长效抗逆转录病毒药物与广谱中和抗体联合策略的进展、挑战与未来方向
Long-Acting Antiretroviral Drugs Combined with Broadly Neutralizing Antibodies: Progress, Challenges, and Future Directions
DOI: 10.12677/hjbm.2026.164077, PDF,   
作者: 刘丽娟, 何 忻, 黄富礼*：西南医科大学附属医院感染科，四川 泸州；西南医科大学附属医院结核科，四川 泸州
关键词: 长效抗逆转录病毒药物；广谱中和抗体；Lenacapavir；Teropavimab；Zinlirvimab；联合策略；Long-Acting Antiretroviral Drugs； Broadly Neutralizing Antibodies； Lenacapavir； Teropavimab； Zinlirvimab； Combination Strategy
摘要: 联合抗逆转录病毒疗法(ART)已将HIV-1感染从致命性疾病转变为可控的慢性病，但每日终身服药带来的依从性负担、长期药物毒性和社会歧视等问题依然严峻。近年来，以衣壳抑制剂Lenacapavir (LEN)为代表的长效抗病毒药物，以及以Teropavimab (TAB)和Zinlirvimab (ZAB)为代表的广谱中和抗体(bNAbs)取得了突破性进展。将长效抗逆转录病毒药物与bNAbs联合，组成每半年给药一次的治疗方案，为HIV-1感染者治疗模式从每日口服迈向全程长效提供了重要的新路径。本文系统梳理了LEN等长效药物的临床证据及其耐药特征，回顾了bNAbs从单药到联合用药的演进，并重点分析了以“LEN + TAB + ZAB”为代表的联合方案在Ib期和II期临床试验中的疗效、安全性及耐药数据。此外，探讨了bNAbs敏感性筛选的瓶颈、耐药风险以及全球可及性等关键实施挑战，并展望了优化联合方案、简化给药方式和探索功能性治愈的未来方向，旨在为HIV治疗策略的迭代提供参考。
Abstract: Combination antiretroviral therapy (ART) has transformed HIV-1 infection from a fatal disease into a manageable chronic condition; however, challenges such as adherence burden, long-term drug toxicity, and social stigma associated with lifelong daily oral medication remain substantial. In recent years, significant advances have been achieved with long-acting antivirals, particularly the capsid inhibitor Lenacapavir (LEN), as well as broadly neutralizing antibodies (bNAbs) including Teropavimab (TAB) and Zinlirvimab (ZAB). The combination of long-acting antiretroviral agents with bNAbs, administered once every six months, offers a critical new avenue to shift the treatment paradigm for people living with HIV-1 from daily oral pills to fully long-acting regimens. This review systematically summarizes the clinical evidence and resistance profiles of LEN and other long-acting agents, traces the evolution of bNAbs from monotherapy to combination therapy, and places particular emphasis on the efficacy, safety, and resistance data from phase Ib and II clinical trials of the representative combination regimen “LEN + TAB + ZAB”. In addition, it discusses key implementation challenges, including bottlenecks in bNAb susceptibility screening, resistance risks, and global accessibility, and outlines future directions for optimizing combination regimens, simplifying administration, and exploring functional cure, with the aim of providing a reference for the iterative advancement of HIV treatment strategies.
文章引用：刘丽娟, 何忻, 黄富礼. 长效抗逆转录病毒药物与广谱中和抗体联合策略的进展、挑战与未来方向[J]. 生物医学, 2026, 16(4): 757-766. https://doi.org/10.12677/hjbm.2026.164077

参考文献

[1] WHO (2026) HIV and AIDS.
https://www.who.int/news-room/fact-sheets/detail/hiv-aids
[2] Sun, Y. and Wang, L. (2024) Development of Anti-HIV Therapeutics: From Conventional Drug Discovery to Cutting-Edge Technology. Pharmaceuticals, 17, Article 887.
https://doi.org/10.3390/ph17070887
[3] Foka, F.E.T. and Mufhandu, H.T. (2023) Current Arts, Virologic Failure, and Implications for AIDS Management: A Systematic Review. Viruses, 15, Article 1732.
