Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection
Bepirovirsen 治疗慢性乙型肝炎感染的疗效和安全性
Published November 8, 2022
发布时间 2022 年 11 月 8 日
发布时间 2022 年 11 月 8 日
N Engl J Med 2022;387:1957-1968
N Engl J Med 2022;387：1957-1968 年
N Engl J Med 2022;387：1957-1968 年
DOI: 10.1056/NEJMoa2210027
DOI： 10.1056/NEJMoa2210027
DOI： 10.1056/NEJMoa2210027
Abstract 抽象
Background 背景
Bepirovirsen is an antisense oligonucleotide that targets all hepatitis B virus (HBV) messenger RNAs and acts to decrease levels of viral proteins.
Bepirovirsen 是一种反义寡核苷酸，靶向所有乙型肝炎病毒 （HBV） 信使 RNA，并起到降低病毒蛋白水平的作用。
Bepirovirsen 是一种反义寡核苷酸，靶向所有乙型肝炎病毒 （HBV） 信使 RNA，并起到降低病毒蛋白水平的作用。
Methods 方法
We conducted a phase 2b, randomized, investigator-unblinded trial involving participants with chronic HBV infection who were receiving or not receiving nucleoside or nucleotide analogue (NA) therapy. Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4). Groups 1, 2, and 3 received loading doses of bepirovirsen. The composite primary outcome was a hepatitis B surface antigen (HBsAg) level below the limit of detection and an HBV DNA level below the limit of quantification maintained for 24 weeks after the planned end of bepirovirsen treatment, without newly initiated antiviral medication.
我们进行了一项 2b 期、随机、研究者非盲法试验，涉及正在接受或未接受核苷或核苷酸类似物 （NA） 治疗的慢性 HBV 感染参与者。参与者被随机分配（以 3：3：3：1 的比例）每周皮下注射 300 毫克剂量的贝匹罗韦森，持续 24 周（第 1 组），贝贝罗韦森，剂量 300 毫克，持续 12 周，然后 150 毫克，持续 12 周（第 2 组），贝贝罗韦森，剂量 300 毫克，持续 12 周，然后安慰剂 12 周（第 3 组）， 或安慰剂 12 周，然后 bepirovirsen 剂量为 300 毫克，持续 12 周（第 4 组）。第 1 、 2 和 3 组接受负荷剂量的 bepirovirsen。复合主要结局是乙型肝炎表面抗原 （HBsAg） 水平低于检测限，HBV DNA 水平低于定量限，在计划结束贝吡罗韦森治疗后维持 24 周，未开始使用新开始的抗病毒药物。
我们进行了一项 2b 期、随机、研究者非盲法试验，涉及正在接受或未接受核苷或核苷酸类似物 （NA） 治疗的慢性 HBV 感染参与者。参与者被随机分配（以 3：3：3：1 的比例）每周皮下注射 300 毫克剂量的贝匹罗韦森，持续 24 周（第 1 组），贝贝罗韦森，剂量 300 毫克，持续 12 周，然后 150 毫克，持续 12 周（第 2 组），贝贝罗韦森，剂量 300 毫克，持续 12 周，然后安慰剂 12 周（第 3 组）， 或安慰剂 12 周，然后 bepirovirsen 剂量为 300 毫克，持续 12 周（第 4 组）。第 1 、 2 和 3 组接受负荷剂量的 bepirovirsen。复合主要结局是乙型肝炎表面抗原 （HBsAg） 水平低于检测限，HBV DNA 水平低于定量限，在计划结束贝吡罗韦森治疗后维持 24 周，未开始使用新开始的抗病毒药物。
下载研究摘要的 PDF。
Results 结果
The intention-to-treat population comprised 457 participants (227 receiving NA therapy and 230 not receiving NA therapy). Among those receiving NA therapy, a primary-outcome event occurred in 6 participants (9%; 95% credible interval, 0 to 31) in group 1, in 6 (9%; 95% credible interval, 0 to 43) in group 2, in 2 (3%; 95% credible interval, 0 to 16) in group 3, and 0 (0%; post hoc credible interval, 0 to 8) in group 4. Among participants not receiving NA therapy, a primary-outcome event occurred in 7 participants (10%; 95% credible interval, 0 to 38), 4 (6%; 95% credible interval, 0 to 25), 1 (1%; post hoc credible interval, 0 to 6), and 0 (0%; post hoc credible interval, 0 to 8), respectively. During weeks 1 through 12, adverse events, including injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase levels, were more common with bepirovirsen (groups 1, 2, and 3) than with placebo (group 4).
意向治疗人群包括 457 名参与者 （227 名接受 NA 治疗，230 名未接受 NA 治疗）。在接受 NA 治疗的患者中，第 1 组 6 名参与者 （9%;95% 可信区间，0 至 31），第 2 组 6 名参与者 （9%;95% 可信区间，0 至 43），第 3 组 2 名参与者 （3%;95% 可信区间，0 至 16） 和第 4 组 0 名 （0%;事后可信区间，0 至 8） 发生主要结局事件。在未接受 NA 治疗的参与者中，主要结局事件分别发生在 7 名参与者 （10%;95% 可信区间，0 至 38）、4 名 （6%;95% 可信区间，0 至 25）、1 名 （1%;事后可信区间，0 至 6） 和 0 名 （0%;事后可信区间，0 至 8） 中。在第 1 周至第 12 周，贝吡罗韦森组（第 1、2 和 3 组）的不良事件（包括注射部位反应、发热、疲劳和丙氨酸氨基转移酶水平升高）比安慰剂组（第 4 组）更常见。
意向治疗人群包括 457 名参与者 （227 名接受 NA 治疗，230 名未接受 NA 治疗）。在接受 NA 治疗的患者中，第 1 组 6 名参与者 （9%;95% 可信区间，0 至 31），第 2 组 6 名参与者 （9%;95% 可信区间，0 至 43），第 3 组 2 名参与者 （3%;95% 可信区间，0 至 16） 和第 4 组 0 名 （0%;事后可信区间，0 至 8） 发生主要结局事件。在未接受 NA 治疗的参与者中，主要结局事件分别发生在 7 名参与者 （10%;95% 可信区间，0 至 38）、4 名 （6%;95% 可信区间，0 至 25）、1 名 （1%;事后可信区间，0 至 6） 和 0 名 （0%;事后可信区间，0 至 8） 中。在第 1 周至第 12 周，贝吡罗韦森组（第 1、2 和 3 组）的不良事件（包括注射部位反应、发热、疲劳和丙氨酸氨基转移酶水平升高）比安慰剂组（第 4 组）更常见。
Conclusions 结论
In this phase 2b trial, bepirovirsen at a dose of 300 mg per week for 24 weeks resulted in sustained HBsAg and HBV DNA loss in 9 to 10% of participants with chronic HBV infection. Larger and longer trials are required to assess the efficacy and safety of bepirovirsen. (Funded by GSK; B-Clear ClinicalTrials.gov number, NCT04449029.)
在这项 2b 期试验中，每周 300 毫克剂量的贝吡罗韦森持续 24 周导致 9% 至 10% 的慢性 HBV 感染参与者持续 HBsAg 和 HBV DNA 丢失。需要更大规模和更长的试验来评估贝匹罗韦森的有效性和安全性。（由 GSK 资助;B-清除 ClinicalTrials.gov 编号，NCT04449029。
在这项 2b 期试验中，每周 300 毫克剂量的贝吡罗韦森持续 24 周导致 9% 至 10% 的慢性 HBV 感染参与者持续 HBsAg 和 HBV DNA 丢失。需要更大规模和更长的试验来评估贝匹罗韦森的有效性和安全性。（由 GSK 资助;B-清除 ClinicalTrials.gov 编号，NCT04449029。
Chronic hepatitis B virus (HBV) infection is a major worldwide health problem, with an estimated 1.5 million new infections and 820,000 deaths each year (predominantly from cirrhosis and hepatocellular carcinoma).1,2 The goal of therapy is to achieve functional cure — that is, long-term hepatitis B surface antigen (HBsAg) loss, with or without HBsAg seroconversion (positive for antibodies against HBsAg [anti-HBs]), and sustained undetectable HBV DNA after cessation of therapy.3-5 Despite prolonged treatment with nucleoside or nucleotide analogue (NA) therapy (first-line treatment for HBV infection),6 fewer than 5% of patients have HBsAg loss after 12 months of treatment,5,7–11 which underscores the need for therapies capable of achieving functional cure.
慢性乙型肝炎病毒 （HBV） 感染是一个主要的全球性健康问题，估计每年有 150 万新感染和 820,000 例死亡（主要死于肝硬化和肝细胞癌）。1,2 治疗的目标是实现功能性治愈，即乙型肝炎表面抗原 （HBsAg） 长期丢失，伴或不伴 HBsAg 血清转换（HBsAg 抗体 [抗-HBs] 阳性），以及停止治疗后持续检测不到的 HBV DNA。3-5 尽管长期使用核苷或核苷酸类似物 （NA） 疗法（HBV 感染的一线治疗）进行治疗，6 但只有不到 5% 的患者在治疗 12 个月后出现 HBsAg 消失，5,7-11 这强调了对能够实现功能性治愈的疗法的需求。
慢性乙型肝炎病毒 （HBV） 感染是一个主要的全球性健康问题，估计每年有 150 万新感染和 820,000 例死亡（主要死于肝硬化和肝细胞癌）。1,2 治疗的目标是实现功能性治愈，即乙型肝炎表面抗原 （HBsAg） 长期丢失，伴或不伴 HBsAg 血清转换（HBsAg 抗体 [抗-HBs] 阳性），以及停止治疗后持续检测不到的 HBV DNA。3-5 尽管长期使用核苷或核苷酸类似物 （NA） 疗法（HBV 感染的一线治疗）进行治疗，6 但只有不到 5% 的患者在治疗 12 个月后出现 HBsAg 消失，5,7-11 这强调了对能够实现功能性治愈的疗法的需求。
Bepirovirsen (GSK3228836), a 2′-O-methoxyethyl modified antisense oligonucleotide, targets all HBV RNAs, including HBV messenger RNA and pregenomic RNA.10 In a phase 2a trial, 4 weeks of bepirovirsen elicited a rapid and dose-dependent reduction in HBsAg levels and, in some participants, transient HBsAg loss.12 Immunostimulatory activity of bepirovirsen through toll-like receptor 8 (TLR8) may be correlated with HBsAg reduction.13
Bepirovirsen （GSK3228836） 是一种 2′-O-甲氧基乙基修饰的反义寡核苷酸，靶向所有 HBV RNA，包括 HBV 信使 RNA 和前基因组 RNA。10 在一项 2a 期试验中，4 周的贝吡罗维森导致 HBsAg 水平快速且剂量依赖性降低，并且在一些参与者中，导致短暂的 HBsAg 丢失。12 贝吡罗韦森通过 toll 样受体 8 （TLR8） 的免疫刺激活性可能与 HBsAg 降低相关。13
Bepirovirsen （GSK3228836） 是一种 2′-O-甲氧基乙基修饰的反义寡核苷酸，靶向所有 HBV RNA，包括 HBV 信使 RNA 和前基因组 RNA。10 在一项 2a 期试验中，4 周的贝吡罗维森导致 HBsAg 水平快速且剂量依赖性降低，并且在一些参与者中，导致短暂的 HBsAg 丢失。12 贝吡罗韦森通过 toll 样受体 8 （TLR8） 的免疫刺激活性可能与 HBsAg 降低相关。13
We conducted a phase 2b trial (B-Clear) to investigate the efficacy and safety of 12- and 24-week bepirovirsen treatment in participants with chronic HBV infection either receiving stable NA therapy or not receiving NA therapy. To assess durability of response, the primary efficacy outcome was HBsAg and HBV DNA loss for 24 weeks after the discontinuation of bepirovirsen treatment in the absence of newly initiated antiviral treatment.
我们进行了一项 2b 期试验 （B-Clear），以研究 12 周和 24 周 bepirovirsen 治疗对接受稳定 NA 治疗或未接受 NA 治疗的慢性 HBV 感染参与者的疗效和安全性。为了评估反应的持久性，主要疗效结局是在没有新开始的抗病毒治疗的情况下，停止贝匹罗韦森治疗后 24 周的 HBsAg 和 HBV DNA 丢失。
我们进行了一项 2b 期试验 （B-Clear），以研究 12 周和 24 周 bepirovirsen 治疗对接受稳定 NA 治疗或未接受 NA 治疗的慢性 HBV 感染参与者的疗效和安全性。为了评估反应的持久性，主要疗效结局是在没有新开始的抗病毒治疗的情况下，停止贝匹罗韦森治疗后 24 周的 HBsAg 和 HBV DNA 丢失。
Methods 方法
Participants 参与者
Participants were 18 years of age or older with documented chronic HBV infection for at least 6 months and an HBsAg level of more than 100 IU per milliliter. Participants who were receiving NA therapy were on a stable NA regimen and had an HBV DNA level of less than 90 IU per milliliter and an alanine aminotransferase (ALT) level less than or equal to 2 times the upper limit of the normal range. Participants who were not receiving NA therapy had never received such therapy or had ended NA therapy at least 6 months before screening and had an HBV DNA level of more than 2000 IU per milliliter and an ALT level of less than 3 times the upper limit of the normal range. Key exclusion criteria were the presence of hepatitis C, human immunodeficiency, or hepatitis D virus infection; cirrhosis; hepatocellular carcinoma; and interferon-containing therapy within 12 months before screening (Table S7 in the Supplementary Appendix, available with the full text of this article at NEJM.org).
参与者年满 18 岁，有记录的慢性 HBV 感染至少 6 个月，HBsAg 水平超过每毫升 100 IU。接受 NA 治疗的参与者接受稳定的 NA 方案，HBV DNA 水平低于每毫升 90 IU，丙氨酸氨基转移酶 （ALT） 水平小于或等于正常范围上限的 2 倍。未接受 NA 治疗的参与者从未接受过此类治疗或在筛选前至少 6 个月结束 NA 治疗，并且 HBV DNA 水平超过每毫升 2000 IU，ALT 水平低于正常范围上限的 3 倍。关键的排除标准是存在丙型肝炎、人类免疫缺陷或丁型肝炎病毒感染;肝硬化;肝癌;和筛选前 12 个月内接受过含干扰素的治疗（补充附录中的表 S7，可在 NEJM.org 处获得本文的全文）。
参与者年满 18 岁，有记录的慢性 HBV 感染至少 6 个月，HBsAg 水平超过每毫升 100 IU。接受 NA 治疗的参与者接受稳定的 NA 方案，HBV DNA 水平低于每毫升 90 IU，丙氨酸氨基转移酶 （ALT） 水平小于或等于正常范围上限的 2 倍。未接受 NA 治疗的参与者从未接受过此类治疗或在筛选前至少 6 个月结束 NA 治疗，并且 HBV DNA 水平超过每毫升 2000 IU，ALT 水平低于正常范围上限的 3 倍。关键的排除标准是存在丙型肝炎、人类免疫缺陷或丁型肝炎病毒感染;肝硬化;肝癌;和筛选前 12 个月内接受过含干扰素的治疗（补充附录中的表 S7，可在 NEJM.org 处获得本文的全文）。
Trial Design 试验设计
B-Clear was a phase 2b, randomized, parallel-cohort trial conducted from July 27, 2020, to March 18, 2022, at 123 sites in 22 countries (see the Supplementary Appendix). The trial sponsor and participants were unaware of the trial-group assignments, which were known to the investigators. Randomization was performed with the use of an interactive Web-response system, with stratification according to hepatitis B e antigen (HBeAg) status (positive or negative) and baseline HBsAg level (≤3 or >3 log10 IU per milliliter).
B-Clear 是一项 2b 期、随机、平行队列试验，于 2020 年 7 月 27 日至 2022 年 3 月 18 日在 22 个国家的 123 个地点进行（见补充附录）。试验申办者和参与者不知道研究者知道的试验组分配。使用交互式网络响应系统进行随机化，根据乙型肝炎 e 抗原 （HBeAg） 状态（阳性或阴性）和基线 HBsAg 水平（≤3 或 >3 log10 IU/毫升）进行分层。
B-Clear 是一项 2b 期、随机、平行队列试验，于 2020 年 7 月 27 日至 2022 年 3 月 18 日在 22 个国家的 123 个地点进行（见补充附录）。试验申办者和参与者不知道研究者知道的试验组分配。使用交互式网络响应系统进行随机化，根据乙型肝炎 e 抗原 （HBeAg） 状态（阳性或阴性）和基线 HBsAg 水平（≤3 或 >3 log10 IU/毫升）进行分层。
Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4) (Figure 1). Loading doses of bepirovirsen (300 mg, in groups 1, 2, and 3) or placebo (in group 4) were administered on days 4 and 11. Participants were followed for up to 55 weeks, with a 24-week treatment period and a 24-week follow-up period. Participants receiving NA therapy continued such therapy during the trial.
参与者被随机分配（以 3：3：3：1 的比例）每周皮下注射 300 毫克剂量的贝匹罗韦森，持续 24 周（第 1 组），贝贝罗韦森，剂量 300 毫克，持续 12 周，然后 150 毫克，持续 12 周（第 2 组），贝贝罗韦森，剂量 300 毫克，持续 12 周，然后安慰剂 12 周（第 3 组）， 或安慰剂 12 周，然后 bepirovirsen 剂量为 300 毫克，持续 12 周（第 4 组）（图 1）。在第 4 天和第 11 天给予负荷剂量的贝匹罗韦森（300 mg，第 1、2 和 3 组）或安慰剂（第 4 组）。参与者被随访长达 55 周，包括 24 周的治疗期和 24 周的随访期。接受 NA 治疗的参与者在试验期间继续这种治疗。
参与者被随机分配（以 3：3：3：1 的比例）每周皮下注射 300 毫克剂量的贝匹罗韦森，持续 24 周（第 1 组），贝贝罗韦森，剂量 300 毫克，持续 12 周，然后 150 毫克，持续 12 周（第 2 组），贝贝罗韦森，剂量 300 毫克，持续 12 周，然后安慰剂 12 周（第 3 组）， 或安慰剂 12 周，然后 bepirovirsen 剂量为 300 毫克，持续 12 周（第 4 组）（图 1）。在第 4 天和第 11 天给予负荷剂量的贝匹罗韦森（300 mg，第 1、2 和 3 组）或安慰剂（第 4 组）。参与者被随访长达 55 周，包括 24 周的治疗期和 24 周的随访期。接受 NA 治疗的参与者在试验期间继续这种治疗。
Figure 1 图1
Trial Design. 试验设计。
Participants receiving stable nucleoside or nucleotide analogue (NA) therapy were expected to continue NA therapy during the trial; participants not receiving NA therapy at trial entry were expected to continue without NA therapy during the trial. Participants receiving stable NA therapy and participants not currently receiving NA therapy underwent randomization separately. Doses were administered once weekly as two subcutaneous injections (two syringes total; one syringe contained either bepirovirsen at a dose of 150 mg or placebo). The loading dose (LD) of bepirovirsen (300 mg, in groups 1, 2, and 3) or placebo (in group 4) was administered on days 4 and 11.
Trial Oversight 试验监督
The sponsor, GSK, designed and oversaw the trial conduct and data collection and analysis. Professional writers paid by the sponsor prepared the first draft of the manuscript under the authors’ direction. The manuscript was reviewed and edited by all the authors. All the authors made the decision to submit the manuscript for publication and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol (available at NEJM.org). An independent data monitoring committee reviewed unblinded data. The trial was conducted in accordance with the Declaration of Helsinki, the Council for International Organizations of Medical Sciences International Ethical Guidelines for Biomedical Research Involving Human Subjects, the Good Clinical Practice guidelines of the International Council for Harmonisation, and all applicable laws and regulations in participating countries. The protocol and amendments were reviewed and approved by local institutional review boards or independent ethics committees. Written informed consent was obtained from all the participants.
申办方 GSK 设计并监督试验实施以及数据收集和分析。由赞助商支付的专业作家在作者的指导下准备了手稿的初稿。手稿由所有作者审阅和编辑。所有作者都决定提交手稿以供发表，并保证数据的准确性和完整性以及试验对方案的忠实度（可在 NEJM.org 上获得）。一个独立的数据监测委员会审查了非盲数据。该试验是根据赫尔辛基宣言、国际医学科学组织理事会、涉及人类受试者的生物医学研究国际伦理准则、国际协调委员会的良好临床实践指南以及参与国的所有适用法律和法规进行的。该方案和修正案由当地机构审查委员会或独立的伦理委员会审查和批准。已获得所有参与者的书面知情同意书。
申办方 GSK 设计并监督试验实施以及数据收集和分析。由赞助商支付的专业作家在作者的指导下准备了手稿的初稿。手稿由所有作者审阅和编辑。所有作者都决定提交手稿以供发表，并保证数据的准确性和完整性以及试验对方案的忠实度（可在 NEJM.org 上获得）。一个独立的数据监测委员会审查了非盲数据。该试验是根据赫尔辛基宣言、国际医学科学组织理事会、涉及人类受试者的生物医学研究国际伦理准则、国际协调委员会的良好临床实践指南以及参与国的所有适用法律和法规进行的。该方案和修正案由当地机构审查委员会或独立的伦理委员会审查和批准。已获得所有参与者的书面知情同意书。
Outcomes 结果
The primary composite efficacy outcome was an HBsAg level below the lower limit of detection (0.05 IU per milliliter) and an HBV DNA level below the lower limit of quantification (20 IU per milliliter) maintained for 24 weeks after the planned end of bepirovirsen treatment in the absence of any medication initiated for the purpose of suppressing HBV replication (groups 1, 2, and 3) (Table S1). Group 4 (placebo-first group) was included to allow evaluation of the effect of a loading dose and evaluation of safety in the first 12 weeks, but the trial was not powered to assess the primary outcome in this group. An additional prespecified analysis used a modified version of the primary outcome that permitted “blips” (single-time-point increases in the HBsAg level to greater than or equal to the lower limit of detection or in the HBV DNA level to greater than or equal to the lower limit of quantification) in the response (Table S8).
主要复合疗效结果是 HBsAg 水平低于检测下限（0.05 IU/mL）和 HBV DNA 水平低于定量下限（20 IU/mL）在计划结束 bepirovirsen 治疗后 24 周内维持在没有任何药物以抑制 HBV 复制为目的（第 1 组， 2 和 3）（表 S1）。纳入第 4 组（安慰剂第一组）是为了评估负荷剂量的效果和前 12 周的安全性评估，但该试验无法评估该组的主要结局。另一项预先指定的分析使用了主要结局的修改版本，该版本允许在反应中出现“瞬点”（HBsAg 水平的单时间点增加至大于或等于检测下限或 HBV DNA 水平大于或等于定量下限）（表 S8）。
主要复合疗效结果是 HBsAg 水平低于检测下限（0.05 IU/mL）和 HBV DNA 水平低于定量下限（20 IU/mL）在计划结束 bepirovirsen 治疗后 24 周内维持在没有任何药物以抑制 HBV 复制为目的（第 1 组， 2 和 3）（表 S1）。纳入第 4 组（安慰剂第一组）是为了评估负荷剂量的效果和前 12 周的安全性评估，但该试验无法评估该组的主要结局。另一项预先指定的分析使用了主要结局的修改版本，该版本允许在反应中出现“瞬点”（HBsAg 水平的单时间点增加至大于或等于检测下限或 HBV DNA 水平大于或等于定量下限）（表 S8）。
Secondary efficacy outcomes included the difference between groups 1 and 2, groups 1 and 3, and groups 2 and 3 in the proportion of participants having a primary-outcome event; the proportion of participants having an HBsAg level below the lower limit of detection and an HBV DNA level below the lower limit of quantification at the end of treatment; log changes from baseline in HBsAg and HBV DNA levels (according to category of HBsAg or HBV DNA level); actual values and change from baseline in HBsAg, HBV DNA, HBeAg, and anti-HBs levels; and ALT normalization (ALT level less than or equal to the upper limit of the normal range) in the absence of newly initiated antiviral treatment in participants with an ALT level above the upper limit of the normal range at baseline.
次要疗效结局包括第 1 组和第 2 组、第 1 组和第 3 组以及第 2 组和第 3 组之间发生主要结局事件的参与者比例的差异;治疗结束时 HBsAg 水平低于检测下限且 HBV DNA 水平低于定量下限的参与者比例;记录 HBsAg 和 HBV DNA 水平相对于基线的变化（根据 HBsAg 的类别或 HBV DNA 水平）;HBsAg、HBV DNA、HBeAg 和抗 HBs 水平的实际值和相对于基线的变化;和 ALT 正常化（ALT 水平小于或等于正常范围的上限），在基线时 ALT 水平高于正常范围上限的参与者中没有新开始的抗病毒治疗。
次要疗效结局包括第 1 组和第 2 组、第 1 组和第 3 组以及第 2 组和第 3 组之间发生主要结局事件的参与者比例的差异;治疗结束时 HBsAg 水平低于检测下限且 HBV DNA 水平低于定量下限的参与者比例;记录 HBsAg 和 HBV DNA 水平相对于基线的变化（根据 HBsAg 的类别或 HBV DNA 水平）;HBsAg、HBV DNA、HBeAg 和抗 HBs 水平的实际值和相对于基线的变化;和 ALT 正常化（ALT 水平小于或等于正常范围的上限），在基线时 ALT 水平高于正常范围上限的参与者中没有新开始的抗病毒治疗。
Safety outcomes included clinical assessments, laboratory measurements, and adverse events. Increases in ALT levels, as well as class effects of antisense oligonucleotides (renal injury, injection-site reactions, thrombocytopenia, and vascular inflammation and complement activation), were evaluated as adverse events of special interest (Table S9).
