Efficacy of antiviral therapy in adults with chronic hepatitis B according to baseline hepatitis B virus DNA and alanine aminotransferase concentrations: a systematic review and meta-analysis.

To inform 2024 WHO guidelines on CHB and the potential expansion of treatment threshold recommendations, we conducted two linked systematic reviews and meta-analyses; this analysis examines the efficacy of antiviral therapy in adults with non-cirrhotic CHB according to baseline HBV DNA and ALT concentrations.

为了为2024年WHO关于CHB的指南和治疗阈值建议的潜在扩展提供信息，我们进行了两项相关的系统评价和荟萃分析；本分析研究了根据基线HBV DNA和ALT浓度，抗病毒治疗在非肝硬化CHB成人中的疗效。

Methods

In this systematic reviewand meta-analysis, we searched PubMed, Embase, Web of Science, and the Cochrane Library for randomised controlled trials (RCTs) and non-randomised (prospective or retrospective) confounder-controlled cohort studies of antiviral therapy versus placebo or no treatment in people with CHB, published in any language between Jan 1, 2000, and 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2000年1月1日至2023年2月6日期间发表的随机对照试验(RCTs)和非随机（前瞻性或回顾性）混杂因素控制队列研究，这些研究比较了慢性乙型肝炎(CHB)患者接受抗病毒治疗与安慰剂或无治疗的效果，研究语种不限。

We also reviewed the reference lists of included studies and systematic reviews to identify RCTs published before 2000.

我们还审查了纳入研究和系统评价的参考文献列表，以识别2000年之前发表的随机对照试验(RCTs)。

Eligible studies reported baseline HBV DNA and ALT concentrations of adults with CHB, had less than 30% of participants with cirrhosis at baseline, and reported on at least one of our predefined outcomes.

符合条件的研究报告了慢性乙型肝炎（CHB）成人患者的基线HBV DNA和ALT浓度，基线时肝硬化患者比例不超过30%，并且报告了我们预定义的至少一个结果。

We excluded studies focused exclusively on pregnant women, individuals co-infected with HIV, hepatitis C virus, or hepatitis D virus, or individuals with primary conditions other than CHB, and studies that included participants who had received anti-HBV therapy in the 6 months before study enrolment.

我们排除了专门针对孕妇、HIV、丙型肝炎病毒或丁型肝炎病毒感染的共感染个体，或除CHB以外的主要疾病条件的个体的研究，以及包括在研究登记前6个月内接受过抗HBV治疗的参与者的研究。

We extracted aggregate data to examine clinical outcomes (ie, hepatocellular carcinoma, cirrhosis, all-cause mortality, and liver-related mortality) and intermediate outcomes (ie, liver fibrosis, liver necroinflammation, ALT normalisation, HBsAg and HBeAg seroclearance and seroconversion, and HBV DNA suppression) stratified by baseline HBV DNA concentration (<2000 IU/mL, 2000-19 999 IU/mL, 20 000-199 999 IU/mL, 200 000-1 999 999 IU/mL, 2 000 000-19 999 999 IU/mL, and ≥20 000 000 IU/mL) and ALT (less than the upper limit of normal [ULN], 1·0-1·9 × ULN, and ≥2·0 × ULN).

我们提取了汇总数据，以检查临床结果（即肝细胞癌、肝硬化、全因死亡率和肝相关死亡率）和中间结果（即肝纤维化、肝坏死性炎症、ALT正常化、HBsAg和HBeAg血清清除和血清转换以及HBV DNA抑制），并根据基线HBV DNA浓度（<2000 IU/mL、2000-19 999 IU/mL、20 000-199 999 IU/mL、200 000-1 999 999 IU/mL、2 000 000-19 999 999 IU/mL和≥20 000 000 IU/mL）和ALT（小于正常上限[ULN]、1·0-1·9 × ULN和≥2·0 × ULN）进行分层。

We used random-effects meta-analysisto pool unadjusted risk ratios (RRs) from RCTs and adjusted or unadjusted hazard ratios (aHRs or HRs) or unadjusted RRs for non-randomised studies.

我们使用随机效应的荟萃分析来汇总来自随机对照试验的未调整风险比（RRs）和调整或未调整的风险比（aHRs或HRs）或非随机研究的未调整RRs。

We estimated the number needed to treat (NNT) to prevent one case of hepatocellular carcinoma with nucleoside or nucleotide (nucleos[t]ide) analogue treatment.

我们估计了使用核苷或核苷酸类似物治疗预防一例肝细胞癌所需的治疗人数（NNT）。

The study was registered with PROSPERO (CRD42023437560).

该研究已在PROSPERO注册（CRD42023437560）。

Results

Of 13 224 articles screened, 24 met the inclusion criteria, including 16 studies on nucleos(t)ide analogues (12 RCTs and four non-randomised studies) and eight studies on interferon alfa-2-based therapy (four RCTs and four non-randomised studies).