https://doi.org/10.3390/v15081732
[4] Ransley, G., Zimba, S., Gadama, Y., Saylor, D. and Benjamin, L. (2022) Trends and Clinical Characteristics of HIV and Cerebrovascular Disease in Low-and Middle-Income Countries (LMICs) between 1990 and 2021. Current HIV/AIDS Reports, 19, 548-565.
https://doi.org/10.1007/s11904-022-00627-9
[5] Rueda, S., Mitra, S., Chen, S., Gogolishvili, D., Globerman, J., Chambers, L., et al. (2016) Examining the Associations between HIV-Related Stigma and Health Outcomes in People Living with HIV/AIDS: A Series of Meta-Analyses. BMJ Open, 6, e011453.
https://doi.org/10.1136/bmjopen-2016-011453
[6] Brizzi, M., Pérez, S.E., Michienzi, S.M. and Badowski, M.E. (2023) Long-Acting Injectable Antiretroviral Therapy: Will It Change the Future of HIV Treatment? Therapeutic Advances in Infectious Disease, 10, 1-15.
[7] Thavarajah, J.J., Hønge, B.L. and Wejse, C.M. (2024) The Use of Broadly Neutralizing Antibodies (bNAbs) in HIV-1 Treatment and Prevention. Viruses, 16, Article 911.
https://doi.org/10.3390/v16060911
[8] Caskey, M., Klein, F., Lorenzi, J.C.C., Seaman, M.S., West, A.P., Buckley, N., et al. (2015) Viraemia Suppressed in HIV-1-Infected Humans by Broadly Neutralizing Antibody 3bnc117. Nature, 522, 487-491.
https://doi.org/10.1038/nature14411
[9] Ko, S., Pegu, A., Rudicell, R.S., Yang, Z., Joyce, M.G., Chen, X., et al. (2014) Enhanced Neonatal Fc Receptor Function Improves Protection against Primate SHIV Infection. Nature, 514, 642-645.
https://doi.org/10.1038/nature13612
[10] Swindells, S., Andrade-Villanueva, J., Richmond, G.J., Rizzardini, G., Baumgarten, A., Masiá, M., et al. (2020) Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression. New England Journal of Medicine, 382, 1112-1123.
https://doi.org/10.1056/nejmoa1904398
[11] Orkin, C., Arasteh, K., Górgolas Hernández-Mora, M., Pokrovsky, V., Overton, E.T., Girard, P., et al. (2020) Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection. New England Journal of Medicine, 382, 1124-1135.
https://doi.org/10.1056/nejmoa1909512
[12] Jaeger, H., Overton, E.T., Richmond, G., Rizzardini, G., Andrade-Villanueva, J.F., Mngqibisa, R., et al. (2021) Long-Acting Cabotegravir and Rilpivirine Dosed Every 2 Months in Adults with HIV-1 Infection (ATLAS-2M), 96-Week Results: A Randomised, Multicentre, Open-Label, Phase 3b, Non-Inferiority Study. The Lancet HIV, 8, e679-e689.
https://doi.org/10.1016/s2352-3018(21)00185-5
[13] Chounta, V., Overton, E.T., Mills, A., Swindells, S., Benn, P.D., Vanveggel, S., et al. (2021) Patient-Reported Outcomes through 1 Year of an HIV-1 Clinical Trial Evaluating Long-Acting Cabotegravir and Rilpivirine Administered Every 4 or 8 Weeks (ATLAS-2m). The Patient-Patient-Centered Outcomes Research, 14, 849-862.
https://doi.org/10.1007/s40271-021-00524-0
[14] Cutrell, A.G., Schapiro, J.M., Perno, C.F., Kuritzkes, D.R., Quercia, R., Patel, P., et al. (2021) Exploring Predictors of HIV-1 Virologic Failure to Long-Acting Cabotegravir and Rilpivirine: A Multivariable Analysis. AIDS, 35, 1333-1342.
https://doi.org/10.1097/qad.0000000000002883
[15] Rizzardini, G., Overton, E.T., Orkin, C., Swindells, S., Arasteh, K., Górgolas Hernández-Mora, M., et al. (2020) Long-Acting Injectable Cabotegravir + Rilpivirine for HIV Maintenance Therapy: Week 48 Pooled Analysis of Phase 3 ATLAS and FLAIR Trials. JAIDS Journal of Acquired Immune Deficiency Syndromes, 85, 498-506.
