Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption

Abstract

Background: The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART).

Methods: We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART.

Results: A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 μg per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P=0.04 by a two-sided Fisher's exact test in the A5340 trial; and 80% vs. 13%, P<0.001 by a two-sided Fisher's exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization-resistant virus.

Conclusions: VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326 .).

Figures

Figure 1. Trial Designs

As shown in Panel A, the A5340 trial had two steps. In step 1, participants received an intravenous infusion of VRC01 (at a dose of 40 mg per kilogram of body weight) (triangles) 1 week before and 2 and 5 weeks after discontinuation of antiretroviral therapy (ART). ART was discontinued 1 week after the first VRC01 infusion. The treatment interruption was open-ended, and participants were monitored weekly until viral rebound. On confirmed plasma viral rebound, participants entered step 2 and ART was reinitiated. Participants were then followed until plasma viremia decreased below 50 copies per milliliter. HIV env sequencing (gray circles) was performed with the use of plasma samples obtained before the initiation of ART and after viral rebound. As shown in Panel B, in the National Institutes of Health (NIH) trial, participants received infusions of VRC01 (at a dose of 40 kg per kilogram) (triangles) 3 days before and 14 to 28 days after discontinuation of ART, and monthly thereafter. Infectious viral isolates (orange circles) were generated from samples obtained before VRC01 infusion and after plasma viral rebound. HIV env sequencing (gray circles) was performed with the use of plasma samples obtained before the initiation of ART and after viral rebound.

Figure 2. Plasma Viremia and Levels of VRC01 in Trial Participants after Discontinuation of ART

Panel A shows the plasma viremia of participants in the A5340 trial after the interruption of therapy. The gray dotted line indicates the limit of detection of the assay (HIV RNA level, 20 copies per milliliter). Panel B shows the plasma viremia of NIH trial participants after interruption of therapy. The gray dotted line indicates the limit of detection of the assay (HIV RNA level, 40 copies per milliliter). Panel C shows the Kaplan–Meier curve of plasma viral suppression (

Figure 3. Rebound Virus Clonality and Resistance to VRC01

Panels A through D show maximum likelihood phylogenetic trees of single-genome sequencing–derived env sequences from pre-ART and rebound plasma virus and neutralization titers to VRC01 from four participants. Participants A04, A05, and A03 had early viral rebound despite high levels of VRC01; Participant A07 had delayed rebound with lower plasma VRC01 levels. Black rectangles indicate pre-ART plasma env sequences, and red and orange rectangles indicate the env sequences from the first and second weeks of detectable viremia. The scale bar indicates genetic distance. Fifty percent inhibitory concentration (IC50) neutralization titers are shown to the side of each tree aligned to the specific envelope glycoprotein that was cloned and tested for phenotypic features. Asterisks indicate bootstrap support of greater than 80%. As shown in Panel A, Participant A04 had monoclonal rebound with VRC01-resistant virus. As shown in Panel B, Participant A05 had polyclonal rebound with VRC01-resistant virus. As shown in Panel C, Participant A03 had polyclonal rebound with VRC01-resistant virus. Multiple rebound lineages arise clustered within one area of the phylogeny. Sequences from Participant A03 were tested for clustering; Slatkin–Maddison and Hudson’s “nearest neighbor” tests support sequence compartmentalization (P<0.001 and P = 0.004, respectively). As shown in Panel D, Participant A07 had polyclonal rebound of VRC01-sensitive virus. As shown in Panels E and F, pre-ART and rebound Env pseudotyped virus from the eight participants with available samples were compared for changes in neutralization sensitivity by IC50 (truncated at 25 μg per milliliter) (Panel E) and 80% inhibitory concentration (IC80) (truncated at 50 μg per milliliter) (Panel F) with the use of multilevel random-effects models (random intercept and slope) to account for multiple clones per participant at each time point. A two-sided P value for the estimated difference in pre-ART and rebound resistance was calculated. Mean titers are shown for pre-ART virus on the left and rebound virus on the right.

Figure 4. Characterization of Autologous, Replication-Competent HIV Isolates before and after Infusions of VRC01 and Discontinuation of ART in the NIH Trial

Panel A shows neutralization of preinfusion autologous viral isolates by VRC01 and other monoclonal antibodies. Susceptibility of preinfusion infectious isolates obtained from eight trial participants to neutralization by VRC01 and other broadly neutralizing antibodies (3BNC117, 10–1074, and PGT121) and anti-CD4 antibody (UB-421) is shown. The percent suppression of HIV was calculated with the use of the following formula: (1 − [luciferase activity in the presence of test antibody ÷ luciferase activity in the presence of control antibody IgG]) × 100. Luciferase activity was expressed in relative light units. Gray horizontal bars indicate mean values. P values were computed with the use of a paired permutation test. Panel B shows neutralization of preinfusion and postinfusion viral isolates by VRC01 in seven trial participants from whom infectious isolates could be recovered at both time points. Gray horizontal bars indicate mean values. The P value for each participant was computed with the use of the Wilcoxon–Mann–Whitney test.