J Infect Dis ：为何女性比男性需要更多药物预防HIV感染？

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根据北卡罗来纳大学的一项最新研究，女性需要每天服用抗病毒药物Truvada预防HIV感染，而男性只需要每周服用两次，这种差别主要是由于不同组织对HIV病毒的易感性以及Truvada到达不同组织的效率不同所导致。相关研究结果发表在国际学术期刊Journal of Infectious Diseases 上。

这项研究为HIV预防策略的变动提供了一个很好的案例，或为临床试验设计带来许多提示。

文章作者Angela Kashuba表示：“我们的研究数据表明如何服用抗病毒药物不能一概而论，为了确定如何服用药物才能起到最好的HIV预防作用，我们需要深入了解病人体内哪些部位容易受到感染，同时还需要知道为了避免这些易感部位受到感染需要使用多大的药物剂量。”

之前的临床研究表明Truvada对男性的保护作用更显著，而对女性则没有那么有效。该研究首次通过证明不同组织需要的药物剂量不同解释了上述临床现象。

研究人员发现阴道，子宫颈和直肠组织对Truvada的应答情况都不同。阴道和子宫颈组织需要的药物剂量是直肠组织的大约两倍，主要原因在于能够到达阴道和子宫颈组织的Truvada药物成分非常少。并且阴道和子宫颈组织内供病毒复制的DNA原料更加丰富，因此需要更多的药物来预防感染。

研究人员表示供病毒使用的DNA原料越多，阻断病毒复制所需要的药物剂量就越大，因此他们通过细胞实验和临床试验数据构建了一个数学模型，预测了阴道，子宫颈和直肠组织内的药物/DNA比例，同时也计算出了为防止HIV感染这几种组织所需要的药物剂量。

这项研究表明，身体不同组织受HIV病毒感染的易感性不同，而Truvada药物到达不同组织的效率也不同，因此造成了Truvada药物对男性和女性的保护作用不同。目前，Truvada是FDA批准的唯一一种防止HIV传播的预防药物。

来源：生物谷

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A Translational Pharmacology Approach to Predicting HIV Pre-Exposure Prophylaxis Outcomes in Men and Women Using Tenofovir Disoproxil Fumarate±Emtricitabine

Mackenzie L. Cottrell1, Kuo H. Yang2, Heather M.A. Prince3, Craig Sykes1, Nicole White1, Stephanie Malone1, Evan S. Dellon3, Ryan D. Madanick3, Nicholas J. Shaheen3, Michael G. Hudgens4, Jacob Wulff4, Kristine B. Patterson3, Julie A.E. Nelson5 and Angela D.M. Kashuba1,*

Background. A novel translational pharmacology investigation was conducted by combining an in vitro efficacy target with mucosal tissue pharmacokinetic data and mathematical modeling to determine the number of doses required for effective HIV pre-exposure prophylaxis(PrEP).

Methods. A pharmacokinetic/pharmacodynamic(PK/PD) model was developed by measuring mucosal tissue concentrations of tenofovir, emtricitabine, their active metabolites [tenofovir-diphosphate(TFVdp), emtricitabine-triphosphate(FTCtp)], and competing endogenous nucleotides(dATP, dCTP) in 47 healthy women. TZM-bl and CD4+ cells were used to identify EC90 ratios of TFVdp:dATP and FTCtp:dCTP (alone and in combination) for protection against HIV. Monte-Carlo simulations were then performed to identify minimally effective dosing strategies to protect lower female genital tract(FGT) and colorectal tissues.

Results. Colorectal TFVdp was 10 times higher than FGT while endogenous nucleotides were 7-11 times lower. Our model predicted ≥98% of the population achieve protective mucosal tissue exposure by the third daily dose of tenofovir disoproxil fumarate+emtricitabine. However, a minimum adherence of 6/7(85%) doses/week was required to protect FGT tissue from HIV, while 2/7(28%) doses/week was required for colorectal tissue.

Conclusions. This model is predictive of recent PrEP trial results where 2-3 doses/week was 75-90% effective in men but ineffective in women. These data provide a novel approach for future PrEP investigations that can optimize clinical trial dosing strategies.

http://jid.oxfordjournals.org/co ... dis.jiw077.abstract