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

December 11, 2017 at 8:42 am

PLoS Med. November 4, 2017 V.14 N.11 e1002417.     

Henrich TJ1, Hatano H2, Bacon O2,3, Hogan LE1, Rutishauser R1,2, Hill A4, Kearney MF5, Anderson EM5, Buchbinder SP2,3, Cohen SE2,3, Abdel-Mohsen M2,6, Pohlmeyer CW7, Fromentin R8, Hoh R2, Liu AY2,3, McCune JM1, Spindler J5, Metcalf-Pate K7, Hobbs KS1, Thanh C1, Gibson EA1, Kuritzkes DR9,10, Siliciano RF11,12, Price RW13, Richman DD14,15, Chomont N8, Siliciano JD10, Mellors JW16, Yukl SA17,18, Blankson JN7, Liegler T2, Deeks SG2.

Author information

1 Division of Experimental Medicine, University of California, San Francisco, California, United States of America.

2 Division of HIV, Infectious Diseases and Global Medicine, University of California, San Francisco, California, United States of America.

3 San Francisco Department of Public Health, San Francisco, California, United States of America.

4 Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America.

5 HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.

6 The Wistar Institute, Philadelphia, Pennsylvania, United States of America.

7 Center for AIDS Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

8 Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.

9 Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America.

10 Harvard Medical School, Boston, Massachusetts, United States of America.

11 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

12 Howard Hughes Medical Institute, Baltimore, Maryland, United States of America.

13 Department of Neurology, University of California, San Francisco, California, United States of America.

14 University of California San Diego, La Jolla, California, United States of America.

15 Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America.

16 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

17 San Francisco Veterans Affairs Medical Center, San Francisco, California, United States of America.

18 University of California, San Francisco, California, Unites States of America.

Abstract

BACKGROUND:

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.

METHODS AND FINDINGS:

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.

CONCLUSIONS:

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.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675377/pdf/pmed.1002417.pdf

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Entry filed under: Antirretrovirales, HIV/SIDA, HIV/SIDA HAART, HIV/SIDA Infeccion Aguda / Reciente, REPORTS, Update.

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