Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial
Summary: Background: The administration of broadly neutralising anti-HIV-1 antibodies before latency reversal could facilitate elimination of HIV-1-infected CD4 T cells. We tested this concept by combining the broadly neutralising antibody 3BNC117 in combination with the latency-reversing agent rom...
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-03-01
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| Series: | The Lancet Microbe |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666524721002391 |
| _version_ | 1818488402705645568 |
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| author | Henning Gruell, MD Jesper D Gunst, MD Yehuda Z Cohen, MD Marie H Pahus Jakob J Malin, MD Martin Platten, MD Katrina G Millard, RN Martin Tolstrup, PhD R Brad Jones, PhD Winnifer D Conce Alberto Julio C C Lorenzi, PhD Thiago Y Oliveira, PhD Tim Kümmerle, MD Isabelle Suárez, MD Cecilia Unson-O'Brien, PhD Lilian Nogueira, PhD Rikke Olesen, PhD Lars Østergaard, ProfMD Henrik Nielsen, ProfMD Clara Lehmann, MD Michel C Nussenzweig, ProfMD Gerd Fätkenheuer, ProfMD Florian Klein, ProfMD Marina Caskey, ProfMD Ole S Søgaard, ProfMD |
| author_facet | Henning Gruell, MD Jesper D Gunst, MD Yehuda Z Cohen, MD Marie H Pahus Jakob J Malin, MD Martin Platten, MD Katrina G Millard, RN Martin Tolstrup, PhD R Brad Jones, PhD Winnifer D Conce Alberto Julio C C Lorenzi, PhD Thiago Y Oliveira, PhD Tim Kümmerle, MD Isabelle Suárez, MD Cecilia Unson-O'Brien, PhD Lilian Nogueira, PhD Rikke Olesen, PhD Lars Østergaard, ProfMD Henrik Nielsen, ProfMD Clara Lehmann, MD Michel C Nussenzweig, ProfMD Gerd Fätkenheuer, ProfMD Florian Klein, ProfMD Marina Caskey, ProfMD Ole S Søgaard, ProfMD |
| author_sort | Henning Gruell, MD |
| collection | DOAJ |
| description | Summary: Background: The administration of broadly neutralising anti-HIV-1 antibodies before latency reversal could facilitate elimination of HIV-1-infected CD4 T cells. We tested this concept by combining the broadly neutralising antibody 3BNC117 in combination with the latency-reversing agent romidepsin in people with HIV-1 who were taking suppressive antiretroviral therapy (ART). Methods: We did a randomised, open-label, phase 2A trial at three university hospital centres in Denmark, Germany, and the USA. Eligible participants were virologically suppressed adults aged 18–65 years who were infected with HIV-1 and on ART for at least 18 months, with plasma HIV-1 RNA concentrations of less than 50 copies per mL for at least 12 months, and a CD4 T-cell count of greater than 500 cells per μL. Participants were randomly assigned (1:1) to receive 3BNC117 plus romidepsin or romidepsin alone in two cycles. All participants received intravenous infusions of romidepsin (5 mg/m2 given over 120 min) at weeks 0, 1, and 2 (treatment cycle 1) and weeks 8, 9, and 10 (treatment cycle 2). Those in the 3BNC117 plus romidepsin group received an intravenous infusion of 3BNC117 (30 mg/kg given over 60 min) 2 days before each treatment cycle. An analytic treatment interruption (ATI) of ART was done at week 24 in both groups. Our primary endpoint was time to viral rebound during analytic treatment interruption, which was assessed in all participants who completed both treatment cycles and ATI. We used a log-rank test to compare time to viral rebound during analytic treatment interruption between the two groups. This trial is registered with ClinicalTrials.gov, NCT02850016. It is closed to new participants, and all follow-up is complete. Findings: Between March 20, 2017, and Aug 14, 2018, 22 people were enrolled and randomly assigned, 11 to the 3BNC117 plus romidepsin group and 11 to the romidepsin group. 19 participants completed both treatment cycles and the ATI: 11 in the 3BNC117 plus romidepsin group and 8 in the romidepsin group. The median time to viral rebound during ATI was 18 days (IQR 14–28) in the 3BNC117 plus romidepsin group and 28 days (21–35) in the romidepsin group B (p=0·0016). Although this difference was significant, prolongation of time to viral rebound was not clinically meaningful in either group. All participants in both groups reported adverse events, but overall the combination of 3BNC117 and romidepsin was safe. Two severe adverse events were observed in the romidepsin group during 48 weeks of follow-up, one of which—increased direct bilirubin—was judged to be related to treatment. Interpretation: The combination of 3BNC117 and romidepsin was safe but did not delay viral rebound during analytic treatment interruptions in individuals on long-term ART. The results of our trial could serve as a benchmark for further optimisation of HIV-1 curative strategies among people with HIV-1 who are taking suppressive ART. Funding: amfAR, German Center for Infection Research. |
