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Background Recent studies have proved that tenofovir disoproxil fumarate ( TDF) is associated with a lower risk of hepatocellular carcinoma (HCC) occurrence in chronic hepatitis B (CHB) patients and HCC recurrence in patients who underwent hepatectomy when compared to ETV. However, it is unclear whether TDF and ETV treatment, which are both recommended as first-line antiviral agents to prevent the hepatitis B (HBV ) recurrence after liver transplanta- tion (LT ), are associated with equivalent prognosis. We aim to compare risk of HCC recurrence and survival of patients recieving TDF or ETV after LT for HBV-related HCC. Method We performed a retrospective study including 316 patients who received treatment with ETV or TDF after LT for HBV-related HCC from 2015 January to 2021 Augest. The Recurrence-free survival (RFS) and overall survival (OS) of TDF and ETV groups were analyzed and compared by propensity score-matched (PSM), multivariable Cox regression analysis, competing risk analysis, sensitivity analyses and subgroup analyses. Result Compared with ETV, TDF therapy was associated with significantly higher RFS rates in the entire cohort (P < 0.01), PSM cohort (P < 0.01) and beyond-Milan cohort (P < 0.01). By multivariable analysis, TDF group was associ- ated with significantly lower rates of HCC recurrence (HR, 0.33; 95%CI, 0.14–0.75; P < 0.01). In subgroup analyses, the similar results were observed in patients with following tumor characteristics: Maximum diameter plus number of viable tumor ≥ 5, with MIV or MAT, AFP at LT ≥ 20 ng/ml, and well or moderate tumor grade. Conclusion Tenofovir decrease risk of HBV-Related Hepatocellular Carcinoma recurrence after liver transplantation compared to Entecavir. Keywords Tenofovir disoproxil fumarate, Entecavir, Nucleos(t)ide analogues, Hepatocellular carcinoma, Recurrence, Liver transplantation Jianming Yang, Yewu Chen and Haobin Sun contributed equally to this work Introduction *Correspondence: Liver transplantation (LT) is regarded as the radical Yinan Deng treatments for hepatocellular carcinoma (HCC), one of email@example.com the most common causes of cancer-related mortality in Yang Yang firstname.lastname@example.org the world . However, with the extented indications Guangdong Provincial Key Laboratory of Liver Disease Research, of LT for HCC, the rate of HCC recurrence after LT is Department of Hepatic Surgery and Liver Transplantation Center, The inevitably increasing. It’s reported that the rate of HCC Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China Guangdong Provincial Key Laboratory of Liver Disease Research, recurrence had reached 20–57.8% in 5 years after trans- Guangzhou, China plantation, and the median survival of liver recipients © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Yang et al. Infectious Agents and Cancer (2023) 18:2 Page 2 of 9 was only 10.6–12.2 months [2–4]. HCC recurrence and (CT), ultrasonography or enhanced magnetic resonance metastasis after LT have became the leading factors imaging (MRI). The index date was defined as the date of reducing the curative efficacy of LT. LT for HCC. All patient’s recurrence-free survival (RFS) Chronic hepatitis B (CHB) is one of the leading causes and overall survival (OS) were computed from the index of HCC occurrence world widely, especially in China, date to the confirmation of recurrence, all-cause mor - about 100 million people are infected with HBV and 20% tality, date of secondary-LT for non-HCC, date of anti- of them will progress to chronic infection . Evidences viral therapy changing or last follow up (2021 October). showed that high pre-LT HBV DNA levels (> 5log10 cop- MELD scoring was applied for assessment of