Tenofovir Alafenamide versus Entecavir in the Treatment of Renal Safety in Patients with Chronic Hepatitis B: An Observational Study

Tenofovir Alafenamide versus Entecavir in the Treatment of Renal Safety in Patients with Chronic Hepatitis B: An Observational Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Tenofovir Alafenamide versus Entecavir in the Treatment of Renal Safety in Patients with Chronic Hepatitis B: An Observational Study ding ying Zhou, Lianghui Zhong, Yaqian Mao, Lunli Zhang, Yuanbin Zhong This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5283480/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background and aims: Urinary α 1 -microglobulin (α 1 -MG), β 2 -microglobulin (β 2 -MG), urinary N-acetyl-β-glucosaminidase (NAG) and retinol-binding protein (RBP) have predictive effects on renal tubular injury, the purpose of this study is to investigate whether the renal tubular abnormalities in chronic hepatitis B (CHB) patients during long-term entecavir (ETV) treatment cloud be improved after altering to tenofovir alafenamide(TAF). Methods：This study included 224 CHB patients of abnormal renal tubular markers from June 2022 to September 2023, of which 122 patients continuing ETV and 102 patients of altering to TAF for 6 months. Propensity score matching was used to analyze the differences of renal tubular indexes between the continuing ETV treatment and altering to TAF treatment. Results: A 1:1 propensity score match yielded 62 patients in each treatment group.The baseline characteristics, the ratio of complete virology respond,liver blood phosphorus, the estimated glomerular filtration rate (eGFR), α 1 -MG, β 2 -MG, NAG, RBP were comparable between the two groups. After 6 months, the level of eGFR(ETV:101.5mL/(min*1.73m 2 ),TAF:100.1mL/(min*1.73m 2 ),p>0.05),RBP(△ETV -0.159 △TAF -0.213,p>0.05), the ratio of complete virology response(ETV 87.1% TAF 91.9%,P< 0.05) were statistically different.The difference ratio of α 1 -MG, β 2 -MG, NAG, blood phosphorus was statistically significant（p<0.05）。TAF decreased more than ETV in α1-MG, β2-MG, NAG indicators(△ETV: -4.016, -0.373,-0.852, △TAF: -12.050, -1.272, -5.583），TAF increased less than ETV in blood phosphorus (△ETV +0.019, △TAF -0.286）。 Conclusion: Altering to TAF of CHB patients with renal tubular abnormalities after long-term use of ETV , the treatment efficacy and renal tubular damage can be improved, indicating that TAF has better renal safety than ETV. Chronic Hepatitis B Nucleoside Analogues and Kidney Safety Introduction In March 2024, the World Health Organization (WHO) issued the updated version of the "Guidelines for the Prevention, Diagnosis, Care, and Treatment of Persons with Chronic Hepatitis B." [ 1 ] ,The guide clarifies that the mainline antiviral treatments for hepatitis B at present encompass entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF). It is suggested that chronic hepatitis B (CHB) patients with renal impairment opt for ETV or TAF. However, there is a scarcity of global reports on the adverse effects of ETV and TAF. ETV, being a guanosine nucleoside analogue, acts as a potent inhibitor of HBV.ETV is quickly metabolized into its 5-triphosphate form within cellular environments, demonstrating a potent affinity for hepatitis B virus (HBV) polymerase. Its potency in laboratory settings is 30 times superior to lamivudine. Through its competition with the natural substrate deoxyguanosine triphosphate, the 5-triphosphate form of ETV halts all enzymatic activities of HBV polymerase [ 2 ] .As a result, it yields a significant antiviral action and is chiefly secreted via the urine in its unaltered state.Studies have shown [ 3 ] ETV accumulation over time leads to an increased burden on several different transport systems in the renal tubules, including organic anion transporters, organic cation transporters, the multidrug resistance-associated protein family, and p-glycoprotein, potentially causing renal tubular damage. This may ultimately manifest as abnormalities in urinary microproteins, such as α1-microglobulin (α1-MG) and β2-microglobulin (β2-MG), urinary N-acetyl-β-D-glucosaminidase (NAG), and retinol-binding protein (RBP).and related research [ 4 ] indicates that the long-term administration of ETV results in a certain degree of renal tubular damage. Additionally, it has been demonstrated that urinary levels of microglobulins, including α1-microglobulin (α1-MG) and β2-microglobulin (β2-MG), as well as urinary N-acetyl-β-D-glucosaminidase (NAG) and retinol-binding protein (RBP), can serve as indicators for the early prediction of renal tubular injury induced by ETV.TAF, serving as an ester prodrug of tenofovir (TFV), and TFV, which is a non-cyclic nucleotide phosphonate drug, demonstrates potent and broad-spectrum antiviral activity in vitro, achieved via two phosphorylation steps.As it already incorporates a phosphate moiety, it skips the initial phosphorylation stage and can attach to native deoxyribonucleic acid substrates, hindering the activity of viral polymerases. Furthermore, it embeds itself into viral DNA, halting the replication process of the DNA strand, thus efficiently fighting against the hepatitis B virus.It is primarily eliminated through glomerular filtration and active tubular secretion by the kidneys.To mitigate the nephrotoxicity caused by TFV and to maintain its instability within cells while stabilizing it in plasma esterases, TFV prodrugs such as TDF and TAF have been developed. However, TDF has the potential to inadvertently lead to the accumulation of TFV due to premature hydrolysis, which could potentially result in toxicity to bones and kidneys.To tackle this issue, TAF adjusts TDF by incorporating a phenol and an isopropyl alaninate, thereby bypassing the initial phosphorylation of nucleoside analogues. This modification ensures a controlled rate of nucleoside triphosphate synthesis. Non-cyclic phosphates are inherently monophosphate compounds, and amide ester compounds serve to mask divalent anions, improve permeability, and subsequently modify the cellular distribution of TFV.Thus, while TDF undergoes widespread breakdown, TAF is specifically susceptible to certain enzymes in the cells it aims to affect, such as cathepsin A (Cat A) in peripheral blood mononuclear cells (PBMCs). This selectivity in enzyme sensitivity contributes to its enhanced stability in non-targeted tissues, leading to decreased systemic exposure and a higher concentration of TFV in the targeted cells. [ 5 ] In the currently existing relevant studies [ 6 ] indicates higher bone kidney safety for TAF.However, TAF remains a prodrug of TFV, and therefore there is still a risk of kidney damage associated with its long-term use.Current related research [ 7 ] indicates that long-term use of ETV is associated with a higher risk of renal function decline compared to TAF. Therefore, this study conducts relevant research on the renal safety of switching or not switching to TAF in patients who have already experienced renal tubular damage due to ETV. Methods Research subject Enroll patients diagnosed with chronic hepatitis B (CHB) who have consistently received entecavir (ETV) antiviral therapy and have subsequently developed renal tubular injury. These patients should be recruited from the outpatient department of the Infectious Disease Division at the First Affiliated Hospital of Nanchang University in Jiangxi Province, between the years 2022 and 2023. Subsequently, assign these individuals to either the tenofovir alafenamide (TAF) treatment group (TAF group) or the group that continues with ETV treatment (ETV group). Inclusion Criteria 1）Gender-neutral,Age≥18years，<65years;2）The body mass index (BMI) should be between 18.0 and 35.0 kg/m2 (inclusive).and weight≥40kg;3）At least one year of regular ETV antiviral treatment has been conducted,and if any of the urinary microalbumin test indicators exceeds the upper limit value, it is as follows：Urine α1-MG>=12mg/L;Urine β2-MG>=0.3mg/L;Urine NAG>=11.5U/L;Urine RBP>=0.7mg/L;4）CHB patients with abnormal urinary microalbumin detection after ETV treatment (as above) who switched to TAF treatment. Exclusion Criteria 1）CHB patients who have been diagnosed with kidney disease or have recently taken other nephrotoxic drugs;2）CHB patients with poorly controlled hypertension, diabetes, hyperuricemia, and hyperlipidemia;3）Pregnant women, patients over the age of 65;4）Combine patients with other tumor diseases and those with rheumatological and immune system-related diseases;5）Patients with hepatitis B treated with the combined use of other types of anti-hepatitis B drugs (such as TDF etc.) Research indicators Gather the gender and age of the enrolled patients, along with renal tubular markers: obtain morning urine samples for the analysis of α1-microglobulin (α1-MG), β2-microglobulin (β2-MG), urinary N-acetyl-β-D-glucosaminidase (NAG), urinary retinol-binding protein (RBP), serum creatinine, serum phosphorus, indicators of liver fibrosis, quantification of hepatitis B virus DNA (HBV-DNA), and hepatitis B e antigen (HBeAg). Utilize the testing indicators and reference ranges established by the First Affiliated Hospital of Nanchang University for all markers, and monitor these indicators over a period of 24 weeks. Detection method The HBV viral markers and blood phosphorus levels are determined in