编者按：慢性乙型肝炎的防治与规范化管理始终是全球肝病领域的核心议题与重点攻关方向。近日，美国肝病学会（AASLD）联合感染病学会（IDSA）重磅发布最新版《慢性乙型肝炎治疗指南》。该指南在2015年、2018年两版指南的基础上，历经7年完成重要更新，为全球乙肝诊疗实践提供了兼具循证性与实操性的全新指导框架。新版指南不仅围绕6大关键临床问题给出明确循证推荐，更首次将“医患共同决策”理念系统性纳入核心诊疗原则，强调以患者为中心，鼓励医生在充分沟通病情、治疗目标及潜在获益与风险后，为患者制定个体化抗病毒治疗方案。为深度解读指南更新的核心突破、临床未满足需求及未来研究方向，我们特别邀请到AASLD指南编委联合主席、美国南加利福尼亚大学Norah Terrault教授展开独家专访，访谈内容整理如下。

《国际肝病》

此次AASLD乙肝指南是继2015、2018年后时隔7年的重要更新！相比前两版，本次在哪些方面进行了更新，能否请您为我们具体介绍一下？

Norah Terrault教授：新版AASLD乙肝指南围绕六大关键临床议题展开系统性补充与优化，核心目标在于填补当前诊疗实践中的证据空白，为临床医生提供更契合真实世界需求的规范化指导。其中两大核心板块聚焦乙肝传播的精准防控，具体包括母婴传播的全程阻断策略与高危人群水平传播的精细化防控方案，针对不同暴露场景（如医疗操作防护、无保护性行为等）进一步细化了可落地的防控措施，强化了预防体系的实操性。

在治疗方面，新指南重点回应了三类特殊患者群体的临床困惑，包括免疫耐受期患者的干预时机选择、处于不确定或“灰色地带”的患者的个体化管理，以及长期接受核苷（酸）类似物抗病毒治疗后，符合条件患者的停药评估标准与随访策略，新指南针对这些临床争议焦点给出了明确的循证推荐，为规范化诊疗提供了清晰依据。

此外，肝细胞癌（HCC）筛查的优化是本次指南更新的另一重要亮点，尤其针对HBV/HDV、HBV/HIV共感染等高风险人群，以及HBsAg消失人群的肝癌筛查指征、频率及手段进行了细化。随着功能性治愈成为乙肝治疗的核心目标之一，HBsAg消失人群的长期肝癌风险监测需求日益突出，指南的此次更新恰好填补了该领域的临床证据缺口，为特殊人群的肝癌早筛提供了针对性指导，使新版指南在延续核心框架的基础上，更具临床时效性与实践适配性。

In the current guidelines, we focused on six key questions. Two addressed prevention: preventing mother-to-child transmission (MTCT) and horizontal transmission of hepatitis B. Three tackled specific treatment challenges: managing immune-tolerant patients, those in the indeterminate (or 'gray zone'), and the withdrawal of nucleos(t)ide therapy in patients on long-term suppressive treatment. The final area addressed hepatocellular carcinoma (HCC) surveillance, aiming to fill critical gaps in the literature—particularly for patients with HBV/HDV or HBV/HIV co-infection, and especially for those who have lost hepatitis B surface antigen (HBsAg). With growing emphasis on functional cure, understanding surveillance strategies in this population is essential. These updates build upon our prior guidance, offering a more current perspective on treatment approaches.

《国际肝病》

AASLD、APASL和EASL指南对乙肝管理的推荐有所不同。您觉得新版AASLD 指南与APASL、EASL指南的主要异同是什么？

Norah Terrault教授：新版 AASLD 指南与欧洲肝病学会（EASL）、亚太肝病学会（APASL）指南在核心治疗理念上高度契合，但在具体推荐细则上仍存在一定差异。首先，三者均明确强调对免疫活动期慢性乙型肝炎患者的积极治疗干预，且在免疫耐受期患者及疾病状态不确定的 “灰色地带” 患者治疗态度上逐渐形成共识，均更倾向于摒弃“一刀切”的固定策略，支持结合患者年龄、肝纤维化程度、家族史等个体情况开展灵活化干预。

