CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

464 HIGHER NRTI METABOLITE:ENDOGENOUS NUCLEOTIDE RATIOS IN OLDER HIV+WOMEN ON TDF/FTC Julie B. Dumond 1 , Camden Bay 1 , Julie A. Nelson 1 , Craig Sykes 1 , Kathryn Anastos 2 , Roopali Sharma 3 , Seble Kassaye 4 , Maria Villacres 5 , Ruth Greenblatt 6 , Audrey French 7 , Stephen J. Gange 8 , Igho Ofotokun 9 , Margaret Fischl 10 , David Vance 11 , Adaora Adimora 1 1 University of North Carolina Chapel Hill, Chapel Hill, NC, USA, 2 Albert Einstein College of Medicine, Bronx, NY, USA, 3 Touro College, New York, NY, USA, 4 Georgetown University, Washington, DC, USA, 5 University of Southern California, Los Angeles, CA, USA, 6 University of California San Francisco, San Francisco, CA, USA, 7 Cook County Health & Hospitals System, Chicago, IL, USA, 8 Johns Hopkins University, Baltimore, MD, USA, 9 Emory University, Atlanta, GA, USA, 10 University of Miami, Miami, FL, USA, 11 University of Alabama at Birmingham, Birmingham, AL, USA Background: The Women’s Interagency HIV Study (WIHS) began in 1993, and follow-up of HIV+ women continues as the cohort ages. The altered immune states of aging + HIV may affect intracellular metabolism of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC); increased cellular senescence, as measured by p16 INK4a expression, decreases FTC-triphosphate (FTCtp) concentrations. The effect of age and inflammation on the ratio of intracellular metabolites (IM; tenofovir diphosphate [TFVdp], FTCtp) to their endogenous nucleotides (EN; dATP and dCTP), a potential efficacy and toxicity marker, was assessed in the WIHS. Methods: Frozen paired PBMC and plasma samples fromwomen receiving TDF/FTC 300/200mg with viral load <200 c/mL were obtained and dichotomized by participant age at collection into ≤45yrs and ≥60yrs. PBMC concentrations of TFVdp, FTCtp, dATP, and dCTP were measured by LC-MS/MS. Plasma IL-6 and sCD163 were measured by ELISA. A log-rank test compared ratios between age groups. Spearman’s correlation analysis assessed relationships between IM and EN concentrations, cytokines, and clinical variables. Censored normal multiple linear regression, adjusted for race, smoking, EGFR, and background drugs, assessed relationships between IM, EN, and IM:EN ratios, and age. Results: Demographics are presented in Table 1. Women ≥60yrs had significantly higher TFVdp:dATP (0.54 vs 0.31, p=0.009) and FTC:dCTP (18.9 vs 13.4, p=0.01) ratios compared to women ≤45yrs. In women ≥ 60yrs, TFVdp was correlated with EGFR (rho=-0.38, p=0.002). From the regression analyses, no evidence was found that dATP or dCTP were associated with race, smoking, or EGFR; nor IL-6 or sCD163 with age. In women ≤45yrs, sCD163 and TFVdp were correlated (rho=-0.28; p=0.01); in women ≥60yrs, FTCtp was correlated with sCD163 (rho=0.28, p=0.03) and IL-6 (rho=0.41, p=0.001). In the regression analysis, age influenced dATP and TFVdp, (p=0.02, 0.008, respectively). Conclusion: In cross-sectional analysis, older women demonstrated higher TFVdp:dATP and FTCtp:dCTP ratios. Decreased renal function may contribute to this, though dATP and TFVdp concentrations remained influenced by age after adjusting for EGFR in a regression analysis. The differing associations between cytokines and IMs by age is interesting and warrants further investigation to determine causal factors. Inclusion of men and additional immune markers are needed to fully elucidate aging effects on TDF/FTC intracellular metabolism and potential clinical consequences.

465 ETRAVIRINE PHARMACOKINETICS IN TREATMENT-EXPERIENCED CHILDREN AGES 1- <6 YEARS

Christine E. MacBrayne 1 , Richard Rutstein 2 , Ram Yogev 3 , AndrewWiznia 4 , Lee Fairlie 5 , Bobbie Graham 6 , Carmelita Alvero 7 , Jack Moye 8 , Ellen Townley 9 , Herta Crauwels 10 , Xavier Woot de Trixhe 10 , Lotke Tambuyzer 10 , Simon Vanveggel 10 , Magda Opsomer 10 , Jennifer J. Kiser 1 1 University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 2 Children’s Hospital of Philadelphia, Philadelphia, PA, USA, 3 Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA, 4 Albert Einstein College of Medicine, Bronx, NY, USA, 5 University of the Witwatersrand, Acornhoek, South Africa, 6 Frontier Science & Technology Research Foundation, Inc, Amherst, NY, USA, 7 Harvard University, Cambridge, MA, USA, 8 National Institute of Child Health and Human Development, Bethesda, MD, USA, 9 NIAID, Rockville, MD, USA, 10 Janssen, Beerse, Belgium Background: IMPAACT P1090 is a Phase I/II study of etravirine (ETR) pharmacokinetics (PK), dose- finding, and safety in antiretroviral (ARV) treatment-experienced HIV-infected children 1 to <6 yrs from the U.S., South Africa (SA) and Brazil. Methods: Treatment-experienced children on a failing ARV regimen for ≥8 wk or on a treatment interruption for ≥4 wk with a history of virologic failure (VF) were enrolled into one of two age cohorts (2-<6 yr; 1-<2 yr). ETR was combined with at least two active ARVs, one of which was a ritonavir-boosted protease inhibitor (PI/r). ETR was dosed by weight-band. Participants 8-<10 kg received 75mg twice daily [bid]; 10-<20 kg, 100mg bid; and 20-<25 kg, 125mg bid. Tablets were swallowed whole or dispersed in liquid. All participants underwent 12-hr PK sampling on day 14 (±4 days). Participants with ETR AUC12h <10th percentile of adults (<2350 ng*hr/mL) had an individual ETR dose increase and repeat PK. For each cohort, PK and safety were confirmed in the first six participants before further enrolling at the same dose. The target geometric mean ETR AUC12h was 2713 to 6783 ng*hr/mL (60-150% of adult AUC12h). Criteria for acceptable safety included no suspected adverse drug reaction resulting in death, life-threatening toxicity, any grade 4 event, or ≥3 participants discontinuing due to grade ≥3 toxicity. Results: Twenty-one participants (nine each from SA and Brazil, three from U.S.) received ETR weight-band based doses. Demographics, ETR dosing and PK are shown for each cohort in the table. Both cohorts passed pre-determined PK and safety criteria, but seven (33%) children, all taking ETR dispersed, had an AUC12h of <2350 ng*hr/mL and underwent an ETR dose increase. Geometric mean ETR AUC12hr was significantly higher in participants that swallowed the tablet whole vs. dispersed, 7943 ng*hr/mL (n=6) vs. 2697 ng*hr/mL (n=15), respectively (p=0.0002). After a median (range) follow-up of 62 (9-234) weeks, three (14%) participants (2/3 with day 14 AUC12h <2350 ng*hr/mL) have discontinued due to VF. One participant discontinued due to a treatment-related toxicity (grade 4 lipase).

Poster Abstracts

CROI 2018 166