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.
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。