| first_indexed | 2024-12-10T16:50:39Z |
| format | Article |
| id | doaj.art-b572a4bc81f74c27b4e7e697acac132e |
| institution | Directory Open Access Journal |
| issn | 2666-5247 |
| language | English |
| last_indexed | 2024-12-10T16:50:39Z |
| publishDate | 2022-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | The Lancet Microbe |
| spelling | doaj.art-b572a4bc81f74c27b4e7e697acac132e2022-12-22T01:40:55ZengElsevierThe Lancet Microbe2666-52472022-03-0133e203e214Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trialHenning Gruell, MD0Jesper D Gunst, MD1Yehuda Z Cohen, MD2Marie H Pahus3Jakob J Malin, MD4Martin Platten, MD5Katrina G Millard, RN6Martin Tolstrup, PhD7R Brad Jones, PhD8Winnifer D Conce Alberto9Julio C C Lorenzi, PhD10Thiago Y Oliveira, PhD11Tim Kümmerle, MD12Isabelle Suárez, MD13Cecilia Unson-O'Brien, PhD14Lilian Nogueira, PhD15Rikke Olesen, PhD16Lars Østergaard, ProfMD17Henrik Nielsen, ProfMD18Clara Lehmann, MD19Michel C Nussenzweig, ProfMD20Gerd Fätkenheuer, ProfMD21Florian Klein, ProfMD22Marina Caskey, ProfMD23Ole S Søgaard, ProfMD24Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; German Center for Infection Research (DZIF) Bonn-Cologne, Cologne, GermanyDepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, DenmarkLaboratory of Molecular Immunology, The Rockefeller University, New York, NY, USADepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, DenmarkDepartment I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanyDepartment I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Wisplinghoff Laboratories, Cologne, GermanyLaboratory of Molecular Immunology, The Rockefeller University, New York, NY, USADepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, DenmarkDivision of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, NY, USADivision of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, NY, USALaboratory of Molecular Immunology, The Rockefeller University, New York, NY, USALaboratory of Molecular Immunology, The Rockefeller University, New York, NY, USADepartment I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Praxis am Ebertplatz, Cologne, GermanyDepartment I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; German Center for Infection Research (DZIF) Bonn-Cologne, Cologne, GermanyLaboratory of Molecular Immunology, The Rockefeller University, New York, NY, USALaboratory of Molecular Immunology, The Rockefeller University, New York, NY, USADepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, DenmarkDepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, DenmarkDepartment of Infectious Diseases, Aalborg University Hospital, Aalborg, DenmarkDepartment I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; German Center for Infection Research (DZIF) Bonn-Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, GermanyLaboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USADepartment I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; German Center for Infection Research (DZIF) Bonn-Cologne, Cologne, GermanyLaboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; German Center for Infection Research (DZIF) Bonn-Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, GermanyLaboratory of Molecular Immunology, The Rockefeller University, New York, NY, USADepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Correspondence to: Prof Ole S Søgaard, Department of Infectious Diseases, Aarhus University Hospital, 8200 Aarhus N, DenmarkSummary: Background: The administration of broadly neutralising anti-HIV-1 antibodies before latency reversal could facilitate elimination of HIV-1-infected