Cheng-Hao Tseng1, Yao-Chun Hsu2, Tzu-Haw Chen1, Fanpu Ji3, I-Sung Chen1, Ying-Nan Tsai1, Hoang Hai4, Le Thi Thanh Thuy4, Tetsuya Hosaka5, Hitomi Sezaki5, John A Borghi6, Ramsey Cheung7, Masaru Enomoto4, Mindie H Nguyen8. 1. Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan. 2. Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Division of Gastroenterology, Fu Jen Catholic University Hospital, New Taipei, Taiwan. 3. Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; National Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. 4. Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan. 5. Department of Hepatology, Toranomon Hospital, Tokyo, Japan. 6. Lane Medical Library and Knowledge Management Center, Stanford University, Palo Alto, CA, USA. 7. Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA. 8. Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA. Electronic address: mindiehn@stanford.edu.
Abstract
BACKGROUND: It is unclear whether tenofovir disoproxil fumarate and entecavir differ in their association with risk of hepatocellular carcinoma in patients with chronic hepatitis B, and previous meta-analyses have shown conflicting conclusions with substantial heterogeneity. We aimed to analyse the updated data and elucidate the source of heterogeneity. METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane library for relevant studies with time-to-event data for incident hepatocellular carcinoma occurring in patients with chronic hepatitis B who received tenofovir disoproxil fumarate or entecavir monotherapy with follow-up of at least 1 year. Studies published between Jan 1, 2006, and April 17, 2020, and abstracts from international conferences in 2018 and 2019 were included. We pooled covariate adjusted hazard ratios (HRs) for hepatocellular carcinoma using a random-effects model, assessed heterogeneity among included studies using the I2 statistic and Cochran's Q test, and identified the source of heterogeneity using prespecified subgroup analyses. This study is registered with PROSPERO, ID CRD42020176513. FINDINGS: 31 studies involving 119 053 patients were analysed. The 5-year cumulative incidence of hepatocellular carcinoma was 5·97% (95% CI 5·81-6·13, 28 studies) for entecavir and 3·06% (2·86-3·26, 13 studies) for tenofovir disoproxil fumarate in studies with unmatched populations (p<0·0001). For all eight studies matched by propensity score, the 5-year cumulative incidence was 3·44% (95% CI 3·08-3·80) for entecavir and 3·39% (2·94-3·83) for tenofovir disoproxil fumarate (p=0·87). Analysis of 14 comparative studies with covariate adjustment found that tenofovir disoproxil fumarate and entecavir had similar risk of hepatocellular carcinoma (primary outcome); adjusted HR 0·88, 95% CI 0·73-1·07; p=0·20), although heterogeneity was significant (I2=56·4%, p=0·0038). In a subgroup analysis for hospital-based clinical cohorts, there was no difference in hepatocellular carcinoma incidence between the two regimens (adjusted HR 1·03, 95% CI 0·88-1·21; I2=0%). However, tenofovir disoproxil fumarate was associated with a lower risk of hepatocellular carcinoma compared with entecavir in administrative database research (adjusted HR 0·67, 0·59-0·76; I2=0%). INTERPRETATION: Our study found no significant difference between tenofovir disoproxil fumarate and entecavir in their association with incident hepatocellular carcinoma. We suggest that treatment should be guided by patient tolerability and affordability rather than whether one drug is more effective than the other. FUNDING: Supported in part by E-DA Hospital (EDAHP 106008; EDAHP 103046).
BACKGROUND: It is unclear whether tenofovir disoproxil fumarate and entecavir differ in their association with risk of hepatocellular carcinoma in patients with chronic hepatitis B, and previous meta-analyses have shown conflicting conclusions with substantial heterogeneity. We aimed to analyse the updated data and elucidate the source of heterogeneity. METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane library for relevant studies with time-to-event data for incident hepatocellular carcinoma occurring in patients with chronic hepatitis B who received tenofovir disoproxil fumarate or entecavir monotherapy with follow-up of at least 1 year. Studies published between Jan 1, 2006, and April 17, 2020, and abstracts from international conferences in 2018 and 2019 were included. We pooled covariate adjusted hazard ratios (HRs) for hepatocellular carcinoma using a random-effects model, assessed heterogeneity among included studies using the I2 statistic and Cochran's Q test, and identified the source of heterogeneity using prespecified subgroup analyses. This study is registered with PROSPERO, ID CRD42020176513. FINDINGS: 31 studies involving 119 053 patients were analysed. The 5-year cumulative incidence of hepatocellular carcinoma was 5·97% (95% CI 5·81-6·13, 28 studies) for entecavir and 3·06% (2·86-3·26, 13 studies) for tenofovir disoproxil fumarate in studies with unmatched populations (p<0·0001). For all eight studies matched by propensity score, the 5-year cumulative incidence was 3·44% (95% CI 3·08-3·80) for entecavir and 3·39% (2·94-3·83) for tenofovir disoproxil fumarate (p=0·87). Analysis of 14 comparative studies with covariate adjustment found that tenofovir disoproxil fumarate and entecavir had similar risk of hepatocellular carcinoma (primary outcome); adjusted HR 0·88, 95% CI 0·73-1·07; p=0·20), although heterogeneity was significant (I2=56·4%, p=0·0038). In a subgroup analysis for hospital-based clinical cohorts, there was no difference in hepatocellular carcinoma incidence between the two regimens (adjusted HR 1·03, 95% CI 0·88-1·21; I2=0%). However, tenofovir disoproxil fumarate was associated with a lower risk of hepatocellular carcinoma compared with entecavir in administrative database research (adjusted HR 0·67, 0·59-0·76; I2=0%). INTERPRETATION: Our study found no significant difference between tenofovir disoproxil fumarate and entecavir in their association with incident hepatocellular carcinoma. We suggest that treatment should be guided by patient tolerability and affordability rather than whether one drug is more effective than the other. FUNDING: Supported in part by E-DA Hospital (EDAHP 106008; EDAHP 103046).
Authors: Darren Jun Hao Tan; Cheng Han Ng; Phoebe Wen Lin Tay; Nicholas Syn; Mark D Muthiah; Wen Hui Lim; Ansel Shao Pin Tang; Kai En Lim; Grace En Hui Lim; Nobuharu Tamaki; Beom Kyung Kim; Margaret Li Peng Teng; James Fung; Rohit Loomba; Mindie H Nguyen; Daniel Q Huang Journal: JAMA Netw Open Date: 2022-06-01
Authors: Takashi Motomura; Sriram Amirneni; Ricardo Diaz-Aragon; Lanuza A P Faccioli; Michelle R Malizio; Michael C Coard; Zehra N Kocas-Kilicarslan; Carla Frau; Nils Haep; Alina Ostrowska; Rodrigo M Florentino; Alejandro Soto-Gutierrez Journal: J Pers Med Date: 2021-06-30