Randomized Clinical Trial to Assess the Impact of the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01 on HIV-1 Persistence in Individuals on Effective ART

Sharon A Riddler, Lu Zheng, Christine M Durand, Justin Ritz, Richard A Koup, Julie Ledgerwood, Robert T Bailer, Susan L Koletar, Joseph J Eron, Michael C Keefer, Bernard J C Macatangay, Joshua C Cyktor, John W Mellors, AIDS Clinical Trials Group A5342 Protocol Team, Mark Hite, Jan Clark, David Currin, Mandy Tipton, Renee Weinman, Sara Onesi, Christine Hurley, Catherine A Bunce, Sheryl Storey, Shelia Dunaway, Nina Lambert, Baiba Berzins, Joan Gottesman, Michael Leonard, Graham Ray, Pat Kittelson, Connie Benson, Leticia Muttera, Teri Flynn, Amy Sbrolla, Ilene Wiggins, Jamilla Howard, Roberto C Arduino, Aristoteles E Villamil, Lisa Kessels, Teresa Spitz, Danielle Campbell, Mwenda Kudumu, Thucuma Sise, Apsara Nair, Jenifer Baer, Kim Epperson, Alan Perelson, Cheryl Jennings, Randall Tressler, Ed Acosta, Joseph Casazza, Alex Benns, Sharon A Riddler, Lu Zheng, Christine M Durand, Justin Ritz, Richard A Koup, Julie Ledgerwood, Robert T Bailer, Susan L Koletar, Joseph J Eron, Michael C Keefer, Bernard J C Macatangay, Joshua C Cyktor, John W Mellors, AIDS Clinical Trials Group A5342 Protocol Team, Mark Hite, Jan Clark, David Currin, Mandy Tipton, Renee Weinman, Sara Onesi, Christine Hurley, Catherine A Bunce, Sheryl Storey, Shelia Dunaway, Nina Lambert, Baiba Berzins, Joan Gottesman, Michael Leonard, Graham Ray, Pat Kittelson, Connie Benson, Leticia Muttera, Teri Flynn, Amy Sbrolla, Ilene Wiggins, Jamilla Howard, Roberto C Arduino, Aristoteles E Villamil, Lisa Kessels, Teresa Spitz, Danielle Campbell, Mwenda Kudumu, Thucuma Sise, Apsara Nair, Jenifer Baer, Kim Epperson, Alan Perelson, Cheryl Jennings, Randall Tressler, Ed Acosta, Joseph Casazza, Alex Benns

Abstract

Background: Broadly neutralizing monoclonal antibodies (bnMAbs) may promote clearance of HIV-1-expressing cells through antibody-dependent cell-mediated cytotoxicity. We evaluated the effect of the CD4-binding site bnMAb, VRC01, on measures of HIV-1 persistence in chronically infected individuals.

Methods: A5342 was a phase 1, randomized, double-blind, placebo-controlled, parallel-arm study. Participants on effective antiretroviral therapy (ART) were randomized to receive 2 infusions of VRC01 (40 mg/kg) at entry and week 3, and 2 infusions of placebo (saline) at weeks 6 and 9; or 2 infusions of placebo at entry and week 3, and 2 infusions of VRC01 at weeks 6 and 9.

Results: Infusion of VRC01 was safe and well tolerated. The median fold-change in the cell-associated HIV-1 RNA/DNA ratio from baseline to week 6 was 1.12 and 0.83 for the VRC01 and placebo arms, respectively, with no significant difference between arms (P = .16). There were no significant differences in the proportions with residual plasma viremia ≥1 copies/mL or in phorbol 12-myristate 13-acetate/ionomycin-induced virus production from CD4+ T cells between arms (both P > .05).

Conclusions: In individuals with chronic HIV-1 infection on ART, VRC01 infusions were safe and well tolerated but did not affect plasma viremia, cellular HIV-1 RNA/DNA levels, or stimulated virus production from CD4+ T cells.

Clinicaltrialsgov identifier: NCT02411539.

Keywords: HIV-1 cure; HIV-1 persistence; VRC01; bnMAb; clinical trial.

Figures

Figure 1.
Figure 1.
Study design.
Figure 2.
Figure 2.
Consolidated Standards of Reporting Trials (CONSORT) diagram.

