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Long-term prognosis of HBV-cirrhosis hepatocellular carcinoma recurrence and mortality rates post-treatment with antivirals TDF, TAF, ETV and curative radiofrequency ablation is still controversial Dina Johar* Department of Biochemistry and Nutrition, Faculty of Women for Arts, Sciences and Education, Ain Shams University, Heliopolis, Cairo, Egypt *Dina Johar, PhD Department of Biochemistry and Nutrition Faculty of Women for Arts, Sciences, and Education Ain Shams University, Cairo, Egypt Phone:+2 01060782045 Email: dinajohar@gu.edu.eg • To whom correspondence should be addressed Abstract The efficiency of antiviral agents for hepatitis B cirrhosis-related hepatocellular carcinoma (HCC) is still an important clinical challenge with high recurrence rates. In this commentary, we focus on recent findings from Xu et al. We highlight the potential benefit of studying HBV genotypes and subgenotypes as possible mechanisms behind different responses to antivirals. Mechanisms of viral reactivation that parallel HCC recurrence remain uncovered. The commentary is a significant step forward in understanding the nuanced approach to managing HCC recurrence and mortality rate in HBV-cirrhosis patients, offering valuable insights for clinical decision-making. Keywords HBV-related HCC, TDF, TAF, ETV, recurrence, mortality Core Tip A similar virological response to TDF, TAF, and ETV treatment in the first 6-12 months may require further investigation to understand early treatment dynamics. Understanding how HBV genotypes and subgenotypes influence chronic active HBV infection is crucial. Investigating potential molecular mechanisms that explain recurrence rate differences helps develop predictive models for individualized treatment selection. Background The paper entitled “Effect of antiviral therapy on 3-year recurrence and prognosis of hepatocellular carcinoma after curative radiofrequency ablation” by Xu et al. (1) is a robust retrospective cohort study that comprehensively evaluates long-term prognostic effects of advanced nucleos(t)ide analogs (NAs): ETV, TDF, and TAF on HBV-cirrhosis HCC patients post-RFA outcomes. The study identified four independent predictors of post-RFA HCC recurrence. The study findings recommend TDF or TAF as preferred antiviral agents for the long-term management of such patients. The three antiviral agents had a similar impact on the three-year mortality rate. The study used a substantial sample size (n=319) with a follow-up period of 144 weeks, across multiple time points (6, 12, 24, 36 months), although the sample sizes in the TDF (n=76) and TAF (n=52) groups are relatively small. Two of the major determinants of the outcome of chronic HBV infection are the HBV genotypes and subgenotypes. While Xu et al. adhered to established diagnostic guidelines, there are at least ten different confirmed HBV genotypes (A-J). There is limited knowledge about how different genotypes and subgenotypes of HBV affect the risk of HCC recurrence in patients with HBV-cirrhosis related HCC. The best way to find out is through long-term, population-based studies. These studies should compare people with different genotypes and follow them over time. For example, there is a substantial homogeneity of HBV subtypes found in Egypt, a country with a comparably high HBV-cirrhosis-related HCC, mostly genotype D, subgenotype D3, hepatitis B surface antigen (HBsAg) subtype ayw2, with a prevalence of the Major Hydrophilic Region (MHR) mutations (2). Genotype D is related to more advanced liver disease, i.e., HCC, than other genotypes (3) and is an independent risk for Fulminant Hepatitis (FH) (4). Whether new classes of drugs are needed to manage chronic HBV, whether a cure is possible, or even necessary, has not been addressed. The goal of new therapies for chronic hepatitis B should be to achieve a virological cure. Current NAs can slow down HBV replication and help improve liver damage. However, they rarely fully clear chronic HBV infections. There is an urgent need for new drugs and more effective strategies to combat the virus, which eventually will help get rid of the cancer. Still, more research is needed to find clear links between specific genotypes and risks like cirrhosis or HCC. Some research has been carried out in areas such as Asia and Alaska, but many genotypes, including A1 and D, have not been studied in long-term, prospective research. Data is missing for some genotypes and subgenotypes, such as A3, E, F4, and H, regarding their impact on health. Collaboration between multiple institutions from different countries enhances the strength of these studies. Retrospective and prospective studies examined serum HBV DNA levels, liver function, complication rates, and hospital stay duration (5, 6). A study looked at whether high-dose TDF therapy can stop HBV-related HCC recurrence. They designed a study where everyone received the same treatment, with no comparison group. The goal was to determine if using high-dose TDF is practical in real-world settings. They enrolled 10 patients in September 2015 and monitored their progress for three months or until they had to discontinue treatment early. They found that high doses of TDF, up to five times the recommended amount, are poorly tolerated by many patients. These doses also do not effectively stop HBV from replicating as HCC progresses (7). In 2018, a study looked at 607 patients with HBV-related HCC who had surgery or RFA. They divided them into three groups based on their antiviral drugs. The first group, with 261 patients, did not get antiviral treatment. The second group, with 90 patients, received low-strength NAs. The last group, with 256 patients, was treated with high-strength NAs. The main goal was to see