CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Conclusions: Plasma levels of VDBP rose significantly in the first 24 wks after initiation of TDF/3TC/EFV, followed by a more modest increase from 24 to 48 wks. This change was observed in concert with elevations iPTH and BTMs, despite stable 25OHD levels, supporting a potential mechanistic role for VDBP in bone loss associated with TDF therapy. 791 Determinants of Parathyroid Hormone Levels in HIV-positive Tenofovir-treated Patients with Normal Renal Function Letizia Marinaro ; Andrea Calcagno; Jessica Cusato; Elisabetta Scarvaglieri; Marco Simiele; Maria CristinaTettoni; LauraTrentini; Antonio D’Avolio; Giovanni Di Perri; Stefano Bonora Unit of Infectious Diseases, Turin, Italy Background: Secondary hyperparathyroidismmay develop in HIV-positive patients in case of vitamin D deficiency and calcium or phosphorus metabolism disorders. Traditional (age, gender, BMI) and therapeutic determinants [tenofovir (TDF) exposure] have been described but the role of TDF exposure as well as of genetic polymorphisms in key genes is currently unknown. Methods: Adult HIV-positive patients on TDF-containing HAARTs since at least six months, presenting estimated creatinine clearance (eCRCL) above 60 ml/min, with no significant comorbidity (hypertension, diabetes, urinary tract abnormalities), signing an informed consent were included. Twelve-hours TDF plasma (pC 12 ) and urinary concentration (uC 12 ) were measured through validated HPLC/MS-MS method. Results are expressed as medians (IQR); non parametric tests were used for all analysis. Single Nucleotide Polymorphisms (SNPs) in the following genes were obtained through real-time PCR: ABCB1, ABCC2, ABCC4, ABCC10, SLC22A6, SLC28A2, CYP27B1, CYP24A1, VDR. Results: 294 patients (75.2%male, 84.4% Caucasian) were enrolled. Age, BMI and eCRCL were 46 years (39.7-52), 23.7 kg/m 2 (22-26.5) and 91.6 ml/min (79.5-107) respectively. Median CD4 were 552 cell/uL (409-713) and 278 patients (94.6%) presented a plasma viral load <50 copies/mL after 55.2 months (27.8-88) of TDF intake. Vitamin D, parathyroid hormone (PTH) and phosphorus were 21.2 ng/dL (13.8-31.3), 52.2 pg/mL (40-66.4) and 3 mg/dL (2.7-3.4) with respectively 72.3%, 15% and 16.8% of patients presenting vitamin D deficiency (<30 ng/mL), secondary hyperparathyroidism (>79.6 pg/mL) and hypophosphoremia (<2.6 mg/dL). At multivariate linear regression (including also age, gender, BMI and time on TDF) vitamin D levels (p>0.001), cirrhosis (p=0.04) and the vitamin D receptor uncommon variants Cdx2 (rs11568820, p=0.025) were independent predictors of PTH. At multivariate linear regression PTH levels (p=0.023), HAART class (NNRTIs associated with the lowest levels, p=0.005), SLC28A2 124 (rs11854484, p=0.037) SNP and TDF urinary output (urinary TDF/plasma TDF, p=0.038) were independent predictors of phosphorus levels. Conclusions: A significant proportion of patients on long-term TDF-based treatment showed vitamin D deficiency and secondary hyperparathyroidism: the latter is more common in cirrhotic patients and in patients with non-functional vitamin D receptor. Genetic and pharmacokinetic markers can be used to identify patients at higher risk of hypophosphatemia and bone metabolism dysfunction. 2:30 pm– 4:00 pm Renal Dysfunction: ART and Biomarkers 792 Elevated Tenofovir Exposure via Intensive PK Monitoring Is AssociatedWith Progressive Kidney Function Decline Sanjiv M. Baxi 1 ; Rebecca Scherzer 1 ; Ruth M. Greenblatt 1 ; Howard Minkoff 2 ; Kathryn Anastos 5 ; Mardge H. Cohen 4 ; Mary A.Young 3 ; Monica Gandhi 1 ; Michael G. Shlipak 1 1 University of California San Francisco, San Francisco, CA, US; 2 State University of New York Downstate Medical Center, Brooklyn, NY, US; 3 Georgetown University, Washington, DC, US; 4 John Stroger (formerly Cook County) Hospital, Chicago, IL, US; 5 Montefiore Medical Center, University Hospital for Albert Einstein College of Medicine, Bronx, NY, US Background: Tenofovir disoproxil fumarate (TDF) is commonly used for HIV treatment, but risk factors for tenofovir (TFV)-associated kidney disease are relatively understudied. Among a diverse cohort of HIV-infected women on TFV-based therapy, we performed intensive pharmacokinetic (PK) studies to measure TFV exposure and assess its association with subsequent kidney function. Methods: The Women’s Interagency HIV Study (WIHS) is a multicenter, prospective cohort of representative HIV-infected women. Participants on TFV-based therapy (n=105) underwent 24-hour intensive PK sampling after witnessed dose under routine-use, steady-state conditions. Serial creatinine measures allowed assessment of kidney function (estimated GFR [eGFR] by the CKD-EPI collaboration equation) over the succeeding 7 years in all participants. Multivariable linear mixed models were used to evaluate the relationship between TFV area-under-the-time-concentration-curves (AUCs) at baseline with subsequent kidney function. Additional covariates adjusted for in the models include baseline age, baseline diabetes and hypertension, race, body mass index (BMI), ritonavir (RTV) use, duration of prior TFV exposure, CD4 cell count and viral load. Results: The mean age of 105 participants was 43 (range 39-65) years; 63%were African-American, 25% Hispanic and 12%white. Baseline BMI was weakly positively correlated with eGFR ( ρ =0.22, p=0.019) and negatively with TFV AUC ( ρ =0.24, p=0.012). The figure shows the trajectory of eGFR over time by tertile of TFV AUC. The eGFR was significantly lower at baseline in the highest compared with lowest tertiles (mean ± SE) of TFV AUC (80 ± 4.3 vs. 104 ± 2.5 ml/min, p<.0001). By year 7, this difference had widened (72.4 ± 4.9 vs. 104.9 ± 2.9, p<.0001). After multivariable adjustment with baseline variables, the highest tertile of TFV AUC remained associated with significantly lower eGFR relative to the lowest tertile at both baseline (-15, 95% CI: -25 to -5, p=0.0047) and year 7 (-23, 95% CI: -34 to -12, p=0.0002). The association of TFV AUC with eGFR did not differ by BMI, concomitant use of RTV or age (tests for interaction p>0.1). THURSDAY, FEBRUARY 26, 2015 Session P-Q8 Poster Session Poster Hall

Poster Abstracts

Figure. Association of baseline tenofovir area-under-the-time-concentration-curves tertile with estimated glomerular filtration trajectory in 105 HIV-infected women.

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CROI 2015