CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

transition to LPV/r-based ART, thought to be adherence-related. Median NVP trough concentration at 1 and 2 wks was 3.01 mcg/mL (at median 15 hrs); 48% of concentrations were below the therapeutic target of 3.0 mcg/mL (including 10% BQL, indicating non-adherence); concentrations did not correlate with the magnitude of decline in HIV RNA log copies/mL at either 2 or 4 wks. Conclusion: NVP, ZDV, 3TC started in the first week of life was safe and effective, even among infants with NVP levels below the ideal therapeutic PK target. Although poor tolerability often led to transient viral rebound following transition to LPV/r-based ART, almost all children were able to achieve HIV RNA declines to < 400 copies/mL by 12 weeks of life.

828 SIMILAR EFFICACY AND SAFETY OF DOLUTEGRAVIR BETWEEN AGE GROUPS OF PEDIATRIC PATIENTS Pierre Frange , Veronique Avettand-Fenoel, Florence Veber, Stephane Blanche Necker Hospital, Paris, France Background: Dolutegravir (DTG)-based cART are now approved for use in HIV+ children aged ≥6 years in many countries worldwide. However, published data about its efficacy and its safety profile in the pediatric population are scarce, especially in youngest children. This retrospective monocentric study compared data about safety and efficacy of DTG in patients followed in a French pediatric unit and divided into three groups of age at the time of DTG initiation: 5-12 (Group 1), 12-18 (Group 2) and ≥ 18 year old (Group 3). Methods: Clinical and biological data from 109 patients, who initiated DTG- based cART between January 2014 and December 2017 were retrospectively analysed: 33 in Group 1, 51 in Group 2 and 25 in Group 3. The primary endpoint was the proportion of patients who reached virological suppression (i.e. plasma viral load (PVL) <50 copies/mL obtained ≤ 3 months after DTG initiation) for viremic patients, and remained controlled until the last follow-up visit for all patients. The secondary endpoint was safety. Results: Most of the individuals were antiretroviral experienced (91.7%) and 12 (11%) were previously exposed to INSTI. INSTI-associated resistance associated mutations (RAMs) were previously isolated in 4 patients: E157Q in 2 cases, N155H in 2 individuals (who were treated with twice-daily DTG). The proportions of patients with virological suppression at baseline in each of the groups were 66.7%, 54.9% and 56.0%. Median follow-up was 24 months (range 6-54). Sustained virological success was obtained in 79.8% of patients, with similar rates observed in the 3 groups (87.9%, 72.5% and 84.0%, p=0.22). With reinforced measures to improve adherence, undetectable PVL was obtained at the last visit in 88.1% of patients, with similar proportions in the 3 groups (93.9%, 84.3% and 88.0%, p=0.51). Sustained virological success and undetectable PVL at the last visit were obtained in 91.7% and 100.0% of INSTI-experienced patients, respectively. No emergence of resistance mutation was observed in the 22 patients with virological failure. DTG was well tolerated; only 1 patient (Group 2) stopped treatment for severe drug-related side effect (dizziness, sleep disturbance). None of the three Grade 3 laboratory events were study drug related. Conclusion: Virological efficacy and safety of DTG were similar between the 3 groups of age. Because of its high genetic barrier to resistance, DTG could be especially useful in the paediatric population, in which the risk of poor treatment adherence is high. 829LB PK AND 4-WEEK OUTCOMES OF DOLUTEGRAVIR DISPERSIBLE TABLETS IN HIV-INFECTED CHILDREN Theodore Ruel 1 , Edward P. Acosta 2 , Rajendra P. Singh 3 , Carmelita Alvero 4 , Kathleen George 5 , Stephanie Popson 6 , Mattie Bartlett 6 , Ann Buchanan 7 , Cindy Brothers 7 , Lucy Koech 8 , Tichaona Vhembo 9 , Rohan Hazra 10 , Ellen Townley 11 , AndrewWiznia 12 , for the IMPAACT P1093 Team

Poster Abstracts

827 IN SILICO PREDICTION OF DOLUTEGRAVIR PHARMACOKINETICS & DOSE OPTIMISATION IN NEONATES Fazila S. Bunglawala , Rajith Kumar Reddy Rajoli, Andrew Owen, Marco Siccardi University of Liverpool, Liverpool, UK Background: Dolutegravir (DTG) is a selective and potent HIV-1 integrase inhibitor and has potential for treatment of neonates with HIV infection and use as prophylaxis of perinatal transmission. Safety and pharmacokinetics (PK) of DTG have previously been studied in pediatric patients and current studies are investigating the appropriate dose in infants aged > 4 weeks. Dose optimisation in neonatal patients is complex and physiologically-based pharmacokinetic (PBPK) modelling may help inform knowledge gaps in the absence of empirical data. The aim of this study was to simulate the PK of DTG in neonates to help identify an appropriate dosing regimen using PBPK modelling. Methods: The PBPK model was designed in Simbiology (MATLAB R2018a) incorporating neonatal maturation characteristics and a description of physiological and anatomical growth data from various sources. Experimental in vitro data for DTG was integrated into the model to aid prediction of DTG PK in the neonatal population. DTG is predominantly metabolised by UGT1A1 and CYP3A4 and the PBPK model was qualified using clinical data from the surrogate substrates raltegravir (UGT1A1) and midazolam (CYP3A4) in neonates. Additionally, DTG adult and paediatric clinical data were used for the validation of the PBPK model. The model was assumed to be qualified if the simulated values were within 0.5-1.5 fold of the mean reported values as per convention for the approach. Results: A combination of different DTG single and multiple dose strategies were simulated in 100 healthy neonates with the aim of achieving plasma exposure comparable to therapeutic levels observed in paediatric patients (C trough : 0.90 mg/L and AUC 24 : 46 mg.h/L). The PK parameters are summarised in Table 1. Regimens 1-3 result in PK parameters comparable to those in paediatric patients, with convenient dosing schedules. Conclusion: Due to the lack of clinical PK data, neonates represent a vulnerable population. Clinical trials in neonates are extremely difficult to conduct and dose prediction is therefore beneficial to inform trial design. The combination of rapid development and immature ontogeny make it difficult to easily scale existing doses. PBPK modelling allows these changes to be represented mathematically, and should result in more accurate predictions. The presented data can be used to inform neonatal clinical trials to help accelerate dose optimisation in this population.

CROI 2019 322