CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Methods: An existing and validated p-PBPK model of maternal darunavir/ritonavir exposure was coded in Berkeley Madonna to allow expansion with a feto-placental unit and include bidirectional placental transport of darunavir, at term. In order to parameterize the model, we determined maternal-to-fetal (mtf) and fetal-to-maternal (ftm) darunavir/ ritonavir placental clearance with an ex vivo human cotyledon perfusion model. Simulated maternal PK profiles were compared with observed clinical data to verify the validity of the maternal model aspect. Next, population fetal PK profiles were simulated for different darunavir/ritonavir dosing regimens. These profiles were compared with available cord blood concentrations in vivo. Results: An average (±SD) mtf cotyledon clearance of 0.91±0.11 mL/min and ftm of 1.6±0.3 mL/min was determined (n=6 perfusions). Scaled placental transfer was included into a feto-placental unit and integrated in the p-PBPK model. For darunavir 600/100mg twice a day, the simulated fetal plasma C max , C trough , T max and T 1/2 were; 1.1 mg/L, 0.57 mg/L, 3 hours, and 21 hours, respectively. This indicates that the fetal population C trough is higher than the protein-adjusted EC 90 for wild type virus (0.20 mg/L) and around the EC 90 for resistance virus (0.55 mg/L). The simulated ftm plasma concentration ratio (range) over a dosing interval was 0.30 (0.16 - 0.37), compared to a median (range) ratio for observed darunavir ctm plasma ratio of 0.18 (0 - 0.82). Conclusion: A p-PBPK model for maternal darunavir exposure was extended with a feto-placental unit. The simulated fetal darunavir plasma concentrations were in the range of observed cord blood concentrations. This advanced model provides a valuable tool in assessing the implications of new dosing regimens, optimizing the safety of maternal pharmacotherapy, and optimizing fetal antiretroviral treatment. 754 SUBSTANTIALLY LOWER RILPIVIRINE PLASMA CONCENTRATIONS DURING PREGNANCY Angela Colbers 1 , Stein Schalkwijk 1 , Deborah Konopnicki 2 , Andrea Gingelmaier 3 , John Lambert 4 , Ineke van der Ende 5 , José Moltó 6 , David M. Burger 1 , for the PANNA network 1 Radboud Univ Med Cntr, Nijmegen, Netherlands, 2 Saint-Pierre Univ Hosp, Brussels, Belgium, 3 Klinikum der Univ München, München, Germany, 4 Mater Misericordiae Univ Hosp Dublin, Dublin, Ireland, 5 Erasmus Univ Med Cntr, Rotterdam, Netherlands, 6 Fundació Lluita Contra la Sida, Badalona, Spain Background: During pregnancy adequate antiretroviral exposure is important to prevent treatment failure, resistance and mother-to-child transmission (MTCT). However, pregnancy-related physiological changes may result in decreased antiretroviral exposure. Limited data is available on the pharmacokinetics (PK) of rilpivirine (RPV) during pregnancy. We aimed to study the PK of RPV during pregnancy, including placental transfer. Methods: An open-label, multi-centre phase IV study in HIV-1-infected pregnant women recruited in HIV treatment centers in Europe (PANNA Network). Patients treated with RPV 25mg once daily during pregnancy had intensive steady-state 24-hour PK profiles in the third trimester and postpartum. RPV was taken with food. When feasible, cord blood and matching maternal blood samples were taken at delivery to asses placental transfer. RPV plasma concentrations were determined with a validated LC-MS method. The proposed minimum effective concentration of RPV was 0.04 mg/L (based on ECHO/THRIVE PK data). Results: Fifteen patients (10 black, 2 white, 2 Asian and 1 other) with a median (range) age of 30 (19-36) years were included in the analysis. Median (range) gestational age at delivery was 40 weeks (38-42); birth weight was 3480 (2770-4470) gr. Approaching delivery all patients had a VL <50 cps/mL. No children were HIV-infected, no birth defects were reported. 15 PK curves during 3rd trimester and postpartumwere available. Geometric Mean Ratios (90% confidence interval) of PK parameters third trimester/postpartum were: 0.53 (0.45-0.63) for AUC0-24; 0.63 (0.54-0.74) for Cmax; and 0.46 (0.37-0.56) for C0h. Two out of 15 patients had a sub-therapeutic C0h in the third trimester, no sub- therapeutic levels were observed postpartum. The median (range, n=5) ratio of cord blood/maternal plasma RPV concentrations was 0.5 (0.35-0.81). Conclusion: In this study exposure to RPV was about 50% lower in the third trimester of pregnancy, however, in this limited number of patients, maternal VL was suppressed close to delivery and no MTCT took place. It is important that RPV is taken with a meal during pregnancy and we would advice TDM in the third trimester to avoid sub-therapeutic exposure. 