accordance with the standards and reference value ranges established by the Clinical Laboratory of the First Affiliated Hospital of Nanchang University. Renal function was assessed using the Hitachi 7600 automatic biochemical analyzer in conjunction with compatible reagents, with the reference range for blood creatinine levels set between 57-97μmol/L. Liver fibrosis indicators were measured using ultrasound technology for transient elastography (TE), where values exceeding 7.0Kpa are deemed abnormal. The urine α1-microglobulin (α1-MG), urine β2-microglobulin (β2-MG), and urine N-acetyl-β-D-glucosaminidase (NAG), as well as urine retinol-binding protein (RBP) test kits were supplied by Chongqing Bosstai Biotechnology Co., Ltd. The operational procedures were conducted following the manufacturer's instruction manual, with the respective reference ranges being 0 -12mg/L, 0.1-0.3 mg/L, 0-11.5U/L, and 0-0.7 mg/L. Statistical methods The analysis of data was executed with the aid of SPSS statistical software, version 26.0. Initially, data imputation was undertaken to secure a full dataset, and the comparison of count data between two groups was executed using the Chi-square test or Fisher's exact probability test. For quantitative data that adhered to a normal distribution, the values were denoted as x±s, and the paired t-test was applied for comparing two groups; for quantitative data that did not adhere to a normal distribution, the values were denoted as M(P25 to P75), and the Wilcoxon signed-rank test was applied for comparing two groups. A P value of less than 0.05 (P<0.05) was considered to be statistically significant. Results This investigation encompassed a total of 224 individuals diagnosed with hepatitis B, who were categorized into two distinct cohorts based on their medication regimen in response to abnormal renal tubular indicators: 122 subjects persisted with Entecavir (ETV) therapy, while 102 transitioned to Tenofovir Alafenamide (TAF) treatment. Following a 24-week period of observation, the mean glomerular filtration rate (GFR) was determined to be 103.25 ± 2.30 mL/(min*1.73m^2) for the ETV cohort and 100.22 ± 2.37 mL/(min*1.73m^2) for the TAF cohort, indicating no statistically significant difference (p > 0.05).In terms of HBV-DNA (ETV: positive 2 cases, low viral load 6 cases, negative 114 cases; TAF: positive 0 cases, low viral load 16 cases, negative 86 cases; the complete viral response rates were 93.44% and 84.31% respectively), the difference was statistically significant (P < 0.05).The ETV group and the TAF group showed no statistically significant difference in HBeAg seroconversion (ETV group: 88 cases negative, 34 cases positive; TAF group: 68 cases negative, 34 cases positive, with negative conversion rates of 72.1% and 66.7%, respectively; P > 0.05).After 24 weeks, there were statistically significant differences between the two groups in liver stiffness index, blood phosphorus, and urinary β2-MG (ETV M (P25,P75): 7.49, 1.07, 0.31 vs TAF M (P25,P75): 6.93, 0.93, 0.26, Z=-2.84, -2.39, -2.04, P < 0.05). There were no significant statistical differences between the two groups in the remaining indicators, as shown in Table 1. Upon the exclusion of confounding factors and the application of 1:1 propensity score matching (PSM), 62 patients were selected for each treatment cohort. Following a 24-week period, no significant statistical differences were noted in kidney-related indicators between the two cohorts, as indicated in Table 2 . And after 24 weeks, there was no significant statistical difference in eGFR between the two groups (ETV: 101.56 ± 3.35 mL/(min*1.73m^2) vs TAF: 100.17 ± 3.55 mL/(min*1.73m^2), p > 0.05), and the changes in eGFR over the 24-week period were not significantly different between the two groups (Z=-1.672, P > 0.05).The change in RBP levels before and after 24 weeks (△ETV: 0.159 vs △TAF: 0.213, p > 0.05) exhibited no significant statistical variation; However, the difference in HBV-DNA levels (ETV group: positive in 2 cases, negative in 54 cases, and low viral load in 6 cases vs TAF group: positive in 0 cases, negative in 57 cases, and low viral load in 5 cases, with a complete viral response rate of 87.09% and 91.93%; Z=-8.951, p < 0.05) was statistically significant, as shown in Table 4. Serological conversion of HBeAg (ETV group: 42 cases negative conversion, 20 cases positive; TAF group: 45 cases negative conversion, 17 cases positive, with negative conversion rates of 67.74% and 72.58%, respectively) showed no statistically significant difference (P > 0.05),This is illustrated inas shown in Table 3 .The liver stiffness indicators did not exhibit a significant statistical difference between the two groups, nor in their alterations following the 24-week period (p > 0.05).The alterations in the levels of α1-MG, β2-MG, NAG, and blood phosphorus, both pre- and post-intervention at 24 weeks, were found to be statistically significant between the two groups (△ETV: -4.016, -0.374, -0.853, + 0.019 vs △TAF: -12.050, -1.272, -5.583, -0.286, with Z=-3.158, -2.983, -2.643, -3.226, and p < 0.05). This is illustrated in Table 5 . Table 1.24 weeks later, the relevant indicators of the two groups before PSM ETV TAF Z/t value P value examples 122 102 eGFR (mL/(min*1.73m2), x ± s) 103.25 ± 2.30 100.22 ± 2.37 -1.12 0.266 Liver stiffness (Kpa,M( P25,P75 )) 7.49(6.80,7.49) 6.93(6.92,6.93) -2.84 0.005 Blood phosphorus (mmol/L, M ༈P25,P75 )) 1.07(0.97,1.07) 0.93(0.91,0.96) -2.39 0.019 Urine α1-MG(mg/LM( P25,P75 )) 10.85(6.32,18.16) 11.10(6.71,16.04) -1.42 0.16 Urine β2-MG(mg/L,M( P25,P75 )) 0.31(0.18,0.63) 0.26(0.16,0.49) -2.04 0.044 Urine NAG(U/L,M( P25,P75 )) 11.33(9.69,11.48) 12.10(8.37,14.01) 0.35 0.729 Urine RBP(mg/L,M( P25,P75 )) 0.33(033,0.33) 0.38(0.30,0.4) 1.57 0.12 *eGFR, estimated glomerular filtration rate; TAF, tenofovir alafenamide;ETV, entecavir Table 2 24 weeks later, the relevant indicators of the two groups after PSM ETV TAF Z/t value P value examples 62 62 eGFR (mL/(min*1.73m2), x ± s) 101.56 ± 3.35 100.17 ± 3.55 -0.28 0.784 Liver stiffness (Kpa,M( P25,P75 )) 7.43(5.80, 7.54) 6.92(6.45, 7.17) -0.49 0.628 Blood phosphorus (M(mmol/L, P25,P75 )) 1.04(0.88, 1.07) 0.94(0.92, 1.04) 0.05 0.961 Urine α1-MG(mg/LM( P25,P75 )) 12.45(7.25, 20.77) 10.44(5.89, 14.41) -1.68 0.099 Urine β2-MG(mg/L,M( P25,P75 )) 0.31(0.19, 0.74) 0.26(0.16, 0.51) 0.74 0.461 Urine NAG(U/L,M( P25,P75 )) 11.38(10.82, 13.47) 12.01(6.65, 14.14) -0.57 0.574 Urine RBP(mg/L,M( P25,P75 )) 0.33(0.31, 0.38) 0.38(0.30, 0.39) 1.49 0.14 *eGFR, estimated glomerular filtration rate; TAF, tenofovir alafenamide;ETV, entecavir Table3. Comparison of HBeAg seroconversion rates between two groups after 24 weeks Before PSM After PSM ETV(n=122) TAF(n=102) ETV(n=62) TAF(n=62) Negative 88 68 42 45 Positive 34 34 20 17 X 2 value 0.785 0.347 P value 0.376 0.556 * TAF, tenofovir alafenamide；ETV，entecavir;HBeAg,hepatitis B e antigen Table 4. The HBV-DNA response effect after 24 weeks between the two groups Before PSM After PSM ETV（n=124） TAF(n=102) Z/t value P value ETV(n=62) TAF(n=62) Z/t value P value Positive 2 0 -12.426 0 2 0 -8.951 0 Negative 114 86 54 57 Low viral load 6 16 6 5 *HBV-DNA,hepatitis B virus DNA; TAF, tenofovir alafenamide；ETV，entecavir;Low viral load,HBV-DNA levels below 2000 IU/mL. Table 5 Change in the magnitude of related indicators after 24 weeks between two groups after PSM ETV(∆, x ± s) TAF(∆, x ± s) Z value P value ∆ eGFR (-)0.736 ± 1.514 (-)10.380 ± 4.486 -1.672 0.094 ∆ Liver stiffness (-)0.389 ± 0.237 (-)0.970 ± 0.464 -0.505 0.614 ∆ Blood phosphorus (+)0.019 ± 0.019 (-)0.286 ± 0.209 -3.226 0.001 ∆ Urine α1-MG (-)4.016 ± 1.677 (-)12.050 ± 2.034 -3.158 0.002 ∆ Urineβ2-MG (-)0.374 ± 0.572 (-)1.272 ± 0.608 -2.983 0.003 ∆ UrineN AG (-)0.853 ± 0.684 (-)5.583 ± 1.345 -2.643 0.008 ∆ Urine RBP (-)0.159 ± 0.022 (-)0.213 ± 0.048 -1.773 0.076 *eGFR, estimated glomerular filtration rate; TAF, tenofovir alafenamide;ETV, entecavir Discussion Among the primary anti-hepatitis B virus medications, entecavir (ETV) and tenofovir alafenamide (TAF) are extensively utilized for their high efficacy, minimal side effects, and favorable cost-effectiveness ratios. During prolonged antiviral therapy, the clinical response is frequently indicated by the impact on hepatitis B virus DNA (HBV-DNA) levels. Per the guidelines of the American Association for the Study of Liver Diseases (AASLD), HBV-DNA levels below 2000 IU/mL are classified as low viremia. A low viral load is correlated with a heightened risk of liver cancer, particularly in individuals with cirrhosis [ 8 ] .In this investigation, among renal tubular index abnormalities patients with suboptimal viral response to ETV, those who either persisted with ETV or transitioned to TAF therapy for 24 weeks exhibited notable differences. Specifically, among patients who continued ETV, there were 2 instances of HBV-DNA positivity and 6 cases of low viral load. Conversely, in the group that switched to TAF, there were no cases of positivity and 5 instances of low viral load. Although the rates of HBeAg seroconversion did not differ significantly between the two treatments (ETV: 67.74%, TAF: 72.58%), TAF demonstrated a marginally higher seroconversion rate. Should future studies include a larger sample size, additional evidence may emerge. TAF appears to offer a higher rate of complete viral response compared