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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

  • Jesper D. Gunst
  • Marie H. Pahus
  • Miriam Rosás-Umbert
  • I. Na Lu, University of Münster
  • ,
  • Thomas Benfield, Københavns Universitet
  • ,
  • Henrik Nielsen, Aalborg Universitet
  • ,
  • Isik S. Johansen, Syddansk Universitet
  • ,
  • Rajesh Mohey
  • ,
  • Lars Østergaard
  • Vibeke Klastrup
  • ,
  • Maryam Khan, Imperial College London, National Institute for Health Research
  • ,
  • Mariane H. Schleimann
  • ,
  • Rikke Olesen
  • Henrik Støvring
  • Paul W. Denton, University of Nebraska Omaha
  • ,
  • Natalie N. Kinloch, Simon Fraser University, University of British Columbia
  • ,
  • Dennis C. Copertino, Cornell University
  • ,
  • Adam R. Ward, Cornell University
  • ,
  • Winiffer D.Conce Alberto, Cornell University
  • ,
  • Silke D. Nielsen
  • Maria C. Puertas, Irsi-Caixa AIDS Research Institute, ISCIII
  • ,
  • Victor Ramos, Rockefeller University
  • ,
  • Jacqueline D. Reeves, Monogram Biosciences
  • ,
  • Christos J. Petropoulos, Monogram Biosciences
  • ,
  • Javier Martinez-Picado, Irsi-Caixa AIDS Research Institute, ISCIII, The University of Vic - Central University of Catalonia, ICREA
  • ,
  • Zabrina L. Brumme, Simon Fraser University, University of British Columbia
  • ,
  • R. Brad Jones, Cornell University
  • ,
  • Julie Fox, Guy's and St Thomas' NHS Foundation Trust, University College London Great Ormond Street National Institute for Health Research Biomedical Research Centre Institute of Child Health
  • ,
  • Martin Tolstrup
  • Michel C. Nussenzweig, Rockefeller University
  • ,
  • Marina Caskey, Rockefeller University
  • ,
  • Sarah Fidler, Imperial College London, National Institute for Health Research
  • ,
  • Ole S. Søgaard

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.

OriginalsprogEngelsk
TidsskriftNature Medicine
Vol/bind28
Nummer11
Sider (fra-til)2424-2435
ISSN1078-8956
DOI
StatusUdgivet - nov. 2022

Bibliografisk note

Funding Information:
We thank all study participants who devoted time to our research as well as every clinical research unit involved in the study: at Aarhus University Hospital—study nurses Yordanos Yehdego, Ane Søndergaard and Ann Bach, physicians Janne T. Martinsen and Nina B. Stærke and lab technician Lene S. Jøhnke; at Copenhagen University Hospital–Amager and Hvidovre—study nurses Dorthe K. Petersen and Louise Krohn-Dehli and lab technician Anna L. Sørensen; at Aalborg University Hospital—study nurses Maria R. Juhl and Kristine T. Pedersen; at Odense University Hospital—study nurses Susan O. Lindvig and Bente Ramskover; at Regional Hospital Herning—study nurses Kirsten Lillevang and Heidi G. Sørensen; at Imperial College Hospital—study nurses Rebecca Hall, Claire Petersen and Shelly Page, physician John Thornhill, lab technician Andrew O Lovell and study coordinator Tom Cole; at King’s College London—study nurses Anele Waters, Rebekah Roberts, Hiromi Uzu and Andrea Berlanga and study coordinator Alice Sharp; and at the Danish Good Clinical Practice Units—monitors Lene Brandsborg, Inge M. Burmeister and Stine K. Hovgaard. We acknowledge Rockefeller University for providing 3BNC117 and Bristol-Myers Squibb Company (Celgene Corporation) for providing the RMD as well as the Labcorp-Monogram Biosciences Clinical Reference Laboratory for performing the phenotypic resistance assays with project management from Y. Lie and C. Kang. Finally, we would like to acknowledge the amazing support and help from the late Amin Alamshah, a kind and brilliant clinical project manager at the Imperial College Center for Translational and Experimental Medicine, who tragically lost his life before the completion of this study. The funders were not involved in the study design/operations, data collection/analysis/interpretation or preparation of the manuscript. This study is funded by the Danish Council for Independent Research (grant numbers: 7016-00022 and 9060-00023B to O.S.S.), the Central Region Denmark Research Fund, The Danish Regions’ Medicine and Treatment Fund, Aarhus University and Next Experimental Therapy Partnership. Research reported in this publication was also supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (award number: UM1AI164565 to R.B.J.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. N.N.K. received a Vanier Award from the Canadian Institutes for Health Research. Z.L.B. received a scholar award from the Michael Smith Foundation for Health Research. Study drugs were donated free of charge by The Rockefeller University (3BNC117) and Celgene (romidepsin) for use in this trial. None of the specific sources of funding had any role in the conceptualization, design, data collection, analysis, decision to publish or preparation of the manuscript.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

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