Early intervention with 3BNC117 and romidepsin at antiretroviral treatment initiation in people with HIV-1: a phase 1b/2a, randomized trial.

Autor: Gunst JD; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark., Pahus MH; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark., Rosás-Umbert M; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark., Lu IN; Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany., Benfield T; Department of Infectious Diseases, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark., Nielsen H; Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark.; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark., Johansen IS; Department of Infectious Diseases, Odense University Hospital, University of Southern Denmark, Odense, Denmark., Mohey R; Department of Internal Medicine, Regional Hospital Herning, Herning, Denmark., Østergaard L; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark., Klastrup V; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark., Khan M; Department of Infectious Diseases, Imperial College Hospital, London, UK.; The National Institute for Health Research, Imperial Biomedical Research Centre, London, UK., Schleimann MH; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark., Olesen R; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark., Støvring H; Department of Public Health, Aarhus University, Aarhus, Denmark., Denton PW; Department of Biology, University of Nebraska at Omaha, Omaha, NE, USA., Kinloch NN; Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada., Copertino DC; Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.; Department of Microbiology and Immunology, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA., Ward AR; Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY, USA., Alberto WDC; Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.; Department of Microbiology and Immunology, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA., Nielsen SD; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark., Puertas MC; IrsiCaixa AIDS Research Institute, Badalona, Spain.; CIBERINFEC, Madrid, Spain., Ramos V; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA., Reeves JD; Labcorp-Monogram Biosciences, South San Francisco, CA, USA., Petropoulos CJ; Labcorp-Monogram Biosciences, South San Francisco, CA, USA., Martinez-Picado J; IrsiCaixa AIDS Research Institute, Badalona, Spain.; CIBERINFEC, Madrid, Spain.; University of Vic-Central University of Catalonia, Vic, Spain.; Catalan Institution for Research and Advanced Studies, Barcelona, Spain., Brumme ZL; Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada., Jones RB; Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.; Department of Microbiology and Immunology, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA., Fox J; Department of Genitourinary Medicine and Infectious Disease, Guy's and St Thomas' National Health Service Trust, London, UK.; Department of Genitourinary Medicine and Infectious Disease, The National Institute for Health Research Biomedical Research Centre, King's College London, London, UK., Tolstrup M; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark., Nussenzweig MC; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA.; Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA., Caskey M; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA., Fidler S; Department of Infectious Diseases, Imperial College Hospital, London, UK.; The National Institute for Health Research, Imperial Biomedical Research Centre, London, UK., Søgaard OS; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. olesoega@rm.dk.; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark. olesoega@rm.dk.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2022 Nov; Vol. 28 (11), pp. 2424-2435. Date of Electronic Publication: 2022 Oct 17.
DOI: 10.1038/s41591-022-02023-7
Abstrakt: Attempts to reduce the human immunodeficiency virus type 1 (HIV-1) reservoir and induce antiretroviral therapy (ART)-free virologic control have largely been unsuccessful. In this phase 1b/2a, open-label, randomized controlled trial using a four-group factorial design, we investigated whether early intervention in newly diagnosed people with HIV-1 with a monoclonal anti-HIV-1 antibody with a CD4-binding site, 3BNC117, followed by a histone deacetylase inhibitor, romidepsin, shortly after ART initiation altered the course of HIV-1 infection ( NCT03041012 ). The trial was undertaken in five hospitals in Denmark and two hospitals in the United Kingdom. The coprimary endpoints were analysis of initial virus decay kinetics and changes in the frequency of CD4 + T cells containing intact HIV-1 provirus from baseline to day 365. Secondary endpoints included changes in the frequency of infected CD4 + T cells and virus-specific CD8 + T cell immunity from baseline to day 365, pre-ART plasma HIV-1 3BNC117 sensitivity, safety and tolerability, and time to loss of virologic control during a 12-week analytical ART interruption that started at day 400. In 55 newly diagnosed people (5 females and 50 males) with HIV-1 who received random allocation treatment, we found that early 3BNC117 treatment with or without romidepsin enhanced plasma HIV-1 RNA decay rates compared to ART only. Furthermore, 3BNC117 treatment accelerated clearance of infected cells compared to ART only. All groups had significant reductions in the frequency of CD4 + T cells containing intact HIV-1 provirus. At day 365, early 3BNC117 + romidepsin was associated with enhanced HIV-1 Gag-specific CD8 + T cell immunity compared to ART only. The observed virological and immunological effects of 3BNC117 were most pronounced in individuals whose pre-ART plasma HIV-1 envelope sequences were antibody sensitive. The results were not disaggregated by sex. Adverse events were mild to moderate and similar between the groups. During a 12-week analytical ART interruption among 20 participants, 3BNC117-treated individuals harboring sensitive viruses were significantly more likely to maintain ART-free virologic control than other participants. We conclude that 3BNC117 at ART initiation enhanced elimination of plasma viruses and infected cells, enhanced HIV-1-specific CD8 + immunity and was associated with sustained ART-free virologic control among persons with 3BNC117-sensitive virus. These findings strongly support interventions administered at the time of ART initiation as a strategy to limit long-term HIV-1 persistence.
(© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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