Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial

Jesper D. Gunst; Jesper F. Højen; Marie H. Pahus; Miriam Rosás-Umbert; Birgitte Stiksrud; James H. McMahon; Paul W. Denton; Henrik Nielsen; Isik S. Johansen; Thomas Benfield; Steffen Leth; Jan Gerstoft; Lars Østergaard; Mariane H. Schleimann; Rikke Olesen; Henrik Støvring; Line Vibholm; Nina Weis; Anne M. Dyrhol-Riise; Karen B. H. Pedersen; Jillian S.Y. Lau; Dennis C. Copertino; Noemi Linden; Tan T. Huynh; Victor Ramos; R. Brad Jones; Sharon R. Lewin; Martin Tolstrup; Thomas A. Rasmussen; Michel C. Nussenzweig; Marina Caskey; Dag Henrik Reikvam; Ole S. Søgaard

doi:10.1038/s41591-023-02547-6

Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial

Jesper D. Gunst
, Jesper F. Højen
, Marie H. Pahus
, Miriam Rosás-Umbert
, Birgitte Stiksrud
, James H. McMahon
, Paul W. Denton
, Henrik Nielsen
, Isik S. Johansen
, Thomas Benfield
, Steffen Leth
, Jan Gerstoft
, Lars Østergaard
, Mariane H. Schleimann
, Rikke Olesen
, Henrik Støvring
, Line Vibholm
, Nina Weis
, Anne M. Dyrhol-Riise
, Karen B. H. Pedersen

Jillian S.Y. Lau, Dennis C. Copertino, Noemi Linden, Tan T. Huynh, Victor Ramos, R. Brad Jones, Sharon R. Lewin, Martin Tolstrup, Thomas A. Rasmussen, Michel C. Nussenzweig, Marina Caskey, Dag Henrik Reikvam, Ole S. Søgaard^*

^*Corresponding author for this work

Aarhus University
Aarhus University Hospital
Oslo University Hospital
The Alfred Hospital
University of Nebraska at Omaha
Copenhagen University Hospital
University of Copenhagen
Gødstrup Hospital
Rigshospitalet
University of Oslo
The Peter Doherty Institute for Infection and Immunity
Royal Melbourne Hospital
Weill Cornell Medicine
Weill Cornell Graduate School of Medical Sciences
Rockefeller University
Aalborg University Hospital
Aalborg University
University of Melbourne

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 .

Original language	English
Journal	Nature Medicine
Volume	29
Issue number	10
Pages (from-to)	2547-2558
ISSN	1078-8956
DOIs	https://doi.org/10.1038/s41591-023-02547-6
Publication status	Published - Oct 2023

Funding

We thank all study participants who devoted time to our research as well as every clinical research unit involved in the study. We acknowledge The Rockefeller University for providing 3BNC117 and 10-1074 and Mologen AG (now part of Gilead Sciences, Inc.) for providing lefitolimod. The funders were not involved in the study design/operations, data collection/analysis/interpretation or preparation of the manuscript. The study was funded through a Gilead HIV Cure grant to O.S.S. Study drugs were donated free of charge by The Rockefeller University (3BNC117 and 10–1074) and Mologen AG/Gilead Sciences, Inc. (lefitolimod) for use in this trial. J.D.G. is supported by the Lundbeck Foundation (R381–2021–1405). P.W.D. is supported by the National Institute of General Medical Sciences of the National Institutes of Health under award P20 GM103427. Partial support for virologic analysis was provided by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award R01AI47845 (RBJ), supported by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, the National Institute on Drug Abuse and the National Heart, Lung, and Blood Institute. S.R.L. is supported by funding from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award UM1AI126611-01 and the National Health and Medical Research Council (NHMRC) of Australia (1135851 and 1149990). S.R.L. is an NHMRC Practitioner Fellow. O.S.S. is also supported by the Danish Council for Independent Research (grant 9060-00023B) and the Lundbeck Foundation (R313-2019-790). 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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Gunst, J. D., Højen, J. F., Pahus, M. H., Rosás-Umbert, M., Stiksrud, B., McMahon, J. H., Denton, P. W., Nielsen, H., Johansen, I. S., Benfield, T., Leth, S., Gerstoft, J., Østergaard, L., Schleimann, M. H., Olesen, R., Støvring, H., Vibholm, L., Weis, N., Dyrhol-Riise, A. M., ... Søgaard, O. S. (2023). Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial. Nature Medicine, 29(10), 2547-2558. https://doi.org/10.1038/s41591-023-02547-6

@article{601227842e204387bc8e643b608821f5,

title = "Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial",

abstract = "Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85\% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36\% (4/11) in the placebo/bNAb group compared to 0\% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 .",

author = "Gunst, \{Jesper D.\} and H{\o}jen, \{Jesper F.\} and Pahus, \{Marie H.\} and Miriam Ros{\'a}s-Umbert and Birgitte Stiksrud and McMahon, \{James H.\} and Denton, \{Paul W.\} and Henrik Nielsen and Johansen, \{Isik S.\} and Thomas Benfield and Steffen Leth and Jan Gerstoft and Lars {\O}stergaard and Schleimann, \{Mariane H.\} and Rikke Olesen and Henrik St{\o}vring and Line Vibholm and Nina Weis and Dyrhol-Riise, \{Anne M.\} and Pedersen, \{Karen B. H.\} and Lau, \{Jillian S.Y.\} and Copertino, \{Dennis C.\} and Noemi Linden and Huynh, \{Tan T.\} and Victor Ramos and Jones, \{R. Brad\} and Lewin, \{Sharon R.\} and Martin Tolstrup and Rasmussen, \{Thomas A.\} and Nussenzweig, \{Michel C.\} and Marina Caskey and Reikvam, \{Dag Henrik\} and S{\o}gaard, \{Ole S.\}",

