CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

457 ASSOCIATION BETWEEN INTEGRASE INHIBITOR HAIR CONCENTRATIONS AND WEIGHT GAIN IN WOMEN Cecile D. Lahiri 1 , Cyra Christina Mehta 1 , Christine D. Angert 1 , Craig Sykes 2 , Sheri Weiser 3 , Deborah Gustafson 4 , Audrey French 5 , Adaora Adimora 2 , Deborah Konkle-Parker 6 , Anjali Sharma 7 , Hector Bolivar 8 , Seble Kassaye 9 , Igho Ofotokun 1 , Elizabeth T. Golub 10 , Anandi N. Sheth 1 1 Emory University, Atlanta, GA, USA, 2 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 3 University of California San Francisco, San Francisco, CA, USA, 4 SUNY Downstate Medical Center, Brooklyn, NY, USA, 5 Stroger Hospital of Cook County, Chicago, IL, USA, 6 University of Mississippi Medical Center, Jackson, MS, USA, 7 Albert Einstein College of Medicine, Bronx, NY, USA, 8 University of Miami, Miami, FL, USA, 9 Georgetown University, Washington, DC, USA, 10 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Background: Integrase strand-transfer inhibitors (INSTIs) were associated with body weight gain among women living with HIV (WLH) in the Women’s Interagency HIV Study (WIHS). Hair drug concentrations measure cumulative exposure and are associated with toxicity in other antiretroviral therapy (ART) medications. For the first time, we report the relationship between INSTI hair concentrations and weight change in WLH. Methods: Data from 2006-2017 were analyzed from virally-suppressed (<1000 cop/mL) WLH in WIHS who switched/added raltegravir (RAL) or dolutegravir (DTG) to ART with quantifiable hair concentrations. Body weights were measured 6-12 months pre- and 6-18 months post INSTI switch/add. Hair concentrations were measured with validated liquid chromatography/tandem mass spectrometry assays 6-18 months post INSTI switch/add and dichotomized at the median. Linear models assessed the association between dichotomized INSTI hair concentration and weight change from pre-switch/add. The association between clinically significant weight gain (≥7%) and INSTI hair concentrations was assessed through Wilcoxon Rank Sum Tests and chi-square tests. Results: 136 WLH contributed 231 hair samples with mean 1.9 years (±0.12) follow up. Mean age was 49.6(±9.2), 73(54%) Black, baseline BMI 30.4 kg/ m 2 (±9.5), 75(55%) were on DTG, and 61(45%) on RAL. Mean body weight change was +0.7 kg (±3.8) for RAL and +0.8 kg (±5.4) for DTG. No significant associations were seen between body weight change as a continuous variable with either RAL or DTG hair concentrations (p=0.2554 and p=0.2826, respectively). Median RAL and DTG hair concentrations were not significantly different in WLH with ≥7%weight gain compared to <7%: 0.71 ng/mg (Q1:0.55, Q3:1.10) vs 0.84 ng/mg (Q1:0.40, Q3:1.44), p=0.4735 and 793.0 pg/ mg (Q1:316, Q3:1270) vs 409.0 pg/mg (Q1:198, Q3:714), p=0.1037 respectively (Figure). With combined INSTI groups, 14 of 24(58%) WLH with ≥7%weight gain had hair concentrations above the median vs 51 of 109(47%) with <7% weight gain, p=0.3057. Conclusion: In virally-suppressed WLH, the effect of RAL and DTG cumulative drug exposure on body weight change over the short term appears to be limited. In addition to further pharmacologic assessments, other mechanisms to explain INSTI-associated weight gain should be explored.

1 University of North Texas, Fort Worth, TX, USA, 2 MedStar Health Research Institute, Hyattsville, MD, USA, 3 University of Washington, Seattle, WA, USA, 4 Johns Hopkins University, Baltimore, MD, USA Background: Several studies of pregnant women on TDF/FTC report lower TFV exposures in the 2nd and 3rd trimesters due to pregnancy-related increased volume of distribution and renal clearance. The Partners Demonstration Project showed the largest decline during pregnancy compared to non-pregnant women – 45% to 58% in TFV and active TFV diphosphate concentrations, respectively. We hypothesized that doubling the PrEP dose in pregnancy maintains the target plasma, PBMC, and tissue concentrations of TDF/FTC associated with high levels of HIV protection. Methods: To estimate the TDF/FTC exposure associated with a 2-fold dose increase, we began with a prior population PK model of plasma TFV based on data fromMTN-001, updated the model based on Partners Demonstration Project pregnancy cohort PK data, and performed an in silico simulation. We updated our prior model (NONMEMwith FOCEI method for parameter estimation) by replacing creatinine clearance with trimester of pregnancy as a time-dependent covariate on clearance as the optimized final model. As the revised model fit the data well, we used it for further simulation. We simulated 1,000 women starting with a “standard” oral 300 mg daily oral TDF dose prior to pregnancy. Upon becoming pregnant, the simulated patients were split into 2 study arms through the 3 trimesters of pregnancy: 1 arm continuing on a “standard” dose and the other arm receiving “double” the standard dose. The estimated protective trough TFV concentration benchmark (35.5 ng/mL) was based on 90% sensitivity threshold for daily dosing in non-pregnant women in HPTN 066. Results: In the non-pregnant population, our simulation showed 3.7% of women on a standard regimen would have trough levels below the protective threshold. In contrast, we found that 31.5%, 47.2%, and 62.6% of trough concentrations in the 1st, 2nd, and 3rd trimesters, respectively, were below the protective threshold (Figure). By comparison, in the simulated double dose group, only 4.4%, 7.9%, and 14.4% of troughs fell below protective levels in the 1st, 2nd, and 3rd trimesters, respectively. Conclusion: Our simulation shows >50% of research participants on standard dosing will have 3rd trimester trough plasma TFV concentrations below levels associated with protection. The double dose armmedian TFV concentration in pregnancy is very similar to non-pregnant standard dose median TFV. The simulation provides the quantitative basis for a prospective study to evaluate a double dose to adjust for TFV PK changes in pregnancy.

Poster Abstracts

459 GENITAL INFLAMMATION DOES NOT DECREASE VAGINAL TFV LEVELS IN WOMEN TAKING ORAL PrEP Jill Blumenthal 1 , Mackenzie L.Cottrell 2 , Stephen A. Rawlings 1 , Scott N. Peterson 1 , Eric Ellorin 1 , Alexis Kay 1 , Peter L. Anderson 3 , Sara Gianella 1 , Sheldon Morris 1 1 University of California San Diego, San Diego, CA, USA, 2 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 3 University of Colorado, Aurora, CO, USA Background: African studies demonstrate that genital inflammation decreases tenofovir (TFV) gel’s efficacy. We evaluated the impact of inflammation and

458 CLINICAL TRIAL SIMULATION TO IMPROVE HIV PREEXPOSURE PROPHYLAXIS DOSING IN PREGNANCY

Ayyappa Chaturvedula 1 , Rachel K. Scott 2 , Michael J. Fossler 1 , Maria Pyra 3 , Kenneth K. Mugwanya 3 , Nelly R. Mugo 3 , Jared Baeten 3 , Craig W. Hendrix 4

CROI 2020 161