prognosis ies/ml) and post-LT HBV recurrence are reported as before LT . predictors of HCC recurrence after LT . On the con- All patients have received lowdose hepatitis B immune trary, long-term therapy of nucleos(t)ide analogues (NAs) globulin (HBIG) combining with long-term NAs treat- would decreasing the risk of HCC recurrence after LT ment (TDF, 0.3 g/d; ETV, 0.5 g/d) after LT. According to through reducing HBV load and preventing HBV recur- the Chinese Technical Specifications For Follow-up after rence [7, 8]. Tenofovir disoproxil fumarate (TDF) and Liver Transplantation , the follow-up protocol was Entecavir (ETV) are both the first-line treatment for the identical between patients receiving ETV or TDF as fol- prevention of HBV recurrence after LT in clinical prac- low: Each patients were suggested to follow up once a tice guideline because of their equally high antiviral week within first 3 months after LT, once 2 weeks within efficacy and high genetic barriers to resistance [9, 10]. forth to sixth months, once a months within seventh to Several studys have proved that TDF is associated with a twelfth months and then every 3–6 months. Evaluation lower risk of HCC occurrence in CHB patients and HCC item included ultrasonography, Contrast-enhanced CT, recurrence in patients who underwent hepatectomy liver function tests, serum alpha-fetoprotein (AFP) and when compared to ETV [11–14]. Nevertheless, it remains blood concentration of Tacrolimus (FK506) or Ciclo- unclear whether TDF and ETV treatment are associated sporin. Enhanced MRI or Positron emission tomography- with equivalent prognosis in patients who underwent LT computed tomography (PET-CT) was conducted when for HBV-related HCC. progression of HCC was not confirmatory by CT during u Th s, we conduct this retrospective cohort study to follow-up. review and compare the risk of HCC recurrence and sur- vival of patients receiving TDF or ETV therapy after LT Statistical analysis for HBV-related HCC. Continuous data were summarized as median (range) without normal distribution, and Student t test and Methods Wilcoxon rank test were applied for comparison of con- Study population tinuous variables with or without normal distribution. We collated 377 consecutive patients received LT for Categorical data which were expressed as exact number HCC from 2015 January to 2021 Augest at The Third and proportion were compared using Chi-square and Affiliated Hospital of Sun-Yet Sen University (Guang - Fisher’s test. Survival curves of RFS and OS were esti- zhou, China). All the clinical data were obtained from mated by Kaplan–Meier method and compared by a log- hospital electronic database. Patients with non-HBV- rank test. Multivariable analysis were conducted by Cox related HCC (n = 30), co-infection of hepatitis C or E regression models, and variables with P < 0.05 in Univari- virus (n = 5), follow-up time that less than 2 months ables analysis were eligible for the Cox regression models, without any events (recurrence or death, n = 9), regimen and the independent risk factors in multivariate analysis which combined with other anti-HBV drugs or did not were futher used to conduct subgroup analyses. Compet- include ETV and TDF (n = 9), died in 1-month periop- ing risk analysis was applied to adjust competing risk of erative period (n = 8) were excluded. The final popula - the probability of death and secondary LT. tion of 316 patients (44 with TDF, 272 with ETV) were To avoid selection bias and potential confounding, we analyzed. This study was approved by the institutional performed Propensity Score Matched (PSM) analysis. review boards of The Third Affiliated Hospital of Sun-Yet A 1:2 nearest neighbor matching scheme with a caliper Sen University, Guangzhou, China (Ethics Approval No. size of 0.1 was used to identified the final PSM cohort, 02-028-01). propensity scores were computed through the follow- ing 21 variables: age; gender; locoregional therapy (LRT) Outcomes and follow‑up assessment before LT; Maximum tumor diameter; number of lesion; The primary outcome is HCC recurrence which was macrovascular invasion (MAV); macrovascular tumor defined using the same criteria as for the diagnosis of thrombus; microvascular tumor invasion (MIV); sat- HCC with Contrast-enhanced computed tomography ellite nodule; differentiation of tumor; serum levels of Y ang et al. Infectious Agents and Cancer (2023) 18:2 Page 3 of 9 HBVDNA, AFP, PT, FIB, INR, ALB, Cr, TB before LT; cohort. The other variables have no significant difference valley concentration of FK506 or Ciclosporin in 1 month; between two groups. steatosis of donor liver; cold ischemia time and MELD score. Furthermore, Milan Criteria (MC) was used to Survival analysis of the entire cohort stratify the population into two cohort, meeting-MC In the entire cohort, 133(42.1%) patients developed HCC cohort was considered to be with low risk of HCC recur- recurrence and 21 (6.6%) patients died. The TDF group rence, and beyond-MC cohort was considered to be with showed a significantly better RFS compared with the high risk of HCC recurrence relatively. ETV group (83.6% vs. 45.4% at 5-year P < 0.01, Fig. 1A). Missing values accounted for 0.1% of the baseline data, However, OS was not significantly different between two which were regarded as random occurrences, and Mul- group (P = 0.59, Fig. 1B). tivariate Imputation via Chained Equation (MICE) was In the multivariable Cox regression model, the TDF applied for estimating the missing values. P < 0.05 was group was associated with a significantly lower risk of considered as statistically significant. All statistical analy - HCC recurrence than the ETV group (hazard ratio [HR], ses were performed using SPSS 25.0 software (SPSS, Inc. 0.33;95% confidence interval [CI], 0.14–0.75; P < 0.01), an IBM Company, Chicago, IL, USA)and R statistical which was independent to other predictive factors software, version 4.1.0, (R foundation Inc; http:// cran.r- (Table 2). Other significant factors associated with HCC proje ct. org/). The R packages including mice, MatchIt, recurrence were maximum diameter plus number of cmprisk, survival, survminer, tableone, and ggplot2 were lesion (2.32; 1.32–4.09, P < 0.01), MIV (2.55; 1.48–4.39, used to analyze the statistics and create the figures and P < 0.01), Macrovascular tumor thrombus (1.84; 1.25– tables. 2.71, P < 0.01), AFP (2.07; 1.38–3.13, P < 0.01), and differ - entiation of tumor (1.23; 1.06–1.43, P < 0.01). Moreover, this result remains stable after adjusting competing risk of secondary-LT and non-HCC-related death (0.32; 0.13– Results 0.79, P = 0.014). Baseline characteristics The baseline characteristics were presented in Table 1. Survival analyses of PSM cohort and meeting Among the entire cohort of 306, the median age was or beyond‑MC cohort 52 years old, ranging from 22 to 77. The median MELD Among the PSM cohort (38 with TDF vs 68 with ETV), score was 12, ranging from 6.4 to 49.0 points. Because the TDF group had significantly better RFS rate than the of long-term intake of antiviral drugs before LT, most of ETV group (0.26; 0.09–0.73; P < 0.01; Fig. 2A). The esti - patients had relatively low HBVDNA load of ≤ 10 cop- mated 5-year RFS rates of TDF and ETV group were 87% ies/ml (n = 279, 88.2%). Most of tumors have microvas- versus 48%. In the meeting-MC cohort, the RFS curve cular invasion (n = 196, 62.0%) and nearly half of patients showed no significant difference between TDF and ETV received LRT before LT (n = 149, 47.2%), which