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Clinical Implications of Detectable Baseline Hepatitis C Virus-Genotype 1 NS3/4A-Protease Variants on the Efficacy of Boceprevir Combined With Peginterferon/Ribavirin.

Howe JA, Long J, Black S, Chase R, McMonagle P, Curry S, Thompson S, DiNubile MJ, Howe AY - Open Forum Infect Dis (2014)

Bottom Line: NS3-protease-polymorphisms emerging coincident with virologic failure on boceprevir/P/R regimens were identified as resistance-associated variants (RAVs).For the 510 poor IFN-responders, SVR24 rates were 8 of 36 subjects (22.2% [11.7%, 38.1%]) when baseline RAVs were detected vs 174 of 474 subjects (36.7% [32.5%, 41.1%]) when baseline RAVs were not detected (relative likelihood of SVR24 [95% CI], 0.61 [0.32, 1.05]).Baseline protease-variants appear to negatively impact SVR rates for boceprevir/P/R regimens only when associated with decreased boceprevir susceptibility in vitro after a poor IFN-response during the lead-in period.

View Article: PubMed Central - PubMed

Affiliation: Merck Research Laboratories , Kenilworth, New Jersey.

ABSTRACT

Background: We analyzed the impact of pretreatment variants conferring boceprevir-resistance on sustained virologic response (SVR) rates achieved with boceprevir plus peginterferon-α/ribavirin (P/R) for hepatitis C virus (HCV)-genotype-1 infection.

Methods: NS3-protease-polymorphisms emerging coincident with virologic failure on boceprevir/P/R regimens were identified as resistance-associated variants (RAVs). Baseline samples pooled from 6 phase II or phase III clinical trials were analyzed for RAVs by population sequencing. Interferon (IFN)-responsiveness was predefined as >1 log reduction in HCV-RNA level during the initial 4-week lead-in treatment with P/R before boceprevir was added. The effective boceprevir-concentration inhibiting RAV growth by 50% (EC50) was determined using a replicon assay relative to the wild-type referent.

Results: Sequencing was performed in 2241 of 2353 patients (95.2%) treated with boceprevir. At baseline, RAVs were detected in 178 patients (7.9%), including 153 of 1498 genotype-1a infections (10.2%) and 25 of 742 genotype-1b infections (3.4%) (relative risk, 3.03; 95% confidence interval [CI], [2.01, 4.58]). For IFN-responders, SVR24 (SVR assessed 24 weeks after discontinuation of all study medications) rates were 78% and 76% with or without RAVs detected at baseline, respectively. For the 510 poor IFN-responders, SVR24 rates were 8 of 36 subjects (22.2% [11.7%, 38.1%]) when baseline RAVs were detected vs 174 of 474 subjects (36.7% [32.5%, 41.1%]) when baseline RAVs were not detected (relative likelihood of SVR24 [95% CI], 0.61 [0.32, 1.05]). Sustained virologic response was achieved in 7 of 8 (87.5%) IFN-nonresponders with baseline variants exhibiting ≤2-fold increased EC50 for boceprevir in a replicon assay, whereas only 1 of 15 (7%) IFN-nonresponders with baseline RAVs associated with ≥3-fold increased EC50 achieved SVR.

Conclusions: Baseline protease-variants appear to negatively impact SVR rates for boceprevir/P/R regimens only when associated with decreased boceprevir susceptibility in vitro after a poor IFN-response during the lead-in period.

No MeSH data available.


Related in: MedlinePlus

Frequency and distribution of specific amino acid substitutions among the 178 patients with RAVs detected by population sequencing at baseline. Results are shown separately for genotype-1a and genotype-1b variants. Abbreviations: GT, genotype; RAV, resistance-associated variant.
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OFU078F1: Frequency and distribution of specific amino acid substitutions among the 178 patients with RAVs detected by population sequencing at baseline. Results are shown separately for genotype-1a and genotype-1b variants. Abbreviations: GT, genotype; RAV, resistance-associated variant.

Mentions: Population NS3-sequence data were obtained at baseline from 2241 of 2352 (95.3%) boceprevir recipients, including 1498 of 1571 (95.4%) with genotype-1a infections and 742 of 756 (98.1%) with genotype-1b infections. Baseline characteristics were generally similar in patients with or without baseline RAVs, except that genotype 1a infections were disproportionately represented among the RAVs (Table 1). At baseline, no RAVs were detected by population sequencing in 2063 of 2241 (92%) of patients. Baseline RAVs were identified in 178 of 2241 (7.9%) patients at 8 positions (V36, T54, V55, V107, R155, V158, I170, and M175) of the 11 defined boceprevir resistance-associated NS3-loci. Resistance-associated variants were found in 153 of 1498 (10.2%) patients with genotype-1a virus and in 25 of 742 (3.4%) patients with genotype-1b virus (relative risk of detected RAV at baseline [95% confidence interval] = 3.03 [2.01, 4.58]). In genotype-1a infections, the most common substitutions were I170V, V55A, T54S, and V55I; in genotype-1b infections, the most common substitutions were T54S, V55A, and V107I (Figure 1). No other substitution occurred in ≥10% of cases. The large majority of boceprevir recipients included in our analysis population were treatment-naive at study entry: 1906 of 2352 patients (81.0%) overall, including 159 of 178 patients (89.3%) with RAVs detected at baseline, and 1652 of 2063 patients (80.1.3%) without RAVs detected at baseline. No patient had received a direct-acting antiviral drug before enrollment.Table 1.