安全性结局包括临床评估、实验室测量和不良事件。ALT 水平的增加以及反义寡核苷酸的类别效应 （肾损伤、注射部位反应、血小板减少症、血管炎症和补体激活） 被评估为特别关注的不良事件 （表 S9）。
安全性结局包括临床评估、实验室测量和不良事件。ALT 水平的增加以及反义寡核苷酸的类别效应 （肾损伤、注射部位反应、血小板减少症、血管炎症和补体激活） 被评估为特别关注的不良事件 （表 S9）。
Statistical Analysis 统计分析
We planned to enroll approximately 440 participants: approximately 66 participants receiving NA therapy and 66 not receiving NA therapy in each of groups 1, 2, and 3 and approximately 22 participants receiving NA therapy and 22 not receiving NA therapy in group 4. This sample size was chosen on the basis of a Bayesian model and selected to provide at least a 75% posterior probability of the true response rate exceeding a fixed threshold under a range of assumed values for the threshold of interest and true response rate (Table S3).
我们计划招募大约 440 名参与者：第 1、2 和 3 组各约有 66 名接受 NA 治疗的参与者和 66 名未接受 NA 治疗的参与者，第 4 组约有 22 名接受 NA 治疗的参与者和 22 名未接受 NA 治疗的参与者。该样本量是根据贝叶斯模型选择的，并选择以提供在感兴趣阈值和真实响应率的假设值范围内，真实响应率超过固定阈值的至少 75% 的后验概率（表 S3）。
我们计划招募大约 440 名参与者：第 1、2 和 3 组各约有 66 名接受 NA 治疗的参与者和 66 名未接受 NA 治疗的参与者，第 4 组约有 22 名接受 NA 治疗的参与者和 22 名未接受 NA 治疗的参与者。该样本量是根据贝叶斯模型选择的，并选择以提供在感兴趣阈值和真实响应率的假设值范围内，真实响应率超过固定阈值的至少 75% 的后验概率（表 S3）。
An estimation approach with no hypothesis testing was used to analyze the primary outcome. A Bayesian hierarchical model (including baseline stratification factors) was used to calculate the point estimate of the primary outcome and 95% credible interval. If the Bayesian hierarchical model did not converge, a post hoc unstratified Bayesian analysis was performed (see the Methods section in the Supplementary Appendix).
采用无假设检验的估计方法分析主要结局。使用贝叶斯分层模型 （包括基线分层因子） 计算主要结局的点估计和 95% 可信区间。如果贝叶斯分层模型没有收敛，则执行事后未分层贝叶斯分析（参见补充附录中的方法部分）。
采用无假设检验的估计方法分析主要结局。使用贝叶斯分层模型 （包括基线分层因子） 计算主要结局的点估计和 95% 可信区间。如果贝叶斯分层模型没有收敛，则执行事后未分层贝叶斯分析（参见补充附录中的方法部分）。
Efficacy objectives were assessed with the use of estimands (i.e., precise descriptions of the treatment effect reflecting the clinical question posed by a given clinical-trial objective). The primary estimand was the proportion of participants in groups 1, 2, and 3 who had a primary-outcome event, regardless of completion of treatment, interruptions in treatment, or adherence to treatment had they not been affected by wide disruptive events (e.g., the coronavirus disease 2019 pandemic). A receiver-operating-characteristic analysis explored a range of baseline HBsAg cutoff points as a predictor of response.
使用估计量评估疗效目标（即，对治疗效果的精确描述反映了给定临床试验目标提出的临床问题）。主要估计值是第 1 组、第 2 组和第 3 组参与者发生主要结局事件的比例，无论治疗是否完成、治疗中断或治疗依从性如何，如果他们没有受到广泛的破坏性事件（例如，2019 年冠状病毒病大流行）的影响。受试者手术特征分析探讨了一系列基线 HBsAg 截断点作为反应的预测因子。
使用估计量评估疗效目标（即，对治疗效果的精确描述反映了给定临床试验目标提出的临床问题）。主要估计值是第 1 组、第 2 组和第 3 组参与者发生主要结局事件的比例，无论治疗是否完成、治疗中断或治疗依从性如何，如果他们没有受到广泛的破坏性事件（例如，2019 年冠状病毒病大流行）的影响。受试者手术特征分析探讨了一系列基线 HBsAg 截断点作为反应的预测因子。
Safety analyses included a descriptive summary of adverse-event incidence (including comparison of the first 12 weeks of treatment in groups 1, 2, and 3 with placebo in group 4), vital signs, and laboratory data. Efficacy analyses were conducted in the intention-to-treat population, which included all randomly assigned participants, on the basis of the trial-group assignment. Safety analyses were conducted in all the participants who had undergone randomization and received at least one dose of bepirovirsen or placebo and were based on the trial agent received. As prespecified, analyses of all outcomes were conducted separately for participants receiving NA therapy and those not receiving NA therapy. Additional details are available in the Supplementary Appendix.
安全性分析包括不良事件发生率的描述性总结（包括第 1 、 2 和 3 组治疗前 12 周与第 4 组安慰剂的比较）、生命体征和实验室数据。根据试验组分配，在意向治疗人群中进行疗效分析，其中包括所有随机分配的参与者。对所有接受随机分组并接受至少一剂 bepirovirsen 或安慰剂的参与者进行安全性分析，并基于接受的试验药物。根据预先指定，对接受 NA 治疗的参与者和未接受 NA 治疗的参与者分别进行所有结局分析。补充附录中提供了其他详细信息。
安全性分析包括不良事件发生率的描述性总结（包括第 1 、 2 和 3 组治疗前 12 周与第 4 组安慰剂的比较）、生命体征和实验室数据。根据试验组分配，在意向治疗人群中进行疗效分析，其中包括所有随机分配的参与者。对所有接受随机分组并接受至少一剂 bepirovirsen 或安慰剂的参与者进行安全性分析，并基于接受的试验药物。根据预先指定，对接受 NA 治疗的参与者和未接受 NA 治疗的参与者分别进行所有结局分析。补充附录中提供了其他详细信息。
Results 结果
Participants 参与者
The intention-to-treat population included 457 participants (227 receiving NA therapy and 230 not receiving NA therapy); 13 participants (6%) receiving NA therapy and 23 (10%) not receiving NA therapy prematurely discontinued bepirovirsen or placebo, of whom 5 participants (2%) and 8 (3%), respectively, discontinued owing to adverse events (Fig. S2). The demographic and clinical characteristics of the participants at baseline were similar across trial groups (Table 1). In general, participants were representative of the population with chronic HBV infection (Table S10).
意向治疗人群包括 457 名参与者 （227 名接受 NA 治疗，230 名未接受 NA 治疗）;13 名接受 NA 治疗的参与者 （6%） 和 23 名未接受 NA 治疗的参与者 （10%） 提前停用贝吡罗韦森或安慰剂，其中 5 名参与者 （2%） 和 8 名 （3%） 因不良事件而停药（图 S2）。各试验组基线时参与者的人口统计学和临床特征相似（表 1）。一般来说，参与者代表了慢性 HBV 感染人群（表 S10）。
意向治疗人群包括 457 名参与者 （227 名接受 NA 治疗，230 名未接受 NA 治疗）;13 名接受 NA 治疗的参与者 （6%） 和 23 名未接受 NA 治疗的参与者 （10%） 提前停用贝吡罗韦森或安慰剂，其中 5 名参与者 （2%） 和 8 名 （3%） 因不良事件而停药（图 S2）。各试验组基线时参与者的人口统计学和临床特征相似（表 1）。一般来说，参与者代表了慢性 HBV 感染人群（表 S10）。
Table 1 表1
| Characteristic | Receiving NA Therapy | Not Receiving NA Therapy | ||||||
|---|---|---|---|---|---|---|---|---|
| Group 1 (N=68) | Group 2 (N=68) | Group 3 (N=68) | Group 4 (N=23) | Group 1 (N=70) | Group 2 (N=68) | Group 3 (N=68) | Group 4 (N=24) | |
| Age — yr | 49.0±11.5 | 46.1±12.6 | 47.4±11.2 | 49.8±11.2 | 44.5±11.1 | 43.8±9.9 | 40.7±11.1 | 42.4±12.0 |
| Male sex — no. (%) | 48 (71) | 49 (72) | 51 (75) | 17 (74) | 33 (47) | 41 (60) | 39 (57) | 11 (46) |
| Body-mass index† | 24.66±4.07 | 24.30±4.14 | 24.92±2.90 | 23.67±2.48 | 25.25±4.77 | 25.26±4.30 | 24.52±3.65 | 23.70±4.42 |
| Race or ethnic group — no. (%)‡ | ||||||||
| Asian | 36 (53) | 35 (51) | 36 (53) | 12 (52) | 37 (53) | 44 (65) | 38 (56) | 12 (50) |
| White | 30 (44) | 32 (47) | 26 (38) | 11 (48) | 24 (34) | 20 (29) | 24 (35) | 11 (46) |
| Black | 2 (3) | 1 (1) | 4 (6) | 0 | 9 (13) | 4 (6) | 6 (9) | 1 (4) |
| American Indian or Alaska Native | 0 | 0 | 1 (1) | 0 | 0 | 0 | 0 | 0 |
| Mixed race | 0 | 0 | 1 (1) | 0 | 0 | 0 | 0 | 0 |
| ALT ≤ULN — no. (%)§¶ | 62 (91) | 60 (90) | 62 (91) | 21 (91) | 50 (71) | 48 (71) | 47 (69) | 15 (62) |
| HBsAg ≤3 log10 IU/ml — no. (%)¶ | 19 (28) | 23 (34) | 19 (28) | 3 (13) | 12 (17) | 15 (22) | 11 (16) | 5 (21) |
| HBsAg — log10 IU/ml | 3.29±0.62 | 3.26±0.61 | 3.33±0.59 | 3.43±0.43 | 3.72±0.77 | 3.65±0.72 | 3.66±0.67 | 3.76±0.79 |
| HBV DNA — log10 IU/ml | 0.48±0.64 | 0.39±0.60 | 0.55±0.66 | 0.40±0.62 | 5.02±1.53 | 5.14±1.56 | 5.57±1.65 | 5.00±1.55 |
| Negative HBeAg status — no. (%)¶ | 50 (74) | 47 (70) | 44 (65) | 16 (70) | 49 (70) | 52 (76) | 52 (76) | 17 (71) |
| Receiving current NA therapy for ≥3 yr — no. (%)¶ | 47 (69) | 45 (67) | 43 (63) | 20 (87) | N/A | N/A | N/A | N/A |
| Current NA drugs — no. (%)¶ | ||||||||
| Entecavir | 38 (56) | 25 (37) | 20 (29) | 10 (43) | N/A | N/A | N/A | N/A |
| Tenofovir disoproxil | 24 (35) | 36 (54) | 33 (49) | 11 (48) | N/A | N/A | N/A | N/A |
| Tenofovir alafenamide | 9 (13) | 6 (9) | 17 (25) | 2 (9) | ||||
| Lamivudine | 1 (1) | 1 (1) | 1 (1) | 0 | N/A | N/A | N/A | N/A |
| Adefovir dipivoxil | 0 | 1 (1) | 0 | 0 | N/A | N/A | N/A | N/A |
| Emtricitabine | 0 | 0 | 1 (1) | 0 | N/A | N/A | N/A | N/A |
Demographic and Clinical Characteristics of the Participants at Baseline (Intention-to-Treat Population).
基线参与者的人口统计学和临床特征（意向治疗人群）。*
基线参与者的人口统计学和临床特征（意向治疗人群）。*
*
Plus–minus values are means ±SD. Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4). Loading doses of bepirovirsen (300 mg, in groups 1, 2, and 3) or placebo (in group 4) were administered on days 4 and 11. HBeAg denotes hepatitis B e antigen, HBsAg hepatitis B surface antigen, HBV hepatitis B virus, NA nucleoside or nucleotide analogue, and N/A not applicable.
†
The body-mass index is the weight in kilograms divided by the square of the height in meters.
‡
Race or ethnic group was reported by the participant.
§
The upper limit of the normal range (ULN) for alanine aminotransferase (ALT) is 40 IU per liter for men and 33 IU per liter for women.
¶
Data were missing for 1 participant in group 2 who was receiving NA therapy, so the denominator is 67 rather than 68.