to ETV, and for chronic hepatitis B patients with a poor response to long-term ETV treatment, switching to TAF enhances viral response efficiency.Consequently, for individuals suffering from chronic hepatitis B who have experienced kidney tubular injury and exhibit a low viral load as a result of prolonged exposure to ETV, transitioning to TAF therapy may represent a beneficial therapeutic strategy. The hepatitis B virus is a significant contributor to liver cirrhosis, a condition that arises from recurrent liver damage and subsequent healing processes, which trigger an overproduction of collagen and alterations in the extracellular matrix by hepatic stellate cells [ 9 ] .In this study, we assessed the extent of liver fibrosis, also known as liver stiffness, in hepatitis B patients by employing transient elastography (TE), a technique grounded in ultrasound technology. It is important to note that the liver stiffness index may be influenced by various factors, including postprandial fullness, inflammation, passive venous congestion, portal hypertension, and biliary obstruction [ 10 ] .In this study, patients with clear hepatitis B cirrhosis and liver dysfunction were excluded. The findings suggest a significant disparity in the extent of liver fibrosis between the group that continued ETV treatment and the group that switched to TAF treatment after 24 weeks, prior to propensity score matching (PSM). Median values indicate that the liver fibrosis indicators for the TAF group are lower. Might this imply that TAF is more effective in improving liver fibrosis than ETV? After accounting for confounding variables, no significant statistical disparity was observed in the data comparison and their deviations from baseline between the two groups at the 24-week mark. This could be attributed to the fact that, prior to controlling for these variables, the baseline values for the ETV group were higher, resulting in a skewed difference. Additionally, all liver fibrosis indicators for the patients in this study fell within the normal range, which might explain why TAF and ETV had minimal impact on them. Should patients with hepatitis B cirrhosis be included in future studies to monitor the effects of these two drugs on their liver fibrosis indicators, it is possible that distinct effects would become apparent. Furthermore, ultrasound-based elastography can be influenced by numerous unpredictable factors. To achieve a comprehensive evaluation and validation, it would be advisable to incorporate additional indicators such as liver color Doppler ultrasound, portal vein pressure, and blood liver fibrosis tests in subsequent analyses. Reports indicate that nucleoside analogues can induce Fanconi syndrome, characterized by varying levels of dysfunction in the proximal renal tubules. Symptoms include hypophosphatemia, hypouricemia, aminoaciduria, and glycosuria. Hypophosphatemia, in particular, may result in impaired bone mineralization, osteomalacia, and an increased risk of fractures [ 11 , 12 ] . Consequently, when it comes to kidney injury induced by nucleoside analogues, the primary damage is inflicted upon the renal tubules. Hence, indicators that monitor renal tubular injury should exhibit greater sensitivity than eGFR. In this research, the serum phosphorus levels at week 24 exhibited a significant difference when compared to the baseline values for both the ETV group and the TAF switch group. The ETV group demonstrated an upward trend in variation, whereas TAF continued to decline. This result may be attributed to factors including diet, gastrointestinal absorption, renal absorption, and phosphate transport. Therefore, relying exclusively on blood phosphorus levels to assess renal function remains questionable. For future investigations, it is advisable to incorporate comprehensive evaluation indicators such as urinary phosphorus, urinary microalbumin, and the urinary microalbumin-to-creatinine ratio. Urine α1-MG is a protein with a low molecular weight of 27 kDa, initially identified over half a century ago. In individuals with healthy kidneys, α1-MG protein readily traverses the glomerular membrane, with nearly 99% subsequently being reabsorbed and metabolized by the cells of the proximal tubule [ 13 ] , consequently, an elevation in urinary α1-MG serves as an early indicator of renal impairment, predominantly affecting the proximal renal tubules. Its notable stability within urine has led to its adoption as a marker for tubular dysfunction, setting it apart from other markers of the tubules [ 14 ] . Urine RBP and urine β2-MG are also biomarkers of renal tubular dysfunction, with their low molecular weights being 21 kDa and 11 kDa, respectively,They can also be freely filtered by the glomerulus and almost completely reabsorbed by the proximal tubule [ 15 ] . NAG, a lysosomal hydrolase with a molecular weight of 150 kDa, is exclusively secreted into the urine by damaged proximal renal tubular cells. The increase in its levels indicates damage to the tubular structure [ 16 ] . In summary, this study employed urinary biomarkers α1-MG, β2-MG, NAG, and RBP to evaluate early tubular injury. Following 24 weeks of treatment, the TAF group exhibited notably reduced levels of urinary α1-MG, β2-MG, and NAG compared to the ETV group. However, no significant difference in urinary RBP levels was observed between the two groups. Additionally, after 24 weeks, there were no significant differences in renal tubular indicators or estimated Glomerular Filtration Rate (eGFR) between the two groups. This could be attributed to the fact that the study primarily focused on outcomes related to early tubular injury, whereas eGFR predominantly indicates glomerular damage. After 24 weeks, renal tubular indicators remained statistically similar between the two groups, potentially due to baseline disparities in renal tubular indicator levels, which undermined the statistical significance of the results. Upon data adjustment, a clear and significant difference in the variation of three renal tubular indicators became evident, with the TAF group demonstrating a more pronounced advantage in the reversal of renal tubular injury.In current research, urinary RBP primarily functions as a significant indicator for the prediction of diabetic nephropathy [ 17 ] . However, this study involved patients who had already been screened out for renal dysfunction and underlying diseases associated with hepatitis B, hence no significant difference was observed between the two groups. Conclusions For chronic hepatitis B patients who develop kidney tubular injury with low levels of viral replication while on ETV therapy, transitioning to TAF can not only reverse the kidney tubular damage but also enhance the efficacy of the antiviral response. This underscores the significance for clinicians to evaluate the early kidney injury induced by nucleos(t)ide analogues, facilitating early detection, diagnosis, and intervention. Declarations Acknowledgements None. Author contributions ZD and ZY contributed to the study design, data collection, analysis, quality checking and editing the manuscript. MY and ZLH has contributed to data collection. ZLL has contributed to review and editing the manuscript. ZY (guarantor) takes the responsibility for the content of the manuscript, including the data and analysis. Funding This study had no financial support. Data availability Data are available by the corresponding author upon reasonable request. Ethics approval and consent to participate The study was approved by the Committee of the First Affiliated Hospital of Nanchang University of China (Batch number: IIT2024206). The need for informed consent was waived for patients by the Committee of the First Affiliated Hospital of Nanchang University of China. Consent for publication Not applicable. Clinical trial number Not applicable. Competing interests The authors declare no competing interests. References Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection[R]. Geneva: World Health Organization, 2024. Opio C K, Lee W M, Kirkpatrick P. Entecavir[J]. Nature Reviews Drug Discovery, 2005, 4(7): 535-536. Yang X, Ma Z, Zhou S, et al. Multiple Drug Transporters Are Involved in Renal Secretion of Entecavir[J]. Antimicrobial Agents and Chemotherapy, 2016, 60(10): 6260-6270. Che Yuanmei, Wang liang, Zhang Lunli, et al.. 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Liver fibrosis assessment: MR and US elastography[J]. Abdominal Radiology (New York), 2022, 47(9): 3037-3050. Fujii T, Kawasoe K, Ohta A, et al. A case of entecavir-induced Fanconi syndrome[J]. CEN case reports, 2019, 8(4): 256-260. Gara N, Zhao X, Collins M T, et al. Renal tubular dysfunction during long‐term adefovir or tenofovir therapy in chronic hepatitis B[J]. Alimentary Pharmacology & Therapeutics, 2012, 35(11): 1317-1325. B A, L L, T B, et al. alpha(1)-Microglobulin: a yellow-brown lipocalin[J]. Biochimica et biophysica acta, 2000, 1482(1-2). Ishiwata S, Matsue Y, Nakamura Y, et al. Clinical and prognostic values of urinary alpha1-microglobulin as a tubular marker in acute heart failure[J]. International Journal of Cardiology, 2021, 338: 115-120. Norden A G W, Lapsley M, Unwin R J. Urine retinol-binding protein 4: a functional biomarker of the proximal renal tubule[J]. Advances in Clinical Chemistry, 2014, 63: 85-122. Norden A G W, Gardner S C. Lysosomal enzymuria is a feature of hereditary Fanconi syndrome and is related to elevated CI-mannose-6-P-receptor excretion[J]. Cai F, Zhang L, Zhao P, et al. Urinary RBP as an Independent Predictor of Renal Outcome in Diabetic Nephropathy[J]. Disease Markers, 2022(9687868): 13. