Extrahepatic Malignancies and Antiviral Drugs for Chronic Hepatitis B: A Nationwide Cohort Study

Hur, Moon Haeng; Lee, Dong Hyeon; Lee, Jeong-Hoon; Kim, Mi-Sook; Park, Jeayeon; Shin, Hyunjae; Chung, Sung Won; Cho, Hee Jin; Park, Min Kyung; Jang, Heejoon; Lee, Yun Bin; Yu, Su Jong; Lee, Sang Hyub; Jung, Yong Jin; Kim, Yoon Jun; Yoon, Jung-Hwan

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Original Article

Extrahepatic Malignancies and Antiviral Drugs for Chronic Hepatitis B: A Nationwide Cohort Study

Moon Haeng Hur¹, Dong Hyeon Lee^1,2, Jeong-Hoon Lee^1,3, 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: JHLeeMD@snu.ac.kr

Received: January 20, 2024 Revised: April 12, 2024 Accepted: May 9, 2024

ABSTRACT

Background/Aims
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.
Methods
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.
Results
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<0.1, 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).
Conclusions
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