Abstract：
In the monotherapy arms of the phase 2 JADE study (ClinicalTrials.gov Identifier: NCT03361956) evaluating the safety and efficacy of JNJ-56136379 (capsid assembly modulator-class E) with/without nucleos(t)ide analogue (NA), viral breakthroughs (VBT) were observed, leading to JNJ-56136379 monotherapy discontinuation. We present the viral sequencing analysis of JNJ-56136379±NA-treated hepatitis B virus (HBV)-infected patients.
The HBV full genome was sequenced using next generation sequencing. Baseline amino acid (aa) polymorphisms were defined as changes versus the universal HBV reference sequence (sequence read frequency >15%). Emerging mutations were defined as aa changes versus baseline sequence (frequency <1% at baseline and ≥15% post-baseline).
6/28 JNJ-56136379 75 mg monotherapy arm patients experienced VBT; all 6 had emerging JNJ-56136379-resistant variants T33N (n = 5; fold change [FC] = 85) or F23Y (n = 1; FC = 5.2). 1/32 JNJ-56136379 250 mg arm patients (genotype-E) had <1 log10 IU/mL decline in HBV DNA at Week 4, experienced VBT at Week 8, and carried the I105T baseline polymorphism (FC = 7.9), but had no emerging variants. Eight additional monotherapy-treated patients had shallow second phases of their HBV DNA profile and emerging T33N (n = 7) or F23Y (n = 1) variants. NA initiation (switch [75 mg arm]; add-on [250 mg arm]) in all monotherapy patients with VBT resulted in HBV DNA decline in all patients. No VBT was observed during JNJ-56136379+NA combination therapy.
JNJ-56136379 monotherapy resulted in VBT and was associated with the selection of JNJ-56136379-resistant variants. Efficacy of NA treatment (de novo combination or rescue therapy for VBT) was not impacted, confirming the lack of cross-resistance between these drug classes.
NCT03361956.
The HBV full genome was sequenced using next generation sequencing. Baseline amino acid (aa) polymorphisms were defined as changes versus the universal HBV reference sequence (sequence read frequency >15%). Emerging mutations were defined as aa changes versus baseline sequence (frequency <1% at baseline and ≥15% post-baseline).
6/28 JNJ-56136379 75 mg monotherapy arm patients experienced VBT; all 6 had emerging JNJ-56136379-resistant variants T33N (n = 5; fold change [FC] = 85) or F23Y (n = 1; FC = 5.2). 1/32 JNJ-56136379 250 mg arm patients (genotype-E) had <1 log10 IU/mL decline in HBV DNA at Week 4, experienced VBT at Week 8, and carried the I105T baseline polymorphism (FC = 7.9), but had no emerging variants. Eight additional monotherapy-treated patients had shallow second phases of their HBV DNA profile and emerging T33N (n = 7) or F23Y (n = 1) variants. NA initiation (switch [75 mg arm]; add-on [250 mg arm]) in all monotherapy patients with VBT resulted in HBV DNA decline in all patients. No VBT was observed during JNJ-56136379+NA combination therapy.
JNJ-56136379 monotherapy resulted in VBT and was associated with the selection of JNJ-56136379-resistant variants. Efficacy of NA treatment (de novo combination or rescue therapy for VBT) was not impacted, confirming the lack of cross-resistance between these drug classes.
NCT03361956.
摘要：
目的：在2期JADE研究（ClinicalTrials.gov标识符：NCT03361956）的单药治疗组中，评估JNJ-56136379（衣壳组装调节剂E类）有/无核苷（t）ide类似物（NA）的安全性和有效性，观察到病毒突破（VBT），导致JNJ-56136379单药治疗停药。我们提出了JNJ-56136379±NA治疗的乙型肝炎病毒（HBV）感染患者的病毒测序分析。
方法：使用下一代测序对HBV全基因组进行测序。基线氨基酸（aa）多态性被定义为与通用HBV参考序列（序列读取频率>15％）的变化。新出现的突变定义为相对于基线序列的aa变化(基线时频率<1%,基线后频率≥15%)。
结果：6/28JNJ-5613637975mg单药治疗组患者出现VBT；所有6例均出现了JNJ-56136379耐药变异体T33N（n=5；倍数变化[FC]=85）或F23Y（n=1；FC=5.2）。1/32JNJ-56136379250毫克手臂患者（基因型E）在第4周HBVDNA下降<1log10IU/mL，在第8周经历VBT，并携带I105T基线多态性（FC=7.9），但没有新出现的变体。另外八名单药治疗的患者的HBVDNA谱和新出现的T33N（n=7）或F23Y（n=1）变异的浅第二阶段。NA启动（开关[75毫克臂];添加[250毫克臂]）在所有单一治疗患者VBT导致HBVDNA下降。在JNJ-56136379+NA联合治疗期间未观察到VBT。
结论：JNJ-56136379单药治疗导致VBT，并与JNJ-56136379耐药变体的选择相关。NA治疗（VBT的从头联合治疗或抢救治疗）的疗效没有受到影响，确认这些药物类别之间缺乏交叉耐药性。
背景：NCT03361956。
方法：使用下一代测序对HBV全基因组进行测序。基线氨基酸（aa）多态性被定义为与通用HBV参考序列（序列读取频率>15％）的变化。新出现的突变定义为相对于基线序列的aa变化(基线时频率<1%,基线后频率≥15%)。
结果：6/28JNJ-5613637975mg单药治疗组患者出现VBT；所有6例均出现了JNJ-56136379耐药变异体T33N（n=5；倍数变化[FC]=85）或F23Y（n=1；FC=5.2）。1/32JNJ-56136379250毫克手臂患者（基因型E）在第4周HBVDNA下降<1log10IU/mL，在第8周经历VBT，并携带I105T基线多态性（FC=7.9），但没有新出现的变体。另外八名单药治疗的患者的HBVDNA谱和新出现的T33N（n=7）或F23Y（n=1）变异的浅第二阶段。NA启动（开关[75毫克臂];添加[250毫克臂]）在所有单一治疗患者VBT导致HBVDNA下降。在JNJ-56136379+NA联合治疗期间未观察到VBT。
结论：JNJ-56136379单药治疗导致VBT，并与JNJ-56136379耐药变体的选择相关。NA治疗（VBT的从头联合治疗或抢救治疗）的疗效没有受到影响，确认这些药物类别之间缺乏交叉耐药性。
背景：NCT03361956。
