Ning HB, Jin HM, Peng Z, Li K, Shang J. Bone and renal safety of initial antiviral therapy using tenofovir alafenamide fumarate or entecavir for chronic hepatitis B. World J Gastroenterol 2026; 32(22): 117500 [DOI: 10.3748/wjg.v32.i22.117500]
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Ning HB, Jin HM, Peng Z, Li K, Shang J. Bone and renal safety of initial antiviral therapy using tenofovir alafenamide fumarate or entecavir for chronic hepatitis B. World J Gastroenterol 2026; 32(22): 117500 [DOI: 10.3748/wjg.v32.i22.117500]
Author contributions: Ning HB designed the research and wrote the first manuscript; Ning HB, Jin HM, Peng Z and Li K contributed to conceiving the research and analyzing data; Ning HB and Shang J conducted the analysis and provided guidance for the research; all authors reviewed and approved the final manuscript.
Institutional review board statement: This study was approved by the Ethic Committee of Henan Provincial People's Hospital, No. 21, 2019.
Informed consent statement: All the study subjects provided informed consent.
Conflict-of-interest statement: There is no conflict of interest.
Data sharing statement: No additional data are available.
Received: January 6, 2026 Revised: January 29, 2026 Accepted: March 17, 2026 Published online: June 14, 2026 Processing time: 142 Days and 17.9 Hours
Abstract
BACKGROUND
Nucleoside/nucleotide analogs are currently the core drugs for antiviral treatment of chronic hepatitis B (CHB). Among them, entecavir (ETV) and tenofovir alafenamide fumarate (TAF) exhibit potent antiviral effects with low resistance rates and are recommended as first-line treatment regimens in domestic and international guidelines.
AIM
To evaluate bone and renal safety in patients with CHB receiving initial treatment with TAF or ETV.
METHODS
This study included 95 treatment-naive patients with CHB and were treated at the Infectious Diseases Department of Henan Provincial People’s Hospital from August 2019 to June 2020. They were assigned to either the TAF group (n = 45, 25 mg/day) or the ETV group (n = 50, 0.5 mg/day) according to the antiviral treatment plan. Patients’ basic clinical data were collected. Their bone mineral density, bone-related markers, and various renal function indicators were also measured and compared.
RESULTS
The study cohort had a mean age of 41.01 ± 11.67 years and a cirrhosis prevalence of 18.9%. At baseline, serum Ca (2.33 ± 0.13 vs 2.30 ± 0.15, t = 0.935, P = 0.352), serum P (1.12 ± 0.21 vs 1.12 ± 0.19, t = 0.026, P = 0.980), and 25-hydroxyvitamin D3 [25(OH)D] (22.67 ± 7.98 vs 24.96 ± 11.30, t = 1.122, P = 0.265) were comparable across groups. When the follow-up was extended to 96W, the abnormality rates of urinary A1M (4.4% vs 20.0%, χ2 = 5.193, P = 0.023), N-acetyl-beta-D-glucosaminidase (6.7% vs 24.0%, χ2 = 5.352, P = 0.021), and urine cystatin (4.4% vs 18.0%, χ2 = 4.251, P = 0.039) exhibited marked between-group differences.
CONCLUSION
For patients with CHB on long-term nucleoside drug use, comprehensive monitoring of bone and renal safety should be conducted as treatment duration increases. In this study, TAF outperforms ETV in renal tubular safety after long-term application.
Core Tip: Nucleoside/nucleotide analogs are currently the core drugs for the antiviral treatment of chronic hepatitis B (CHB). Among them, entecavir (ETV) and tenofovir alafenamide fumarate (TAF) are recommended as first-line treatment regimens in domestic and international guidelines due to their potent antiviral activity and low resistance rates. However, direct comparative data between TAF and ETV remain limited, particularly in long-term follow-up studies of Chinese CHB populations. The long-term differences in bone and renal safety between TAF and ETV warrant further investigation. Therefore, this study aims to provide critical insights for optimizing individualized treatment strategies for CHB by comparing the clinical efficacy and safety profiles of ETV and TAF.
