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2026年欧洲肝病学会年会（EASL 2026）于2026年5月27日-30日在西班牙•巴塞罗那顺利举行。作为全球肝病学领域的学术盛会，本届大会汇聚国际顶尖专家学者，共同探讨肝病学、胃肠病学、移植外科及传染病学等领域的最新研究进展与临床实践突破。

大会设置前沿学术报告、高互动性研讨会及专题论坛，为与会者提供深度交流与专业提升的高端平台。为及时传递大会精华内容，肝胆相照平台全程跟踪报道，本篇精选慢性乙型肝炎领域热点研究进行整理，以传递大会的最新动态和精彩看点。

01 OS-072

GSK3965193 在慢性乙型肝炎（CHB）患者中的安全性、耐受性、药代动力学及药效学研究

Safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK3965193 in patients with chronic hepatitis B (CHB)

作者：Martin Leivers, Stephen Atkinson, Sarah Mole, Christine Livingston, Ahmed Nader, B S Pooja, Susmita Sanyal, Eric Billaud, Caroline Jezequel, Marie-Noëlle Hilleret, Pietro Lampertico, Young-Suk Lim, Jeong Heo, Won Young Tak, Ashley Brown, Daniel Forton, Curtis Cooper, Carla Coffin, Anchalee Avihingsanon, Shilpy Joshi, Michael Maguire, Puneet Dhawan, Kiran Gumireddy, Anil Kesarwani, Nadia Noormohamed

研究背景与目的▼

GSK3965193（GSK193）是一种新型口服小分子PAPD5/7抑制剂。PAPD5/7属于人体非经典poly(A)聚合酶，GSK193通过destabilization（不稳定化）HBVRNA，从而降低乙型肝炎表面抗原（HBsAg）水平。本项首次人体研究旨在评估GSK193在慢性乙型肝炎（CHB）患者中的安全性、耐受性、药代动力学（PK）及药效学（PD）特征。

Background and aims：GSK3965193 (GSK193) is a novel, orally bioavailable, small molecule inhibitor of the human non-canonical poly(A) polymerases PAPD5/7, designed to reduce the HBV antigen HBsAg through destabilization of HBV RNA. This first-in-patient study aimed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GSK193 in patients with chronic hepatitis B (CHB)..

研究方法▼

本研究为一项多中心、随机、双盲、安慰剂对照I期临床研究（ClinicalTrials.gov：NCT05330455）。在研究第3部分中，正在接受核苷类似物治疗的HBeAg阳性及阴性患者，被随机分配接受GSK193（0.5mg，每日一次；n=14）或安慰剂（每日一次；n=4）治疗28天。研究评估内容包括：药代动力学（PK）；药效学指标（HBV生物标志物）；安全性监测。此外，还在基线、第15天及第29天进行了神经传导功能检测。

Method：This was a multicenter, randomized, double-blind, placebo-controlled phase 1 study (ClinicalTrials.gov: NCT05330455). In Part 3 of the study, HBeAg-positive and HBeAg-negative patients on nucleoside analogs were randomized to GSK193 (0.5 mg, QD; n = 14) or placebo (QD; n = 4) for 28 days. PK, PD (HBV biomarkers), and safety monitoring, including nerve conduction assessments at baseline, days 15 and 29, were assessed.

研究结果▼

在本研究所测试剂量及疗程下，GSK193表现出可接受的安全性及良好的耐受性。在第3部分研究中，未出现严重治疗相关不良事件（TEAEs），亦未观察到≥2级以上TEAEs。最常见的不良事件包括头晕、疲劳、味觉异常及头痛，这些事件在GSK193组中的发生频率高于安慰剂组。神经传导检测未观察到明显异常变化。

药代动力学方面，GSK193吸收迅速，中位Tmax为3.0小时，中位半衰期（t1/2）为7.9小时。连续每日给药28天后未观察到明显药物蓄积。0.5mg剂量给药后，血浆药物浓度可维持超过经蛋白结合校正后的临床前肝脏EC90靶浓度达24小时，验证了PK模型预测结果。

GSK193治疗后，HBsAg最大平均降幅为0.50log10IU/ml[95%可信区间(CrI)：0.3–0.7]，明显高于安慰剂组的0.08log10IU/ml（95%CrI：0.05–0.09）。个体患者中，GSK193组观察到的HBsAg最大降幅可达1.66log10IU/ml，而安慰剂组仅为0.10log10IU/ml。平均而言，GSK193在24天内达到最大HBsAg降幅。停药后，HBsAg水平通常在2周内回升至基线水平。

Results：GSK193 had an acceptable safety profile and was well tolerated in CHB patients at the tested dose and duration. In Part 3, no serious treatment-emergent adverse events (TEAEs) or TEAEs > Grade 2 occurred. The most common TEAEs were dizziness, fatigue, dysgeusia, and headache, all of which occurred more frequently with GSK193 than placebo. No significant changes were observed in nerve conduction assessments.

