Broadly neutralizing antibodies in adult males living with HIV undergoing analytical treatment interruption: secondary and exploratory outcomes of the phase II randomized controlled RIO trial

Abstract RIO is an ongoing phase 2 double-blind randomized placebo-controlled human trial. Sixty-eight adult men living with human immunodeficiency virus (HIV), who were predominantly white and initiated antiretroviral therapy (ART) during primary or early-stage infection, underwent treatment interruption and were randomly assigned to a group receiving one or two doses of two long-acting broadly neutralizing antibodies (bNAbs) 3BNC117-LS and 10-1074-LS (arm A, n = 34) or saline (arm B, n = 34). The primary clinical study met its primary endpoint and was published elsewhere, demonstrating significantly delayed viral rebound and prolonged ART-free control in participants receiving bNAbs compared with placebo. The infusions were generally safe and well tolerated, with no study-related serious adverse events reported. The most common reported treatment-related adverse events were fatigue, lethargy and somnolence. Here we report on prespecified secondary analyses examining viral rebound, antibody sensitivity and reservoir dynamics, as well as prespecified exploratory analyses of rebound virus evolution and autologous antibody activity. Preinfusion reservoir measurements showed low levels of intact proviral HIV-1 DNA in circulating CD4 + T cells in both arms. The rebounding viruses in participants who received the antibodies showed significant selection for resistance to 10-1074-LS but not to 3BNC117-LS. Notably, there was a significant correlation between greater initial reservoir sensitivity to autologous antibodies and 10-1074 and time to rebound. Finally, comparison of preinfusion and prerebound HIV-1 proviral reservoir showed a decrease in intact but not defective proviruses in arm A but not in arm B. Together, these findings suggest that baseline humoral immunity and prolonged exposure to LS-bNAbs jointly shape post-treatment viral rebound dynamics in individuals who initiate ART during primary infection. ClinicalTrials.gov identifier: NCT04319367 .

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Journal
Nature Medicine
Published
2026-09-15
DOI
https://doi.org/10.1038/s41591-026-04644-8
Primary Topic
HIV Research and Treatment
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article
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article

Broadly neutralizing antibodies in adult males living with HIV undergoing analytical treatment interruption: secondary and exploratory outcomes of the phase II randomized controlled RIO trial

Michel C. Nussenzweig, Simon Collins, Chloe Orkin, Marcílio Jorge Fumagalli et al.
Nature Medicine
HIV Research and Treatment
article

Broadly neutralizing antibodies in adult males living with HIV undergoing analytical treatment interruption: secondary and exploratory outcomes of the phase II randomized controlled RIO trial

Michel C. Nussenzweig, Simon Collins, Chloe Orkin, Marcílio Jorge Fumagalli, Panagiota Zacharopoulou, Hanna Box, Marina Caskey, Julie Fox, Amanda Clarke, John Frater, Mariângela de Oliveira Silva, Ole S. Søgaard, Emanuela Falaschetti, Nicola Robison, Anna Kaczynska, Thiago Y. Oliveira, Sarah Fidler, Anna Gazumyan, Rebecca Sutherland, Louise-Rae Cherrill, Michael S. Seaman, Sophie Espinosa, Mila Janković, Tamara Elliott, Sabine Kinloch-Loes, Marius Allombert, Christy Lavine, Alison Uriel, Cintia Bittar, Brianna J. Hernandez, Helen Brown, Ágata Lopes-Ribeiro, Sarah Pett, Ming Lee, Marta Boffito
article en

Abstract

Abstract RIO is an ongoing phase 2 double-blind randomized placebo-controlled human trial. Sixty-eight adult men living with human immunodeficiency virus (HIV), who were predominantly white and initiated antiretroviral therapy (ART) during primary or early-stage infection, underwent treatment interruption and were randomly assigned to a group receiving one or two doses of two long-acting broadly neutralizing antibodies (bNAbs) 3BNC117-LS and 10-1074-LS (arm A, n = 34) or saline (arm B, n = 34). The primary clinical study met its primary endpoint and was published elsewhere, demonstrating significantly delayed viral rebound and prolonged ART-free control in participants receiving bNAbs compared with placebo. The infusions were generally safe and well tolerated, with no study-related serious adverse events reported. The most common reported treatment-related adverse events were fatigue, lethargy and somnolence. Here we report on prespecified secondary analyses examining viral rebound, antibody sensitivity and reservoir dynamics, as well as prespecified exploratory analyses of rebound virus evolution and autologous antibody activity. Preinfusion reservoir measurements showed low levels of intact proviral HIV-1 DNA in circulating CD4 + T cells in both arms. The rebounding viruses in participants who received the antibodies showed significant selection for resistance to 10-1074-LS but not to 3BNC117-LS. Notably, there was a significant correlation between greater initial reservoir sensitivity to autologous antibodies and 10-1074 and time to rebound. Finally, comparison of preinfusion and prerebound HIV-1 proviral reservoir showed a decrease in intact but not defective proviruses in arm A but not in arm B. Together, these findings suggest that baseline humoral immunity and prolonged exposure to LS-bNAbs jointly shape post-treatment viral rebound dynamics in individuals who initiate ART during primary infection. ClinicalTrials.gov identifier: NCT04319367 .

Nature Medicine
Brighton and Sussex Medical School (GB), Universidade Federal de Minas Gerais (BR), Beth Israel Deaconess Medical Center (US), NHS Lothian (GB), St Thomas' Hospital (GB), Universidade de Ribeirão Preto (BR), Howard Hughes Medical Institute (US), Institut Pasteur (FR), Queen Mary University of London (GB), Royal Free London NHS Foundation Trust (GB), Universidade de São Paulo (BR), Guy's and St Thomas' NHS Foundation Trust (GB), Université Paris Cité (FR), Central and North West London NHS Foundation Trust (GB), Barts Health NHS Trust (GB), Western General Hospital (GB), Aarhus University Hospital (DK), University of Oxford (GB), Manchester University NHS Foundation Trust (GB), NIHR Imperial Biomedical Research Centre (GB), Chelsea and Westminster Hospital (GB), Oxford BioMedica (United Kingdom) (GB), University Hospitals Sussex NHS Foundation Trust (GB), Clinics Hospital of Ribeirão Preto (BR), University College London (GB), Imperial College London (GB), Rockefeller University (US)
Good health and well-being
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HIV Research and Treatment
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