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. PedersenJillian 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 af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

31 Citationer (Scopus)

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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 .

Originalsprog	Engelsk
Tidsskrift	Nature Medicine
Vol/bind	29
Nummer	10
Sider (fra-til)	2547-2558
Antal sider	12
ISSN	1078-8956
DOI	https://doi.org/10.1038/s41591-023-02547-6
Status	Udgivet - okt. 2023

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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

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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 .",

keywords = "Adjuvants, Immunologic, Antibodies, Neutralizing, Broadly Neutralizing Antibodies, Female, HIV Antibodies/therapeutic use, HIV Infections, HIV-1, Humans, Male, Toll-Like Receptor 9/therapeutic use",

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 = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

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, bind 29, nr. 10, s. 2547-2558. https://doi.org/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. / Gunst, Jesper D.; Højen, Jesper F.; Pahus, Marie H. et al.
I: Nature Medicine, Bind 29, Nr. 10, 10.2023, s. 2547-2558.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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.

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 .

KW - Adjuvants, Immunologic

KW - Antibodies, Neutralizing

KW - Broadly Neutralizing Antibodies

KW - Female

KW - HIV Antibodies/therapeutic use

KW - HIV Infections

KW - HIV-1

KW - Humans

KW - Male

KW - Toll-Like Receptor 9/therapeutic use

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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

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