Simbarashe Takuva1,2,3, Shelly T Karuna1, Michal Juraska1, Erika Rudnicki1, Srilatha Edupuganti4, Maija Anderson1, Robert De La Grecca1, Martin R Gaudinski5, Alice Sehurutshi6, Catherine Orrell7, Logashvari Naidoo8, Javier Valencia9, Larissa M Villela10, Stephen R Walsh11, Philip Andrew12, Carissa Karg1, April Randhawa1, John Hural1, Margarita M Gomez Lorenzo13, David N Burns13, Julie Ledgerwood5, John R Mascola5, Myron Cohen14, Lawrence Corey1, Kathy Mngadi15, Nyaradzo M Mgodi16. 1. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA. 2. Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. 3. School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa. 4. Division of Infectious Disease, Department of Medicine, Emory University, Atlanta, GA. 5. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. 6. Botswana Harvard AIDS Institute, Gaborone, Botswana, South Africa. 7. Department of Medicine, Desmond Tutu HIV Center, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. 8. South African Medical Research Council, Durban, South Africa. 9. Asociacion Civil Impacta Salud y Educacion, Lima, Peru. 10. Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz (INI-Fiocruz), Rio de Janeiro, Brazil. 11. Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA. 12. Family Health International, Durham, NC. 13. Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. 14. Department of Medicine, University of North Carolina, Chapel Hill, NC. 15. Aurum Institute, Johannesburg, South Africa; and. 16. University of Zimbabwe Clinical Trials Research Center, Harare, Zimbabwe.
Abstract
BACKGROUND: The antibody-mediated prevention (AMP) studies (HVTN 703/HPTN 081 and HVTN 704/HPTN 085) are harmonized phase 2b trials to assess HIV prevention efficacy and safety of intravenous infusion of anti-gp120 broadly neutralizing antibody VRC01. Antibodies for other indications can elicit infusion-related reactions (IRRs), often requiring premedication and limiting their application. We report on AMP study IRRs. METHODS: From 2016 to 2018, 2699 HIV-uninfected, at-risk men and transgender adults in the Americas and Switzerland (704/085) and 1924 at-risk heterosexual women in sub-Saharan Africa (703/081) were randomized 1:1:1 to VRC01 10 mg/kg, 30 mg/kg, or placebo. Participants received infusions every 8 weeks (n = 10/participant) over 72 weeks, with 104 weeks of follow-up. Safety assessments were conducted before and after infusion and at noninfusion visits. A total of 40,674 infusions were administered. RESULTS: Forty-seven participants (1.7%) experienced 49 IRRs in 704/085; 93 (4.8%) experienced 111 IRRs in 703/081 (P < 0.001). IRRs occurred more frequently in VRC01 than placebo recipients in 703/081 (P < 0.001). IRRs were associated with atopic history (P = 0.046) and with younger age (P = 0.023) in 703/081. 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. All reactions were managed successfully without sequelae. CONCLUSIONS: IRRs in the AMP studies were uncommon, typically mild or moderate, successfully managed at the research clinic, and resolved without sequelae. Analysis is ongoing to explore potential IRR mechanisms.
BACKGROUND: The antibody-mediated prevention (AMP) studies (HVTN 703/HPTN 081 and HVTN 704/HPTN 085) are harmonized phase 2b trials to assess HIV prevention efficacy and safety of intravenous infusion of anti-gp120 broadly neutralizing antibody VRC01. Antibodies for other indications can elicit infusion-related reactions (IRRs), often requiring premedication and limiting their application. We report on AMP study IRRs. METHODS: From 2016 to 2018, 2699 HIV-uninfected, at-risk men and transgender adults in the Americas and Switzerland (704/085) and 1924 at-risk heterosexual women in sub-Saharan Africa (703/081) were randomized 1:1:1 to VRC01 10 mg/kg, 30 mg/kg, or placebo. Participants received infusions every 8 weeks (n = 10/participant) over 72 weeks, with 104 weeks of follow-up. Safety assessments were conducted before and after infusion and at noninfusion visits. A total of 40,674 infusions were administered. RESULTS: Forty-seven participants (1.7%) experienced 49 IRRs in 704/085; 93 (4.8%) experienced 111 IRRs in 703/081 (P < 0.001). IRRs occurred more frequently in VRC01 than placebo recipients in 703/081 (P < 0.001). IRRs were associated with atopic history (P = 0.046) and with younger age (P = 0.023) in 703/081. 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. All reactions were managed successfully without sequelae. CONCLUSIONS: IRRs in the AMP studies were uncommon, typically mild or moderate, successfully managed at the research clinic, and resolved without sequelae. Analysis is ongoing to explore potential IRR mechanisms.
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