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      High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials

      research-article
      1 , 2 , , 1 , 1 , 1 , 2 , 1 , 1 , 1 , 1 , 1 , 3 , 4 , 5 , 6 , 1 , 1 , 7 , 1 , 1 , 8 , 9 , 10 , 8 , 9 , 11 , 2 , 7 , 12 , 13 , 14 , 13 , 14 , 15 , 16 , 17 , 18 , 1 , 19 , 20 , 21 , 22 , 23 , 24 , 1 , 25 , 26
      Nature Communications
      Nature Publishing Group UK
      HIV infections, Applied mathematics, Scientific data, Antibodies

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          Abstract

          The Antibody Mediated Prevention (AMP) trials (NCT02716675 and NCT02568215) demonstrated that passive administration of the broadly neutralizing monoclonal antibody VRC01 could prevent some HIV-1 acquisition events. Here, we use mathematical modeling in a post hoc analysis to demonstrate that VRC01 influenced viral loads in AMP participants who acquired HIV. Instantaneous inhibitory potential (IIP), which integrates VRC01 serum concentration and VRC01 sensitivity of acquired viruses in terms of both IC50 and IC80, follows a dose-response relationship with first positive viral load ( p = 0.03), which is particularly strong above a threshold of IIP = 1.6 ( r = -0.6, p = 2e-4). Mathematical modeling reveals that VRC01 activity predicted from in vitro IC80s and serum VRC01 concentrations overestimates in vivo neutralization by 600-fold (95% CI: 300–1200). The trained model projects that even if future therapeutic HIV trials of combination monoclonal antibodies do not always prevent acquisition, reductions in viremia and reservoir size could be expected.

          Abstract

          Antibody Mediated Prevention (AMP) trials showed that the broadly neutralizing antibody VRC01 could prevent some HIV-1 acquisitions. Here the authors use VRC01 levels and the sensitivity of each acquired HIV virus to predict viral loads in the AMP studies and show that VRC01 influenced viral loads, though potency was lower in vivo than expected.

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          Most cited references65

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          seaborn: statistical data visualization

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            Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men

            Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition. We randomly assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC-TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC-TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P=0.005). In the FTC-TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC-TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P=0.57). Oral FTC-TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT00458393.).
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              Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women

              New England Journal of Medicine, 367(5), 399-410
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                Author and article information