Citation: Ning HB, Jin HM, Peng Z, Li K, Shang J. Bone and renal safety of initial antiviral therapy using tenofovir alafenamide fumarate or entecavir for chronic hepatitis B. World J Gastroenterol 2026; 32(22): 117500
Chronic hepatitis B (CHB) is a global public health issue caused by hepatitis B virus infection. Prolonged infection can lead to liver cirrhosis, liver failure, and even hepatocellular carcinoma[1]. Nucleoside/nucleotide analogs (NAs) are the core drugs for the current antiviral treatment of CHB. Among them, entecavir (ETV) and tenofovir alafenamide fumarate (TAF) are recommended as first-line treatment options in domestic and foreign guidelines owing to their potent antiviral effects and low drug resistance rates[2]. However, concerns regarding the long-term safety of NA therapy—especially its potential effects on bone and kidney function—persist in clinical practice. Although tenofovir disoproxil fumarate (TDF), which was used earlier, has significant efficacy, it poses risks of renal tubular injury and decreased bone mineral density (BMD)[3]. TAF is a novel tenofovir prodrug that delivers the active drug more effectively to hepatocytes, thereby reducing the required dosage and systemic exposure. Compared to TDF, this improves renal and skeletal safety[4]. Although clinical trials have demonstrated TAF efficacy and safety in suppressing hepatitis B virus DNA, real-world data are essential to confirm these findings in a broader patient population[5]. Nevertheless, potential differences in bone and renal safety between TAF and ETV during long-term therapy remain to be confirmed by real-world data.
The nephrotoxicity mechanism of TDF likely results from mitochondrial damage in proximal renal tubular cells, triggering elevated levels of renal tubular markers [such as β2-microglobulin and α1-microglobulin (A1M)] in urine[6]. Despite its good renal safety, long-term ETV use may affect renal tubular function through unknown mechanisms[7]. TAF exhibits a satisfactory renal safety profile. For instance, Agarwal et al[8] demonstrated that patients receiving TAF maintained stable renal function over 96 weeks, whereas those receiving TDF therapy exhibited a significant decline in creatinine clearance. Similarly, Buti et al[9] linked TAF to a modest increase in serum creatinine and a slight decrease in glomerular filtration rate. In terms of bone metabolism, NAs may induce bone loss by interfering with osteoblast activity or calcium (Ca)-phosphorus (P) metabolism, especially in elderly or CHB patients with osteoporosis risk[10]. Due to its lower systemic exposure, TAF has shown better bone and renal safety than TDF in clinical trials[11].
Currently, although domestic and international guidelines emphasize the need for bone and kidney monitoring for patients undergoing NA treatment, a unified standard regarding monitoring frequency and indicators remains unavailable[12]. Notably, direct comparative data between TAF and ETV are scarce, especially for long-term follow-up studies in the Chinese CHB population. Furthermore, the existing literature predominantly compares TDF with TAF, leaving long-term differences in bone and renal safety between TAF and ETV inadequately explored. Through a prospective follow-up on CHB patients who initially received TAF or ETV treatment, this study analyzed changes in BMD, bone metabolism markers, and renal function indicators within 96 weeks, aiming to provide a basis for clinically selecting a safer antiviral regimen. The latest research indicates that TAF may be more suitable for patients with baseline renal dysfunction or a high risk of osteoporosis while maintaining efficacy[13], but data from the Chinese population requires supplementation. Therefore, the study results provide important references for optimizing individualized treatment strategies for CHB.
MATERIALS AND METHODS
Research participants
This study retrospectively enrolled 95 CHB patients who visited the Department of Infectious Diseases of Henan Provincial People’s Hospital between August 2019 and June 2020.
The specific eligibility criteria: (1) Hepatitis B surface antigen positive or a CHB history of > 6 months; (2) Treatment-naive status, defined as no previous exposure to antiviral drugs approved or clinically tested, and used TAF (25 mg/day) or ETV (0.5 mg/day) in our study; (3) Age > 18 years; and (4) Provision of written informed consent.
The exclusion criteria: (1) Hepatitis C virus/hepatitis D virus/human immunodeficiency virus co-infections; (2) Liver tumors and other organ system tumors; (3) Severe kidney, cardiovascular, lung, or nervous system diseases; (4) The need for immunotherapy drugs, antitumor drugs, or medications that affect bone and kidney metabolism; (5) Planned/current pregnancy or non-contraception during the research; (6) Previous interferon treatment; or (7) Decompensated cirrhosis, Child-Turcotte-Pugh grade B or C.
Eligible patients were assigned to two treatment groups according to the antiviral scheme: TAF (25 mg/day) or ETV (0.5 mg/day). Approval from the Medical Ethics Committee of Henan Provincial People’s Hospital was obtained before study commencement (Ethics Approval Document No. 21, 2019).
