CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

Sherika Hanley 10 , Mariam Aziz 11 , Katy Hayward 12 , Mark Mirochnick 13 , Pearl Samson 6 , for the IMPAACT 2007 Study Team 1 University of Chicago, Chicago, IL, USA, 2 University of California San Diego, La Jolla, CA, USA, 3 Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA, 4 National Institute of Child Health and Human Development, Bethesda, MD, USA, 5 DAIDS, NIAID, Rockville, MD, USA, 6 Harvard T.H. Chan School of Public Health, Boston, MA, USA, 7 FHI 360, Durham, NC, USA, 8 Frontier Science & Technology Research Foundation, Inc, Amherst, NY, USA, 9 University of the Witwatersrand, Soweto, South Africa, 10 CAPRISA, Durban, South Africa, 11 Rush University Medical Center, Chicago, IL, USA, 12 ViiV Healthcare, Research Triangle Park, NC, USA, 13 Boston University, Boston, MA, USA Background: Lack of adequate safety and pharmacokinetic (PK) data limits antiretroviral (ARV) prophylaxis and treatment options in HIV-exposed neonates. Maraviroc (MVC), a CCR5 receptor antagonist approved for use in adults, has potential for use in prophylaxis and treatment of HIV-exposed or infected neonates. Methods: IMPAACT 2007 is an ongoing Phase I, multi-center, open-label study of MVC safety and PK in HIV-exposed neonates on standard ARV prophylaxis. Study design includes two sequential dosing cohorts starting MVC by day 3 of life. Cohort 1 infants received two single 8mg/kg MVC doses one week apart with intensive PK sampling after the initial dose. Based on PK data from Cohort 1, Cohort 2 infants receive 8 mg/kg MVC twice daily through 6 weeks of life with intensive PK sampling at Weeks 1 and 4. Due to a known PK interaction between MVC and efavirenz (EFV) in adults, cohorts were stratified by exposure to maternal EFV. PK samples were analyzed for MVC concentration by validated high-performance liquid chromatography. PK parameters were estimated using standard non-compartmental methods. MVC exposure target is Cavg ≥ 75ng/ mL, from adult treatment studies. Laboratory and clinical evaluations assessed infant safety at entry and Weeks 1, 2, 6, 16 in Cohort 1; Weeks 1, 4, 6, 12, 16 in Cohort 2. Results: Forty-seven MVC-naïve, HIV-exposed neonates have enrolled; 15 in Cohort 1, 32 in Cohort 2 (median gestational age 39 weeks, 51%male) from the USA(20), Thailand(3), Kenya(2), and South Africa(22). PK data are available for 13 Cohort 1 infants and 21 Cohort 2 infants; data from 4 additional infants pending. All Cohort 1 infants (n=13) met the PK target after the initial dose. Median exposure for Cohort 2 infants (n=22) exceeded the PK target but variability in exposure was high, with 17-33% of infants below the PK target at Weeks 1 and 4, respectively (Table 1). The proportion of infants who achieved the PK target was similar between EFV-naïve and EFV-exposed infants. No Grade 3+ toxicities or early study discontinuations noted due to MVC. Conclusion: Maraviroc appears safe when used in the first 6 weeks of life. MVC exposures met treatment PK targets in most infants receiving 8 mg/kg twice daily, but with considerable variability in exposure. Maternal EFV use appeared to have no effect on MVC exposure and there were no study discontinuations due to toxicity or intolerance. The final MVC dose recommendation will be determined accounting for patient variability.