                Contributors
                dreeves@fredhutch.org
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                14 December 2023
                14 December 2023
                2023
                : 14
                : 8299
                Affiliations
                [1 ]Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, ( https://ror.org/007ps6h72) Seattle, WA USA
                [2 ]Department of Global Health, University of Washington, ( https://ror.org/00cvxb145) Seattle, WA USA
                [3 ]Public Health Sciences Division, Fred Hutchinson Cancer Center, ( https://ror.org/007ps6h72) Seattle, WA USA
                [4 ]Department of Biostatistics, University of Washington, ( https://ror.org/00cvxb145) Seattle, WA USA
                [5 ]Department of Surgery, Duke University Medical Center, ( https://ror.org/03njmea73) Durham, NC USA
                [6 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Perelman School of Medicine, , University of Pennsylvania, ; Philadelphia, PA USA
                [7 ]Department of Medicine, University of Washington, ( https://ror.org/00cvxb145) Seattle, WA USA
                [8 ]GRID grid.416657.7, ISNI 0000 0004 0630 4574, National Institute for Communicable Diseases, , National Health Laboratory Service, ; Johannesburg, South Africa
                [9 ]Antibody Immunity Research Unit, Faculty of Health Sciences, University of the Witwatersrand, ( https://ror.org/03rp50x72) Johannesburg, South Africa
                [10 ]GRID grid.16463.36, ISNI 0000 0001 0723 4123, Centre for the AIDS Programme of Research in South Africa, , University of KwaZulu-Natal, ; Durban, South Africa
                [11 ]GRID grid.7836.a, ISNI 0000 0004 1937 1151, Division of Medical Virology, Faculty of Health Sciences, , University of Cape Town and National Health Laboratory Service, ; Cape Town, South Africa
                [12 ]Department of Microbiology, University of Washington, ( https://ror.org/00cvxb145) Seattle, WA USA
                [13 ]Center for Human Systems Immunology, Duke University, ( https://ror.org/00py81415) Durham, NC USA
                [14 ]Departments of Surgery, Immunology, and Molecular Genetics and Microbiology, Duke University, ( https://ror.org/00py81415) Durham, NC USA
                [15 ]Family Health International, ( https://ror.org/007kp6q87) Durham, NC USA
                [16 ]Clinical Trials Research Centre, University of Zimbabwe College of Health Sciences, ( https://ror.org/04ze6rb18) Harare, Zimbabwe
                [17 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, , National Institutes of Health, ; Bethesda, MD USA
                [18 ]Institute for Global Health and Infectious Diseases, The University of North Carolina at Chapel Hill, ( https://ror.org/0130frc33) Chapel Hill, NC USA
                [19 ]Department of Laboratory Medicine and Pathology, University of Washington, ( https://ror.org/00cvxb145) Seattle, WA USA
                [20 ]South African Medical Research Council, HPRU, ( https://ror.org/05q60vz69) Durban, South Africa
                [21 ]Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, ( https://ror.org/03p74gp79) Cape Town, South Africa
                [22 ]Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, ( https://ror.org/008s83205) Birmingham, AL USA
                [23 ]Facultad de Medicina Humana, Universidad Nacional de la Amazonia Peru, ( https://ror.org/05h6yvy73) Iquitos, Peru
                [24 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Division of Infectious Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, , New York-Presbyterian/Columbia University Irving Medical Center, ; New York, NY USA
                [25 ]GreenLight Biosciences, ( https://ror.org/04zr4fy40) Medford, MA USA
                [26 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Division of Infectious Diseases, Department of Medicine, , Emory University School of Medicine, ; Atlanta, GA USA
                Author information
                http://orcid.org/0000-0001-5684-9538
                http://orcid.org/0000-0003-2258-5276
                http://orcid.org/0000-0003-1404-4322
                http://orcid.org/0000-0003-1546-6172
                http://orcid.org/0000-0002-4381-1124
                http://orcid.org/0000-0003-0333-5925
                http://orcid.org/0000-0002-5056-2664
                http://orcid.org/0000-0002-0920-2915
                http://orcid.org/0000-0002-2662-9427
                http://orcid.org/0000-0003-0856-6319
                http://orcid.org/0000-0002-9773-0071
                http://orcid.org/0000-0001-8690-9896
                http://orcid.org/0000-0002-2598-1621
                http://orcid.org/0000-0002-8393-8103
                http://orcid.org/0000-0003-3961-7828
                http://orcid.org/0000-0003-0125-1226
                http://orcid.org/0000-0002-2009-3270
                http://orcid.org/0000-0001-8076-1931
                http://orcid.org/0000-0002-2179-2436
                http://orcid.org/0000-0001-8441-5737
                http://orcid.org/0000-0002-5972-0948
                http://orcid.org/0000-0001-5946-9733
                Article
                43384
                10.1038/s41467-023-43384-y
                10721814
                38097552
                4873222c-378a-4168-a9d5-ca3936d37200
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 13 June 2023
                : 7 November 2023
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000060, U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID);
                Award ID: K25 AI155224
                Award ID: UM1 AI068635
                Award ID: UM1 AI068635
                Award ID: 4 R37 AI054165-21
                Award ID: UM1 AI068614
                Award ID: P30 AI064518
                Award ID: UM1 AI068619
                Award ID: R01 AI150500
                Award Recipient :
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
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                © Springer Nature Limited 2023

                Uncategorized
                hiv infections,applied mathematics,scientific data,antibodies
                Uncategorized
                hiv infections, applied mathematics, scientific data, antibodies

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