Natural history of chronic hepatitis B in untreated adults without cirrhosis according to baseline hepatitis B virus DNA and alanine aminotransferase concentrations: a systematic review and meta-analysis.

Historically, WHO and professional society guidelines have recommended treatment for individuals at high risk of disease progression, including those with hepatitis B virus (HBV) DNA concentrations >20 000 IU/mL.

历史上，世界卫生组织(WHO)和专业学会的指南推荐对疾病进展风险高的个体进行治疗，包括那些乙型肝炎病毒(HBV) DNA浓度>20000 IU/mL的患者。

Whether individuals at lower risk, including those with HBV DNA <20 000 IU/mL and normal alanine aminotransferase concentrations, benefit from treatment remains uncertain.

对于低风险个体，包括那些HBV DNA <20 000 IU/mL和正常丙氨酸氨基转移酶浓度的患者，是否能从治疗中获益仍不确定。

To inform 2024 WHO guidelines and the potential expansion of treatment threshold recommendations, we conducted two linked systematic reviews and meta-analyses; this analysis examines the incidenceof clinical outcomes in untreated adults with non-cirrhotic CHB stratified by baseline HBV DNA and ALT concentrations.

为了向2024年世界卫生组织指南提供信息，并探讨治疗阈值建议的潜在扩展，我们进行了两项相关的系统评价和荟萃分析；本分析研究了基线HBV DNA和ALT浓度分层的未治疗慢性乙型肝炎成人患者的临床结果发生率。

Methods

In this systematic reviewand meta-analysis, we searched PubMed, Embase, Web of Science, and the Cochrane Library for longitudinal prospective and retrospective cohort studies, randomised controlled trials, and non-randomised studies of interventions, published in any language, from Jan 1, 2000, to Feb 6, 2023.

在这项系统评价和荟萃分析中，我们检索了PubMed、Embase、Web of Science和Cochrane图书馆，寻找从2000年1月1日至2023年2月6日发表的纵向前瞻性队列研究、回顾性队列研究、随机对照试验和非随机干预研究，包括任何语言的文献。

We also reviewed the reference lists of included studies and systematic reviews and consulted networks of experts to identify other data sources.

我们还审查了纳入研究和系统评价的参考文献列表，并咨询了专家网络，以识别其他数据来源。

Included studies followed up adults (≥18 years) with non-cirrhotic CHB who had no history of antiviral therapy at enrolment, had baseline HBV DNA quantification and ALT measurement, had a follow-up period of at least 48 weeks, and assessed one or more of six key clinical outcomes (hepatocellular carcinoma, cirrhosis, liver-related mortality, all-cause mortality, liver decompensation, and indication for liver transplantation) or six additional outcomes (advanced liver fibrosis, progression of liver fibrosis, becoming eligible for antiviral treatment, hepatitis flare, and HBsAg and HBeAg seroclearance).

纳入的研究随访了成年（≥18岁）非肝硬化性慢性乙型肝炎（CHB）患者，这些患者在入组时没有抗病毒治疗史，有基线HBV DNA定量和ALT测量，随访期至少为48周，并评估了六个关键临床结果（肝细胞癌、肝硬化、肝相关死亡、全因死亡、肝功能失代偿和肝移植指征）或六个附加结果（高级肝纤维化、肝纤维化进展、符合抗病毒治疗指征、肝炎发作和HBsAg和HBeAg血清清除）。

Outcomes were required to be stratified by HBV DNA concentrations (<200 IU/mL, <2000 IU/mL, 2000-19 999 IU/mL, 20 000-199 999 IU/mL, and ≥200 000 IU/mL) or ALT concentrations (less than the upper limit of normal [ULN], 1·0-1·9 × ULN, and ≥2·0 × ULN).

结果需要按HBV DNA浓度（<200 IU/mL，<2000 IU/mL，2000-19 999 IU/mL，20 000-199 999 IU/mL和≥200 000 IU/mL）或ALT浓度（低于正常上限[ULN]，1·0-1·9 × ULN和≥2·0 × ULN）进行分层。

We excluded studies that focused solely on individuals who were pregnant; were co-infected with HIV, hepatitis C virus, or hepatitis D virus; or had another underlying condition other than CHB.

我们排除了仅关注孕妇、合并HIV、丙型肝炎病毒或丁型肝炎病毒感染者，或有除慢性乙型肝炎（CHB）以外的其他基础疾病的个体的研究。

We extracted aggregate data and used random-effects meta-analysisto pool incidencerates per 100 person-years.

我们提取了汇总数据，并使用随机效应的荟萃分析来合并每100人年发生率。

This study was registered with PROSPERO (CRD42023431652).

本研究已在PROSPERO注册（CRD42023431652）。

Results

Of 13 231 studies screened, 71 met the inclusion criteria.

在筛选的13,231项研究中，有71项符合纳入标准。

A concentration-response relationship was observed between single baseline HBV DNA measurements and hepatocellular carcinoma incidencerates per 100 person-years: 0·131 (95% CI 0·097 to 0·177, I2=0%) for HBV DNA concentrations <200 IU/mL, 0·176 (0·117-0·266, I2=88%) for <2000 IU/mL, 0·311 (0·245-0·393, I2=13%) for 2000-19 999 IU/mL, 0·862 (0·725-1·026, I2=0%) for 20 000-199 999 IU/mL, and 0·941 (0·668-1·324, I2=58%) for ≥200 000 IU/mL (p<0·0001 for between-group difference).

