Clin Gastroenterol Hepatol. 2019 Jul 12. pii: S1542-3565(19)30743-8. doi: 10.1016/j.cgh.2019.07.010. [Epub ahead of print]
Outcomes of Long-term Treatment of Chronic HBV Infection With Entecavir or Other Agents From a Randomized Trial in 24 Countries.
Hou JL1, Zhao W2, Lee C3, Hann HW4, Peng CY5, Tanwandee T6, Morozov V7, Klinker H8, Sollano JD9, Streinu-Cercel A10, Cheinquer H11, Xie Q12, Wang YM13, Wei L14, Jia JD15, Gong G16, Han KH17, Cao W18, Cheng M19, Tang X20, Tan D21, Ren H22, Duan Z23, Tang H24, Gao Z25, Chen S26, Lin S27, Sheng J28, Chen C29, Shang J30, Han T31, Ji Y32, Niu J33, Sun J34, Chen Y34, Cooney EL35, Lim SG36.
Author information
1
Department of Infectious Diseases, Institute of Hepatology, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: [email protected].
2
2nd Hospital Nanjing, Nanjing, China.
3
Daegu Catholic University Hospital, Daegu, Korea.
4
Thomas Jefferson University Hospital, Philadelphia, PA, USA.
5
China Medical University Hospital, Taichung, Taiwan.
6
Faculty of Medicine Siriraj Hospital, Bangkok, Thailand.
7
LLC Medical Company "Hepatolog", Samara, Russian Federation.
8
University of Würzburg Medical Center, Würzberg, Germany.
9
Cardinal Santos Medical Center, Manila, Philippines.
10
Carol Davila University of Medicine and Pharmacy, National Institute for Infectious Diseases "Prof. Dr. Matei Bals", Bucharest, Romania.
11
Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.
12
Shanghai Rui Jin Hospital, Shanghai, China.
13
Southwest Hospital, Chongqing, China.
14
Peking University People's Hospital, Beijing, China.
15
Beijing Friendship Hospital, Capitol Medical University, Beijing, China.
16
The Second Xiangya Hospital of Central South University, Changsha, China.
17
Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
18
Tianjin Second People's Hospital, Tianjin, China.
19
Affiliated Hospital of Guiyang Medical College, Guiyang, China.
20
Guangzhou No.8 People's Hospital, Guangzhou, China.
21
Xiangya Hospital, Central South University, Changsha, China.
22
The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
23
Beijing YouAn Hospital, Capital Medical University, Beijing, China.
24
West China Hospital, Sichuan University, Chengdu, China.
25
The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
26
Jinan Infectious Disease Hospital, Jinan, China.
27
The First Affiliated Hospital of Xi'An Jiaotong University, Xi'An, China.
28
The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
29
85th Hospital of People's Liberation Army, Shanghai, China.
30
Henan Provincial People's hospital, Zhengzhou, China.
31
Tianjin Third Central Hospital, Tianjin, China.
32
Shanghai Jing'an District Central Hospital, Shanghai, China.
33
The First Hospital of Jilin University, Changchun, China.
34
Department of Infectious Diseases, Institute of Hepatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
35
Bristol-Myers Squibb Inc., Wallingford, CT, USA.
36
National University Health System, National University of Singapore, Singapore.
Abstract
BACKGROUND & AIMS:
Treatment of chronic hepatitis B virus (HBV) infection with entecavir suppresses virus replication and reduces disease progression, but could require life-long therapy. To investigate clinical outcome events and safety associated with long-term treatment with entecavir, we followed patients treated with entecavir or another standard of care HBV nucleos(t)ide analogue for up to 10 years. We assessed long-term outcomes and relationships with virologic response.
METHODS:
Patients with chronic HBV infection at 299 centers in Asia, Europe, and North and South America were randomly assigned to groups that received entecavir (n=6216) or an investigator-selected non-entecavir HBV nucleos(t)ide analogue (n=6162). Study participants were followed for up to 10 years in hospital-based or community clinics. Key endpoints were time to adjudicated clinical outcome events and serious adverse events. In a sub-study, we examined relationships between these events and virologic response.
RESULTS:
There were no significant differences between groups in time to event assessments for primary endpoints including malignant neoplasms, liver-related HBV disease progression, and death. There were no differences between groups in the secondary endpoints of non-hepatocellular carcinoma, malignant neoplasms, or hepatocellular carcinoma. In a sub-study of 5305 patients in China, virologic response, regardless of treatment group, was associated with a reduced risk of liver-related HBV disease progression (hazard ratio, 0.09; 95% CI, 0.038-0.221) and hepatocellular carcinoma (hazard ratio, 0.03; 95% CI, 0.009-0.113). Twelve patients given entecavir (0.2%) and 50 patients given non-entecavir drugs (0.8%) reported treatment-related serious adverse events.
CONCLUSIONS:
In a randomized controlled trial of patients with chronic HBV infection, we associated entecavir therapy with a low rate of adverse events over 10 years of follow up. Patients receiving entecavir vs another nucleos(t)ide analogue had comparable rates of liver- and non-liver-related clinical outcome events. Participants in a China cohort who maintained a virologic response, regardless of treatment group, had a reduced risk of HBV-related outcome events including hepatocellular carcinoma. ClinicalTrials.gov identifier no: NCT00388674.
