Safety and efficacy of VRC01 broadly neutralising antibodies in adults with acutely treated HIV (RV397): a phase 2, randomised, double-blind, placebo-controlled trial

Abstract

Background: HIV-1-specific broadly neutralising antibodies such as VRC01 could promote HIV remission by halting viral replication and clearing infected cells. We investigated whether VRC01 could promote sustained viral control off antiretroviral therapy (ART) in adults who initiated ART during acute HIV infection.

Methods: We did a randomised, double-blind, placebo-controlled trial at the Thai Red Cross AIDS Research Centre in Bangkok, Thailand. Eligible participants were aged 20-50 years, had initiated ART during acute infection (ie, Fiebig stages I-III), had been taking ART for more than 24 months, had fewer than 50 HIV-1 RNA copies per mL on three consecutive measurements, had more than 400 CD4 cells per μL, had fewer than ten copies of integrated HIV-1 DNA per 106 peripheral blood mononuclear cells, and were in generally good health. Eligible participants were randomly assigned (3:1) based on computer-generated lists with a blocking factor of 4 to receive VRC01 (40 mg/kg) or placebo (saline) intravenously every 3 weeks for up to 24 weeks during analytic interruption of ART, followed by continued observation off all therapies. Randomisation was stratified by Fiebig stage (I vs II vs III) at HIV diagnosis. Participants were monitored closely and resumed ART if 1000 or more HIV-1 RNA copies were detected per mL of plasma. The primary outcomes were the frequency of serious adverse events and the proportion of participants with fewer than 50 HIV-1 RNA copies per mL 24 weeks after treatment interruption. Efficacy analyses included all participants who received at least one full dose of study product, and safety analyses included all participants exposed to any study product. The trial was registered with ClinicalTrials.gov, number NCT02664415. This trial is completed.

Findings: Between Aug 8, 2016, and Jan 9, 2017, 19 men were randomly assigned, 14 to the VRC01 group and five to the placebo group. One participant in the VRC01 group received a partial infusion without undergoing treatment interruption. The other 18 participants all received at least one full study infusion and underwent ART interruption. No serious adverse events were reported in either group. Only one participant in the VRC01 group achieved the primary efficacy endpoint of viral suppression 24 weeks after ART interruption. The other 17 restarted ART because of a confirmed recording of 1000 or more HIV-1 RNA copies per mL before 24 weeks.

Interpretation: VRC01 monotherapy in individuals who initiated ART during acute HIV infection was well tolerated but did not significantly increase the number of participants with viral suppression 24 weeks after ART interruption. Further development of VRC01 and other immunotherapies for HIV will probably occur as part of combination regimens that include several treatments directed against unique therapeutic targets.

Funding: US Department of the Army, US National Institutes of Health, and the Thai Red Cross AIDS Research Centre.

Conflict of interest statement

DECLARATION OF INTERESTS

Trevor Crowell has received a speaker fee from Gilead Sciences. Nicolas Chomont has served on the scientific advisory board of Theravectys. Jintanat Ananworanich has participated in advisory meetings for ViiV Healthcare, Merck, AbbVie, Gilead, and Roche. The remaining authors report no relevant conflicts of interest.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Figures

Figure 1.. CONSORT Flow Diagram

This diagram displays the progression of participants through screening, enrollment, allocation, and follow-up in the RV397 parallel, randomised clinical trial of VRC01 40 mg/kg or placebo administered intravenously to participants who initiated antiretroviral therapy during acute HIV infection, using the standard recommended by the CONSORT Group. The study had a target enrollment of 24 participants, but enrollment was halted early because changes in VRC01 packaging and stability testing procedures introduced barriers to the importation of study product into Thailand. Twenty-three participants were enrolled, four were withdrawn prior to randomization because of the unavailability of study product in-country, and 19 were randomised with five assigned to the placebo arm and 14 to VRC01. One participant in the VRC01 arm experienced severe generalised urticaria during the first study infusion and did not complete the infusion or undergo treatment interruption. This participant was included in analyses of safety data but no other analyses. Eighteen participants completed at least one study product infusion, underwent treatment interruption, and were included in all analyses.

Figure 2.. Plasma HIV-1 RNA after Treatment Interruption and ART Resumption

Plasma HIV-1 RNA for placebo (red) and VRC01 (black) recipients shows viral rebound by week 24 in all except one VRC01 recipient (panel A). Time to HIV-1 RNA ≥20 copies per mL did not reach the threshold for statistical significance comparing VRC01 to placebo recipients (panel B). Time to HIV-1 RNA ≥1000 copies per mL, the threshold for ART resumption, was significantly delayed in VRC01 compared to placebo recipients (panel C). After ART resumption, there was no difference in the time to achieving viral suppression <20 copies/mL between VRC01 and placebo recipients (panel D). All participants achieved undetectable HIV-1 RNA within 5 weeks (panel E).

Figure 3.. Serum VRC01 Concentrations

Serum VRC01 concentrations are plotted longitudinally for all participants (panel A) and participant 3499 (panel B). In all VRC01 recipients, the target trough of 50 μg per mL was exceeded throughout the dosing interval. No VRC01 was detected in the serum of placebo recipients. The timing of each study infusion is indicated by arrows and the timing of ART resumption is indicated by a vertical dashed line.

Figure 4.. Total and Integrated HIV DNA

The frequencies of CD4+ T-cells that harbor total (panel A) and integrated (panel B) HIV-1 DNA remained low in both the placebo (red) and VRC01 (black) arms throughout the period before, during, and after treatment interruption. Median values for the total and integrated HIV-1 DNA measurements for each arm and at each time point are reported below the x-axis. Viral rebound was associated with a small, transient increase in total and integrated HIV-1 DNA in the placebo group at the time of ART resmnption with a return at six months after ART resmnption to levels observed before analytic treatment interruption. There were no significant differences in total or integrated HIV-1 DNA between placebo and VRC01 recipients at any of the time points tested (all p>0⋅05). There was no statistically significant correlation (p<0⋅05) between total HIV-1 DNA (panel C) or integrated HIV-1 DNA (panel D) and time to HIV-1 RNA ≥20 copies per mL. Correlation analyses were repeated with only VRC01 recipients (r and p in parentheses).