Single nucleotide polymorphisms in the bepirovirsen binding site have limited impact on treatment response in chronic hepatitis B.

This analysis of the B-Clear study (NCT04449029) evaluated the frequency of baseline and treatment-emergent SNPs in the bepirovirsen binding site and their association with virological response.

本研究对B-Clear研究（NCT04449029）的分析评估了基线和治疗后出现的SNPs在bepirovirsen结合位点的频率，以及它们与病毒学应答的关联。

Methods

HBV sequencing was attempted for all baseline samples collected from B-Clear participants and for selected post-baseline samples from participants meeting predefined resistance-monitoring criteria.

对所有来自B-Clear参与者的基础样本以及符合预定义耐药监测标准的参与者选定的基线后样本进行了HBV测序尝试。

Participants were categorized according to nucleos(t)ide analogue (NA) treatment status and hepatitis B surface antigen (HBsAg) response.

根据核苷（酸）类似物（NA）治疗状态和乙型肝炎表面抗原（HBsAg）反应将参与者进行分类。

SNPs were identified using next-generation sequencing and reported if the allelic frequency was ≥5%.

通过下一代测序鉴定SNPs，并在等位基因频率≥5%时进行报告。

The effects of binding site SNPs on viral fitness and susceptibility to bepirovirsen were assessed in vitro.

在体外评估了结合位点SNPs对病毒适应性和对bepirovirsen敏感性的影响。

Results

Baseline sequences were obtained for 40% (90/226) and 96% (219/229) of On-NA and Not-on-NA participants, respectively.

在On-NA和Not-on-NA参与者中，分别有40%（90/226）和96%（219/229）获得了基线序列。

Baseline SNPs were identified in 7% (22/309) of participants.

在参与者中，有7%（22/309）识别出了基线SNPs。

These participants showed numerically smaller HBsAg reductions than those without SNPs, but 18% (4/22) achieved transient HBsAg loss.

这些参与者显示出的乙型肝炎表面抗原（HBsAg）减少数值上小于没有单核苷酸多态性（SNPs）的参与者，但有18%（4/22）实现了HBsAg的暂时性消失。

Post-baseline sequences were obtained for 22% (49/226) and 62% (143/229) of On-NA and Not-on-NA participants, respectively.

在基线后，分别有22%（49/226）和62%（143/229）的正在接受核苷（酸）类似物治疗（On-NA）和未接受核苷（酸）类似物治疗（Not-on-NA）的参与者获得了序列。

Of 16 post-baseline SNPs, eight were treatment-emergent.

在16个基线后的SNP中，有八个是治疗后出现的。

SNPs were detected at 12 of the 20 binding site positions; however, only two SNPs had an allelic frequency >50% (C1589A [max 99%] and C1600T [max 99%]).

在20个结合位点位置中检测到SNP；然而，只有两个SNP的等位基因频率>50%（C1589A [最大99%] 和 C1600T [最大99%]）。

Six SNPs showed sufficient viral fitness to be evaluated for susceptibility to bepirovirsen in vitro.

六种SNP显示出足够的病毒适应性，以在体外评估其对bepirovirsen的易感性。

C1589A demonstrated the largest reduction in susceptibility (4.1-fold) to bepirovirsen.

C1589A显示出对bepirovirsen的易感性降低最大（4.1倍）。

Conclusions

Most participants achieved >1 log reductions in HBsAg, including transient HBsAg loss in some.

大多数参与者实现了HBsAg的>1 log降低，包括一些人的HBsAg暂时性丧失。

Although participants with baseline SNPs showed numerically smaller HBsAg reductions, further investigation is required to better understand potential mechanisms of resistance to bepirovirsen.

尽管携带基线SNPs的参与者在HBsAg降低上数值上较小，但需要进一步研究以更好地理解对贝匹罗韦森潜在耐药机制。

impact_and_implications

HBV sequence polymorphisms can contribute to antiviral resistance in the treatment of chronic HBV infection.

HBV序列多态性可能有助于慢性HBV感染治疗中的抗病毒耐药性。

Therefore, it is important for healthcare professionals to understand the prevalenceand emergence of single nucleotide polymorphisms (SNPs) within the bepirovirsen binding site and their potential impact on virological response.

因此，对于医疗保健专业人员来说，了解bepirovirsen结合位点内单核苷酸多态性（SNPs）的流行情况及其对病毒学反应的潜在影响非常重要。

Findings from this phase IIb clinical study demonstrate that the vast majority (92%) of non-responders, partial responders, or relapsers did not harbor bepirovirsen binding site SNPs.

这项IIb期临床研究的发现表明，绝大多数（92%）的无应答者、部分应答者或复发者并未携带bepirovirsen结合位点SNPs。

Moreover, participants with binding site SNPs (7% of participants) still achieved reductions in hepatitis B surface antigen.

此外，携带结合位点SNPs的参与者（占参与者的7%）仍然实现了乙型肝炎表面抗原的降低。

These results suggest that routine testing for specific HBV variants prior to bepirovirsen administration is not currently warranted, and that resistance due to altered sequence complementarity is likely minimal and multifactorial. Ongoing phase III studies of bepirovirsen will provide additional context to further evaluate the need for variant testing and to better elucidate potential resistance mechanisms.

这些结果表明，在贝匹罗韦森给药前常规进行特定HBV变异检测目前尚无必要，且由于序列互补性改变导致的耐药性可能很小且是多因素的。正在进行的贝匹罗韦森III期研究将提供额外的背景信息，以进一步评估变异检测的需要，并更好地阐明潜在的耐药机制。