Anderson Peter L, García-Lerma J Gerardo, Heneine Walid
aDepartment of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado bLaboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Curr Opin HIV AIDS. 2016 Jan;11(1):94-101. doi: 10.1097/COH.0000000000000213.
To discuss nondaily preexposure prophylaxis (PrEP) modalities that may provide advantages compared with daily PrEP in cost and cumulative toxicity, but may have lower adherence forgiveness.
Animal models have informed our understanding of early viral transmission events, which help guide event-driven PrEP dosing strategies. These models indicate early establishment of viral replication in rectal or cervicovaginal tissues, so event-driven PrEP should rapidly deliver high mucosal drug concentrations within hours of the potential exposure event. Macaque models have demonstrated the high biological efficacy for event-driven dosing of oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) against both vaginal and rectal virus transmission. In humans, the IPERGAY study demonstrated 86% efficacy for event-driven oral TDF/FTC dosing among men who have sex with men (MSM), while no similar efficacy data are available on women or heterosexual men. The HPTN 067 study showed that certain MSM populations adhere well to nondaily PrEP, whereas other populations of women adhere more poorly to nondaily versus daily regimens. Pharmacokinetic studies following oral TDF/FTC dosing in humans indicate that TFV-diphosphate (the active form of TFV) accumulates to higher concentrations in rectal versus cervicovaginal tissue, but nonadherence in trials complicates the interpretation of differential mucosal drug concentrations.
Event-driven dosing for TFV-based PrEP has promise for HIV prevention in MSM. Future research of event-driven PrEP in women and heterosexual men should be guided by a better understanding of the importance of mucosal drug concentrations for PrEP efficacy and its sensitivity to adherence.
探讨非每日暴露前预防（PrEP）模式，与每日PrEP相比，其在成本和累积毒性方面可能具有优势，但依从性宽容度可能较低。
动物模型有助于我们理解早期病毒传播事件，这有助于指导事件驱动的PrEP给药策略。这些模型表明病毒在直肠或宫颈阴道组织中早期建立复制，因此事件驱动的PrEP应在潜在暴露事件发生后的数小时内迅速在黏膜部位达到高药物浓度。猕猴模型已证明，事件驱动的口服替诺福韦酯（TDF）和恩曲他滨（FTC）给药对阴道和直肠病毒传播具有很高的生物学疗效。在人类中，IPERGAY研究表明，对于男男性行为者（MSM），事件驱动的口服TDF/FTC给药的疗效为86%，而关于女性或异性恋男性则没有类似的疗效数据。HPTN 067研究表明，某些MSM人群对非每日PrEP的依从性良好，而其他女性人群对非每日方案的依从性则比每日方案差。对人类口服TDF/FTC给药后的药代动力学研究表明，TFV-二磷酸（TFV的活性形式）在直肠组织中积累的浓度高于宫颈阴道组织，但试验中的不依从性使对不同黏膜药物浓度的解释变得复杂。
基于TFV的PrEP的事件驱动给药在预防男男性行为者感染HIV方面具有前景。未来对女性和异性恋男性的事件驱动PrEP研究应以更好地理解黏膜药物浓度对PrEP疗效的重要性及其对依从性的敏感性为指导。