https://doi.org/10.1097/qai.0000000000002466
[16] Dvory-Sobol, H., Shaik, N., Callebaut, C. and Rhee, M.S. (2022) Lenacapavir: A First-in-Class HIV-1 Capsid Inhibitor. Current Opinion in HIV and AIDS, 17, 15-21.
https://doi.org/10.1097/coh.0000000000000713
[17] Jogiraju, V., Pawar, P., Yager, J., Ling, J., Shen, G., Chiu, A., et al. (2025) Pharmacokinetics and Safety of Once-Yearly Lenacapavir: A Phase 1, Open-Label Study. The Lancet, 405, 1147-1154.
https://doi.org/10.1016/s0140-6736(25)00405-2
[18] Subramanian, R., Tang, J., Zheng, J., Lu, B., Wang, K., Yant, S.R., et al. (2023) Lenacapavir: A Novel, Potent, and Selective First-in-Class Inhibitor of HIV-1 Capsid Function Exhibits Optimal Pharmacokinetic Properties for a Long-Acting Injectable Antiretroviral Agent. Molecular Pharmaceutics, 20, 6213-6225.
https://doi.org/10.1021/acs.molpharmaceut.3c00626
[19] Segal-Maurer, S., DeJesus, E., Stellbrink, H., Castagna, A., Richmond, G.J., Sinclair, G.I., et al. (2022) Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection. New England Journal of Medicine, 386, 1793-1803.
https://doi.org/10.1056/nejmoa2115542
[20] Ogbuagu, O., Molina, J., Chetchotisakd, P., Ramgopal, M.N., Sanchez, W., Brunetta, J., et al. (2025) Efficacy and Safety of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People with Multidrug-Resistant HIV-1: Week 104 Results of a Phase 2/3 Trial. Clinical Infectious Diseases, 80, 566-574.
https://doi.org/10.1093/cid/ciae423
[21] Bekker, L.G., Das, M., Abdool Karim, Q., Ahmed, K., Batting, J., Brumskine, W., et al. (2024) Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women. The New England Journal of Medicine, 391, 1179-1192.
[22] Kelley, C.F., Acevedo-Quiñones, M., Agwu, A.L., Avihingsanon, A., Benson, P., et al. (2025) Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons. The New England Journal of Medicine, 392, 1261-1276.
[23] Margot, N.A., Jogiraju, V., Pennetzdorfer, N., Naik, V., VanderVeen, L.A., Ling, J., et al. (2025) Resistance Analyses in Heavily Treatment-Experienced People with HIV Treated with the Novel HIV Capsid Inhibitor Lenacapavir after 2 Years. The Journal of Infectious Diseases, 231, 1239-1245.
https://doi.org/10.1093/infdis/jiaf050
[24] Demirdjian, S., Naik, V., Margot, N., Falkard, B. and Callebaut, C. (2025) Phenotypic Characterization of Replication‐Impaired Lenacapavir‐Resistant HIV Clinical Isolates. Journal of Medical Virology, 97, e70340.
https://doi.org/10.1002/jmv.70340
[25] Selzer, L., VanderVeen, L.A., Parvangada, A., Martin, R., Collins, S.E., Mehrotra, M., et al. (2025) Susceptibility Screening of HIV-1 Viruses to Broadly Neutralizing Antibodies, Teropavimab and Zinlirvimab, in People with HIV-1 Suppressed by Antiretroviral Therapy. JAIDS Journal of Acquired Immune Deficiency Syndromes, 98, 64-71.
https://doi.org/10.1097/qai.0000000000003528
[26] van Zyl, G., Prochazka, M., Schmidt, H.A., Orrell, C., Schapiro, J.M., McCluskey, S.M., et al. (2025) Lenacapavir-Associated Drug Resistance: Implications for Scaling up Long-Acting HIV Pre-Exposure Prophylaxis. The Lancet HIV, 12, e732-e736.
https://doi.org/10.1016/s2352-3018(25)00128-6
[27] Caskey, M., Schoofs, T., Gruell, H., Settler, A., Karagounis, T., Kreider, E.F., et al. (2017) Antibody 10-1074 Suppresses Viremia in HIV-1-Infected Individuals. Nature Medicine, 23, 185-191.