include group (P = 0.25). In contrast, the TDF group presented TACE, RFA and gamma knife. Owing to LRT, 8 patients significantly better RFS rate than the ETV group in the were observed with no viable tumor through CT or beyond-MC cohort (0.29; 0.13–0.66, P < 0.01; Fig. 2C). MRI imaging and 25 patients were histologically com- In order to further reduce the effect of confounding, we firmed to be with no survival tumor. The median maxi - conducted a PSM analysis of beyond-MC cohort, which mum diameter of tumor was 3.8 cm, ranging from 0 to showed similar result to that of before-PSM cohort 17.4 cm. The average level of serum AFP before sugery (P = 0.046). Nevertheless, the OS analyses again shown was 6551.75 ng/L, ranging from 0.2 to 484, 000 ng/L. For no significant difference between two drugs in the PSM pathology features, the differentiation of tumor were pre - cohort (P = 0.51. Figure 2B) and beyond-MC cohort dominantly moderate (n = 223, 70.5%). The average cold (P = 0.56; Fig. 2D). ischemia time (CIT) was 374 min, ranging from 215 to 660 min. Subgroup and sensitivity analyses Patients were divided into groups regarding their anti- As presented in subgroup analyses (Fig. 3), TDF therapy viral therapy after LT. The median ages of ETV and TDF showed a significantly better effect on reducing risk of groups were 52 and 50 years, respectively. Compared to HCC recurrence in patients with following tumor char- ETV group, TDF group had significantly less patients acteristics: Maximum diameter plus number of viable with MIV (65.8% vs 38.6%, P < 0.05) and macrovascu- tumor ≥ 5, with MIV or MAT, AFP at LT ≥ 20 ng/ml, and lar tumor thrombus (29.4% vs 13.6%, P < 0.05), and sig- well or moderate tumor grade. nificantly more severe steatosis of donor liver (0% vs 4%; In order to decrease potential confounding, we con- P < 0.05), and shorter follow up time (15.5 months vs ducted the following sensitivity analyses:first, given that 24.0 months), which were mostly balanced in the PSM Yang et al. Infectious Agents and Cancer (2023) 18:2 Page 4 of 9 Table 1 Baseline characteristics of patients recieving TDF or ETV therapy after LT for HBV-related HCC in the entire cohort and PSM cohort Characteristics Entire cohort (n = 316) Propensity socre matched cohort (n = 106) ETV (n = 272) TDF (n = 44) P value ETV (n = 68) TDF (n = 38) P value Demographic characteristics Male gender, n (%) 254 (93.4) 41 (93.2) 1.000 63 (92.6) 35 (92.1) 1.000 Age (median [IQR]) 52 [46, 59] 50 [44, 54] 0.055 52 [46, 56] 50 [44, 55] 0.410 LRT before LT, n (%) 127 (46.7) 22 (50) 0.806 31 (45.6) 20 (52.6) 0.622 Tumor characteristics Maximum tumor size (median (IQR)), cm 3.8 (2.1, 6.0) 3.5 (2.5, 5.1) 0.449 35.0 [17.8, 56.2] 34.5 [25.0, 50.0] 0.739 Number of lesion ≥ 3, n (%) 139 (51.1) 21 (47.1) 0.800 32 (47.1) 19 (50.0) 0.930 MAV, n (%) 90 (33.1) 10 (22.7) 0.232 16 (23.5) 10 (26.3) 0.933 MIV, n (%) 179 (65.8) 17 (38.6) 0.001 34 (50.0) 15 (39.5) 0.401 Macrovascular tumor thrombus, n (%) 80 (29.4) 7 (13.6) 0.046 14 (20.6) 6 (15.8) 0.729 Differentiation of tumor, n (%) 0.791 0.639 None survival tumor 23 (8.5) 2 (4.5) 5 (7.4) 2 (5.3) Well 22 (8.1) 3 (6.8) 4 (5.9) 3 (7.9) Moderate 191 (70.2) 32 (72.7) 46 (67.6) 29 (76.3) Poor 36 (13.2) 7 (15.9) 13 (19.1) 4 (10.5) Satellite nodule, n (%) 62 (22.8) 7 (15.9) 0.407 13 (19.1) 7 (18.4) 1.000 Beyond MC, n (%) 83 (30.5) 14 (31.8) 1.000 25 (36.8) 11 (28.9) 0.548 Laboratory findings before LT AFP (median [IQR]), ng/ml 32.8 [5.9, 617.7] 36.1 [6.5, 270.8] 0.820 32.4 [6.2, 544.5] 22.8 [7.4, 183.2] 0.849 PT (median [IQR]), sec 14.9 [13.8, 17.2] 14.8 [13.8, 19.0] 0.602 15.4 [13.7, 17.9] 15.3 [13.9, 19.6] 0.843 FIB (median [IQR]), g/L 2.7 [2.0, 3.7] 2.8 [1.7, 3.7] 0.805 2.5 [1.9, 3.8] 2.7 [1.7, 3.5] 0.963 INR (median [IQR]) 