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5283480","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":370806280,"identity":"d7ee6ded-4a59-4289-97dd-08ae97ddc4f3","order_by":0,"name":"ding ying Zhou","email":"","orcid":"","institution":"First Affiliated Hospital of Nanchang University","correspondingAuthor":false,"prefix":"","firstName":"ding","middleName":"ying","lastName":"Zhou","suffix":""},{"id":370806281,"identity":"82e5a153-a911-4fec-81e8-430357ad2b88","order_by":1,"name":"Lianghui Zhong","email":"","orcid":"","institution":"Zhongshan Second People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lianghui","middleName":"","lastName":"Zhong","suffix":""},{"id":370806282,"identity":"9c6b3746-d65a-46e2-b6c8-15b1a19dbe96","order_by":2,"name":"Yaqian Mao","email":"","orcid":"","institution":"First Affiliated Hospital of Nanchang University","correspondingAuthor":false,"prefix":"","firstName":"Yaqian","middleName":"","lastName":"Mao","suffix":""},{"id":370806283,"identity":"37647098-637f-4a8f-b8fe-08b1c5f6e789","order_by":3,"name":"Lunli Zhang","email":"","orcid":"","institution":"First Affiliated Hospital of Nanchang University","correspondingAuthor":false,"prefix":"","firstName":"Lunli","middleName":"","lastName":"Zhang","suffix":""},{"id":370806284,"identity":"8dd267a6-391f-4c7e-a0cb-bbb96acc4069","order_by":4,"name":"Yuanbin Zhong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwUlEQVRIiWNgGAWjYBAC+8PMBx8kVNTI8ROv5zhbssGDM8eMJRuI1nKex0zyYRtz4oYDxOpgbOYxNkhgY2PcfDx5A8OPim2EtTAzsxU+SOCRYTY786yAsefMbcJa2JiZNxskSLCxmd3IMWBmbCNCCw8zg5lEggEzj/EMYrVIMLMAtSQwSxhIEKvFgBkYyAkHjhlIAP1ykCi/GPAfPvjw57+a+v725I0PflQQoQUJJBgcIEk9WAupOkbBKBgFo2CEAABvFjpo8miC3wAAAABJRU5ErkJggg==","orcid":"","institution":"First Affiliated Hospital of Nanchang University","correspondingAuthor":true,"prefix":"","firstName":"Yuanbin","middleName":"","lastName":"Zhong","suffix":""}],"badges":[],"createdAt":"2024-10-17 14:08:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5283480/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5283480/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":97692520,"identity":"4b53adf3-54b7-4ffd-8381-c7db770aefe9","added_by":"auto","created_at":"2025-12-08 11:09:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":705546,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5283480/v1/92dfa050-2e1d-41d7-a43b-778bff3cc92a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Tenofovir Alafenamide versus Entecavir in the Treatment of Renal Safety in Patients with Chronic Hepatitis B: An Observational Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003e In March 2024, the World Health Organization (WHO) issued the updated version of the \"Guidelines for the Prevention, Diagnosis, Care, and Treatment of Persons with Chronic Hepatitis B.\"\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e,The guide clarifies that the mainline antiviral treatments for hepatitis B at present encompass entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF). It is suggested that chronic hepatitis B (CHB) patients with renal impairment opt for ETV or TAF. However, there is a scarcity of global reports on the adverse effects of ETV and TAF. ETV, being a guanosine nucleoside analogue, acts as a potent inhibitor of HBV.ETV is quickly metabolized into its 5-triphosphate form within cellular environments, demonstrating a potent affinity for hepatitis B virus (HBV) polymerase. Its potency in laboratory settings is 30 times superior to lamivudine. Through its competition with the natural substrate deoxyguanosine triphosphate, the 5-triphosphate form of ETV halts all enzymatic activities of HBV polymerase\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e.As a result, it yields a significant antiviral action and is chiefly secreted via the urine in its unaltered state.Studies have shown\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003eETV accumulation over time leads to an increased burden on several different transport systems in the renal tubules, including organic anion transporters, organic cation transporters, the multidrug resistance-associated protein family, and p-glycoprotein, potentially causing renal tubular damage. This may ultimately manifest as abnormalities in urinary microproteins, such as α1-microglobulin (α1-MG) and β2-microglobulin (β2-MG), urinary N-acetyl-β-D-glucosaminidase (NAG), and retinol-binding protein (RBP).and related research\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003eindicates that the long-term administration of ETV results in a certain degree of renal tubular damage. Additionally, it has been demonstrated that urinary levels of microglobulins, including α1-microglobulin (α1-MG) and β2-microglobulin (β2-MG), as well as urinary N-acetyl-β-D-glucosaminidase (NAG) and retinol-binding protein (RBP), can serve as indicators for the early prediction of renal tubular injury induced by ETV.TAF, serving as an ester prodrug of tenofovir (TFV), and TFV, which is a non-cyclic nucleotide phosphonate drug, demonstrates potent and broad-spectrum antiviral activity in vitro, achieved via two phosphorylation steps.As it already incorporates a phosphate moiety, it skips the initial phosphorylation stage and can attach to native deoxyribonucleic acid substrates, hindering the activity of viral polymerases. Furthermore, it embeds itself into viral DNA, halting the replication process of the DNA strand, thus efficiently fighting against the hepatitis B virus.It is primarily eliminated through glomerular filtration and active tubular secretion by the kidneys.To mitigate the nephrotoxicity caused by TFV and to maintain its instability within cells while stabilizing it in plasma esterases, TFV prodrugs such as TDF and TAF have been developed. However, TDF has the potential to inadvertently lead to the accumulation of TFV due to premature hydrolysis, which could potentially result in toxicity to bones and kidneys.To tackle this issue, TAF adjusts TDF by incorporating a phenol and an isopropyl alaninate, thereby bypassing the initial phosphorylation of nucleoside analogues. This modification ensures a controlled rate of nucleoside triphosphate synthesis. Non-cyclic phosphates are inherently monophosphate compounds, and amide ester compounds serve to mask divalent anions, improve permeability, and subsequently modify the cellular distribution of TFV.Thus, while TDF undergoes widespread breakdown, TAF is specifically susceptible to certain enzymes in the cells it aims to affect, such as cathepsin A (Cat A) in peripheral blood mononuclear cells (PBMCs). This selectivity in enzyme sensitivity contributes to its enhanced stability in non-targeted tissues, leading to decreased systemic exposure and a higher concentration of TFV in the targeted cells.\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003eIn the currently existing relevant studies\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003eindicates higher bone kidney safety for TAF.However, TAF remains a prodrug of TFV, and therefore there is still a risk of kidney damage associated with its long-term use.Current related research\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003eindicates that long-term use of ETV is associated with a higher risk of renal function decline compared to TAF. Therefore, this study conducts relevant research on the renal safety of switching or not switching to TAF in patients who have already experienced renal tubular damage due to ETV.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eResearch subject\u003c/p\u003e\n\u003cp\u003eEnroll patients diagnosed with chronic hepatitis B (CHB) who have consistently received entecavir (ETV) antiviral therapy and have subsequently developed renal tubular injury. These patients should be recruited from the outpatient department of the Infectious Disease Division at the First Affiliated Hospital of Nanchang University in Jiangxi Province, between the years 2022 and 2023. Subsequently, assign these individuals to either the tenofovir alafenamide (TAF) treatment group (TAF group) or the group that continues with ETV treatment (ETV group).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Inclusion Criteria\u003c/p\u003e\n\u003cp\u003e1）Gender-neutral,Age\u0026ge;18years，\u0026lt;65years;2）The body mass index (BMI) should be between 18.0 and 35.0 kg/m2 (inclusive).and weight\u0026ge;40kg;3）At least one year of regular ETV antiviral treatment has been conducted,and if any of the urinary microalbumin test indicators exceeds the upper limit value, it is as follows：Urine \u0026alpha;1-MG\u0026gt;=12mg/L;Urine \u0026beta;2-MG\u0026gt;=0.3mg/L;Urine \u0026nbsp; NAG\u0026gt;=11.5U/L;Urine RBP\u0026gt;=0.7mg/L;4）CHB patients with abnormal urinary microalbumin detection after ETV treatment (as above) who switched to TAF treatment.