Following administration, GSK193 was rapidly absorbed, with a median Tmax of 3.0 h and median t1/2 of 7.9 h. No accumulation was observed after 28 daily doses. A plasma target concentration corresponding to the protein-binding-adjusted preclinical liver EC90 was exceeded for 24 hours following the 0.5 mg dose, confirming PK model-based predictions.

GSK193 treatment resulted in a posterior mean maximum HBsAg reduction from baseline of 0.50 log10 IU/mL (95% credible interval [CrI]: 0.3, 0.7), which was higher than in the placebo group (0.08 log10 IU/mL; 95% CrI: 0.05, 0.09). Individually, the highest observed maximum reduction of HBsAg levels with GSK193 was 1.66 log10 IU/mL compared to 0.10 log10 IU/mL with placebo. On average, this maximum reduction was achieved within 24 days with GSK193. Upon cessation of GSK193 administration, HBsAg levels generally rebounded to baseline within 2 weeks.

研究结论▼

在本研究剂量下，GSK193具有良好的耐受性、安全性及药代动力学特征，并初步显示出通过降低HBsAg实现抗病毒活性的潜力，支持其作为慢性乙型肝炎治疗方案组成部分进一步开展临床研究。

Conclusion: GSK193 at the tested dose was tolerated, showed favorable safety and pharmacokinetic profile, and demonstrated preliminary evidence of antiviral activity through HBsAg reduction, supporting further clinical development of GSK193 as part of a regimen for treating CHB.

02 OSS-073

单次VRON-0200初始免疫激活治疗联合每月一次抗病毒联合方案，可使慢性乙型肝炎患者获得快速、深度且持久的HBsAg下降

A single VRON-0200 prime dose, followed by a monthly antiviral combination regimen, resulted in rapid, profound, and durable HBsAg declines in chronically hepatitis B-infected patients

作者：Edward J. Gane, Sue Currie, Tien Huey Lim, Andrew Luber, Marie Bonhomme, Grace Wong

研究背景与目的▼

VRON-0200是一种免疫调节剂，包含针对HBV core和pol抗原（但不针对S抗原）的免疫检查点调节成分，旨在增强、拓宽并延长T细胞免疫反应。Ib期研究显示，单次给予VRON-0200即可诱导抗HBV免疫激活/恢复，并带来持久的HBsAg下降。本研究旨在评估：在接受核苷（酸）类似物（NUCs）治疗的慢性乙型肝炎（CHB）患者中，单用VRON-0200或联合研究性抗病毒药物时的安全性、免疫原性以及HBsAg应答情况。

Background and aims：VRON-0200 is an immune-modulator containing a checkpoint modifier targeting HBV core and pol (but not S) antigens, designed to enhance, broaden, and prolong T-cell responses. The Phase 1b study demonstrated that VRON-0200 induces anti-HBV immune activation/restoration, with durable HBsAg declines after a single dose. This study evaluated the safety, immunogenicity, and HBsAg responses in chronic hepatitis B (CHB) patients on nucleos(t)ide analogues (NUCs) who received VRON-0200 alone or in combination with investigational antivirals.

研究方法▼

NUCs治疗后病毒已被抑制、且HBsAg<500IU/ml（队列1和2；C1/2）或HBsAg<1,000IU/ml（队列3；C3）的CHB患者被随机分组，于第1天接受肌肉注射VRON-0200初始免疫激活（prime），并根据分组于第91天接受或不接受VRON-0200加强治疗（boost）。队列3患者在接受VRON-0200初始治疗后，于第28天开始接受elebsiran联合tobevibart（E+T）方案，共6次、每月一次，并根据分组于第196天接受或不接受VRON-0200加强治疗。研究进行了安全性、病毒学及免疫学评估。HBsAg采用ELISA检测（检测下限LLOD：0.05IU/ml），T细胞频率采用IFN-γELISpot方法检测。

Method：CHB patients with NUC-suppressed disease and HBsAg <500 IU/mL (Cohorts 1 and 2; C1/2), or HBsAg <1,000 IU/mL (Cohort 3; C3), were randomized to receive intramuscular VRON-0200 prime on Day 1, with or without a VRON-0200 boost on Day 91. Cohort 3 received VRON-0200 prime followed by six monthly doses of elebsiran plus tobevibart (E+T) starting on Day 28, either alone or with a VRON-0200 boost on Day 196. Safety, virologic, and immunologic assessments were performed. HBsAg levels were measured by ELISA (LLOD: 0.05 IU/mL), and T-cell frequencies were measured using IFN-γ ELISpot assays.

