Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus–infected patients†

Abstract

Boceprevir is a hepatitis C virus (HCV) nonstructural protein (NS) 3/4A protease inhibitor that is currently being evaluated in combination with peginterferon alfa-2b and ribavirin in phase 3 studies. The clinical resistance profile of boceprevir is not characterized in detail so far. The NS3 protease domain of viral RNA was cloned from HCV genotype 1-infected patients (n ‫؍‬ 22). A mean number of 47 clones were sequenced before, at the end, and after treatment with 400 mg boceprevir twice or three times daily for 14 days for genotypic, phenotypic, and viral fitness analysis. At the end of treatment, a wild-type NS3 protease sequence was observed with a mean frequency of 85.9%. In the remaining isolates, five previously observed resistance mutations (V36M/A, T54A/S, R155K/T, A156S, V170A) and one mutation (V55A) with unknown resistance to boceprevir were detected either alone or in combination. Phenotypic analysis in the HCV replicon assay showed low (V36G, T54S, R155L; 3.8-to 5.5-fold 50% inhibitory concentration [IC 50 ]), medium (V55A, R155K, V170A, T54A, A156S; 6.8-to 17.7-fold IC 50 ) and high level (A156T; >120-fold IC 50 ) resistance to boceprevir. The overall frequency of resistant mutations and the level of resistance increased with greater declines in mean maximum HCV RNA levels. Two weeks after the end of treatment, the frequency of resistant variants declined and the number of wild-type isolates increased to 95.5%. With the exception of V36 and V170 variants all resistant mutations declined by more than 50%. Mathematical modeling revealed impaired replicative fitness for all single mutations, whereas for combined mutations a relative increase of replication efficiency was suggested. Conclusion: During boceprevir monotherapy, resistance mutations at six positions within the NS3 protease were detected by way of clonal sequence analysis. All mutations are associated with reduced replicative fitness estimated by mathematical modeling and show cross-resistance to telaprevir.

An Indicator for Evaluating the Risk of Cancerous Transformations of Human Induced Pluripotent Stem Cells

“…We read with interest the article by Susseret et al 1 They successfully showed the characterization of resistance to boceprevir in patients infected with hepatitis C virus (HCV) genotype 1. 1 In the near future, antiviral effects in HCV infection genotype 1 for the combination of boceprevir with various drugs (interferon, statins, and ribavirin) would be considered by replicon systems.…”

“…1 In the near future, antiviral effects in HCV infection genotype 1 for the combination of boceprevir with various drugs (interferon, statins, and ribavirin) would be considered by replicon systems.…”

“…1 Here, we discuss another issue illustrating the confusion of terms. This concern is minor in terms of public health, but a source of diagnostic problem for liver specialists and important for patients who develop benign hepatocellular nodules.…”

Characterization of telaprevir treatment outcomes and resistance in patients with prior treatment failure: Results from the REALIZE trial

“…13,15,16 In addition to these positions, the use of boceprevir has been associated with the emergence of resistance at positions 55 and 170. 14 Here we report the findings from a subanalysis of the Phase 3 telaprevir REALIZE trial, in which treatment outcomes and the emergence of viral variants were further characterized in patients with prior peginterferon/ribavirin treatment failure who did not achieve an SVR with subsequent telaprevir-based therapy. We explored whether the use of a peginterferon/ ribavirin lead-in, HCV genotype subtype, or prior peginterferon/ribavirin response category had an effect on treatment outcome or the emergence of variants.…”

“…Therefore, during treatment with DAAs, such as telaprevir and boceprevir, there is the potential for selection of preexisting viral variants with decreased susceptibility to DAAs with a similar mechanism of action. [13][14][15] In HCV genotype 1-infected patients, the use of telaprevir was associated with the emergence of resistant variants at NS3 amino acid positions 36, 54, 155, and 156. 13,15,16 In addition to these positions, the use of boceprevir has been associated with the emergence of resistance at positions 55 and 170.…”