1.2 [1.0, 1.4] 1.2 [1.1, 1.7] 0.353 1.2 [1.0, 1.5] 1.2 [1.1, 1.6] 0.624 TB (median [IQR]), umol/L 24.0 [13.3, 42.2] 23.1 [12.4, 84.4] 0.787 21.4 [13.5, 49.0] 21.7 [12.8, 63.0] 0.715 ALB (median [IQR]), g/L 36.3 [32.3, 40.4] 34.9 [31.4, 38.7] 0.179 35.6 [31.6, 40.5] 35.9 [32.8, 39.5] 0.911 Cr (median [IQR]), umol/L 73.0 [63.0, 84.0] 70.5 [60.0, 88.8] 0.953 77.0 [65.0, 84.2] 70.5 [60.5, 85.8] 0.420 MELD score (median [IQR]) 9.9 [7.6, 14.1] 11.0 [7.5, 20.5] 0.216 11.6 [11.6, 43.6] 11.6 [11.6, 43.6] 0.417 HBVDNA ≥ 5log10 copy/ml, n (%) 32 (11.8) 5 (11.4) 1.000 8 (11.8) 5 (13.2) 1.000 HBV recurrence after LT 55 (20.2) 3 (6.8) 0.055 10 (14.7) 3 (7.9) 0.474 Other characteristics Steatosis of donor liver (median [IQR]),% 0.0 [0.0, 9.0] 4.0 [0.0, 19.2] 0.015 4.0 [0.0, 10.0] 4.5 [0.0, 16.8] 0.630 Valley concentration of FK506 (> 10 ng/ml)or 64 (23.5) 6 (13.6) 0.204 9 (13.2) 6 (15.8) 0.943 Ciclosporinin (> 300 ng/ml)in 1 month, n (%) CIT (median [IQR]) 360 [340,4 17] 359.0 [300, 391] 0.110 364 [323, 412] 355.0 [300, 388] 0.141 Follow up time (median[IQR]), month 24.0 [13.0, 39.0] 15.5 [8.0, 29.0] 0.004 26.0 [16.8, 39.8] 16.0 [9.2, 29.0] 0.010 LRT, locoregional treatment; LT, liver transplantation; MAV, macrovascular invasion; MIV, microvascular invasion; MC, Milan criteria; AFP, alpha-fetoprotein; PT, prothrombin time; FIB, fibrinogen; INR, international normalized ratio; TB, total bilirubin; ALB, albumin; Cr, creatinine; MELD, Model for End-stage Liver Disease; CIT, cold ischemia time; IQR, interquartile ranges TDF was applied later than ETV in China, we excluded ETV, P = 0.092, not shown in data). Second, we excluded cases before the first use of TDF (ie, cases before 2016, those who have had received LRT ≥ 3 times (n = 48) and n = 22), and our results remianed unchanged (aHR, observed that the result were similar (aHR, 0.38; 95%CI, 0.34; 95%CI, 0.15–0.77, P = 0.010). What’s more, when 0.15–0.94, P = 0.037); Finally, our result were again excluded those with a follow-up time less than 1 year similar when excluded cases that experienced intrahe- (n = 78), the TDF again associated with a lower risk of patic recurrence (n = 87, aHR, 0.13; 95%CI, 0.02–0.96, HCC recurrence compared with ETV (aHR, 0.15; 95%CI, P = 0.046). When excluded cases of extrahepatic recur- 0.04–0.62, P = 0.009), and the difference of follow-up rence (n = 100), the anti-tumor effect of TDF was not times was eradicated (28 month of TDF vs 32 month of observed (aHR, 0.30; 95%CI, 0.07–1.28, P = 0.102). Y ang et al. Infectious Agents and Cancer (2023) 18:2 Page 5 of 9 Fig. 1 Recurrence-free and overall survival of the entire cohort of patients receiving TDF or ETV therapy after LT for HBV-related HCC. TDF = tenofovir disoproxil fumarate; ETV = entecavir; LT = liver transplantation; HBV = hepatitis B virus; HCC = hepatocellular carcinoma. A. Comparison of Recurrence-free Survival in entire cohort. B. Comparison of Overall Survival in entire cohort Table 2 Univariable and Multivariable analysis for hepatocellular carcinoma (HCC) recurrence after LT in the entire cohort Characteristics Univariate Multivariate HR 95%CI P aHR 95%CI P Male gender (vs female) 3.95 1.25–12.41 0.019 2.05 0.64–6.58 0.230 Age ≥ 60y (vs < 60y) 0.84 0.55–1.26 0.394 NAs ( TDF vs ETV ) 0.29 0.13–0.67 0.003 0.33 0.14–0.75 0.008 LRT before LT 0.90 0.64–1.27 0.558 Maximum diameter plus number of lesion > 5 (vs ≤ 5) 4.28 2.50–7.34 < 0.001 2.32 1.32–4.09 0.004 MAV 2.27 1.61–3.19 < 0.001 1.22 0.84–1.78 0.302 MIV 5.41 3.25–9.00 < 0.001 2.55 1.48–4.39 < 0.001 Macrovascular tumor thrombus 3.97 2.81–5.59 < 0.001 1.84 1.25–2.71 0.002 AFP > 20 ng/ml (vs ≤ 20 ng/ml) 3.12 2.10–4.63 < 0.001 2.07 1.38–3.13 < 0.001 PT > 14.5 s (vs ≤ 14.5 s) 1.03 0.73–1.45 0.884 FIB > 1.7 g/L (vs ≤ 1.7 g/L) 1.56 0.95–2.56 