The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption

Abstract

Objectives: Therapies to achieve sustained antiretroviral therapy-free HIV remission will require validation in analytic treatment interruption (ATI) trials. Identifying biomarkers that predict time to viral rebound could accelerate the development of such therapeutics.

Design: A pooled analysis of participants from six AIDS Clinical Trials Group ATI studies to identify predictors of viral rebound.

Methods: Cell-associated DNA (CA-DNA) and CA-RNA were quantified in pre-ATI peripheral blood mononuclear cell samples, and residual plasma viremia was measured using the single-copy assay.

Results: Participants who initiated antiretroviral therapy (ART) during acute/early HIV infection and those on a non-nucleoside reverse transcriptase inhibitor-containing regimen had significantly delayed viral rebound. Participants who initiated ART during acute/early infection had lower levels of pre-ATI CA-RNA (acute/early vs. chronic-treated: median <92 vs. 156 HIV-1 RNA copies/10 CD4 cells, P < 0.01). Higher pre-ATI CA-RNA levels were significantly associated with shorter time to viral rebound (≤4 vs. 5-8 vs. >8 weeks: median 182 vs. 107 vs. <92 HIV-1 RNA copies/10 CD4 cells, Kruskal-Wallis P < 0.01). The proportion of participants with detectable plasma residual viremia prior to ATI was significantly higher among those with shorter time to viral rebound.

Conclusion: Higher levels of HIV expression while on ART are associated with shorter time to HIV rebound after treatment interruption. Quantification of the active HIV reservoir may provide a biomarker of efficacy for therapies that aim to achieve ART-free HIV remission.

Fig. 1. Virologic suppression after treatment interruption stratified by timing of ART initiation and ART regimen

(a) Cumulative percentage of participants who maintained virologic suppression after treatment interruption based on two viral load thresholds. (b) Cumulative percentage of participants who remained suppressed stratified by treatment initiated during acute, early, or chronic HIV infection at the 200 HIV RNA copies/mL and (c) 1,000 HIV RNA copies/mL viral rebound thresholds. (d) Cumulative percentage of participants who remained suppressed stratified by ART regimen (NNRTI vs. non-NNRTI) at the 200 HIV RNA copies/mL and (e) 1,000 HIV RNA copies/mL thresholds. The 200 HIV RNA copies/mL threshold required a subsequent confirmatory viral load ≥200 HIV RNA copies/mL. *P-value <0.05 by Fisher’s exact testing.

Fig. 2. CD4+ cell loss after treatment interruption

CD4+ cell loss at the time of HIV RNA ≥200 copies/mL threshold (a) by timing of ART initiation, (b) screening CD4+ cell count, and (c) nadir CD4+ count. CD4+ cell loss at the time of HIV RNA ≥1,000 copies/mL threshold (d) by timing of ART initiation, (e) screening CD4+ cell count, and (f) nadir CD4+ count.

Fig. 3. Association of Pre-ATI levels of CA-RNA, CA-DNA, and residual viremia with timing of viral rebound

Levels of pre-ATI (a) CA-RNA and (c) CA-DNA categorized by timing of viral rebound to HIV RNA ≥200 copies/mL. Levels of pre-ATI (b) CA-RNA and (d) CA-DNA categorized by timing of viral rebound to HIV RNA ≥1,000 copies/mL. (e) Proportion of individuals with pre-ATI residual plasma viremia ≥1 HIV RNA copy/mL by viral rebound timing at the 200 HIV RNA copy/mL and (f) 1,000 HIV RNA copies/mL HIV rebound thresholds. Open symbols represent values from participants treated during chronic infection and closed symbols represent values from participants treated during acute infection. Median values and significance by Wilcoxon rank sum tests are shown.

Fig. 4. Two-covariate Cox models of CA-RNA with 6 other factors as predictors of viral rebound time to ≥200 HIV-1 RNA copies/mL

CA-RNA and CA-DNA are evaluated as log₁₀ HIV-1 RNA copies/10⁶ CD4+ cells and residual viremia as a dichotomous variable (≥1 HIV-1 RNA copies/mL). Cox models with nadir CD4+ count and ART regimen were restricted to participants treated during chronic infection. OR, odds ratio; CI, confidence interval.