抗逆转录病毒治疗浓度在肠道与淋巴结组织中存在差异，并且与新型 RT-ddPCR 检测法检测到的 HIV 病毒转录相关。
Antiretroviral Therapy Concentrations Differ in Gut vs. Lymph Node Tissues and Are Associated With HIV Viral Transcription by a Novel RT-ddPCR Assay.
机构信息
Division of Infectious Diseases, HIV, and Global Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA.
San Francisco VA Medical Center (SFVAMC), San Francisco, CA.
出版信息
J Acquir Immune Defic Syndr. 2020 Apr 15;83(5):530-537. doi: 10.1097/QAI.0000000000002287.
BACKGROUND
Most HIV-infected cells during antiretroviral therapy (ART) persist in lymphoid tissues. Studies disagree on whether suboptimal tissue ART concentrations contribute to ongoing HIV replication during viral suppression.
METHODS
We performed a cross-sectional study in virally-suppressed HIV+ participants measuring lymphoid tissue ART [darunavir (DRV), atazanavir (ATV), and raltegravir (RAL)] concentrations by LC-MS/MS assay. Tissue and plasma ART concentrations were used to estimate TPRs and drug-specific tissue:inhibitory concentration ratios (TICs). HIV DNA and sequentially produced HIV RNA transcripts were quantified from rectal biopsies using droplet digital PCR (ddPCR) assays.
RESULTS
Tissue samples were collected in duplicate from 19 participants: 38 rectal, 8 ileal (4 RAL, 2 DRV, 2 ATV), and 6 lymph node (4 RAL, 2 DRV) samples. Overall, median TICs were higher for RAL than DRV or ATV (both P = 0.006). Median TICs were lower in lymph nodes vs. ileum (0.49 vs. 143, P = 0.028) or rectum (33, P = 0.019), and all ART levels were below target concentrations. Higher rectal TICs were associated with lower HIV RNA transcripts (read-through, long LTR, and Nef, P all < 0.026) and a lower long LTR RNA/long LTR DNA ratio (P = 0.021).
CONCLUSIONS
We observed higher tissue ART concentrations in ileum and rectum compared with lymph nodes. We observed higher HIV transcription in participants with lower rectal ART concentrations. These findings add to the limited data supporting the idea that viral transcription may be influenced by ART concentrations in lymphoid tissues. Further exploration of tissue pharmacokinetics is needed in future HIV eradication strategies.
背景
在抗逆转录病毒治疗（ART）期间，大多数 HIV 感染细胞仍存在于淋巴组织中。研究结果对 ART 浓度不理想是否会导致病毒抑制期间持续的 HIV 复制存在分歧。
方法
我们对病毒抑制的 HIV+参与者进行了一项横断面研究，通过 LC-MS/MS 测定法测量了淋巴组织中的 ART [达芦那韦（DRV）、阿扎那韦（ATV）和拉替拉韦（RAL）]浓度。利用组织和血浆 ART 浓度来估计 TPR 和药物特异性组织：抑制浓度比（TIC）。使用液滴数字 PCR（ddPCR）检测从直肠活检中定量 HIV DNA 和随后产生的 HIV RNA 转录本。
结果
从 19 名参与者中采集了组织样本的双份重复样本：38 份直肠、8 份回肠（4 份 RAL、2 份 DRV、2 份 ATV）和 6 份淋巴结（4 份 RAL、2 份 DRV）样本。总体而言，RAL 的 TIC 中位数高于 DRV 或 ATV（均 P = 0.006）。淋巴结中的 TIC 中位数低于回肠（0.49 比 143，P = 0.028）或直肠（33，P = 0.019），所有 ART 水平均低于目标浓度。较高的直肠 TIC 与较低的 HIV RNA 转录物相关（通读、长 LTR 和 Nef，均 P < 0.026）和较低的长 LTR RNA/长 LTR DNA 比值（P = 0.021）。
结论
我们观察到回肠和直肠中的组织 ART 浓度高于淋巴结。我们观察到较低直肠 ART 浓度的参与者中 HIV 转录较高。这些发现增加了支持病毒转录可能受淋巴组织中 ART 浓度影响的有限数据。在未来的 HIV 清除策略中，需要进一步探索组织药代动力学。
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