Clin Mol Hepatol > Volume 30(3); 2024 > Article
Clinical and Molecular Hepatology 2024;30(3): 500-514.
Extrahepatic malignancies and antiviral drugs for chronic hepatitis B: A nationwide cohort study
Moon Haeng Hur1, Dong Hyeon Lee1,2, Jeong-Hoon Lee1,3 , Mi-Sook Kim4, Jeayeon Park1, Hyunjae Shin1, Sung Won Chung1, Hee Jin Cho1, Min Kyung Park1, Heejoon Jang2, Yun Bin Lee1, Su Jong Yu1, Sang Hyub Lee1, Yong Jin Jung2, Yoon Jun Kim1, Jung-Hwan Yoon1
1Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
2Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
3Genome Insight Inc., San Diego, CA, USA
4Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Korea
Correspondence :  Jeong-Hoon Lee ,
Tel: +82-2-2072-2228, Fax: +82-2-743-6701, Email:
Received: January 20, 2024  Revised: April 12, 2024   Accepted: May 9, 2024
*Moon Haeng Hur and Dong Hyeon Lee contributed equally to this work.
Chronic hepatitis B (CHB) is related to an increased risk of extrahepatic malignancy (EHM), and antiviral treatment is associated with an incidence of EHM comparable to controls. We compared the risks of EHM and intrahepatic malignancy (IHM) between entecavir (ETV) and tenofovir disoproxil fumarate (TDF) treatment.
Using data from the National Health Insurance Service of Korea, this nationwide cohort study included treatment-naïve CHB patients who initiated ETV (n=24,287) or TDF (n=29,199) therapy between 2012 and 2014. The primary outcome was the development of any primary EHM. Secondary outcomes included overall IHM development. E-value was calculated to assess the robustness of results to unmeasured confounders.
The median follow-up duration was 5.9 years, and all baseline characteristics were well balanced after propensity score matching. EHM incidence rate differed significantly between within versus beyond 3 years in both groups (P<0.01, Davies test). During the first 3 years, EHM risk was comparable in the propensity score-matched cohort (5.88 versus 5.84/1,000 person-years; subdistribution hazard ratio [SHR]=1.01, 95% confidence interval [CI]=0.88–1.17, P=0.84). After year 3, however, TDF was associated with a significantly lower EHM incidence compared to ETV (4.92 versus 6.91/1,000 person-years; SHR=0.70, 95% CI=0.60–0.81, P<0.01; E-value for SHR=2.21). Regarding IHM, the superiority of TDF over ETV was maintained both within (17.58 versus 20.19/1,000 person-years; SHR=0.88, 95% CI=0.81–0.95, P<0.01) and after year 3 (11.45 versus 16.20/1,000 person-years; SHR=0.68, 95% CI=0.62–0.75, P<0.01; E-value for SHR=2.30).
TDF was associated with approximately 30% lower risks of both EHM and IHM than ETV in CHB patients after 3 years of antiviral therapy.
KeyWords: Non-liver cancer; Hepatitis B virus; Antiviral treatment; Tenofovir; Entecavir

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