拉沙热抗病毒药物临床应用研究进展

doi:10.19803/j.1672-8629.20250485

摘要/Abstract

摘要： 目的综述拉沙热（Lassa Fever,LF）抗病毒药物研究进展,为突破当前治疗瓶颈提供参考。方法通过检索PubMed、Web of Science、中国知网等数据库,归纳法维拉韦、利巴韦林及免疫治疗的临床应用效果,并总结具有潜力的小分子药物的作用机制。结果法维拉韦、利巴韦林和免疫治疗均表现出一定的疗效,利巴韦林联合法维拉韦或地塞米松在临床中已有救治成功的案例。国内外针对利巴韦林的使用剂量及疗程存在争议,且现有证据不足以支持常规使用利巴韦林治疗LF。法维拉韦的心脏安全性也仍需进一步评估。多种小分子抑制剂也显示出广阔的临床应用前景。结论目前全球范围内尚无获批的特异性抗拉沙病毒（Lassa Virus,LASV）药物,但针对病毒生命周期不同环节的多种候选药物研究已取得显著进展,联合用药及多靶点治疗的策略将成为未来的重要研究方向。

关键词: 拉沙热, 拉沙病毒, 抗病毒药物, 免疫治疗, 小分子抑制剂, 研究进展

Abstract: Objective To summarize recent advances in antiviral drugs for Lassa fever (LF) and provide insights into current therapeutic bottlenecks. Methods Such databases as PubMed, Web of Science and the China National Knowledge Infrastructure (CNKI) were searched for literature about the clinical efficacy of favipiravir, ribavirin, and immunotherapy, as well as the mechanisms of promising small-molecule drugs. Results Favipiravir, ribavirin, and immunotherapy all proved to be effective against LF. Desirable outcomes resulted from ribavirin in combination with either favipiravir or dexamethasone. However, the appropriate dosage of ribavirin and course of treatment remained controversial, and there was too little evidence to recommend ribavirin for routine treatment of LF. Moreover, the cardiac safety of favipiravir needed to be assessed. However, a variety of small-molecule inhibitors promised wide applications. Conclusion Although no specific antiviral drug has been approved globally for the treatment of LASV, significant progress has been made in developing candidate therapeutics that target different stages of the viral life cycle. Combination therapy and multi-target strategies will be priorities of subsequent research.

Key words: Lassa Fever, Lassa Virus, Antiviral Drugs, Immunotherapy, Small-Molecule Inhibitor, Research Progress

中图分类号:

R978
R994.11

王冉冉, 马瑞泽, 陈志海. 拉沙热抗病毒药物临床应用研究进展[J]. 中国药物警戒, 2025, 22(12): 1321-1327.

WANG Ranran, MA Ruize, CHEN Zhihai. Research Progress in Clinical Applications of Antiviral Drugs for Lassa Fever[J]. Chinese Journal of Pharmacovigilance, 2025, 22(12): 1321-1327.

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https://zgywjj.magtechjournal.com/CN/Y2025/V22/I12/1321

