CROI 2019 Abstract eBook

Abstract eBook

Oral Abstracts

45 SAFETY AND PHARMACOKINETICS OF MONOCLONAL ANTIBODY, VRC01LS, IN HIV-EXPOSED NEWBORNS

CD56+CD16+ NK subset and a weak but polyfunctional HIV-1-specific CD8 T cell response. 44 NEONATAL ART < 7 DAYS VS 7-28 DAYS REDUCED TIME TO SUPPRESSION Alfredo Tagarro 1 , Sara Dominguez Rodriguez 1 , Thanyawee Puthanakit 2 , Paolo Palma 3 , Caroline Foster 4 , Thidarat Jupimai 2 , Nicola Cotugno 3 , Jintanat Ananworanich 5 , Santiago Jimenez de Ory 6 , Paola Zangari 3 , Maria Luisa Navarro 6 , Paolo Rossi 3 , Eleni Nastuoli 7 , Carlo Giaquinto 8 , Pablo Rojo Conejo 1 , for the EPIICAL Consortium 1 Hospital Universitario 12 de Octubre, Madrid, Spain, 2 Chulalongkorn University, Bangkok, Thailand, 3 Bambino Gesu Children’s Hospital, Rome, Italy, 4 Imperial College Healthcare NHS Trust, London, UK, 5 Walter Reed Army Institute of Research, Silver Spring, MD, USA, 6 Hospital General Universitario Gregorio Marañón, Madrid, Spain, 7 Great Ormond Street NHS Foundation Trust, London, UK, 8 University of Padova, Padova, Italy Background: Early antiretroviral therapy (ART) in children is associated with better clinical and virological outcome. Few data are available about long-term outcome of children starting ART in the neonatal period. Our hypothesis is that HIV-perinatally infected neonates initiating ART within <7 days of life have a better long-term clinical and virological response than neonates treated ≥7 days and ≤28 days of life. Methods: 44 children with perinatal HIV aged ≤28 days at start of ART were included from 4 cohorts (11%UK, 52% Spain, 7% Italy, and 29% Thailand). Primary endpoints were clinical - mortality, and progression to AIDS – and virological: time to suppression, time to virological failure, and proportion of time suppressed. Data were collected up to 15-years of follow-up. Those subjects who received triple postpartum prophylaxis and subsequently transitioned to ART within <15 days were considered as starting ART from date of prophylaxis initiation. A flexible spline interval censored survival model was applied adjusting for CD4 and viral load (VL) at the start of ART. Results: 57%were female and 35% preterm. Median follow-up was 11.5[IQR 8.2-15.6] years. No patient died. 84% received postpartum prophylaxis. At ART initiation, children were aged 15.5 [0.00;24.2] days, with CD4 total 2766[2126;3368], CD4:CD8 2.5[1.6;3.1], and log10VL 4.2[2.9;5.2] copies/ ml. 36/44 (83%) ever suppressed (VL≤50). Time to viral suppression was 0.57[0.25;1.04] years. 12/44 (34%) had subsequent virological failure after suppression (median time to failure, 2.40 [1.01;9.61] years). Participants had 2.9 ±1.8 ART regimen switches, 26% progressed to AIDS. 19/44 (43%) patients started ART <7 days of age. Viral load was higher in children treated <7 days (log10VL 4.4 [4.2;5.4] vs 3.3 [2.9;4.4], p=0.018). Time to suppression was shorter in those treated in the first 7 days of life (18.9[7;41.7] y 44.1[24.6;61.0] weeks, p = 0.038). The probability of suppression decreased by 24% for each week the ART initiation was delayed (aHR=0.76 [0.6;0.97], p=0.035, Figure 1). No differences were observed in progression to AIDS, ART switches, time to immunological recovery (CD4:CD8>1), time to virological failure or proportion of time suppressed. Conclusion: Even among children initiating ART<28 days of age, children starting ART in the first week of life suppress earlier. There was similar long- term clinical, virological and immunological outcomes in children treated <7 days vs. 7 to 28 days.

