Antiretroviral Therapy Concentrations Differ in Gut vs. Lymph Node Tissues and Are Associated With HIV Viral Transcription by a Novel RT-ddPCR Assay
Autor: | Lee, Sulggi A, Telwatte, Sushama, Hatano, Hiroyu, Kashuba, Angela DM, Cottrell, Mackenzie L, Hoh, Rebecca, Liegler, Teri J, Stephenson, Sophie, Somsouk, Ma, Hunt, Peter W, Deeks, Steven G, Yukl, Steven, Savic, Radojka M |
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Rok vydání: | 2020 |
Předmět: |
CD4-Positive T-Lymphocytes
Adult Male Anti-HIV Agents Biopsy Atazanavir Sulfate antiretroviral therapy Clinical Sciences HIV Infections Virus Replication Real-Time Polymerase Chain Reaction Ileum Raltegravir Potassium Virology Genetics pharmacodynamics Humans Highly Active lymphoid tissue Darunavir HIV transcription Gastrointestinal Tract Cross-Sectional Studies Infectious Diseases HIV-1 Public Health and Health Services HIV/AIDS San Francisco Female Lymph Nodes Infection pharmacokinetics |
Zdroj: | Journal of acquired immune deficiency syndromes (1999), vol 83, iss 5 |
Popis: | BackgroundMost 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.MethodsWe 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.ResultsTissue 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).ConclusionsWe 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. |
Databáze: | OpenAIRE |
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