4 University of the Witwatersrand, Johannesburg, South Africa, 5 NIH, Rockville, MD, USA, 6 NIH, Bethesda, MD, USA, 7 Perinatal HIV Research Unit, Soweto, South Africa, 8 Frontier Science & Technology Research Foundation, Inc, Amherst, NY, USA, 9 University of Cape Town, Cape Town, South Africa, 10 Boston University, Boston, MA, USA, 11 University of California San Diego, La Jolla, CA, USA Background: Abacavir (ABC) is licensed for infants >3 months of age while WHO recommends use in HIV-infected children ≥4 weeks of age and ≥3 kg. ABC is metabolized in the liver via UDPGT and ADH enzymes, and information describing ABC disposition during the first fewmonths of life is lacking. We describe ABC pharmacokinetic (PK) and safety data in HIV-infected normal and low birth weight (LBW) infants initiating ABC within the first 3 months of life. Methods: IMPAACT P1106 is an opportunistic, multi-arm study of PK and safety in LBW infants conducted in South Africa on antiretroviral and antituberculosis medicines. Arm 5 included HIV-infected infants receiving ABC, lamivudine and lopinavir/ritonavir. Plasma samples for ABC PK assessment were collected pre-dose (C0), 1.5- and 4-hours post-dose at study weeks 2, 10, and 24, with C0 samples at weeks 6 and 16. ABC concentrations were measured by LC-MS/MS and ABC PK parameters estimated using a population approach. Adverse events (AE) were evaluated from entry to week 24. Results: Twenty-five infants (18 LBW) were included in the analysis. Median entry age was 44 days (range 11 to 78 days). Twelve (48%) infants were male and 22 (88%) black African. Median ABC dose was 10 (6-13) mg/kg BID and ABC concentrations were available for 24 (195 observations) infants with median (range) birth weight 2190 g (1360-3260) and median gestational age 36 weeks (32-37). ABC plasma concentrations were described by a 1-compartment model. Infant body weight (BW) and post-menstrual age (PMA=gestational age+postnatal age [PNA]) influenced ABC PK parameters. ABC oral clearance (CL/F) increased by 2% per PMA week. Infant characteristics and ABC PK parameters per PK visit are shown in Table 1. One infant died of unknown cause 3 days after entry. Fourteen infants had Grade 3/4 AEs, among which most common were gastroenteritis (n=4) and respiratory infection (n=4) and all of which improved except for malnutrition (n=1), underweight (n=1) and a respiratory infection (n=1) present at the last study visit. No hypersensitivity was reported. All AEs were assessed as unrelated to ABC, except for one possibly related Grade 2 alanine aminotransferase where all antiretrovirals were stopped for 2 weeks until resolution then restarted without further complications. Conclusion: ABC was well tolerated in LBW infants. ABC exposures were relatively high compared to older infants during the first 3 months of life but decreased rapidly as infants matured. 844 ABACAVIR DOSING, EFFECTIVENESS, AND SAFETY IN YOUNG INFANTS LIVING WITH HIV IN EUROPE Siobhan Crichton 1 , Intira J. Collins 1 , Anna Turkova 1 , Luminita Ene 2 , Luisa Galli3, Magdalena Marczynska 4 , Maria Luisa Navarro 5 , Lars Naver 6 , Antoni Noguera- Julian 7 , Yulia Plotnikova 8 , Henriëtte J. Scherpbier 9 , Alla Volokha 10 , Evgenly Voronin 11 , Ali Judd 1 , for the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) 1 MRC Clinical Trials Unit at UCL, London, UK, 2 Infectious and Tropical Diseases Hospital "Dr Victor Babes", Bucharest, Romania, 3 University of Florence, Florence, Italy, 4 Medical University of Warsaw, Warsaw, Poland, 5 Hospital General Universitario Gregorio Marañón, Madrid, Spain, 6 Karolinska Institute, Stockholm, Sweden, 7 Hospital Sant Joan de Déu Barcelona, Esplugues, Spain, 8 Irkutsk Regional Center for Prevention and Control of AIDS and Infectious Diseases, Irkutsk, Russian Federation, 9 Emma Children's Hospital/Academic Medical Center, Amsterdam, Netherlands, 10 Shupyk National Medical Academy of Postgraduate Education, Kyiv, Ukraine, 11 Republican Clinical Infectious Hospital, Saint-Petersburg, Russia Background: The World Health Organization recommends abacavir (ABC) as the preferred/alternative backbone for 1st line regimens in children with HIV from age 28 days. There are limited data available on safety and tolerability of ABC in young infants aged <3 months.

Poster Abstracts

843 ABACAVIR SAFETY AND PHARMACOKINETICS IN NORMAL AND LOW BIRTH WEIGHT INFANTS WITH HIV Tim R. Cressey 1 , Adrie Bekker 2 , Mae Cababasay 3 , Jiajia Wang 3 , Firdose Nakwa 4 , Elizabeth Smith 5 , Jack Moye 6 , Avy Violari 7 , Mark Cotton 2 , Bobbie Graham 8 , Lubbe Wiesner 9 , Helena Rabie 2 , Mark Mirochnick 10 , Edmund V. Capparelli 11 , for the IMPAACT P1106 Team 1 Chiang Mai University, Chiang Mai, Thailand, 2 Stellenbosch University, Cape Town, South Africa, 3 Harvard T.H. Chan School of Public Health, Boston, MA, USA,

CROI 2020 314