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Abstract：
BACKGROUND: 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.
METHODS: 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-1BaL 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.
RESULTS: 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 (p24day15 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.
CONCLUSIONS: 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.
BACKGROUND: EDCTP2, Gilead Sciences, Vetenskapsrådet.
METHODS: 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-1BaL 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.
RESULTS: 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 (p24day15 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.
CONCLUSIONS: 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.
BACKGROUND: EDCTP2, Gilead Sciences, Vetenskapsrådet.
摘要：
背景：尚未评估撒哈拉以南非洲男性按需HIV暴露前预防（PrEP）的功效，插入性行为的按需PrEP给药要求仍然未知。
方法：HIV阴性男性13-24岁，要求自愿医疗男性包皮环切术（VMMC），纳入开放标签随机对照试验(NCT03986970)，并以1：1：1：1：1：1：1：1：1为对照组或接受富马酸恩曲他滨-替诺福韦酯（F/TDF）或恩曲他滨-替诺福韦艾拉酚胺（F/TAF）的八个组中的一个或两天，然后割礼5或21小时。主要结果是离体HIV-1BaL攻击后的包皮p24浓度。次要结果包括外周血单核细胞（PBMC）p24浓度，包皮组织中的药物浓度，PBMC,血浆和包皮CD4+/CD4细胞。在控制臂中，非配制替诺福韦-恩曲他滨(TFV-FTC)或TAF-FTC的暴露后预防(PEP)活性在HIV-1攻击后1,24,48或72h进行离体给药评估.
结果：分析了144名参与者。使用F/TDF或F/TAF的PrEP可在PrEP给药后5和21小时预防包皮和PBMC的离体感染。F/TDF和F/TAF之间没有差异（p24day15几何平均比1.06，95％置信区间：0.65-1.74）。额外的离体给药没有进一步增加抑制。在控制臂中，PEP离体给药有效达48次暴露后逐渐减少，与TFV-FTC相比，TAF-FTC显示出延长的保护作用。与F/TDF相比，接受F/TAF的参与者在包皮组织和PBMC中的TFV-DP浓度更高，与剂量和采样间隔无关；但F/TAF并未赋予包皮HIV靶细胞优先的TFV-DP分布。两种药物方案的FTC-TP浓度相当，比包皮中的TFV-DP高1log。
结论：在离体HIV攻击前5或21小时给予两次剂量的F/TDF或F/TAF可在包皮组织中提供保护。有必要对性交前PrEP进行进一步的临床评估。
背景：EDCTP2，吉利德科学，Vetenskapsrädet.
方法：HIV阴性男性13-24岁，要求自愿医疗男性包皮环切术（VMMC），纳入开放标签随机对照试验(NCT03986970)，并以1：1：1：1：1：1：1：1：1为对照组或接受富马酸恩曲他滨-替诺福韦酯（F/TDF）或恩曲他滨-替诺福韦艾拉酚胺（F/TAF）的八个组中的一个或两天，然后割礼5或21小时。主要结果是离体HIV-1BaL攻击后的包皮p24浓度。次要结果包括外周血单核细胞（PBMC）p24浓度，包皮组织中的药物浓度，PBMC,血浆和包皮CD4+/CD4细胞。在控制臂中，非配制替诺福韦-恩曲他滨(TFV-FTC)或TAF-FTC的暴露后预防(PEP)活性在HIV-1攻击后1,24,48或72h进行离体给药评估.
结果：分析了144名参与者。使用F/TDF或F/TAF的PrEP可在PrEP给药后5和21小时预防包皮和PBMC的离体感染。F/TDF和F/TAF之间没有差异（p24day15几何平均比1.06，95％置信区间：0.65-1.74）。额外的离体给药没有进一步增加抑制。在控制臂中，PEP离体给药有效达48次暴露后逐渐减少，与TFV-FTC相比，TAF-FTC显示出延长的保护作用。与F/TDF相比，接受F/TAF的参与者在包皮组织和PBMC中的TFV-DP浓度更高，与剂量和采样间隔无关；但F/TAF并未赋予包皮HIV靶细胞优先的TFV-DP分布。两种药物方案的FTC-TP浓度相当，比包皮中的TFV-DP高1log。
结论：在离体HIV攻击前5或21小时给予两次剂量的F/TDF或F/TAF可在包皮组织中提供保护。有必要对性交前PrEP进行进一步的临床评估。
背景：EDCTP2，吉利德科学，Vetenskapsrädet.