Clinical Implications of Detectable Baseline Hepatitis C Virus-Genotype 1 NS3/4A-Protease Variants on the Efficacy of Boceprevir Combined With Peginterferon/Ribavirin.

Howe JA, Long J, Black S, Chase R, McMonagle P, Curry S, Thompson S, DiNubile MJ, Howe AY - Open Forum Infect Dis (2014)

Frequency and distribution of specific amino acid substitutions among the 178 patients with RAVs detected by population sequencing at baseline. Results are shown separately for genotype-1a and genotype-1b variants. Abbreviations: GT, genotype; RAV, resistance-associated variant.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4281806&req=5

OFU078F1: Frequency and distribution of specific amino acid substitutions among the 178 patients with RAVs detected by population sequencing at baseline. Results are shown separately for genotype-1a and genotype-1b variants. Abbreviations: GT, genotype; RAV, resistance-associated variant.
Mentions: Population NS3-sequence data were obtained at baseline from 2241 of 2352 (95.3%) boceprevir recipients, including 1498 of 1571 (95.4%) with genotype-1a infections and 742 of 756 (98.1%) with genotype-1b infections. Baseline characteristics were generally similar in patients with or without baseline RAVs, except that genotype 1a infections were disproportionately represented among the RAVs (Table 1). At baseline, no RAVs were detected by population sequencing in 2063 of 2241 (92%) of patients. Baseline RAVs were identified in 178 of 2241 (7.9%) patients at 8 positions (V36, T54, V55, V107, R155, V158, I170, and M175) of the 11 defined boceprevir resistance-associated NS3-loci. Resistance-associated variants were found in 153 of 1498 (10.2%) patients with genotype-1a virus and in 25 of 742 (3.4%) patients with genotype-1b virus (relative risk of detected RAV at baseline [95% confidence interval] = 3.03 [2.01, 4.58]). In genotype-1a infections, the most common substitutions were I170V, V55A, T54S, and V55I; in genotype-1b infections, the most common substitutions were T54S, V55A, and V107I (Figure 1). No other substitution occurred in ≥10% of cases. The large majority of boceprevir recipients included in our analysis population were treatment-naive at study entry: 1906 of 2352 patients (81.0%) overall, including 159 of 178 patients (89.3%) with RAVs detected at baseline, and 1652 of 2063 patients (80.1.3%) without RAVs detected at baseline. No patient had received a direct-acting antiviral drug before enrollment.Table 1.

Bottom Line: NS3-protease-polymorphisms emerging coincident with virologic failure on boceprevir/P/R regimens were identified as resistance-associated variants (RAVs).For the 510 poor IFN-responders, SVR24 rates were 8 of 36 subjects (22.2% [11.7%, 38.1%]) when baseline RAVs were detected vs 174 of 474 subjects (36.7% [32.5%, 41.1%]) when baseline RAVs were not detected (relative likelihood of SVR24 [95% CI], 0.61 [0.32, 1.05]).Baseline protease-variants appear to negatively impact SVR rates for boceprevir/P/R regimens only when associated with decreased boceprevir susceptibility in vitro after a poor IFN-response during the lead-in period.

View Article: PubMed Central - PubMed

Affiliation: Merck Research Laboratories , Kenilworth, New Jersey.

ABSTRACT

Background: We analyzed the impact of pretreatment variants conferring boceprevir-resistance on sustained virologic response (SVR) rates achieved with boceprevir plus peginterferon-α/ribavirin (P/R) for hepatitis C virus (HCV)-genotype-1 infection.

Methods: NS3-protease-polymorphisms emerging coincident with virologic failure on boceprevir/P/R regimens were identified as resistance-associated variants (RAVs). Baseline samples pooled from 6 phase II or phase III clinical trials were analyzed for RAVs by population sequencing. Interferon (IFN)-responsiveness was predefined as >1 log reduction in HCV-RNA level during the initial 4-week lead-in treatment with P/R before boceprevir was added. The effective boceprevir-concentration inhibiting RAV growth by 50% (EC50) was determined using a replicon assay relative to the wild-type referent.

Results: Sequencing was performed in 2241 of 2353 patients (95.2%) treated with boceprevir. At baseline, RAVs were detected in 178 patients (7.9%), including 153 of 1498 genotype-1a infections (10.2%) and 25 of 742 genotype-1b infections (3.4%) (relative risk, 3.03; 95% confidence interval [CI], [2.01, 4.58]). For IFN-responders, SVR24 (SVR assessed 24 weeks after discontinuation of all study medications) rates were 78% and 76% with or without RAVs detected at baseline, respectively. For the 510 poor IFN-responders, SVR24 rates were 8 of 36 subjects (22.2% [11.7%, 38.1%]) when baseline RAVs were detected vs 174 of 474 subjects (36.7% [32.5%, 41.1%]) when baseline RAVs were not detected (relative likelihood of SVR24 [95% CI], 0.61 [0.32, 1.05]). Sustained virologic response was achieved in 7 of 8 (87.5%) IFN-nonresponders with baseline variants exhibiting ≤2-fold increased EC50 for boceprevir in a replicon assay, whereas only 1 of 15 (7%) IFN-nonresponders with baseline RAVs associated with ≥3-fold increased EC50 achieved SVR.

Conclusions: Baseline protease-variants appear to negatively impact SVR rates for boceprevir/P/R regimens only when associated with decreased boceprevir susceptibility in vitro after a poor IFN-response during the lead-in period.

No MeSH data available.


Related in: MedlinePlus