CROI 2016 Abstract eBook

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Poster Abstracts

Metabolomics was performed by LC/MS/MS and GC/MS. Integrative analysis of metabolite, laboratory, and clinical data used Metaboanalyst and R. Multivariate logistic regression was done in SAS. Results: Participants were predominantly male, black, with high prevalence of HCV (60%, 75%, and 60%, respectively) and renal dysfunction (40% had estimated GFR (eGFR) <90). Of >300 metabolites detected, 15 distinguished cocaine users from controls in HIV- and HIV+ cohorts, mapping to oxidative stress, altered tryptophan catabolism, phenylalanine/tyrosine/dopamine, and linoleic acid metabolism (p<0.05, FDR<0.10). Metabolites altered in cocaine users included uremic solutes indicative of early renal dysfunction, which correlated inversely with eGFR (c-glycosyl-tryptophan [c-glyTrp], pseudouridine, N6-carbamoyl-threonine, kynurenine, N-acetylated amino acids; p<0.05). Heme, a pro-oxidant with inflammatory and nephrotoxic activity, and kynurenine:tryptophan ratio (marker of tryptophan catabolism associated with immune activation) were also elevated. AUROC identified c-glyTrp and pseudouridine as uremic solutes with good classification power for eGFR <90 vs >90 (AUROC c-glyTrp single marker 83%; c-glyTrp combined with serum creatinine 95% vs 92% for creatinine alone; n=95). Cocaine use was associated with eGFR <90 in logistic models adjusted for older age, race, HIV, and HCV (OR 3.4, CI 1.3-8.7; p=0.01) and HCV status modified this association (OR 6.1, CI 1.6-23.6; p<0.01). Conclusions: Cocaine use is associated with early markers of renal dysfunction in HIV and HCV infection. Tryptophan catabolism, oxidative stress, and pro-oxidant and nephrotoxic effects of circulating heme may contribute to mechanisms involved in cocaine-associated comorbidities that are augmented by these viral infections. 694 Bone Loss With Antiretroviral Therapy Is AssociatedWith Phosphaturia Robert Kalayjian 1 ; Jeffrey Albert 2 ; Serge Cremers 3 ; Karin Klingman 4 ; Carl Fichtenbaum 5 ; Joseph J. Eron 6 ;ToddT. Brown 7 ; BabafemiTaiwo 8 ; for the AIDS ClinicalTrials Group Protocol Team A5303 1 MetroHlth Med Cntr, Cleveland, OH, USA; 2 Case Western Reserve Univ, Cleveland, OH, USA; 3 Columbia Univ, New York, NY, USA; 4 NIAID, NIH, Bethesda, MD, USA; 5 Univ of Cincinnati, Cincinnati, OH, USA; 6 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 7 Johns Hopkins Univ, Baltimore, MD, USA; 8 Feinberg Sch of Med, Northwestern Univ, Chicago, IL, USA Background: Initial antiretroviral therapy (ART) is associated with bone mineral density (BMD) loss. ACTG A5303, a randomized trial of initial tenofovir disoproxil fumarate (TDF) vs maraviroc (MVC)-containing ART over 48 weeks showed greater bone loss with TDF, consistent with known bone effects of TDF. The mechanisms of TDF-associated bone loss are not known, but urinary phosphate wasting from TDF-induced renal tubulopathy may contribute to this loss. Objective: To examine associations between phosphaturia and changes in BMD in ACTG A5303 Methods: The contributions of phosphaturia to changes in hip or spine BMD (based on dual energy x-ray absorptiometry) from baseline to week 48 were assessed using multivariable linear regression in subjects with complete data through week 48. Phosphaturia was estimated by calculating the area under the curve of the fractional excretion of phosphorus at weeks 0, 4, 24 & 48 (FEP-AUC). Adjusting variables included age, sex, race/ethnicity, BMI, week 48 viral load & changes in CD4 from baseline to week 48. Results: Among the 163 participants included in this analysis, 15 (9%) were women. Women were significantly older than men (med age 41 vs 33 yrs; P=0.01). The mean FEP-AUC over 48 weeks was similar between women and men (9.8 vs 10.5%, respectively; P=0.7) but tended to be higher in women and men who were randomized to TDF vs MVC (10.8 vs 10.0%, P=0.07). Higher FEP-AUC was