Abstract
Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg–1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg–1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.
Highlights
Human immunodeficiency virus-1-specific broadly neutralizing monoclonal antibodies that target the HIV-1 envelope (Env) protein are currently under development as potential tools to treat and prevent HIV-1 infection
The first participant was enrolled on 17 January 2017, the last on 22 January 2019 and the final study visit was completed on 8 July 2019
After determination that PGT121 administered at 30 mg kg–1 was safe and well tolerated in Groups 1 and 2, Part 2 of the study was initiated with HIV-infected participants not on antiretroviral therapy (ART) and viremic (n = 13) being enrolled in Group 3
Summary
At the last available time point for each participant, all samples remained ADA negative with the exception of samples from two participants (PTID 7945 from Group 2, at 30 mg kg–1 dose, and 2305 from Group 3) that gave positive signals on day 168 and were confirmed by PGT121 competition assay (Extended Data Fig. 2a,b). For participant 1536, some rebound viruses retained sensitivity to PGT121 while others were completely resistant; the phylogenetic tree suggests that the re-emerging sensitive forms were very closely related to a baseline lineage (Extended Data Fig. 5). In some participants, such as 2305, 2936 and 2990, the model predicted that a resistant population log[10] cp ml–1 log[10] cp ml–1 log[10] cp ml–1 a
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