[28] Mendoza, P., Gruell, H., Nogueira, L., Pai, J.A., Butler, A.L., Millard, K., et al. (2018) Combination Therapy with Anti-Hiv-1 Antibodies Maintains Viral Suppression. Nature, 561, 479-484.
https://doi.org/10.1038/s41586-018-0531-2
[29] Bar-On, Y., Gruell, H., Schoofs, T., Pai, J.A., Nogueira, L., Butler, A.L., et al. (2018) Safety and Antiviral Activity of Combination HIV-1 Broadly Neutralizing Antibodies in Viremic Individuals. Nature Medicine, 24, 1701-1707.
https://doi.org/10.1038/s41591-018-0186-4
[30] Gaebler, C., Nogueira, L., Stoffel, E., Oliveira, T.Y., Breton, G., Millard, K.G., et al. (2022) Prolonged Viral Suppression with Anti-HIV-1 Antibody Therapy. Nature, 606, 368-374.
https://doi.org/10.1038/s41586-022-04597-1
[31] Schiering, K., Beiersdorfer, M. and Hoelzemer, A. (2025) Harnessing Innate Immunity: Natural Killer Cells and Innate Immune Responses in Reservoir Clearance. Current Opinion in HIV and AIDS, 20, 552-558.
https://doi.org/10.1097/coh.0000000000000972
[32] Schou, M.D., Søgaard, O.S. and Rasmussen, T.A. (2023) Clinical Trials Aimed at HIV Cure or Remission: New Pathways and Lessons Learned. Expert Review of Anti-Infective Therapy, 21, 1227-1243.
https://doi.org/10.1080/14787210.2023.2273919
[33] (2026) 513—HIV-1 Reservoir Decay during Broadly Neutralizing Antibody Therapy in the RIO Trial.
https://www.croiconference.org/abstract/3845-2025/
[34] Gruell, H. and Schommers, P. (2022) Broadly Neutralizing Antibodies against HIV-1 and Concepts for Application. Current Opinion in Virology, 54, Article 101211.
https://doi.org/10.1016/j.coviro.2022.101211
[35] Mahomed, S., Pillay, K., Hassan-Moosa, R., Galvão, B.P.G.V., Burgers, W.A., Moore, P.L., et al. (2025) Clinical Trials of Broadly Neutralizing Monoclonal Antibodies in People Living with HIV—A Review. AIDS Research and Therapy, 22, Article No. 44.
https://doi.org/10.1186/s12981-025-00734-8
[36] Tebas, P. (2025) Future of bNAbs in HIV Treatment. Current HIV/AIDS Reports, 22, Article No. 34.
https://doi.org/10.1007/s11904-025-00744-1
[37] Gautam, R., Nishimura, Y., Gaughan, N., Gazumyan, A., Schoofs, T., Buckler-White, A., et al. (2018) A Single Injection of Crystallizable Fragment Domain-Modified Antibodies Elicits Durable Protection from SHIV Infection. Nature Medicine, 24, 610-616.
https://doi.org/10.1038/s41591-018-0001-2
[38] Eron, J.J., Little, S.J., Crofoot, G., Cook, P., Ruane, P.J., Jayaweera, D., et al. (2024) Safety of Teropavimab and Zinlirvimab with Lenacapavir Once Every 6 Months for HIV Treatment: A Phase 1b, Randomised, Proof-of-Concept Study. The Lancet HIV, 11, e146-e155.
https://doi.org/10.1016/s2352-3018(23)00293-x
[39] Kuritzkes, D.R. (2023) Broadly Neutralizing Antibodies and Long-Acting Antiretroviral Drugs as Treatments for HIV. Current Opinion in HIV and AIDS, 18, 225-228.
https://doi.org/10.1097/coh.0000000000000801
[40] Eron, J.J., Cook, P.P., Mehrotra, M.L., Huang, H., Caskey, M., Crofoot, G.E., et al. (2025) Lenacapavir Plus 2 Broadly Neutralizing Antibodies, Teropavimab and Zinlirvimab, for People with HIV-1 Highly Susceptible to Either Teropavimab or Zinlirvimab. Journal of Infectious Diseases, 231, 1440-1444.
