CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Conclusions: RTD was present in 20% of renal biopsies and comprised three distinct pathological injury patterns with considerable clinical overlap. Of these, ATI was strongly associated with TDF and ATV exposure. 795 Safety of Tenofovir Alafenamide in Renal Impairment Anton Pozniak 2 ; Jose R Arribas 3 ; Samir K. Gupta 4 ; Frank A. Post 5 ; Anchalee Avihingsanon 6 ; Gordon Crofoot 7 ; Kenneth A. Lichtenstein 8 ; Moti Ramgopal 9 ; Ploenchan Chetchotisakd 10 ; Marshall W. Fordyce 1 1 Gilead Sciences Inc, Foster City, CA, US; 2 Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom; 3 Hospital Universitario La Paz, Madrid, Spain; 4 Indiana University School of Medicine, Indianapolis, IN, US; 5 King’s College Hospital NHS Foundation Trust, London, United Kingdom; 6 HIV-NAT, Thai Red Cross AIDS Research Center and Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 7 Crofoot Research, Houston, TX, US; 8 National Jewish Health, Denver, CO, US; 9 Midway Research Center, Ft. Pierce, FL, US; 10 Khon Kaen University, Khon Kaen, Thailand Background: Tenofovir (TFV) is renally eliminated, and the prodrug, tenofovir disoproxil fumarate (TDF), has been associated with renal toxicity and reduced bone mineral density (BMD), and must be dose adjusted in patients with estimated glomerular filtration rate (eGFR) < 50mL/min. Tenofovir alafenamide (TAF) is a novel prodrug of TFV that is not renally eliminated and at clinical doses results in 90% lower plasma TFV levels as compared to TDF. The safety and efficacy of a once-daily single tablet regimen of elvitegravir, cobicistat, emtricitabine, and TAF (E/C/F/TAF) was assessed in HIV-1 infected patients with mild to moderate renal impairment. Methods: Virologically suppressed adults with stable eGFR CG (CockroftGault) of 30 to 69 mL/min had their treatment switched from both TDF- and non-TDF-containing regimens to open-label E/C/F/TAF. Week 24 efficacy and safety data are described, including tests of renal function and BMD. Actual GFR (aGFR) was assessed with iohexol clearance in a subset of subjects. Results: Of 242 subjects enrolled and dosed, mean age was 58 years (range: 24 – 82), 18% Black, 39% hypertension, and 14% diabetes. 65%were taking TDF-containing regimens prior to switch. At baseline, median eGFR C-G was 55.6 mL/min (33% eGFR C-G 30-49 mL/min). 95% of subjects maintained HIV-1 VL <50 c/mL at Week 24 (FDA Snapshot). At Week 24, the median (Q1, Q3) change from baseline eGFR C-G was -0.4 (-4.7, 4.5) mL/min, eGFR-cystatin C 3.8 (-4.8, 11.2) mL/min/1.73m2, and aGFR (n=32, 68.8% TDF at baseline) was 0.1 (-4.3, 4.4) mL/min, indicating that GFR was not affected by E/C/F/TAF. Two subjects (0.8%) discontinued study drug for decreased GFR by eGFR C-G and eGFR-cystatin C, neither with evidence of renal tubulopathy. The prevalence of clinically significant proteinuria (UPCR > 200 mg/g) and albuminuria (UACR ≥ 30 mg/g) decreased from 42% to 21% and 49% to 27%, respectively. Significant decreases in urine retinol binding protein to creatinine ratio, beta2microglobulin to creatinine ratio, and fractional excretion of uric acid were observed (p<0.001 for all). Hip and spine BMD percentage change from baseline to Week 24 was 0.74% (-0.71, 2.03) and 1.27% (-0.44, 3.83) (median, IQR), respectively. Conclusions: These 24 week data support the virologic efficacy and renal and bone safety of once daily single-tablet E/C/F/TAF for use in HIV+ patients with mild and moderate renal impairment (eGFR 30 to 69 mL/min). Switch to E/C/F/TAF was associated with no change in aGFR and with reductions in proteinuria. 796 Elevated Nonclassical Monocytes and Urine Fibrotic Markers in HIV Albuminuria Brooks I. Mitchell ; Mary Margeret Byron; Roland C. Ng; Dominic C. Chow; Pichaya O-charoen; Lishomwa C. Ndhlovu; Cecilia M. Shikuma University of Hawaii, Honolulu, HI, US Background: Presence of albuminuria (ALB) predicts an accelerated loss in renal function. Rates of ALB are high among HIV-infected individuals on antiretroviral therapy (ART). We investigated the relationship of monocyte (MO) subsets and urine inflammatory and fibrotic markers to ALB in stable HIV-infected subjects on ART. Methods: Cross-sectional analyses on Hawaii Aging with HIV-CVD cohort subjects ≥ 40 years old and on ART ≥ 6 months. MO subsets (classical, intermediate, non-classical) were determined in banked peripheral blood mononuclear cells (PBMC) using multi-parametric flow cytometry. Entry random urine samples were assessed for albumin/creatinine ratios (ACR). Urine samples were measured for inflammatory (IP-10, MCP-1, and IL-18) and fibrotic (TGF- β 1 , TGF- β 2 , TGF- β 3 , collagen IV, and TIMP-1) markers using Luminex technology. Statistical analyses performed were Wilcoxon Rank and chi-squared tests, Pearson correlations, and multivariable linear regressions. Results: Among 96 HIV-infected subjects with measured ACR (87%male, 59% Caucasian, and 89% undetectable HIV RNA with median CD4 of 495.5 cells/ μ L), 18 patients (19%) had ALB [89%with moderate ALB (ACR 30-300 mg/g) and 11%with severe ALB (ACR > 300 mg/g)]. Subjects with ALB were older (median age 57 vs. 50, p =0.013), and had higher rates of hypertension (67% vs. 31%, p =0.010) and use of ACE inhibitors and/or ARBs (50% vs. 15%, p =0.004); but did not differ in rates of diabetes (10%) or use of Tenofovir (77%) or Ritonavir (38%). Only non-classical (CD14 low/+ CD16 + ) MO subset was significantly elevated in subjects with ALB (2.68x10 7 cells/ μ L vs. 1.96x10 7 cells/ μ L, p =0.034) and was correlated to ACR (r=0.238, p =0.019). Non-classical MO subset, but not other subsets, was a significant predictor of ALB independent of hypertension, BMI, and total cholesterol/ HDL ratio ( β =0.223, p =0.021). In 37 subjects assessed for urinary biomarkers, only urine TGF- β 1 and collagen IV had significantly higher average net MFI in albuminuric compared to non-albuminuric subjects (TGF- β 1 ; 14.4 vs. 3.5, p =0.039 and collagen IV; 1160.9 vs. 702.0, p =0.042). Levels of urine TGF- β 1 showed a significant correlation with ACR (r=0.336, p =0.042) and non-classical MO subset (r=0.464, p =0.017). Conclusions: ALB in HIV-infected individuals on ART is associated with elevated levels of non-classical MO and urine pro-fibrotic factors. Alterations in MO subsets and pro-fibrotic factors may play a important role in kidney injury during chronic HIV infection. 797 Kidney Dysfunction and Markers of Inflammation in the Multicenter AIDS Cohort Study Alison G. Abraham 1 ; Annie Darilay 2 ; Heather McKay 1 ; Joseph B. Margolick 1 ; Michelle M. Estrella 3 ; Frank J. Palella 4 ; Robert Bolan 5 ; Charles R. Rinaldo 6 ; Lisa P. Jacobson 1 1 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US; 2 AstraZeneca, Gaithersburg, MD, US; 3 Johns Hopkins University School of Medicine, Baltimore, MD, US; 4 Northwestern University, Feinberg School of Medicine, Chicago, IL, US; 5 Los Angeles LGBT Center, Los Angeles, CA, US; 6 University of Pittsburgh, Pittsburgh, PA, US Background: HIV-associated chronic immune activation and inflammation may contribute to increased risk for kidney disease among HIV-infected (HIV+) individuals, even after viral suppression. We examined associations between inflammatory processes and kidney function in treated and virally suppressed HIV+ and HIV– men from the Multicenter AIDS Cohort Study. Methods: Glomerular filtration rate (GFR) was directly measured using decay of plasma iohexol concentration. Twelve markers of inflammation were measured from stored blood samples (C-Reactive Protein, Soluble TNF-receptor 2, Soluble Interleukin (IL) 2-receptor- α , Soluble GP130, Soluble CD27, Monocyte Chemoattractant Protein-1, Interferon γ -Induced Protein 10, TNF- α , IL-6, Soluble CD14, IL-8, IL-10). Exploratory factor analysis (EFA) was used to identify underlying inflammatory processes, and factors were validated in an independent dataset. The validated factor scores were used in adjusted logistic regression analyses to evaluate their associations with kidney outcomes: reduced GFR (GFR ≤ 90 ml/min/1.73m 2 ); hyperfiltration (GFR >140 ml/min/1.73m 2 - 1 ml/min/1.73m 2 for each year over age 40); and urine protein:creatinine ratio (uPCr) category ( ≤ 100, 100-200, >200 mg/g). Results: 434 HIV+men, all on antiretroviral therapy and 80% virally suppressed, and 200 HIV- men had available GFR determinations and inflammatory biomarker levels. HIV+ men had higher levels of cystatin C (median: 0.79 versus 0.75 mg/dl) and uPCr (median: 98 versus 66 mg/g). From the EFA, three factors were retained that accounted for 60% of the total variance in inflammatory marker levels; only the first two factors could be replicated in a validation set. Factor 1 (dominated by markers: sTNF receptor 2, sIL 2-receptor- α , sGP130, sCD27, and sCD14) scores (shown in the Figure) were significantly (p<0.05) related to a greater odds of GFR ≤ 90 ml/min/1.73m 2 (OR=2.0), a greater odds of uPCr >200 mg/g (OR=2.2), and a lower odds of hyperfiltration (OR=0.5), as well as with a history of diabetes (OR=1.6) and a history of hypertension (OR=1.3). Levels of all of these markers except GP130 were significantly higher in HIV+men. Factor 2 (dominated by markers: IL-6, IL-8 and TNF- α ) was not significantly associated with any kidney outcomes.

Poster Abstracts

485

CROI 2015