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. We acknowledge The Rockefeller University for providing 3BNC117 and 10-1074 and Mologen AG (now part of Gilead Sciences, Inc.) for providing lefitolimod. The funders were not involved in the study design/operations, data collection/analysis/interpretation or preparation of the manuscript. The study was funded through a Gilead HIV Cure grant to O.S.S. Study drugs were donated free of charge by The Rockefeller University (3BNC117 and 10{\textendash}1074) and Mologen AG/Gilead Sciences, Inc. (lefitolimod) for use in this trial. J.D.G. is supported by the Lundbeck Foundation (R381{\textendash}2021{\textendash}1405). P.W.D. is supported by the National Institute of General Medical Sciences of the National Institutes of Health under award P20 GM103427. Partial support for virologic analysis was provided by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award R01AI47845 (RBJ), supported by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, the National Institute on Drug Abuse and the National Heart, Lung, and Blood Institute. S.R.L. is supported by funding from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award UM1AI126611-01 and the National Health and Medical Research Council (NHMRC) of Australia (1135851 and 1149990). S.R.L. is an NHMRC Practitioner Fellow. O.S.S. is also supported by the Danish Council for Independent Research (grant 9060-00023B) and the Lundbeck Foundation (R313-2019-790). 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. ",

year = "2023",

month = oct,

doi = "10.1038/s41591-023-02547-6",

language = "English",

volume = "29",

pages = "2547--2558",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

number = "10",

}

Gunst, JD, Højen, JF, Pahus, MH, Rosás-Umbert, M, Stiksrud, B, McMahon, JH, Denton, PW, Nielsen, H, Johansen, IS, Benfield, T, Leth, S, Gerstoft, J, Østergaard, L, Schleimann, MH, Olesen, R, Støvring, H, Vibholm, L, Weis, N, Dyrhol-Riise, AM, Pedersen, KBH, Lau, JSY, Copertino, DC, Linden, N, Huynh, TT, Ramos, V, Jones, RB, Lewin, SR, Tolstrup, M, Rasmussen, TA, Nussenzweig, MC, Caskey, M, Reikvam, DH & Søgaard, OS 2023, 'Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial', Nature Medicine, vol. 29, no. 10, pp. 2547-2558. https://doi.org/10.1038/s41591-023-02547-6

TY - JOUR

T1 - Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence

T2 - the randomized phase 2a TITAN trial

AU - Gunst, Jesper D.

AU - Højen, Jesper F.

AU - Pahus, Marie H.

AU - Rosás-Umbert, Miriam

AU - Stiksrud, Birgitte

AU - McMahon, James H.

AU - Denton, Paul W.

AU - Nielsen, Henrik

AU - Johansen, Isik S.

AU - Benfield, Thomas

AU - Leth, Steffen

AU - Gerstoft, Jan

AU - Østergaard, Lars

AU - Schleimann, Mariane H.

AU - Olesen, Rikke

AU - Støvring, Henrik

AU - Vibholm, Line

AU - Weis, Nina

AU - Dyrhol-Riise, Anne M.

AU - Pedersen, Karen B. H.

AU - Lau, Jillian S.Y.

AU - Copertino, Dennis C.

AU - Linden, Noemi

AU - Huynh, Tan T.

AU - Ramos, Victor

AU - Jones, R. Brad

AU - Lewin, Sharon R.

AU - Tolstrup, Martin

AU - Rasmussen, Thomas A.

AU - Nussenzweig, Michel C.

AU - Caskey, Marina

AU - Reikvam, Dag Henrik

AU - Søgaard, Ole S.

N1 - Funding Information: We thank all study participants who devoted time to our research as well as every clinical research unit involved in the study. We acknowledge The Rockefeller University for providing 3BNC117 and 10-1074 and Mologen AG (now part of Gilead Sciences, Inc.) for providing lefitolimod. The funders were not involved in the study design/operations, data collection/analysis/interpretation or preparation of the manuscript. The study was funded through a Gilead HIV Cure grant to O.S.S. Study drugs were donated free of charge by The Rockefeller University (3BNC117 and 10–1074) and Mologen AG/Gilead Sciences, Inc. (lefitolimod) for use in this trial. J.D.G. is supported by the Lundbeck Foundation (R381–2021–1405). P.W.D. is supported by the National Institute of General Medical Sciences of the National Institutes of Health under award P20 GM103427. Partial support for virologic analysis was provided by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award R01AI47845 (RBJ), supported by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, the National Institute on Drug Abuse and the National Heart, Lung, and Blood Institute. S.R.L. is supported by funding from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award UM1AI126611-01 and the National Health and Medical Research Council (NHMRC) of Australia (1135851 and 1149990). S.R.L. is an NHMRC Practitioner Fellow. O.S.S. is also supported by the Danish Council for Independent Research (grant 9060-00023B) and the Lundbeck Foundation (R313-2019-790). 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.

PY - 2023/10

Y1 - 2023/10

N2 - Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 .

AB - Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 .

U2 - 10.1038/s41591-023-02547-6

DO - 10.1038/s41591-023-02547-6

M3 - Journal article

C2 - 37696935

AN - SCOPUS:85170556818

SN - 1078-8956

VL - 29

SP - 2547

EP - 2558

JO - Nature Medicine

JF - Nature Medicine

IS - 10

ER -

Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial

Abstract

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