0.08 INR > 1.1 (vs ≤ 1.1) 0.92 0.65–1.31 0.662 TB > 34.2umol/L (vs ≤ 34.2umol/L) 1.28 0.91–1.80 0.154 ALB > 36 g/L (vs ≤ 36 g/L) 0.79 0.56–1.11 0.181 Cr > 116umol/L (vs ≤ 116umol/L) 0.90 0.42–1.93 0.788 MELD > 15 (vs ≤ 15) 1.14 0.77–1.67 0.515 HBVDNA > 5log10 copies/ml (vs ≤ 5log10 copies/ml) 1.14 0.68–1.89 0.626 Poor differentiation 1.44 1.26–1.65 < 0.001 1.23 1.06–1.43 0.005 Satellite nodule 2.21 1.54–3.18 < 0.001 1.17 0.80–1.71 0.418 Valley concentration of FK506 (> 10 ng/ml)or Ciclosporinin 1.25 0.85–1.84 0.255 (> 300 ng/ml) in 1 month after LT Steatosis of donor liver 0.79 0.56–1.11 0.172 CIT > 300 min (vs ≤ 300 min) 1.32 0.65–2.70 0.446 LRT, locoregional treatment; LT, liver transplantation; MAV, macrovascular invasion; MIV, microvascular invasion; MC, Milan criteria; AFP, alpha-fetoprotein; PT, prothrombin time; FIB, fibrinogen; INR, international normalized ratio; TB, total bilirubin; ALB, albumin; Cr, creatinine; MELD, Model for End-stage Liver Disease; CIT, cold ischemia time; HR, hazard ratio; CI, confidence interval; aHR, adjusted hazard ratio Yang et al. Infectious Agents and Cancer (2023) 18:2 Page 6 of 9 Fig. 2 Recurrence-free and overall survival of the PSM and beyond-MC cohort of patients receiving TDF or ETV therapy after LT for HBV-related HCC. PSM = propensity score matching; MC = Milan criteria. A. Comparison of Recurrence-free Survival in PSM cohort. B. Comparison of Overall Survival in PSM cohort. C. Comparison of Recurrence-free Survival in beyond-MC cohort. D. Comparison of Overall Survival in beyond-MC cohort HBV recurrence after LT HBV recurrence was defined as reapperance of HBsAg, HBeAg or HBV-DNA during follow up time. In our study, 58 patients were observed to develop HBV recur- rence and there was a trend that TDF group experienced less HBV recurrence compared with ETV (6.8% vs 20.2%, P = 0.055; Table 1). Discussion Recent studies has shown that TDF treatment was asso- ciated with lower risk of HCC than ETV in patients with chronic HBV Infection, and decrease recurrence of HBV- related HCC after hepatectomy [11–14, 17–22]. How- ever, there is no article reporting the same effect of TDF Fig. 3 Forestplot for subgroup analysis of the comparison on those patients who underwent LT as far. The patho - between TDF and ETV. HR, hazard ratio; CI = confidence interval; physiological condition of these patients are completely Diameter plus num = maximum size plus number of viable tumor; different from that of patients with mere cirrhosis or MIV = microvascular invasion; MAT = macrovascular tumor thrombus; AFP = alpha- fetoprotein underwent hepatectomy. Even though LT is supposed to Y ang et al. Infectious Agents and Cancer (2023) 18:2 Page 7 of 9 completely remove the tumors, there is still opportunity ETV groups might incline to be consistent, which could for HCC to progress when considering the recurrence also partly explain the negative result of OS analyses. of HBV, circulatory tumor cells and change of immune- It is noteworthy that the follow-up times of TDF group microenvironment. Theoretically, in liver transplanta - was shorter than ETV group, which could be attribute tion, liver as the primary reservoir of HBV is completely to the later application of TDF in China. Therefore, our removed, and serum HBsAg or HBV-DNA could not results should be interpreted with caution in that some be detected in most LT-receivers. However, HBV from patients in TDF group are supposed to experience HCC extrahepatic reservoirs still remains as the source of HBV recurrence following prolonged follow-up. In order to recurrence, which might cause HCC recurrence after LT reduce bias from different follow-up, we conducted a . Therefore, in order to curb HBV and HCC recurrence sensitivity analysis