Elizabeth J. McFarland 1 , Coleen K. Cunningham 2 , Edmund V. Capparelli 3 , Petronella Muresan 4 , Elizabeth Smith 5 , Charlotte Perlowski 6 , Leavitt Morrison 7 , Patricia Morgan 6 , Adrian B. McDermott 8 , Rohan Hazra 9 , John R. Mascola 8 , Barney S. Graham 8 , for the IMPAACT P1112 Protocol Team 1 University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 2 Duke University, Durham, NC, USA, 3 University of California San Diego, La Jolla, CA, USA, 4 Harvard T.H. Chan School of Public Health, Boston, MA, USA, 5 DAIDS, NIAID, Rockville, MD, USA, 6 FHI 360, Durham, NC, USA, 7 Harvard University, Boston, MA, USA, 8 Vaccine Research Center, NIAID, Bethesda, MD, USA, 9 National Institute of Child Health and Human Development, Bethesda, MD, USA Background: Vertical HIV transmission occurs despite use of antiretroviral therapy (ART). A broadly neutralizing monoclonal antibody, administered to HIV-exposed infants might further prevent transmission. VRC01LS, modified from VRC01, has an extended half-life and may be a feasible adjunct to ART prophylaxis. Methods: This is an open label safety and pharmacokinetic study of VRC01LS administered to HIV-exposed infants. Cohort 1 infants (non-breastfeeding) receive subcutaneous (SC) Dose 1 (80mg for birth weights 2.0 to <4.5kg) within 72 hours of birth. Cohort 2 (breastfeeding) receive Dose 1 within 5 days of birth and Dose 2 (100mg SC) at Week 12, if still breastfeeding. All infants and their mothers receive ART to prevent HIV transmission. Safety is assessed post vaccination at 4 hours, Day 1, 14, 28, 56, Week 12, and then every 12 weeks through Week 96. Cohort 2 also has safety assessments at Week 14 and 16. Preliminary VRC01 pharmacokinetic parameters are determined through Week 12. Results: Cohort 1 (n=10) and 2 (n=11) fully accrued from 8 sites (6 in the US, 1 site each in Zimbabwe and South Africa) with no HIV transmissions. All infants received Dose 1. Ten in Cohort 2 received Dose 2, as of the April 2018 safety analysis. Birth weight ranged from 2.5-4.1kg. VRC01LS was well tolerated with no treatment related toxicities >grade 2. Local reactions (all grade 1 or 2; 95% resolved by 24 hr) were common after Dose 1, occurring in 5/10 (50%) and 9/11 (82%) infants in Cohort 1 and 2, respectively, but less frequent after Dose 2, occurring in 2/10 (20%) infants. Plasma VRC01LS levels for Dose 1 (Cohorts combined) are available at Days 1 (n=14), 7 (n=5), 14 (n=20), 28 (n=20), 56 (n=17), and Week 12 (n=12) and compared to previously reported levels at Day 28 (n=13) and Day 56 (n=12) for 20mg/kg and 40mg/kg VRC01 given SC at birth (Figure). VRC01LS was rapidly absorbed following SC administration, with all Day 1 levels >100mcg/mL. VRC01LS levels were significantly greater than VRC01 levels at Day 28 (p=0.0018) and Day 56 (p=0.0019) despite the lower weight- band dosing (VRC01LS 20-32mg/kg vs. VRC01 40mg/kg). At Week 12, the median VRC01LS level was 39.1mcg/mL and all infants’ levels were >20mcg/mL. Conclusion: Preliminary results indicate that VRC01LS administered to neonates via the SC route at birth and age 12 weeks is well tolerated with mild- moderate transient local reactions. VRC01LS with its extended half-life could achieve target levels for the duration of breastfeeding with infrequent dosing.

Oral Abstracts

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CROI 2019