CD4 T cells. We tested this concept by combining the broadly neutralising antibody 3BNC117 in combination with the latency-reversing agent romidepsin in people with HIV-1 who were taking suppressive antiretroviral therapy (ART). Methods: We did a randomised, open-label, phase 2A trial at three university hospital centres in Denmark, Germany, and the USA. Eligible participants were virologically suppressed adults aged 18–65 years who were infected with HIV-1 and on ART for at least 18 months, with plasma HIV-1 RNA concentrations of less than 50 copies per mL for at least 12 months, and a CD4 T-cell count of greater than 500 cells per μL. Participants were randomly assigned (1:1) to receive 3BNC117 plus romidepsin or romidepsin alone in two cycles. All participants received intravenous infusions of romidepsin (5 mg/m2 given over 120 min) at weeks 0, 1, and 2 (treatment cycle 1) and weeks 8, 9, and 10 (treatment cycle 2). Those in the 3BNC117 plus romidepsin group received an intravenous infusion of 3BNC117 (30 mg/kg given over 60 min) 2 days before each treatment cycle. An analytic treatment interruption (ATI) of ART was done at week 24 in both groups. Our primary endpoint was time to viral rebound during analytic treatment interruption, which was assessed in all participants who completed both treatment cycles and ATI. We used a log-rank test to compare time to viral rebound during analytic treatment interruption between the two groups. This trial is registered with ClinicalTrials.gov, NCT02850016. It is closed to new participants, and all follow-up is complete. Findings: Between March 20, 2017, and Aug 14, 2018, 22 people were enrolled and randomly assigned, 11 to the 3BNC117 plus romidepsin group and 11 to the romidepsin group. 19 participants completed both treatment cycles and the ATI: 11 in the 3BNC117 plus romidepsin group and 8 in the romidepsin group. The median time to viral rebound during ATI was 18 days (IQR 14–28) in the 3BNC117 plus romidepsin group and 28 days (21–35) in the romidepsin group B (p=0·0016). Although this difference was significant, prolongation of time to viral rebound was not clinically meaningful in either group. All participants in both groups reported adverse events, but overall the combination of 3BNC117 and romidepsin was safe. Two severe adverse events were observed in the romidepsin group during 48 weeks of follow-up, one of which—increased direct bilirubin—was judged to be related to treatment. Interpretation: The combination of 3BNC117 and romidepsin was safe but did not delay viral rebound during analytic treatment interruptions in individuals on long-term ART. The results of our trial could serve as a benchmark for further optimisation of HIV-1 curative strategies among people with HIV-1 who are taking suppressive ART. Funding: amfAR, German Center for Infection Research.http://www.sciencedirect.com/science/article/pii/S2666524721002391 |
| spellingShingle | Henning Gruell, MD Jesper D Gunst, MD Yehuda Z Cohen, MD Marie H Pahus Jakob J Malin, MD Martin Platten, MD Katrina G Millard, RN Martin Tolstrup, PhD R Brad Jones, PhD Winnifer D Conce Alberto Julio C C Lorenzi, PhD Thiago Y Oliveira, PhD Tim Kümmerle, MD Isabelle Suárez, MD Cecilia Unson-O'Brien, PhD Lilian Nogueira, PhD Rikke Olesen, PhD Lars Østergaard, ProfMD Henrik Nielsen, ProfMD Clara Lehmann, MD Michel C Nussenzweig, ProfMD Gerd Fätkenheuer, ProfMD Florian Klein, ProfMD Marina Caskey, ProfMD Ole S Søgaard, ProfMD Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial The Lancet Microbe |
| title | Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial |
| title_full | Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial |
| title_fullStr | Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial |
| title_full_unstemmed | Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial |
| title_short | Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial |
| title_sort | effect of 3bnc117 and romidepsin on the hiv 1 reservoir in people taking suppressive antiretroviral therapy roadmap a randomised open label phase 2a trial |
| url | http://www.sciencedirect.com/science/article/pii/S2666524721002391 |
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