新版AASLD指南与EASL指南的主要差异体现在三个方面：首先是免疫活动期的定义标准不同，AASLD将其界定为丙氨酸氨基转移酶（ALT）水平≥2倍正常上限，其中e抗原阳性患者需同时满足HBV DNA≥20000 IU/mL，e抗原阴性患者需满足HBV DNA≥2000 IU/mL；而EASL的定义更为宽松，ALT水平＞正常上限即纳入免疫活动期范畴，且e抗原阳性与阴性患者的HBV DNA阈值均统一设定为2000 IU/mL。其次是核苷（酸）类似物（NAs）的停药策略分歧，EASL与APASL均支持对达到特定应答标准的患者进行停药尝试，而新版AASLD指南明确反对常规停药，推荐患者持续接受NAs治疗直至HBsAg消失，这一差异的核心逻辑在于AASLD认为，停药带来的临床获益相对有限，而潜在风险更为突出，如可能诱发严重的肝脏炎症急性加重、病毒学反弹，且多数患者最终需重新启动治疗，因此更倾向于采取保守的持续抑制治疗策略。总之，尽管AASLD指南的整体表述看似更为复杂，但新版指南的核心目标与EASL、APASL一致，均强调赋予临床医生更多自主权，开展更具个体化的、以患者为中心的诊疗服务，并且在所有诊疗场景中，我们都高度重视医患共同决策的重要性。

Well, I think a new guideline is going to be released, so the recommendations might be different.

So, perhaps I can best talk about AASLD versus EASL, and actually, they work quite similarly, but the primary differences are that: We both emphasize the treatment of immune-active hepatitis B, but we define it somewhat differently. For AASLD, we define immune-active disease as having an ALT level two times the upper limit of normal or greater, a viral load of 20,000 IU/mL, HBeAg-positive, and HBsAg of 2,000 IU/mL or greater. Whereas EASL uses anything greater than the upper limit of normal for ALT, and uses 2,000 IU/mL for both HBeAg-positive and HBsAg. So we differ in that aspect. But we both have a similar approach in terms of the immune-tolerant phase. And we now, I think, are both more permissive of treatment in that group as well as in the gray-zone patients. So I think in that way, we've moved similarly to being more permissive of treatment.

The other thing we differ on is that EASL is much more in favor of doing withdrawal of nucleos(t)ide therapy, whereas our new guidance actually came out against withdrawal routinely. We feel that people should continue on nucleos(t)ide therapy until they achieve HBsAg loss because, in our view, the benefits in terms of EASL's approach were relatively modest and the potential harms were high—flares and the need to restart therapy. So we favor not stopping, whereas EASL favors withdrawal in patients who are viewed to be good candidates. So I think that that's kind of a major change. APASL is also more in favor of withdrawal. So that's probably one of the major differences between our AASLD and EASL guidance.

But what I want to stress is that while we may look like we're still a little bit more complex overall, the guidance now is intended to give clinicians more permission to do more individualized, patient-centered care. And we really emphasize shared decision-making in every setting, really. So that's, I think, one of the things that's key.

《国际肝病》

乙肝管理仍存在许多挑战。您认为当前最需要解决的问题是什么？新版指南能否提供答案，还是仍需更多研究？

Norah Terrault教授：当前乙肝管理仍面临诸多亟待解决的临床挑战，新版AASLD指南虽针对部分关键问题给出了针对性循证推荐，但仍有不少问题需要更多高质量研究提供证据支持。由于现有证据强度尚未达到理想水平，指南中的许多推荐意见仍为条件性推荐，而非强推荐。例如，对于HBV DNA水平低于2000 IU/mL但未达到检测下限、且ALT正常的患者，目前包括 AASLD 在内的全球主流指南均暂不建议启动抗病毒治疗，但这类患者的长期疾病进展风险、肝纤维化进展速率及潜在干预价值仍存在较大争议，亟需开展大样本、长期随访的队列研究，明确其临床结局与个体化管理策略。此外，HBV 与其他肝脏疾病的共病问题（尤其是代谢相关脂肪性肝病）日益成为全球乙肝管理的新兴挑战，这类合并症可能通过协同损伤机制改变 HBV 的自然病史，加速肝纤维化进展并升高肝癌发生风险，进而影响治疗时机选择与方案制定，但其具体相互作用机制及优化管理路径仍需更多转化医学与临床研究提供证据。同时，以“治疗作为预防”为目的的干预策略，即仅为预防病毒传播而非预防肝癌或疾病进展而启动治疗，这一策略方案目前仍缺乏充足的循证医学证据支持，新版指南的相关推荐主要基于现有病毒学认知、治疗安全性数据及公共卫生层面的潜在获益，其长期临床价值、成本效益比及适用人群范围，仍需更多前瞻性研究进一步验证。

随着新型疗法的研发与应用，功能性治愈逐渐成为乙肝治疗的核心目标与重要方向，这一诊疗理念的转变也将深刻影响未来临床实践的核心逻辑，指南也需随着相关研究证据的积累持续迭代更新，以更好地适配新型诊疗格局，为全球乙肝患者提供更精准、个体化的管理方案。

Well, of course, we need more research — as I mentioned, many of our guideline recommendations remain conditionalbecause the supporting evidence is not yet as strong as we would like. There’s a clear need for improved data, particularly for certain patient groups. For example: patients with HBV DNA levels below 2,000 IU/mL but not fully undetectable. Right now, all guidelines recommend against treating these individuals (since their ALT is normal), but perhaps we need more evidence to reassess this approach.

