核苷（酸）类似物治疗慢性乙型肝炎的安全性研究进展

doi:10.19803/j.1672-8629.20250189

摘要/Abstract

摘要： 目的总结长期口服核苷（酸）类似物（NAs）治疗慢性乙型肝炎（CHB）的安全性,为临床用药提供参考。方法通过系统分析药品说明书、临床试验、上市后监测数据以及真实世界队列数据,比较恩替卡韦（ETV）、富马酸替诺福韦二吡呋酯（TDF）、富马酸丙酚替诺福韦（TAF）及艾米替诺福韦（TMF）的肾安全性、骨安全性和血脂安全性相关风险。结果 NAs总体安全性良好,但长期使用可能引发肾功能下降、低磷血症及血脂安全性。TAF和TMF的肾安全性及骨安全性优于TDF,但TAF和TMF可能存在影响血脂健康的风险。结论临床需根据患者个体差异选择NAs,定期监测患者的肾功能、骨密度及血脂等指标,确保安全用药。

关键词: 慢性乙型肝炎, 核苷（酸）类似物, 肾脏安全性, 骨安全性, 血脂异常

Abstract: Objective To explore the safety of long-term oral nucleos(t)ide analogues (NAs) in treating chronic hepatitis B (CHB) and to provide references for clinical practice. Methods By analyzing drug inserts, results of clinical trials, data on post-marketing surveillance and real-world cohort data, the risks of nephrotoxicity, bone toxicity, and dyslipidemia were compared between entecavir (ETV), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF) and tenofovir amibufenamide (TMF). Results NAs were generally safe, but chronic use might lead to decreased renal function, hypophosphatemia and dyslipidemia. TAF and TMF caused significantly lower nephrotoxicity and bone toxicity than TDF, but were associated with a higher risk of hyperlipidemia. Conclusion NAs should be selected based on differences between individual patients. TAF/TMF is the first option for patients with renal insufficiency or at high risk of bone metabolism. For patients with cardiovascular risks or dyslipidemia, TAF/TMF should be used with caution.

Key words: Chronic Hepatitis B, Nucleos(t)ide Analogues, Nephrotoxicity, Bone Toxicity, Dyslipidemia

中图分类号:

朱昊旻, 李月, 张梦蝶, 高力宏, 王佳, 李歆, 陶田甜. 核苷（酸）类似物治疗慢性乙型肝炎的安全性研究进展[J]. 中国药物警戒, 2025, 22(11): 1315-1320.

ZHU Haomin, LI Yue, ZHANG Mengdie, GAO Lihong, WANG Jia, LI Xin, TAO Tiantian. Safety of Long-Term Oral Nucleos(t)ide Analogues Therapy for Chronic Hepatitis B[J]. Chinese Journal of Pharmacovigilance, 2025, 22(11): 1315-1320.

