in all 3 drug targets in 30 subjects. In the 7 genotype 1b infected subjects, treatment-emergent variants were observed in NS3 in 4 subjects, in NS5A in 2 subjects, and in both NS3 and NS5A in 1 subject. No genotype 1b infected subjects had treatment-emergent variants in all 3 drug targets.
Table 5. Treatment-emergent amino acid substitutions in the pooled analysis of Exviera and ombitasvir/paritaprevir/ritonavir, with and without RBV regimens in Phase 2b and Phase 3 clinical trials (N=2510)
a. Observed in at least 2 subjects of the same subtype.
b. N=66 for the NS5B target.
c. Substitutions were observed in combination with other emergent substitutions at NS3 position R155 or D168.
d. Observed in combination in genotype 1b-infected subjects.
e. Observed in combination in 6% (4/67) of the subjects.
Note: The following variants were selected in cell culture but were not treatment-emergent: NS3 variants A156T in genotype 1a, and R155Q and D168H in genotype 1b; NS5A variants Y93C/H in genotype 1a, and L31F/V or Y93H in combination with L28M, L31F/V or P58S in genotype 1b; and NS5B variants Y448H in genotype 1a, and M414T and Y448H in genotype 1b.
Persistence of resistance-associated substitutions
The persistence of dasabuvir, ombitasvir and paritaprevir resistance-associated amino acid substitutions in NS5B, NS5A and NS3, respectively, was assessed in genotype 1a-infected subjects in Phase 2b trials. Dasabuvir treatment-emergent variants M414T, G554S, S556G, G558R or D559G/N in NS5B were observed in 34 subjects. Ombitasvir treatment-emergent variants M28T, M28V or Q30R in NS5A were observed in 32 subjects. Paritaprevir treatment-emergent variants V36A/M, R155K or D168V were observed in NS3 in 47 subjects.
NS3 variants V36A/M and R155K and NS5B variants M414T and S556G remained detectable at post-treatment Week 48, whereas NS3 variant D168V and all other NS5B variants were not observed at post-treatment Week 48. All treatment-emergent variants in NS5A remained detectable at post-treatment Week 48. Due to high SVR rates in genotype 1b, trends in persistence of treatment-emergent variants in this genotype could not be established.
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 Exviera and ombitasvir/paritaprevir/ritonavir -resistance-associated substitutions on future treatment is unknown.
Cross-resistance
Cross-resistance is expected among NS5A inhibitors, NS3/4A protease inhibitors, and non-nucleoside NS5B inhibitors by class. The impact of prior dasabuvir, ombitasvir, or paritaprevir treatment experience on the efficacy of other NS5A inhibitors, NS3/4A protease inhibitors, or NS5B inhibitors has not been studied.
Clinical efficacy and safety
The efficacy and safety of Exviera in combination with ombitasvir/paritaprevir/ritonavir with and without ribavirin was eva luated in six randomised Phase 3 clinical trials, including one trial exclusively in subjects with compensated cirrhosis (Child-Pugh A), in over 2,300 subjects with genotype 1 chronic hepatitis C infection as summarised in Table 6.
Table 6. Phase 3 randomised, global multicentre trials conducted with Exviera and ombitasvir/paritaprevir/ritonavir with or without ribavirin (RBV).
1. Double-blind unless otherwise noted.
2. Treated is defined |