Primary Outcome 主要结果
In group 1, a primary-outcome event occurred in 6 participants (9%; 95% credible interval, 0 to 31) receiving NA therapy and in 7 (10%; 95% credible interval, 0 to 38) not receiving NA therapy. In group 2, a primary-outcome event occurred in 6 participants (9%; 95% credible interval, 0 to 43) receiving NA therapy and in 4 (6%; 95% credible interval, 0 to 25) not receiving NA therapy. In group 3, a primary-outcome event occurred in 2 participants (3%; 95% credible interval, 0 to 16) receiving NA therapy and in 1 (1%; post hoc credible interval, 0 to 6) not receiving NA therapy (Table 2).
在第 1 组中，主要结局事件发生在 6 名接受 NA 治疗的参与者 （9%;95% 可信区间，0 至 31） 和 7 名 （10%;95% 可信区间，0 至 38） 未接受 NA 治疗的参与者中。在第 2 组中，接受 NA 治疗的 6 名参与者 （9%;95% 可信区间，0 至 43） 和 4 名 （6%;95% 可信区间，0 至 25） 未接受 NA 治疗的参与者发生了主要结局事件。在第 3 组中，主要结局事件发生在 2 名接受 NA 治疗的参与者 （3%;95% 可信区间，0 至 16） 和 1 名 （1%;事后可信区间，0 至 6） 未接受 NA 治疗（表 2）。
在第 1 组中，主要结局事件发生在 6 名接受 NA 治疗的参与者 （9%;95% 可信区间，0 至 31） 和 7 名 （10%;95% 可信区间，0 至 38） 未接受 NA 治疗的参与者中。在第 2 组中，接受 NA 治疗的 6 名参与者 （9%;95% 可信区间，0 至 43） 和 4 名 （6%;95% 可信区间，0 至 25） 未接受 NA 治疗的参与者发生了主要结局事件。在第 3 组中，主要结局事件发生在 2 名接受 NA 治疗的参与者 （3%;95% 可信区间，0 至 16） 和 1 名 （1%;事后可信区间，0 至 6） 未接受 NA 治疗（表 2）。
Table 2 表2
| Variable | Receiving NA Therapy | Not Receiving NA Therapy | ||||||
|---|---|---|---|---|---|---|---|---|
| Group 1 (N=68) | Group 2 (N=68) | Group 3 (N=68) | Group 4 (N=23) | Group 1 (N=70) | Group 2 (N=68) | Group 3 (N=68) | Group 4 (N=24) | |
| Primary-outcome event — no. of participants (%)† | 6 (9) | 6 (9) | 2 (3) | 0 | 7 (10) | 4 (6) | 1 (1) | 0 |
| Point estimate of response — % (95% credible interval) | 9 (0–31) | 9 (0–43) | 3 (0–16) | 2 (0–8)‡ | 10 (0–38) | 6 (0–25) | 2 (0–6)‡ | 2 (0–8)‡ |
Primary Outcome (Intention-to-Treat Population).
主要结果（意向治疗人群）。*
主要结果（意向治疗人群）。*
*
Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4). Loading doses of bepirovirsen (300 mg, in groups 1, 2, and 3) or placebo (in group 4) were administered on days 4 and 11.
†
The primary outcome was an HBsAg level below the lower limit of detection (0.05 IU per milliliter) and an HBV DNA level below the lower limit of quantification (20 IU per milliliter) maintained for 24 weeks after the planned end of bepirovirsen treatment, without newly initiated antiviral medication.
‡
Shown are point estimates and credible intervals from post hoc unstratified Bayesian analysis owing to nonconvergence of the prespecified stratified Bayesian hierarchical model. Additional details are provided in the Methods section in the Supplementary Appendix.
When we used the modified primary-outcome definition that allowed for “blips” (single-time-point increases in the HBsAg level to greater than or equal to the lower limit of detection or in the HBV DNA level to greater than or equal to the lower limit of quantification) in response, in group 1, a total of 7 participants (10%; 95% credible interval, 0 to 36) receiving NA therapy and 10 (14%; 95% credible interval, 0 to 64) not receiving NA therapy had a response. Additional results are presented in Table S11.
当我们使用修改后的主要结局定义时，允许“瞬点”（HBsAg 水平单时间点增加至大于或等于检测下限或 HBV DNA 水平大于或等于定量下限）作为响应，在第 1 组中，共有 7 名参与者（10%;95% 可信区间， 0 至 36） 接受 NA 治疗和 10 （14%;95% 可信区间，0 至 64） 未接受 NA 治疗有反应。其他结果见表 S11。
当我们使用修改后的主要结局定义时，允许“瞬点”（HBsAg 水平单时间点增加至大于或等于检测下限或 HBV DNA 水平大于或等于定量下限）作为响应，在第 1 组中，共有 7 名参与者（10%;95% 可信区间， 0 至 36） 接受 NA 治疗和 10 （14%;95% 可信区间，0 至 64） 未接受 NA 治疗有反应。其他结果见表 S11。
In group 1, a total of 16% of the participants receiving NA therapy and 25% of those not receiving NA therapy with a low HBsAg level (≤3 log10 IU per milliliter) at baseline had a primary-outcome event, as compared with 6% and 7% of participants, respectively, with a high HBsAg level (>3 log10 IU per milliliter) at baseline (Fig. S3). A receiver-operating-characteristic analysis in group 1 indicated that an HBsAg level of approximately 3000 IU per milliliter (3.5 log10 IU per milliliter) at baseline may be an appropriate cutoff point for predicting response (Fig. S4). At the cutoff point of 3000 IU or less per milliliter in group 1, a total of 5 of 43 participants (12%) receiving NA therapy and 6 of 24 (25%) not receiving NA therapy had a primary-outcome event.
在第 1 组中，基线时 HBsAg 水平较低（≤3 log10 IU/mL）的接受 NA 治疗的参与者中共有 16% 和 25% 未接受 NA 治疗的参与者发生主要结果事件，而基线时 HBsAg 水平较高（>3 log10 IU/mL）的参与者分别为 6% 和 7%（图 S3）。第 1 组的受试者操作特征分析表明，基线时 HBsAg 水平约为 3000 IU/毫升（3.5 log10 IU/mL）可能是预测反应的合适临界点（图 S4）。在第 1 组每毫升 3000 IU 或更低的临界点，43 名接受 NA 治疗的参与者中有 5 名 （12%） 和未接受 NA 治疗的 24 名参与者中有 6 名 （25%） 发生了主要结局事件。
在第 1 组中，基线时 HBsAg 水平较低（≤3 log10 IU/mL）的接受 NA 治疗的参与者中共有 16% 和 25% 未接受 NA 治疗的参与者发生主要结果事件，而基线时 HBsAg 水平较高（>3 log10 IU/mL）的参与者分别为 6% 和 7%（图 S3）。第 1 组的受试者操作特征分析表明，基线时 HBsAg 水平约为 3000 IU/毫升（3.5 log10 IU/mL）可能是预测反应的合适临界点（图 S4）。在第 1 组每毫升 3000 IU 或更低的临界点，43 名接受 NA 治疗的参与者中有 5 名 （12%） 和未接受 NA 治疗的 24 名参与者中有 6 名 （25%） 发生了主要结局事件。
Among HBeAg-negative participants, a primary-outcome event occurred in those receiving NA therapy and in those not receiving NA therapy (in group 1, 10% of participants receiving NA therapy and 14% of those not receiving NA therapy). Among HBeAg-positive participants, a primary-outcome event occurred only in those receiving NA therapy (in group 1, 6% of participants receiving NA therapy and 0% of those not receiving NA therapy) (Fig. S3).
在 HBeAg 阴性参与者中，接受 NA 治疗的患者和未接受 NA 治疗的参与者（在第 1 组中，接受 NA 治疗的参与者为 10%，未接受 NA 治疗的参与者为 14%）。在 HBeAg 阳性参与者中，主要结局事件仅发生在接受 NA 治疗的参与者中（在第 1 组中，接受 NA 治疗的参与者为 6%，未接受 NA 治疗的参与者为 0%）（图 S3）。
在 HBeAg 阴性参与者中，接受 NA 治疗的患者和未接受 NA 治疗的参与者（在第 1 组中，接受 NA 治疗的参与者为 10%，未接受 NA 治疗的参与者为 14%）。在 HBeAg 阳性参与者中，主要结局事件仅发生在接受 NA 治疗的参与者中（在第 1 组中，接受 NA 治疗的参与者为 6%，未接受 NA 治疗的参与者为 0%）（图 S3）。
Secondary Outcomes 次要结果
Between-Group Differences in Primary Results
主要结果的组间差异
The differences between groups 1 and 2, groups 1 and 3, and groups 2 and 3 in the proportion of participants having a primary-outcome event are shown in the Results section in the Supplementary Appendix.
第 1 组和第 2 组、第 1 组和第 3 组以及第 2 组和第 3 组之间在发生主要结果事件的参与者比例方面的差异显示在补充附录的结果部分。
第 1 组和第 2 组、第 1 组和第 3 组以及第 2 组和第 3 组之间在发生主要结果事件的参与者比例方面的差异显示在补充附录的结果部分。
HBsAg and HBV DNA Levels
HBsAg 和 HBV DNA 水平
Decreases in HBsAg and HBV DNA levels were dependent on the duration of bepirovirsen treatment (Figs. S5 and S6). The percentage of participants within each category of HBsAg level over time is shown in Figure 2 and Figure S7. For many participants, HBsAg and HBV DNA levels increased after treatment discontinuation (Figs. S7 and S8). Individual HBsAg levels over time according to baseline HBsAg level in group 1 are shown in Figure S9.
HBsAg 和 HBV DNA 水平的降低取决于 bepirovirsen 治疗的持续时间（图 S5 和 S6）。图 2 和图 S7 显示了随时间变化的 HBsAg 水平中每类参与者的百分比。对于许多参与者来说，HBsAg 和 HBV DNA 水平在停止治疗后升高（图 S7 和 S8）。根据第 1 组中的基线 HBsAg 水平，随时间变化的单个 HBsAg 水平如图 S9 所示。
HBsAg 和 HBV DNA 水平的降低取决于 bepirovirsen 治疗的持续时间（图 S5 和 S6）。图 2 和图 S7 显示了随时间变化的 HBsAg 水平中每类参与者的百分比。对于许多参与者来说，HBsAg 和 HBV DNA 水平在停止治疗后升高（图 S7 和 S8）。根据第 1 组中的基线 HBsAg 水平，随时间变化的单个 HBsAg 水平如图 S9 所示。
Figure 2 图2
Percentage of Participants within HBsAg Categories over Time (Group 1, Intention-to-Treat Population).
随时间推移 HBsAg 类别中的参与者百分比（第 1 组，意向治疗人群）。
随时间推移 HBsAg 类别中的参与者百分比（第 1 组，意向治疗人群）。
Shown are five categories of hepatitis B surface antigen (HBsAg) level. Participants in group 1 received loading doses of bepirovirsen on days 4 and 11. Percentages were calculated on the basis of the total number of participants in the intention-to-treat population. (At the time of the European Association for the Study of the Liver presentation,14,15 percentages were calculated on the basis of available data at the trial visit of interest.)
In group 1, 43 participants (63%) receiving NA therapy and 41 (59%) not receiving NA therapy had an HBsAg level of less than 100 IU per milliliter by the end of treatment; the values were 26 (38%) and 20 (29%), respectively, at 24 weeks after the end of treatment (Figure 2). By the end of treatment in group 1, a total of 18 participants (26%) receiving NA therapy and 20 (29%) not receiving NA therapy had an HBsAg level below the lower limit of detection; at 24 weeks after the end of treatment, the values were 8 (12%) and 10 (14%), respectively (Figure 2 and Fig. S10). In group 1, a total of 34 participants (50%) receiving NA therapy and 35 (50%) not receiving NA therapy had a decrease of at least 3 log10 IU per milliliter in the HBsAg level at the end of treatment; the incidence of relapse at the end of the trial was lowest in group 1 (Fig. S11).
在第 1 组中，43 名接受 NA 治疗的参与者 （63%） 和 41 名未接受 NA 治疗的参与者 （59%） 在治疗结束时 HBsAg 水平低于每毫升 100 IU;治疗结束后 24 周的值分别为 26 （38%） 和 20 （29%） （图 2）。到第 1 组治疗结束时，共有 18 名接受 NA 治疗的参与者 （26%） 和 20 名未接受 NA 治疗的参与者 （29%） 的 HBsAg 水平低于检测下限;在治疗结束后 24 周，该值分别为 8 （12%） 和 10 （14%） （图 2 和图 S10）。在第 1 组中，共有 34 名接受 NA 治疗的参与者 （50%） 和 35 名未接受 NA 治疗的参与者 （50%） 在治疗结束时 HBsAg 水平每毫升至少降低 3 log10 IU;第 1 组试验结束时的复发率最低（图 S11）。
在第 1 组中，43 名接受 NA 治疗的参与者 （63%） 和 41 名未接受 NA 治疗的参与者 （59%） 在治疗结束时 HBsAg 水平低于每毫升 100 IU;治疗结束后 24 周的值分别为 26 （38%） 和 20 （29%） （图 2）。到第 1 组治疗结束时，共有 18 名接受 NA 治疗的参与者 （26%） 和 20 名未接受 NA 治疗的参与者 （29%） 的 HBsAg 水平低于检测下限;在治疗结束后 24 周，该值分别为 8 （12%） 和 10 （14%） （图 2 和图 S10）。在第 1 组中，共有 34 名接受 NA 治疗的参与者 （50%） 和 35 名未接受 NA 治疗的参与者 （50%） 在治疗结束时 HBsAg 水平每毫升至少降低 3 log10 IU;第 1 组试验结束时的复发率最低（图 S11）。
Among participants not receiving NA therapy, the number in group 1 who had an HBV DNA level below the lower limit of quantification was 26 (37%) at the end of treatment and 19 (27%) at 24 weeks after the end of treatment, as compared with 20 (29%) and 15 (22%), respectively, in group 2; 18 (26%) and 9 (13%), respectively, in group 3; and 4 (17%) at both time points in group 4. Data excluding participants who received newly initiated antiviral medication are shown in Figure S8. Among participants in group 1 not receiving NA therapy, a decrease of at least 3 log10 IU per milliliter in the HBV DNA level was observed in 27 participants (39%) at the end of treatment and in 18 (26%) at 24 weeks after the end of treatment (Fig. S12).
在未接受 NA 治疗的参与者中，第 1 组中 HBV DNA 水平低于定量下限的人数在治疗结束时为 26 人 （37%），在治疗结束后 24 周为 19 人 （27%），而第 2 组分别为 20 人 （29%） 和 15 人 （22%）;第 3 组分别为 18 例 （26%） 和 9 例 （13%）;第 4 组的两个时间点都有 4 个 （17%）。不包括接受新开始的抗病毒药物的参与者的数据如图 S8 所示。在未接受 NA 治疗的第 1 组参与者中，观察到 27 名参与者 （39%） 在治疗结束时和 18 名参与者 （26%） 在治疗结束后 24 周观察到 HBV DNA 水平每毫升至少降低 3 log10 IU（图 S12）。
在未接受 NA 治疗的参与者中，第 1 组中 HBV DNA 水平低于定量下限的人数在治疗结束时为 26 人 （37%），在治疗结束后 24 周为 19 人 （27%），而第 2 组分别为 20 人 （29%） 和 15 人 （22%）;第 3 组分别为 18 例 （26%） 和 9 例 （13%）;第 4 组的两个时间点都有 4 个 （17%）。不包括接受新开始的抗病毒药物的参与者的数据如图 S8 所示。在未接受 NA 治疗的第 1 组参与者中，观察到 27 名参与者 （39%） 在治疗结束时和 18 名参与者 （26%） 在治疗结束后 24 周观察到 HBV DNA 水平每毫升至少降低 3 log10 IU（图 S12）。
Levels of HBeAg and Anti-HBs
HBeAg 和抗 HBs 水平
Of the participants who were positive for HBeAg and negative for antibodies against hepatitis B e (anti-HBe) at baseline, 10 of 63 (16%) receiving NA therapy and 8 of 41 (20%) not receiving NA therapy had HBeAg loss at 24 weeks after the end of treatment; 7 participants (11%) receiving NA therapy and 8 (20%) not receiving NA therapy had seroconversion (HBeAg loss and positivity for anti-HBe). Of the participants who had a primary-outcome event, 7 (50%) receiving NA therapy and 6 (50%) not receiving NA therapy had anti-HBs at the end of the trial.
在基线时 HBeAg 阳性且乙型肝炎 e 抗体 （抗-HBe） 阴性的参与者中，接受 NA 治疗的 63 名患者中有 10 名 （16%） 和未接受 NA 治疗的 41 名患者中有 8 名 （20%） 在治疗结束后 24 周时 HBeAg 消失;7 名接受 NA 治疗的参与者 （11%） 和 8 名未接受 NA 治疗的参与者 （20%） 出现血清转换 （HBeAg 缺失和抗 HBe 阳性）。在发生主要结局事件的参与者中，7 名 （50%） 接受 NA 治疗和 6 名 （50%） 未接受 NA 治疗在试验结束时存在抗 HBs。
在基线时 HBeAg 阳性且乙型肝炎 e 抗体 （抗-HBe） 阴性的参与者中，接受 NA 治疗的 63 名患者中有 10 名 （16%） 和未接受 NA 治疗的 41 名患者中有 8 名 （20%） 在治疗结束后 24 周时 HBeAg 消失;7 名接受 NA 治疗的参与者 （11%） 和 8 名未接受 NA 治疗的参与者 （20%） 出现血清转换 （HBeAg 缺失和抗 HBe 阳性）。在发生主要结局事件的参与者中，7 名 （50%） 接受 NA 治疗和 6 名 （50%） 未接受 NA 治疗在试验结束时存在抗 HBs。
ALT Levels ALT 水平
Overall, 39 of 225 participants receiving NA therapy (17%) and 93 of 227 not receiving NA therapy (41%) had a transient increase in the ALT level to at least 3 times the upper limit of the normal range between randomization and the end of follow-up (Table S6). At baseline, most participants (91% of those receiving NA therapy and 70% of those not receiving NA therapy) had an ALT level at or below the upper limit of the normal range (Table 1). The median time to ALT normalization for participants with an ALT level above the upper limit of the normal range at baseline is shown in Figure S13 and Table S12.
总体而言，接受 NA 治疗的 225 名参与者中有 39 名 （17%） 和未接受 NA 治疗的 93 名参与者中有 41 名 （41%） 的 ALT 水平短暂增加，至少是随机分组和随访结束之间正常范围上限的 3 倍（表 S6）。在基线时，大多数参与者（91% 的接受 NA 治疗的患者和 70% 的未接受 NA 治疗的患者）的 ALT 水平等于或低于正常范围的上限（表 1）。基线时 ALT 水平高于正常范围上限的参与者的 ALT 正常化的中位时间如图 S13 和表 S12 所示。
总体而言，接受 NA 治疗的 225 名参与者中有 39 名 （17%） 和未接受 NA 治疗的 93 名参与者中有 41 名 （41%） 的 ALT 水平短暂增加，至少是随机分组和随访结束之间正常范围上限的 3 倍（表 S6）。在基线时，大多数参与者（91% 的接受 NA 治疗的患者和 70% 的未接受 NA 治疗的患者）的 ALT 水平等于或低于正常范围的上限（表 1）。基线时 ALT 水平高于正常范围上限的参与者的 ALT 正常化的中位时间如图 S13 和表 S12 所示。
Adverse Events 不良事件
During weeks 1 through 12, when comparison between bepirovirsen and placebo was possible, adverse events were more common during bepirovirsen treatment in groups 1, 2, and 3 (in 78%, 85%, and 76%, respectively, of participants receiving NA therapy and in 90%, 82%, and 87%, respectively, of those not receiving NA therapy) than during receipt of placebo in group 4 (in 43% of those receiving NA therapy and 54% of those not receiving NA therapy) (Table 3). For example, injection-site reactions, pyrexia, fatigue, and increased ALT levels were reported more frequently with bepirovirsen than with placebo (Tables S13 and S14). The majority of adverse events reported were those captured under adverse events of special interest.
在第 1 周至第 12 周，当贝吡罗韦森和安慰剂进行比较时，第 1、2 和 3 组贝吡罗韦森治疗期间的不良事件更常见（接受 NA 治疗的参与者分别为 78%、85% 和 76%，未接受 NA 治疗的参与者分别为 90%、82% 和 87%）比第 4 组接受安慰剂期间（接受 NA 治疗的参与者为 43%，未接受 NA 治疗的参与者为 54%）（表例如，与安慰剂相比，贝匹罗韦森组更频繁地报告注射部位反应、发热、疲劳和 ALT 水平升高（表 S13 和 S14）。报告的大多数不良事件是在特别关注的不良事件下捕获的不良事件。
在第 1 周至第 12 周，当贝吡罗韦森和安慰剂进行比较时，第 1、2 和 3 组贝吡罗韦森治疗期间的不良事件更常见（接受 NA 治疗的参与者分别为 78%、85% 和 76%，未接受 NA 治疗的参与者分别为 90%、82% 和 87%）比第 4 组接受安慰剂期间（接受 NA 治疗的参与者为 43%，未接受 NA 治疗的参与者为 54%）（表例如，与安慰剂相比，贝匹罗韦森组更频繁地报告注射部位反应、发热、疲劳和 ALT 水平升高（表 S13 和 S14）。报告的大多数不良事件是在特别关注的不良事件下捕获的不良事件。
Table 3 表3
| Adverse Event | Receiving NA Therapy | Not Receiving NA Therapy | ||||||
|---|---|---|---|---|---|---|---|---|
| Group 1 (N=68) | Group 2 (N=67) | Group 3 (N=68) | Group 4 (N=23) | Group 1 (N=70) | Group 2 (N=67) | Group 3 (N=68) | Group 4 (N=24) | |
| number of participants (percent) | ||||||||
| Visits at wk 1–12 (when group 4 received placebo) | ||||||||
| Any adverse event | 53 (78) | 57 (85) | 52 (76) | 10 (43) | 63 (90) | 55 (82) | 59 (87) | 13 (54) |
| Any grade 3 or 4 adverse event† | 5 (7) | 9 (13) | 5 (7) | 0 | 10 (14) | 9 (13) | 7 (10) | 0 |
| Any serious adverse event‡ | 1 (1) | 1 (1) | 3 (4) | 0 | 3 (4) | 0 | 0 | 0 |
| Adverse events of special interest§ | ||||||||
| Injection-site reaction | 38 (56) | 47 (70) | 43 (63) | 3 (13) | 50 (71) | 41 (61) | 46 (68) | 3 (12) |
| Vascular inflammation and complement activation | 24 (35) | 31 (46) | 30 (44) | 1 (4) | 45 (64) | 38 (57) | 42 (62) | 6 (25) |
| Thrombocytopenia | 12 (18) | 9 (13) | 11 (16) | 3 (13) | 21 (30) | 17 (25) | 19 (28) | 4 (17) |
| Increased ALT level | 7 (10) | 10 (15) | 6 (9) | 0 | 15 (21) | 12 (18) | 11 (16) | 1 (4) |
| Renal injury | 2 (3) | 6 (9) | 6 (9) | 0 | 5 (7) | 3 (4) | 9 (13) | 1 (4) |
| All visits | ||||||||
| Any adverse event | 56 (82) | 59 (88) | 53 (78) | 16 (70) | 65 (93) | 60 (90) | 62 (91) | 19 (79) |
| Any adverse event leading to discontinuation of trial agent | 2 (3) | 3 (4) | 3 (4) | 0 | 3 (4) | 1 (1) | 5 (7) | 0 |
| Any grade 3 or 4 adverse event† | 7 (10) | 11 (16) | 8 (12) | 0 | 16 (23) | 15 (22) | 13 (19) | 4 (17) |
| Any serious adverse event‡ | 1 (1) | 1 (1) | 4 (6) | 0 | 6 (9) | 2 (3) | 3 (4) | 0 |
| Adverse events of special interest§ | ||||||||
| Injection-site reaction | 41 (60) | 49 (73) | 43 (63) | 11 (48) | 52 (74) | 41 (61) | 49 (72) | 12 (50) |
| Vascular inflammation and complement activation | 30 (44) | 34 (51) | 31 (46) | 10 (43) | 49 (70) | 40 (60) | 46 (68) | 12 (50) |
| Thrombocytopenia | 19 (28) | 16 (24) | 12 (18) | 6 (26) | 32 (46) | 21 (31) | 21 (31) | 6 (25) |
| Increased ALT level | 7 (10) | 10 (15) | 6 (9) | 6 (26) | 20 (29) | 19 (28) | 16 (24) | 5 (21) |
| Renal injury | 4 (6) | 9 (13) | 6 (9) | 2 (9) | 7 (10) | 6 (9) | 9 (13) | 3 (12) |
Safety Summary (Safety Population).
安全摘要（安全人群）。*
安全摘要（安全人群）。*
*
Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4). Loading doses of bepirovirsen (300 mg, in groups 1, 2, and 3) or placebo (in group 4) were administered on days 4 and 11. In group 2, one participant receiving NA therapy and one not receiving NA therapy did not receive any bepirovirsen treatment and were therefore not included in the safety population.
†
Adverse events were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, corrected version 2.1. Grade 1 indicates a mild event, grade 2 a moderate event, grade 3 a severe event, grade 4 a potentially life-threatening event, and grade 5 death.
‡
A serious adverse event is defined as an adverse event that, at any dose of bepirovirsen or placebo, results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or clinically significant disability or incapacity, or is a congenital anomaly or birth defect.
§
The adverse events of special interest were defined according to standardized Medical Dictionary for Regulatory Activities (MedDRA) queries or MedDRA high-level terms or individual preferred terms (see Table S9 in the Supplementary Appendix). The adverse event of special interest “vascular inflammation and complement activation” included preferred terms such as injection-site pruritus and injection-site swelling. Injection-site reactions were the most commonly reported events in the trial.
During weeks 1 through 12, no participants in group 4 (placebo) had serious adverse events; five participants receiving NA therapy (one in group 1, one in group 2, and three in group 3) and three participants not receiving NA therapy (all in group 1) had serious adverse events. Grade 3 or 4 adverse events occurred in 7 to 13% of participants receiving NA therapy and in 10 to 14% of those not receiving NA therapy in groups 1, 2, and 3, as compared with 0 in group 4. After the treatment period (during weeks 25 through 48), the frequency of reported adverse events was generally similar among the trial groups and of low frequency for individual reported events (Tables S15 and S16).
在第 1 周至第 12 周期间，第 4 组（安慰剂）的受试者没有发生严重的不良事件;5 名接受 NA 治疗的参与者 （1 名在第 1 组，1 名在第 2 组，3 名） 和 3 名未接受 NA 治疗的参与者 （都在第 1 组） 发生了严重的不良事件。第 1、2 和 3 组接受 NA 治疗的参与者中有 7% 至 13% 发生 3 级或 4 级不良事件，未接受 NA 治疗的参与者中有 10% 至 14% 发生 3 级或 4 级不良事件，而第 4 组为 0 级不良事件。治疗期后（第 25 周至第 48 周），试验组之间报告的不良事件频率通常相似，而个体报告事件的频率较低（表 S15 和 S16）。
在第 1 周至第 12 周期间，第 4 组（安慰剂）的受试者没有发生严重的不良事件;5 名接受 NA 治疗的参与者 （1 名在第 1 组，1 名在第 2 组，3 名） 和 3 名未接受 NA 治疗的参与者 （都在第 1 组） 发生了严重的不良事件。第 1、2 和 3 组接受 NA 治疗的参与者中有 7% 至 13% 发生 3 级或 4 级不良事件，未接受 NA 治疗的参与者中有 10% 至 14% 发生 3 级或 4 级不良事件，而第 4 组为 0 级不良事件。治疗期后（第 25 周至第 48 周），试验组之间报告的不良事件频率通常相似，而个体报告事件的频率较低（表 S15 和 S16）。
During weeks 1 through 48, the proportion of participants who reported adverse events was higher among those not receiving NA therapy than among those receiving NA therapy (Table 3), with a higher incidence of increased ALT level, increased aspartate aminotransferase level, decreased platelet count, decreased complement factor C3 level, and decreased complement factor C4 level (Tables S17 and S18). In patients receiving NA therapy and in those not receiving NA therapy, the most common adverse events were injection-site reactions (erythema, pain, and pruritus). Overall, 17 participants had adverse events leading to discontinuation of bepirovirsen or placebo, with 0 to 4% frequency among participants receiving NA therapy and 0 to 7% frequency among those not receiving NA therapy (Table 3).
在第 1 周至第 48 周期间，未接受 NA 治疗的参与者报告不良事件的比例高于接受 NA 治疗的参与者（表 3），ALT 水平升高、天冬氨酸转氨酶水平升高、血小板计数降低、补体因子 C3 水平降低和补体因子 C4 水平降低的发生率更高（表 S17 和 S18）。在接受 NA 治疗和未接受 NA 治疗的患者中，最常见的不良事件是注射部位反应（红斑、疼痛和瘙痒）。总体而言，17 名参与者发生了导致停用贝吡罗韦森或安慰剂的不良事件，接受 NA 治疗的参与者发生率为 0% 至 4%，未接受 NA 治疗的参与者发生率为 0% 至 7%（表 3）。
在第 1 周至第 48 周期间，未接受 NA 治疗的参与者报告不良事件的比例高于接受 NA 治疗的参与者（表 3），ALT 水平升高、天冬氨酸转氨酶水平升高、血小板计数降低、补体因子 C3 水平降低和补体因子 C4 水平降低的发生率更高（表 S17 和 S18）。在接受 NA 治疗和未接受 NA 治疗的患者中，最常见的不良事件是注射部位反应（红斑、疼痛和瘙痒）。总体而言，17 名参与者发生了导致停用贝吡罗韦森或安慰剂的不良事件，接受 NA 治疗的参与者发生率为 0% 至 4%，未接受 NA 治疗的参与者发生率为 0% 至 7%（表 3）。
Grade 3 or 4 adverse events occurred in 74 participants overall, with 0 to 16% frequency among those receiving NA therapy and 17 to 23% frequency among those not receiving NA therapy. Serious adverse events were reported in 6 participants (3%) receiving NA therapy and 11 (5%) not receiving NA therapy; 1 serious adverse event in participants receiving NA therapy and 3 in those not receiving NA therapy were considered by the investigator to be related to bepirovirsen treatment (Table 3 and Tables S19 and S20). No deaths were reported. The most common adverse events of special interest were injection-site reactions, reported in 48 to 74% of participants across trial groups and participants receiving or not receiving NA therapy (Table 3).
总共 74 名参与者发生了 3 级或 4 级不良事件，接受 NA 治疗的患者发生率为 0% 至 16%，未接受 NA 治疗的患者发生率为 17% 至 23%。6 名接受 NA 治疗的参与者 （3%） 和 11 名 （5%） 未接受 NA 治疗的参与者报告了严重不良事件;研究者认为接受 NA 治疗的参与者中有 1 例严重不良事件，未接受 NA 治疗的参与者中有 3 例严重不良事件与贝吡罗韦森治疗有关（表 3 和表 S19 和 S20）。没有死亡报告。特别关注的最常见不良事件是注射部位反应，在试验组中 48% 至 74% 的参与者以及接受或未接受 NA 治疗的参与者中报告（表 3）。
总共 74 名参与者发生了 3 级或 4 级不良事件，接受 NA 治疗的患者发生率为 0% 至 16%，未接受 NA 治疗的患者发生率为 17% 至 23%。6 名接受 NA 治疗的参与者 （3%） 和 11 名 （5%） 未接受 NA 治疗的参与者报告了严重不良事件;研究者认为接受 NA 治疗的参与者中有 1 例严重不良事件，未接受 NA 治疗的参与者中有 3 例严重不良事件与贝吡罗韦森治疗有关（表 3 和表 S19 和 S20）。没有死亡报告。特别关注的最常见不良事件是注射部位反应，在试验组中 48% 至 74% 的参与者以及接受或未接受 NA 治疗的参与者中报告（表 3）。
Discussion 讨论
In this phase 2b trial, bepirovirsen at a dose of 300 mg per week for 24 weeks (group 1) resulted in 9 to 10% of participants having HBsAg and HBV DNA loss for 24 weeks after the end of bepirovirsen treatment. Results were similar in participants receiving NA therapy and those not receiving NA therapy.
在这项 2b 期试验中，贝吡罗韦森剂量为每周 300 毫克，持续 24 周（第 1 组），导致 9% 至 10% 的参与者在贝吡罗韦森治疗结束后 24 周内出现 HBsAg 和 HBV DNA 丢失。接受 NA 治疗的参与者和未接受 NA 治疗的参与者的结果相似。
在这项 2b 期试验中，贝吡罗韦森剂量为每周 300 毫克，持续 24 周（第 1 组），导致 9% 至 10% 的参与者在贝吡罗韦森治疗结束后 24 周内出现 HBsAg 和 HBV DNA 丢失。接受 NA 治疗的参与者和未接受 NA 治疗的参与者的结果相似。
Results for the modified primary outcome, which permitted “blips” in response, were consistent with the primary analysis, with 10 to 14% of the participants having an outcome event. HBV DNA “blips” after HBV DNA loss are a known phenomenon when stopping NA therapy and are suggested to represent spontaneous fluctuations due to a release of virions from hepatic reservoirs.16,17 The “blips” in HBsAg seen in the B-Clear trial may have a similar cause.
修改后的主要结局（允许响应中出现 “blips”）的结果与主要分析一致，10% 至 14% 的参与者发生了结局事件。HBV DNA 丢失后的 HBV DNA“光点”是停止 NA 治疗时的已知现象，并且被认为代表由于病毒粒子从肝储库中释放而引起的自发波动。16,17 在 B-Clear 试验中看到的 HBsAg 中的“光点”可能具有类似的原因。
修改后的主要结局（允许响应中出现 “blips”）的结果与主要分析一致，10% 至 14% 的参与者发生了结局事件。HBV DNA 丢失后的 HBV DNA“光点”是停止 NA 治疗时的已知现象，并且被认为代表由于病毒粒子从肝储库中释放而引起的自发波动。16,17 在 B-Clear 试验中看到的 HBsAg 中的“光点”可能具有类似的原因。
HBsAg loss is rarely achieved with currently available HBV treatments. New therapies are being developed for the treatment of chronic HBV infection, including small interfering RNAs (siRNAs).18,19 Clinical trials with siRNAs have shown HBsAg reduction to less than 100 IU per milliliter in up to 70% of participants, but no, or very few, participants had HBsAg loss.20-23 To put the results of the B-Clear trial in context, in group 1, a total of 9% of the participants receiving NA therapy and 10% of those not receiving NA therapy had both HBsAg and HBV DNA loss maintained for 24 weeks after the end of bepirovirsen treatment. The immunostimulatory activity of bepirovirsen may be mediated through TLR813; this mode of action may explain differences seen as compared with other new HBV therapies. These findings may represent progress in the search for achieving a functional cure. Optimization of response will most likely require combination therapy to target multiple steps of the HBV life cycle, stimulate the immune system, or both.18,19 Studies are ongoing that combine bepirovirsen with other therapies (e.g., an inhibitor of PAPD5 and PAPD7 [ClinicalTrials.gov number, NCT05330455], pegylated interferon therapy [NCT04676724], and ASO-HBV vaccine [NCT03866187]) to enable more patients to have a response.
目前可用的 HBV 治疗很少能实现 HBsAg 的损失。正在开发治疗慢性 HBV 感染的新疗法，包括小干扰 RNA （siRNA）。18,19 siRNA 临床试验显示，高达 70% 的参与者的 HBsAg 降低到每毫升 100 IU 以下，但没有或很少有参与者出现 HBsAg 丢失。20-23 为了将 B-Clear 试验的结果放在上下文中，在第 1 组中，共有 9% 的接受 NA 治疗的参与者和 10% 的未接受 NA 治疗的参与者在 bepirovirsen 治疗结束后 HBsAg 和 HBV DNA 丢失维持了 24 周。贝吡罗韦森的免疫刺激活性可能通过 TLR8介导 13;这种作用方式可以解释与其他新的 HBV 疗法相比的差异。这些发现可能代表了寻求功能性治愈的进展。优化反应很可能需要联合治疗，以针对 HBV 生命周期的多个步骤、刺激免疫系统或两者兼而有之。18,19 正在进行的研究将贝吡罗韦森与其他疗法（例如，PAPD5 和 PAPD7 抑制剂 [ClinicalTrials.gov 编号，NCT05330455]、聚乙二醇干扰素疗法 [NCT04676724] 和 ASO-HBV 疫苗 [NCT03866187]）相结合，以使更多患者能够产生反应。
目前可用的 HBV 治疗很少能实现 HBsAg 的损失。正在开发治疗慢性 HBV 感染的新疗法，包括小干扰 RNA （siRNA）。18,19 siRNA 临床试验显示，高达 70% 的参与者的 HBsAg 降低到每毫升 100 IU 以下，但没有或很少有参与者出现 HBsAg 丢失。20-23 为了将 B-Clear 试验的结果放在上下文中，在第 1 组中，共有 9% 的接受 NA 治疗的参与者和 10% 的未接受 NA 治疗的参与者在 bepirovirsen 治疗结束后 HBsAg 和 HBV DNA 丢失维持了 24 周。贝吡罗韦森的免疫刺激活性可能通过 TLR8介导 13;这种作用方式可以解释与其他新的 HBV 疗法相比的差异。这些发现可能代表了寻求功能性治愈的进展。优化反应很可能需要联合治疗，以针对 HBV 生命周期的多个步骤、刺激免疫系统或两者兼而有之。18,19 正在进行的研究将贝吡罗韦森与其他疗法（例如，PAPD5 和 PAPD7 抑制剂 [ClinicalTrials.gov 编号，NCT05330455]、聚乙二醇干扰素疗法 [NCT04676724] 和 ASO-HBV 疫苗 [NCT03866187]）相结合，以使更多患者能够产生反应。
The B-Clear data suggest that the HBsAg level at baseline may predict response. Participants with a low HBsAg level at baseline were more likely to have a primary-outcome event than those with a high level at baseline, findings that are consistent with previous observations and that highlight the importance of baseline HBsAg levels in predicting response as seen with other HBV therapies.12,24 We found substantial decreases in HBsAg levels in participants with a high HBsAg level at baseline, but the reductions were often not enough to result in HBsAg loss. A receiver-operating-characteristic analysis suggested that an HBsAg level of 3000 IU per milliliter at baseline may be an appropriate cutoff point as a predictor of response.
