Comparable outcomes between Besifovir and other antiviral therapies in hepatocellular carcinoma development among patients with chronic hepatitis B

초록

Background and aims: Besifovir dipivoxil maleate (BSV), an acyclic nucleotide phosphonate, has potent antiviral efficacy against chronic hepatitis B (CHB), similar to other antiviral agents, such as entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF). This study compares outcomes between BSV and the other antiviral agents in hepatocellular carcinoma (HCC) development among patients with CHB. Method: We conducted a retrospective cohort of 2, 684 treatmentnaïve patients with CHB who started their first-line antiviral therapy (AVT) between May 2017 and April 2022 with ETV (n = 840), TAF (n = 706), TDF (n = 666), or BSV (n = 472) at six tertiary medical institutions in South Korea. The incidence and hazard ratio (HR) were calculated using Kaplan-Meier and Cox regression analyses, respectively. Selection bias was minimized using inverse probability of treatment weighting (IPTW) and propensity score matching (PSM). Results: Compared to the patients with other antiviral agents, BSV users showed a higher proportion of male patients (61.2% vs. 50.1– 56.2%), alcohol intake >20 g/day (12.1% vs. 5.5–11.2%), and cirrhosis (37.9% vs. 30.5–34.3%). The incidence of HCC in BSV users (n = 6, 4.4 per 1000 person-years [PYs]) was similar to that in TAF users (8.5 per 1000 PYs, log-rank P = 0.111, HR 2.098, 95% confidence interval [CI] 0.827–5.324), however, significantly lower than those in ETV (n = 38, 12.7 per 1000 PYs, log-rank P = 0.026, HR 2.603, 95% CI 1.087–6.233) and TDF users (12.7 per 1000PYs, log-rank P = 0.035, HR 2.539, 95% CI 1.034–6.234). After applying 1:1:1:1 IPTW, the incidence of HCC in BSV users (n = 7 of 591, 3.8 per 1000 PYs) was similar to that in TAF users (n = 17 of 713, 8.6 per 1000 PYs, adjusted HR [aHR] 2.324, 95% CI 0.894–6.043), however, significantly lower than in ETV (n = 32 of 706, 12.4 per 1000 PYs, aHR 2.795 (95% CI 1.138–6.866, E-value 5.035) and TDF users (n = 34 of 674, 14.6 per 1000 PYs, aHR 3.322 (95% CI 1.334– 8.274, E- value 6.099). Following separated 1:1 PSM (all 472 pairs), the incidence of HCC in BSV users (n = 6, 4.4 per 1000 PYs) was similar to that in TAF users (n = 12, 8.6 per 1000 PYs, log-rank P = 0.782, aHR 1.167, 95% CI 0.392–3.471), however, significantly lower than in ETV (n = 27, 15.2 per 1000 PYs, log-rank P = 0.025, aHR 2.978, 95% CI 1.024–8.659, E-value 5.404), and TDF users (n = 27, 16.6 per 1000 PYs, log-rank P = 0.025, aHR 3.000, 95% CI 1.090–8.254, E-value 5.449). Conclusion: BSV showed comparable outcomes in HCC development among patients with CHB compared to TAF, ETV, and TDF. Given the small number of events and the relatively short follow-up duration observed in BSV users, further long-term analysis is warranted.