References

    1. Chun TW, Fauci AS. Latent reservoirs of HIV: obstacles to the eradication of virus. Proc Natl Acad Sci U S A 1999; 96:10958–61.
    1. Finzi D, Blankson J, Siliciano JD, et al. . Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 1999; 5:512–7.
    1. Besson GJ, Lalama CM, Bosch RJ, et al. . HIV-1 DNA decay dynamics in blood during more than a decade of suppressive antiretroviral therapy. Clin Infect Dis 2014; 59:1312–21.
    1. Ferrari G, Pollara J, Kozink D, et al. . An HIV-1 gp120 envelope human monoclonal antibody that recognizes a C1 conformational epitope mediates potent antibody-dependent cellular cytotoxicity (ADCC) activity and defines a common ADCC epitope in human HIV-1 serum. J Virol 2011; 85:7029–36.
    1. Margolis DM, Koup RA, Ferrari G. HIV antibodies for treatment of HIV infection. Immunol Rev 2017; 275:313–23.
    1. Stephenson KE, Barouch DH. Broadly neutralizing antibodies for HIV eradication. Curr HIV/AIDS Rep 2016; 13:31–7.
    1. Morris L, Mkhize NN. Prospects for passive immunity to prevent HIV infection. PLoS Med 2017; 14:e1002436.
    1. Barouch DH, Whitney JB, Moldt B, et al. . Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 2013; 503:224–8.
    1. Shingai M, Nishimura Y, Klein F, et al. . Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature 2013; 503:277–80.
    1. Bruel T, Guivel-Benhassine F, Amraoui S, et al. . Elimination of HIV-1-infected cells by broadly neutralizing antibodies. Nat Commun 2016; 7:10844.
    1. Bar KJ, Sneller MC, Harrison LJ, et al. . Effect of HIV antibody VRC01 on viral rebound after treatment interruption. N Engl J Med 2016; 375:2037–50.
    1. Caskey M, Klein F, Lorenzi JC, et al. . Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 2015; 522:487–91.
    1. Ledgerwood JE, Coates EE, Yamshchikov G, et al. ; VRC 602 Study Team Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin Exp Immunol 2015; 182:289–301.
    1. Lynch RM, Boritz E, Coates EE, et al. . Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci Transl Med 2015; 7:319ra206.
    1. Schoofs T, Klein F, Braunschweig M, et al. . HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1. Science 2016; 352:997–1001.
    1. Caskey M, Schoofs T, Gruell H, et al. . Antibody 10-1074 suppresses viremia in HIV-1-infected individuals. Nat Med 2017; 23:185–91.
    1. Scheid JF, Horwitz JA, Bar-On Y, et al. . HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature 2016; 535:556–60.
    1. Crowell TA, Colby DJ, Pinyakorn S, et al. ; RV397 and RV254/SEARCH010 Study Groups HIV-specific broadly-neutralizing monoclonal antibody, VRC01, minimally impacts time to viral rebound following treatment interruption in virologically-suppressed, HIV-infected participants who initiated antiretroviral therapy during acute HIV infection. Paper presented at: International AIDS Society Conference on HIV Science; July 23–26, 2017; Paris, France.
    1. Cillo AR, Vagratian D, Bedison MA, et al. . Improved single-copy assays for quantification of persistent HIV-1 viremia in patients on suppressive antiretroviral therapy. J Clin Microbiol 2014; 52:3944–51.
    1. Hong F, Aga E, Cillo AR, et al. . Novel assays for measurement of total cell-associated HIV-1 DNA and RNA. J Clin Microbiol 2016; 54:902–11.
    1. Cillo AR, Hong F, Tsai A, et al. . Blood biomarkers of expressed and inducible HIV-1. AIDS 2018; 32:699–708.
    1. Gaudinski MR, Coates EE, Houser KV, et al. ; VRC 606 Study Team Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: a phase 1 open-label clinical trial in healthy adults. PLoS Med 2018; 15:e1002493.
    1. Gilbert PB, Juraska M, deCamp AC, et al. . Basis and statistical design of the passive HIV-1 antibody mediated prevention (AMP) test-of-concept efficacy trials. Stat Commun Infect Dis. In press.
    1. Van Zyl GU, Katusiime MG, Wiegand A, et al. . No evidence of HIV replication in children on antiretroviral therapy. J Clin Invest 2017; 127:3827–34.
    1. Wiegand A, Spindler J, Hong FF, et al. . Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART. Proc Natl Acad Sci U S A 2017; 114:E3659–68.
    1. Gandhi RT, Coombs RW, Chan ES, et al. . No effect of raltegravir intensification on viral replication markers in the blood of HIV-1-infected patients receiving antiretroviral therapy. J Acquir Immune Defic Syndr 2012; 59:229–35.
    1. McMahon D, Jones J, Wiegand A, et al. . Short-course raltegravir intensification does not reduce persistent low-level viremia in patients with HIV-1 suppression during receipt of combination antiretroviral therapy. Clin Infect Dis 2010; 50:912–9.
    1. Dinoso JB, Kim SY, Wiegand AM, et al. . Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A 2009; 106:9403–8.
    1. Llibre JM, Buzón MJ, Massanella M, et al. . Treatment intensification with raltegravir in subjects with sustained HIV-1 viraemia suppression: a randomized 48-week study. Antivir Ther 2012; 17:355–64.
    1. Buzón MJ, Massanella M, Llibre JM, et al. . HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med 2010; 16:460–5.
    1. Cillo AR, Hilldorfer BB, Lalama CM, et al. . Virologic and immunologic effects of adding maraviroc to suppressive antiretroviral therapy in individuals with suboptimal CD4+ T-cell recovery. AIDS 2015; 29:2121–9.
    1. Walker LM, Huber M, Doores KJ, et al. ; Protocol G Principal Investigators Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 2011; 477:466–70.
    1. Wu X, Yang ZY, Li Y, et al. . Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 2010; 329:856–61.
    1. Lu CL, Murakowski DK, Bournazos S, et al. . Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Science 2016; 352:1001–4.
    1. Cohen YZ, Lorenzi JCC, Krassnig L, et al. . Relationship between latent and rebound viruses in a clinical trial of anti-HIV-1 antibody 3BNC117. J Exp Med 2018; 215:2311–24.
    1. Mujib S, Liu J, Rahman A, et al. . Comprehensive cross-clade characterization of antibody-mediated recognition, complement-mediated lysis, and cell-mediated cytotoxicity of HIV-1 envelope-specific antibodies toward eradication of the HIV-1 reservoir. J Virol. In press.
    1. Musick A, Spindler J, Keele B, et al. . A small fraction of proviruses in expanded clones express unspliced HIV RNA in vivo. Paper presented at: Conference on Retroviruses and Opportunistic Infections; February 13–16, 2017; Boston, MA.
    1. Bird C, Burke J, Gleeson PA, McCluskey J. Expression of human immunodeficiency virus 1 (HIV-1) envelope gene products transcribed from a heterologous promoter. Kinetics of HIV-1 envelope processing in transfected cells. J Biol Chem 1990; 265:19151–7.
    1. Gama L, Koup RA. New-generation high-potency and designer antibodies: role in HIV-1 treatment. Annu Rev Med 2018; 69:409–19.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe