Won-Mook Choi^1,†, Terry Cheuk-Fung Yip^2,†, Grace Lai-Hung Wong^2,*,†, W. Ray Kim³, Leland J. Yee⁴, Craig Brooks-Rooney⁵, Tristan Curteis⁶, Harriet Cant⁶, Chien-Hung Chen⁷, Chi-Yi Chen⁸, Yi-Hsiang Huang^9,10, Young-Joo Jin¹¹, Dae Won Jun¹², Jin-Wook Kim^13,14, Neung Hwa Park^15,16, Cheng-Yuan Peng^17,18, Hyun Phil Shin¹⁹, Jung Woo Shin¹⁵, Yao-Hsu Yang^20,21, Young-Suk Lim^1,*

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

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.