Acute HIV-1 infection viremia associate with rebound upon treatment interruption

Abstract

Background: Analytic treatment interruption (ATI) studies evaluate strategies to potentially induce remission in people living with HIV-1 but are often limited in sample size. We combined data from four studies that tested three interventions (vorinostat/hydroxychloroquine/maraviroc before ATI, Ad26/MVA vaccination before ATI, and VRC01 antibody infusion during ATI).

Methods: The statistical validity of combining data from these participants was evaluated. Eleven variables, including HIV-1 viral load at diagnosis, Fiebig stage, and CD4⁺ T cell count were evaluated using pairwise correlations, statistical tests, and Cox survival models.

Findings: Participants had homogeneous demographic and clinical characteristics. Because an antiviral effect was seen in participants who received VRC01 infusion post-ATI, these participants were excluded from the analysis, permitting a pooled analysis of 53 participants. Time to viral rebound was significantly associated with variables measured at the beginning of infection: pre-antiretroviral therapy (ART) viral load (HR = 1.34, p = 0.022), time to viral suppression post-ART initiation (HR = 1.07, p < 0.001), and area under the viral load curve (HR = 1.34, p = 0.026).

Conclusions: We show that higher viral loads in acute HIV-1 infection were associated with faster viral rebound, demonstrating that the initial stage of HIV-1 infection before ART initiation has a strong impact on viral rebound post-ATI years later.

Funding: This work was supported by a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the US Department of the Army (W81XWH-18-2-0040). This research was funded, in part, by the US National Institute of Allergy and Infectious Diseases (AAI20052001) and the I4C Martin Delaney Collaboratory (5UM1AI126603-05).

Keywords: HIV-1 acute infection; HIV-1 cure; Translation to patients; analytic treatment interruption; correlates of HIV-1 rebound.

Figure 1.. Viral Load Area Under the Curve (VL AUC) at HIV-1 diagnosis.

The upper panel (A) is a schematic description of the VL AUC calculations as a function of the Fiebig stage and viral load at HIV-1 diagnosis. Viral load kinetics are figured in blue with a representative curve. Diagnosis is marked with a dotted red line. VL measures obtained following diagnosis are shown in black and serve to calculate the real AUC. The imputed AUC corresponds to the period prior to diagnosis (without VL measurements) and is shaded in grey. The lower panel represents the imputed VL AUC (B), actual VL AUC (C) and total VL AUC (D) calculated for the 67 participants in our study. The total VL AUC used for analysis is the sum of the imputed and actual AUC.

Figure 2.. Participants without intervention, VHM and Ad26/MVA interventions were pooled for correlates analysis with time to rebound measured at HIV-1 RNA ≥1000 copies/mL.

(A) The length of time each participant spent on ART before ART interruption (ATI) is shown on the left and the time to viral rebound on the right. ART duration is in years while time to viral rebound is in days. (B) Time to viral load rebound measured at HIV-1 RNA ≥1000 copies/mL did not differ across interventions with respect to the median (Kruskal-Wallis test) and the variance (Brown-Forsythe test) of the outcome (N = 26, N = 9, N = 18, and N = 13 for the no intervention, VHM, Ad26/MVA and VRC01 groups, respectively). (C) Effect of each intervention against the pooled ‘no intervention’ group tested by Cox regression multivariate model adjusted by Fiebig stage as Fiebig stages differed across interventions (N = 26, N = 9, N = 18, and N = 13 for the no intervention, VHM, Ad26/MVA and VRC01 groups, respectively). Intervention effects were tested using all the participants per study and an adjustment was added to account for potential confounding by Fiebig stages which differed significantly across the studies.

Figure 3.. Multiple correlations among baseline variables at HIV-1 diagnosis.

(A) Spearman correlations between continuous baseline variables are shown for pairwise variables. Significant correlations are shown in red (positive) or blue (negative) (N = 53). (B - E) Comparison of baseline variables by Fiebig stage (N = 9, N = 12, N = 23 and N = 7 for FI, FII, FIII and FIV, respectively). Tested variables were viral load (VL) at HIV-1 diagnosis, VL AUC, pre-ART CD8 cell counts and pre-ART CD4/CD8 T cell ratio. The total VL AUC used for analysis is the sum of the imputed and actual AUC. Kruskal-Wallis test was used to compare across all Fiebig stages and Mann Whitney U test was used to compare each Fiebig stage to Fiebig stage I (marked with asterisks).

Figure 4.. Time to rebound did not differ across Fiebig stages.

Kaplan-Meier survival curves for Fiebig stage compared the time to viral rebound of Fiebig stages I to IV for (A) HIV-1 RNA ≥1000 copies/mL and (B) HIV-1 RNA ≥20 copies/mL. Kruskal-Wallis test was used to compare across all Fiebig stages and Mann Whitney U test (represented with asterisks) used to compare each Fiebig stage to Fiebig stage I for time to rebound at (C) HIV-1 RNA ≥1000 copies/mL and (D) HIV-1 RNA ≥20 copies/mL. (N = 9, N = 12, N = 23 and N = 7 for FI, FII, FIII and FIV, respectively).

Figure 5.. Viral load variables at diagnosis impacted time to viral rebound (HIV-1 RNA ≥1000 copies/mL).

Cox regression univariate models show the impact of clinical variables measured at HIV-1 diagnosis (A) or prior to the ATI (B) on the time to viral rebound (N = 53). (C-F) Kaplan-Meier survival curves for the baseline variables associated with time to rebound selected through Cox regression model for (C) viral load at diagnosis, (D) pre-ART CD4, (E) total viral load AUC and (F) weeks to viral suppression. Categories were divided using maximally selected rank statistics (N = 26, N = 9 and N = 18 for the no intervention, VHM and Ad26/MVA groups, respectively).

Figure 6.. Sensitivity analysis of the Cox regression results to the treatment interventions.

Results are shown for time to rebound at HIV-1 RNA ≥1000 copies/mL. The sensitivity of the correlates is evaluated by removing each treatment at a time or simultaneously to test if the model remains significant.