SEARCHRCTinfectious disease, immunology

RCT·infectious disease, immunology, clinical trial, epidemiology, public health·PMC10363420

Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition

eBioMedicine · 45 authors, 23 centres

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TL;DR

This analysis of data from the AMP clinical trials found that higher serum concentrations of the HIV-1 antibody VRC01 were associated with a lower likelihood of acquiring HIV-1 and higher prevention efficacy. The study suggests that antibody concentration may be a useful marker for future dosing regimen design.

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This study analyzed data from the phase 2b Antibody Mediated Prevention (AMP) trials to investigate how the serum concentration of the broadly neutralizing antibody VRC01 relates to the prevention of HIV-1 acquisition. The central findings were that higher VRC01 serum concentrations at the time of exposure were inversely correlated with the likelihood of HIV-1 acquisition and positively correlated with VRC01 prevention efficacy. Body weight was inversely associated with HIV-1 acquisition in both placebo and VRC01 groups but did not modify VRC01's preventive effect. Simulation studies suggested fixed dosing could have comparable efficacy to weight-based dosing. Limitations include uncertainties in estimating the exact time of infection and variability in concentrations. The findings suggest serum concentration may inform dosing strategies for future bnAb trials.

STUDY TYPE

RCT

SPECIALTY

infectious disease

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AI pipeline

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ORIGINAL PAPER

PMC10363420

Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition

eBioMedicine

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ABSTRACT

Summary 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 10.13039/100000002 National Institutes of Health , 10.13039/100000060 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 , 10.13039/100006510 Duke University (AI P30 AI064518) and 10.13039/100007812 University of Washington (P30 AI027757) Centers for AIDS Research ; R37AI054165 from NIAID to the FHCC; and OPP1032144 CA-VIMC 10.13039/100000865 Bill & Melinda Gates Foundation .

CITATION EXPORT

Kelly E. Seaton, Yunda Huang, Shelly Karuna et al.. Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition. eBioMedicine. (2023). https://doi.org/10.1016/j.ebiom.2023.104590

AUTHORS

45 · 23 CENTRES

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

aDuke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA
bVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
cDepartment of Global Health, University of Washington, Seattle, WA, 98195, USA
dDepartments of Microbiology and Medicine, University of Washington, Seattle, WA, 98195, USA
eDivision of Medical Virology, Institute of Infectious Disease & Molecular Medicine, University of Cape Town and National Health Laboratory Service, South Africa
fDepartment of Biostatistics, University of Washington, Seattle, WA, 98195, USA
gThayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USA
hVaccine Research Center, Bethesda, MD, USA
iFamily Health International, Durham, NC, 27710, USA
jVia Libre CRS, Lima, Peru
kDepartment of Medicine, Division of Infectious Disease and Department of Family Medicine in the David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
lPerinatal HIV Research Unit (PHRU), Wits Health Consortium, Soweto, Johannesburg, South Africa
mDesmond Tutu Health Foundation, University of Cape Town (Institute of Infectious Disease and Molecular Medicine, and Department of Medicine), Observatory, 7925, Cape Town, South Africa
nPenn Center for AIDS Research, Infectious Disease Division, University of Pennsylvania, 3400 Civic Center Boulevard Building 421, Philadelphia, PA, 19104, USA
oAsociacion Civil Impacta Salud y Educación, San Miguel Clinical Research Center, Lima, Peru
pDivision of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA
qUniversity of Zimbabwe-University of California San Francisco (UZ-UCSF) Collaborative Research Programme, Harare, Zimbabwe, South Africa
rDepartments of Medicine and Laboratory Medicine, University of Washington, Seattle, WA, 98195, USA
sDivision of Medical Virology, University of Cape Town, Anzio Road, Observatory, 7925, Cape Town, South Africa
tNational Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, 2192, South Africa
uAntibody Immunity Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2000, South Africa
vCentre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, 4041, South Africa
wInstitute of Global Health and Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA