VIEKIRA XR(dasabuvir, ombitasvir, paritaprevir, and ritonavir)extended-release tablets(二十九)
) subjects through Post-Treatment Week 24, and were no longer detectable through Post-Treatment Week 48.
Among HCV genotype 1b infected subjects who experienced virologic failure with a regimen including ombitasvir and paritaprevir, a treatment-emergent NS5A Y93H substitution persisted through at least Post-Treatment Week 48 in 2/2 subjects, and a NS3 D168V treatment-emergent substitution persisted through Post-Treatment Week 24 in 2/4 subjects, but was no longer detectable through Post-Treatment Week 48 (0/4 subjects).
The lack of detection of virus containing a resistance-associated substitution does not indicate that the resistant virus is no longer present at clinically significant levels. The long-term clinical impact of the emergence or persistence of virus containing VIEKIRA XR-resistance-associated substitutions is unknown.
Effect of Baseline HCV Polymorphisms on Treatment Response
A pooled analysis of subjects in the Phase 3 clinical trials of dasabuvir, ombitasvir, and paritaprevir with or without ribavirin was conducted to explore the association between baseline HCV NS5B, NS5A, or NS3 resistance-associated polymorphisms and treatment outcome. Baseline samples from HCV genotype 1a infected subjects who experienced virologic failure (n=47), as well as samples from a subset of demographically matched subjects who achieved SVR (n=94), were analyzed to compare the frequencies of resistance-associated polymorphisms in these two populations. The NS3 Q80K polymorphism was detected in approximately 38% of subjects in this analysis and was enriched approximately 2-fold in virologic failure subjects compared to SVR-achieving subjects. Ombitasvir resistance-associated polymorphisms in NS5A (pooling data from all resistance-associated amino acid positions) were detected in approximately 22% of subjects in this analysis and similarly were enriched approximately 2-fold in virologic failure subjects. Dasabuvir resistance-associated polymorphisms in NS5B were detected in approximately 5% of subjects in this analysis and were not enriched in virologic failure subjects.
In contrast to the Phase 3 subset analysis, no association of NS3 or NS5A polymorphisms and treatment outcome was seen in an analysis of noncirrhotic HCV genotype 1a-infected subjects (n=174 for NS3 and n=183 for NS5A) who received dasabuvir, ombitasvir, and paritaprevir with or without ribavirin (for 12 or 24 weeks) in a Phase 2b trial.
Baseline HCV polymorphisms are not expected to have a substantial impact on the likelihood of achieving SVR when VIEKIRA XR is used as recommended for HCV genotype 1a and 1b infected patients, based on the low virologic failure rates observed in clinical trials.
Cross-resistance
Cross-resistance is expected among NS5A inhibitors, NS3/4A protease inhibitors, and non-nucleoside NS5B-palm inhibitors by class. Dasabuvir retained full activity against HCV replicons containing a single NS5B L159F, S282T, or V321A substitution, which are associated with resistance or prior exposure to nucleot(s)ide analogue NS5B polymerase inhibitors. In clinical trials of the components of VIEKIRA XR, no subjects who experienced virologic failure had treatment-emergent substitutions potentially associated with resistance to nucleot(s)ide analogue NS5B polymerase inhibitors.
The impact of prior dasabuvir, ombitasvir, or paritaprevir treatment experience on the efficacy of other NS5B inhibitors, NS5A inhibitors, or NS3/ |
