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HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study

Henrich, Timothy J ; Hatano, Hiroyu ; Bacon, Oliver ; Hogan, Louise E ; Rutishauser, Rachel ; Hill, Alison ; Kearney, Mary F ; Anderson, Elizabeth M ; Buchbinder, Susan P ; Cohen, Stephanie E ; Abdel-Mohsen, Mohamed ; Pohlmeyer, Christopher W ; Fromentin, Remi ; Hoh, Rebecca ; Liu, Albert Y ; McCune, Joseph M ; Spindler, Jonathan ; Metcalf-Pate, Kelly ; Hobbs, Kristen S ; Thanh, Cassandra ; Gibson, Erica A ; Kuritzkes, Daniel R ; Siliciano, Robert F ; Price, Richard W ; Richman, Douglas D ; Chomont, Nicolas ; Siliciano, Janet D ; Mellors, John W ; Yukl, Steven A ; Blankson, Joel N ; Liegler, Teri ; Deeks, Steven G Bekker, Linda-Gail

PLoS medicine, 2017-11, Vol.14 (11), p.e1002417-e1002417 [Periódico revisado por pares]

United States: Public Library of Science

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HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study
Autor: Henrich, Timothy J ; Hatano, Hiroyu ; Bacon, Oliver ; Hogan, Louise E ; Rutishauser, Rachel ; Hill, Alison ; Kearney, Mary F ; Anderson, Elizabeth M ; Buchbinder, Susan P ; Cohen, Stephanie E ; Abdel-Mohsen, Mohamed ; Pohlmeyer, Christopher W ; Fromentin, Remi ; Hoh, Rebecca ; Liu, Albert Y ; McCune, Joseph M ; Spindler, Jonathan ; Metcalf-Pate, Kelly ; Hobbs, Kristen S ; Thanh, Cassandra ; Gibson, Erica A ; Kuritzkes, Daniel R ; Siliciano, Robert F ; Price, Richard W ; Richman, Douglas D ; Chomont, Nicolas ; Siliciano, Janet D ; Mellors, John W ; Yukl, Steven A ; Blankson, Joel N ; Liegler, Teri ; Deeks, Steven G
Bekker, Linda-Gail
Assuntos: Acquired immune deficiency syndrome ; Adult ; AIDS ; Animal tissues ; Anti-Retroviral Agents - therapeutic use ; Antiretroviral agents ; Antiretroviral drugs ; Antiretroviral therapy ; Antiviral agents ; Assaying ; Biology and Life Sciences ; Biomarkers - analysis ; Blood ; Bone marrow ; Cancer ; CD30 antigen ; CD4 antigen ; Cell culture ; Cerebrospinal fluid ; Cytokines ; Deoxyribonucleic acid ; Development and progression ; DNA ; Dosage and administration ; Drug therapy ; Emtricitabine ; Evaluation ; Flow Cytometry ; Funding ; Genomes ; Health behavior ; HIV ; HIV infection ; HIV infections ; HIV Infections - drug therapy ; HIV Infections - immunology ; HIV Infections - virology ; HIV-1 ; Human immunodeficiency virus ; Humans ; Ileum ; Immunology ; Infections ; Infectious diseases ; Latent infection ; Leukocytes (mononuclear) ; Lymph ; Lymph nodes ; Lymphocytes ; Lymphocytes T ; Male ; Mathematical models ; Medical research ; Medicine ; Medicine and Health Sciences ; Mice ; Middle Aged ; Mouse devices ; Observational studies ; Peripheral blood mononuclear cells ; Phenotype ; Prophylaxis ; Prospective Studies ; Public health ; Rectum ; Recurrence ; Remission ; Research and analysis methods ; Ribonucleic acid ; RNA ; Secondary Prevention ; Software ; Supervision ; Tenofovir ; Tissues ; Treatment Outcome ; Tumor markers ; Tumor necrosis factor-TNF ; Viremia
É parte de: PLoS medicine, 2017-11, Vol.14 (11), p.e1002417-e1002417
Notas: ObjectType-Case Study-2
SourceType-Scholarly Journals-1
ObjectType-Feature-4
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ObjectType-Report-1
ObjectType-Article-3
I have read the journal's policy and the authors of this manuscript have the following competing interests: AYL has led trials in which Gilead has donated study drug. SEC was the protocol co-chair an a site principle investigator of the US PrEP demonstration project for which Gilead donated study drug. JWM has share options in C0-Crystal, Inc; is on the scientific advisory board for Gilead Sciences; and has received research funding from Gilead Sciences, Janssen Pharmaceuticals, and Abbott Molecular. SGD declares the research group has received external funding to support our research from ViiV, Gilead, and Merck. He is also a guest editor for the PLOS Medicine special issue on Advances in HIV Prevention, Treatment and Cure. DRK is a consultant, research support and speaker for Gilead; a consultant for Janssen; a consultant, research support and speaker for Merck; a consultant and research support for ViiV.
Descrição: It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART. Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection. We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.
Editor: United States: Public Library of Science
Idioma: Inglês

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HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study

United States: Public Library of Science

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