参考文献

[1] ASOGUN D, AROGUNDADE B, UNUABONAH F, et al.A Review of the Epidemiology of Lassa Fever in Nigeria[J]. Microorganisms, 2025, 13(6): 1419.
[2] OGUNDELE GO, JOLAYEMI KO, BELLO S.Lassa Fever in West Africa: a Systematic Review and Meta-Analysis of Attack Rates, Case Fatality Rates and Risk Factors[J]. BMC Public Health, 2025, 25(1): 2948.
[3] LIU QY.The First Imported Case of Lassa Fever in China-Implications for Global Health Surveillance[J]. Biomed Environ Sci, 2025, 38(3): 277-278.
[4] LIU ZL, LI ZH, LIU Q, et al.Recent Progress in the Development of Inhibitors of the Lassa Virus[J]. Chinese Journal of Zoonoses(中国人兽共患病学报), 2024, 40(6): 578-589.
[5] WU CT, WAN B, HE T, et al.Research Progress on Lassa Fever[J]. Journal of Modern Clinical Medicine(现代临床医学), 2025, 51(2): 153-156.
[6] GARRY RF.Lassa Fever-the Road Ahead[J]. Nature Reviews Microbiology, 2023, 21(2): 87-96.
[7] GUO J, WAN Y, LIU Y, et al.Identification of Residues in Lassa Virus Glycoprotein 1 Involved in Receptor Switch[J]. Virol Sin, 2024, 39(4): 600-608.
[8] WITWIT H, BETANCOURT CA, CUBITT B, et al.Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication[J]. Viruses, 2024, 16(9): 1362.
[9] OESTEREICH L, RIEGER T, LÜDTKE A, et al. Efficacy of Favipiravir Alone and in Combination with Ribavirin in a Lethal, Immunocompetent Mouse Model of Lassa Fever[J]. Journal of Infectious Diseases, 2016, 213(6): 934-938.
[10] SAFRONETZ D, ROSENKE K, WESTOVER JB, et al.the Broad-spectrum Antiviral Favipiravir Protects Guinea Pigs from Lethal Lassa Virus Infection Post-Disease Onset[J]. Scientific Reports, 2015, 5(1): 14775.
[11] LINGAS G, ROSENK K, SAFRONETZ D, et al.Lassa Viral Dynamics in Non-Human Primates Treated with Favipiravir or Ribavirin[J]. PLoS Comput Biol, 2021, 17(1): e1008535.
[12] Drugs.dxy. Favipiravir Tablets[EB/OL]. (2020-10-26) [2025-10-29]. https://drugs.dxy.cn/pc/drug/yLvp2KP1bNhYvSPZCVddQSQ?ky=法维拉韦.
[13] DOGAN M, BAVKIZ D, YILMAZ L, et al.Evaluation of the Effect of Favipiravir on QT Intervals in COVID-19 Patients with and without Diabetes Mellitus[J]. Journal of the College of Physicians and Surgeons Pakistan, 2024, 34(6): 659-666.
[14] ERAMEH C, AYODEJI OO, MENEGUIM A, et al.Electrocardio-graphic Alterations in Patients Treated for Acute Lassa Fever: Description of Results from a PhaseⅡ Clinical Trial in Nigeria[J]. Journal of Infection and Public Health, 2025, 18(9): 102858.
[15] FURUTA Y, GOWEN BB, TAKAHASHI K, et al.Favipiravir (T-705), a Novel Viral RNA Polymerase Inhibitor[J]. Antiviral Research, 2013, 100(2): 446-454.
[16] RAABE VN, KANN G, RIBNER BS, et al.Favipiravir and Ribavirin Treatment of Epidemiologically Linked Cases of Lassa Fever[J]. Clinical Infectious Diseases, 2017, 65(5): 855-859.
[17] SALAM AP, DUVIGNAUD A, JASPARD M, et al.Ribavirin for Treating Lassa Fever: a Systematic Review of Pre-Clinical Studies and Implications for Human Dosing[J]. PLoS Negl Trop Dis, 2022, 16(3): e0010289.
[18] MC CORMICK JB, KING IJ, WEBB PA, et al.Lassa Fever[J]. New England Journal of Medicine, 1986, 314(1): 20-26.
[19] OGBAINI-EMOVON E, AKPEDE G, OKOGBENIN S, et al. Virus Load Kinetics in Lassa Fever Patients Treated with Ribavirin: a Retrospective Cohort Study from Southern Nigeria[J]. Open Forum Infect Dis, 2024, 11(10): ofae575.
[20] OKOGBENIN S, ERAMEH C, OKOEGUALE J, et al.Two Cases of Lassa Fever Successfully Treated with Ribavirin and Adjunct Dexamethasone for Concomitant Infections[J]. Emerg Infect Dis, 2022, 28(10): 2060-2063.