associated with significantly more bone in loss in spine but not hip, which was evident mainly in women (P=0.04 for interactions with sex). Each 10% average FEP increase over 48 weeks was associated with BMD spine loss of -14.9% [95%CI;-15.4,-14.3%] in women, but only -0.9% [-4.7, 2.8%] in men. The significant differences between treatment arms persisted in these models, however, so the effect of TDF on BMD was only slightly attenuated by inclusion of FEP-AUC in the models, from -1.7% [-2.9,-0.5%] to -1.6% [-2.9,-0.5%] in BMD spine loss with TDF vs MVC. Conclusions: Phosphaturia was associated with bone loss with the initiation of either TDF or MVC over 48 weeks, that was evident primarily in women. The detrimental bone effects of TDF were not explained by phosphaturia, however. 695LB Immunologic Effects of Maraviroc vs Tenofovir and Associations With Bone Loss Ellen S. Chan 1 ; Paria Mirmonsef 2 ;ToddT. Brown 3 ; Alan L. Landay 4 ; Ighovwerha Ofotokun 5 ; M. N.Weitzmann 5 ; Jeff Martinson 2 ; Jill Plants 2 ; Heather J. Ribaudo 6 ; BabafemiTaiwo 7 1 Harvard Univ, Boston, MA, USA; 2 Rush Univ Med Cntr, Chicago, IL, USA; 3 Johns Hopkins Univ, Baltimore, MD, USA; 4 Rush Univ, Chicago, IL, USA; 5 Emory Univ Sch of Med, Atlanta, GA, USA; 6 Harvard Sch of PH, Boston, MA, USA; 7 Feinberg Sch of Med, Northwestern Univ, Chicago, IL, USA Background: The anti-inflammatory and immune modulating effects of maraviroc (MVC) and their hypothetical clinical associations are unclear. We compared immune biomarker changes with MVC vs. tenofovir disoproxil fumarate (TDF) in ACTG A5303 where MVC led to less bone loss than TDF in initial ART. Methods: A5303 was a 48 week double-blind, placebo-controlled trial conducted in the US. Participants were HIV-1-infected, ART- naïve with viral load (VL)>1000 c/mL, R5 tropism on Trofile, and were randomized 1:1 to MVC 150mg or TDF 300mg QD, stratified by VL< and ≥100,000 c/mL and age < and ≥30 yrs. All participants received darunavir 800mg, ritonavir 100mg, and emtricitabine 200mg QD. A total of 32 biomarkers were assayed at weeks 0 and 48, including soluble biomarkers measured by ELISA, CD4/CD8 counts, activated (CD38/HLA-DR) and senescent (CD28/CD57) T-cells, monocytes (CD14/CD16), B cells and NK cells. Hip BMD was determined using DXA scans at weeks 0 and 48. Analyses were as-treated. Wilcoxon signed-rank tests evaluated within group differences. Stratified Wilcoxon rank sum tests evaluated differences between treatment groups stratified by age stratum. Spearman correlations evaluated associations between %change in BMD and biomarkers. All tests were 2-sided and conservatively interpreted at 0.5% significance level. Results: There were 230 participants in the as-treated population (MVC=119; TDF=111): 9% female; median age 33 yrs, 44%White, 31% Black, 22% Hispanic; median VL 4.5 log 10 c/mL. The MVC group had greater increases in CD4 count, smaller decreases in CD8 count, and smaller increases in CD4:CD8 ratio observed over 48 weeks compared to the TDF group (Table 1). There were significant declines in all soluble biomarkers except for IL-6 and sCD14 where the declines were apparent only in MVC group. No evidence of differences between treatment groups was found in changes in soluble or cellular biomarkers (p>0.10). Significant associations between hip BMD %change and soluble/cellular biomarkers were not found in either group, except for a marginal negative association with %change in IL-6 (r=-0.23, p=0.016) found in TDF but not MVC group. Conclusions: Initiating ART with MVC compared to TDF in A5303 resulted in greater increase in CD4 count and smaller decline in CD8 count, but less rise in CD4:CD8 ratio. Changes in soluble or cellular biomarkers of inflammation and immune activation were not different between MVC and TDF groups. A consistent immunologic driver to differential bone loss was not seen.

Poster Abstracts

288

CROI 2016

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