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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 - 27/05/21

Doi : 10.1016/S1473-3099(20)30692-7 
Yao-Chun Hsu, MD a, b, c, d, h, Chi-Yi Chen, MD e, I-Wei Chang, MD f, g, Chi-Yang Chang, ProfMD h, Chun-Ying Wu, ProfMD i, j, Teng-Yu Lee, MD k, l, Ming-Shiang Wu, ProfMD m, Ming-Jong Bair, MD n, o, Jyh-Jou Chen, MD p, Chieh-Chang Chen, MD m, Cheng-Hao Tseng, MD q, Chi-Ming Tai, MD c, Yen-Tsung Huang, ScD r, Wen-Hui Ku, MD s, Lein-Ray Mo, MD t, Jaw-Town Lin, ProfMD u, ⁎
a Centre for Liver Diseases, E-Da Hospital, Kaohsiung, Taiwan 
b School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan 
c Department of Internal Medicine, Division of Gastroenterology and Hepatology, E-Da Hospital and I-Shou University, Kaohsiung, Taiwan 
d Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan 
e Division of Gastroenterology and Hepatology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan 
f Department of Laboratory Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 
g Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 
h Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei City, Taiwan 
i Department of Medical Research, Division of Translational Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 
j Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan 
k Department of Internal Medicine, Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan 
l Department of Medicine, Chung Shan Medical University, Taichung, Taiwan 
m Department of Internal Medicine, NationalTaiwan University Hospital, Taipei, Taiwan 
n Department of Internal Medicine, Division of Gastroenterology, Taitung Mackay Memorial Hospital, Taitung, Taiwan 
o Department of Internal Medicine, Mackay Medical College, New Taipei City, Taiwan 
p Department of Internal Medicine, Chi-Mei Medical Centre, Liouying Hospital, Tainan, Taiwan 
q Division of Gastroenterology and Hepatology, E-Da Cancer Hospital and I-Shou University, Kaohsiung, Taiwan 
r Institute of Statistical Science, Academia Sinica, Taipei, Taiwan 
s Taipei Institute of Pathology, Taipei, Taiwan 
t Department of Internal Medicine, Tainan Municipal Hospital, Tainan, Taiwan 
u Digestive Medicine Centre, China Medical University Hospital, Taichung, Taiwan 

* Correspondence to: Prof Jaw-Town Lin, Digestive Medicine Centre, China Medical University Hospital, Taichung 40447, Taiwan Digestive Medicine Centre China Medical University Hospital Taichung 40447 Taiwan

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.

Funding

The Taiwan Ministry of Science and Technology, E-Da Hospital, the Taipei Institute of Pathology, Gilead Sciences.

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Vol 21 - N° 6

P. 823-833 - juin 2021 Retour au numéro
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