Residual risk of HCC during long-term oral nucleos(t)ide analogues (NUCs) in patients with CHB – Is one NUC better than the other?

Abstract

Antiviral therapy with oral nucleos(t)ide analogues (NUCs) is recommended by international guidelines for patients with chronic hepatitis B (CHB) who have treatment indications, 1-3 as NUCs are effective in suppressing HBV DNA and reducing the risk of hepatic events and hepatocellular carcinoma (HCC). 4,5 Entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the 3 recommended NUCs, with high genetic barriers to resistance as well as favorable safety profiles. 1,3,6 In a recent issue of Journal of Hepatology, Kim and co-workers reported the findings of a retrospective cohort study of 2,897 patients with CHB recruited from 4 academic teaching hospitals in South Korea. 7 The authors compared the 5-year cumulative probabilities of HCC and death or liver transplantation in patients with or without compensated cirrhosis who had received ETV and TDF as the first antiviral agent. With several statistical approaches, including propensity score (PS)-matched and inverse probability of treatment weighting analyses, the authors did not demonstrate any difference in HCC incidence nor in other clinical outcomes. 7 The yearly HCC rates were approximately 4.3% and 3.4% for ETV-and TDF-treated patients with compensated cirrhosis (adjusted hazard ratio [aHR] 0.83; 95% CI 0.60-1.13; p = 0.25) and 0.58% and 0.76% for the corresponding patients without cirrhosis (aHR 1.60; 95% CI 0.95-2.71, p = 0.07).This study adds fuel to the heated debate: is TDF better than ETV in terms of risk reduction of HCC? An earlier report from the same country reported different observations. 8 Choi and co-workers showed a significantly lower HCC risk in TDF-treated patients, compared to ETV-treated patients, in a nationwide historical population cohort study of 24,156 previously treatment-naïve patients with CHB (11,464 started with ETV, 12,692 started with TDF), as well as a hospital cohort of 2,701 patients with CHB (1,560 ETV, 1,141 TDF). 8 The authors reported a consistent HCC risk reduction with TDF treatment,

Comment on – A multi-center study of entecavir vs. tenofovir on prognosis of treatment-naïve chronic hepatitis B in the Republic of Korea

“…published their study showing that TDF was superior for preventing HCC, as shown in multivariable Cox regression analysis and PS-weighted analysis, with hazard ratios ranging from 0.32-0.36, but not in PS-matched analysis (p = 0.06). 8,9 We totally agree with Jennifer JA et al, 10 as randomized studies seem unlikely, additional observational studies are still needed. Considering limitations and bias, all of these studies should be evaluated by a group of experts to classify the quality of such evidence.…”

Reply to: “Comment on – A multi-center study of entecavir vs. tenofovir on prognosis of treatment-naïve chronic hepatitis B in the Republic of Korea”

“…Actually, the controversy concerning which antiviral agent is better in improving prognosis among patients with chronic HBV infection remains, however, the level of evidence favoring the use of any specific antiviral agent has been weak. [3][4][5][6][7] First, as pointed out, patients with decompensated cirrhosis were not included in our study. Even though we also recognize that decompensated cirrhosis is a well-known risk factor of HCC development, we should take note of the major aim of the study design at this point of time.…”

“…HCC development. However, since a shortage of liver donation has been a serious problem in the Republic of Korea (average waiting time of 1,934 days in 2017), 9 the causes of death among those who died before HCC development were liver-related clinical events in most cases. Therefore, the difference between the preventive efficacies of 2 antivirals against hepatocarcinogenesis is not likely to have widened owing to such a point.…”

“…In this article, the authors proposed a new classification of portal vein thrombosis (PVT) with treatment strategies in liver transplantation (LT). They defined complex PVT as Grade 4 PVT by Yerdel's classification 2 and Grades 3 and 4 PVT by Jamieson's classification, 3 represented by diffuse splanchnic venous thrombosis including not only the main PV and proximal superior mesenteric vein (SMV) but also the distal SMV. By presenting multiple cases from previous reports of renoportal anastomosis, left gastric-portal anastomosis, peri-choledochal vein-portal anastomosis, or other various types of shunt-portal anastomosis, they suggested that non-anatomical anastomosis is recommended for Yerdel's Grade 4 advanced PVT.…”

Secondary prevention for hepatocellular carcinoma in patients with chronic hepatitis B: are all the nucleos(t)ide analogues the same?

“…An ongoing hot discussion in the field is whether one NA is better than the other in reducing HCC risk [14]. The first large-scale cohort study that compared the effectiveness of entecavir and TDF on reducing HCC was a Korean nationwide cohort study by Choi et al They showed that TDF treatment was associated with a lower risk of HCC than entecavir treatment, and concordant result was shown in a hospital cohort [15].…”