在筛选的13 224篇文章中，有24篇文章符合纳入标准，包括16项关于核苷（酸）类似物的研究（12项随机对照试验和四项非随机研究）以及八项关于干扰素alfa-2为基础的治疗的研究（四项随机对照试验和四项非随机研究）。

In adults with HBV DNA concentrations ≥20 000 IU/mL or elevated ALT (ie, ≥1·0 × ULN) at baseline, nucleos(t)ide analogue therapy was associated with a reduced risk of hepatocellular carcinoma (in non-randomised studies) and improvements in multiple intermediate outcomes (ie, liver fibrosis, necroinflammation, ALT normalisation, HBV DNA suppression, and HBeAg seroclearance and seroconversion), with certainty of evidence ranging from very low to high.

在基线时HBV DNA浓度≥20 000 IU/mL或ALT升高（即，≥1·0 × ULN）的成年患者中，核苷（酸）类似物治疗与肝细胞癌风险降低（在非随机研究中）以及在多个中间结果上的改善（即，肝纤维化、坏死性炎症、ALT正常化、HBV DNA抑制以及HBeAg血清清除和血清转换）相关，证据的确凿性范围从非常低到高。

In adults with baseline HBV DNA concentrations <20 000 IU/mL, nucleos(t)ide analogue therapy had no statistically significant effect on the risk of hepatocellular carcinoma, and no other outcomes were evaluated.

在基线HBV DNA浓度小于20 000 IU/mL的成人中，核苷(酸)类似物治疗对肝细胞癌的风险没有统计学上的显著影响，且未评估其他结果。

From non-randomised studies, the aHRs for the risk of hepatocellular carcinoma with nucleos(t)ide analogue therapy were 0·72 (95% CI 0·43-1·20) for HBV DNA <2000 IU/mL, 0·45 (0·14-1·47) for 2000-19 999 IU/mL, and 0·39 (0·29-0·54; I2=0·0%) for ≥20 000 IU/mL.

从非随机研究中得出，核苷(酸)类似物治疗对肝细胞癌风险的调整危险比(aHRs)分别为：HBV DNA小于2000 IU/mL时为0.72 (95% 置信区间 0.43-1.20)，2000-19 999 IU/mL时为0.45 (0.14-1.47)，以及大于等于20 000 IU/mL时为0.39 (0.29-0.54; I2=0.0%)。

For adults with normal baseline ALT, nucleos(t)ide analogue therapy showed some efficacy for HBV DNA suppression (RR 31·50, 95% CI 2·02-492·36), but no efficacy for the remaining outcomes.

对于基线ALT正常的成人，核苷（酸）类似物治疗对HBV DNA抑制有一定效果（RR 31·50, 95% CI 2·02-492·36），但对其他结果无效果。

Overall, higher certainty of evidence was seen with higher baseline HBV DNA or ALT concentrations.

总体而言，基线HBV DNA或ALT浓度越高，证据的确定性越高。

The between-study heterogeneity for pooled estimates varied across outcomes (I2 range 0·0-82·7%) but was low for most analyses (median I2=0·0%, IQR 0·0-25·5).

汇总估计值之间的研究异质性因结果而异（I2范围0·0-82·7%），但大多数分析的异质性较低（中位数I2=0·0%，四分位数间距0·0-25·5）。

Of the 16 RCTs, six were rated to have a low risk of bias, four were rated intermediate, and six as high.

在16项随机对照试验中，有六项被评为低偏倚风险，四项被评为中等偏倚风险，六项被评为高偏倚风险。

Of the eight non-randomised studies, four each were rated as fair and poor quality, respectively.

在八项非随机研究中，各有四项被评为中等和较差质量。

The estimated NNT for nucleos(t)ide analogue therapy to prevent one case of hepatocellular carcinoma was 149 for baseline HBV DNA <2000 IU/mL over a median treatment duration of 12·0 years (IQR 4·1-26·2), 45 for HBV DNA 2000-19 999 IU/mL over 10·6 years (3·7-24·0), and 15 for HBV DNA ≥20 000 IU/mL over 13·6 years (6·7-22·1).

核苷（酸）类似物治疗预防一例肝细胞癌的估计NNT（需治疗人数）为：基线HBV DNA <2000 IU/mL时，中位治疗时间为12.0年（四分位数间距4.1-26.2年），NNT为149；HBV DNA 2000-19999 IU/mL时，中位治疗时间为10.6年（四分位数间距3.7-24.0年），NNT为45；HBV DNA ≥20000 IU/mL时，中位治疗时间为13.6年（四分位数间距6.7-22.1年），NNT为15。

interpretation

Evidence supports the efficacy of nucleos(t)ide analogue therapy in adults with HBV DNA ≥20 000 IU/mL or elevated ALT.

证据支持核苷(酸)类似物治疗在HBV DNA ≥20 000 IU/mL或ALT升高成年患者中的疗效。

However, the efficacy of nucleos(t)ide analogues remains uncertain in adults with HBV DNA <20 000 IU/mL or normal ALT.

然而，在HBV DNA <20 000 IU/mL或ALT正常的成年患者中，核苷(酸)类似物的疗效仍然不确定。

Future research should prioritise establishing treatment benefits in these groups, especially in high-burden settings in sub-Saharan Africa.

未来的研究应优先确定这些群体的治疗益处，特别是在撒哈拉以南非洲的高负担环境中。

funding

WHO.

世界卫生组织。