CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Results: Birth weight centile was lower in the HIV+ group compared to controls [median 25 IQR (9.5-55.9) vs. 53.5 (30.75-70.75), p=0.0008]. There was a significant increase in E2 levels frommid to late gestation in HIV+ women on PI-based regimens, but not in women on PI-sparing regimens or HIV-uninfected controls. E2 levels in the cord were significantly higher in the PI-cART group compared to controls [median 23.9 ng/mL IQR (16.36-36.40) vs. 15.68 (12.19-21.21, p=0.0018], as were DHEAS levels and the E2/SHBG index. There was a positive correlation between cord E2 and DHEAS levels in the PI-cART group (r=0.47; p=0.0013). Cord E2 levels correlated inversely with birth weight centile in the PI-cART exposed women (r= -0.41; p=0.007), but not in controls or non-PI-cART exposed women. Conclusion: Our data suggest that PI-cART use in pregnancy may be associated with higher than normal levels of E2, perhaps stimulated by increased production of DHEAS. An association between high cord E2 levels and fetal growth restriction was observed in PI-cART exposed pregnant women. 757 RALTEGRAVIR PHARMACOKINETICS AND SAFETY IN HIV-1 EXPOSED NEONATES: DOSE-FINDING STUDY Diana F. Clarke 1 , Edward Acosta 2 , Anne Chain 3 , Mae Cababasay 4 , Jiajia Wang 5 , Hedy Teppler 6 , Elizabeth Smith 7 , Rohan Hazra 8 , Mark Mirochnick 9 , for the IMPAACT P1110 ProtocolTeam 1 Boston Med Cntr, Boston, MA, USA, 2 Univ of Alabama at Birmingham, Birmingham, AL, USA, 3 Merck Rsr Labs, Rahway, NJ, USA, 4 Harvard Univ, Boston, MA, USA, 5 Merck Rsr Labs, North Wales, PA, USA, 6 DAIDS, NIAID, Rockville, MD, USA, 7 NICHD, Bethesda, MD, USA, 8 Boston Univ, Boston, MA, USA Background: Raltegravir (RAL) has potential for use as prophylaxis of perinatal transmission and early intensive treatment of neonates with HIV infection. Safety and pharmacokinetics (PK) of RAL was studied to determine the appropriate dose of RAL oral granules for suspension during the first 6 weeks of life. Methods: IMPAACT P1110 is a phase I multicenter trial enrolling full-term HIV-1 exposed neonates at high risk of acquiring HIV-1-infection, with or without in utero RAL exposure. Study design included two cohorts: cohort 1 infants received 2 single RAL doses 1 week apart; cohort 2 infants received daily RAL dosing for first 6 weeks of life. PK data from Cohort 1 (previously reported) and from older infants and children were combined in a population PK model and simulations were used to select this daily RAL dosing regimen for evaluation in RAL naïve infants in Cohort 2: 1.5 mg/kg daily starting within 48 hours of life through day 7; 3 mg/kg twice daily on days 8-28 of life; 6 mg/kg twice daily after 4 weeks of age. Four plasma samples were collected after the initial dose and on the 3 mg/kg dose between 15-18 days of life; sparse sampling was obtained when doses were changed. Samples were analyzed for RAL concentrations using a validated HPLC-MS-MS method. AUC was estimated using the trapezoidal method. Protocol exposure targets for each subject are AUC24 12-40mg*h/L, AUC12 6-20 mg*h/L, C12 or C24 > 33ng/mL. Safety was assessed based on clinical and laboratory evaluations. Results: Twenty-six RAL-naïve infants were enrolled in Cohort 2. Evaluable PK results and 6 week safety data are available for 25 infants. After the first dose of 1.5 mg/kg, geometric mean (GM) RAL AUC24 was 38.2 mg*h/L and C24 was 948 ng/mL. On 3 mg/kg twice daily the GM RAL AUC12 was 14.3 mg*h/L and Cl2 estimated to be 176.1 ng/mL. There were no safety concerns associated with daily RAL administration through 6 weeks of life. Conclusion: Daily RAL was safe and well tolerated during the first 6 weeks’ of life. All GM protocol exposure targets were met. In some infants AUC24 following the initial dose was slightly above target range but this was considered acceptable given the rapid increase in RAL metabolism over the first week of life. The PK targets and the safety guidelines have been met for RAL-unexposed infants in cohort 2 using the specified dosing regimen.

Poster and Themed Discussion Abstracts

758 PHARMACOKINETICS OF NEVIRAPINE PROPHYLAXIS IN HIV-EXPOSED LOW BIRTH WEIGHT INFANTS

Adrie Bekker 1 , Avy Violari 2 , Mae Cababasay 3 , Jiajia Wang 3 , Lubbe Wiesner 4 , Edmund Capparelli 5 , Mark Cotton 1 , Firdose Nakwa 2 , Mark Mirochnick 6 , for the IMPAACT P1106Team 1 Stellenbosch Univ, Cape Town, South Africa, 2 Univ of Witwatersrand, Johannesburg, South Africa, 3 Harvard Univ, Boston, MA, USA, 4 Univ of Cape Town, Cape Town, South Africa, 5 Univ of California San Diego, La Jolla, CA, USA, 6 Boston Med Cntr, Boston, MA, USA Background: There are limited data on nevirapine (NVP) pharmacokinetics (PK) and safety in low birth weight (LBW) infants (< 2500g). Methods: IMPAACT P1106 is a Phase IV study on PK and safety in LBW infants receiving antiretroviral and tuberculosis medicines as part of their clinical care in two South African sites. Arm 1 focused on NVP for HIV-1 prophylaxis. Infants were stratified by birth weight (<1400 g, 1400 - <1800 g, and 1800 - <2500g). NVP was dosed at 2 mg/kg once daily (birth to 14 days of age), followed by 4 mg/kg once daily. Infant characteristics, PK samples and safety data were collected at study entry (day 7-14 of age) and at 4, 6, 10, 16 and 24 weeks of age. An adverse event (AE) was classified as expected (associated with prematurity) or unexpected. Plasma samples were assayed for NVP by LC-MS with lower limit of detection of 0.02 μg/ml. The NVP trough target was > 0.1 μg/ml. Results: Forty LBW infants, mean birth weight of 1675 g (range 950-2460 g) and mean gestational age of 33 weeks (range 28-40 weeks) were enrolled. NVP trough concentrations were available for 27 infants (94 observations) with mean weight of 2147 g (range 965 – 6050 g) and mean postmenstrual age of 37 weeks (range 29 – 56 weeks) at time of PK sampling. Mean NVP trough concentration across all visits was 1.87 μg/mL (range < 0.02 - 10.69 μg/mL). NVP trough concentrations were < 0.1 μg/ml in 6/94 (6%) observations. Below target samples were all from later visits (median postmenstrual age 44 weeks; median weight of 3903 grams) on infants already discharged to home and receiving NVP from caregiver. At the initial visit, lower gestational age was associated with higher NVP concentration. Across all visits, NVP trough concentrations were inversely related (p=0.001) to infant postnatal age (see figure). Three infants died; 2 from sudden unexpected death and 1 from confirmed septicemia. Ten infants had Grade 3/4 unexpected AEs, most common being pneumonia (n=4). Nine infants had Grade 3/4 expected AEs, most common being presumed or confirmed sepsis (n=6). All AEs were assessed as unrelated to NVP.

CROI 2017 328