\u003c/p\u003e\n\u003cp\u003eExclusion Criteria\u003c/p\u003e\n\u003cp\u003e1）CHB patients who have been diagnosed with kidney disease or have recently taken other nephrotoxic drugs;2）CHB patients with poorly controlled hypertension, diabetes, hyperuricemia, and hyperlipidemia;3）Pregnant women, patients over the age of 65;4）Combine patients with other tumor diseases and those with rheumatological and immune system-related diseases;5）Patients with hepatitis B treated with the combined use of other types of anti-hepatitis B drugs (such as TDF etc.)\u003c/p\u003e\n\u003cp\u003eResearch indicators\u003c/p\u003e\n\u003cp\u003eGather the gender and age of the enrolled patients, along with renal tubular markers: obtain morning urine samples for the analysis of\u0026nbsp;\u0026alpha;1-microglobulin (\u0026alpha;1-MG),\u0026nbsp;\u0026beta;2-microglobulin (\u0026beta;2-MG), urinary N-acetyl-\u0026beta;-D-glucosaminidase (NAG), urinary retinol-binding protein (RBP), serum creatinine, serum phosphorus, indicators of liver fibrosis, quantification of hepatitis B virus DNA (HBV-DNA), and hepatitis B e antigen (HBeAg). Utilize the testing indicators and reference ranges established by the First Affiliated Hospital of Nanchang University for all markers, and monitor these indicators over a period of 24 weeks.\u003c/p\u003e\n\u003cp\u003eDetection method\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;The HBV viral markers and blood phosphorus levels are determined in accordance with the standards and reference value ranges established by the Clinical Laboratory of the First Affiliated Hospital of Nanchang University. Renal function was assessed using the Hitachi 7600 automatic biochemical analyzer in conjunction with compatible reagents, with the reference range for blood creatinine levels set between 57-97\u0026mu;mol/L. Liver fibrosis indicators were measured using ultrasound technology for transient elastography (TE), where values exceeding 7.0Kpa are deemed abnormal. The urine\u0026nbsp;\u0026alpha;1-microglobulin (\u0026alpha;1-MG), urine\u0026nbsp;\u0026beta;2-microglobulin (\u0026beta;2-MG), and urine N-acetyl-\u0026beta;-D-glucosaminidase (NAG), as well as urine retinol-binding protein (RBP) test kits were supplied by Chongqing Bosstai Biotechnology Co., Ltd. The operational procedures were conducted following the manufacturer\u0026apos;s instruction manual, with the respective reference ranges being 0 -12mg/L, 0.1-0.3 mg/L, 0-11.5U/L, and 0-0.7 mg/L.\u003c/p\u003e\n\u003cp\u003eStatistical methods\u003c/p\u003e\n\u003cp\u003eThe analysis of data was executed with the aid of SPSS statistical software, version 26.0. Initially, data imputation was undertaken to secure a full dataset, and the comparison of count data between two groups was executed using the Chi-square test or Fisher\u0026apos;s exact probability test. For quantitative data that adhered to a normal distribution, the values were denoted as x\u0026plusmn;s, and the paired t-test was applied for comparing two groups; for quantitative data that did not adhere to a normal distribution, the values were denoted as M(P25 to P75), and the Wilcoxon signed-rank test was applied for comparing two groups. A P value of less than 0.05 (P\u0026lt;0.05) was considered to be statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThis investigation encompassed a total of 224 individuals diagnosed with hepatitis B, who were categorized into two distinct cohorts based on their medication regimen in response to abnormal renal tubular indicators: 122 subjects persisted with Entecavir (ETV) therapy, while 102 transitioned to Tenofovir Alafenamide (TAF) treatment. Following a 24-week period of observation, the mean glomerular filtration rate (GFR) was determined to be 103.25\u0026thinsp;\u0026plusmn;\u0026thinsp;2.30 mL/(min*1.73m^2) for the ETV cohort and 100.22\u0026thinsp;\u0026plusmn;\u0026thinsp;2.37 mL/(min*1.73m^2) for the TAF cohort, indicating no statistically significant difference (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).In terms of HBV-DNA (ETV: positive 2 cases, low viral load 6 cases, negative 114 cases; TAF: positive 0 cases, low viral load 16 cases, negative 86 cases; the complete viral response rates were 93.44% and 84.31% respectively), the difference was statistically significant (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).The ETV group and the TAF group showed no statistically significant difference in HBeAg seroconversion (ETV group: 88 cases negative, 34 cases positive; TAF group: 68 cases negative, 34 cases positive, with negative conversion rates of 72.1% and 66.7%, respectively; P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).After 24 weeks, there were statistically significant differences between the two groups in liver stiffness index, blood phosphorus, and urinary β2-MG (ETV M (P25,P75): 7.49, 1.07, 0.31 vs TAF M (P25,P75): 6.93, 0.93, 0.26, Z=-2.84, -2.39, -2.04, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). There were no significant statistical differences between the two groups in the remaining indicators, as shown in Table\u0026nbsp;1.\u003c/p\u003e \u003cp\u003eUpon the exclusion of confounding factors and the application of 1:1 propensity score matching (PSM), 62 patients were selected for each treatment cohort. Following a 24-week period, no significant statistical differences were noted in kidney-related indicators between the two cohorts, as indicated in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. And after 24 weeks, there was no significant statistical difference in eGFR between the two groups (ETV: 101.56\u0026thinsp;\u0026plusmn;\u0026thinsp;3.35 mL/(min*1.73m^2) vs TAF: 100.17\u0026thinsp;\u0026plusmn;\u0026thinsp;3.55 mL/(min*1.73m^2), p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), and the changes in eGFR over the 24-week period were not significantly different between the two groups (Z=-1.672, P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).The change in RBP levels before and after 24 weeks (△ETV: 0.159 vs △TAF: 0.213, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) exhibited no significant statistical variation; However, the difference in HBV-DNA levels (ETV group: positive in 2 cases, negative in 54 cases, and low viral load in 6 cases vs TAF group: positive in 0 cases, negative in 57 cases, and low viral load in 5 cases, with a complete viral response rate of 87.09% and 91.93%; Z=-8.951, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) was statistically significant, as shown in Table\u0026nbsp;4. Serological conversion of HBeAg (ETV group: 42 cases negative conversion, 20 cases positive; TAF group: 45 cases negative conversion, 17 cases positive, with negative conversion rates of 67.74% and 72.58%, respectively) showed no statistically significant difference (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05),This is illustrated inas shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.The liver stiffness indicators did not exhibit a significant statistical difference between the two groups, nor in their alterations following the 24-week period (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).The alterations in the levels of α1-MG, β2-MG, NAG, and blood phosphorus, both pre- and post-intervention at 24 weeks, were found to be statistically significant between the two groups (△ETV: -4.016, -0.374, -0.853, +\u0026thinsp;0.019 vs △TAF: -12.050, -1.272, -5.583, -0.286, with Z=-3.158, -2.983, -2.643, -3.226, and p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). This is illustrated in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1.24\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eweeks later, the relevant indicators of the two groups before PSM\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eETV\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTAF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ/t value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eexamples\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eeGFR\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(mL/(min*1.73m2), x\u0026thinsp;\u0026plusmn;\u0026thinsp;s)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e103.25\u0026thinsp;\u0026plusmn;\u0026thinsp;2.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100.22\u0026thinsp;\u0026plusmn;\u0026thinsp;2.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.266\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLiver stiffness\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(Kpa,M( P25,P75 ))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.49(6.80,7.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.93(6.92,6.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-2.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBlood phosphorus\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(mmol/L, M ༈P25,P75 ))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.07(0.97,1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.93(0.91,0.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-2.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUrine α1-MG(mg/LM( P25,P75 ))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.85(6.32,18.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.10(6.71,16.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-1.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUrine β2-MG(mg/L,M( P25,P75 ))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.31(0.18,0.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.26(0.16,0.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-2.