Department of Medicine, Imperial College London, London, UK.
Guys and St Thomas' NHS Foundation Trust and King's College London, London, UK.
J Antimicrob Chemother. 2021 Jul 15;76(8):2129-2136. doi: 10.1093/jac/dkab136.
To characterize their potential use in pre-exposure prophylaxis (PrEP) we compared the pharmacokinetics of raltegravir and lamivudine in genital tissue against ex vivo tissue infection with HIV-1.
Open-label trial of 36 HIV-negative females and males randomized to 7 days raltegravir 400 mg twice daily and 7 days raltegravir 400 mg+lamivudine 150 mg twice daily (after washout), or vice versa. Blood, saliva, rectal fluid, rectal tissue, vaginal fluid and vaginal tissue were sampled at baseline and on and off PrEP during a total of 12 days, for pharmacokinetics and antiviral activity via ex vivo HIV-1BaL challenge. Ex vivo infectivity was compared with baseline. The trial has been registered in https://clinicaltrials.gov/ with the identifier NCT03205566.
Steady state for both drugs was reached by day 4. Dosing with raltegravir alone provided modest ex vivo HIV protection with higher drug levels in rectal tissue and vaginal tissue than in plasma on and off PrEP. Off PrEP, plasma and vaginal concentrations declined rapidly, while persisting in the rectum. On PrEP, the highest lamivudine concentrations were in the rectum, followed by vaginal tissue then plasma. Lamivudine washout was rapid in plasma, while persisting in the rectum and vagina. Raltegravir/lamivudine increased ex vivo protection on and off PrEP compared with raltegravir alone, reaching maximum protection at day 2 in rectal tissue and at day 8 in vaginal tissue.
Raltegravir 400 mg+lamivudine 150 mg showed high levels of ex vivo HIV protection, associated with high drug concentrations persisting after discontinuation in vaginal and rectal compartments, supporting further investigation of these agents for PrEP.
为了研究它们在暴露前预防（PrEP）中的潜在用途，我们比较了雷替拉韦和拉米夫定在生殖器组织中的药代动力学与 HIV-1 体外组织感染。
对 36 名 HIV 阴性的女性和男性进行开放标签试验，随机分为 7 天雷替拉韦 400mg 每日两次+7 天雷替拉韦 400mg+拉米夫定 150mg 每日两次（洗脱期），或反之。在总共 12 天的时间内，在基线和 PrEP 期间采集血液、唾液、直肠液、直肠组织、阴道液和阴道组织样本，进行药代动力学和通过 HIV-1BaL 体外挑战的抗病毒活性检测。将体外感染性与基线进行比较。该试验已在 https://clinicaltrials.gov/ 注册，标识符为 NCT03205566。
第 4 天达到了两种药物的稳态。单独使用雷替拉韦提供了适度的体外 HIV 保护，在 PrEP 期间和之后，直肠组织和阴道组织中的药物水平高于血浆。停药后，血浆和阴道浓度迅速下降，而在直肠中持续存在。在 PrEP 期间，最高的拉米夫定浓度出现在直肠，其次是阴道组织，然后是血浆。拉米夫定洗脱在血浆中迅速，而在直肠和阴道中持续存在。雷替拉韦/拉米夫定与单独使用雷替拉韦相比，增加了 PrEP 期间和之后的体外保护作用，在直肠组织中在第 2 天达到最大保护，在阴道组织中在第 8 天达到最大保护。
雷替拉韦 400mg+拉米夫定 150mg 显示出高水平的体外 HIV 保护作用，与停药后在阴道和直肠隔室中持续存在的高药物浓度相关，支持进一步研究这些药物在 PrEP 中的应用。