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参考文献

[1] HUI Z, YU W, FUZHEN W, et al.New Progress in HBV Control and The Cascade of Health Care for People Living with HBV in China: Evidence from The Fourth National Serological Survey, 2020[J]. Lancet Reg Health West Pac, 2024, 51: 101193.
[2] YAN R, SUN M, YANG H, et al.2024 Latest Report on Hepatitis B Virus Epidemiology in China: Current Status, Changing Trajectory, and Challenges[J]. Hepatobiliary Surg Nutr, 2025, 14(1): 66-77.
[3] YOU H, WANG F, LI T, et al.Guidelines for the Prevention and Treatment of Chronic Hepatitis B (version 2022)[J]. Journal of Practical Hepatology(实用肝脏病杂志), 2023, 26(3): 457-478.
[4] LI HS, MA H, ZHANG C.Effects of Nucleos(t) ide Analogues on Renal Function in Patients with Chronic Hepatitis B[J]. Chinese Journal of Medicine(中国医刊), 2019, 54(3): 341-345.
[5] LIU Z, ZHAO Z, MA X, et al.Renal and Bone Side Effects of Long-Term Use of Entecavir, Tenofovir Disoproxil Fumarate, and Tenofovir Alafenamide Fumarate in Patients with Hepatitis B: a Network Meta-Analysis[J]. BMC Gastroenterol, 2023, 23(1): 384.
[6] ZHANG H, HU Y, WU M, et al.Randomised Clinical Trial: Safety, Efficacy and Pharmacokinetics of HS-10234 Versus Tenofovir for the Treatment of Chronic Hepatitis B Infection[J]. Aliment Pharmacol Ther, 2021, 53(2): 243-252.
[7] YANG YL, FENG TZ.A Case of Increased Creatine Kinase and Myalgia Induced by Entecavir[J]. Inner Mongolia Medical Journal(内蒙古医学杂志), 2016, 48(2): 124.
[8] LIU XL, YANG JQ, FENG SF.A Case of Lactic Acidosis Caused by Entecavir[J]. Journal of Jinan University(Natural Science & Medicine Edition)(暨南大学学报自然科学与医学版), 2013, 34(4): 445-446.
[9] JUNG TY, JUN DW, LEE KN, et al.Fatal Lactic Acidosis in Hepatitis B Virus-Associated Decompensated Cirrhosis Treated with Tenofovir: a Case Report[J]. Medicine (Baltimore), 2017, 96(25): e7133.
[10] LANGE CM, BOJUNGA J, HOFMANN WP, et al.Severe Lactic Acidosis during Treatment of Chronic Hepatitis B with Entecavir in Patients with Impaired Liver Function[J]. Hepatology, 2009, 50(6): 2001-2006.
[11] LIU X, CHEN L, ZHAO L.Study on Mining of Signals of Adverse Drug Reactions of Entecavir and Tenofovir Disoproxil Based on the US FAERS Database[J]. Chinese Journal of Hepatology(中华肝脏病杂志), 2021, 29(9): 830-836.
[12] WEI AH, ZENG L, WANG L, et al.Adverse Event Analysis and Renal Safety Comparison of Tenofovir Disoproxil and Tenofovir Alafenamide Based on FAERS Database[J]. Chinese Journal of Pharmacoepidemiology(药物流行病学杂志), 2023, 32(12): 1362-1370.
[13] ZHU M, JIA L, WANG Y, et al.Comparative Evaluation of Adverse Drug Reactions for Tenofovir Alafenamide and Tenofovir Disoproxil Fumarate Using the FAERS Database: a Disproportionality Analysis[J]. Expert Opin Drug Saf, 2024, 24(9): 1073-1082.
[14] WONG GL, SETO W, WONG VW, et al.Review Article: Long-Term Safety of Oral Anti-Viral Treatment for Chronic Hepatitis B[J]. Aliment Pharmacol Ther, 2018, 47(6): 730-737.
[15] GUAN HC, YUAN WJ.Impact of Long-Term Treatment with Nucleoside (Nucleotide) Analogues on Renal Function in Patients with Chronic Hepatitis B and Exploration of Its Mechanism[J]. National Medical Journal of China(中华医学杂志), 2020, 100(35): 2797-2800.
[16] HOU J, ZHAO W, LEE C, et al.Outcomes of Long-Term Treatment of Chronic HBV Infection with Entecavir or Other Agents from a Randomized Trial in 24 Countries[J]. Clin Gastroenterol Hepatol, 2020, 18(2): 457-467.
[17] JUNG C, KIM HW, AHN SH, et al.Tenofovir Is Associated with Higher Risk of Kidney Function Decline Than Entecavir in Patients with Chronic Hepatitis B[J]. Clin Gastroenterol Hepatol, 2022, 20(4): 956-958.
[18] UDOMPAP P, KIM D, AHMED A, et al.Longitudinal Trends in Renal Function in Chronic Hepatitis B Patients Receiving Oral Antiviral Treatment[J]. Aliment Pharmacol Ther, 2018, 48(11-12): 1282-1289.
[19] HEATHCOTE E J, MARCELLIN P, BUTI M, et al.Three-Year Efficacy and Safety of Tenofovir Disoproxil Fumarate Treatment for Chronic Hepatitis B[J]. Gastroenterology, 2011, 140(1): 132-143.
[20] MARCELLIN P, GANE E, BUTI M, et al.Regression of Cirrhosis during Treatment with Tenofovir Disoproxil Fumarate for Chronic Hepatitis B: a 5-Year Open-Label Follow-Up Study[J]. Lancet, 2013, 381(9865): 468-475.
[21] AGARWAL K, BRUNETTO M, SETO WK, 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.
[22] CHAN H L Y, BUTI M, LIM Y, et al. Long-Term Treatment with Tenofovir Alafenamide for Chronic Hepatitis B Results in High Rates of Viral Suppression and Favorable Renal and Bone Safety[J]. Am J Gastroenterol, 2024, 119(3): 486-496.
[23] LI Z, LI L, NIU X, et al.Switching from Entecavir to Tenofovir Alafenamide for Chronic Hepatitis B Patients with Low-Level Viraemia[J]. Liver Int, 2021, 41(6): 1254-1264.
[24] JUNG C, KIM HW, AHN SH, et al.Higher Risk of Kidney Function Decline with Entecavir than Tenofovir Alafenamide in Patients with Chronic Hepatitis B[J]. Liver Int, 2022, 42(5): 1017-1026.
[25] DAS S, WANG W, GANESAN M, et al. An Ultralong-Acting Tenofovir ProTide Nanoformulation Achieves Monthslong HBV Suppression[J]. Sci Adv, 2022, 8(51): eade9582.
[26] MEHELLOU Y, RATTAN HS, BALZARINI J.The ProTide Prodrug Technology: from the Concept to the Clinic[J]. J Med Chem, 2018, 61(6): 2211-2226.
[27] LIU Z, JIN Q, ZHANG Y, et al.Randomised Clinical Trial: 48 Weeks of Treatment with Tenofovir Amibufenamide Versus Tenofovir Disoproxil Fumarate for Patients with Chronic Hepatitis B[J]. Aliment Pharmacol Ther, 2021, 54(9): 1134-1149.
[28] LIU Z, JIN Q, ZHANG Y, et al.96-Week Treatment of Tenofovir Amibufenamide and Tenofovir Disoproxil Fumarate in Chronic Hepatitis B Patients[J]. Journal of Clinical and Translational Hepatology, 2023, 11(3): 649-660.
[29] LI L, ZHOU J, LI Y, et al.Effectiveness and Safety of Tenofovir Amibufenamide and Its Comparison with Tenofovir Alafenamide in Patients with Chronic Hepatitis B: Results from a Retrospective Real-World Study[J]. Front Pharmacol, 2023, 14: 1165990.
[30] PENG W, JIANG C, YANG F, et al.Tenofovir Amibufenamide vs Tenofovir Alafenamide for Treating Chronic Hepatitis B: a Real-World Study[J]. World J Gastroenterol, 2023, 29(44): 5907-5918.
[31] Experts Committee of Management of Side Effects of Nucleos(t)Ide Analogues for Hepatitis B Virus. Consensus on Management of Side Effects of Nucleos(t)ide Analogues for Hepatitis B Virus[J]. Chinese Journal of Liver Diseases(Electronic Version)(中国肝脏病杂志电子版), 2016, 8(3): 10-14.
[32] YIP TC, LAI JC, YAM TF, et al.Long-Term Use of Tenofovir Disoproxil Fumarate Increases Fracture Risk in Elderly Patients with Chronic Hepatitis B[J]. J Hepatol, 2024, 80(4): 553-563.
[33] GE W, WEI Z, XIE H.Insights into Fracture Risk with Tenofovir and Entecavir: Evidence from Pharmacovigilance Data[J]. J Hepatol, 2025, 82(3): e149-e150.
[34] KIM E, LEE HW, KIM SS, et al.Tenofovir Disoproxil Fumarate Versus Tenofovir Alafenamide on Risk of Osteoporotic Fracture in Patients with Chronic Hepatitis B: a Nationwide Claims Study in South Korea[J]. Aliment Pharmacol Ther, 2023, 58(11-12): 1185-1193.
[35] ZHANG Q, LIANG J, YIN J, et al.Real-Life Impact of Tenofovir Disoproxil Fumarate and Entecavir Therapy on Lipid Profile, Glucose, and Uric Acid in Chronic Hepatitis B Patients[J]. J Med Virol, 2022, 94(11): 5465-5474.
[36] CHENG P, FENG I, CHEN J, et al.Body Weight Increase and Metabolic Derangements after Tenofovir Disoproxil Fumarate Switch to Tenofovir Alafenamide in Patients with Chronic Hepatitis B[J]. Aliment Pharmacol Ther, 2024, 59(2): 230-238.
[37] MILINKOVIC A, BERGER F, ARENAS-PINTO A, et al.Reversible Effect on Lipids by Switching from Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide and Back[J]. AIDS, 2019, 33(15): 2387-2391.
[38] SUZUKI K, SUDA G, YAMAMOTO Y, et al.Effect of Switching from Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide on Lipid Profiles in Patients with Hepatitis B[J]. PLoS One, 2022, 17(1): e0261760.
[39] ZHAO WJ, LIU Y, LI JY, et al.A Meta-Analysis of the Effects of Antiviral Therapy with Tenofovir Alafenamide Fumarate on Lipid Profile and Body Weight[J]. Chinese Journal of AIDS & STD(中国艾滋病性病), 2023, 29(2): 238-244.
[40] HONG H, CHOI W, LEE D, et al.Cardiovascular Risk in Chronic Hepatitis B Patients Treated with Tenofovir Disoproxil Fumarate or Tenofovir Alafenamide[J]. Clin Mol Hepatol, 2024, 30(1): 49-63.
[41] ROADE L, RIVEIRO-BARCIELA M, ESTEBAN R, et al.Long-term Efficacy and Safety of Nucleos(t)ides Analogues in Patients with Chronic Hepatitis B[J]. Ther Adv Infect Dis, 2021, 8: 229787294.
[42] CHIODINI I, D'ANGELA D, FALCHETTI A, et al.Areas of Uncertainty on the Diagnosis, Treatment, and Follow-Up of Hypophos-phatemia in Adults: an Italian Delphi Consensus[J]. J Endocrinol Invest, 2025, 48(2): 257-267.
[43] Expert Group on Kidney Clinical Quality Control Center in Shanghai. Guidelines for Early Screening, Diagnosis, Prevention and Treatment of Chronic Kidney Disease (2022 Edition)[J]. Chinese Journal of Nephrology(中华肾脏病杂志), 2022, 38(5): 453-464.