METHODS: Dolutegravir, tenofovir, lamivudine and efavirenz concentrations were measured across 13 CNS regions plus plasma in samples collected during autopsy in 49 Ugandan decedents. Median time from death to autopsy was 8 (IQR 5,15) hours. To evaluate postmortem redistribution, a time course study was performed in a mouse model.
RESULTS: Regions with the highest penetration ratios were choroid plexus/arachnoid (dolutegravir and tenofovir), CSF (lamivudine), and cervical spinal cord/meninges (efavirenz); the lowest were corpus callosum (dolutegravir and tenofovir), frontal lobe (lamivudine), and parietal lobe (efavirenz). On average, brain concentrations were 84%, 87%, and 76% of CSF for dolutegravir, tenofovir, and lamivudine respectively. Postmortem redistribution was observed in the mouse model, with tenofovir and lamivudine concentration increased by 350% and efavirenz concentration decreased by 24% at 24-hours post-mortem.
CONCLUSIONS: Analysis of postmortem tissue provides a unique opportunity to investigate CNS antiretroviral penetration. Regional differences were observed paving the way to identify mechanisms of viral compartmentalization and/or neurotoxicity.
方法:Dolutegravir,替诺福韦,在49名乌干达死者的尸检过程中收集的13个CNS区域以及血浆中测量了拉米夫定和依法韦仑的浓度。从死亡到尸检的中位时间为8(IQR5,15)小时。为了评估死后的再分配,在小鼠模型中进行了时程研究.
结果:穿透率最高的区域是脉络丛/蛛网膜(dolutegravir和替诺福韦),CSF(拉米夫定),和颈脊髓/脑膜(依法韦仑);最低的是call体(dolutegravir和替诺福韦),额叶(拉米夫定),和顶叶(efavirenz)。平均而言,大脑浓度为84%,87%,76%的脑脊液用于dolutegravir,替诺福韦,分别为拉米夫定。在小鼠模型中观察到死后再分布,替诺福韦和拉米夫定浓度增加350%,依法韦仑浓度在死后24小时下降24%。
结论:死后组织分析为研究CNS抗逆转录病毒渗透提供了一个独特的机会。观察到区域差异为识别病毒区室化和/或神经毒性的机制铺平了道路。