Department of Microbiology and Immunology, Drexel University College of Medicine, 245 N. 15th Street, New College Building, Philadelphia PA 19102, USA.
Antimicrob Agents Chemother. 2011 May;55(5):1831-42. doi: 10.1128/AAC.00976-10. Epub 2011 Feb 22.
The discovery of the human immunodeficiency virus type 1 (HIV-1) in 1982 soon led to the identification and development of antiviral compounds to be used in treatment strategies for infected patients. Early in the epidemic, drug monotherapies frequently led to treatment failures because the virus quickly developed resistance to the single drug. Following the advent of highly active antiretroviral therapy (HAART) in 1995, dramatic improvements in HIV-1-infected patient health and survival were realized as more refined combination therapies resulted in reductions in viral loads and increases in CD4+ T-cell counts. In the absence of an effective vaccine, prevention of HIV-1 infection has also gained traction as an approach to curbing the pandemic. The development of compounds as safe and effective microbicides has intensified and has focused on blocking the transmission of HIV-1 during all forms of sexual intercourse. Initial preclinical investigations and clinical trials of microbicides focused on single compounds effective against HIV-1. However, the remarkable successes achieved using combination therapy to treat systemic HIV-1 infection have subsequently stimulated the study and development of combination microbicides that will simultaneously inhibit multiple aspects of the HIV-1 transmission process by targeting incoming viral particles, virus-infected cells, and cells susceptible to HIV-1 infection. This review focuses on existing and developing combination therapies, covering preclinical development, in vitro and in vivo efficacy studies, and subsequent clinical trials. The shift in focus within the microbicide development field from single compounds to combination approaches is also explored.
1982 年发现人类免疫缺陷病毒 1 型（HIV-1）后，很快就鉴定和开发了抗病毒化合物，用于感染患者的治疗策略。在疫情早期，由于病毒很快对单一药物产生耐药性，药物单药治疗经常导致治疗失败。1995 年高效抗逆转录病毒疗法（HAART）问世后，由于更精细的联合疗法降低了病毒载量并增加了 CD4+T 细胞计数，HIV-1 感染患者的健康和生存状况得到了显著改善。在没有有效疫苗的情况下，预防 HIV-1 感染也已成为遏制大流行的一种方法。作为安全有效的杀微生物剂的化合物的开发已经加强，并集中在阻断所有形式的性传播中 HIV-1 的传播。最初针对 HIV-1 的单一化合物有效的杀微生物剂的临床前研究和临床试验。然而，随后用联合疗法治疗系统性 HIV-1 感染所取得的显著成功，刺激了对联合杀微生物剂的研究和开发，这些杀微生物剂将通过针对传入的病毒颗粒、受感染的病毒细胞和易受 HIV-1 感染的细胞，同时抑制 HIV-1 传播过程的多个方面。本综述重点介绍现有的和正在开发的联合疗法，涵盖临床前开发、体外和体内疗效研究以及随后的临床试验。还探讨了杀微生物剂开发领域从单一化合物到联合方法的重点转移。
