Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV, Hepatitis, STD, and Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Curr Opin HIV AIDS. 2012 Nov;7(6):505-13. doi: 10.1097/COH.0b013e328358e484.
Oral and topical pre-exposure prophylaxis (PrEP) with antiretroviral drugs are novel biomedical interventions recently found to prevent HIV transmission among high-risk populations. In this review, we outline lessons learned from animal studies and discuss next steps in preclinical PrEP research including the study of new PrEP modalities, pharmacologic correlates of protection, and biological factors that may modulate PrEP efficacy.
Studies using macaque or humanized mice models of mucosal simian immunodeficiency virus (SIV), HIV, or simian/human immunodeficiency virus (SHIV) transmission have provided efficacy data against rectal and vaginal infection. A multitude of oral and topical PrEP regimens including drugs such as tenofovir (TFV), tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) were tested against either wild-type or drug-resistant viruses. These models have also helped define prophylactic windows of protection of nondaily dosing and are being used increasingly to study pharmacokinetic and pharmacodynamic relationships.
As human data from PrEP trials validate animal models or help fine tune them, it is expected that these models will play increasingly important roles in PrEP development as the field extends into new drug classes and combinations, episodic dosing, and novel long-acting drug formulations. By providing both efficacy and pharmacologic information these models can define correlates and mechanisms of protection, inform dose selection, and advance the most promising PrEP candidates and dosing modalities.
最近发现，使用抗逆转录病毒药物进行口腔和局部暴露前预防（PrEP）是一种新的医学干预措施，可预防高危人群中的 HIV 传播。在这篇综述中，我们概述了从动物研究中吸取的经验教训，并讨论了临床前 PrEP 研究的下一步措施，包括新的 PrEP 方式、保护的药理学相关性以及可能调节 PrEP 疗效的生物学因素的研究。
使用猴免疫缺陷病毒（SIV）、HIV 或猴/人免疫缺陷病毒（SHIV）黏膜感染的猕猴或人源化小鼠模型进行的研究提供了针对直肠和阴道感染的疗效数据。多种口服和局部 PrEP 方案，包括替诺福韦（TFV）、替诺福韦二吡呋酯（TDF）和恩曲他滨（FTC）等药物，已针对野生型或耐药病毒进行了测试。这些模型还帮助确定了非每日剂量的预防保护窗口期，并且越来越多地用于研究药代动力学和药效学关系。
随着 PrEP 试验的人体数据验证或帮助调整动物模型，预计这些模型将在 PrEP 开发中发挥越来越重要的作用，因为该领域扩展到新的药物类别和组合、间歇性给药以及新型长效药物制剂。这些模型通过提供疗效和药理学信息，可以确定保护的相关性和机制，为剂量选择提供信息，并推进最有前途的 PrEP 候选药物和给药方式。
