CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

808 NEVIRAPINE PK, VIROLOGICAL OUTCOME, AND AES IN AFRICAN CHILDREN ON PAEDIATRIC FDCS Andrzej Bienczak 1 , Paolo Denti 1 , Adrian Cook 2 , Lubbe Wiesner 1 , Diana Gibb 2 , David M. Burger 3 , Sarah Walker 2 , Helen Mcilleron 1 , for the CHAPAS-3 StudyTeam 1 Univ of Cape Town, Cape Town, South Africa, 2 Univ Coll London, London, UK, 3 Radboud Univ Med Cntr, Nijmegen, Netherlands Background: Nevirapine is the only non-nucleoside reverse transcriptase inhibitor currently available as a paediatric fixed-dose combination tablet and is widely used in African children. Nonetheless, the number of investigations into pharmacokinetic determinants of virological suppression is limited and the predictive power of the current therapeutic range has not been evaluated in this population, limiting treatment optimisation. Methods: We analysed data from 219 initially antiretroviral treatment (ART)-naïve African children (aged 0.3–13 years) from the CHAPAS-3 study treated with nevirapine, lamivudine, and either abacavir, stavudine, or zidovudine, and followed up to 144 weeks. Pharmacokinetic non-linear mixed effects model derived nevirapine trough concentrations (Cmin) and other factors were tested for associations with viral load (VL) >100 copies/mL and transaminase increases >grade 1 using proportional hazard and logistic models. Nevirapine Cmin most predictive of non-suppression and transaminase elevations was sought using likelihood profiling. Results: Pre-ART VL, adherence and nevirapine Cmin were associated with VL non-suppression (hazard-ratio [HR]=2.08 [95% CI: 1.50-2.90, p<0.001] for 10-fold higher pre-ART VL, HR=0.78 [95% CI: 0.68–0.90, p<0.001] for 10% improvement in adherence and HR=0.94 [95% CI: 0.90-0.99, p=0.014] for a 1mg/L increase in nevirapine Cmin). There were additional effects of pre-ART CD4% and clinical site. The risk of virological suppression increased approximately linearly as Cmin decreased and there was no clear Cmin threshold predictive of virological non-suppression. Transient transaminase elevations >grade 1 were associated with high Cmin (>12.4 mg/L), HR=5.18 (95%CI 1.95–13.80, p<0.001). Conclusion: Higher nevirapine concentrations were associated with significantly better virological outcomes but a meaningful cut-off predictive of increased risk of VL non- suppression could not be identified, possibly due to the effects of the ART companion drugs. Adverse events were rare. Although we detected an association between nevirapine Cmin >12.4 mg/L and transient transaminase elevations, this finding is unlikely to be clinically significant . Treatment initiation at lower VL and higher CD4%, increased adherence, and maintaining average Cmin higher than the current target, could have a positive effect on virological suppression in African children treated with nevirapine. 809 AN EASY-TO-USE PAEDIATRIC DOSING TOOL: ONE MG/KG DOSE DOES NOT FIT ALL Paolo Denti 1 , Nandita Sugandhi 2 , Tim R. Cressey 3 , Mark Mirochnick 4 , Edmund V. Capparelli 5 , Martina Penazzato 6 , for the Paediatric ARVWorking Group 1 Univ of Cape Town, Cape Town, South Africa, 2 Clinton Hlth Access Initiative, New York, NY, USA, 3 Prog for HIV Prevention and Treatment, Chiang Mai, Thailand, 4 Boston Med Cntr, Boston, MA, USA, 5 Univ of California San Diego, La Jolla, CA, USA, 6 WHO, Geneva, Switzerland Background: When designing safe and effective dosing regimens for children, the first assumption is to aim for drug exposures similar to those observed in successfully treated adults. Therefore, correctly scaling pharmacokinetics (PK) to children is a key first step. While several factors may contribute to difference in PK between children and adults, body size alone explains most of the changes down to children of 3 years of age. Allometric scaling describes the nonlinear effect of body size on PK parameters. This nonlinearity explains why using the same mg/kg dose in children and adults is incorrect, and causes under-dosing. Allometric scaling is widely used in PK modelling, but it is not uncommon for “first guess” paediatric dosing regimens to still incorrectly use constant mg/kg dosing. This is arguably due to the lack of accessibility of PK modelling results to clinicians. The objective of this work is to bridge this gap by proposing an intuitive and easy-to-use tool to assist researchers not conversant in PK modelling to design and evaluate paediatric dosing regimens. Methods: The tool was designed using Microsoft Excel - chosen for its ubiquitousness and familiarity amongst clinicians - with easy steps to follow and results displayed in graphical form. The tool uses allometric scaling to adjust for the effect of body size on clearance and compares the expected exposure in terms of area under the concentration- time curve (AUC). Analysis of multiple drugs in a fixed-dose combination is possible, defining the separate amounts for each component and different tolerance ranges for the target exposure. Standard dosing weight-bands can be used, or boundaries can be customised to explore alternative approaches. Results: The implementation of the tool has been validated by assessing current paediatric dosing regimens. The outputs produced are closely in line with results from PK modelling and generally coherent with those obtained in confirmatory clinical trials. In particular, the doses predicted using the tool are more accurate than those obtained with the constant mg/kg approach. Conclusion: The purpose of the tool is to assist in the design of clinical trials for dosing in paediatrics, and is meant as a first step, not a substitute to confirmatory studies. The use of this tool (and thus allometric scaling) for study design would represent a significant step ahead from the constant mg/kg paradigm, possibly leading to improvements in the efficacy of paediatric dosing trials. 810 SERTRALINE PHARMACOKINETICS IN HIV-INFECTED ON ARV AND UNINFECTED YOUTH Nathan Hanan 1 , Mary Paul 2 , Yanling Huo 3 , Edmund Capparelli 1 , Suad Kapetanovic 4 , J. L. Ariansen 5 , Elizabeth Smith 6 , Pim Brouwers 4 , Brookie Best , for the IMPAACT P1080 Protocol Team 1 Univ of California San Diego, La Jolla, CA, USA, 2 Baylor Coll of Med, Houston, TX, USA, 3 Harvard Univ, Boston, MA, USA, 4 NIMH, Rockville, MD, USA, 5 FHI 360, Durham, NC, USA, 6 NIAID, Rockville, MD, USA Background: Sertraline (SRT) is a selective serotonin reuptake inhibitor eliminated by hepatic metabolism by cytochrome P450 (CYP) enzymes: 2B6, 2D6, 2C9, 2C19 and 3A4, glucuronyl transferases, and monoamine oxidase A & B. SRT is often titrated to effectiveness. Due to comorbidities and interactions, the appropriate starting dose and titration range may require adjustment in pediatrics. This is the first report of SRT pharmacokinetics (PK) in HIV-1 infected and uninfected youth. Methods: IMPAACT P1080 is a multicenter pilot PK study of psychiatric medications prescribed in youth. Eligible participants were treated with and stable on SRT, >6 to <25 years old, and: 1) HIV-uninfected (HIV(-)), 2) HIV-1 infected on a ritonavir-boosted protease inhibitor (PI/r), or 3) HIV-1 infected on efavirenz (EFV). Target enrollment was 45

Poster and Themed Discussion Abstracts

CROI 2017 350