that excluded cases before the first use after LT, it is necessary to explore which antiviral drug is of TDF and those with a follow-up times less than 1 year, more efficient. and the TDF still associated with a lower risk of HCC In our cohort study, we analyzed patients who were recurrence compared with ETV. treated with TDF (n = 44) and ETV (n = 276) after LT According to the present studies, two potential mech- for HBV-related HCC and found that TDF therapy was anisms may explain our result. Firstly, post-LT HBV associated with a significantly lower risk of HCC recur - recurrence is known as a risk factor of HCC recurrence rence than ETV treatment, which was observed in entire after LT , and TDF might reduce HCC recurrence cohort, PSM cohort, beyond-MC cohort, multivariate via inhibiting HBV recurrence. TDF and ETV are not analysis, competing risk analysis, subgroup analyses and completely similar types of NAs in that TDF belongs to sensitivity analyses. Other independent risk factors of nucleotide analogues and ETV belongs to nucleoside HCC recurrence, such as microvascular invasion, were analogues. Nucleotide analogues could cause higher consistent with present studies . In subgroup analy- serum interferon-λ3 level, which was proved to have a ses (as Fig. 3 shows), the anti-tumor effect of TDF was strong effect on tumor or HBsAg inhibition, and immune mostly observed in patients with more-aggressive HCC. modulation [26–28]. In our study, TDF showed a better For these patients, We speculate that the circular HBV- trend of effect on inhibiting HBV recurrence than ETV, DNA had integrated into the extrahepatic tumor cells which was comparable with present study  and sup- , and increasing viral load caused by HBV recur- ports these postulation. Secondly, as Murata K’s study rence might contribute to the extrahepatic HCC recur- showed , interleukin (IL)-10 inhibit antigen-specific rence . TDF may perform a more effective inhibition CD8+ −T cells and IL-12 directly stimulates T cells on HBV replication and recurrence than ETV. The result and NK cells to induce IFN-γ.Pretreatment of peripheral of sensitivity analyses, which excluded cases of intrahe- blood mononuclear cells with TDF inhibited production patic or extrahepatic HCC recurrence, also support this of IL-10, but induced production of IL-12p70 and tumor speculation. necrosis factor (TNF)-αin a dose-dependent manner, The results of the tumor differentiation subgroup were which was not observed with ETV. unexpected, which could be ascribed to the fact that pre- Nevertheless, there are limitations in our study. The operative LRT might cause poor-differentiated tumors to major one is that as a retrospective study with small be completely necrotic and fall into well-or-moderate- sample size based on observational data, our study may differentiated group. Indeed, the recurrence rate of well- be subjected to selection bias and confounding, though or-moderate-differentiated group have reached up to we applied various statistical approaches including mul- 36.7% (Fig. 3), which indicated that this factor might not tivariable adjustment, PSM, competing risk analysis, be able to predict low HCC recurrence risk or well prog- subgroup analyses and sensitivity analyses to adjust the nosis in our study. In order to reduce confounding from differences of clinical characteristics between ETV and LRT, we performed a sensivity analysis that excluded TDF group, unmeasured biases and confounding still any patients who received LRT ≥ 3 times (n = 48) and exist. In addition, some patients get the antiviral drugs observed that the result were similar (aHR, 0.38; 95%CI, from other hospital or pharmacy after discharging, which 0.15–0.94, P = 0.037). led to a consequence that we