Background

Expanding antiviral therapy to people with chronic hepatitis B virus (HBV) infection who are ineligible to receive treatment under current international criteria has been increasingly debated. Evidence to support this approach is scarce, especially in Africa. We aimed to address this knowledge gap by analysing the clinical outcomes of people with chronic hepatitis B in The Gambia who were untreated and ineligible for antiviral therapy at diagnosis.

Methods

Between Dec 7, 2011, and Jan 24, 2014, we implemented the prospective PROLIFICA cohort study in The Gambia. Participants with chronic hepatitis B aged 16 years or older were recruited after large-scale, community-based HBV screening; blood bank-based HBV screening in Edward Francis Small Teaching Hospital, Banjul; and prospective follow-up of HBsAg-positive individuals via historical, population-based HBsAg serosurveys in two rural villages (Keneba and Manduar). Participants underwent HBV serology and other laboratory tests, fasting FibroScan, and abdominal ultrasound. Survival data were collected between Dec 7, 2011, and Aug 17, 2021. Between Oct 9, 2018, and Aug 17, 2021, all HBsAg-positive participants enrolled in the 2011–14 cohort were invited for a reassessment. For this analysis, we included HBsAg-positive people and excluded all participants who were eligible for treatment according to the 2012 European Association for the Study of the Liver (EASL) criteria at baseline and those who were treated irrespective of treatment eligibility. The primary outcome was all-cause mortality, assessed in all treatment-ineligible and treatment-naive participants with follow-up data. The secondary outcome, analysed in those who were reassessed, was disease progression, defined as becoming eligible for antivirals per 2017 EASL criteria; having an increase in liver fibrosis of at least one stage; or having a clinical diagnosis of hepatic decompensation or hepatocellular carcinoma.

Findings

943 HBsAg-positive people with chronic hepatitis B were recruited to the PROLIFICA study. Of these 943, 58 (6%) fulfilled 2012 EASL treatment eligibility criteria at baseline, 35 (4%) were ineligible for treatment but received antiviral therapy, and 44 (5%) were immediately lost to follow-up. Thus, 806 (85%) participants were analysed for the primary outcome (486 [60%] were male and 320 [40%] were female). After a median follow-up of 6·11 years (IQR 5·34–6·80), 708 (88%) participants were confirmed to be alive at last surveillance, 71 (9%) were lost to follow-up and were censored, and 27 (3%) died, giving an all-cause mortality rate of 582 per 100 000 person-years (95% CI 399–849). Of the 27 people who died, five (19%) had liver-related deaths. Of 708 participants confirmed to be alive, 544 (77%) attended follow-up and were assessed for the secondary outcome. Disease progression occurred in 36 (7%) participants: five (1%) became newly eligible for antiviral therapy per EASL 2017 criteria without liver fibrosis progression; 18 (3%) had liver fibrosis progression alone; 13 (2%) had liver fibrosis progression and newly fulfilled the treatment criteria; and none had hepatic decompensation or developed hepatocellular carcinoma. In multivariable analysis adjusted for sex and age, only a baseline HBV DNA of 20 000 IU/mL or more, compared with the baseline HBV DNA of 2000 IU/mL or lower as the reference, was significantly associated with liver disease progression (odds ratio 5·39, 95% CI 1·37–21·23).

Interpretation

Among people with chronic hepatitis B who were ineligible for antiviral therapy in The Gambia, all-cause mortality and liver disease progression were low. The clinical benefit of expanding antiviral therapy in this subgroup of patients remains uncertain.

Funding

European Commission, Medical Research Council UK Research and Innovation, and Gilead Sciences.

中文翻译：

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冈比亚未经治疗的慢性乙型肝炎成人患者的临床结果：前瞻性 PROLIFICA 队列研究数据分析

 背景

将抗病毒治疗范围扩大到根据当前国际标准没有资格接受治疗的慢性乙型肝炎病毒 （HBV） 感染者，已经引起了越来越多的争论。支持这种方法的证据很少，尤其是在非洲。我们旨在通过分析冈比亚慢性乙型肝炎患者的临床结局来解决这一知识差距，这些患者在诊断时未经治疗且不适合抗病毒治疗。

 方法

在 2011 年 12 月 7 日至 2014 年 1 月 24 日期间，我们在冈比亚实施了前瞻性 PROLIFICA 队列研究。16 岁或以上的慢性乙型肝炎参与者是在大规模、基于社区的 HBV 筛查后招募的;在班珠尔 Edward Francis Small Teaching Hospital 进行基于血库的 HBV 筛查;以及通过在两个农村 （Keneba 和 Manduar） 进行基于人群的历史 HBsAg 血清调查对 HBsAg 阳性个体进行前瞻性随访。参与者接受了 HBV 血清学和其他实验室检查、空腹 FibroScan 和腹部超声检查。生存数据是在 2011 年 12 月 7 日至 2021 年 8 月 17 日之间收集的。在 2018 年 10 月 9 日至 2021 年 8 月 17 日期间，所有参加 2011-14 队列的 HBsAg 阳性参与者都被邀请进行重新评估。在本分析中，我们纳入了 HBsAg 阳性人群，并排除了所有在基线时根据 2012 年欧洲肝脏研究协会 （EASL） 标准有资格接受治疗的参与者，以及无论治疗资格如何而接受治疗的参与者。主要结局是全因死亡率，在所有不符合治疗条件和未接受过治疗的参与者中进行评估，并提供随访数据。在接受重新评估的患者中分析的次要结局是疾病进展，定义为根据 2017 年 EASL 标准符合抗病毒药物的条件;肝纤维化增加至少一个阶段;或临床诊断为肝功能失代偿或肝细胞癌。

 发现

943 名 HBsAg 阳性慢性乙型肝炎患者被招募到 PROLIFICA 研究中。在这 943 例中，58 例 （6%） 在基线时符合 2012 年 EASL 治疗资格标准，35 例 （4%） 不符合治疗条件但接受了抗病毒治疗，44 例 （5%） 立即失访。因此，对 806 名 （85%） 参与者进行了主要结局分析（486 名 [60%] 为男性，320 名 [40%] 为女性）。中位随访 6·11 年 （IQR 5·34–6·80） 后，708 名 （88%） 参与者被确认在最后一次监测中存活，71 名 （9%） 失访并被删失，27 名 （3%） 死亡，全因死亡率为 582/100 000 人年 （95% CI 399-849）。在 27 名死亡者中，有 5 人 （19%） 与肝脏有关的死亡。在确认存活的 708 名参与者中，544 名 （77%） 参加了随访并接受了次要结局评估。36 名 （7%） 参与者出现疾病进展：5 名 （1%） 根据 EASL 2017 标准新符合抗病毒治疗条件，没有肝纤维化进展;18 例 （3%） 仅出现肝纤维化进展;13 例 （2%） 出现肝纤维化进展，新近达到治疗标准;没有人出现肝功能失代偿或发展为肝细胞癌。在根据性别和年龄调整的多变量分析中，只有基线 HBV DNA 为 20 000 IU/mL 或更高，与基线 HBV DNA 为 2000 IU/mL 或更低相比，与肝病进展显著相关（比值比 5·39,95% CI 1·37-21·23）。

 解释

在冈比亚不适合抗病毒治疗的慢性乙型肝炎患者中，全因死亡率和肝病进展率较低。在该亚组患者中扩大抗病毒治疗的临床益处仍不确定。

 资金

欧盟委员会、英国医学研究委员会研究与创新委员会和吉利德科学公司。