[21] WHO. Clinical Management of Patients with Viral Haemorrhagic Fever: a Pocket Guide for Front-Line Health Workers[EB/OL]. (2016-01-02)[2025-10-29]. https://www.who.int/publications/i/item/9789241549608.
[22] National Health Commission of the People's Republic of China. Notice on Issuing the Prevention and Control Guidelines and Clinical Diagnosis and Treatment Protocols for Six Infectious Diseases Including Ebola Hemorrhagic Fever[EB/OL]. (2008-07-23) [2025-10-28]. https://www.nhc.gov.cn/wjw/gfxwj/200807/3bfd21df7f914428b55586e595aeaf0d.shtml.
[23] Drugs.dxy. Ribavirin Injection[EB/OL]. (2025-05-11)[2025-10-29]. https://drugs.dxy.cn/pc/drug/y_YLgXuqeD56fJGiOG9WCGw?ky=利巴韦林.
[24] CHENG HY, FRENCH CE, SALAM AP, et al.Lack of Evidence for Ribavirin Treatment of Lassa Fever in Systematic Review of Published and Unpublished Studies[J]. Emerg Infect Dis, 2022, 28(8): 1559-1568.
[25] EBERHARDT KA, MISCHLINGER J, JORDAN S, et al.Ribavirin for the Treatment of Lassa Fever: a Systematic Review and Meta-Analysis[J]. International Journal of Infectious Diseases, 2019, 87: 15-20.
[26] FENG YL, LI W, JIANG MF, et al.Laboratory Diagnosis and Molecular Epidemiological Characterization of the First Imported Case of Lassa Fever in China[J]. Biomed Environ Sci, 2025, 38(3): 279-289.
[27] RAN QH, CHEN H, HUANG L, et al.The First Case of Lassa Fever in China[J]. Electronic Journal of Emerging Infectious Diseases,August(新发传染病电子杂志), 2024, 9(4): 1-5.
[28] YaleNews. In Memoriam: Physician-Virologist Who Pioneered Study of Virus Relationship, Jordi Casals-Ariet/Yale News[EB/OL]. (2004-02-20)[2025-07-13]. https://news.yale.edu/2004/02/20/memoriam-physician-virologist-who-pioneered-study-virus-relationship-jordi-casals-ariet.
[29] FRAME JD, VERBRUGGE GP, GILL RG, et al.the Use of Lassa Fever Convalescent Plasma in Nigeria[J]. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1984, 78(3): 319-324.
[30] MARIËN J, NUISMER SL, MAGASSOUBA N, et al. Serosurveillance Identifies an Endemic Hotspot of Lassa Fever in Faranah, Upper Guinea[J/OL]. The Journal of Infectious Diseases, (2025-06-13)[2025-07-13]. https://pubmed.ncbi.nlm.nih.gov/40509999/.
[31] JAHRLING PB, PETERS CJ, STEPHEN EL.Enhanced Treatment of Lassa Fever by Immune Plasma Combined with Ribavirin in Cynomolgus Monkeys[J]. Infect Dis, 1984, 149(3): 420-427.
[32] CROSS RW, MIRE CE, BRANCO LM, et al.Treatment of Lassa Virus Infection in Outbred Guinea Pigs with First-in-Class Human Monoclonal Antibodies[J]. Antiviral Research, 2016, 133: 218-222.
[33] MIRE CE, CROSS RW, GEISBERT JB, et al.Human-Monoclonal-Antibody Therapy Protects Nonhuman Primates against Advanced Lassa Fever[J]. Nature Medicine, 2017, 23(10): 1146-1149.
[34] CROSS RW, HEINRICH ML, FENTON KA, et al.a Human Monoclonal Antibody Combination Rescues Nonhuman Primates from Advanced Disease Caused by the Major Lineages of Lassa Virus[J]. Proceedings of the National Academy of Sciences, 2023, 120(34): e2304876120.
[35] CROSS RW, FENTON KA, WOOLSEY C, et al.Monoclonal Antibody Therapy Protects Nonhuman Primates against Mucosal Exposure to Lassa Virus[J]. Cell Reports Medicine, 2024, 5(2): 101392.
[36] WANG MKM, REN T, LIU H, et al.Critical Role for Cholesterol in Lassa Fever Virus Entry Identified by a Novel Small Molecule Inhibitor Targeting the Viral Receptor LAMP1[J]. PLoS Pathogens, 2018, 14(9): e1007322.
[37] ZHANG X, YAN F, TANG K, et al.Identification of a Clinical Compound Losmapimod That Blocks Lassa Virus Entry[J]. Antiviral Research, 2019, 167: 68-77.
