A randomized controlled safety/efficacy trial of therapeutic vaccination in HIV-infected individuals who initiated antiretroviral therapy early in infection

Abstract

Despite substantial clinical benefits, complete eradication of HIV has not been possible using antiretroviral therapy (ART) alone. Strategies that can either eliminate persistent viral reservoirs or boost host immunity to prevent rebound of virus from these reservoirs after discontinuation of ART are needed; one possibility is therapeutic vaccination. We report the results of a randomized, placebo-controlled trial of a therapeutic vaccine regimen in patients in whom ART was initiated during the early stage of HIV infection and whose immune system was anticipated to be relatively intact. The objectives of our study were to determine whether the vaccine was safe and could induce an immune response that would maintain suppression of plasma viremia after discontinuation of ART. Vaccinations were well tolerated with no serious adverse events but produced only modest augmentation of existing HIV-specific CD4⁺ T cell responses, with little augmentation of CD8⁺ T cell responses. Compared with placebo, the vaccination regimen had no significant effect on the kinetics or magnitude of viral rebound after interruption of ART and no impact on the size of the HIV reservoir in the CD4⁺ T cell compartment. Notably, 26% of subjects in the placebo arm exhibited sustained suppression of viremia (<400 copies/ml) after treatment interruption, a rate of spontaneous suppression higher than previously reported. Our findings regarding the degree and kinetics of plasma viral rebound after ART interruption have potentially important implications for the design of future trials testing interventions aimed at achieving ART-free control of HIV infection.

Fig. 1.. Trial design.

(A) Consolidated Standards of Reporting Trials (CONSORT) flow diagram for the trial. CONSORT diagram delineates the study enrollment of 31 subjects who underwent randomization to the placebo or vaccine groups. (B) Schematics of study design. Blue arrows indicate time of HIV pDNA/IL-12 or placebo administration. Red arrows indicate time of HIV rVSVgag or placebo administration.

Fig. 2.. Effect of therapeutic vaccination on immunologic and virologic parameters

(A) Levels of longitudinal plasma viremia of the study participants in the vaccine (n=14) and placebo (n=15) groups during the ATI phase are shown. (B) Levels of plasma viremia in the vaccine and placebo groups were compared using the Wilcoxon rank-sum test at the end of treatment interruption periods to determine the anti-viral efficacy of the therapeutic vaccine regimen. Gray horizontal bars indicate geometric mean values. The limit of detection of plasma viremia (gray dotted line) was 40 copies/ml of HIV RNA. (C) Proportion of subjects remaining off ART during the 16-week treatment interruption phase of the study. The horizontal axis gives the time in days since stopping ART. One subject in the placebo group broke protocol and prematurely re-started ART prior to day 112 (the end of the treatment interruption phase); data for this subject were censored at day 72. P value calculated by exact log rank. Also shown are Kaplan-Meier analysis of suppression of plasma viremia following cessation of ART. Duration of plasma viremia under 40 and 400 copies of HIV RNA/ml following discontinuation of ART was compared between the groups, respectively. (D) Proportions of visits with plasma viremia <400 copies/ml. Per-subject proportions of study visits with plasma viremia <400 copies/ml following discontinuation of ART were compared between the vaccine and placebo groups using the Wilcoxon rank-sum test. (E) CD4⁺ T cell counts of study subjects prior to (baseline), at the end of the treatment interruption phase (ATI), and at the end of study (EOS). Vaccine and placebo arms were compared using a mixed model after log transformation of CD4⁺ T cell counts. Fixed effects included arm, time (treated as categorical), and arm by time interaction. The p-value was based on the arm by time interaction.

Fig. 3.. Relationship between therapeutic vaccination, timing of plasma viral rebound, and outcome of treatment interruption with HIV reservoirs.

(A) Effect of therapeutic vaccination on HIV reservoirs. Levels of HIV DNA, cell-associated HIV RNA, and replication-competent virus in the CD4⁺ T cells of study subjects in the vaccine and placebo groups were determined during the vaccination period prior to discontinuation of ART. Vaccine and placebo arms were compared using a mixed model with the same fixed effects as in Figure 2E. (B) Relationship between the size of HIV reservoirs and timing of plasma viral rebound following cessation of ART. The impact of the size of HIV reservoirs (HIV DNA, cell-associated HIV RNA, and replication-competent virus in CD4⁺ T cells) on the timing of plasma viral rebound >40 copies/ml following discontinuation of ART was examined in all study participants as a whole using the Spearman rank correlation coefficient. (C) Relationship between the size of HIV reservoirs and levels of plasma viremia following discontinuation of ART. The effect of the size of HIV reservoirs (HIV DNA, cell-associated HIV RNA, and replication-competent virus in CD4⁺ T cells) on the capacity and the level of control of plasma viremia at the end of treatment interruption periods was examined in all study participants as a whole using the Spearman rank correlation coefficient..