A randomized trial to assess anti-HIV activity in female genital tract secretions and soluble mucosal immunity following application of 1% tenofovir gel.
A randomized trial to assess anti-HIV activity in female genital tract secretions and soluble mucosal immunity following application of 1% tenofovir gel.
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DOI：
10.1371/journal.pone.0016475
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发表时间：
2011-01-25
期刊：
影响因子：
3.7
通讯作者：
Herold BC
中科院分区：
文献类型：
--
作者：
Keller MJ;Madan RP;Torres NM;Fazzari MJ;Cho S;Kalyoussef S;Shust G;Mesquita PM;Louissaint N;Chen J;Cohen HW;Diament EC;Lee AC;Soto-Torres L;Hendrix CW;Herold BC
临床前和早期临床杀微生物剂研究并没有一致地预测疗效试验的结果。为了解决这一空白，在一项双盲、安慰剂对照的替诺福韦凝胶试验中，研究人员评估了杀微生物剂的候选生物标志物的药效学和安全性。替诺福韦凝胶是第一个显示出对HIV获得有显著保护的杀微生物剂。30名妇女被随机分配，连续14天每天服用一剂替诺福韦或安慰剂凝胶。采用荧光素酶法测定第0、3、7、14和21天宫颈阴道灌洗（CVL）的抗hiv活性，作为替代药效学指标。内源性抗大肠杆菌和HSV-2的活性以及免疫介质的浓度在CVL中被量化作为候选的安全性生物标志物。测量CVL和血液中的替诺福韦水平。与使用替诺福韦凝胶的女性在第0天生殖道分泌物中的内源性抗hiv活性和安慰剂组女性的CVL活性相比，在应用替诺福韦凝胶的女性的CVL中检测到抗hiv活性显著增加。该活性与替诺福韦CVL浓度显著相关（r = 0.6, p<0.001），符合乙状结肠Emax药效学模型。使用替诺福韦的妇女的CVL抗艾滋病毒活性在精液中引入病毒时持续存在，而内源性抗艾滋病毒活性下降。替诺福韦不会引发炎症反应，也不会导致内源性抗菌活性或免疫介质的持续丧失。替诺福韦凝胶对可溶性黏膜免疫无不良影响。CVL中抗hiv活性的增加，在精液中持续存在，并与替诺福韦浓度相关，这与最近的临床试验中观察到的疗效一致。这些结果促进了量化的CVL抗hiv活性作为组织药效学的替代品和作为产品粘附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更能预测杀微生物剂功效的模型的发展。ClinicalTrials.gov NCT00594373
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 Emax 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
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影响因子：
3.7
作者：
Rohan LC;Moncla BJ;Kunjara Na Ayudhya RP;Cost M;Huang Y;Gai F;Billitto N;Lynam JD;Pryke K;Graebing P;Hopkins N;Rooney JF;Friend D;Dezzutti CS
通讯作者：
Dezzutti CS
影响因子：
9.8
作者：
Hein, M;Valore, EV;Ganz, T
通讯作者：
Ganz, T
DOI：
10.1097/01.qai.0000167155.44980.e8
发表时间：
2005-08-01
影响因子：
3.6
作者：
Hawkins, T;Veikley, W;Kearney, BP
通讯作者：
Kearney, BP
影响因子：
3.8
作者：
Keller, Marla J.;Guzman, Esmeralda;Herold, Betsy C.
通讯作者：
Herold, Betsy C.
影响因子：
3.7
作者：
Keller, Marla J.;Mesquita, Pedro M. M.;Herold, Betsy C.
通讯作者：
Herold, Betsy C.