Detection methods
The blood routine, liver biochemical indexes, renal function, serum P/Ca, and virological indicators were all measured according to the standards and reference value ranges of our hospital’s Laboratory Department. The BMD detection equipment used was DEX A Dual-Energy X-ray Absorptiometry (Hologic QDR 2000, Hologic, Inc., United States). The Hologic QDR 2000 automatic internal quality control system was applied, with machine precision reaching 0.4%. The representative lumbar vertebrae L1-4 and the left femur were selected as the observation indicators, with the bone density values in units of g/cm2.
Data processing
Demographics and clinical baseline information (e.g., age, sex, liver cirrhosis status, and other comorbidities) of all enrolled subjects were collected. BMD (assessed via dual-energy X-ray detection), bone marker levels, and renal function indexes at baseline, 48 weeks, and 96 weeks were also obtained. The baseline data of 95 patients were analyzed using descriptive statistics.
Statistical analysis
Statistical analyses of epidemiological associations were performed using SPSS software (SPSS Inc., version 24.0, Chicago, IL, United States). The differences in serum Ca, P, and bone markers at baseline, 48 weeks, and 96 weeks across treatment groups were compared by two independent sample t-tests. Two independent samples χ2 were used to test inter-group variations in low bone mass (LBM) prevalence and renal function indicator abnormality rates across time points. Numerical variables that followed a normal distribution were represented by the mean ± SD, while those with a skewed distribution were described as the median (interquartile range). α = 0.05 is the significance level throughout.
RESULTS
Baseline data
In our case series, the mean age (years) and male-to-female ratio were 41.01 ± 11.67 and 1.37/1, respectively, with a cirrhosis incidence of 18.9%. The sex ratio (TAF: 1.81 vs ETV: 1.08), average age (TAF: 40.20 ± 11.08 vs ETV: 41.74 ± 12.24), and comorbidities (TAF: 15.56% vs ETV: 12.00%) were comparable among the TAF- and ETV-treated patients (P > 0.05). At baseline, serum Ca (2.33 ± 0.13 vs 2.30 ± 0.15, t = 0.935, P = 0.352), serum P (1.12 ± 0.21 vs 1.12 ± 0.19, t = 0.026, P = 0.980), and 25-hydroxyvitamin D3 [25(OH)D] (22.67 ± 7.98 vs 24.96 ± 11.30, t = 1.122, P = 0.265) did not significantly differ across the cohorts (Table 1). The LBM prevalence (11.1% vs 18.0%, χ2 = 0.895, P = 0.344), the blood testing results of urea (4.4% vs 0.0%, χ2 = 2.270, P = 0.132), creatinine (11.1% vs 18.0%, χ2 = 0.895, P = 0.344), retinol-binding protein (RBP) (15.6% vs 18.0%, χ2 = 0.101, P = 0.751), cystatin C (Cys-C) (4.4% vs 0.0%, χ2 = 2.270, P = 0.132), or the urine findings of A1M (15.6% vs 10.0%, χ2 = 0.662, P = 0.416), N-acetyl-beta-D-glucosaminidase (NAG) (22.2% vs 22.0%, χ2 = 0.001, P = 0.979), and urine cystatin (15.6% vs 14.0%, χ2 = 0.046, P = 0.831) at baseline did not show notable differences (Table 2).
Table 1 Baseline condition description of 95 patients, n (%)/mean ± SD/median (Q1, Q3).
Inter-group comparison of bone and renal safety indexes at 48 weeks
For bone indexes, at the 48-week follow-up, serum Ca (TAF group vs ETV group: 2.42 ± 0.38 vs 2.31 ± 0.15, t = 1.499, P = 0.140), serum P (TAF group vs ETV group: 1.06 ± 0.14 vs 1.00 ± 0.18, t = 1.190, P = 0.239), and 25(OH)D (TAF group vs ETV group: 24.26 ± 9.74 vs 22.74 ± 9.37, t = 0.555, P = 0.581) remained non-significantly different (Table 3). Similarly, for renal safety indexes, statistical significance was absent when detecting LBM prevalence (TAF group vs ETV group: 11.1% vs 18.0%, χ2 = 0.891, P = 0.344), blood urea (TAF group vs ETV group: 8.9% vs 6.0%, χ2 = 0.290, P = 0.591), and creatinine (TAF group vs ETV group: 2.2% vs 6.0%, χ2 = 0.838, P = 0.360), RBP (TAF group vs ETV group: 11.1% vs 8.0%, χ2 = 0.267, P = 0.605), and Cys-C (TAF group vs ETV group: 15.6% vs 10.0%, χ2 = 0.662, P = 0.416) in blood tests, as well as A1M (TAF group vs ETV group: 6.7% vs 6.0%, χ2 = 0.018, P = 0.894), NAG (TAF group vs ETV group: 15.6% vs 12.0%, χ2 = 0.254, P = 0.615), and urine cystatin (TAF group vs ETV group: 6.7% vs 16.0%, χ2 = 2.015, P = 0.156) in urine tests at 48 weeks (Table 4).