观察到单次基线HBV DNA测量值与每100人年肝细胞癌发生率之间存在浓度-反应关系：HBV DNA浓度<200 IU/mL时为0.131 (95% CI 0.097至0.177, I2=0%)，<2000 IU/mL时为0.176 (0.117-0.266, I2=88%)，2000-19 999 IU/mL时为0.311 (0.245-0.393, I2=13%)，20 000-199 999 IU/mL时为0.862 (0.725-1.026, I2=0%)，以及≥200 000 IU/mL时为0.941 (0.668-1.324, I2=58%) (组间差异的p<0.0001)。

Similar concentration-response patterns were observed for development of cirrhosis (0·298 [95% CI 0·214-0·415], two studies, for <200 IU/mL; 0·300 [0·146-0·616], I2=88%, for <2000 IU/mL; 0·712 [0·624-0·814], I2=46%, for 2000-19 999 IU/mL; 1·436 [0·991-2·082], I2=76%, for 20 000-199 999 IU/mL; and 2·193 [1·690-2·846], I2=82%, for ≥200 000 IU/mL) and liver-related mortality (0·086 [95% CI 0·054-0·136], one study; 0·083 [0·015-0·451], I2=0%; 0·303 [0·228-0·402], I2=0%; 0·766 [0·591-0·993], one study; and 1·118 [0·951-1·314], two studies), but no concentration-response relationship was observed between a single baseline HBV DNA assessment and all-cause mortality or liver decompensation.

对于肝硬化的发展，观察到类似的浓度-反应模式（<200 IU/mL时为0.298 [95% CI 0.214-0.415]，两项研究；<2000 IU/mL时为0.300 [0.146-0.616]，I2=88%；2000-19 999 IU/mL时为0.712 [0.624-0.814]，I2=46%；20 000-199 999 IU/mL时为1.436 [0.991-2.082]，I2=76%；以及≥200 000 IU/mL时为2.193 [1.690-2.846]，I2=82%）以及与肝相关死亡率（一项研究为0.086 [95% CI 0.054-0.136]；0.083 [0.015-0.451]，I2=0%；0.303 [0.228-0.402]，I2=0%；一项研究为0.766 [0.591-0.993]；以及两项研究为1.118 [0.951-1.314]），但未观察到单次基线HBV DNA评估与全因死亡率或肝失代偿之间存在浓度-反应关系。

Compared with ALT below the ULN, incidencerates of hepatocellular carcinoma, cirrhosis, and liver-related mortality were higher in individuals with baseline ALT concentrations 1·0-1·9 × ULN or ≥2·0 × ULN.

与低于正常上限（ULN）的丙氨酸氨基转移酶（ALT）相比，基线ALT浓度在1.0-1.9×ULN或≥2.0×ULN的个体中，肝细胞癌、肝硬化和与肝相关的死亡率更高。

A similar pattern was not found for all-cause mortality, and other outcomes were not meta-analysed due to small numbers.

所有原因的死亡率并未发现类似模式，其他结果由于数量较少未进行荟萃分析。

Within the HBV DNA strata of <2000 IU/mL, 2000-19 999 IU/mL, and ≥200 000 IU/mL, hepatocellular carcinoma incidencerates were 2-3 times higher in individuals with ALT 1·0-1·9 × ULN than in those with ALT concentrations less than the ULN.

在HBV DNA水平<2000 IU/mL、2000-19 999 IU/mL和≥200 000 IU/mL的分层中，ALT水平在1·0-1·9 × ULN的个体的肝细胞癌发病率是ALT浓度低于ULN个体的2-3倍。

Individuals with persistently low HBV DNA concentrations (<2000 IU/mL) or persistently normal ALT concentrations across multiple assessments had slightly lower hepatocellular carcinoma incidencerates compared with those assessed by a single measurement.

在多次评估中，HBV DNA浓度持续低于2000 IU/mL或ALT浓度持续正常的个体，其肝细胞癌发病率与单次测量评估的个体相比略有降低。

Our risk of bias assessment found 15 (21%) of 71 studies to be rated as good quality, 40 (56%) as fair quality, and 16 (23%) as poor quality.

我们的偏倚风险评估发现71项研究中有15项（21%）被评为良好质量，40项（56%）评为一般质量，16项（23%）评为差质量。

interpretation

These findings, alongside the linked systematic reviewand meta-analysisof antiviral treatment efficacy, supported the 2024 WHO guidelines expansion of treatment criteria to include individuals with HBV DNA concentrations >2000 IU/mL and ALT concentrations above the ULN.

这些发现，连同相关的系统评价和抗病毒治疗效果的荟萃分析，支持了2024年世界卫生组织指南的治疗标准扩展，包括HBV DNA浓度>2000 IU/mL和ALT浓度高于正常上限的个体。

For those with HBV DNA concentrations <2000 IU/mL and persistently normal ALT concentrations, treatment can be deferred.

对于HBV DNA浓度<2000 IU/mL且ALT浓度持续正常的患者，可以推迟治疗。

funding

WHO.

世界卫生组织。