Characterization of Telaprevir Treatment Outcomes and Resistance in Patients With Prior Treatment Failure: Results From the REALIZE Trial
Characterization of Telaprevir Treatment Outcomes and Resistance in Patients With Prior Treatment Failure: Results From the REALIZE Trial
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DOI：
10.1002/hep.25962
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发表时间：
2012-12-01
期刊：
影响因子：
13.5
通讯作者：
Picchio, Gaston
中科院分区：
文献类型：
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作者：
De Meyer, Sandra;Dierynck, Inge;Picchio, Gaston
在iii期REALIZE研究中，662名先前聚乙二醇干扰素/利巴韦林治疗失败的基因型1型丙型肝炎病毒（HCV）感染患者（包括复发者、部分应答者和无应答者）被随机分为立即给予12周的泰拉韦（T12/PR48）或随后给予4周的聚乙二醇干扰素/利巴韦林（T12/PR48），或12周的安慰剂（PR48），联合总共48周的聚乙二醇干扰素α -2a/利巴韦林。持续病毒学应答（SVR）率分别为64% （T12/PR48）、66%（引入T12/PR48）和17% （PR48）。该分析旨在描述未达到SVR的telaprevir治疗患者的治疗结果和出现的病毒变异。在基线、治疗期间和随访期间进行HCV NS3.4A群体测序。telaprevir耐药变异分为低水平（3- 25倍50%抑制浓度[IC50]增加：V36A/M、T54A/S、R155I/K/M/T和A156S）和高水平（bbb25倍IC50增加：V36M+R155K和A156T/V）耐药。耐药变异在基线时并不常见。总体而言，18%（分别为52%、19%和1%的先前无效反应者和部分缓解者）的特拉普利韦治疗患者在治疗期间出现病毒学失败，是否引入特拉普利韦治疗无显著差异。在替雷韦治疗阶段的病毒学失败主要与更高水平的耐药性相关；聚乙二醇干扰素/利巴韦林治疗阶段的病毒学失败与较高或较低水平或野生型变异相关，具体取决于基因型。在完成指定治疗的患者中，有9%的患者复发，并且通常与低水平耐药变异或野生型相关。研究结束时（中位随访11个月），58%的非svr患者不再检测到耐药变异。结论：在REALIZE研究中，非svr患者中出现的变异，不论是否使用了引入剂，都是相似的，并且与之前报道的一致。在大多数患者中，耐药变异随着时间的推移变得无法检测到。(肝脏病学56:2106 2012;2115)
In the Phase 3 REALIZE study, 662 genotype 1 hepatitis C virus (HCV)-infected patients with prior peginterferon/ribavirin treatment failure (including relapsers, partial, and null responders) were randomized to 12 weeks of telaprevir given immediately (T12/PR48) or following 4 weeks of peginterferon/ribavirin (lead-in T12/PR48), or 12 weeks of placebo (PR48), combined with a total of 48 weeks of peginterferon alfa-2a/ribavirin. Sustained virologic response (SVR) rates were 64% (T12/PR48), 66% (lead-in T12/PR48), and 17% (PR48). This analysis aimed to characterize treatment outcomes and viral variants emerging in telaprevir-treated patients not achieving SVR. HCV NS3.4A population sequencing was performed at baseline, during treatment, and follow-up. Telaprevir-resistant variants were classified into lower-level (3- to 25-fold 50% inhibitory concentration [IC50] increase: V36A/M, T54A/S, R155I/K/M/T, and A156S) and higher-level (>25-fold IC50 increase: V36M+R155K and A156T/V) resistance. Resistant variants were uncommon at baseline. Overall, 18% (52%, 19%, and 1% of prior null and partial responders and relapsers, respectively) of telaprevir-treated patients had on-treatment virologic failure, with no significant difference with or without a lead-in. Virologic failure during the telaprevir-treatment phase was predominantly associated with higher-level resistance; virologic failure during the peginterferon/ribavirin-treatment phase was associated with higher- or lower-level, or wildtype variants, depending on genotype. Relapse occurred in 9% of patients completing assigned treatment and was generally associated with lower-level resistant variants or wildtype. Resistant variants were no longer detectable by study end (median follow-up of 11 months) in 58% of non-SVR patients. Conclusion: In REALIZE, variants emerging in non-SVR, telaprevir-treated patients were similar irrespective of the use of a lead-in and were consistent with those previously reported. In most patients, resistant variants became undetectable over time. (HEPATOLOGY 2012;56:2106-2115)