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.044\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUrine NAG(U/L,M( P25,P75 ))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.33(9.69,11.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.10(8.37,14.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.729\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUrine RBP(mg/L,M( P25,P75 ))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.33(033,0.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.38(0.30,0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e*eGFR, estimated glomerular filtration rate; TAF, tenofovir alafenamide;ETV, entecavir\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e24 weeks later, the relevant indicators of the two groups after PSM\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eETV\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTAF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ/t value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eexamples\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eeGFR\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(mL/(min*1.73m2), x\u0026thinsp;\u0026plusmn;\u0026thinsp;s)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101.56\u0026thinsp;\u0026plusmn;\u0026thinsp;3.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100.17\u0026thinsp;\u0026plusmn;\u0026thinsp;3.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.784\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLiver stiffness\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(Kpa,M( P25,P75 ))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.43(5.80, 7.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.92(6.45, 7.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.628\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBlood phosphorus\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(M(mmol/L, P25,P75 ))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.04(0.88, 1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.94(0.92, 1.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.961\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUrine α1-MG(mg/LM( P25,P75 ))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.45(7.25, 20.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.44(5.89, 14.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-1.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.099\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUrine β2-MG(mg/L,M( P25,P75 ))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.31(0.19, 0.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.26(0.16, 0.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.461\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUrine NAG(U/L,M( P25,P75 ))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.38(10.82, 13.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.01(6.65, 14.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.574\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUrine RBP(mg/L,M( P25,P75 ))\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.33(0.31, 0.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.38(0.30, 0.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e*eGFR, estimated glomerular filtration rate; TAF, tenofovir alafenamide;ETV, entecavir\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"554\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 13.6755%;\"\u003e\n \u003cp\u003eTable3. Comparison of \u0026nbsp;HBeAg seroconversion rates between two groups after 24 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.1258%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 15.8113%;\"\u003e\n \u003cp\u003eBefore\u0026nbsp;PSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 18.1291%;\"\u003e\n \u003cp\u003eAfter PSM\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.1258%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.1954%;\"\u003e\n \u003cp\u003eETV(n=122)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.6159%;\"\u003e\n \u003cp\u003eTAF(n=102)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4371%;\"\u003e\n \u003cp\u003eETV(n=62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.6921%;\"\u003e\n \u003cp\u003eTAF(n=62)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.1258%;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.1954%;\"\u003e\n \u003cp\u003e88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.6159%;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4371%;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.6921%;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.1258%;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.1954%;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.6159%;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4371%;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.6921%;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.1258%;\"\u003e\n \u003cp\u003eX\u003csup\u003e2\u003c/sup\u003e \u003cstrong\u003evalue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 15.8113%;\"\u003e\n \u003cp\u003e0.785\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 18.1291%;\"\u003e\n \u003cp\u003e0.347\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.1258%;\"\u003e\n \u003cp\u003eP \u003cstrong\u003evalue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 15.8113%;\"\u003e\n \u003cp\u003e0.376\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 18.1291%;\"\u003e\n \u003cp\u003e0.556\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 45.7781%;\"\u003e\n \u003cp\u003e* TAF, tenofovir alafenamide；ETV，entecavir;HBeAg,hepatitis B e antigen\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\" style=\"width: 12.5445%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable\u003c/strong\u003e 4. \u003cstrong\u003eThe HBV-DNA response effect after 24 weeks between the two groups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 2.5931%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 11.435%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBefore\u003c/strong\u003e PSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 11.605%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAfter PSM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 2.5931%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.1457%;\"\u003e\n \u003cp\u003eETV（n=124）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.4858%;\"\u003e\n \u003cp\u003eTAF(n=102)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.4655%;\"\u003e\n \u003cp\u003eZ/t\u0026nbsp;value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.338%;\"\u003e\n \u003cp\u003eP\u0026nbsp;value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.2307%;\"\u003e\n \u003cp\u003eETV(n=62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.1457%;\"\u003e\n \u003cp\u003eTAF(n=62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.4655%;\"\u003e\n \u003cp\u003eZ/t\u0026nbsp;value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.7631%;\"\u003e\n \u003cp\u003eP\u0026nbsp;value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 2.5931%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePositive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.1457%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.4858%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 2.4655%;\"\u003e\n \u003cp\u003e-12.426\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 2.338%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.2307%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.1457%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 2.4655%;\"\u003e\n \u003cp\u003e-8.951\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 2.7631%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 2.5931%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNegative\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.1457%;\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.4858%;\"\u003e\n \u003cp\u003e86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.2307%;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.1457%;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 2.5931%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLow viral load\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.1457%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.4858%;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.2307%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.1457%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\" style=\"width: 27.9286%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e*HBV-DNA,hepatitis B virus DNA;\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;TAF, tenofovir\u003c/strong\u003e \u003cstrong\u003ealafenamide；ETV，entecavir;Low viral load,HBV-DNA levels below 2000 IU/mL.