Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition
Creators: name: Clark, Jesse
name: Hidalgo, Jose A.
name: Laher, Fatima
name: Hural, John
name: Yates, Nicole L.
name: Brackett, Caroline
name: Weiner, Joshua A.
name: Rudnicki, Erika
name: Sarzotti-Kelsoe, Marcella
name: Gonzales, Pedro
name: deCamp, Allan C.
name: Tomaras, Georgia D.
name: Corey, Lawrence
name: Heptinstall, Jack R.
name: Mascola, John R.
name: Huang, Yunda
name: Angier, Heather
name: Karuna, Shelly
name: Williamson, Carolyn
name: Zhang, Lily
name: Randhawa, April
name: Cohen, Myron S.
name: Juraska, Michal
name: Mullins, James I.
name: Sampson, Mark
name: Seaton, Kelly E.
name: Andrew, Philip
name: McDermott, Adrian B.
name: Rossenkhan, Raabya
name: Ackerman, Margaret E.
name: Montefiori, David
name: Morris, Lynn
name: Kenny, Avi
name: Chiong, Kelvin
name: Giorgi, Elena E.
name: Gilbert, Peter B.
name: Mgodi, Nyaradzo
name: Edupuganti, Srilatha
name: McElrath, M. Julianna
name: Rojas, Michelle
name: Frank, Ian
name: Edlefsen, Paul T.
name: Sawant, Sheetal
name: Zhang, Lu
name: Orrell, Catherine
Publisher: name: Elsevier
Year: 2023

description: <p>BACKGROUND: The phase 2b proof-of-concept Antibody Mediated Prevention (AMP) trials showed that VRC01, an anti-HIV-1 broadly neutralising antibody (bnAb), prevented acquisition of HIV-1 sensitive to VRC01. To inform future study design and dosing regimen selection of candidate bnAbs, we investigated the association of VRC01 serum concentration with HIV-1 acquisition using AMP trial data. METHODS: The case-control sample included 107 VRC01 recipients who acquired HIV-1 and 82 VRC01 recipients who remained without HIV-1 during the study. We measured VRC01 serum concentrations with a qualified pharmacokinetic (PK) Binding Antibody Multiplex Assay. We employed nonlinear mixed effects PK modelling to estimate daily-grid VRC01 concentrations. Cox regression models were used to assess the association of VRC01 concentration at exposure and baseline body weight, with the hazard of HIV-1 acquisition and prevention efficacy as a function of VRC01 concentration. We also compared fixed dosing vs. body weight-based dosing via simulations. FINDINGS: Estimated VRC01 concentrations in VRC01 recipients without HIV-1 were higher than those in VRC01 recipients who acquired HIV-1. Body weight was inversely associated with HIV-1 acquisition among both placebo and VRC01 recipients but did not modify the prevention efficacy of VRC01. VRC01 concentration was inversely correlated with HIV-1 acquisition, and positively correlated with prevention efficacy of VRC01. Simulation studies suggest that fixed dosing may be comparable to weight-based dosing in overall predicted prevention efficacy. INTERPRETATION: These findings suggest that bnAb serum concentration may be a useful marker for dosing regimen selection, and operationally efficient fixed dosing regimens could be considered for future trials of HIV-1 bnAbs. FUNDING: Was provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Center [FHCC]; 2R37 054165 to the FHCC; UM1 AI068618, to HVTN Laboratory Center, FHCC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, Duke University (AI P30 AI064518) and University of Washington (P30 AI027757) Centers for AIDS Research; R37AI054165 from NIAID to the FHCC; and OPP1032144 CA-VIMC Bill &amp; Melinda Gates Foundation.</p>