Table 3 Inter-group comparison of bone and renal safety indexes at the 48-week follow-up, mean ± SD/median (Q1, Q3).
Comparative assessment of bone and renal safety indexes at 96 weeks
At the 96-week follow-up, the two groups were equivalent in bone indexes serum Ca (TAF group vs ETV group: 2.33 ± 0.12 vs 2.41 ± 0.47, t = 0.637, P = 0.529), serum P (TAF group vs ETV group: 1.11 ± 0.40 vs 1.00 ± 0.16, t = 0.945, P = 0.353), and 25(OH)D (TAF group vs ETV group: 22.15 ± 7.23 vs 25.18 ± 10.11, t = 0.863, P = 0.397; Table 5). The LBM prevalence (TAF group vs ETV group: 11.1% vs 22.0%, χ2 = 2.005, P = 0.157), or the blood testing results of urea (TAF group vs ETV group: 6.7% vs 8.0%, χ2 = 0.062, P = 0.804), creatinine (TAF group vs ETV group: 6.7% vs 10.0%, χ2 = 0.341, P = 0.559), RBP (TAF group vs ETV group: 11.1% vs 18.0%, χ2 = 0.891, P = 0.344), and Cys-C (TAF group vs ETV group: 13.3% vs 22.0%, χ2 = 1.211, P = 0.271) did not differ significantly. However, the inter-group differences in urine findings of A1M (TAF group vs ETV group: 4.4% vs 20.0%, χ2 = 5.193, P = 0.023), NAG (TAF group vs ETV group: 6.7% vs 24.0%, χ2 = 5.352, P = 0.021), and urine cystatin (TAF group vs ETV group: 4.4% vs 18.0%, χ2 = 4.251, P = 0.039) reached statistical significance (Table 6).
Table 5 Inter-group comparison of bone and renal safety indexes at the 96-week follow-up, mean ± SD/median (Q1, Q3).
NAs such as ETV and TAF are extensively used in the antiviral treatment of CHB owing to their potent inhibition of viral replication[14-17]. However, the bone and renal safety issues associated with long-term medication have attracted increasing attention. Through a 96-week follow-up observation of two groups of patients, this study compared TAF and ETV effects on bone metabolism and renal function in patients with CHB, providing a certain basis for clinical drug selection.
The two cohorts were found to exhibit non-significant differences in BMD, serum Ca, P, and 25(OH)D across all measured timelines (baseline, 48 weeks, and 96 weeks; P > 0.05), suggesting little short-term effects of the two drugs on bone metabolism. These results corroborate previous findings[18,19]: As an upgraded TDF version, TAF targets hepatocytes, markedly reducing drug exposure in bones and thus decreasing the inhibitory effect on osteoblasts. A global multicenter study also confirmed that after 96 weeks of treatment, the decline in hip and spine BMD values in TAF-treated patients was markedly reduced compared to TDF-managed cases (P < 0.001), but the difference was not significant compared with ETV[20,21]. The non-significant inter-group difference in LBM prevalence in our study likely resulted from the short follow-up duration or a small sample size. Thus, extended follow-ups are warranted in future research to observe the longer-term changes in bone metabolism.
Most importantly, the present study identified statistically lower abnormality rates of urinary A1M, NAG, and urine cystatin in the TAF group vs the ETV group at 96 weeks (P < 0.05). These indexes are sensitive markers of early renal tubular injury, and their increase suggests proximal renal tubular reabsorption dysfunction[22,23]. The renal safety advantage of TAF likely reflects its pharmacokinetic properties: TAF demonstrates greater stability in the bloodstream and requires only one-tenth the dose of TDF to achieve comparable antiviral efficacy, resulting in reduced accumulation of active metabolites in renal tissues[24]. Despite its low nephrotoxicity profile, recent evidence suggests that ETV induces energy metabolism disorders in renal tubular cells by inhibiting mitochondrial DNA polymerase γ.
