New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, Louisiana, USA.
Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
Antimicrob Agents Chemother. 2017 Dec 21;62(1). doi: 10.1128/AAC.01644-17. Print 2018 Jan.
Oral preexposure prophylaxis (PrEP) has been approved for prophylaxis of HIV-1 transmission but is associated with high costs and issues of adherence. Protection from anal transmission of HIV using topical microbicides and methods congruent with sexual behavior offers the promise of improved adherence. We compared the pharmacokinetics (PK) and efficacy of iso-osmolar (IOsm) and hypo-osmolar (HOsm) rectal enema formulations of tenofovir (TFV) in rhesus macaques. Single-dose PK of IOsm or HOsm high-dose (5.28 mg/ml) and low-dose (1.76 mg/ml) formulations of TFV enemas were evaluated for systemic uptake in blood, colorectal biopsy specimens, and rectal CD4 T cells. Markedly higher TFV concentrations were observed in plasma and tissues after administration of the HOsm high-dose formulation than with all other formulations tested. TFV and TFV diphosphate (TFV-DP) concentrations in tissue correlated for the HOsm high-dose formulation, demonstrating rapid uptake and transformation of TFV to TFV-DP in tissues. TFV-DP amounts in tissues collected at 1 and 24 h were 7 times and 5 times higher, respectively ( < 0.01), than the ones collected in tissues with the IOsm formulation. The HOsm high-dose formulation prevented infection in challenges of rectal tissues collected at 1, 24, and 72 h after the intrarectal dosing, whereas the same TFV dose formulated as an IOsm enema was less effective.
口服暴露前预防（PrEP）已被批准用于预防 HIV-1 传播，但与高成本和依从性问题相关。使用局部杀微生物剂和与性行为一致的方法预防艾滋病毒经肛门传播，有望提高依从性。我们比较了泰诺福韦（TFV）等渗（IOsm）和低渗（HOsm）直肠灌肠制剂在恒河猴中的药代动力学（PK）和疗效。评估了 IOsm 或 HOsm 高剂量（5.28mg/ml）和低剂量（1.76mg/ml）TFV 灌肠剂单次剂量 PK 对血液、结直肠活检标本和直肠 CD4 T 细胞的全身摄取情况。与其他所有测试制剂相比，HOsm 高剂量制剂给药后，在血浆和组织中观察到明显更高的 TFV 浓度。HOsm 高剂量制剂的组织中 TFV 和 TFV 二磷酸（TFV-DP）浓度相关，表明 TFV 在组织中快速摄取和转化为 TFV-DP。1 小时和 24 小时收集的组织中 TFV-DP 含量分别高出 7 倍（<0.01）和 5 倍（<0.01），高于 IOsm 制剂收集的组织中的含量。HOsm 高剂量制剂可预防直肠组织在直肠内给药后 1、24 和 72 小时采集的挑战中感染，而相同 TFV 剂量制成的 IOsm 灌肠剂效果较差。
