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 6 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 PBMC samples, and residual plasma viremia (RV) was measured using the single-copy assay. Results Participants who initiated ART during acute/early HIV infection and those on an NNRTI-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/106 CD4+ cells, P<0.01). Higher pre-ATI CA-RNA levels were significantly associated with shorter time to viral rebound (≤4 wks vs. 5–8 wks vs. >8 wks: median 182 vs. 107 vs. <92 HIV-1 RNA copies/106 CD4+ cells, Kruskal-Wallis P<0.01). The proportion of participants with detectable RV prior to ATI was significantly higher among those with shorter time to viral rebound. Conclusions 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.

Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency

“…circulating resting CD4 + T cells obtained via apheresis. Changes in HIV RNA levels within the resting CD4 + T cell pool are most likely to represent the true reversal of latency and recent upregulation of HIV proviral expression, rather than HIV expression in the "active reservoir" of HIV-RNA-expressing cells found in circulating total CD4 + T cell pools (15). Further, the measurement of resting CD4 + T cell-associated HIV RNA (rca-HIV RNA) in 36 replicate pools of 1 million resting CD4 + T cells ensures a robust and precise assessment of changes in HIV RNA expression (4).…”

HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption

“…PK-parameters were estimated by performing a non-compartmental analysis (NCA) using WinNonlin 6.3. Kaplan–Meier survival curves were used to compare time to rebound in trial participants to participants in previous ATI studies conducted by ACTG 29 . To exclude the possibility that the observed delay in rebound is confounded by clinical factors, we compared the clinical variables between the control (ACTG trial participants) and treated group using a two-sided Fisher's Exact test for categorical variables (gender and CD4 Nadir) and an unpaired Wilcoxon test (two-sided) for continuous variables (age, years on ART and CD4 count before ATI initiation) (Supplementary Table 7).…”

“…The left y -axis shows plasma viral loads in RNA copies per ml (black curves), and right y -axis shows antibody levels measured by ELISA (red curves). Average rebound time point (2.6 weeks, Supplementary Table 6) in 52 ACTG trial participants who underwent ATI without antibody treatment 29 is shown with dotted lines. Grey areas indicate ART therapy.…”

Novel Assays for Measurement of Total Cell-Associated HIV-1 DNA and RNA

“…Prior work showed that CA HIV-1 DNA and RNA remain detectable in most chronically infected individuals despite suppressive ART (7,8). Although the association of CA HIV-1 DNA and RNA levels with the size of the latent HIV-1 reservoir has been called into question (9), recent studies suggest that CA HIV-1 DNA and RNA levels may predict the time to virological rebound after ART cessation and thus may serve as clinically relevant biomarkers (10,11).…”