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChange in the magnitude of related indicators after 24 weeks between two groups after PSM\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eETV(∆, x\u0026thinsp;\u0026plusmn;\u0026thinsp;s)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTAF(∆, x\u0026thinsp;\u0026plusmn;\u0026thinsp;s)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e∆ eGFR\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(-)0.736\u0026thinsp;\u0026plusmn;\u0026thinsp;1.514\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(-)10.380\u0026thinsp;\u0026plusmn;\u0026thinsp;4.486\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-1.672\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e∆ Liver stiffness\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(-)0.389\u0026thinsp;\u0026plusmn;\u0026thinsp;0.237\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(-)0.970\u0026thinsp;\u0026plusmn;\u0026thinsp;0.464\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.505\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.614\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e∆ Blood phosphorus\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(+)0.019\u0026thinsp;\u0026plusmn;\u0026thinsp;0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(-)0.286\u0026thinsp;\u0026plusmn;\u0026thinsp;0.209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-3.226\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e∆ Urine α1-MG\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(-)4.016\u0026thinsp;\u0026plusmn;\u0026thinsp;1.677\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(-)12.050\u0026thinsp;\u0026plusmn;\u0026thinsp;2.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-3.158\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e∆ Urineβ2-MG\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(-)0.374\u0026thinsp;\u0026plusmn;\u0026thinsp;0.572\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(-)1.272\u0026thinsp;\u0026plusmn;\u0026thinsp;0.608\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-2.983\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e∆ UrineN AG\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(-)0.853\u0026thinsp;\u0026plusmn;\u0026thinsp;0.684\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(-)5.583\u0026thinsp;\u0026plusmn;\u0026thinsp;1.345\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-2.643\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e∆ Urine RBP\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(-)0.159\u0026thinsp;\u0026plusmn;\u0026thinsp;0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(-)0.213\u0026thinsp;\u0026plusmn;\u0026thinsp;0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-1.773\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.076\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e*eGFR, estimated glomerular filtration rate; TAF, tenofovir alafenamide;ETV, entecavir\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAmong the primary anti-hepatitis B virus medications, entecavir (ETV) and tenofovir alafenamide (TAF) are extensively utilized for their high efficacy, minimal side effects, and favorable cost-effectiveness ratios. During prolonged antiviral therapy, the clinical response is frequently indicated by the impact on hepatitis B virus DNA (HBV-DNA) levels. Per the guidelines of the American Association for the Study of Liver Diseases (AASLD), HBV-DNA levels below 2000 IU/mL are classified as low viremia. A low viral load is correlated with a heightened risk of liver cancer, particularly in individuals with cirrhosis\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e.In this investigation, among renal tubular index abnormalities patients with suboptimal viral response to ETV, those who either persisted with ETV or transitioned to TAF therapy for 24 weeks exhibited notable differences. Specifically, among patients who continued ETV, there were 2 instances of HBV-DNA positivity and 6 cases of low viral load. Conversely, in the group that switched to TAF, there were no cases of positivity and 5 instances of low viral load. Although the rates of HBeAg seroconversion did not differ significantly between the two treatments (ETV: 67.74%, TAF: 72.58%), TAF demonstrated a marginally higher seroconversion rate. Should future studies include a larger sample size, additional evidence may emerge. TAF appears to offer a higher rate of complete viral response compared to ETV, and for chronic hepatitis B patients with a poor response to long-term ETV treatment, switching to TAF enhances viral response efficiency.Consequently, for individuals suffering from chronic hepatitis B who have experienced kidney tubular injury and exhibit a low viral load as a result of prolonged exposure to ETV, transitioning to TAF therapy may represent a beneficial therapeutic strategy. The hepatitis B virus is a significant contributor to liver cirrhosis, a condition that arises from recurrent liver damage and subsequent healing processes, which trigger an overproduction of collagen and alterations in the extracellular matrix by hepatic stellate cells\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e.In this study, we assessed the extent of liver fibrosis, also known as liver stiffness, in hepatitis B patients by employing transient elastography (TE), a technique grounded in ultrasound technology. It is important to note that the liver stiffness index may be influenced by various factors, including postprandial fullness, inflammation, passive venous congestion, portal hypertension, and biliary obstruction\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.In this study, patients with clear hepatitis B cirrhosis and liver dysfunction were excluded. The findings suggest a significant disparity in the extent of liver fibrosis between the group that continued ETV treatment and the group that switched to TAF treatment after 24 weeks, prior to propensity score matching (PSM). Median values indicate that the liver fibrosis indicators for the TAF group are lower. Might this imply that TAF is more effective in improving liver fibrosis than ETV? After accounting for confounding variables, no significant statistical disparity was observed in the data comparison and their deviations from baseline between the two groups at the 24-week mark. This could be attributed to the fact that, prior to controlling for these variables, the baseline values for the ETV group were higher, resulting in a skewed difference. Additionally, all liver fibrosis indicators for the patients in this study fell within the normal range, which might explain why TAF and ETV had minimal impact on them. Should patients with hepatitis B cirrhosis be included in future studies to monitor the effects of these two drugs on their liver fibrosis indicators, it is possible that distinct effects would become apparent. Furthermore, ultrasound-based elastography can be influenced by numerous unpredictable factors. To achieve a comprehensive evaluation and validation, it would be advisable to incorporate additional indicators such as liver color Doppler ultrasound, portal vein pressure, and blood liver fibrosis tests in subsequent analyses.\u003c/p\u003e \u003cp\u003eReports indicate that nucleoside analogues can induce Fanconi syndrome, characterized by varying levels of dysfunction in the proximal renal tubules. Symptoms include hypophosphatemia, hypouricemia, aminoaciduria, and glycosuria. Hypophosphatemia, in particular, may result in impaired bone mineralization, osteomalacia, and an increased risk of fractures\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Consequently, when it comes to kidney injury induced by nucleoside analogues, the primary damage is inflicted upon the renal tubules. Hence, indicators that monitor renal tubular injury should exhibit greater sensitivity than eGFR. In this research, the serum phosphorus levels at week 24 exhibited a significant difference when compared to the baseline values for both the ETV group and the TAF switch group. The ETV group demonstrated an upward trend in variation, whereas TAF continued to decline. This result may be attributed to factors including diet, gastrointestinal absorption, renal absorption, and phosphate transport. Therefore, relying exclusively on blood phosphorus levels to assess renal function remains questionable. For future investigations, it is advisable to incorporate comprehensive evaluation indicators such as urinary phosphorus, urinary microalbumin, and the urinary microalbumin-to-creatinine ratio.