Markowitz Martin, Gettie Agegnehu, St Bernard Leslie, Grasperge Brooke, Vargo Ryan, Pham Michelle, Fillgrove Kerry, Dube Neal, Diamond Tracy L, Hazuda Daria J, Grobler Jay A
Aaron Diamond AIDS Research Center, New York, New York, USA.
Tulane National Primate Research Center, Covington, Louisiana, USA.
J Int AIDS Soc. 2025 Jun;28(6):e26507. doi: 10.1002/jia2.26507.
Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) with robust antiretroviral activity. The efficacy of ISL administered for post-exposure prophylaxis (PEP) was evaluated in a simian immunodeficiency virus (SIV) rhesus macaque intravenous (IV) challenge model.
Twelve rhesus macaques were challenged with SIVmac251 via IV administration. After 24 hours, six animals received ISL 3.9 mg/kg (the minimum effective dose that gives maximal protection) and six animals were untreated controls. In stage 1, treated animals received 4 weekly oral doses of ISL and were monitored for SIV infection for 7 weeks after the last dose. In stage 2, uninfected, treated animals from stage 1 were challenged similarly; 24 hours after challenge, 3 weekly oral doses of ISL 3.9 mg/kg were initiated. The treated animals were monitored for 7 weeks, as in stage 1. Uninfected, treated animals (from stage 2) entered stage 3. In stage 3, the animals were challenged as in stage 2; 24 hours after challenge, 2 weekly oral doses of ISL 3.9 mg/kg were initiated. The treated animals were monitored for 7 weeks, as before. Finally, in stage 4, uninfected, treated animals were challenged using IV administration and 24 hours later were treated with a single oral dose of ISL 3.9 mg/kg and monitored for 7 weeks. Infection was monitored through plasma viral RNA and proviral DNA amplification. Virus-specific antibody responses were measured using a commercial assay. ISL concentrations in plasma and ISL triphosphate (ISL-TP) levels in peripheral blood mononuclear cells were measured longitudinally.
All untreated controls were viraemic 7 days after SIVmac251 IV challenge. All six ISL-treated animals were completely protected in stages 1-3 (Fisher exact test p = 0.0022). In stage 4, two of six ISL-treated animals became infected with wild-type SIVmac251: viraemia was observed at days 14 and 49 in the two animals (Fisher exact test p = 0.06). Both animals had unquantifiable ISL-TP on the day viraemia was observed.
Two weekly oral doses of ISL 3.9 mg/kg, administered 24 hours post IV SIV exposure, prevents infection of rhesus macaques. These results support further investigation of a long-acting oral NRTTI for PEP.
依斯拉曲韦（ISL）是一种具有强大抗逆转录病毒活性的核苷类逆转录酶易位抑制剂（NRTTI）。在恒河猴静脉注射（IV）感染猴免疫缺陷病毒（SIV）的挑战模型中评估了ISL用于暴露后预防（PEP）的疗效。
12只恒河猴通过静脉注射感染SIVmac251。24小时后，6只动物接受3.9mg/kg的ISL（给予最大保护的最小有效剂量），6只动物作为未治疗对照。在第1阶段，治疗组动物每周口服4次ISL，并在最后一剂后监测7周的SIV感染情况。在第2阶段，第1阶段未感染的治疗组动物接受类似的挑战；挑战后24小时，开始每周口服3次3.9mg/kg的ISL。治疗组动物如在第1阶段一样监测7周。未感染的治疗组动物（来自第2阶段）进入第3阶段。在第3阶段，动物如在第2阶段一样接受挑战；挑战后24小时，开始每周口服2次3.9mg/kg的ISL。治疗组动物如之前一样监测7周。最后，在第4阶段，未感染的治疗组动物通过静脉注射接受挑战，24小时后口服单次剂量3.9mg/kg的ISL并监测7周。通过血浆病毒RNA和前病毒DNA扩增监测感染情况。使用商业检测方法测量病毒特异性抗体反应。纵向测量血浆中的ISL浓度和外周血单核细胞中的三磷酸ISL（ISL-TP）水平。
所有未治疗的对照在SIVmac251静脉注射挑战后7天出现病毒血症。所有6只接受ISL治疗的动物在第1 - 3阶段均得到完全保护（Fisher精确检验p = 0.0022）。在第4阶段，6只接受ISL治疗的动物中有2只感染了野生型SIVmac251：在这两只动物中分别在第14天和第49天观察到病毒血症（Fisher精确检验p = 0.06）。在观察到病毒血症的当天，两只动物的ISL-TP均无法检测到。
在静脉注射SIV暴露后24小时给予每周两次口服剂量3.9mg/kg的ISL可预防恒河猴感染。这些结果支持对用于PEP的长效口服NRTTI进行进一步研究。
