Extrahepatic malignancies and antiviral drugs for chronic hepatitis B: A nationwide cohort study

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<0.01, 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).

Conclusion: 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: Antiviral treatment; Entecavir; Hepatitis B virus; Non-liver cancer; Tenofovir.

Figure 1.

Patient flow diagram. Specific diagnostic and procedural codes are presented in Supplementary Table 1. CHB, chronic hepatitis B; ETV, entecavir; HCV, hepatitis C virus; HDV, hepatitis D virus; HIV, human immunodeficiency virus; NA, nucleos(t)ide-analogue; NHIS, National Health Insurance Service; TDF, tenofovir disoproxil fumarate.

Figure 2.

Cumulative incidence of extrahepatic malignancies in propensity score-matched cohort. Analysis was performed after propensity score matching. Intrahepatic malignancy development and death were treated as competing events. ETV, entecavir; TDF, tenofovir disoproxil fumarate.

Figure 3.

Risk of extrahepatic malignancy in the propensity score-matched cohort according to prespecified subgroups. SHR, subdistribution hazard ratio; CI, confidence interval; ETV, entecavir; P_interaction, P-value for interaction; TDF, tenofovir disoproxil fumarate. *High, middle, and low socioeconomic statuses indicate socioeconomic status within the ≥75th, 25th–75th, and <25th percentiles, respectively.