Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial
Jesper Damsgaard Gunst, Jesper Falkesgaard Højen, Marie H. Pahus, Míriam Rosás-Umbert, Birgitte Stiksrud, James McMahon, Paul W. Denton, Henrik Nielsen, Işık Somuncu Johansen, Thomas Benfield, Steffen Leth, Jan Gerstoft, Lars Østergaard, Mariane Høgsbjerg Schleimann, Rikke Olesen, Henrik Støvring, Line K. Vibholm, Nina Weis, Anne Ma Dyrhol‐Riise, Karen Brorup Pedersen, Jillian S. Y. Lau, Dennis C. Copertino, Noemi Linden, Tan Thinh Huynh, Víctor Ramos, R. Brad Jones, Sharon R. Lewin, Martin Tolstrup, Thomas A. Rasmussen, Michel C. Nussenzweig, Marina Caskey, Dag Henrik Reikvam, Ole S. Søgaard
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 .