CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

516 ABCB1 Polymorphism Affects Tenofovir Exposure as Determined by Areas-Under-the-Time-Concentration-CurveWith 24-hour Intensive Pharmacokinetic Monitoring Sanjiv M. Baxi 1 ; Peter Bacchetti 1 ; Mardge Cohen 2 ; Jack A. Dehovitz 3 ; Kathryn Anastos 4 ; Stephen J. Gange 5 ; Mary A.Young 6 ; Monica Gandhi 1 ; Bradley Aouizerat 1

1 University of California San Francisco, San Francisco, CA, US; 2 John Stroger (formerly Cook County) Hospital, Chicago, IL, US; 3 State University of New York Downstate Medical Center, Brooklyn, NY, US; 4 Montefiore Medical Center, University Hospital for Albert Einstein College of Medicine, Bronx, NY, US; 5 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US; 6 Georgetown University, Washington, DC, US Background: Although tenofovir (TFV) is commonly used in HIV treatment and prevention, pharmacogenomic studies of this agent are limited. Modeling of genetic factors with other determinants of exposure is important. We performed intensive pharmacokinetic (iPK) studies in a diverse cohort of HIV-infected women and identified single nucleotide polymorphisms (SNPs) in genes associated with tenofovir (TFV) metabolism. Models with genetic and non-genetic factors were fit to fully assess contributors to TFV exposure. Methods: The Women’s Interagency HIV Study (WIHS) is a multicenter, prospective cohort of representative HIV-infected women. Participants on TFV-based therapy underwent 24-hour iPK sampling after a witnessed dose under steady-state conditions. Factors that affect PK were measured, including race, age, ritonavir (RTV) use, baseline kidney function (by estimated GFR via serum creatinine) and weight. Participant areas under the time concentration curve (AUCs) were calculated using the trapezoidal rule. Genetic data were collected on all participants. SNPs with an allele frequency of >0.05 were screened in three genes identified as important in the PK of TFV, specifically the ATP-binding cassette (ABC) B1, ABCC2 and organic anion transporter 1 (OAT1). Each SNP was evaluated as a single addition to an established model with non-genetic factors. Results: Of 93 participants, 61%were African-American, 60.2% used RTV, and 9.7% had an eGFR <70 mL/min. Median (range) TDF AUC was 3340 (1026-9356) ng × h/ml and BMI 27 (15-62) kg/m 2 . None of 88 SNPs met our a priori p<0.001 threshold for association with TDF AUC in multivariate modeling; rs4728707 in ABCB1 (CC versus CA; 8.1% allele frequency, no AA) had the smallest observed p-value (1.29 fold effect, 95% CI 1.02, 1.63; p=0.03). Of non-genetic factors, increasing BMI was associated with lower log TDF AUC, while age, ritonavir use and baseline eGFR were associated with higher log TDF AUC ( Table ). Due to non-normality of residuals, we repeated the model using robust standard errors and rs472870 had CI 1.09 to 1.54 with p=0.004.

