Background
Broadly neutralizing monoclonal antibodies (bNAbs) suppress HIV RNA and may promote HIV remission. We evaluated safety and pharmacokinetics (PK) of intravenous VRC07-523LS, PGDM1400LS, and PGT.121.414.LS in children with HIV on suppressive antiretroviral treatment (ART).
Methods
Children eligible for the safety and PK phase of the Tatelo Plus / IMPAACT 2042 Study received ART from <7 days of life, with HIV RNA <40 copies/mL for ≥24 weeks prior to enrollment. Dolutegravir-based ART was continued during this phase of the study. All bNAbs were dosed at 20mg/kg/dose. Through week 16 of the study, 6 participants received PGDM1400LS at Week 0 and 8, and PGT.121.414.LS at week 12. Six participants received PGT.121.414.LS at Week 0 and 8, and PGDM1400LS at week 12. All 12 participants received VRC07-523LS at Week 8 and 12. At Week 16, after 2 doses for each bNAb, we evaluated bNAb concentrations assessed by validated multiplex pharmacokinetics Binding Antibody Multiplex Assay (PK-BAMA). Measured troughs (for PGDM1400LS and PGT.121.414.LS) or troughs predicted by population PK models (for VRC07-523LS) at Week 16 were used to determine future dosing.
Results
Median age was 7.8 years at enrollment (range 1.5, 9.5 years; 75% female), and median CD4 cell count was 1238 (range 645, 2683) cells/mm3. All infusions occurred on schedule to completion. Infusions were well-tolerated without infusion reactions or grade 3 or 4 adverse events. The estimated geometric mean of pre-dose Week 16 troughs was 108.3 mcg/mL (95% CI 72.3-162.3) for PGDM1400LS, 194.4 mcg/mL (95% CI 113.8 – 254.0) for PGT.121.414.LS, and 108.8 mcg/mL (95% CI 68.4-173.1) for VRC07-523LS (Figure 1). The VRC07-523LS and PGDM1400LS trough concentrations were below levels predicted based on adult PK analyses.
Conclusions
IV infusions of VRC07-523LS, PGDM1400LS, and PGT.121.414.LS were well tolerated in children, and the alternating dosing schedule allowed two infusions per monthly visit. In children, steady-state troughs were lower than predicted for VRC07-523LS and PGDM1400LS, and a pre-specified increase to 25mg/kg/dose for these agents was used in the next phase of the study, with ongoing PK monitoring of all three agents.
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