CROI 2016 Abstract eBook

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Poster Abstracts

715 Higher Plasma Cell-Free DNA Levels Are AssociatedWith Younger Age and HIV Infection Omair Arshad; Izabelle Gadawski; Beheroze Sattha; Hélène Côté ; for the Canadian Institutes of Health ResearchTeam on Cellular Aging and HIV Comorbidities inWomen and Children (CARMA cohort) Univ of British Columbia, Vancouver, BC, Canada Background: HIV infection and antiretroviral treatment are associated with mitochondrial dysfunction, cytotoxicity, and chronic inflammation; all processes that can contribute to the accelerated aging seen in persons living with HIV. Increased cell-free nuclear (cf-nDNA) and mitochondrial (cf-mtDNA) DNA levels are generally associated with poorer health outcomes, and cf-mtDNA is particularly pro-inflammatory. We investigated cf-DNA levels in participants of the CARMA cohort. Methods: Our observational cross-sectional study included 92 HIV-infected (HIV+; aged 4-63y), 45 HIV-exposed uninfected (HEU; 2-18y), and 24 HIV-unexposed uninfected (HUU; 15-78y) participants. The latter two groups were combined into one HIV-uninfected group (HIV-). Fresh whole blood (WB) was spun at 14,000xg and the plasma filtered (0.45 µm) to fully remove cells and platelets. MtDNA and nDNA levels were measured in both filtered plasma and WB via multiplex qPCR. Associations with age and HIV infection were investigated among children or adults by Student’s -test and by correlations. Significant univariate associations were further investigated through multivariable linear regression analyses. Results: Within-participant cf-mtDNA were higher (median 6x) than cf-nDNA levels but the two were highly correlated across the HIV+ (n=92, r=0.80, p<0.0001) and HIV- (n=69, r=0.70, p<0.0001) groups. No correlation was seen between cf- and WB DNA levels. Age was negatively correlated with cf-mtDNA and nDNA in both the HIV+ (n=92, rho≤-0.26, p≤0.013) and HIV- (n=69, rho≤-0.35, p≤0.004) groups. HIV infection itself was associated with higher cf-mtDNA (p=0.004) and cf-nDNA (p=0.003) in pediatric participants (2-19y, n=72) but not in adults. In a multivariable model (n=161), younger age (p<0.0001) and HIV infection (HIV+ vs. HIV-; p≤0.026) were independently associated with higher cf-mtDNA and nDNA. Among HIV+ participants, CD4 + T cell count was positively correlated with both cf-mtDNA and nDNA (n=52, r≥0.36, p≤0.009). Too few participants had a detectable HIV pVL to investigate it as a predictor of cf-DNA. In a multivariable model of the HIV+ group (n=52), both younger age (p≤0.009) and higher CD4 + count (p≤0.019) were independently associated with higher cf-mtDNA and nDNA. Conclusions: Children have more circulating cf-mtDNA and nDNA than older persons, and that those living with HIV have further increased levels, possibly impacting aging processes. A larger sample size will be needed to verify whether this association exists in adults. 716 Peak HIV Viral Load Is AssociatedWith Increased Blood Mitochondrial DNA Mutations Adam S. Ziada 1 ; Jarek Ignas-Menzies 1 ; MengYing Lu 1 ; Beheroze Sattha 1 ; Sara Saberi 1 ; P. Richard Harrigan 2 ; Hélène Côté 1 ; for the Canadian INstitute of Health ResearchTeam on Cellular Aging and HIV Comorbidities inWomen and Children (CARMA) 1 Univ of British Columbia, Vancouver, BC, Canada; 2 BC Cntr for Excellence in HIV/AIDS, Vancouver, BC, Canada Background: People living with HIV experience accelerated aging. The oxidative stress theory of aging states that the accumulation of mtDNA mutations over time leads to tissue aging and dysfunction. Somatic mtDNA point mutations are implicated in age-associated diseases such as those seen in HIV+ individuals. Both the virus and the antiretroviral drugs can negatively impact mtDNA as well as increase oxidative stress and may therefore contribute to accelerated aging. We hypothesized that mtDNA somatic substitutions would increase with age, and HIV infection. Methods: Participants in this cross-sectional study were HIV+ (n=92, 12 <19y) and HIV- (n=72, 13<19y) female participants enrolled in the CARMA cohort, not infected with hepatitis C or B virus, and either current or never (but not past) smokers. Whole blood DNA was extracted and somatic mtDNA substitution mutation rates in the D loop region were quantified blindly via a next generation sequencing assay that distinguishes ”true” mtDNA substitutions from background ones introduced via PCR or sequencing errors. After sorting and aligning, mtDNA somatic substitution rates per 100,000bp were calculated. Factors associated with mtDNA mutations were investigated through Spearman’s correlations, Mann-Whitney tests, and ANCOVA of log 10 values as appropriate. Results: Measured blood mtDNA mutation rates met quality control for 78 HIV+ and 64 HIV- individuals (median [IQR] (range) of 3.6 [2.3-6.1] (0.0-25.0)) aged 1-75 years. Ages were similar between the two groups (p=0.15) and all HIV+ children had undetectable pVL while this was true for 59% of adults. Approximately 40% of adults were current smoker in both groups. A significant correlation was seen between mtDNA mutation rates and age (rho=0.29, p<0.001) but there was no association with HIV+ status (p=0.96) or smoking (current vs. never, p=0.84). Among HIV+ adults, higher mtDNA mutation rates were associated with peak HIV pVL recorded (> vs. ≤100,000 copies/mL, p=0.015) but not current HIV pVL (rho=0.003, p=0.67), CD4+ count (rho=0.015, p=0.34), or CD4 nadir (rho=0.021, p=0.25). In a multivariable model of HIV+ adult participants that included age and peak pVL, only the latter (p<0.01) remained independently associated with mtDNA mutations rates. Conclusions: Somatic mtDNA mutations can be measured in blood and their rate increases with age, consistent with current theories of aging. Our results further suggest that high HIV viremia may also induce aging-like mtDNA damage. 717 Equivalent Decline in Inflammation Markers With Tenofovir Alafenamide and Tenofovir DF Grace A. McComsey 1 ; NicholasT. Funderburg 2 ; Manjusha Kulkarni 2 ; Hui C. Liu 3 ;Yafeng Zhang 3 ; Jason Dinoso 3 ; Andrew Cheng 3 ; Scott McCallister 3 ; Marshall Fordyce 3 ; Moupali Das 3 1 Case Western Reserve Univ, Cleveland, OH, USA; 2 Ohio State Univ, Columbus, OH, USA; 3 Gilead Scis, Inc, Foster City, CA, USA Background: Initiation of antiretroviral therapy (ART) reduces both immune activation and systemic inflammation. We examined changes in biomarkers of monocyte activation (sCD14, sCD163), and systemic (IL-6, hsCRP, sTNFR-I and D-dimer) and vascular (Lp-PLA2) inflammation in a randomized, controlled trial comparing elvitegravir/cobicistat/ emtricitabine/tenofovir alfenamide (E/C/F/TAF) to E/C/F/tenofovir disoproxil fumarate (TDF) in treatment-naïve adults.

Poster Abstracts

297

CROI 2016