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