每天一次的替诺福韦酯富马酸富马酸酯在未接受治疗的台湾

StephenW

Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial

    Yao-Chun Hsu, MD
    Chi-Yi Chen, MD
    I-Wei Chang, MD
    Prof Chi-Yang Chang, MD
    Prof Chun-Ying Wu, MD
    Teng-Yu Lee, MD
    et al.
    Show all authors

Published:January 29, 2021DOI:https://doi.org/10.1016/S1473-3099(20)30692-7

Summary
Background
Antiviral therapy for patients with non-cirrhotic chronic hepatitis B and minimally raised alanine aminotransferase (ALT) is controversial. We aimed to investigate the efficacy and safety of tenofovir disoproxil fumarate in reducing the risk of disease progression in this patient population.
Methods
TORCH-B is a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial done at six teaching hospitals in Taiwan that enrolled patients with chronic hepatitis B. Eligible patients were aged 25–70 years and had substantial viraemia (viral DNA >2000 IU/mL) and minimally raised serum ALT concentrations more than one-fold but less than two-fold the upper limit of normal (ULN). Exclusion criteria included liver cirrhosis and previous antiviral treatment. Eligible participants were randomly assigned (1:1), stratified by site with a fixed block size of ten, to receive either 300 mg of oral tenofovir disoproxil fumarate or placebo once daily for 3 years. The participants, investigators, research coordinators, pathologists, laboratory personnel, and staff involved in patient care or assessment were masked to treatment assignment. 0·5 mg/day of oral entecavir was added to rescue acute hepatitis flare. The coprimary outcomes were change in necroinflammation severity on the Knodell scale and change in fibrosis stage on the Ishak scale and were evaluated in the modified intention-to-treat population, which comprised all patients with paired liver biopsies. Safety was evaluated in all patients who were randomly assigned. This trial is registered at ClinicalTrials.gov, NCT01522625, and is completed.
Findings
From Jan 30, 2012, to Nov 10, 2015, 875 patients were screened and 160 were randomly assigned to receive either tenofovir disoproxil fumarate (n=79) or placebo (n=81). The coprimary outcomes were assessed in 146 patients (73 in each group). Liver fibrosis progressed (an increase of ≥1 stage) in 19 (26%, 95% CI 17–38) of 73 patients in the tenofovir disoproxil fumarate group and in 34 (47%, 35–59) of 73 patients in the placebo group (relative risk [RR] 0·56, 95% CI 0·35–0·88; p=0·013), whereas necroinflammation progressed (an increase of ≥2 points) in five (7%, 95% CI 2–15) patients in the tenofovir disoproxil fumarate group and in 12 (16%, 9–27) patients in the placebo group (RR 0·42, 95% CI 0·15–1·12; p=0·084). Two (3%) of 79 patients in the tenofovir disoproxil fumarate group and 13 (16%) of 81 patients in the placebo group had acute hepatitis flare requiring add-on entecavir (RR 0·16, 95% CI 0·04–0·68; p=0·013). The two groups were otherwise similar in occurrences of adverse events. No patients died.
Interpretation
Tenofovir disoproxil fumarate reduces the risk of progression in liver fibrosis in patients with chronic hepatitis B and minimally raised ALT, but its effect on necroinflammation is non-significant.

StephenW

每天一次的替诺福韦酯富马酸富马酸酯在未接受治疗的台湾慢性乙型肝炎和丙氨酸转氨酶（TORCH-B）最低升高的患者中：一项多中心，双盲，安慰剂对照，平行组，随机试验

    徐耀春医师
    陈志义医学博士
    张爱伟医学博士
    张志扬教授
    吴春英教授
    李登宇医学博士
    等。
    显示所有作者

发布时间：2021年1月29日DOI：https：//doi.org/10.1016/S1473-3099（20）30692-7

概要
背景
对于非肝硬化慢性乙型肝炎和丙氨酸转氨酶（ALT）升高很少的患者，抗病毒治疗存在争议。我们旨在研究替诺福韦富马酸替诺福韦酯在降低该患者人群疾病进展风险中的功效和安全性。
方法
TORCH-B是一项多中心，双盲，安慰剂对照，平行组，随机试验，在台湾的六家教学医院进行，招募了慢性乙型肝炎患者。符合条件的患者年龄在25-70岁之间，并患有严重的病毒血症（病毒性DNA> 2000 IU / mL），且血清ALT浓度最低升高至正常上限（ULN）的1倍以上至2倍以下。排除标准包括肝硬化和以前的抗病毒治疗。符合条件的参与者被随机分配（1：1），按固定区块大小为10的位置分层，每天接受300 mg口服替诺福韦酯富马酸替诺福韦或安慰剂，为期3年。参加者，研究者，研究协调员，病理学家，实验室人员以及参与患者护理或评估的人员被掩盖在治疗分配中。每天口服0·5 mg恩替卡韦，以挽救急性肝炎发作。共同的主要结果是在Knodell量表上的坏死性炎症严重程度改变和在Ishak量表上的纤维化阶段改变，并在改良的意向性治疗人群中进行评估，该人群包括所有配对的肝活检患者。在所有随机分配的患者中评估安全性。该试验已在ClinicalTrials.gov上注册，编号为NCT01522625，现已完成。
发现
从2012年1月30日到2015年11月10日，对875例患者进行了筛查，随机分配了160例患者接受替诺福韦富马酸替诺福韦酯（n = 79）或安慰剂（n = 81）。共评估了146例患者的主要疗效（每组73例）。替诺福韦酯富马酸酯组73例患者中有19例（26％，95％CI 17-38）肝纤维化进展（≥1期增加）安慰剂组73例中34例（47％，35-59）肝纤维化进展组（相对危险度[RR] 0·56，95％CI 0·35-0·88； p = 0·013），而坏死炎症进展（增加≥2分）的比例为5（7％，95％CI 2）替诺福韦富马酸替诺福韦酯组有15例患者，安慰剂组有12例（16％，9–27）（RR 0·42，95％CI 0·15-1·12； p = 0·084）。替诺福韦酯富马酸替诺福韦酯组79例患者中有2（3％）安慰剂组81例患者中13例（16％）有需要加用恩替卡韦的急性肝炎发作（RR 0·16，95％CI 0·04-0 ·68； p = 0·013）。否则两组的不良事件发生率相似。没有患者死亡。
解释
替诺福韦酯富马酸替诺福韦降低了慢性乙型肝炎和ALT最低程度升高的肝纤维化进展的风险，但对坏死性炎症的影响不显着。