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

• Published in: Nature medicine Vol. 29; no. 10; pp. 2547 - 2558
• Main Authors: Gunst, Jesper D., Højen, Jesper F., Pahus, Marie H., Rosás-Umbert, Miriam, Stiksrud, Birgitte, McMahon, James H., Denton, Paul W., Nielsen, Henrik, Johansen, Isik S., Benfield, Thomas, Leth, Steffen, Gerstoft, Jan, Østergaard, Lars, Schleimann, Mariane H., Olesen, Rikke, Støvring, Henrik, Vibholm, Line, Weis, Nina, Dyrhol-Riise, Anne M., Pedersen, Karen B. H., Lau, Jillian S. Y., Copertino, Dennis C., Linden, Noemi, Huynh, Tan T., Ramos, Victor, Jones, R. Brad, Lewin, Sharon R., Tolstrup, Martin, Rasmussen, Thomas A., Nussenzweig, Michel C., Caskey, Marina, Reikvam, Dag Henrik, Søgaard, Ole S.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 692/308/2779/777; 692/699/255/1901; Adjuvants, Immunologic; Agonists; Antibodies; Antibodies, Neutralizing; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; Antiviral agents; Biomedical and Life Sciences; Biomedicine; Broadly Neutralizing Antibodies - therapeutic use; Cancer Research; Female; HIV; HIV Antibodies - therapeutic use; HIV Infections; HIV-1; Human immunodeficiency virus; Humans; Immunotherapy; Infectious Diseases; Male; Metabolic Diseases; Molecular Medicine; Neurosciences; Neutralizing; Placebos; TLR9 protein; Toll-Like Receptor 9 - antagonists & inhibitors; Toll-Like Receptor 9 - immunology; Toll-like receptors
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-023-02547-6

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 . In people with HIV-1 undergoing antiretroviral treatment interruption, lefitolimod combined with broadly neutralizing antibodies (bNAbs) did not delay viral rebound beyond that achieved with bNAbs alone, raising the question of how to optimize combination immunotherapy to control HIV-1.