Background:
Human immunodeficiency virus type 1 (HIV-1) specific broadly neutralizing monoclonal antibodies (bNAbs) have to date shown limited therapeutic efficacy when administered as monotherapy or as a cocktail of two antibodies. A combination of three bNAbs provides improved neutralization coverage of global viruses. Here we show that a triple bNAb cocktail targeting three distinct epitopes on HIV-1 Env results in long-term virologic control in persons living with HIV-1 (PLWH) following discontinuation of antiretroviral therapy (ART).
Methods:
We first evaluated the pharmacokinetics of the bNAbs PGT121, PGDM1400, and VRC07-523LS, which target the V3 glycan supersite, V2 apex, and CD4 binding site, respectively. We then assessed the therapeutic efficacy of up to six monthly infusions of this triple bNAb cocktail in 12 PLWH who discontinued ART after the first antibody infusion (NCT03721510). Participants were not screened for bNAb sensitivity at baseline.
Results:
83% of participants (10 of 12) maintained virologic suppression for the duration of the antibody dosing period for at least 28 weeks. Moreover, 42% of participants (5 of 12) demonstrated virologic suppression for the duration of follow-up for at least 38-44 weeks, despite the decline of serum bNAb concentrations to low or undetectable levels. Early viral rebound in 2 individuals correlated with baseline resistance to PGT121 and PGDM1400, whereas late viral rebound in 5 participants in the context of declining bNAb levels was characterized by both sensitive and resistant rebound virus.
Conclusions:
Our data demonstrate the potential of a triple HIV-1 bNAb cocktail to provide long-term virologic control in the majority of PLWH in the absence of ART. Long-acting versions of these three bNAbs are currently being developed for HIV-1 prevention and therapy.
