CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

total participants (15 per cohort). Six PK samples were collected per participant: pre-dose, 2, 4, 6, 12 and 24-hours post-dose. A validated LC-MS/MS method quantified SRT and its metabolite N-desmethylsertraline (D-SRT) in plasma. CYP2D6 activity was assessed by urinary dextromethorphan/dextrorphan (DXMO/DXO) ratio using LC-MS/MS. Noncompartmental methods estimated PK parameters, and HIV(-) and PI/r cohorts were compared by the Wilcoxon rank-sum test, two-sided with significance set to p<0.05. Due to low accrual, the EFV group was not included in statistical comparisons of PK parameters. Results: Final results included 31 participants who completed PK visits (16 HIV(-), 12 PI/r, and 3 EFV). The median (range) values for weight, age, and dose were 69.5 (31.5-118.2) kg, 21.8 (9.1-24.7) years, and 75 (12.5-150) mg once daily. SRT exposure was highest for HIV(-) and lowest for EFV cohort. AUC 0-24 , C 0 and C min were significantly higher in HIV(-) compared to PI/r (Table 1). Oral clearance (dose-independent) did not differ significantly between cohorts (p = 0.44), whereas the DXMO/DXO ratio was significantly higher in HIV(-) compared to PI/r cohorts (p = 0.01). Two HIV(-) participants were CYP2D6 poor metabolizers (ln(DXMO/DXO) of > -0.5). Conclusion: HIV(-) cohort had the highest SRT exposure compared to HIV-infected cohorts. Differences between SRT exposure in HIV(-) and PI/r participants appear modest; whether alterations in SRT dose titration ranges for PI/r participants are needed is not clear. Although greater in magnitude, the potential impact of EFV on SRT needs further investigation due to limited numbers of EFV participants. 811 SUBOPTIMAL COTRIMOXAZOLE PROPHYLACTIC CONCENTRATIONS IN CHILDREN Claire Pressiat 1 , Véronique Mea-Assande 2 , Caroline Yonaba 3 , Jean-Marc Treluyer 4 , Désiré Lucien Dahourou 5 , Madeleine Amorissani-Folquet 6 , Stephane Blanche 7 , Valeriane Leroy 8 , Déborah Hirt 9 , for the MONOD Study Group 1 Paris Descartes Univ, Paris, France, 2 PACCI Prog, Abidjan, Cote d’Ivoire, 3 CHU Yalgado Ouédraogo, Ouagadougou, Burkina Faso, 4 Paris Cntr Hosp Group, Paris, France, 5 Cntr de Rsr Intl Pour la Santé, Ouagadougou, Burkina Faso, 6 CHU of Cocody, Abidjan, Cote d’Ivoire, 7 Necker Hosp, Paris, France, 8 INSERM, Toulouse, France, 9 Paris Cntr Hosp Group, Paris, France Background: Cotrimoxazole (sulfamethoxazole (SMX) - trimethoprim (TMP)) is recommended to prevent opportunistic infections in HIV-infected children. Despite the overwhelming use of this medication, few pharmacokinetics (PK) data are available in children. We analyzed the concentrations of cotrimoxazole in a large population of West-African HIV-infected children, to identify factors influencing the PK and to evaluate the prophylactic doses recommended by the World Health Organization (WHO) during childhood. Methods: HIV-infected children aged from 6 months to 2 years were enrolled in a therapeutic cohort, in Burkina Faso and Ivory Coast, offering a combined lopinavir-based antiretroviral therapy with cotrimoxazole prophylaxis (WHO recommended dose: syrup, 200/40 mg of SMX/TMP once daily). Patient’s data, including demographic and clinical variables (age, sex, body weight, time of administration and time of sampling), were collected prospectively from inclusion (at ART initiation) and monthly visits until 25 months. Pharmacokinetic samples were taken during the initial treatment cohort at the month 6 (M6), M19 and M25 visits. For each visit, one or two samples per child were measured. Plasma concentrations were analyzed using a nonlinear mixed effects modeling, with NONMEM software. Estimated individual PK parameters were used to calculate individual exposures and simulate exposure for different administration schemes. Results: Overall, 136 children (median age [range]): 1.9 years [0.7-4], median weight [range]: 9.5 kg [6-16.3]) were included. Data on a total of 482 plasma concentrations were collected (mean [range]: 3.5 [1-7] per child). Allometry effect significantly improved SMX and TMP pharmacokinetics description, suggesting the appropriateness of a dose/kg regimen. Simulations of the WHO recommended doses resulted in significantly lower SMX and TMP exposures in children from 10 to 15 kg compared to adults, potentially leading to reduce effectiveness of cotrimoxazole. Simulated regimens of 30 – 8 mg/kg for SMX-TMP in the 5 to 10 kg group and 25 – 6 mg/kg for SMX-TMP in the 10 to 15 kg group seems to be the more appropriate doses. Conclusion: While prevalence of opportunistic infections remains high in this context, we observed lower exposures to cotrimoxazole in children than in adults. We suggest revising the current WHO recommendations of cotrimoxazole prophylaxis dosing in HIV-infected children and propose an adapted dose per kg scheme. 