how long patients stayed free of cancer recurrence. Patients on ETV and TDF had fewer recurrences than those on other antivirals (8). Another study followed 1,695 patients who had surgery for HBV-related HCC at Korea’s Barcelona Clinic Liver Cancer stage 0 or A between 2010 and 2018. Of these, 813 patients received ETV while 882 took TDF. The study compared cancer recurrence and overall survival between the two groups, using statistical methods to match patients’ backgrounds and adjust for other confounding factors. The analysis started from the day of their liver surgery. Results showed that patients on TDF had a notably lower chance of their HCC recurrence and survived longer overall than those on ETV (9). Between 2013 and 2017, three hospitals enrolled patients with HBV-related HCC who had surgery or ablation as their first treatment. A 421 patients had part of their liver removed, and 305 received RFA. All of these patients started antiviral medication using either ETV or TDF. The study examined HCC recurrence and mortality rates. Researchers adjusted for factors such as HBV DNA levels, tumour characteristics, and patient demographics. The results showed no significant difference in cancer recurrence or death rates between patients treated with ETV and TDF (10). Patients with HCC who go beyond the Milan criteria tend to have a high chance of HCC recurrence post-surgery. When comparing treatments, TDF significantly reduces the risk of HCC recurrence more than ETV therapy (11). Using propensity score matching from the date of liver resection for HCC, TDF showed better overall survival. It also offered stronger protection of liver function. However, in another study, there was no difference in the rate of HCC recurrence between TDF and ETV treatments (12). Other research shows that TDF works better than ETV for eliminating hepatitis B symptoms after RFA treatment. It helps reduce serum HBV DNA levels and improves the albumin-bilirubin (ALBI) grade more effectively (13) (14). A study in 2024 looked at how TDF and ETV affect long-term health in patients with HCC, fatty liver disease, and HBV. The researchers analyzed patient data using a multivariate Cox proportional hazards model and applied a propensity score matching method. They then compared survival outcomes with Kaplan-Meier survival curves. The results showed that TDF helped improve long-term prognosis for patients (15). The latter discovery was confirmed in 2025 in patients with high HBsAg levels after they had their liver removed (16). A study looked back over ten years, finishing in 2025. It included 1,396 patients with HBV-related cirrhotic HCC who had surgery. The patients were divided into two groups: those who took antiviral medicine and those who did not. The research focused on HCC recurrence, taking into account when the antiviral treatment was started, how well the virus was kept under control, and the levels of HBV DNA. Recurrences were labelled as early if they occurred within two years and late if they occurred after that. The study found that long-term antiviral therapy helped prevent late recurrence after surgery, regardless of whether it was started pre- or post-operation. Patients who responded well to the virus treatment saw the biggest benefit (17). Given such controversial results, in Xu et al. study, being a single-center study, there is potential for selection bias inherent in the retrospective study design. The uneven baseline characteristics across treatment groups, potential need for larger sample size to validate findings, and limited exploration of potential mechanisms are behind the differential recurrence rates achieved with TDF, TAF versus ETV, or even behind the similar impact that the three NAs had on the three-year mortality rate. The study will benefit from extending the follow-up period to provide more comprehensive long-term insights. Considering propensity score matching to reduce potential selection bias. Expanding the research scope through multi-center collaborative study enhances external validity and generalizability. Exploring potential interaction effects between NAs and the molecular mechanisms underlying the differential efficacy of TDF and TAF is insightful. Including more diverse patient populations enhances analytical approach, provides a nuanced understanding of anti-HBV agent effectiveness and contributes to a personalized medicine approach in hepatology. Including sensitivity analyses helps validate findings. Declarations Funding This commentary did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The author declare that no honorarium, grant, or other form of payment was given to anyone to produce the manuscript. Conflict of interest The author declares no conflict of interest exists. Consent to publish Not applicable. Availability of data and materials All data generated or analyzed during this study are included in this published article. Acknowledgment N/A References 1. Xu B, Zhang X, Liu F, Li F, Zhang X, Xiang H, et al. Effect of antiviral therapy on 3-year recurrence and prognosis of hepatocellular carcinoma after curative radiofrequency ablation. World J Gastrointest Oncol 2025;17: 112689. 2. Abu Zeid WA RD, Shemis MA,. Prevalence of mutations within major hydrophilic region of hepatitis B virus and their correlation with genotypes among chronically infected patients in Egypt. Arab Journal of Gastroenterology 2016 17 (2016) 34–40. 3. Thakur V, Guptan RC, Kazim SN, Malhotra V, SK. S. Profile, spectrum and significance of HBV genotypes in chronic liver disease patients in the Indian subcontinent. . J Gastroenterol Hepatol. 2002;17:165-70. 4. Wai CT, Fontana RJ, Polson J, Hussain M, Shakil AO, Han SH, et al. US Acute Liver Failure Study Group. 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