Abstract
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.
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Data availability
Data are not available for download due to privacy/ethical restrictions under the EU GDPR. Specific requests for access to the trial data may be sent to olesoega@rm.dk and access may be provided to a named individual in agreement with the rules and regulations of the Danish Data Protection Agency and the National Committee on Health Research Ethics with a 2-week response timeframe to requests.
Change history
30 April 2025
In the version of the article initially published, the URL embedded in the clinical trial ID NCT03041012 was incorrect and has now been amended in the HTML and PDF versions of the article.
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Acknowledgements
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.
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O.S.S. developed the trial design. J.D.G., M.T., M.C.N., M.C. and O.S.S. wrote the protocol. J.D.G., T.B., H.N., I.S.J., R.M., L.Ø., V.K., J.F., S.F. and O.S.S. did the clinical visits. J.D.G., M.H.P., M.R.-U., I.-N.L., M.K., M.H.S., R.O., P.W.D., N.N.K., D.C.C., A.R.W., W.D.C.A., S.D.N., M.C.P., J.D.R., C.J.P., J.M.-P., Z.L.B., R.B.J., M.T. and O.S.S. did the laboratory assays and validations. V.R. performed the bioinformatic analysis. J.D.G., M.H.P., M.R.-U. and H.S. did the statistical analysis. J.D.G., P.W.D. and O.S.S. drafted the tables and figures. J.D.G. and O.S.S. drafted the article, which all authors critically revised for important intellectual content. J.D.G. and O.S.S. had full access to all the data in the study, verified the data and had final responsibility for the decision to submit for publication.
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M.C.N. is listed as an inventor on patents for the antibody 3BNC117. J.D.R. and C.J.P. are employees of Labcorp-Monogram Biosciences. All other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 A comprehensive CONSORT Flow Diagram.
AE, adverse event; Ag, antigen; ART, antiretroviral therapy; COVID-19, coronavirus disease 2019; RMD, romidepsin; SAE, serious AE.
Extended Data Fig. 2
Distribution between self-report time of infection to study enrollment and outcome of the Asanté HIV-1 Rapid Recency Assay (n = 54).
Extended Data Fig. 3 Transcriptionally (mRNA+) and transcriptionally + translationally (mRNA+p24+) active HIV-1-infected cells following ART initiation.
Changes in HIV-1-infected cells during the first 30 days of ART among the four groups shown as median (error bars represents interquartile ranges) number of CD3+CD8- T cells expressing either HIV-1 mRNA (a) or HIV-1 mRNA and Gag p24 protein (b). ART-control n = 4, ART + 3BNC117 n = 5, ART + RMD n = 4, ART + 3BNC117 + RMD n = 5. ART, antiretroviral therapy; RMD, romidepsin.
Extended Data Fig. 4 Impact of 3BNC117 on translationally (p24+) active HIV-1-infected CD4+ T cell subsets.
Data are shown as in Fig. 3b-e, where the ART alone and ART + RMD groups (who only received ART during the first 10 days) are combined into one group and compared to the two 3BNC117-treated groups. Median (error bars represent interquartile ranges) fold change in CD3+CD8- T cell subsets expressing Gag p24 among the combined ART (n = 15) and ART + 3BNC117 (n = 18) groups. The CD3+CD8- T cells subsets are central memory T cells (TCM) (a), naïve T cells (TN) (b), effector memory T cells (TEM) (c), terminally differentiated T cells (TTD) (d), and T follicular helper cells (TFH) (e). P values comparing within group was calculated using paired two-tailed Wilcoxon test. ART, antiretroviral therapy; IQR, interquartile ranges; RMD, romidepsin.
Extended Data Fig. 5 The frequency of HIV-1 antigen-producing cells.
The individual frequency of induced p24+ CD4+ T cells at ART initiation (day 0) and after 365 days of ART (lines at median) (a) and median changes in these cells between day 0 and 365 after ART initiation (b) among individuals in the four groups. P values comparing within group and between groups were calculated using paired two-tailed Wilcoxon test and two-tailed Mann-Whitney test, respectively. Pie charts showing the status of HIV-1 antigen-producing cells after 365 days of ART per group (column and upper row) and categorized according to pre-ART plasma virus sensitivity (middle row; blue shaded area) or resistance (bottom row; red shaded area) to 3BNC117 (c). A compiled group ART + 3BNC117 + /-RMD is shown is the last column. ART-control n = 12, ART + 3BNC117 n = 14, ART + RMD n = 10, ART + 3BNC117 + RMD n = 13. Ag, antigen; ART, antiretroviral therapy; RMD, romidepsin.
Extended Data Fig. 6 Effect of RMD on transcriptionally (mRNA+) and transcriptionally + translationally (mRNA+p24+) active HIV-1-infected cells.
Data are shown as in Fig. 3f, g. Individual and overall median fold change (column) from pre- to post-RMD infusions in groups ART + RMD (n = 8) and ART + 3BNC117 + RMD (n = 10) on CD3+CD8- T cells expressing HIV-1 mRNA (a) or mRNA and Gag p24 (b). P values comparing within group was calculated using paired two-tailed Wilcoxon test. Due to a faulty mRNA probe in the 2nd batch of FISH-flow cytometry analyses, mRNA data was only available for half of the study population. ART, antiretroviral therapy; RMD, romidepsin.
Extended Data Fig. 7 The frequency of defective HIV-1 proviruses.
The frequency of 3’ (a) and 5’ (b) defective HIV-1 proviruses at ART initiation and after 180 and 365 days of ART among individuals in the four groups (lines at median, error bars represent interquartile ranges). P values comparing within group were calculated using paired two-tailed Wilcoxon test. ART only n = 14, ART + 3BNC117 n = 14, ART + RMD n = 10, ART + 3BNC117 + RMD n = 14. ART, antiretroviral therapy; RMD, romidepsin.
Extended Data Fig. 8 CD4+ T cell count and CD4/CD8 ratio during the study.
Tukey plots depicts the CD4+ T cell count (a) and CD4/CD8 ratio (b) in the four groups at baseline (day 0), the interventional period (day 10–30) and during follow-up (day 90–365). Lines indicates median, boxes represent interquartile ranges and whiskers drawn within the 1.5 IQR values. ART only n = 15, ART + 3BNC117 n = 15, ART + RMD n = 13, ART + 3BNC117 + RMD n = 16. ART, antiretroviral therapy; IQR, interquartile range; RMD, romidepsin.
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Supplementary Figs. 1–5, Supplementary Tables 1–6, CONSORT checklist and study protocol: eCLEAR-001, version 3.1, 18 September 2018.
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Gunst, J.D., Pahus, M.H., Rosás-Umbert, M. et al. Early intervention with 3BNC117 and romidepsin at antiretroviral treatment initiation in people with HIV-1: a phase 1b/2a, randomized trial. Nat Med 28, 2424–2435 (2022). https://doi.org/10.1038/s41591-022-02023-7
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