This study has some limitations. As a single-center retrospective study, the small sample size and narrow follow-up timeframe may be inadequate to capture minor changes in BMD or long-term renal function damage. Meanwhile, due to the nature of the retrospective study, data collection was limited; the integration of dynamic indicators like estimated glomerular filtration rate and blood P are needed for a comprehensive analysis. Notably, the marginally higher baseline urine protein abnormality rate in the TAF group, though not reaching statistical significance, may introduce selection bias, which needs further verification through further research. Therefore, large-scale prospective studies are needed in future investigations.
CONCLUSION
The selection of antiviral drugs for CHB should comprehensively consider treatment efficacy, drug resistance, bone and renal safety, economic factors, and individual patient conditions. For CHB patients with high-risk factors such as osteoporosis or renal dysfunction (e.g., the elderly, diabetic patients), TAF might be a better option.
Li C, Li H, Gong M, Liu Y, Zhang R, Geng J, Wang H, Yu Z, Wang Z, Liu X, Wei J. A Real-World Study on Safety and Efficacy of TAF Treatment in HBV Patients with High Risk of Osteoporosis or Osteopenia in China.Altern Ther Health Med. 2024;30:146-151.
[PubMed] [DOI]
Buti M, Wong DK, Gane E, Flisiak R, Manns M, Kaita K, Janssen HLA, Op den Brouw M, Jump B, Kitrinos K, Crans G, Flaherty J, Gaggar A, Marcellin P. Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with chronic hepatitis B following at least 8 years of therapy: a prespecified follow-up analysis of two randomised trials.Lancet Gastroenterol Hepatol. 2019;4:296-304.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 20][Cited by in RCA: 24][Article Influence: 3.4][Reference Citation Analysis (0)]
Snow-Lampart A, Chappell B, Curtis M, Zhu Y, Myrick F, Schawalder J, Kitrinos K, Svarovskaia ES, Miller MD, Sorbel J, Heathcote J, Marcellin P, Borroto-Esoda K. No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of therapy in patients monoinfected with chronic hepatitis B virus.Hepatology. 2011;53:763-773.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 141][Cited by in RCA: 141][Article Influence: 9.4][Reference Citation Analysis (1)]
Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, Wichroski MJ, Xu D, Yang J, Wilber RB, Colonno RJ. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy.Hepatology. 2009;49:1503-1514.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 675][Cited by in RCA: 626][Article Influence: 36.8][Reference Citation Analysis (1)]
Hosaka T, Suzuki F, Kobayashi M, Fujiyama S, Kawamura Y, Sezaki H, Akuta N, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Kumada H. Renal safety and biochemical changes for 2 years after switching to tenofovir alafenamide from long-term other nucleotide analog treatment in patients with chronic hepatitis B.Hepatol Res. 2022;52:153-164.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 6][Reference Citation Analysis (0)]
Mak LY, Hoang J, Jun DW, Chen CH, Peng CY, Yeh ML, Kim SE, Huang DQ, Jeong JY, Yoon E, Oh H, Tsai PC, Huang CF, Ahn SB, Trinh H, Xie Q, Wong GLH, Enomoto M, Shim JJ, Lee DH, Liu L, Kozuka R, Cho YK, Jeong SW, Kim HS, Trinh L, Dao A, Huang R, Hui RW, Tsui V, Quek S, Khine HHTW, Ogawa E, Dai CY, Huang JF, Cheung R, Wu C, Chuang WL, Lim SG, Yu ML, Yuen MF, Nguyen MH. Longitudinal renal changes in chronic hepatitis B patients treated with entecavir versus TDF: a REAL-B study.Hepatol Int. 2022;16:48-58.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 18][Cited by in RCA: 17][Article Influence: 4.3][Reference Citation Analysis (0)]
Footnotes
Peer review: Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific quality: Grade B, Grade B
Novelty: Grade B, Grade C
Creativity or innovation: Grade C, Grade C
Scientific significance: Grade B, Grade C
P-Reviewer: Bartolini I, PhD, Italy; Heise D, PhD, Germany S-Editor: Li L L-Editor: A P-Editor: Yu HG