755 ELVITEGRAVIR/COBICISTAT PHARMACOKINETICS IN PREGNANCY AND POSTPARTUM Brookie Best 1 , Edmund Capparelli 1 , Alice Stek 2 , Edward Acosta 3 , Elizabeth Smith 4 , Nahida Chakhtoura 5 , Jiajia Wang 6 , Adriane Hernandez 7 , Mark Mirochnick 8 , for the IMPAACT P1026s ProtocolTeam 1 Univ of California San Diego, La Jolla, CA, USA, 2 Univ of Southern California, Los Angeles, CA, USA, 3 Univ of Alabama at Birmingham, Birmingham, AL, USA, 4 DAIDS, NIAID, Rockville, MD, USA, 5 NICHD, Bethesda, MD, USA, 6 Harvard Univ, Boston, MA, USA, 7 Frontier Sci & Tech Rsr, Amherst, NY, USA, 8 Boston Med Cntr, Boston, MA, USA Background: Elvitegravir (EVG), an integrase strand transfer inhibitor, is significantly metabolized by CYP3A and UGT 1A1/3, and must be administered with a pharmacokinetic (PK) booster. It has not been studied in pregnant women or infants. This study described EVG/cobicistat (COBI) exposure during pregnancy compared to postpartum and in infant washout samples after delivery. Methods: IMPAACT protocol P1026s is an ongoing, nonrandomized, open-label, parallel-group, multi-center, international and domestic, phase-IV prospective study of antiretroviral PK in HIV-infected pregnant women. Intensive steady-state 24 hour PK profiles of EVG/COBI following 150/150 mg once-daily dosing were performed during the 2nd trimester (2T), 3rd trimester (3T) and 6-12 weeks postpartum (PP). Infant EVG washout samples were collected if birth weight > 1000 grams and there were no severe malformations or medical conditions. EVG/COBI were measured by validated LC-MS/MS with a quantitation limit of 10 ng/mL. A two-tailed Wilcoxon signed rank test (α = 0.10) was employed for paired within-subject comparison. Results: Twenty-nine subjects from the US were enrolled – 19 black, 3 white, 6 Hispanic, 1 Asian/Pacific Islander with a median age of 29 years at 3T (range 19 – 48). EVG/COBI PK data were available for 16, 20 and 15 women in 2T, 3T and PP, respectively. EVG exposure was lower and clearance was higher in the 2T and 3T compared to PP (Table 1). COBI exposure was lower and clearance higher in the 2T and 3T compared to postpartum, significantly for 3T. Washout EVG/COBI PK data were available for 18 infants; EVG elimination half-life was 7.4 hours (range 4.3 - 13); COBI was undetectable in all infant samples. Viral load at delivery was < 50 copies/mL for 14 of 19 women (74%). Median infant gestational age at birth was 38.8 weeks. Congenital anomalies were reported in 2 infants. Twenty of 26 infants were HIV-negative based on best available data, and 6 are indeterminate or pending thus far. Conclusion: EVG/COBI exposure are substantially lower in pregnancy compared to postpartum. Infant EVG elimination half-life was similar to postpartummaternal subjects and historical non-pregnant adult controls. More PK, safety and outcome data in pregnant women are needed before EVG/COBI can be recommended for use during pregnancy. 756 PROTEASE-INHIBITOR–BASED CART IS ASSOCIATED WITH HIGH ESTRADIOL LEVELS IN PREGNANCY Kayode Balogun 1 , Monica Guzman 1 , Eszter Papp 1 , Mona Loutfy 2 , Mark Yudin 3 , Jay MacGillivray 4 , Kellie Murphy 5 , Sharon Walmsley 6 , Michael Silverman 7 , Lena Serghides 1 1 Univ Hlth Network, Toronto, Ontario, Canada, 2 Women’s Coll Rsr Inst, Toronto, Ontario, Canada, 3 St. Michael’s Hosp, Toronto, Ontario, Canada, 4 Mt Sinai Hosp, Toronto, Ontario, Canada, 5 Univ of Toronto, Toronto, Ontario, Canada, 6 Univ of Western Ontario, London, Ontario, Canada Background: Over 1.5 million HIV-infected (HIV+) women become pregnant annually. Most of these women access combination antiretroviral therapy (cART) for their own health and to prevent perinatal transmission of HIV. Studies have linked protease inhibitor (PI)-based cART to adverse birth outcomes. Endocrine dysfunction is common among HIV+ individuals, and altered levels of estradiol (E2) have been reported in patients on cART. However, no data exist on the effect of cART on E2 in the context of pregnancy. Our objective was to investigate the effect of PI-based cART on E2, and to investigate the association between E2 and adverse birth outcomes in HIV+ pregnant women. Methods: A multi-centre prospective cohort study of 96 pregnant women was conducted between 2010 and 2015 in Toronto, Canada. Plasma samples were collected from HIV+ pregnant women on PI-based regimens (n=46), PI-sparing regimens (n=8), and matched controls (n=42) at 3 different gestational time points defined as early (12-18 weeks), mid (24-28 weeks), and late (34-38 weeks). Maternal and cord plasma samples were also collected at delivery. Plasma levels of E2, sex hormone binding globulin (SHBG), and the E2 precursor dehydroepiandrosterone sulfate (DHEAS) were measured by ELISA. Associations between birth weight and hormone levels were assessed by Spearman correlation.

Poster and Themed Discussion Abstracts

CROI 2017 327