Department of Infectious Disease, Faculty of Medicine, Imperial College London, Norfolk Place, W2 1PG, London, UK.
Medical Research Council/Uganda Virus Research Institute, and London School of Hygiene and Tropical Medicine, Uganda Research Unit, 51-59 Nakiwogo Road, Entebbe, Uganda.
EBioMedicine. 2023 Jul;93:104648. doi: 10.1016/j.ebiom.2023.104648. Epub 2023 Jun 14.
The efficacy of on-demand HIV pre-exposure prophylaxis (PrEP) for men in sub-Saharan Africa has not been evaluated, and the on-demand PrEP dosing requirement for insertive sex remains unknown.
HIV-negative males 13-24 years, requesting voluntary medical male circumcision (VMMC), were enrolled into an open-label randomised controlled trial (NCT03986970), and randomised 1:1:1:1:1:1:1:1:1 to control arm or one of eight arms receiving emtricitabine-tenofovir disoproxil fumarate (F/TDF) or emtricitabine-tenofovir alafenamide (F/TAF) over one or two days, and circumcised 5 or 21 h thereafter. The primary outcome was foreskin p24 concentrations following ex vivo HIV-1 challenge. Secondary outcomes included peripheral blood mononuclear cell (PBMC) p24 concentration, and drug concentrations in foreskin tissue, PBMCs, plasma and foreskin CD4+/CD4-cells. In the control arm, post-exposure prophylaxis (PEP) activity of non-formulated tenofovir-emtricitabine (TFV-FTC) or TAF-FTC was assessed with ex vivo dosing 1, 24, 48 or 72 h post-HIV-1 challenge.
144 participants were analysed. PrEP with F/TDF or F/TAF prevented ex vivo infection of foreskins and PBMCs both 5 and 21 h after PrEP dosing. There was no difference between F/TDF and F/TAF (p24 geometric mean ratio 1.06, 95% confidence interval: 0.65-1.74). Additional ex vivo dosing did not further increase inhibition. In the control arm, PEP ex vivo dosing was effective up to 48 post-exposure diminishing thereafter, with TAF-FTC showing prolonged protection compared to TFV-FTC. Participants receiving F/TAF had higher TFV-DP concentrations in foreskin tissue and PBMCs compared with F/TDF, irrespective of dose and sampling interval; but F/TAF did not confer preferential TFV-DP distribution into foreskin HIV target cells. FTC-TP concentrations with both drug regimens were equivalent and ∼1 log higher than TFV-DP in foreskin.
A double dose of either F/TDF or F/TAF given once either 5 or 21 h before ex vivo HIV-challenge provided protection across foreskin tissue. Further clinical evaluation of pre-coital PrEP for insertive sex is warranted.
EDCTP2, Gilead Sciences, Vetenskapsrådet.
在撒哈拉以南非洲，按需服用 HIV 暴露前预防（PrEP）对男性的疗效尚未得到评估，而插入性性行为的按需 PrEP 给药需求仍不清楚。
13-24 岁要求接受自愿男性包皮环切术（VMMC）的 HIV 阴性男性被纳入一项开放性标签随机对照试验（NCT03986970），并按照 1:1:1:1:1:1:1:1:1 的比例随机分为对照组或 8 个实验组，分别接受恩曲他滨替诺福韦富马酸酯（F/TDF）或恩曲他滨替诺福韦艾拉酚胺（F/TAF）连续服用 1 天或 2 天，然后在 5 或 21 小时后进行包皮环切术。主要结局是体外 HIV-1 攻击后包皮内 p24 浓度。次要结局包括外周血单核细胞（PBMC）p24 浓度以及包皮组织、PBMC、血浆和包皮 CD4+/CD4-细胞中的药物浓度。在对照组中，在 HIV-1 攻击后 1、24、48 或 72 小时进行体外给药，评估非配方替诺福韦-恩曲他滨（TFV-FTC）或 TAF-FTC 的暴露后预防（PEP）活性。
分析了 144 名参与者。F/TDF 或 F/TAF 的 PrEP 预防了包皮和 PBMC 的体外感染，分别在 PrEP 给药后 5 小时和 21 小时。F/TDF 和 F/TAF 之间没有差异（p24 几何平均比 1.06，95%置信区间：0.65-1.74）。额外的体外给药并不能进一步增加抑制作用。在对照组中，PEP 体外给药在暴露后最多有效 48 小时，此后逐渐减少，与 TFV-FTC 相比，TAF-FTC 显示出更长的保护作用。与 F/TDF 相比，无论剂量和采样间隔如何，接受 F/TAF 的参与者在包皮组织和 PBMC 中的 TFV-DP 浓度均较高；但 F/TAF 并未将 TFV-DP 优先分布到包皮中的 HIV 靶细胞中。两种药物方案的 FTC-TP 浓度均相当，且在包皮中的浓度比 TFV-DP 高约 1 个对数。
在体外 HIV 攻击前 5 小时或 21 小时单次给予双倍剂量的 F/TDF 或 F/TAF，可在整个包皮组织中提供保护。需要进一步评估插入性性行为前的 PrEP 进行预防性治疗。
EDCTP2、吉利德科学公司、瑞典研究理事会。
