Department of Medicine, Albert Einstein College of Medicine, New York, New York, United States of America.
PLoS One. 2011 Jan 25;6(1):e16475. doi: 10.1371/journal.pone.0016475.
Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition.
30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood.
A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001) and fit a sigmoid E(max) pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators.
Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development of models more predictive of microbicide efficacy.
ClinicalTrials.gov NCT00594373.
临床前和早期临床杀微生物剂研究并未一致预测疗效试验的结果。为了解决这一差距，在一项双盲、安慰剂对照的替诺福韦凝胶试验中评估了候选杀微生物剂药代动力学和安全性的生物标志物，这是第一个证明对艾滋病毒感染有显著保护作用的杀微生物剂。
30 名妇女被随机分配每天应用一次替诺福韦或安慰剂凝胶，连续 14 天。在第 0、3、7、14 和 21 天通过荧光素酶测定法测量宫颈阴道灌洗液 (CVL)中的抗 HIV 活性，作为药代动力学的替代标志物。CVL 中内源性抗大肠杆菌和单纯疱疹病毒 2 活性和免疫调节剂浓度被量化为安全性的候选生物标志物。CVL 和血液中测量替诺福韦水平。
与妇女阴道分泌物中的内源性抗 HIV 活性相比，使用替诺福韦凝胶的妇女的 CVL 中检测到抗 HIV 活性显著增加，与安慰剂组妇女的 CVL 活性相比也是如此。该活性与 CVL 中替诺福韦浓度显著相关 (r = 0.6，p<0.001)，并符合 sigmoid E(max)药代动力学模型。当精液中引入病毒时，使用替诺福韦凝胶的妇女的 CVL 中的抗 HIV 活性持续存在，而内源性抗 HIV 活性下降。替诺福韦不会引发炎症反应，也不会诱导内源性抗菌活性或免疫调节剂的持续丧失。
替诺福韦凝胶对可溶性粘膜免疫没有不良影响。CVL 中增加的抗 HIV 活性在精液存在的情况下持续存在，与替诺福韦浓度相关，与最近临床试验中观察到的疗效一致。这些结果促进了 CVL 中量化的抗 HIV 活性作为组织药代动力学的替代物，并作为产品依从性的潜在生物标志物。这种简单、可行和廉价的生物测定方法可能会促进开发更能预测杀微生物剂疗效的模型。
ClinicalTrials.gov NCT00594373。
