a (40KD)/ribavirin were analyzed by 
population and clonal sequence analysis as well as phenotypic assay for 
assessment of in vivo mericitabine resistance.
RESULTS: Among 405 patients treated with mericitabine plus peginterferon 
alfa-2a/ribavirin in PROPEL and JUMP-C, virologic breakthrough or nonresponse 
were not observed; 12 patients experienced a partial response. The NS5B S282T 
resistance mutation was not observed in any patient. A number of 
treatment-associated NS5B changes were observed and characterized. A novel 
double mutant (L159F/L320F) with impaired replication capacity was detected in 
one HCV genotype 1b-infected patient. Introduction of double mutant L159F/L320F 
into genotype 1a (H77) and 1b (Con-1) replicons, respectively, increased the 
EC50 for mericitabine by 3.1- and 5.5-fold and the EC90 by 3.1- and 8.9-fold. 
The double mutant also decreased susceptibility to sofosbuvir (GS-7977) and 
GS-938 but not setrobuvir, relative to wild-type.
CONCLUSIONS: A novel and replication-deficient double mutation (L159F/L320F) 
confers low-level resistance to mericitabine and cross-resistance to both 
sofosbuvir and GS-938.
CLINICAL TRIALS REGISTRATION: NCT00869661, NCT01057667.