[41] Ogbuagu, O., Gaur, A., McMahon, J.H., Gorgos, L., Morales-Ramirez, J.O., Workowski, K., et al. (2026) Efficacy and Safety of Lenacapavir, Teropavimab, and Zinlirvimab: Week-26 Primary Outcome Results from a Multicentre, Open-Label, Randomised, Active-Controlled, Phase 2 Study. The Lancet Microbe, 7, Article 101283.
https://doi.org/10.1016/j.lanmic.2025.101283
[42] (2026) 567—Twice-Yearly Lenacapavir, Teropavimab, and Zinlirvimab for HIV-1: Week 52 Resistance Analyses.
https://www.croiconference.org/abstract/1163-2026/
[43] Boyle, S. (2025) EACS 2025: Once-Weekly HIV Pill Maintains Viral Suppression for 96 Weeks.
https://www.emjreviews.com/en-us/amj/microbiology-infectious-diseases/news/eacs-2025-once-weekly-hiv-pill-maintains-viral-suppression-for-96-weeks/
[44] Wu, R.L., Houser, K.V., Gaudinski, M.R., et al. (2025) Safety and Pharmacokinetics of N6LS, a Broadly Neutralising Monoclonal Antibody for HIV: A Phase 1, Open-Label, Dose-Escalation Study in Healthy Adults. The Lancet HIV, 12, e485-e495.
[45] Cooper, S.E., Rosenblatt, J. and Gulick, R.M. (2022) Barriers to Uptake of Long-Acting Antiretroviral Products for Treatment and Prevention of Human Immunodeficiency Virus (HIV) in High-Income Countries. Clinical Infectious Diseases, 75, S541-S548.
https://doi.org/10.1093/cid/ciac716
[46] O’Shea, J.G., Cholli, P., Heil, E.L. and Buchacz, K. (2023) Considerations for Long-Acting Antiretroviral Therapy in Older Persons with HIV. AIDS, 37, 2271-2286.
https://doi.org/10.1097/qad.0000000000003704
[47] Caskey, M. (2020) Broadly Neutralizing Antibodies for the Treatment and Prevention of HIV Infection. Current Opinion in HIV and AIDS, 15, 49-55.
https://doi.org/10.1097/coh.0000000000000600
[48] Moldt, B., Parvangada, A., Martin, R., Pace, C., Balakrishnan, M., Thomsen, N.D., et al. (2021) Evaluation of Broadly Neutralizing Antibody Sensitivity by Genotyping and Phenotyping for Qualifying Participants to HIV Clinical Trials. JAIDS Journal of Acquired Immune Deficiency Syndromes, 88, 61-69.
https://doi.org/10.1097/qai.0000000000002722
[49] Sharma, V.K., Misra, B., McManus, K.T., Avula, S., Nellaiappan, K., Caskey, M., et al. (2020) Characterization of Co-Formulated High-Concentration Broadly Neutralizing Anti-HIV-1 Monoclonal Antibodies for Subcutaneous Administration. Antibodies, 9, Article 36.
https://doi.org/10.3390/antib9030036
[50] Fanjul, F., Gavalda, M., Campins, A., Ferré, A., Martín, L., Peñaranda, M., et al. (2025) HIV Therapy: The Latest Developments in Antiviral Drugs—A Scoping Review. Biomedicines, 13, Article 2629.
https://doi.org/10.3390/biomedicines13112629
[51] Borducchi, E.N., Liu, J., Nkolola, J.P., Cadena, A.M., Yu, W., Fischinger, S., et al. (2018) Antibody and TLR7 Agonist Delay Viral Rebound in Shiv-Infected Monkeys. Nature, 563, 360-364.
https://doi.org/10.1038/s41586-018-0600-6
[52] Nishimura, Y., Gautam, R., Chun, T., Sadjadpour, R., Foulds, K.E., Shingai, M., et al. (2017) Early Antibody Therapy Can Induce Long-Lasting Immunity to Shiv. Nature, 543, 559-563.
https://doi.org/10.1038/nature21435

为你推荐