Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV, Hepatitis, STD, and Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
PLoS One. 2012;7(12):e50632. doi: 10.1371/journal.pone.0050632. Epub 2012 Dec 4.
Daily pre-exposure prophylaxis (PrEP) with Truvada (a combination of emtricitabine (FTC) and tenofovir (TFV) disoproxil fumarate (TDF)) is a novel HIV prevention strategy recently found to prevent HIV transmission in men who have sex with men and heterosexual couples. We previously showed that a coitally-dependent Truvada regimen protected macaques against rectal SHIV transmission. Here we examined FTC and tenofovir TFV exposure in vaginal tissues after oral dosing and assessed if peri-coital Truvada also protects macaques against vaginal SHIV infection.
The pharmacokinetic profile of emtricitabine (FTC) and tenofovir (TFV) was evaluated at first dose. FTC and TFV levels were measured in blood plasma, rectal, and vaginal secretions. Intracellular concentrations of FTC-triphosphate (FTC-TP) and TFV-diphosphate (TFV-DP) were measured in PBMCs, rectal tissues, and vaginal tissues. Efficacy of Truvada in preventing vaginal SHIV infection was assessed using a repeat-exposure vaginal SHIV transmission model consisting of weekly exposures to low doses of SHIV162p3. Six pigtail macaques with normal menstrual cycles received Truvada 24 h before and 2 h after each weekly virus exposure and six received placebo. Infection was monitored by serology and PCR amplification of SHIV RNA and DNA.
As in humans, the concentration of FTC was higher than the concentration of TFV in vaginal secretions. Also as in humans, TFV levels in vaginal secretions were lower than in rectal secretions. Intracellular TFV-DP concentrations were also lower in vaginal tissues than in rectal tissues. Despite the low vaginal TFV exposure, all six treated macaques were protected from infection after 18 exposures or 4 full menstrual cycles. In contrast, all 6 control animals were infected.
We modeled a peri-coital regimen with two doses of Truvada and showed that it fully protected macaques from repeated SHIV exposures. Our results open the possibility for simplified PrEP regimens to prevent vaginal HIV transmission in women.
每日暴露前预防（PrEP）用特鲁瓦达（恩曲他滨[FTC]和替诺福韦[TDF]富马酸酯[TDF]的组合）是一种最近发现的预防 HIV 传播的新策略，可预防男男性行为者和异性恋夫妇中的 HIV 传播。我们之前表明，一种依赖于性行为的特鲁瓦达方案可保护猕猴免受直肠 SHIV 传播。在这里，我们检查了口服给药后阴道组织中的恩曲他滨（FTC）和替诺福韦 TFV 暴露情况，并评估了围性交特鲁瓦达是否也可保护猕猴免受阴道 SHIV 感染。
首次给药时评估了恩曲他滨（FTC）和替诺福韦（TFV）的药代动力学特征。测量了血浆、直肠和阴道分泌物中的 FTC 和 TFV 水平。在 PBMCs、直肠组织和阴道组织中测量了 FTC-三磷酸（FTC-TP）和 TFV-二磷酸（TFV-DP）的细胞内浓度。使用每周接受低剂量 SHIV162p3 的重复暴露阴道 SHIV 传播模型评估特鲁瓦达预防阴道 SHIV 感染的功效。6 只具有正常月经周期的长尾猕猴在每次每周病毒暴露前 24 小时和暴露后 2 小时接受特鲁瓦达治疗，而 6 只接受安慰剂。通过血清学和 SHIV RNA 和 DNA 的 PCR 扩增监测感染。
与人类一样，阴道分泌物中的 FTC 浓度高于 TFV 浓度。与人类一样，阴道分泌物中的 TFV 水平也低于直肠分泌物。阴道组织中的细胞内 TFV-DP 浓度也低于直肠组织。尽管阴道 TFV 暴露水平较低，但在 18 次暴露或 4 个完整月经周期后，所有 6 只接受治疗的猕猴均受到保护而免受感染。相比之下，所有 6 只对照动物均感染。
我们模拟了一种特鲁瓦达两剂的围性交方案，并表明它完全保护猕猴免受重复的 SHIV 暴露。我们的结果为简化预防方案以预防女性阴道 HIV 传播开辟了可能性。