\u003c/p\u003e \u003cp\u003eUrine α1-MG is a protein with a low molecular weight of 27 kDa, initially identified over half a century ago. In individuals with healthy kidneys, α1-MG protein readily traverses the glomerular membrane, with nearly 99% subsequently being reabsorbed and metabolized by the cells of the proximal tubule\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e, consequently, an elevation in urinary α1-MG serves as an early indicator of renal impairment, predominantly affecting the proximal renal tubules. Its notable stability within urine has led to its adoption as a marker for tubular dysfunction, setting it apart from other markers of the tubules\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Urine RBP and urine β2-MG are also biomarkers of renal tubular dysfunction, with their low molecular weights being 21 kDa and 11 kDa, respectively,They can also be freely filtered by the glomerulus and almost completely reabsorbed by the proximal tubule\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. NAG, a lysosomal hydrolase with a molecular weight of 150 kDa, is exclusively secreted into the urine by damaged proximal renal tubular cells. The increase in its levels indicates damage to the tubular structure\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. In summary, this study employed urinary biomarkers α1-MG, β2-MG, NAG, and RBP to evaluate early tubular injury. Following 24 weeks of treatment, the TAF group exhibited notably reduced levels of urinary α1-MG, β2-MG, and NAG compared to the ETV group. However, no significant difference in urinary RBP levels was observed between the two groups. Additionally, after 24 weeks, there were no significant differences in renal tubular indicators or estimated Glomerular Filtration Rate (eGFR) between the two groups. This could be attributed to the fact that the study primarily focused on outcomes related to early tubular injury, whereas eGFR predominantly indicates glomerular damage. After 24 weeks, renal tubular indicators remained statistically similar between the two groups, potentially due to baseline disparities in renal tubular indicator levels, which undermined the statistical significance of the results. Upon data adjustment, a clear and significant difference in the variation of three renal tubular indicators became evident, with the TAF group demonstrating a more pronounced advantage in the reversal of renal tubular injury.In current research, urinary RBP primarily functions as a significant indicator for the prediction of diabetic nephropathy\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. However, this study involved patients who had already been screened out for renal dysfunction and underlying diseases associated with hepatitis B, hence no significant difference was observed between the two groups.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eFor chronic hepatitis B patients who develop kidney tubular injury with low levels of viral replication while on ETV therapy, transitioning to TAF can not only reverse the kidney tubular damage but also enhance the efficacy of the antiviral response. This underscores the significance for clinicians to evaluate the early kidney injury induced by nucleos(t)ide analogues, facilitating early detection, diagnosis, and intervention.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgements\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eZD and ZY contributed to the study design, data collection, analysis, quality checking and editing the manuscript. MY and ZLH has contributed to data collection. ZLL has contributed to review and editing the manuscript. ZY (guarantor) takes the responsibility for the content of the manuscript, including the data and analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFunding\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study had no financial support.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData availability\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData are available by the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Committee of the First Affiliated Hospital of Nanchang University of China (Batch number: IIT2024206). The need for informed consent was waived for patients by the Committee of the First Affiliated Hospital of Nanchang University of China.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eClinical trial number\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGuidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection[R]. Geneva: World Health Organization, 2024.\u003c/li\u003e\n\u003cli\u003eOpio C K, Lee W M, Kirkpatrick P. Entecavir[J]. Nature Reviews Drug Discovery, 2005, 4(7): 535-536.\u003c/li\u003e\n\u003cli\u003eYang X, Ma Z, Zhou S, et al. Multiple Drug Transporters Are Involved in Renal Secretion of Entecavir[J]. Antimicrobial Agents and Chemotherapy, 2016, 60(10): 6260-6270.\u003c/li\u003e\n\u003cli\u003eChe Yuanmei, Wang liang, Zhang Lunli, et al.. Influence of long-term use of entecavir on renal tubular function in patients with chronic hepatitis B[J]. Journal of Clinical Hepatobiliary Studies, 2023, 39(6): 1313-1317.\u003c/li\u003e\n\u003cli\u003eLee W A, Cheng A K. Tenofovir alafenamide fumarate[J]. Antiviral Therapy, 2022, 27(2): 135965352110676.\u003c/li\u003e\n\u003cli\u003eAgarwal K, Brunetto M, Seto W K, et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection[J]. Journal of Hepatology, 2018, 68(4): 672-681.\u003c/li\u003e\n\u003cli\u003eJung C, Kim H W, Ahn S H, et al. Higher risk of kidney function decline with entecavir than tenofovir alafenamide in patients with chronic hepatitis B[J]. Liver International, 2022, 42(5): 1017-1026.\u003c/li\u003e\n\u003cli\u003eKim J H, Sinn D H, Kang W, et al. Low‐level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment[J]. Hepatology, 2017, 66(2): 335-343.\u003c/li\u003e\n\u003cli\u003eTa W. Cellular and molecular mechanisms of fibrosis[J]. The Journal of pathology, 2008, 214(2).\u003c/li\u003e\n\u003cli\u003eOzturk A, Olson M C, Samir A E, et al. Liver fibrosis assessment: MR and US elastography[J]. Abdominal Radiology (New York), 2022, 47(9): 3037-3050.\u003c/li\u003e\n\u003cli\u003eFujii T, Kawasoe K, Ohta A, et al. A case of entecavir-induced Fanconi syndrome[J]. CEN case reports, 2019, 8(4): 256-260.\u003c/li\u003e\n\u003cli\u003eGara N, Zhao X, Collins M T, et al. Renal tubular dysfunction during long‐term adefovir or tenofovir therapy in chronic hepatitis B[J]. Alimentary Pharmacology \u0026amp; Therapeutics, 2012, 35(11): 1317-1325.\u003c/li\u003e\n\u003cli\u003eB A, L L, T B, et al. alpha(1)-Microglobulin: a yellow-brown lipocalin[J]. Biochimica et biophysica acta, 2000, 1482(1-2).\u003c/li\u003e\n\u003cli\u003eIshiwata S, Matsue Y, Nakamura Y, et al. Clinical and prognostic values of urinary alpha1-microglobulin as a tubular marker in acute heart failure[J]. International Journal of Cardiology, 2021, 338: 115-120.\u003c/li\u003e\n\u003cli\u003eNorden A G W, Lapsley M, Unwin R J. Urine retinol-binding protein 4: a functional biomarker of the proximal renal tubule[J]. Advances in Clinical Chemistry, 2014, 63: 85-122.\u003c/li\u003e\n\u003cli\u003eNorden A G W, Gardner S C. Lysosomal enzymuria is a feature of hereditary Fanconi syndrome and is related to elevated CI-mannose-6-P-receptor excretion[J].\u003c/li\u003e\n\u003cli\u003eCai F, Zhang L, Zhao P, et al. Urinary RBP as an Independent Predictor of Renal Outcome in Diabetic Nephropathy[J]. Disease Markers, 2022(9687868): 13.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Chronic Hepatitis B, Nucleoside Analogues, and Kidney Safety","lastPublishedDoi":"10.21203/rs.3.rs-5283480/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5283480/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground and aims: Urinary α\u003csub\u003e1\u003c/sub\u003e-microglobulin (α\u003csub\u003e1\u003c/sub\u003e-MG), β\u003csub\u003e2\u003c/sub\u003e-microglobulin (β\u003csub\u003e2\u003c/sub\u003e-MG), urinary N-acetyl-β-glucosaminidase (NAG) and retinol-binding protein (RBP) have predictive effects on renal tubular injury, the purpose of this study is to investigate whether the renal tubular abnormalities in chronic hepatitis B (CHB) patients during long-term entecavir (ETV) treatment cloud be improved after altering to tenofovir alafenamide(TAF).\u003c/p\u003e\n\u003cp\u003eMethods：This study included 224 CHB patients of abnormal renal tubular markers from June 2022 to September 2023, of which 122 patients continuing ETV and 102 patients of altering to TAF for 6 months. Propensity score matching was used to\u0026nbsp; analyze the differences of renal tubular indexes between the continuing ETV treatment and altering to TAF treatment.\u003cbr\u003e\nResults: A 1:1 propensity score match yielded 62 patients in each treatment group.The baseline characteristics, the ratio of complete virology respond,liver blood phosphorus, the estimated glomerular filtration rate (eGFR), α\u003csub\u003e1\u003c/sub\u003e-MG, β\u003csub\u003e2\u003c/sub\u003e-MG, NAG, RBP were comparable between the two groups. After 6 months, the level of eGFR(ETV:101.5mL/(min*1.73m\u003csup\u003e2\u003c/sup\u003e),TAF:100.1mL/(min*1.73m\u003csup\u003e2\u003c/sup\u003e),p\u0026gt;0.05),RBP(△ETV -0.159 △TAF -0.213,p\u0026gt;0.05), the ratio of complete virology response(ETV 87.1% TAF 91.9%,P\u0026lt; 0.05) were statistically different.The difference ratio of α\u003csub\u003e1\u003c/sub\u003e-MG, β\u003csub\u003e2\u003c/sub\u003e-MG, NAG, blood phosphorus was statistically significant（p\u0026lt;0.05）。TAF decreased more than ETV in α1-MG, β2-MG, NAG indicators(△ETV: -4.016, -0.373,-0.852, △TAF: -12.050, -1.272, -5.583），TAF increased less than ETV in blood phosphorus\u0026nbsp; (△ETV +0.019, △TAF\u0026nbsp; -0.286）。\u003c/p\u003e\n\u003cp\u003eConclusion: Altering to TAF of CHB patients with renal tubular abnormalities after long-term use of ETV , the treatment efficacy and renal tubular damage can be improved, indicating that TAF has better renal safety than ETV.\u003c/p\u003e","manuscriptTitle":"Tenofovir Alafenamide versus Entecavir in the Treatment of Renal Safety in Patients with Chronic Hepatitis B: An Observational Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-30 09:33:55","doi":"10.21203/rs.3.rs-5283480/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0ce2bcad-f91f-4f9d-951e-52d2c430cbd5","owner":[],"postedDate":"October 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-08T11:08:30+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-30 09:33:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5283480","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5283480","identity":"rs-5283480","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}