CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

777 Pharmacokinetics of Daily Nevirapine in Neonates at High Risk of HIV Acquisition Tim R. Cressey 1 ; Baralee Punyawudho 2 ; Saik Urien 3 ; Gonzague Jourdain 4 ; Sophie Le Coeur 5 ; Nicole Ngo-Giang-Huong 6 ; Pra-ornsuda Sukrakanchana 7 ; Suporn Koetsawang 8 ; Marc Lallemant 9 ; for the PHPT-5 StudyTeam. 1 Harvard Sch of PH, Boston, MA, USA; 2 Chiang Mai Univ, Chiang Mai, Thailand; 3 EAU08 Univ Paris Descartes, Paris, France; 4 IRD UMI 174-PHPT, Marseille, France; 5 Inst d’Etudes Démographiques, Paris, France; 6 Prog for HIV Prevention and Treatment/IRD 175, Chiang Mai, Thailand; 7 Prog for HIV Prevention and Treatment/IRD 176, Chiang Mai, Thailand; 8 Mahidol Univ, Bangkok, Thailand; 9 Prog for HIV Prevention and Treatment/IRD 174, Chiang Mai, Thailand Background: Infants born to HIV-infected women with no or a short duration of antiretroviral treatment during pregnancy are at high-risk of perinatal transmission. Nevirapine (NVP) is a key component of antiretroviral (ARV) prophylaxis for infants at high risk of intrapartum HIV infection. We developed a population pharmacokinetic (PK) model to describe NVP concentrations in infants from birth through the first 2 weeks of life. Methods: Infants were enrolled in an adaptive single-arm, multicenter trial in Thailand assessing ‘Perinatal Antiretroviral Intensification’ to prevent mother-to-child transmission of HIV in pregnant women with <8 weeks of triple ARV treatment prior to delivery (ClinicalTrials.gov NCT01511237). Intensification consisted of maternal single-dose NVP (sd-NVP) during labor and an infant 2 week course of AZT+3TC+ NVP, followed by AZT+3TC for 2 weeks. NVP dosing was 2 mg/kg for 7 days, then 4 mg/kg for 7 days. Infant blood samples were draw from the umbilical cord, on the first day of life and at 2 weeks. NVP population PK parameters were estimated using non-linear mixed-effects regression models. Monte Carlo simulations were performed to estimate the probability of achieving target NVP trough concentrations (C24) for prophylaxis (>0.10 mg/L) and for therapeutic efficacy (>3.0 mg/L). Results: Sixty two infants (56%male) were included. At birth, median (range) gestational age was 38.6 (35.7-41.7) weeks and weight was 2.9 (2.3-3.7) kg. NVP concentrations were best described by a one compartment PK model. Body weight influenced oral clearance (CL/F) and volume of distribution (Vd/F). Population estimates of NVP CL/F and Vd/F were 3.67 L/h and 0.144 L, respectively. Based on simulations for a 3 kg infant, without maternal sd-NVP, >88%would have a NVP C24 >0.1 mg/L after 24 hours through 2 weeks. Predictions using the WHO recommended 15 mg once daily dose, >92% of infants have a NVP C24 >0.1 mg/L after 24 hours. For NVP-based therapy, assuming linear kinetics, a 6 mg/kg twice daily dose produced a C24 >3.0 mg/L in 72% of infants at 48 hours and 76% at 2 weeks. With 8 mg/kg twice daily the C24 was predicted to be >3.0 mg/L in 81% of infants at 48 hours and 86% at 2 weeks. Conclusions: The escalating NVP dose in PHPT-5 and the WHO single dose approach rapidly achieve and maintain target prophylactic concentrations over the first 2 weeks of life. Therapeutic NVP doses of 6 to 8 mg/kg twice daily should be studied in infants initiating treatment within the first few days of life. 778 Haematological Toxicity and Neonatal Prophylaxis in Infants at High MTCT Risk Elena Chiappini 1 ; Luminita Ene 2 ; Luisa Galli 1 ; Catiuscia Lisi 1 ; Ruslan Malyuta 3 ; Antoni Noguera-Julian 4 ; Pablo Rojo Conejo 5 ; Christoph Rudin 6 ; Claire Thorne 7 ; for the European Pregnancy and Paediatric HIV Cohort Collaboration in EuroCoord 1 Univ of Florence, Florence, Italy; 2 Victor Babes Hosp, Bucharest, Romania; 3 Perinatal Prevention of AIDS Initiative, Odessa, Ukraine; 4 Hosp Sant Joan de Déu, Barcelona, Spain; 5 Hosp 12 de Octubre, Madrid, Spain; 6 Univ Children’s Hosp Basel, Basel, Switzerland; 7 Univ Coll London, London, UK Background: Guidelines recommend use of combination neonatal prophylaxis (CNP) with 2 or 3 drugs in specific high risk situations. Data on safety of neonatal prophylaxis (NP), particularly CNP, are limited. Our aimwas to identify whether NP type is associated with 1) severe or potentially life-threatening anaemia or neutropenia in the first 6 months of life and 2) haemoglobin (Hb) level and neutrophil count (NC) at ages 0-18 months. Methods: An individual patient-data meta-analysis was conducted within 6 cohorts. Infants born 01/01/96 to 30/06/10, at high risk for acquiring HIV (defined according to US Guidelines) and with HIV status, Hb and NC measures available were included. CNP was defined as ≥2 antiretrovirals given for PMTCT. Hb and NC were graded using 2004 DAIDS paediatric toxicity tables. Adjusted logistic regression models assessing risk of grade 3-4 anaemia / neutropenia in the first 6 months of life included cohort, period, infant HIV and in utero ART exposure a priori . Mixture models of 1) Hb levels and 2) log10-transformed NC were conducted to explore associations with NP type at ages 0-18 months. Results: Of the 1836 infants (969 male), 468 (25%) were preterm (<37 weeks), 1149 (63%) had been exposed to antenatal cART and 398 (22%) received CNP (126 with 3 drugs). Median duration was 5.7 weeks for 1 drug NP and 5.9 weeks for CNP. Overall, 117 (6.7%) infants had Grade 3-4 anaemia at age 0-6 months and 140 (9.1%) had Grade 3-4 neutropenia (Table). Grade 3-4 anaemia was not associated with NP type (AOR 1.09 for 1 drug and 1.70 for 3 drugs vs 2 drug NP, p >0.05), but was with preterm delivery (AOR 1.86 for 33-36 and 2.68 for ≤32 weeks vs term) and in utero ART exposure (data not shown). Infants receiving no NP had increased risk of grade 3-4 neutropenia (AOR 3.26 vs 2 drug NP, p =0.04), as did severe preterm (≤32w) infants (AOR 2.55 vs term, p =0.006). Overall 7746 Hb and NC results were available for 1836 infants up to age 18 months; no significant differences in predicted Hb levels or NC were apparent by NP type (Hb: coefficient -0.189 [95%CI -0.38,0.007], p =0.060; NC: 0.021 [95%CI -0.012, 0.055], p =0.218). Conclusions: A small proportion of infants experienced grade 3-4 haematological toxicity in their first 6 months of life; risk of anaemia was not associated with type of NP exposure in adjusted analysis, whilst among infants receiving NP, there was no significant difference in risk of neutopenia by number of NP drugs.

