A. Khaitan * (1), J. Lindsey (2), E. Capparelli (3), C. Tierney (2), A. Coletti (4), C. Perlowski (4), M. Cotton (5), D. Yin (6), S. Majji (7), J. Moye (7), H. Spiegel (6), P. Harding (8), D. Costello (9), C. Krotje (10), L. Gama (11), D. Persaud (12), E. McFarland (8), IMPAACT 2008 Protocol Team (1) Indiana University School of Medicine, Pediatric Infectious Diseases, Indianapolis, United States, (2) Harvard TH Chan School of Public Health, Center for Biostatistics in AIDS Research, Boston, United States, (3) University of California San Diego, Pediatric Host-Microbe Systems and Therapeutics, San Diego, United States, (4) IMPAACT Operations Center, Durham, United States, (5) FAMCRU, Stellenbosch University, Department Paediatrics and Child Health, Cape Town, South Africa, (6) National Institutes of Health, Division of Aids, Rockville, United States, (7) National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, United States, (8) University of Colorado School of Medicine, Pediatric Infectious Diseases, Aurora, United States, (9) University of California at Los Angeles, MacDonald Research Laboratory, Los Angeles, United States, (10) Frontier Science & Technology Research Foundation, Amherst, United States, (11) National Institutes of Health, National Institute of Allergy and Infectious Diseases, Vaccine Research Center, Bethesda, United States, (12) John Hopkins University, Department of Pediatric Infectious Diseases, Baltimore, United States
BACKGROUND: VRC01 is a broadly neutralizing antibody (bNAb) targeting CD4 binding sites with demonstrated anti-HIV-1 activity in adults. Safety and efficacy in infants living with HIV-1 are unknown.
METHODS: Infants, age <12 weeks initiating antiretroviral therapy (ART), were randomized to four doses (Weeks 0, 2, 6, 10) of open-label, subcutaneous VRC01 (VRC01) at 40mg/kg or no VRC01 (No'VRC01). Follow-up was 48 weeks, with primary safety and efficacy outcomes assessed at Week 14. Laboratory testing included VRC01 plasma troughs, droplet digital PCR for HIV-1 DNA and Genosure® MG and PhenoSense® Neutralization assays for ART and VRC01 resistance.
RESULTS: Infants enrolled (30 to VRC01; 31 to No-VRC01) between April 2019-March 2020 in Malawi, Botswana, Zimbabwe, and Brazil; 84% Black non-Hispanic, 57% female. Baseline characteristics were (VRC01 vs No-VRC01): median age (72 vs 73 days), log10 plasma HIV-1 RNA (4.10 vs 4.35 copies/mL), and log10cellular HIV-1 DNA (3.12 vs 3.16 copies/million PBMCs). Initial ART included nevirapine (53% of VRC01; 29% of No-VRC01) or lopinavir/ritonavir. Baseline ART resistance was detected in 44% (VRC01) and 33% (No-VRC01) of infants, mostly NNRTI. Baseline resistance to VRC01 (IC50 >50mcg/mL) was detected in 5/17 (29%) infants receiving VRC01. All VRC01 doses were administered. Local injection reactions (all Grade ≤2) occurred in '¥90% of infants. Adverse events Grade >3 (none attributed to VRC01) through Week 14 occurred in 40% of VRC01 (95% CI:23%, 59%) and 47% of No-VRC01 (95% CI:28%, 66%), and most were anemia, neutropenia and gastrointestinal disorders. Median (Q1, Q3) VRC01 plasma trough was 83.1 (36.1, 111.8) mcg/mL, however 31% were <50mcg/mL. No VRC01 anti-drug antibodies were detected. HIV'1 DNA log10 copies/million PBMCs median (Q1, Q3) declines from Week 0-14 were 0.41 (0.30, 0.56) in VRC01 and 0.53 (0.33, 0.70) in No'VRC01 (Wilcoxon p=0.42).
CONCLUSIONS: Subcutaneous VRC01 was feasible and no safety concerns were observed in this first treatment study in infants living with HIV-1. HIV-1 DNA declines did not differ by treatment arm, however ART and VRC01 resistance and VRC01 troughs <50 mcg/mL may have lessened VRC01 effectiveness. Further studies are needed to determine optimal approaches with more potent bNAbs for early treatment of perinatal HIV infection.