Abstract

Background: Chronic hepatitis B (CHB) suppressive therapy with tenofovir disoproxil (TDF) or entecavir (ETV) has been shown to reduce the risk of hepatocellular carcinoma (HCC) and mortality. However, controversy exists regarding if one treatment is better than the other.

Methods: All Kaiser Permanente Northern California adult (age >17 years) patients with CHB undergoing suppressive treatment with either TDF or ETV for at least 1 year at any time between 1/1/2006 and 12/31/2021 and with >90% adherence by prescription refill data were included. TDF treated patients were 1:1 propensity score (PS) matched to ETV treated patients on baseline age, sex, race/ethnicity, body-mass index (BMI), diabetes, hyperlipidemia, hypertension, alcohol abuse, HIV, cirrhosis, prior lamivudine treatment, creatinine, hepatitis B DNA and hepatitis B envelope antigen/antibody status. Outcomes of interest included HCC development and mortality and were compared in the overall TDF and ETV cohorts as well as in the PS matched cohorts

Results: A total of 3384 treated HBV patients were included, 1031 (30%) TDF and 2353 (70%) ETV. Compared to ETV, TDF treated patients were younger (mean 48 vs. 52 years), more likely female (39% vs. 34%), thinner (BMI 24 vs. 25 kg/m²), have less diabetes (10% vs. 14%), less hyperlipidemia (21% vs. 32%), less hypertension (21% vs. 31%), more HIV co-infection (4% vs. 0%), less cirrhosis (8% vs. 12%), more prior lamivudine treatment (16% vs. 7%), lower creatinine (0.88 vs. 0.96 mg/dL), lower DNA (6.0 vs. 6.3 million IU/mL) and more envelope antigen positivity (38% vs. 33%). 978 TDF patients were successfully PS matched to ETV patients and differences between groups resolved. Overall and compared to ETV, TDF was associated with reduced HCC (HR: 0.60, 95% CI: 0.4-0.9, p=0.02; Figure 1A) and with reduced mortality (HR: 0.60, 95% CI: 0.4-0.9, p<0.01). In PS matched and compared to ETV, TDF was not associated with reduced HCC (HR: 0.93, 95% CI: 0.4-2.0; p=0.85; Figure 1B) nor with reduced mortality (HR: 0.71, 95% CI: 0.4-1.2, p=0.22).

Conclusion: When comparing overall TDF and ETV treated populations, TDF is better than ETV in HCC and mortality risk reduction. However, this result is likely related to provider treatment patterns where patients with additional risk factors for HCC and mortality are selected to receive ETV over TDF. When these additional risk factors are controlled for in PS matched cohorts, the advantage of TDF over ETV is not distinguishable.