PRELIMINARY COMMUNICATION ONLINE FIRST Association Between Nucleoside Analogues and Risk of Hepatitis B Virus–Related Hepatocellular Carcinoma Recurrence Following Liver Resection Chun-Ying Wu, MD, PhD, MPH Yi-Ju Chen, MD, PhD Hsiu J. Ho, PhD Yao-Chun Hsu, MD, MS Ken N. Kuo, MD Ming-Shiang Wu, MD, PhD Jaw-Town Lin, MD, PhD S URGERY IS CONSIDERED THE STAN- dard curative treatment option for hepatocellular carcinoma (HCC). However, the rate of long-term disease-free survival after liver resection remains unsatisfactory due to persistent high incidences of HCC recurrence. 1 Many factors affect HCC recurrence risk after liver resec- tion, including tumor size and stage, se- rum -fetoprotein level, cirrhosis, hepa- titis B e antigen (HBeAg) status, and hepatitis B virus (HBV) viral load. 2-4 Among these factors, HBV viral load is the most clinically controllable. Higher HBV viral load has been re- ported to be an independent risk fac- tor for HCC recurrence in patients with HBV-related HCC. 5,6 Nucleoside ana- logues are effective in suppressing HBV replication and in ameliorating HBV- related liver disease. 7,8 They have been shown to be associated with a lower risk of HCC and other cirrhosis-related complications in those with chronic hepatitis 9,10 and cirrhosis. 11 However, studies on the effectiveness of nucleo- Author Affiliations: School of Medicine, National Yang- Ming University, Taipei, Taiwan (Drs Chun-Ying Wu and Chen); Division of Gastroenterology (Dr Chun-Ying Wu) and Department of Dermatology (Dr Chen), Taichung Veterans General Hospital, Taichung, Taiwan; Depart- ment of Public Health and Graduate Institute of Clini- cal Medicine, China Medical University, Taichung (Drs Chun-Ying Wu and Hsu); Department of Life Sci- ences, National Chung-Hsing University, Taichung (Dr Chun-Ying Wu); Division of Gastroenterology, National Taiwan University Hospital, Taipei (Drs Ho, Ming-Shiang Wu, and Lin); Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsi- ung, Taiwan (Drs Hsu and Lin); College of Medicine, Taipei Medical College, Taipei (Dr Kuo); Institute of Popu- lation Health Sciences, National Health Research Insti- tutes, Miaoli, Taiwan (Drs Kuo and Lin); and School of Medicine, Fu Jen Catholic University, Taipei (Dr Lin). Corresponding Author: Chun-Ying Wu, MD, PhD, MPH, LLM, School of Medicine, National Yang- Ming University, No. 155, Section 2, Linong Street, Taipei 11221, Taiwan (chun@vghtc.gov.tw). Context Tumor recurrence is a major issue for patients with hepatocellular carci- noma (HCC) following curative liver resection. Objective To investigate the association between nucleoside analogue use and risk of tumor recurrence in patients with hepatitis B virus (HBV)-related HCC after cura- tive surgery. Design, Setting, and Participants A nationwide cohort study between October 2003 and September 2010. Data from the Taiwan National Health Insurance Re- search Database. Among 100 938 newly diagnosed HCC patients, we identified 4569 HBV-related HCC patients who received curative liver resection for HCC between Oc- tober 2003 and September 2010. Main Outcome Measures The risk of first tumor recurrence was compared be- tween patients not taking nucleoside analogues (untreated cohort, n = 4051) and pa- tients taking nucleoside analogues (treated cohort, n = 518). Cumulative incidences and hazard ratios (HRs) were calculated after adjusting for competing mortality. Results The treated cohort had a higher prevalence of liver cirrhosis when compared with the untreated cohort (48.6% vs 38.7%; P .001), but lower risk of HCC recur- rence (n = 106 [20.5%] vs n = 1765 [43.6%]; P .001), and lower overall death (n = 55 [10.6%] vs n=1145 [28.3%]; P .001). After adjusting for competing mortality, the treated cohort had a significantly lower 6-year HCC recurrence rate (45.6%; 95% CI, 36.5%-54.6% vs untreated, 54.6%; 95% CI, 52.5%-56.6%; P .001). Six-year over- all mortalities for treated cohorts were 29.0% (95% CI, 20.0%-38.0%) and for un- treated 42.4% (95% CI, 40.0%-44.7%; P .001). On modified Cox regression analy- sis, nucleoside analogue use (HR, 0.67; 95% CI, 0.55-0.81; P .001), statin use (HR, 0.68; 95% CI, 0.53-0.87; P = .002), and nonsteroidal anti-inflammatory drugs or aspirin use (HR, 0.80; 95% CI, 0.73-0.88; P .001) were independently associated with a re- duced risk of HCC recurrence. Multivariable stratified analyses verified the association in all subgroups of patients, including those who were noncirrhotic (HR, 0.56; 95% CI, 0.42-0.76) and diabetic (HR, 0.52; 95% CI, 0.31-0.89). Conclusion Nucleoside analogue use was associated with a lower risk of HCC re- currence among patients with HBV-related HCC after liver resection. JAMA. 2012;308(18):1906-1913 Published online November 12, 2012. doi:10.1001/2012.jama.11975 www.jama.com For editorial comment see p 1922. 1906 JAMA, November 14, 2012—Vol 308, No. 18 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 02/14/2022