Multivariate Model Assessing Factors Associated with TDF AUC (n=93). Conclusions: A comprehensive evaluation of 88 SNPs spanning three genes associated with TFV exposure assessed in multivariate models with non-genetic factors identified no strong associations, but ABCB1 rs4728707 had an estimated 29% increase in tenofovir AUC in 24 hour iPK monitoring. Genetic evaluations in real-world populations may help define optimal strategies to maximize efficacy and minimize toxicity for treated individuals. 517 Pharmacogenomics of Plasma Tenofovir Clearance and Change in Creatinine Clearance ValentineWanga 1 ; CharlesVenuto 2 ; Gene D. Morse 3 ; Edward A. Acosta 5 ; Eric Daar 4 ; DavidW. Haas 1 ; Chun Li 1 ; Bryan E. Shepherd 1 1 Vanderbilt University School of Medicine, Nashville, TN, US; 2 University of Rochester Medical Center, Rochester, NY, US; 3 State University of New York at Buffalo, Buffalo, NY, US; 4 Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, US; 5 University of Alabama at Birmingham, Birmingham, AL, US Background: Candidate gene studies have reported associations between single nucleotide polymorphisms (SNPs, e.g. ABCC2 -24T Ç C, rs717620) and renal toxicity with tenofovir (TFV) disoproxil fumarate (TDF). We performed genome-wide association analyses of plasma TFV clearance, and change in creatinine clearance (CrCl) in AIDS Clinical Trails Group protocol A5202. Methods: In A5202, 1858 HIV-infected subjects were randomized to double-blinded TDF/emtricitabine or abacavir (ABC)/lamivudine, with either open-label atazanavir/ritonavir or efavirenz. Plasma TFV clearance was estimated from a nonlinear mixed-effects approach. Serum CrCl was determined before entry, at entry, at weeks 4, 8, 16 and 24, and every 12 weeks thereafter. Illumina Human1M-Duo (~1.2 million SNPs) genotypes were from a separate project. TFV clearance analyses included 501 subjects randomized to TDF arms, and CrCl analyses included 1096 subjects randomized to TDF or ABC arms, all with genotype data. Multivariable regression models tested for associations between SNPs and TFV clearance and 6-month CrCl change. ABC arms were included in CrCl analyses as a control to identify SNPs associated with differential CrCl change with TDF, based on a test for interaction. In addition to genome-wide analyses, for TFV clearance we considered all SNPs in 11 candidate genes, and 18 PharmGKB SNPs. For CrCl change we also considered 77 SNPs associated with renal phenotypes in the GWAS Catalog. Results: Median CrCl at baseline was 116 ml/min (IQR 100 to 136). Median CrCl change at 6 months in TDF and ABC arms was -0.5 mL/min (-10.7 to +10.8) and +2.2 (IQR -9.9 to +13.2), respectively. Correcting for multiple comparisons, no SNP was associated with plasma TFV clearance or differential CrCl change between TDF and ABC arms, respectively. In TFV clearance candidate gene analysis, most SNPs evaluated were in ABCC4 . In the ABCC4 region, the lowest p-value was in CLDN10 (rs12866697, P=1.4x10 -3 ). Among African Americans, SLC22A2 rs3127573 was associated with a positive 6-month CrCl change (P = 3.3x10 -5 ). Previously reported SNPs (e.g. ABCC2 -24T Ç C) were not associated with CrCl change at nominal significance. Conclusions: Among A5202 participants randomized to TDF/emtricitabine-containing regimens, no SNP was genome-wide associated with plasma TFV clearance or with differential 6-month CrCl change between TDF and ABC arms. We did not replicate SNPs previously associated with TDF renal toxicity. 518 Variant ITPA Phenotypes Are AssociatedWith Increased Ribavirin Triphosphate Levels Leah C. Jimmerson 1 ;Thomas J. Urban 2 ; Eric Meissner 3 ; Ariel Hodara 1 ; Jacob A. Langness 4 ; Christina Aquilante 1 ; AimeeTruesdale 5 ; Fafa Baouchi-Mokrane 5 ; Michelle Ray 1 ; Jennifer J. Kiser 1 1 University of Colorado, Aurora, CO, US; 2 University of North Carolina, Chapel Hill, NC, US; 3 NIAID, NIH, Bethesda, MD, US; 4 University of Colorado Health, Aurora, CO, US; 5 Denver Health and Hospital Authority, Denver, CO, US Background: Single nucleotide polymorphisms (SNPs) in the rs1127354 and/or rs7270101 genes encoding the inosine triphosphatase (ITPA) enzyme provide protection against ribavirin (RBV)-induced hemolytic anemia. The effect of these SNPs on the active triphosphate (TP) form of RBV has not been assessed. We sought to determine if there was an association between ITPA genetics and RBV TP concentrations in red blood cells (RBC). Methods: RBC were collected from individuals receiving RBV-based HCV treatment. RBV TP concentrations were determined in RBC or dried blood spots using a validated LC-MS/MS assay linear in the range of 0.5-200 pmol/sample, then normalized to cell count (pmol/106 cells). Genotyping of ITPA SNPs was performed using the ABI TaqMan allelic discrimination kit and the BIO-RAD CFX Connect Real-Time PCR Detection System using standard TaqMan Universal PCR conditions. ITPA phenotypes were defined as 100%, 60%, 30%, and 5-10% activity. ANOVA was used for overall comparison between ITPA phenotypes with individual t-tests for differences relative to 100% activity.

Poster Abstracts

339

CROI 2015