研究结果▼

截至2025年12月19日，共纳入35例患者，其中男性28例（80%），亚洲患者30例（86%），中位年龄46岁，基线HBsAg中位值为179IU/ml（范围：10–1169）。在累计12,073个患者安全观察日中，共报告38例治疗相关不良事件（TRAEs），包括4例2级事件和34例1级事件，未发生治疗相关严重不良事件（SAEs）或因不良事件停药。

在C1/2队列中，全部27例患者均完成研究（Day360）。在Day360（即VRON-0200初始给药后第359天）时，23/27（85%）患者仍维持或继续出现HBsAg下降；其中12/23（52%）患者HBsAg下降超过50%，4例患者较基线下降≥1log10IU/ml。加强治疗（boost）并未进一步增强疗效，且HBsAg的下降与基线HBsAg水平无关。IFN-γELISpot检测结果与HBsAg下降之间未观察到明显相关性。

在C3队列中，首次接受E+T治疗后7天内即观察到快速且显著的HBsAg下降：100%患者HBsAg≤2IU/ml，其中1例降至检测下限以下。该下降同样与基线HBsAg水平无关。在Day196（即最后一次E+T给药后28天）时，100%患者HBsAg≤1IU/ml，其中7例患者中的3例已低于检测下限。关于C3队列停用E+T至少3个月后的结果，将在后续公布。

Results：As of December 19, 2025, 35 patients were included: 28 (80%) were male, 30 (86%) were Asian, median age was 46 years, and median baseline HBsAg was 179 IU/mL (range: 10–1169). Across 12,073 patient safety-days, 38 treatment-related adverse events (TRAEs) were reported, including 4 Grade 2 and 34 Grade 1 events, with no treatment-related serious adverse events or discontinuations.

In Cohorts 1/2, all 27 patients reached end-of-study (Day 360). At Day 360, corresponding to 359 days after the VRON-0200 prime dose, 23/27 (85%) patients had sustained and/or continued HBsAg declines; 12/23 (52%) achieved >50% reductions, and 4 patients had ≥1 log10 IU/mL reductions from baseline. A boost dose did not further enhance responses, and HBsAg declines were independent of baseline HBsAg levels. IFN-γ ELISpot responses did not appear to correlate with HBsAg declines.

In Cohort 3, rapid and profound HBsAg declines were observed within 7 days after the first E+T dose, with 100% of patients reaching ≤2 IU/mL and one patient falling below the lower limit of detection. These declines were independent of baseline HBsAg levels. At Day 196 (28 days after the last E+T dose), 100% of patients had HBsAg ≤1 IU/mL, and 3 of 7 patients had levels below the lower limit of detection. Additional Cohort 3 results at least 3 months after the final E+T dose will be reported later.

研究结论▼

本项Ib期研究显示，无论单独使用还是联合抗病毒治疗，VRON-0200均未发现明显安全性问题，且耐受性良好。VRON-0200所诱导的抗HBV活性在联合抗病毒药物后进一步增强，并在所有患者中实现了快速而显著的HBsAg下降。这种新的治疗策略，即先通过VRON-0200“点燃（prime）”抗HBV免疫反应，再通过抗病毒药物清除HBV进一步“助燃（boost）”免疫效应，为VRON-0200作为未来HBV功能性治愈方案核心基础药物提供了支持。目前，IIb期研究（SPARK-B）正在筹备中。

Conclusion:  In this Phase 1b study, VRON-0200 alone or in combination therapy showed no major safety concerns and was well tolerated. VRON-0200-induced anti-HBV activity was enhanced when combined with antivirals and produced rapid and profound HBsAg declines in all patients. This novel approach, in which anti-HBV immunity is “sparked” (primed) by VRON-0200 and subsequently “fanned” (boosted) by antiviral-mediated HBV removal, supports the potential role of VRON-0200 as a foundational backbone agent for future HBV functional cure regimens. A Phase 2b study (SPARK-B) is currently being planned.

03 OS-101-YI

核苷（酸）类似物停药后严重生化学反弹中治疗结束时生物标志物与HBV基因型的关系：PROSTOP联盟五项前瞻性研究结果

Association between end-of-treatment biomarkers and HBV genotype in severe biochemical flares after nucleos(t)ide analogue cessation: results from five prospective studies within the PROSTOP consortium

作者：Fleur Ballet, Arno Furquim d’Almeida, Marte Holmberg, Simon Hume, Anna Pocurull Aparicio, Magnus Lindh, Axelle Vanderlinden, Barbara Testoni, Fabien Zoulim, Benoit Kabamba, Veerle Matheeussen, Kumar Visvanathan, Dag Henrik Reikvam, Niel Hens, Sabela Lens, Alexander Thompson, Asgeir Johannessen, Thomas Vanwolleghem

