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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.

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.

SUBMITTER: Riddler SA

PROVIDER: S-EPMC6195652 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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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.

Riddler Sharon A SA Zheng Lu L Durand Christine M CM Ritz Justin J Koup Richard A RA Ledgerwood Julie J Bailer Robert T RT Koletar Susan L SL Eron Joseph J JJ Keefer Michael C MC Macatangay Bernard J C BJC Cyktor Joshua C JC Mellors John W JW

Open forum infectious diseases 20181020 10

<h4>Background</h4>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.<h4>Methods</h4>A5342 was a phase 1, randomized, double-blind, placebo-controlled, parallel-arm study. Participants on effective antiretroviral therapy (ART) were randomized to receive 2 infusion ...[more]

PMID: 30364428

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Project description:IntroductionThe last 12 years have seen remarkable progress in the isolation and characterization of at least five different epitope classes of HIV-specific broadly neutralizing antibodies (bnAbs). Detailed analyses of these bnAb lineages, maturation pathways and epitopes have created new opportunities for vaccine development. In addition, interest exists in passive administration of monoclonal antibodies as a viable option for HIV prevention.DiscussionRecently, two antibody-mediated prevention (AMP) trials of a passively administered monoclonal antibody targeting the HIV envelope CD4 binding site, called VRC01, provided proof-of-concept that monoclonal antibody infusion could offer protection against HIV acquisition. While the trials failed to show overall protection against HIV acquisition, sub-analyses revealed that VRC01 infusion provided a 75% prevention efficacy against HIV strains that were susceptible to the antibody. The study also demonstrated that in vitro neutralizing activity, measured by the TZM-bl/pseudovirus assay, was able to predict HIV prevention efficacy in humans. In addition, the AMP trials defined a threshold protective concentration, or neutralization titer, for the VRC01 class of bnAbs, explaining the observed low overall efficacy and serving as a benchmark for the clinical testing of new bnAbs, bnAb cocktails and neutralizing antibody-inducing vaccines. Newer bnAbs that exhibit greater potency and breadth of neutralization in vitro than VRC01 are available for clinical testing. Combinations of best-in-class bnAbs with complementary magnitude, breadth and extent of complete neutralization are predicted to far exceed the prevention efficacy of VRC01. Some engineered bi- and trispecific mAbs exhibit similar desirable neutralizing activity and afford advantages for manufacturing and delivery. Modifications that prolong the serum half-life and improve genital tissue persistence offer additional advantages.ConclusionsIterative phase 1 trials are acquiring safety and pharmacokinetic data on dual and triple bnAbs and bi- and trispecific antibodies in preparation for future AMP studies that seek to translate findings from the VRC01 efficacy trials and achieve acceptable levels of overall prevention efficacy.

Dataset Information

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.

Publications

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.

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