Tenofovir vs. entecavir in reducing hepatocellular carcinoma risk in patients with chronic HBV infection?-Still an unsolved question.

HepatoBiliary Surg Nutr 2021;10(1):119-122 | http://dx.doi. org/10.21037/hbsn-2020-3 Chronic hepatitis B virus (CHB) infection affects approximately 250 million persons worldwide (1). CHB is a major risk factor for liver failure, cirrhosis, and hepatocellular carcinoma (HCC), accounting for 45–55% of HCC cases (1). The incidence rates of HCC among CHB patients are 0.02–0.2 per 100 person-years in inactive carriers, 0.3–0.6 per 100 person-years in those without cirrhosis, and 2.2–3.7 per 100 person-years for those with compensated cirrhosis (2). Currently, tenofovir [tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide] and entecavir (ETV) are first-line monotherapies for CHB (3,4). ETV, approved in 2005 by the FDA, is an oral nucleoside analogue with rare resistance in treatment-naïve patients (3,4). TDF, which has been available since 2008, is also a rapidly acting oral nucleotide analogue that has been shown to be highly effective in suppressing HBV replication (3,4). The new version of tenofovir (Tenofovir alafenamide, TAF) can be used safely for those with renal or bone disease was FDA approved in 2016 (3,4). However, HBV is rarely eradicated using either medication, and most patients with HBV infection require long term nucleos(t)ide analogue therapy. There have been no head-to-head randomized clinical trials to compare the efficacy of ETV and tenofovir on longterm HCC risk in patients with CHB. Several observational studies examined these outcomes. In the January 2020 issue of Gastroenterology, Yip et al. published findings from a retrospective cohort study that reported TDF was associated with lower incidence of HCC compared to ETV in treatment-naive patients with chronic HBV in Hong Kong followed from 2008 to 2018 (5). There were 29,350 patients (mean age, 52.9±13.2 years; 63.7% male); 1,309 were first treated with TDF (4.5%) and 28,041 were first treated with ETV (95.5%). Patients treated with TDF were younger (mean age, 43.2 vs. 53.4 years), and a lower proportion had cirrhosis (2.9% vs. 13.6%) than patients treated with ETV. During a median follow-up time of 3.6 years (inter-quartile range, 1.7–5.0 years) after treatment began (mean 2.8 years in TDF and 3.7 years in ETV), 8 patients treated with TDF (0.6%) and 1,386 patients treated with ETV (4.9%) developed HCC as verified by diagnosis codes (155.0 HCC and 155.2 carcinoma of liver) or procedure codes for HCC treatment according to ICD9-CM codes. They used multiple statistical methods such as propensity score matching and weighting, inverse probability of treatment weighting (IPTW) and competitive risk analysis to minimize selection bias in the retrospective cohort study. The propensity score incorporated using 17 baseline characteristics (age, sex, cirrhosis, ascites, hepatic encephalopathy, HBV DNA, HBeAg status, ALT, total bilirubin, INR, platelet, albumin, creatinine, diabetes mellitus, hypertension, dialysis, and calendar year of treatment initiation). Patients treated with TDF had a lower risk of HCC than that in patients treated with ETV after propensity score weighting (hazard ratio, 0.36, 95% CI, 0.16–0.80; P=0.013) and 1:5 matching (hazard ratio, 0.39, 95% CI, 0.18–0.84; P=0.016). The authors suggested a potential biological mechanism that a nucleotide such as Editorial