한빛사 논문
Won-Mook Choi1,†, Terry Cheuk-Fung Yip2,†, Grace Lai-Hung Wong2,*,†, W. Ray Kim3, Leland J. Yee4, Craig Brooks-Rooney5, Tristan Curteis6, Harriet Cant6, Chien-Hung Chen7, Chi-Yi Chen8, Yi-Hsiang Huang9,10, Young-Joo Jin11, Dae Won Jun12, Jin-Wook Kim13,14, Neung Hwa Park15,16, Cheng-Yuan Peng17,18, Hyun Phil Shin19, Jung Woo Shin15, Yao-Hsu Yang20,21, Young-Suk Lim1,*
1Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;
2CUHK Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China;
3Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA;
4Gilead Sciences, Foster City, California, USA;
5Costello Medical Inc, Boston Massachusetts,USA;
6Costello Medical Consulting Ltd, Cambridge, UK;
7Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Taiwan;
8Division of Hepatogastroenterology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital Chia-Yi, Taiwan;
9Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan;
10Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan;
11Digestive Disease Center, Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Republic of Korea;
12Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Republic of Korea;
13Department of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea;
14Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea;
15Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, 877 Bangeojinsunhwando-ro, Dong-gu, Ulsan, 44033, Republic of Korea;
16Biomedical Research Center, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea;
17Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan;
18School of Medicine, China Medical University, Taichung, Taiwan;
19Department of Gastroenterology and Hepatology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Republic of Korea;
20Department of Traditional Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan;
21Health Information and Epidemiology Laboratory, Chang Gung Memorial Hospital, Chiayi, Taiwan.
* Corresponding authors: G.L.-H. Wong, Y.-S. Lim
† Joint first authors
Abstract
Background & aims: The comparative risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving tenofovir disoproxil fumarate (TDF) vs. entecavir (ETV) remains controversial. In this individual patient data (IPD) meta-analysis, we aimed to compare HCC risk between the two drugs and identify subgroups who may benefit more from one treatment than the other.
Methods: Published meta-analyses, electronic databases and congress proceedings were searched to identify eligible studies through January 2021. We compared HCC risk between the two drugs using a multivariable Cox proportional hazards model with anonymised IPD from treatment-naïve patients with CHB receiving TDF or ETV for ≥1 year. Treatment effect consistency was explored in propensity score matching (PSM), weighting (PSW) and subgroup analyses for age, sex, hepatitis B e-antigen (HBeAg) positivity, cirrhosis and diabetes status.
Results: We included 11 studies from Korea, Taiwan and Hong Kong involving 42,939 patients receiving TDF (n = 6,979) or ETV (n = 35,960) monotherapy. Patients receiving TDF had significantly lower HCC risk (adjusted hazard ratio [HR] 0.77; 95% CI 0.61-0.98; p = 0.03). Lower HCC risk with TDF was consistently observed in PSM (HR 0.73; 95% CI 0.59-0.88; p <0.01) and PSW (HR 0.83; 95% CI 0.67-1.03; p = 0.10) analyses and in all subgroups, with statistical significance in the ≥50 years of age (HR 0.76; 95% CI 0.58-1.00; p <0.05), male (HR 0.74; 95% CI 0.58-0.96; p = 0.02), HBeAg-positive (HR 0.69; 95% CI 0.49-0.97; p = 0.03) and non-diabetic (HR 0.79; 95% CI 0.63-1.00; p <0.05) subgroups.
Conclusion: TDF was associated with significantly lower HCC risk than ETV in patients with CHB, particularly those with HBeAg positivity. Longer follow-up may be needed to better define incidence differences between the treatments in various subgroups.
Impact and implications: Previous aggregate data meta-analyses have reported inconsistent conclusions on the relative effectiveness of tenofovir disoproxil fumarate and entecavir in reducing hepatocellular carcinoma risk in patients with chronic hepatitis B (CHB). This individual patient data meta-analysis on 11 studies involving 42,939 patients from Korea, Taiwan and Hong Kong suggested that tenofovir disoproxil fumarate-treated patients have a significantly lower hepatocellular carcinoma risk than entecavir-treated patients, which was observed in all subgroups of clinical interest and by different analytical methodologies. These findings should be taken into account by healthcare providers when determining the optimal course of treatment for patients with CHB and may be considered in ensuring that treatment guidelines for CHB remain pertinent.
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