만성 B형 간염 환자에서 경구용 항바이러스제 사용이 간 외 장기에 미치는 잠재적 발암성의 독성학적 평가에 대한 고찰

Abstract

Background and Aims: Evidence on the carcinogenicity of oral nucleos(t)ide analogues (NAs) is still inconclusive lacking tenofovir disoproxil fumarate (TDF) data in patients with chronic hepatitis B (CHB). We aimed to provide confirmatory results for the relevant issue using a large set of CHB patients with data on all major NA drugs.

Methods: The study population consists of 10,331 patients with CHB receiving primary NA treatment longer than 6 months and 24,836 untreated controls followed at least during the period based on the International Council of Harmonization guidelines. Using an inverse-probability-of-treatment-weighted (IPTW) method, cumulative incidence of extrahepatic cancers was compared between treated and untreated patients and across the cyclopentane (entecavir), L-nucleoside (clevudine, lamivudine, and telvibudine), and acyclic phosphonate categories of NAs (adefovir, besifovir, and tenvofir). Analyses of individual cancers as sub-endpoints were additionally performed.

Results: During averages of 4.1 ± 3.1 years and 6.8 ± 5.5 years in the respective pairs, extrahepatic cancers occurred in 208 treated and 1,014 untreated patients. Cumulative incidence of overall extrahepatic malignancies did not differ between the two groups in the IPTW cohort (HR 1.002, 95% CI [0.859-1.169], p=0.977). Similar statistical trends were observed in analyses across the three NA chemical subsets and untreated set. Per-cancer analyses indicated that NA treatment was significantly associated with increased risks of colorectal/anal cancers and lymphoma (IPTW-adjusted HRs [95% CI], 1.538 [1.175-2.013]; and 1.784 [1.196-2.662]). Inversely, breast cancer and prostate cancer were less prevalent in the NA-treated group, compared to the counterpart (IPTW-adjusted HRs [95% CI], 0.669 [0.462-0.967]; and 0.521 [0.329-0.825]).

Conclusions: We found that long NA treatment had carcinogenic risks for colorectal/anal and lymphoid tissues in CHB patients, although it did not affect most of extrahepatic organs. Protective effects of NAs on breast and prostate cancers should be further confirmed.