Phase I/II study of monoclonal antibody VRC01 with early antiretroviral therapy to promote clearance of HIV-1 infected cells in infants (IMPAACT 2008)


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.