[38] ZHANG X, TANG K, GUO Y. the Antifungal Isavuconazole Inhibits the Entry of Lassa Virus by Targeting the Stable Signal Peptide-GP2 Subunit Interface of Lassa Virus Glycoprotein[J]. Antiviral Research, 2020, 174: 104701.
[39] URATA S, YUN N, PASQUATO A, et al.Antiviral Activity of a Small-Molecule Inhibitor of Arenavirus Glycoprotein Processing by the Cellular Site 1 Protease[J]. Journal of Virology, 2011, 85(2): 795-803.
[40] AMBERG SM, SNYDER B, VLIET-GREGG PA, et al.Safety and Pharmacokinetics of LHF-535, a Potential Treatment for Lassa Fever, in Healthy Adults[J]. Antimicrobial Agents and Chemotherapy, 2022, 66(11): e0095122.
[41] CASHMAN KA, SMITH MA, TWENHAFEL NA, et al.Evaluation of Lassa Antiviral Compound ST-193 in a Guinea Pig Model[J]. Antiviral Res, 2011, 90(1): 70-79.
[42] PENG C, HU J, BAI Y, et al.Coadministration of Ribavirin and Arenaviral Entry Inhibitor LHF-535 Enhances Antiviral Benefit against Authentic Lassa Virus[J]. Virol Sin, 2025, 40(3): 491-494.
[43] ABBAS S, SHAHBAZ M, ALI A, et al.Casticin: a Natural Flavonoid with Promising Pharmacological and Biological Activities[J]. Fitoterapia, 2025, 185: 106746.
[44] NGO N, HENTHORN KS, CISNEROS MI, et al.Identification and Mechanism of Action of a Novel Small-Molecule Inhibitor of Arenavirus Multiplication[J]. Virol, 2023, 97(3): e0012323.
[45] LIU Y, GUO J, CAO J, et al.Screening of Botanical Drugs against Lassa Virus Entry[J]. Journal of Virology, 2021, 95(8): e02429-20.
[46] TANG K, HE S, ZHANG X, et al.Tangeretin, an Extract from Citrus Peels, Blocks Cellular Entry of Arenaviruses That Cause Viral Hemorrhagic Fever[J]. Antiviral Research, 2018, 160: 87-93.
[47] JOSEPH AA, FASIPE OJ, JOSEPH OA, et al.Contemporary and Emerging Pharmacotherapeutic Agents for the Treatment of Lassa Viral Haemorrhagic Fever Disease[J]. Journal of Antimicrobial Chemotherapy, 2022, 77(6): 1525-1531.
[48] FRIESLAND A, ZHAO Y, CHEN YH, et al.Small Molecule Targeting Cdc42-Intersectin Interaction Disrupts Golgi Organization and Suppresses Cell Motility[J]. Proceedings of the National Academy of Sciences, 2013, 110(4): 1261-1266.
[49] PASQUATO A, FERNANDEZ AH, KUNZ S.Studies of Lassa Virus Cell Entry[J]. Methods in Molecular Biology, 2018, 1604: 135-155.
[50] JULANDER JG, DEMAREST JF, TAYLOR R, et al.an Update on the Progress of Galidesivir (BCX4430), a Broad-Spectrum Antiviral[J]. Antiviral Research, 2021, 195: 105180.
[51] GAN L, WU LCL, WOOD JA, et al.a Cell-Penetrating Peptide Enhances Delivery and Efficacy of Phosphorodiamidate Morpholino Oligomers in Mdx Mice[J]. Mol Ther Nucleic Acids, 2022, 30: 17-27.
[52] HUANG C, MANTLO E, PAESSLER S. Lassa Virus NP DEDDh 3'-5' Exoribonuclease Activity is Required for Optimal Viral RNA Replication and Mutation Control[J/OL]. BioRxiv, (2023-12-30)[2025-07-13]. https://pubmed.ncbi.nlm.nih.gov/37090668/.
[53] URATA S, NGO N, DE LA TORRE JC. The PI3K/Akt Pathway Contributes to Arenavirus Budding[J]. Journal of Virology, 2012, 86(8): 4578-4585.
[54] KIM YJ, VENTURINI V, DE LA TORRE JC. Progress in Anti-Mammarenavirus Drug Development[J]. Viruses, 2021, 13(7): 1187.
[55] ALONSO-ROMAN R, MOSIG AS, FIGGE MT, et al.Organ-on-Chip Models for Infectious Disease Research[J]. Nat Microbiol, 2024, 9(4): 891-904.
[56] AKASH S, BAEZA J, MAHMOOD S, et al.Development of a New Drug Candidate for the Inhibition of Lassa Virus Glycoprotein and Nucleoprotein by Modification of Evodiamine as Promising Therapeutic Agents[J]. Front Microbiol, 2023, 14: 1206872.