Abstract：
BACKGROUND: Central nervous system (CNS) compartmentalization provides opportunity for HIV persistence and resistance development. Differences between cerebrospinal fluid (CSF) and cerebral matter regarding HIV persistence are well described. However, CSF is often used as surrogate for CNS drug exposure, and knowledge from solid brain tissue is rare.
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.
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.
摘要：
背景：中枢神经系统（CNS）区室化为HIV持续存在和耐药性发展提供了机会。很好地描述了脑脊液（CSF）和脑物质之间关于HIV持久性的差异。然而,CSF通常用作CNS药物暴露的替代品，来自固体脑组织的知识很少见。
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。
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。
