CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Conclusions: While 2 nd trimester and postpartum ETV PK were similar to non-pregnant adult PK, 3 rd trimester exposure was significantly higher than postpartum and historical controls. The metabolism of ETV is complex; pregnancy, ETV itself and other drugs alter the activity of these pathways. The increased 3 rd trimester exposure may be due to decreases in CYP2C19 activity and ritonavir exposure. No ETV dose change is needed during pregnancy. 893 Pharmacokinetics of Etravirine in HIV-1–Infected Pregnant Women M Ramgopal 1 ; O Osiyemi 2 ; C Zorrilla 3 ; HM Crauwels 4 ; R Ryan 5 ; K Brown 6 ;V Hillewaert 7 ; B Baugh 6 1 Midway Immunology and Research Center, Fort Pierce, FL, US; 2 Triple O Research Institute PA, West Palm Beach, FL, US; 3 University of Puerto Rico School of Medicine, San Juan, US; 4 Janssen Infectious Diseases, Beerse, Belgium; 5 Janssen Research & Development, Titusville, NJ, US; 6 Janssen Therapeutics, Titusville, NJ, US; 7 Janssen Research & Development, Beerse, Belgium Background: Antiretroviral (ARV) therapy during pregnancy has dramatically reduced the risk of mother-to-child transmission. Physiologic changes during pregnancy can affect the PK of ARVs. Methods: Phase IIIb study evaluating HIV-1–infected pregnant women (age ≥ 18 years), in the 2 nd trimester of pregnancy, receiving ETR 200mg bid with other ARVs. ETR plasma concentrations were assessed predose and 1, 2, 3, 4, 6, 9 and 12 hours postdose during the 2 nd and 3 rd trimesters and (6-12 weeks) postpartum. ETR PK parameters were derived using non-compartmental analysis. Safety and efficacy were investigated at each visit and summarized using descriptive statistics. Results: Fifteen women (11 black, 2 Hispanic, 2 white) were enrolled; 13 had evaluable PK. ETR AUC 24h , C min and C max were higher by 46% (LS Means ratio, 90% CI: 1.46, 1.12-1.90), 131% (2.31, 1.26-4.22) and 39% (1.39, 1.15-1.67) during the 2 nd trimester and by 28% (1.28, 0.98-1.69), 93% (1.93, 1.03-3.61) and 31% (1.31, 1.08-1.59) during the 3 rd trimester, versus postpartum. ETR post-partum PK was comparable to historic controls in HIV-1 infected subjects (DUET). Though mean ETR exposures during pregnancy were higher compared to post-partum, the observed exposures were still in range with those previously observed in HIV-1 infected subjects treated with ETR 200 mg bid. Unbound ETR PK will be explored. Median baseline (BL) viral load (VL) was 49 copies/mL; for one woman, BL VL was 54,000 copies/mL and remained detectable throughout the study. All other women had VL<400 copies/mL during pregnancy (>90% had VL<50 copies/mL). The median increases in CD4 from baseline were 29 and 45 cells/mm 3 for the 2 nd and 3 rd trimester respectively, and were >100 cells/mm 3 postpartum. Four subjects had serious adverse events (SAEs), none of which were at least possibly related to ETR (premature rupture of membranes; hypertension; headache; and one subject had 3 SAEs: pregnancy induced hypertension [twice] and premature labor). One subject had a treatment emergent adverse event (atopic dermatitis) that was at least possibly related to study drug. All infants were HIV-negative. Conclusions: ETR exposure increased during pregnancy; this was not associated with an increased occurrence of SAEs. The regimen was well tolerated. Virologic response was maintained throughout the study and there was no mother-to-child transmission. These data indicate ETR 200 mg bid could be a treatment option for HIV-1 infected pregnant women. 894 Pharmacokinetics of Rilpivirine in HIV-InfectedWomen During Pregnancy and Postpartum Mark Mirochnick 1 ; Brookie M. Best 2 ; Alice Stek 3 ; Regis Kreitchmann 8 ; JiajiaWang 4 ; David Shapiro 4 ; Elizabeth Smith 5 ; Lynne Mofenson 6 ;Tim R. Cressey 7 ; Edmund Capparelli 2 1 Boston University School of Medicine, Hingham, MA, US; 2 University of California San Diego, San Diego, CA, US; 3 University of Southern California, Los Angeles, CA, US; 4 Harvard School of Public Health, Boston, MA, US; 5 National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, US; 6 Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, US; 7 Harvard School of Public Health/Chiang Mai University, Chang Mai, Thailand; 8 Irmandade da Santa Casa de Misericordia de Porto Alegre, Porte Alegre, Brazil Background: Rilpivirine (RPV), a 2 nd generation non-nucleoside reverse transcriptase inhibitor, has increased absorption when taken with food and is primarily metabolized by cytochrome P450 3A4. During pregnancy, physiological changes including alterations in intestinal transit time and increased CYP 3A4 activity may impact systemic drug exposure. The impact of pregnancy on RPV pharmacokinetics (PK) is unknown. Methods: IMPAACT Protocol P1026s is an ongoing, multicenter, non-blinded prospective study evaluating the PK of antiretrovirals (ARV) in pregnant HIV-infected women that included a cohort of US pregnant women receiving as part of clinical care combination ARV regimens including RPV 25 mg once daily with food. Intensive steady-state 24 hour PK profiles were performed during the 2 nd trimester, 3 rd trimester and 6-12 weeks postpartum. Maternal and umbilical cord blood samples were obtained at delivery. Plasma RPV concentrations were measured using liquid chromatography-mass spectrometry, with a lower limit of quantitation of 0.010 mcg/mL. The minimum target for RPV AUC 24 was 0.88 mcg*hr/mL, the 10 th percentile AUC for non-pregnant adults. Pairwise comparisons within each subject between time points were performed using a two-sided Wilcoxon signed rank test. Results: RPV PK data were available for 26 women. PK parameters are presented in the table below as median (range). There were no significant differences in any PK parameters for the 2 nd or 3 rd trimester compared to postpartum. Mean (90% CI) for the ratio of 2 nd or 3 rd trimester to postpartum log-transformed pk parameters were 1.05 (0.78-1.32) and 1.01 (0.77-1.24) for AUC and 0.94 (0.69-1.18) and 0.91 (0.70-1.12) for C(24)h, respectively. Median (range) RPV concentrations (mcg/mL) in cord blood and maternal delivery samples, and their ratio were 0.054 (BQL (below quantitation limit) - 0.102), 0.103 (BQL – 0.234) and 0.53 (0.38 – 0.83). RPV was well tolerated by all study mothers. Viral load at delivery was below 400 copies/mL for 22 of 24 women and below 50 copies/mL for 17 of 24. No infants were HIV infected, but infection data through the final 24 week visit are only available for 7 infants.

Poster Abstracts

RPV PK Parameters Conclusions: No significant differences in RPV exposure during pregnancy and postpartumwere observed. The standard RPV dose provides adequate RPV exposure during pregnancy.

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CROI 2015