研究背景与目的▼

乙型肝炎核心相关抗原（HBcrAg）、乙型肝炎核心IgG抗体（anti-HBc）以及HBVRNA是近年来慢性乙型肝炎领域新兴的重要生物标志物，具有预测核苷（酸）类似物（NUC）停药后严重生化学反弹（SBFs；ALT>10×ULN）风险的潜力。近期研究发现，HBVA型基因型（genotypeA）可能是预防严重生化学反弹的保护因素。本研究旨在探讨这些生物标志物与HBV基因型之间的关系，以进一步阐明其可能机制，并为未来治疗策略提供依据。

Background and aims：Hepatitis B core-related antigen (HBcrAg), hepatitis B core IgG antibodies (anti-HBc), and HBV RNA are emerging biomarkers in chronic hepatitis B and have potential value in predicting severe biochemical flares (SBFs; ALT >10×ULN) after nucleos(t)ide analogue (NUC) cessation. Recently, hepatitis B virus (HBV) genotype (gt) A was identified as a protective factor against SBFs. This study aimed to investigate the relationship between these biomarkers and HBV genotype to provide further insight into the mechanisms underlying this protective effect and to guide future treatment strategies.

研究方法▼

研究整合了PROSTOP联盟中五项国际前瞻性NUC停药研究的个体患者数据。所有患者均为HBeAg阴性、长期病毒学抑制状态，且无进展期肝纤维化。研究采用多变量混合线性回归及Logistic回归模型评估生物标志物与HBV基因型之间的关系，并将研究项目作为随机效应纳入分析。模型校正了年龄、性别及log转换后的HBsAg水平。HBcrAg与anti-HBc作为连续log转换变量分析，而HBV RNA 则按“可检测”与“不可检测”进行分类分析。

Method：Individual patient-level data from five international prospective NUC-stop studies within the PROSTOP consortium were pooled. All patients were HBeAg-negative, had long-term virological suppression, and none had advanced liver fibrosis. Multivariate mixed linear and logistic regression models were used to assess associations between biomarkers and HBV genotype, with study included as a random effect. Models were adjusted for age, sex, and log-transformed HBsAg levels. HBcrAg and anti-HBc were analyzed as continuous log-transformed variables, while HBV RNA was analyzed as detectable versus.

研究结果▼

共纳入343例具有HBV基因型数据的患者，其中A型58例（16.9%）、B型70例（20.4%）、C型59例（17.2%）、D型131例（38.2%）、E型23例（6.7%）、F型2例（0.6%）。

HBcrAg、anti-HBc及HBV RNA数据分别可用于320、338及153例患者分析。296例患者同时具有HBcrAg与anti-HBc数据，140例患者同时具有三项生物标志物数据。

与C、D、E型相比，A型患者anti-HBc水平均显著更高，其log10单位差分别为0.52、0.45和0.64（均p<0.001）。相反，与B型和C型相比，A型患者HBcrAg水平均显著更低，其log10单位差分别为−1.09和−1.07（均p<0.001）。与A型相比，D型患者HBV RNA可检测的概率更低（OR0.23，95%CI0.06–0.83，p=0.03）。

Results：A total of 343 patients with available HBV genotype data were included: genotype A, 58 patients (16.9%); genotype B, 70 patients (20.4%); genotype C, 59 patients (17.2%); genotype D, 131 patients (38.2%); genotype E, 23 patients (6.7%); and genotype F, 2 patients (0.6%).

HBcrAg, anti-HBc, and HBV RNA data were available for 320, 338, and 153 patients, respectively. Combined HBcrAg and anti-HBc data were available for 296 patients, and all three biomarkers were available for 140 patients.

Anti-HBc levels were significantly higher in genotype A compared with genotypes C, D, and E, with log10 unit differences of 0.52, 0.45, and 0.64 respectively (all p <0.001). Conversely, HBcrAg levels were significantly lower in genotype A compared with genotypes B and C, with log10 unit differences of −1.09 and −1.07 respectively (all p <0.001).

Compared with genotype A, genotype D was associated with lower odds of having detectable HBV RNA (OR 0.23, 95% CI 0.06–0.83, p = 0.03).

研究结论▼

在这一纳入五项前瞻性NUC停药研究的大型荟萃分析中，HBV A型基因型与更高的anti-HBc水平以及更低的HBcrAg水平显著相关，而这两项指标均被认为是预防严重生化学反弹的重要保护因素。这一关系可能部分解释了HBV A型患者停药后严重肝炎反弹发生率较低的现象，并为未来基于生物标志物指导的个体化NUC停药策略提供了机制学依据。

Conclusion: In this large pooled analysis of five prospective NUC cessation studies, genotype A was significantly associated with higher anti-HBc levels and lower HBcrAg levels, both of which are known protective factors against severe biochemical flares. This relationship may partially explain the lower frequency of severe post-cessation flares observed in patients with HBV genotype A and may provide mechanistic insights to support biomarker-guided individualized NUC cessation strategies.

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