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The Size of the Active HIV Reservoir Predicts Timing of Viral Rebound
Behzad Etemad1, Hayat Ahmed1, Evgenia Aga2, Ronald Bosch2, John W. Mellors3, Daniel Kuritzkes1, Michael Para4, Rajesh T. Gandhi5, Jonathan Li1
1 Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, United States. 2 Harvard School of Public Health, Center for Biostatistics in AIDS Research, Boston, MA, United States. 3 University of Pittsburgh, Pittsburgh, PA, United States. 4 Ohio State University, Columbus, OH, United States. 5 Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
Background: Strategies to achieve sustained ART-free HIV remission will require validation in analytic treatment interruption (ATI) trials. Identifying virologic biomarkers that can predict time to viral rebound could accelerate the development of such therapeutics. We examined the association of pre-ATI cell-associated RNA (CA-RNA), DNA (CA-DNA), and residual viremia (RV) with timing of viral rebound during ATI.
Methods: We performed a retrospective combined analysis of participants from 5 ACTG studies who were virologically suppressed on ART and received no immunologic intervention prior to undergoing ATI. The timing of viral rebound was evaluated at either (1) confirmed viral load ≥200 HIV RNA copies/mL or (2) single viral load ≥1,000 HIV RNA copies/mL. Unspliced CA-RNA and CA-DNA were quantified using qPCR, and RV by the single-copy assay.
Results: Participants who initiated ART during acute/early infection (n=20) had lower levels of pre-ATI CA-RNA than those treated during chronic infection (n=104) (median <1.58 vs. 1.83 log10 HIV-1 RNA copies/106 PBMCs, P<0.01). No significant differences were seen in pre-ATI levels of CA-DNA or RV between those treated during acute/early vs. chronic infection. There were no significant differences by ART regimen (NNRTI vs. PI-based) in pre-ATI CA-RNA, CA-DNA, or RV. Higher pre-ATI CA-RNA levels were significantly associated with shorter time to viral rebound using a threshold of either 200 HIV-1 RNA copies/mL (≤4 wks [N=75] vs. 5-8 wks [N=35] vs. >8 wks [N=14]: 1.83 vs. 1.68 vs.<1.58 log10 HIV-1 RNA copies/106 PBMCs, Kruskal-Wallis P<0.01] or 1,000 HIV-1 RNA copies/mL (1.83 vs. 1.69 vs. <1.58 log10 HIV-1 RNA copies/106 PBMCs, P<0.01). The proportion of participants with detectable RV ≥1 copy/mL was significantly higher in those with shorter time to ≥200 HIV-1 RNA copies/mL (≤ 4 wks vs. 5-8 wks vs. ≥8 wks: 47% vs. 29% vs. 8%, Fisher's P=0.02]. No significant association was seen between CA-DNA levels and timing of viral rebound. A modest correlation was detected between levels of pre-ATI CA-RNA and CA-DNA (Spearman r=0.16, P=0.08).
Conclusions: The size of the active HIV reservoir, as reflected by levels of CA-RNA and RV, is associated with the time to viral rebound after interrupting ART. CA-RNA and RV have the potential to serve as biomarkers of efficacy for therapies aiming to achieve sustained ART-free HIV remission.