More potent antiretroviral therapy regimens with broadly neutralizing antibodies are likely needed to facilitate early clearance of HIV-1 cells in infants
Presenter: Alka Khaitan, MD, Indiana University School of Medicine, Indianapolis, Indiana
Subcutaneous delivery of the monoclonal antibody VRC01 added to early antiretroviral therapy (ART), although safe and feasible, did not result in superior clearance of HIV-1-infected cells compared with ART alone in a phase I/II study of infants living with HIV-1.
VRC01 is a broadly neutralizing antibody (bNAb) that targets the CD4 binding site on the HIV envelope.
“The rapid formation of a latent viral reservoir is a major barrier to ART-free remission,” said lead investigator Alka Khaitan, MD, associate professor of pediatrics, Indiana University School of Medicine, Indianapolis, Indiana. Early ART decreases viral reservoir size in infants. Broadly neutralizing antibodies have potential to further reduce these reservoirs by directly targeting infected cells and by potential immune mechanisms.
The research team hypothesized that VRC01 combined with early ART in infants may further reduce viral reservoirs in infants.
Infants living with HIV-1 aged 72 hours to ≤ 84 days were eligible. All started ART ≤ 14 days before study entry and were randomized to VRC01 at 40 mg/kg subcutaneously at weeks 0, 2, 6, and 10 in addition to ART or ART alone per their respective country’s standard of care regimen. A total of 61 patients were enrolled from Botswana (n = 7), Brazil (n = 6), Malawi (n = 42), and Zimbabwe (n = 6). The primary endpoint was HIV-1 DNA analysis performed at week 14; 30 patients in each arm completed week 14. All patients in the VRC01 arm received all 4 injections. Plasma viral loads at study entry were a median of 4.1 and 4.4 log10 cp/mL in the VRC01 plus ART and ART alone arms, respectively.
Baseline ART consisted of either a nevirapine or lopinavir/ritonavir regimen. ART resistance was detected in 44% of the VRC01 arm and 33% of the control arm. 77% in the VRC01 arm and 89% in the control arm had baseline nevirapine resistance.
More than 90% of infants had local reactions but all were grade ≤ 2 (mild to moderate). Most resolved within 1 day. Adverse events grade ≥ 3 occurred in 40% of the VRC01 arm and 47% of the control arm. There were no significant differences in rates of anemia, neutropenia, or other adverse events between the two arms.
The target VRC01 plasma concentration was 50 µg/mL at day 28. Although median plasma level was 83 µg/mL, 31% had levels lower than the target concentration. These levels were lower than predicted from prior studies of VRC01 in infants exposed to HIV-1, but no antidrug antibodies were detected.
Of 17 infants with available assay results, 29% had half maximal inhibitory concentration (IC50) ≥ 50 µg/mL, which was defined as VCR01-resistant in the primary analysis.
Median HIV-1 plasma RNA declined over 14 weeks in both study arms, with no apparent difference between arms. Even when separated by VCR01 resistance, no resistance, and unknown resistance, no differences in median HIV-1 plasma RNA were observed between arms over 14 weeks.
In the primary efficacy analysis, there was no significant difference between arms in the decline in HIV-1 DNA levels at weeks 0 and 14.
A post hoc analysis found that higher VRC01 concentrations correlated with larger reductions in HIV-1 DNA levels (Spearman correlation -0.42; P = .03).
“More potent ART regimens with combination bNAbs are likely needed to facilitate early clearance of infected cells in infants….Infants are a special population, and additional studies are needed to define how to optimally dose bNAbs in viremic infants to attain efficacy,” summarized Khaitan.
Disclosure
Dr. Khaitan has no relevant financial relationships to disclose.