failed to monitor the long- Another negative result of overall survival analyses term antiviral regimen of these patients after operation, could be attributed to the small sample size and short thus the adherence and duration time of antiviral thera- follow-up duration, therefore larger scale and longer pies couldn’t be guaranteed. Poor adherence to antiviral follow-up duration are mandatory. Moreover, owing to therapies without our monitoring may cause different salvage treatments including locoregional and systemic timing of two drugs and increase risk of HBV-relapse- therapy after HCC recurrence, the OS rate of TDF and induced HCC recurrence eading to bias of our results. Yang et al. Infectious Agents and Cancer (2023) 18:2 Page 8 of 9 6. Li MR, Chen GH, Cai CJ, Wang GY, Zhao H. High hepatitis B virus DNA level Conclusion in serum before liver transplantation increases the risk of hepatocellular In summary, TDF decrease risk of HBV-Related Hepato- carcinoma recurrence. Digestion. 2011;84(2):134–41. cellular Carcinoma recurrence after liver transplantation 7. Wong JS, Wong GL, Tsoi KK, Wong VW, Cheung SY, et al. Meta-analysis: the efficacy of anti-viral therapy in prevention of recurrence after curative compared to ETV. Our findings may be of great signifi - treatment of chronic hepatitis B-related hepatocellular carcinoma. Ali- cance in guiding the use of antiviral regimen after liver ment Pharmacol Ther. 2011;33(10):1104–12. transplantation. 8. Koda M, Nagahara T, Matono T, Sugihara T, et al. Nucleotide analogs for patients with HBV-related hepatocellular carcinoma increase the survival Acknowledgements rate through improved liver function. Intern Med. 2009;48(1):11–7. Not applicable. 9. Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the manage- Author contributions ment of hepatocellular carcinoma. Clin Mol Hepatol. 2022;28(4):583–705 YJM contributes to study design, statistical analysis, data collection and 10. Korean Association for the Study of the Liver (KASL). KASL clinical practice manuscript preparation. DYN, CYW and ZXJ is responsible for study design guidelines for management of chronic hepatitis B. Clin Mol Hepatol. and statistical analysis. SHB, WJF and LZX are responsible for and patients 2022;28(2):276–331. follow-up. FBS, ZT, YSH and YY contribute to revise the manuscript. All authors 11. Choi J, Kim HJ, Lee J, Cho S, Ko MJ, Lim YS. Risk of hepatocellular carci- read and approved the final manuscript. noma in patients treated with entecavir vs tenofovir for chronic hepatitis B: a Korean nationwide cohort study. JAMA Oncol. 2019;5:30–6. Funding 12. Yip TC, Wong VW, Chan HL, Tse YK, Lui GC, Wong GL. Tenofovir is Our original work described in this review article was supported by: the associated with lower risk of hepatocellular carcinoma than entecavir National Natural Science Foundation of China, 81702393, 81770648; Key Scien- in patients with chronic HBV infection in China. Gastroenterology. tific and Technological Projects of Guangdong Province, 2017A020215178. 2020;158(1):215-225.e6. 13. Choi J, Jo C, Lim YS. Tenofovir versus entecavir on recurrence of hepatitis Availability of data and materials B virus-related hepatocellular carcinoma after surgical resection. Hepatol- The data that generate the results of this study are available on request ogy. 2021;73(2):661–73. from the corresponding author: Yang yang. Department of Hepatic Surgery 14. Zhang M, Wang D, Liu H, Li H. 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Infectious Agents and Cancer – Springer Journals
Published: Jan 17, 2023
Keywords: Tenofovir disoproxil fumarate; Entecavir; Nucleos(t)ide analogues; Hepatocellular carcinoma; Recurrence; Liver transplantation
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