CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Methods: Vertically HIV-infected Thai children (N=58) who initiated ART within the first 6 months of life were enrolled. Blood samples were collected prior to, and following ART for at least 12 months. Total and integrated HIV DNA in PBMCs and CD4 T cells were quantified by real-time PCR. The frequency of CD4 T cells producing multiply spliced RNA after PMA/ionomycin stimulation was measured by Tat/rev Induced Limiting Dilution Assay (TILDA). Results: Samples prior to ART were obtained from 10 infants who received prophylactic antiretrovirals (ARV) for a median of 5 IQR [4-6] weeks. Their median age was 11 IQR [8-18] weeks and their median plasma viral load was 5.3 IQR [4.6-5.9] log10 HIV RNA copies/ml. In spite of prophylactic ARV, high levels of total and integrated HIV DNA were measured in CD4 T cells from these infants (Table 1). Baseline HIV viral load strongly correlated with integrated HIV DNA in PBMCs (r=0.83, p=0.005), suggesting that the magnitude of HIV replication impacts the size of the reservoir. CD4 T cells producing tat/rev RNA were detectable in all samples (median 40 IQR [13-69]). In addition, 48 samples were obtained from fully ART-suppressed children with median ART duration of 4 IQR [1.0-5.5] years. Total and integrated HIV DNA levels remained relatively high while TILDA values were extremely low (median 0 IQR [0-2.7] Table 1). Importantly, children who initiated ART within 8 weeks of life showed reduced levels of integrated HIV DNA compared to those who started later (Table 1, p=0.03). Conclusion: Neonatal prophylaxis ARV does not prevent the establishment of a large pool of cells harboring HIV DNA in infants. The frequency of cells with inducible HIV remained low in virally suppressed children, despite high levels of HIV DNA, suggesting that the proviral reservoir is poorly inducible. Notably, early ART (<8 weeks) dramatically restricts the pool of cells harboring integrated HIV DNA.

Poster and Themed Discussion Abstracts

286 CELL-ASSOCIATED HIV RNA PREDICTS POSTTREATMENT HIV CONTROL AND CD4+ T-CELL LOSS Alexander Pasternak , Jan Prins, Ben Berkhout Univ of Amsterdam, Amsterdam, Netherlands Background: For the improved design of strategies towards HIV-1 functional cure, it is important to identify biomarkers that could predict the duration of post-treatment virological control and subsequent disease progression (the rate of CD4+ T-cell loss). Methods: We studied 45 patients that received 24 or 60 weeks of temporary ART initiated at primary HIV infection (PHI) as part of a randomized trial (Primo-SHM study; PLoS Med 2012;9:e1001196). Patients were treated with a quadruple triple-class ART regimen. Cell-associated (CA) HIV nucleic acids (unspliced (US)- gag and multiply spliced (MS)- tat/rev HIV RNA and total HIV DNA) were longitudinally quantified by seminested qPCR every 12 weeks during ART and at the virological setpoint (36 weeks after discontinuation of ART). Results: All patients experienced virological rebound (VR) (plasma viremia >50 copies/ml) within 9 months after therapy interruption. We first assessed the predictive power of the last measurements of the CA HIV biomarkers, CD4+ count, and CD4/CD8 ratio on ART before the therapy interruption, as well as of the duration of temporary ART, for the time to VR (the duration of post-treatment control). US RNA was the only significant predictor of the time to VR (HR=0.29 for patients with US RNA levels below vs. above the median, 95% CI, 0.10-0.83, p=0.021, log-rank test). Subsequently, we have assessed the predictive power of the same biomarkers and plasma viremia, measured at the virological setpoint, for the time to reach the CD4+ count of 350 cells/mm 3 in the absence of treatment. Among the virological markers, MS RNA was the strongest predictor of disease progression, whereas US RNA was not predictive. The median times to 350 cells/mm 3 in patients with MS RNA levels below and above the median were 1180 and 283 days, respectively (p=0.0002, log-rank test). In multivariate Cox regression analysis, CD4+ count (p=0.0004) and MS RNA level (p=0.011) were the only two significant predictors of disease progression. Conclusion: Cell-associated HIV-1 US RNA was the sole predictor of the duration of post-treatment virological control after the interruption of early ART, whereas MS RNA independently predicted subsequent CD4+ T-cell loss. This suggests that reactivation of HIV and CD4+ T-cell loss after ART interruption could be driven by different mechanisms. Further exploration of the predictive potential of these biomarkers in large-scale clinical trials aimed at HIV functional cure is warranted. 287 PRE-ART TUBERCULOSIS AND TB-IRIS AFFECT THE HIV-1 RESERVOIR Camille Lange 1 , Maura Manion 2 , Gregg Roby 3 , Rob Gorelick 4 , Virginia Sheikh 5 , Joseph Adelsberger 6 , Frank Maldarelli 1 , Irini Sereti 2 1 NCI, Frederick, MD, USA, 2 NIAID, Bethesda, MD, USA, 3 NIH, Rockville, MD, USA, 4 AIDS and Cancer Virus Prog, Frederick, MD, USA, 5 FDA, Silver Spring, MD, USA, 6 Leidos Biomed Rsr, Inc, Frederick, MD, USA Background: Tuberculosis (TB) is the most common presenting illness of people living with HIV worldwide. TB-associated immune reconstitution inflammatory syndrome (IRIS) is an aberrant inflammatory response of TB in patients starting antiretroviral therapy (ART), especially with severe CD4 lymphopenia or disseminated TB. Previous studies show TB-IRIS is driven by rapid expansion of activated TB-specific CD4+ T-cells. We hypothesized that pre-ART (baseline) TB and IRIS in HIV-1 infected patients have long-term effects on viral reservoirs. Methods: A single copy assay was used to measure HIV viremia in baseline lymphopenic (BL) patients +/- IRIS to assess if IRIS affected HIV replication >1-2y ART (long term ART); controls had no BL, OI or IRIS. Cell-associated (CA) gag DNA and RNA levels of CD4+ T-cells were used to quantify the CD4+ reservoir, including subgroups of patients with and without TB and IRIS. We also characterized proviral populations in peripheral blood mononuclear cells with single genome sequencing (SGS) of HIV-1 p6-pol (1.1kb) at: pre-ART; 2-8

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