Poster Abstracts

779 Maternal CMV Urinary Shedding in HIV-InfectedWomen and Congenital CMV Infection

Kristina Adachi 1 ; Jiahong Xu 2 ; Bonnie Ank 3 ; D. H.Watts 4 ; Esau C. Joao 5 ; Jose H. Pilotto 6 ;Yvonne J. Bryson 1 ;Valdilea G.Veloso 7 ; Lynne M. Mofenson 8 ; Karin Nielsen-Saines 1 1 Univ of California Los Angeles, Los Angeles, CA, USA; 2 Westat, Inc, Rockville, MD, USA; 3 David Geffen Sch of Med at Univ of California Los Angeles, Los Angeles, CA, USA; 4 Office of the US Global AIDS Coordinator, US Dept of State, Washington, DC, USA; 5 Hosp Fed dos Servidores do Estado, Rio de Janeiro, Brazil; 6 Hosp Geral de Nova Iguaçu, Rio de Janeiro, Brazil; 7 Fiocruz, Rio de Janeiro, Brazil; 8 Previously with NIH, Bethesda, MD, USA Background: Congenital cytomegalovirus (CMV), a cause of hearing loss and developmental delay, may be more prevalent in HIV-exposed infants. We evaluated CMV urinary shedding in HIV-infected pregnant women to determine if HIV-exposed infants born to mothers with CMV shedding were at increased risk for congenital CMV or HIV.

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CROI 2016