812 DOLUTEGRAVIR-BASED CART IN VERTICALLY HIV-1–INFECTED ADOLESCENTS, REAL-WORLD SETTING Coralie Briand 1 , Catherine Dollfus 2 , Marion Caseris 3 , Elie Kantor 4 , Veronique Avettand-Fenoel 1 , Diane Descamps 4 , Veronique Schneider 5 , Marie-Dominique Tabone 2 , Stephane Blanche 1 , Pierre Frange 1 1 Necker Hosp, Paris, France, 2 Trousseau Hosp, Paris, France, 3 Robert Debre Hosp, Paris, France, 4 Bichat Hosp, Paris, France, 5 Tenon Hosp, Paris, France Background: Attaining long-term good therapeutic adherence and viral suppression remains a challenge in perinatally-infected adolescents. Dolutegravir (DTG)-based cART are now approved for use in HIV+ adolescents aged ≥12 years in many countries worldwide. However, published data about efficacy of DTG in this population with high risk of virological failure (VF) are scarce. This multicenter study provides the first data about safety and efficacy of DTG in adolescents in real-life setting. Methods: Clinical and biological data from 50 adolescents, who initiated DTG-based cART between January 2014 and December 2015, were retrospectively analyzed. 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: At baseline, 17/50 adolescents were virologically suppressed. DTG-based HAART maintained virological success in 14/17 patients (82%). The 3 remaining adolescents experienced transient viral rebound, before reaching PVL <50 copies/mL again, without requiring cART change. Thirty-three viremic adolescents were enrolled; all but one were ART-experienced. Sustained virological success was obtained in 19/33 subjects (58%). Three additional adolescents with initial VF reached undetectable PVL at the end of follow-up with reinforced measures to improve adherence. Overall, sustained virological success and undetectable PVL at the last visit were obtained in 66% and 78% of patients, respectively. Compared to patients with virological success, subjects with VF were more often born in Sub-Saharan African countries (94% vs 52%; p=0.004), and had more frequently detectable viremia under ART during the 6 months prior to DTG initiation (82% vs 58%; p=0.03). Gender, age and characteristics of the DTG-based cART (number of pills/ day, dosing frequency, cumulative GSS) were similar in the 2 groups. DTG was well tolerated; only 1 patient stopped treatment for severe drug-related side effect (dizziness, sleep disturbance). No emergence of resistance mutation was observed in patients with VF. Conclusion: DTG was safe and provided good virological efficacy. Because of its high genetic barrier to resistance and small pill burden, DTG could be especially useful in ART- experienced adolescents with high risk of poor treatment adherence. 813 LONG-TERM EFFECTS OF WEEKENDS OFF ART IN HIV-1–INFECTED YOUNG PEOPLE ON EFV+2NRTI Anna Turkova , for the BREATHER (PENTA 16)Trial Group Univ Coll London, London, UK Background: HIV-1 infected young people (YP) facing lifelong antiretroviral therapy (ART) liked short cycle therapy (SCT) with weekends off ART, as demonstrated in the BREATHER trial, showing SCT was non-inferior to continuous ART (CT) over 48 weeks, with similar resistance and safety profiles. Follow-up was extended to minimum 144 weeks, maintaining original randomisation. Methods: BREATHER was a randomised, open-label, non-inferiority trial. YP (8-24yrs) on first-line efavirenz (EFV) +2NRTIs with HIV-RNA (VL) <50c/ml for >12 months were randomised to SCT (5-day on; 2-days off ART) or CT with 12-weekly VL monitoring. Kaplan-Meier methods were used to estimate the proportion with confirmed VL≥50c/ml by arm and differences between arms (12% non-inferiority margin) adjusted for region and age. Results: 194/199 YP consented to long term follow-up (97 SCT, 97 CT). Median [IQR] follow-up was 184 [161-216] weeks; 93%were followed for ≥144 weeks. Over 144 weeks, 15 SCT vs 13 CT had confirmed VL≥50c/ml (difference 1.9%, 90%CI −6.6, 10.4; figure); results were similar in a per-protocol analysis (difference 0.9%, −7.8, 9.6). In total, 27 (28%, 95%CI 19, 37) SCT patients had returned to CT by 144 weeks. Of the 15 SCT with confirmed VL≥50c/ml, 1 resumed CT prior to rebound, the remaining 14 resumed CT on rebound; 13/14 resuppressed, 10 on the same regimen (2 later rebounded) and 3 with a switch to second-line. A further 12 SCT had restarted CT by 144 weeks: 4 for 3 unconfirmed VL≥50c/

Poster and Themed Discussion Abstracts

CROI 2017 351