Antiviral activity of genital tract secretions after oral or topical tenofovir pre-exposure prophylaxis for HIV-1.
Antiviral activity of genital tract secretions after oral or topical tenofovir pre-exposure prophylaxis for HIV-1.
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DOI：
10.1097/qai.0000000000000110
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发表时间：
2014-05-01
期刊：
影响因子：
--
通讯作者：
Hendrix CW
中科院分区：
文献类型：
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作者：
Herold BC;Dezzutti CS;Richardson BA;Marrazzo J;Mesquita PM;Carpenter C;Huber A;Louissaint N;Marzinke MA;Hillier SL;Hendrix CW
需要 HIV-1 暴露前预防 (PrEP) 和杀菌剂功效的替代标志物。一种潜在的替代指标是接触候选产品后宫颈阴道灌洗 (CVL) 中的抗病毒活性。我们使用口服或阴道基于替诺福韦的 PrEP 测量了女性的 CVL 抗病毒活性，并将活性与药物和免疫介质水平相关联。测量了 60 名女性基线和 6 周随机口服给药后的 CVL 中对 HIV-1 和 HSV-2 的抑制活性以及白细胞介素 (IL)-1β、IL-6、IL-8、干扰素-γ、诱导蛋白 10 (IP-10)、巨噬细胞炎症蛋白 (MIP)-1α、MIP-3a、乳铁蛋白、分泌性白细胞蛋白酶抑制剂和防御素的浓度。和外用替诺福韦。通过质谱法测量CVL替诺福韦浓度。每日使用 1% 替诺福韦凝胶后，CVL 抗 HIV 活性≥90% 的女性人数从基线时的 5.0% 显着增加至 89.1%（RR=17.85，p<0.001），但每日口服替诺福韦后没有增加。 CVL 抗 HIV 活性与药物水平相关（替诺福韦凝胶后 Spearman 相关系数为 0.64；p<0.001），但与粘膜免疫介质的浓度无关。两种药物方案均未观察到 CVL 抗 HSV 活性增加，这一观察结果与抑制 HSV-2 感染所需的较高浓度的替诺福韦一致。 CVL 抗 HSV 活性与乳铁蛋白、防御素、IP-10、IL-8 和 MIP-1α 的可检测水平相关，但与药物水平无关。 CVL 可以替代局部而非全身药物疗效，并且可以作为更好地了解调节生殖道分泌物中抗病毒活性的粘膜因素的工具。
Surrogate markers of HIV-1 pre-exposure prophylaxis (PrEP) and microbicide efficacy are needed. One potential surrogate is the antiviral activity in cervicovaginal lavage (CVL) after exposure to candidate products. We measured CVL antiviral activity in women using oral or vaginal tenofovir-based PrEP and correlated activity with drug and immune mediator levels. Inhibitory activity against HIV-1 and HSV-2 and concentrations of interleukin (IL)-1β, IL-6, IL-8, interferon-γ, induced protein 10 (IP-10), macrophage inflammatory protein (MIP)-1α, MIP-3a, lactoferrin, secretory leukocyte protease inhibitor, and defensins were measured in CVL obtained from 60 women at baseline and after 6 weeks of a randomized sequence of oral and topical tenofovir. CVL tenofovir concentrations were measured by mass spectrometry. The number of women with CVL anti-HIV activity ≥90% increased significantly from 5.0% at baseline to 89.1% following daily use of 1% tenofovir gel (RR=17.85, p<0.001), but there was no increase following daily oral tenofovir. The CVL anti-HIV activity correlated with drug levels (Spearman correlation coefficient 0.64 following tenofovir gel; p<0.001), but not with the concentrations of mucosal immune mediators. No increase in CVL anti-HSV activity was observed following either drug regimen, an observation consistent with the higher concentrations of tenofovir needed to inhibit HSV-2 infection. The CVL anti-HSV activity correlated with lactoferrin, defensins, IP-10, IL-8 and detectable levels of MIP-1α, but not with drug levels. CVL may provide a surrogate for local but not systemic drug efficacy and a tool to better understand mucosal factors that modulate antiviral activity in genital tract secretions.