Pons-Faudoa Fernanda P, Sizovs Antons, Shelton Kathryn A, Momin Zoha, Niles Jean A, Bushman Lane R, Xu Jiaqiong, Chua Corrine Ying Xuan, Nichols Joan E, Demaria Sandra, Ittmann Michael M, Hawkins Trevor, Rooney James F, Marzinke Mark A, Kimata Jason T, Anderson Peter L, Nehete Pramod N, Arduino Roberto C, Ferrari Mauro, Sastry K Jagannadha, Grattoni Alessandro
Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.
Department of Comparative Medicine, Michael E. Keeling Center for Comparative Medicine and Research, MD Anderson Cancer Center, Bastrop, TX 78602, USA.
Adv Ther (Weinh). 2021 Mar;4(3). doi: 10.1002/adtp.202000163. Epub 2020 Dec 16.
Pre-exposure prophylaxis (PrEP) using antiretroviral oral drugs is effective at preventing HIV transmission when individuals adhere to the dosing regimen. Tenofovir alafenamide (TAF) is a potent antiretroviral drug, with numerous long-acting (LA) delivery systems under development to improve PrEP adherence. However, none has undergone preventive efficacy assessment. Here we show that LA TAF using a novel subcutaneous nanofluidic implant (nTAF) confers partial protection from HIV transmission. We demonstrate that sustained subcutaneous delivery through nTAF in rhesus macaques maintained tenofovir diphosphate concentration at a median of 390.00 fmol/10 peripheral blood mononuclear cells, 9 times above clinically protective levels. In a non-blinded, placebo-controlled rhesus macaque study with repeated low-dose rectal SHIV challenge, the nTAF cohort had a 62.50% reduction (95% CI: 1.72% to 85.69%; =0.068) in risk of infection per exposure compared to the control. Our finding mirrors that of tenofovir disoproxil fumarate (TDF) monotherapy, where 60.00% protective efficacy was observed in macaques, and clinically, 67.00% reduction in risk with 86.00% preventive efficacy in individuals with detectable drug in the plasma. Overall, our nanofluidic technology shows potential as a subcutaneous delivery platform for long-term PrEP and provides insights for clinical implementation of LA TAF for HIV prevention.
当个体坚持给药方案时，使用抗逆转录病毒口服药物进行暴露前预防（PrEP）可有效预防HIV传播。替诺福韦艾拉酚胺（TAF）是一种强效抗逆转录病毒药物，目前有多种长效（LA）给药系统正在研发中，以提高PrEP的依从性。然而，尚无一种进行过预防效果评估。在此，我们表明，使用新型皮下纳米流体植入物（nTAF）的长效TAF可提供部分预防HIV传播的保护作用。我们证明，通过nTAF在恒河猴体内持续皮下给药，可使外周血单个核细胞中替诺福韦二磷酸的浓度维持在中位数390.00 fmol/10个，比临床保护水平高9倍。在一项非盲、安慰剂对照的恒河猴研究中，对其进行重复低剂量直肠SHIV攻击，与对照组相比，nTAF组每次暴露的感染风险降低了62.50%（95%CI：1.72%至85.69%；P=0.068）。我们的发现与富马酸替诺福韦二吡呋酯（TDF）单药治疗的结果相似，在恒河猴中观察到其保护效果为60.00%，在临床上，血浆中可检测到药物的个体感染风险降低67.00%，预防效果为86.00%。总体而言，我们的纳米流体技术显示出作为长期PrEP皮下给药平台的潜力，并为LA TAF用于HIV预防的临床应用提供了见解。
