TOPICAL MICROBICIDE DRUG COMBINATIONS FOR THE PREVENTION OF SHIV

用于预防 SHIV 的外用杀菌剂药物组合

• 批准号: 8172412
• 负责人: FRANCIS J NOVEMBRE
• 金额: $ 4.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172412
• 关键词: AIDS prevention; Animals; Anti-Retroviral Agents; Attention; Clinical Trials Design; Computer Retrieval of Information on Scientific Projects Database; Dose; Drug Combinations; Female; Follow-Up Studies; Funding; Future; Gel; Generations; Grant; HIV; Heterosexuals; Infection; Institution; Integrase; Integrase Inhibitors; Intervention; Local Microbicides; Macaca; Modeling; Nucleosides; Nucleotides; PRO 2000; Pharmaceutical Preparations; Phase III Clinical Trials; Prevention; Prevention strategy; Prophylactic treatment; RNA-Directed DNA Polymerase; Research; Research Personnel; Resources; Source; Tenofovir; Time; Tissues; United States National Institutes of Health; Vaccines; Vagina; Woman; emtricitabine; high risk; inhibitor/antagonist; microbicide; pandemic disease; prevent; sex; simian human immunodeficiency virus; transmission process; vaginal microbicide; vaginal transmission

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The HIV pandemic continues with an estimated 13,000 new infections each day, the vast majority acquired through heterosexual sex. Currently, no vaccine is available to prevent HIV and it is unlikely that one will be developed soon. This highlights the critical need for an effective, female-controlled HIV prevention strategy such as a vaginally-applied microbicide gel, which can enable women to protect themselves from transmission. Because first generation microbicides have been proved ineffective, highlighted by the disappointing results from the MDP 301 Phase III trial of PRO 2000 vaginal microbicide gel, gels formulated with antiretroviral drugs has gained considerable attention as a potential biomedical intervention to protect high-risk HIV-negative people from becoming infected. These strategies are more promising because they can deliver a high dose of potent drugs that can block HIV replication at the mucosal point of entry. To this end, we have successfully formulated and evaluated several gels containing single or combinations of nucleoside/nucleotide reverse transcriptase (emtricitabine and tenofovir) or integrase (Raltegravir) inhibitors. Our efficacy studies show that gels containing tenofovir (TFV) alone or in combination with emtricitabine (FTC) can fully protect against vaginal transmission using a low-dose, repeat SHIV challenge model in pigtailed macaques. In addition, follow-up studies evaluating the window of protection showed that TFV provided long-lasting protection and remained in vaginal tissues for days following a single gel application, suggesting that non-coital daily gel use may not be necessary to achieve protection. We also completed studies to assess the efficacy of gels with integrase inhibitors and show them to be highly protective for both pre- and post exposure prophylaxis, demonstrating for the first time the utility of this class of drugs. These animal studies advance the field by highlighting the high efficacy of topical antiretroviral prophylaxis and aid in future clinical trial designs.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 艾滋病毒大流行持续，估计每天有13,000种新感染，这是通过异性性别获得的绝大多数感染。目前，尚无疫苗来预防艾滋病毒，不太可能很快开发一种疫苗。这凸显了对有效的，受女性控制的艾滋病毒预防策略（例如阴道施加的杀菌剂凝胶）的迫切需求，这可以使女性能够保护自己免受传播。 由于已经证明了第一代微生物无效，因此由MDP 301 Pro 2000阴道菌心凝胶的MDP 301 III期试验令人失望的结果突显出来，因此用抗逆转录病毒药物配制的凝胶引起了极大的关注，这是一种潜在的生物医学干预，以保护高风险的HIV抗毒性人群免受感染。这些策略更有希望，因为它们可以提供大量的有效药物，这些药物可以阻止粘膜进入点。 为此，我们成功制定并评估了几种含有核苷/核苷酸逆转录酶（Emtricyabine和Tenofovir）或整合酶（Raltegravir）抑制剂的单个或组合的凝胶。 我们的功效研究表明，单独或与Emtritebine（FTC）结合使用含有替诺福韦（TFV）的凝胶可以使用低剂量的，重复的SHIV挑战模型在绒毛猕猴中完全预防阴道传播。 此外，评估保护窗口的随访研究表明，TFV提供了持久的保护，并在单块凝胶应用后仍在阴道组织中持续数天，这表明非野毛每日凝胶可能不需要实现保护。我们还完成了研究，以评估凝胶使用整合酶抑制剂的功效，并表明它们对暴露前和暴露后预防具有高度保护性，这是该类别药物的效用。 这些动物研究通过强调局部抗逆转录病毒预防的高疗效，并有助于将来的临床试验设计提高了该领域。