Infusion Reactions in Persons Receiving the Broadly Neutralizing Antibody VRC01 or Placebo for Reduction of HIV-1 Acquisition: Results From the Phase 2b Antibody Mediated Prevention (AMP) Randomized Trials

Abstract

Background: The AMP studies (HVTN 703/HPTN 081 and HVTN 704/HPTN 085) are two harmonized Phase 2b randomized controlled trials to assess HIV prevention efficacy and safety of intravenous (IV) infusion of anti-gp120 broadly neutralizing monoclonal antibody (mAb) VRC01. MAbs for other indications elicit significant rates of infusion-related reactions (IRRs), often requiring pre-medication and sometimes limiting their application. We report on IRRs observed in the AMP studies.\xa0 \n \nMethods: From 2016-2018, 2,699 HIV-uninfected, at-risk men and transgender adults in the Americas and Switzerland (704/085) and 1,901 at-risk heterosexual women in sub-Saharan Africa (703/081) were randomized 1:1:1 to VRC01 10 mg/kg, 30 mg/kg, or saline placebo. Participants received infusions every 8 weeks (n=10/participant) over 72 weeks, with 104 weeks of follow-up. Safety assessments were conducted pre- and post-infusion and at non-infusion visits. A total of 40,674 infusions were administered. \n \nFindings: Forty-seven participants (1.7%) experienced 49 IRRs in 704/085; 93 (4.8%) experienced 111 IRRs in 703/081 (p<0.01). IRRs occurred more frequently in VRC01 than placebo recipients in 703/081 (p<0.01) but not in 704/085 (p=0.75). Infusion reactions were associated with atopic history (p=0.01 in 704/085 and p<0.01 in 703/081) and, in 703/081, with younger age at enrolment (p<0.01). Four clinical phenotypes of IRRs were observed: urticaria, dyspnea, dyspnea with rash, and “other”. Urticaria was most prevalent, occurring in 25 (0.9%) participants in 704/085 and 41 (2.1%) participants in 703/081. Most IRRs occurred with the initial infusion and incidence diminished through the last infusion. Six (3.8%) IRRs were graded severe, 76 (47.5%) moderate and 78 (48.8%) mild. All reactions were managed successfully without sequelae. \n \nInterpretation: IRRs in the AMP studies were uncommon, typically mild or moderate, successfully managed at the research clinic, and resolved without sequelae. Laboratory analysis is ongoing to explore the potential mechanisms of these IRRs. \n \nTrial Registration: (NCT02716675) (NCT02568215) \n \nFunding Information: AI068614, AI068635, AI068618, AI068619, AI069412. \n \nDeclaration of Interests: NMM, SE, ST, SK, MJ, MRG, MAA, LN, KM RDLG, LC, CK, PA, MMGL have no COI to declare; SRW has received clinical trial funding from Janssen Vaccines. \n \nEthics Approval Statement: The Institutional Review Boards/Ethic Committees of participating CRSs approved the studies, which were conducted under the oversight of the NIAID Data Safety Monitoring Board (DSMB). All participants gave written informed consent in English or a local language of their preference.