B-Clear 数据表明，基线时的 HBsAg 水平可以预测反应。基线时 HBsAg 水平低的参与者比基线时 HBsAg 水平高的参与者更有可能发生主要结局事件，这些发现与之前的观察结果一致，并强调了基线 HBsAg 水平在预测反应中的重要性，就像其他 HBV 疗法一样。12,24 我们发现基线时 HBsAg 水平高的参与者的 HBsAg 水平显着降低，但这种降低通常不足以导致 HBsAg 消失。受试者手术特征分析表明，基线时 HBsAg 水平为每毫升 3000 IU 可能是作为反应预测因子的合适临界点。
B-Clear 数据表明，基线时的 HBsAg 水平可以预测反应。基线时 HBsAg 水平低的参与者比基线时 HBsAg 水平高的参与者更有可能发生主要结局事件，这些发现与之前的观察结果一致，并强调了基线 HBsAg 水平在预测反应中的重要性，就像其他 HBV 疗法一样。12,24 我们发现基线时 HBsAg 水平高的参与者的 HBsAg 水平显着降低，但这种降低通常不足以导致 HBsAg 消失。受试者手术特征分析表明，基线时 HBsAg 水平为每毫升 3000 IU 可能是作为反应预测因子的合适临界点。
Most patients with chronic HBV infection are HBeAg-negative, with the prevalence of this subgroup increasing.25 In HBeAg-negative patients, HBV sequences are potentially integrated (with some HBV sequences deleted) into the host genome, and the integrated HBV DNA is a primary source of HBsAg.26 The HBsAg reductions and loss with bepirovirsen that we observed in HBeAg-negative participants suggest that the bepirovirsen target site is preserved in the majority of integrated HBV-derived transcripts. In HBeAg-positive participants, a primary-outcome event occurred only in those receiving NA therapy. Because the primary driver of response seemed to be the HBsAg level at baseline, the apparent lack of response in HBeAg-positive participants who were not receiving NA therapy may be explained by higher HBsAg levels at baseline in this subgroup, with only two HBeAg-positive participants having a low HBsAg level at baseline.
大多数慢性 HBV 感染患者为 HBeAg 阴性，该亚组的患病率增加。25 在 HBeAg 阴性患者中，HBV 序列可能被整合到宿主基因组中（一些 HBV 序列被删除），而整合的 HBV DNA 是 HBsAg 的主要来源。26 我们在 HBeAg 阴性参与者中观察到的贝吡罗韦森 HBsAg 减少和丢失表明，贝吡罗韦森靶位点保留在大多数整合的 HBV 衍生转录本中。在 HBeAg 阳性参与者中，主要结局事件仅发生在接受 NA 治疗的参与者中。由于反应的主要驱动因素似乎是基线时的 HBsAg 水平，因此未接受 NA 治疗的 HBeAg 阳性参与者明显缺乏反应可能是该亚组中基线时 HBsAg 水平较高，只有两名 HBeAg 阳性参与者在基线时 HBsAg 水平较低。
大多数慢性 HBV 感染患者为 HBeAg 阴性，该亚组的患病率增加。25 在 HBeAg 阴性患者中，HBV 序列可能被整合到宿主基因组中（一些 HBV 序列被删除），而整合的 HBV DNA 是 HBsAg 的主要来源。26 我们在 HBeAg 阴性参与者中观察到的贝吡罗韦森 HBsAg 减少和丢失表明，贝吡罗韦森靶位点保留在大多数整合的 HBV 衍生转录本中。在 HBeAg 阳性参与者中，主要结局事件仅发生在接受 NA 治疗的参与者中。由于反应的主要驱动因素似乎是基线时的 HBsAg 水平，因此未接受 NA 治疗的 HBeAg 阳性参与者明显缺乏反应可能是该亚组中基线时 HBsAg 水平较高，只有两名 HBeAg 阳性参与者在基线时 HBsAg 水平较低。
In patients with HBV, ALT flares can be a result of disease activity, immune clearance of HBV-infected hepatocytes, or drug-induced liver injury.12,27,28 There were two serious adverse events related to ALT changes, which are discussed further in the Results section in the Supplementary Appendix, and one case of Gilbert’s syndrome. Otherwise, increases in ALT levels were asymptomatic and resolved without increases in bilirubin or alkaline phosphatase levels and without evidence of liver dysfunction.
在 HBV 患者中，ALT 发作可能是疾病活动、HBV 感染肝细胞的免疫清除或药物诱导的肝损伤的结果。12,27,28 有两例与 ALT 变化相关的严重不良事件，将在补充附录的结果部分进一步讨论，以及一例吉尔伯特综合征。否则，ALT 水平升高是无症状的，并且在胆红素或碱性磷酸酶水平没有增加且没有肝功能障碍证据的情况下得到解决。
在 HBV 患者中，ALT 发作可能是疾病活动、HBV 感染肝细胞的免疫清除或药物诱导的肝损伤的结果。12,27,28 有两例与 ALT 变化相关的严重不良事件，将在补充附录的结果部分进一步讨论，以及一例吉尔伯特综合征。否则，ALT 水平升高是无症状的，并且在胆红素或碱性磷酸酶水平没有增加且没有肝功能障碍证据的情况下得到解决。
During the first 12 weeks of the trial when group 4 received placebo, adverse events (primarily those identified as adverse events of special interest, including an increased ALT level) were more common with bepirovirsen than with placebo. Other commonly reported adverse events were pyrexia and fatigue. Eight serious adverse events occurred in the first 12 weeks of bepirovirsen treatment and none with receipt of placebo. Overall, injection-site reactions were the most common adverse events; two participants (one receiving NA therapy and one not receiving NA therapy) withdrew owing to an injection-site reaction. Among participants receiving NA and those not receiving NA therapy, bepirovirsen at a dose of 300 mg weekly for 24 weeks did not show any marked difference in safety or side-effect profile as compared with other regimens.
在试验的前 12 周内，当第 4 组接受安慰剂时，贝吡罗韦森组的不良事件（主要是那些被确定为特别关注的不良事件，包括 ALT 水平升高）比安慰剂组更常见。其他常见报告的不良事件是发热和疲劳。在贝皮罗韦森治疗的前 12 周内发生了 8 例严重不良事件，接受安慰剂后没有发生。总体而言，注射部位反应是最常见的不良事件;两名参与者 （一名接受 NA 治疗，一名未接受 NA 治疗） 因注射部位反应而退出。在接受 NA 的参与者和未接受 NA 治疗的参与者中，与其他方案相比，每周 300 毫克剂量的贝吡罗韦森持续 24 周在安全性或副作用方面没有显示出任何显着差异。
在试验的前 12 周内，当第 4 组接受安慰剂时，贝吡罗韦森组的不良事件（主要是那些被确定为特别关注的不良事件，包括 ALT 水平升高）比安慰剂组更常见。其他常见报告的不良事件是发热和疲劳。在贝皮罗韦森治疗的前 12 周内发生了 8 例严重不良事件，接受安慰剂后没有发生。总体而言，注射部位反应是最常见的不良事件;两名参与者 （一名接受 NA 治疗，一名未接受 NA 治疗） 因注射部位反应而退出。在接受 NA 的参与者和未接受 NA 治疗的参与者中，与其他方案相比，每周 300 毫克剂量的贝吡罗韦森持续 24 周在安全性或副作用方面没有显示出任何显着差异。
In this phase 2b trial, 24-week treatment with bepirovirsen at a dose of 300 mg per week induced HBsAg and HBV DNA loss for 24 weeks after the end of treatment. This efficacy was achieved with a single agent (in 10% of participants; 95% credible interval, 0 to 38) and in combination with NA therapy (in 9%; 95% credible interval, 0 to 31). Although this is a relatively low percentage of participants overall, it indicates the possibility of enhanced efficacy with the selection of patients according to baseline characteristics (low HBsAg level at baseline), with combination therapies, or both. Durability of response is being investigated in the B-Sure trial (ClinicalTrials.gov number, NCT04954859), which will follow participants for an additional 33 months and includes criteria for stopping NA therapy. Larger trials and longer follow-up are needed to assess the safety and efficacy of bepirovirsen.
在该 2b 期试验中，每周 300 mg 剂量的贝吡罗韦森治疗 24 周，诱导治疗结束后 24 周内 HBsAg 和 HBV DNA 丢失。这种疗效是通过单一药物 （10% 的参与者;95% 可信区间，0 至 38） 和联合 NA 治疗 （9%;95% 可信区间，0 至 31） 实现的。尽管总体参与者的百分比相对较低，但它表明根据基线特征（基线时 HBsAg 水平低）选择患者、联合疗法或两者兼而有之，可能会增强疗效。B-Sure 试验（ClinicalTrials.gov 编号，NCT04954859）正在调查反应的持久性，该试验将对参与者进行额外的 33 个月随访，包括停止 NA 治疗的标准。需要更大规模的试验和更长的随访来评估 bepirovirsen 的安全性和有效性。
在该 2b 期试验中，每周 300 mg 剂量的贝吡罗韦森治疗 24 周，诱导治疗结束后 24 周内 HBsAg 和 HBV DNA 丢失。这种疗效是通过单一药物 （10% 的参与者;95% 可信区间，0 至 38） 和联合 NA 治疗 （9%;95% 可信区间，0 至 31） 实现的。尽管总体参与者的百分比相对较低，但它表明根据基线特征（基线时 HBsAg 水平低）选择患者、联合疗法或两者兼而有之，可能会增强疗效。B-Sure 试验（ClinicalTrials.gov 编号，NCT04954859）正在调查反应的持久性，该试验将对参与者进行额外的 33 个月随访，包括停止 NA 治疗的标准。需要更大规模的试验和更长的随访来评估 bepirovirsen 的安全性和有效性。
Notes 笔记
This article was published on November 8, 2022, at NEJM.org.
本文发表于 2022 年 11 月 8 日，NEJM.org。
本文发表于 2022 年 11 月 8 日，NEJM.org。
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
作者提供的数据共享声明与本文的全文一起可在 NEJM.org 上获得。
作者提供的数据共享声明与本文的全文一起可在 NEJM.org 上获得。
Supported by GSK.
由 GSK 支持。
由 GSK 支持。
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
作者提供的披露表格可在 NEJM.org 上与本文的全文一起获得。
作者提供的披露表格可在 NEJM.org 上与本文的全文一起获得。
We thank Sheekha Amin and Anna Dawe of Fishawack Indicia, part of Fishawack Health, for writing and editing assistance with an earlier version of the manuscript, including developing the initial draft on the basis of author direction, assembling tables and figures, collating authors’ comments, grammatical editing, and referencing.