Another critical and emerging area is the coexistence of HBV with other liver diseases — particularly metabolic dysfunction-associated steatotic liver disease (MASLD). We all recognize that this combination may alter the natural history of HBV, increase the risk of hepatocellular carcinoma (HCC), and potentially justify different treatment considerations. These are just a few examples.

Clearly, as we advance toward functional cure with new therapies (such as PCSK9 inhibitors, which we’re hearing about at this meeting), our approach to treatment strategies may also evolve. Therefore, guidelines will need to adapt accordingly.

I’ll also highlight one additional area: our recommendation on ‘treatment as prevention’ — treating individuals solely to prevent transmission to others (not to prevent HCC or disease progression). However, there is currently very limited data to support this recommendation. We made this suggestion based on existing knowledge about viral transmission dynamics, but we would benefit significantly from stronger evidence to inform this approach.

《国际肝病》

新版指南的更新会如何影响未来的乙肝研究方向？您最期待哪些领域取得突破？

Norah Terrault教授：新版AASLD乙肝指南的发布为全球慢乙肝研究指明了清晰方向，为临床未被满足的诊疗需求明确了核心探索靶点。我们期待未来在乙肝功能性治愈领域能够取得更大突破，尤其是推动更多患者实现HBsAg消失，且这一目标应重点聚焦于更年轻的患者群体。已有充分临床研究证实，女性在50岁以下、男性在40岁以下达成HBsAg消失，能显著降低长期肝癌发生风险与肝脏相关死亡率，带来更优的远期预后。目前，多款针对乙肝功能性治愈的新型药物（如靶向病毒生命周期关键环节的创新制剂）及联合治疗方案已进入临床研发阶段，这些创新疗法的临床数据备受全球肝病领域关注，其研究结果将为下一版AASLD指南的更新提供关键循证医学证据，推动诊疗标准的持续迭代。

当然，乙肝领域任何一项新的突破性进展都令人倍感振奋。目前，全球已有多家制药企业在积极布局乙肝新型药物及联合治疗方案的研发，但多数项目仍处于临床前或早期临床试验阶段，其长期疗效与安全性仍需更多数据验证。尤其值得关注的是，对于通过新型疗法实现HBsAg消失的患者，我们亟需开展更长周期的随访研究，一方面明确HBsAg消失这一功能性治愈关键指标的持久性，另一方面进一步验证该指标是否能切实转化为肝癌发生风险的降低及肝脏相关死亡率的下降。

此外，针对此前提及的临床关键缺口，我们仍需开展更多针对性的高质量研究，例如 HBV与代谢相关脂肪性肝病等其他肝脏疾病共存患者的病理生理相互作用机制及个体化优化治疗策略、“治疗作为预防”干预模式的长期临床获益与卫生经济学数据、HBV DNA低载量（低于2000 IU/mL但未达检测下限）且ALT正常患者的自然病史特征、疾病进展风险分层及最佳干预时机等。同时，关于NAs停药后的长期安全性、病毒学反弹风险与远期临床结局，以及免疫耐受期患者、疾病状态不确定的“灰色地带”患者的个体化治疗指征与方案选择等争议性问题，仍需依托大样本、多中心、长期随访的临床队列研究提供更坚实的循证医学证据，进而持续完善全球乙肝诊疗体系，最终实现改善全球乙肝患者预后、提升其长期生活质量的核心目标。

Well, as I’ve highlighted, I’m hopeful we’ll see more HBsAg loss. And I’m particularly optimistic that we’ll observe this outcome not only more frequently, but also in younger patients — because we know that achieving HBsAg loss at a younger age (under 50 for women, under 40 for men) is strongly associated with the best long-term outcomes. I’m genuinely excited by the potential of these emerging therapeutics, especially if they enable HBsAg loss in younger individuals. I believe this will have a significant impact on the next set of guidelines.

Of course, I’d welcome any therapeutic breakthrough. There are many promising new drugs from pharmaceutical companies, as well as innovative drug combinations — but it’s still early days. In particular, for therapies that drive HBsAg loss, we’ll need long-term data to confirm durability and demonstrate that such loss translates into tangible benefits, including reduced risks of liver cancer and liver-related mortality. I’m hopeful that will be the case. But of course, we’ll need to see additional evidence as well.

（来源：《国际肝病》编辑部）

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