我们感谢 Fishawack Health 旗下 Fishawack Indicia 的 Sheekha Amin 和 Anna Dawe 为早期版本的手稿提供写作和编辑帮助，包括根据作者方向开发初稿、汇编表格和图表、整理作者的评论、语法编辑和参考文献。
我们感谢 Fishawack Health 旗下 Fishawack Indicia 的 Sheekha Amin 和 Anna Dawe 为早期版本的手稿提供写作和编辑帮助，包括根据作者方向开发初稿、汇编表格和图表、整理作者的评论、语法编辑和参考文献。
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Published online: November 8, 2022
Published in issue: November 24, 2022
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From the Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, and the State Key Laboratory of Liver Research, University of Hong Kong, Hong Kong (M.-F.Y.), and Nanfang Hospital, Southern Medical University, Guangzhou (J. Hou) — all in China; National University Health System, Singapore (S.-G.L.); the University of Rzeszow, College of Medical Sciences, Centrum Medyczne w Lancucie, Lancut (R.P.), and the Faculty of Health Sciences in Bytom, Medical University of Silesia, Katowice (E.J.) — both in Poland; the Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital (K. Tsuji), and Hiroshima University Hospital (M.I.), Hiroshima, and Kagawa Prefectural Central Hospital, Takamatsu (K. Takaguchi) — all in Japan; Toronto General Hospital, Toronto (H.L.A.J.), and the Department of Medicine, University of Saskatchewan, Regina (A.W.) — both in Canada; Erasmus Medical Center, Rotterdam, the Netherlands (H.L.A.J.); Regional Institute of Gastroenterology and Hepatology and Babeş-Bolyai University, Department of Clinical Psychology and Psychotherapy, International Institute for Advanced Study of Psychotherapy and Applied Mental Health, Cluj-Napoca (C.P.), Dr. Victor Babes Clinical Hospital of Infectious and Tropical Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest (C.P.P.), Spitalul Clinic de Boli Infectioase si Pneumoftiziologie, Craiova (G.D.), Sfanta Cuvioasa Parascheva Infectious Diseases Clinical Hospital, Galati (M.A.), and “Grigore T. Popa” University of Medicine and Pharmacy, Iasi (A.V.) — all in Romania; Hospital Italiano de Buenos Aires, Buenos Aires (A.G.); Modern Medicine Clinic, Moscow (T.S.); Université de Paris-Cité and INSERM Unité Mixte de Recherche 1149, Department of Hepatology, Assistance Publique–Hôpitaux de Paris Hôpital Beaujon, Clichy, France (T.A.); Korea University Ansan Hospital, Ansan (H.J.Y.), and the College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital (J. Heo), and Inje University Busan Paik Hospital (S.-J.P.), Busan — all in South Korea; the University of Medicine and Hospital for Active Treatment Sofiamed, Sofia, Bulgaria (N.I.); Luigi Sacco Hospital, Milan (G.R.), and Azienda Ospedaliero–Universitaria di Modena, Baggiovara Hospital, Modena (P.A.) — both in Italy; GSK, Durham, NC (J.C., D.T.); GSK, Stevenage (R.E., G.Q., L.M., S.K., F.C.), and GSK, Brentford (H.P.) — both in the United Kingdom; GSK, Dubai, United Arab Emirates (T.L.); and GSK, Collegeville, PA (M.P.).
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- We must let the research question drive study methods, BMJ, (q173), (2024).https://doi.org/10.1136/bmj.q173
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Trial Design.
Participants receiving stable nucleoside or nucleotide analogue (NA) therapy were expected to continue NA therapy during the trial; participants not receiving NA therapy at trial entry were expected to continue without NA therapy during the trial. Participants receiving stable NA therapy and participants not currently receiving NA therapy underwent randomization separately. Doses were administered once weekly as two subcutaneous injections (two syringes total; one syringe contained either bepirovirsen at a dose of 150 mg or placebo). The loading dose (LD) of bepirovirsen (300 mg, in groups 1, 2, and 3) or placebo (in group 4) was administered on days 4 and 11.
Percentage of Participants within HBsAg Categories over Time (Group 1, Intention-to-Treat Population).
Shown are five categories of hepatitis B surface antigen (HBsAg) level. Participants in group 1 received loading doses of bepirovirsen on days 4 and 11. Percentages were calculated on the basis of the total number of participants in the intention-to-treat population. (At the time of the European Association for the Study of the Liver presentation,14,15 percentages were calculated on the basis of available data at the trial visit of interest.)
Other
Tables
| Characteristic | Receiving NA Therapy | Not Receiving NA Therapy | ||||||
|---|---|---|---|---|---|---|---|---|
| Group 1 (N=68) | Group 2 (N=68) | Group 3 (N=68) | Group 4 (N=23) | Group 1 (N=70) | Group 2 (N=68) | Group 3 (N=68) | Group 4 (N=24) | |
| Age — yr | 49.0±11.5 | 46.1±12.6 | 47.4±11.2 | 49.8±11.2 | 44.5±11.1 | 43.8±9.9 | 40.7±11.1 | 42.4±12.0 |
| Male sex — no. (%) | 48 (71) | 49 (72) | 51 (75) | 17 (74) | 33 (47) | 41 (60) | 39 (57) | 11 (46) |
| Body-mass index† | 24.66±4.07 | 24.30±4.14 | 24.92±2.90 | 23.67±2.48 | 25.25±4.77 | 25.26±4.30 | 24.52±3.65 | 23.70±4.42 |
| Race or ethnic group — no. (%)‡ | ||||||||
| Asian | 36 (53) | 35 (51) | 36 (53) | 12 (52) | 37 (53) | 44 (65) | 38 (56) | 12 (50) |
| White | 30 (44) | 32 (47) | 26 (38) | 11 (48) | 24 (34) | 20 (29) | 24 (35) | 11 (46) |
| Black | 2 (3) | 1 (1) | 4 (6) | 0 | 9 (13) | 4 (6) | 6 (9) | 1 (4) |
| American Indian or Alaska Native | 0 | 0 | 1 (1) | 0 | 0 | 0 | 0 | 0 |
| Mixed race | 0 | 0 | 1 (1) | 0 | 0 | 0 | 0 | 0 |
| ALT ≤ULN — no. (%)§¶ | 62 (91) | 60 (90) | 62 (91) | 21 (91) | 50 (71) | 48 (71) | 47 (69) | 15 (62) |
| HBsAg ≤3 log10 IU/ml — no. (%)¶ | 19 (28) | 23 (34) | 19 (28) | 3 (13) | 12 (17) | 15 (22) | 11 (16) | 5 (21) |
| HBsAg — log10 IU/ml | 3.29±0.62 | 3.26±0.61 | 3.33±0.59 | 3.43±0.43 | 3.72±0.77 | 3.65±0.72 | 3.66±0.67 | 3.76±0.79 |
| HBV DNA — log10 IU/ml | 0.48±0.64 | 0.39±0.60 | 0.55±0.66 | 0.40±0.62 | 5.02±1.53 | 5.14±1.56 | 5.57±1.65 | 5.00±1.55 |
| Negative HBeAg status — no. (%)¶ | 50 (74) | 47 (70) | 44 (65) | 16 (70) | 49 (70) | 52 (76) | 52 (76) | 17 (71) |
| Receiving current NA therapy for ≥3 yr — no. (%)¶ | 47 (69) | 45 (67) | 43 (63) | 20 (87) | N/A | N/A | N/A | N/A |
| Current NA drugs — no. (%)¶ | ||||||||
| Entecavir | 38 (56) | 25 (37) | 20 (29) | 10 (43) | N/A | N/A | N/A | N/A |
| Tenofovir disoproxil | 24 (35) | 36 (54) | 33 (49) | 11 (48) | N/A | N/A | N/A | N/A |
| Tenofovir alafenamide | 9 (13) | 6 (9) | 17 (25) | 2 (9) | ||||
| Lamivudine | 1 (1) | 1 (1) | 1 (1) | 0 | N/A | N/A | N/A | N/A |
| Adefovir dipivoxil | 0 | 1 (1) | 0 | 0 | N/A | N/A | N/A | N/A |
| Emtricitabine | 0 | 0 | 1 (1) | 0 | N/A | N/A | N/A | N/A |
*
Plus–minus values are means ±SD. Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4). Loading doses of bepirovirsen (300 mg, in groups 1, 2, and 3) or placebo (in group 4) were administered on days 4 and 11. HBeAg denotes hepatitis B e antigen, HBsAg hepatitis B surface antigen, HBV hepatitis B virus, NA nucleoside or nucleotide analogue, and N/A not applicable.
†
The body-mass index is the weight in kilograms divided by the square of the height in meters.
‡
Race or ethnic group was reported by the participant.
§
The upper limit of the normal range (ULN) for alanine aminotransferase (ALT) is 40 IU per liter for men and 33 IU per liter for women.
¶
Data were missing for 1 participant in group 2 who was receiving NA therapy, so the denominator is 67 rather than 68.
Demographic and Clinical Characteristics of the Participants at Baseline (Intention-to-Treat Population).*
| Variable | Receiving NA Therapy | Not Receiving NA Therapy | ||||||
|---|---|---|---|---|---|---|---|---|
| Group 1 (N=68) | Group 2 (N=68) | Group 3 (N=68) | Group 4 (N=23) | Group 1 (N=70) | Group 2 (N=68) | Group 3 (N=68) | Group 4 (N=24) | |
| Primary-outcome event — no. of participants (%)† | 6 (9) | 6 (9) | 2 (3) | 0 | 7 (10) | 4 (6) | 1 (1) | 0 |
| Point estimate of response — % (95% credible interval) | 9 (0–31) | 9 (0–43) | 3 (0–16) | 2 (0–8)‡ | 10 (0–38) | 6 (0–25) | 2 (0–6)‡ | 2 (0–8)‡ |
Primary Outcome (Intention-to-Treat Population).*
| Adverse Event | Receiving NA Therapy | Not Receiving NA Therapy | ||||||
|---|---|---|---|---|---|---|---|---|
| Group 1 (N=68) | Group 2 (N=67) | Group 3 (N=68) | Group 4 (N=23) | Group 1 (N=70) | Group 2 (N=67) | Group 3 (N=68) | Group 4 (N=24) | |
| number of participants (percent) | ||||||||
| Visits at wk 1–12 (when group 4 received placebo) | ||||||||
| Any adverse event | 53 (78) | 57 (85) | 52 (76) | 10 (43) | 63 (90) | 55 (82) | 59 (87) | 13 (54) |
| Any grade 3 or 4 adverse event† | 5 (7) | 9 (13) | 5 (7) | 0 | 10 (14) | 9 (13) | 7 (10) | 0 |
| Any serious adverse event‡ | 1 (1) | 1 (1) | 3 (4) | 0 | 3 (4) | 0 | 0 | 0 |
| Adverse events of special interest§ | ||||||||
| Injection-site reaction | 38 (56) | 47 (70) | 43 (63) | 3 (13) | 50 (71) | 41 (61) | 46 (68) | 3 (12) |
| Vascular inflammation and complement activation | 24 (35) | 31 (46) | 30 (44) | 1 (4) | 45 (64) | 38 (57) | 42 (62) | 6 (25) |
| Thrombocytopenia | 12 (18) | 9 (13) | 11 (16) | 3 (13) | 21 (30) | 17 (25) | 19 (28) | 4 (17) |
| Increased ALT level | 7 (10) | 10 (15) | 6 (9) | 0 | 15 (21) | 12 (18) | 11 (16) | 1 (4) |
| Renal injury | 2 (3) | 6 (9) | 6 (9) | 0 | 5 (7) | 3 (4) | 9 (13) | 1 (4) |
| All visits | ||||||||
| Any adverse event | 56 (82) | 59 (88) | 53 (78) | 16 (70) | 65 (93) | 60 (90) | 62 (91) | 19 (79) |
| Any adverse event leading to discontinuation of trial agent | 2 (3) | 3 (4) | 3 (4) | 0 | 3 (4) | 1 (1) | 5 (7) | 0 |
| Any grade 3 or 4 adverse event† | 7 (10) | 11 (16) | 8 (12) | 0 | 16 (23) | 15 (22) | 13 (19) | 4 (17) |
| Any serious adverse event‡ | 1 (1) | 1 (1) | 4 (6) | 0 | 6 (9) | 2 (3) | 3 (4) | 0 |
| Adverse events of special interest§ | ||||||||
| Injection-site reaction | 41 (60) | 49 (73) | 43 (63) | 11 (48) | 52 (74) | 41 (61) | 49 (72) | 12 (50) |
| Vascular inflammation and complement activation | 30 (44) | 34 (51) | 31 (46) | 10 (43) | 49 (70) | 40 (60) | 46 (68) | 12 (50) |
| Thrombocytopenia | 19 (28) | 16 (24) | 12 (18) | 6 (26) | 32 (46) | 21 (31) | 21 (31) | 6 (25) |
| Increased ALT level | 7 (10) | 10 (15) | 6 (9) | 6 (26) | 20 (29) | 19 (28) | 16 (24) | 5 (21) |
| Renal injury | 4 (6) | 9 (13) | 6 (9) | 2 (9) | 7 (10) | 6 (9) | 9 (13) | 3 (12) |
*
Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4). Loading doses of bepirovirsen (300 mg, in groups 1, 2, and 3) or placebo (in group 4) were administered on days 4 and 11. In group 2, one participant receiving NA therapy and one not receiving NA therapy did not receive any bepirovirsen treatment and were therefore not included in the safety population.
†
Adverse events were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, corrected version 2.1. Grade 1 indicates a mild event, grade 2 a moderate event, grade 3 a severe event, grade 4 a potentially life-threatening event, and grade 5 death.
‡
A serious adverse event is defined as an adverse event that, at any dose of bepirovirsen or placebo, results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or clinically significant disability or incapacity, or is a congenital anomaly or birth defect.
§
The adverse events of special interest were defined according to standardized Medical Dictionary for Regulatory Activities (MedDRA) queries or MedDRA high-level terms or individual preferred terms (see Table S9 in the Supplementary Appendix). The adverse event of special interest “vascular inflammation and complement activation” included preferred terms such as injection-site pruritus and injection-site swelling. Injection-site reactions were the most commonly reported events in the trial.
Safety Summary (Safety Population).*
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