CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

Conclusion: Weight-band based ETR dosing achieved predefined AUC12h targets in HIV-infected children receiving an ARV regimen including a PI/r, but 33%, all taking dispersed tablets, had AUC12h <10th percentile of the adult AUC12h. To date, ETR is well-tolerated and the rate of VF in these 21 treatment- experienced children is low.

467 NR1I2 RS2472677 AND ABCG2 RS2231142 INFLUENCE DOLUTEGRAVIR CONCENTRATIONS IN PLASMA Emilie R. Elliot 1 , Megan Neary 2 , Laura Else 2 , Saye Khoo 2 , Graeme Moyle 1 , Daniel F. Carr 2 , Xinzhu Wang 3 , Myra McClure 3 , Andrew Owen 2 , Marta Boffito 1 1 Chelsea and Westminster Hospital, London, UK, 2 University of Liverpool, Liverpool, UK, 3 Imperial College London, London, UK Background: Dolutegravir (DTG) is a preferred agent in most guidelines but real life data are emerging showing higher rates of neuropsychiatric toxicity than seen in licensing trials. Supra-therapeutic DTG concentrations may predispose to side effects in certain individuals, but this remains to be conclusively demonstrated. This study investigated the association between pharmacogenetic variants linked to DTG metabolism and plasma DTG concentrations. Methods: Pooled data from six Phase I and III clinical studies were analysed in subjects receiving 50 mg DTG once daily alone or as part of combination therapy. Following consent at screening for a pharmacogenetics substudy, whole blood was collected on day 1 of each study. All subjects underwent intensive PK sampling. Steady-state DTG plasma concentrations were determined using validated LC-MS/MS or UPLC. CYP3A4*22 c522-191C>T (rs35599367), CYP3A5*3 6986A>G (rs776746), ABCG2 421C>A (rs2231142), NR1I2 63396C>T (rs2472677) and NR1I2 44477A>G (rs1523130) were genotyped using allelic discrimination assays. UGT1A1 (*1, *28, *36 & *37) were genotyped using an Agena MassArray iPLEX assay. All genotypes were checked for Hardy-Weinberg equilibrium. Variables were tested for normal distribution (Shapiro-Wilk test) and normality was improved using log 10 transformation where indicated. Associations between subject genotype and DTG Cmax, logCmin and AUC0-24 were determined through univariate and multivariate linear regressions. Results: 83 subjects were included (58 HIV-infected and 25 healthy adults; 62 men, 21 women). 64 participants were caucasian , 15 black, 2 asian and 2 mixed–race. ABCG2 421C>A (rs2231142) and NR1I2 63396C>T (rs2472677) were associated with higher DTG Cmax (P=0.002, β=1002 & P=0.039, β=318 respectively). There were no other significant genetic associations. Importantly, both genetic associations remained in an analysis restricted to caucasians. Body weight was associated with lower Cmax and AUC (P=0.007, β=-28 and P=0.012, β=-373 respectively) and DTG AUC was significantly higher in the black versus non-black subgroup (P=0.022, β=10204). Conclusion: This is the first study to demonstrate that NR1I2 63396C>T influences DTG plasma Cmax. Our results also confirm the association between ABCG2 421C>A and Cmax. The association with Cmax but not AUC or Cmin may signal an impact upon DTG absorption but further research is warranted to confirm the associations and their mechanisms and to investigate the putative relationship with pharmacodynamics. 468 PHARMACOKINETICS OF DOLUTEGRAVIR WITH AND WITHOUT DARUNAVIR/COBICISTAT Emilie R. Elliot 1 , Maddalena Cerrone 1 , Laura Else 2 , Alieu Amara 2 , Elisa Bisdomini 1 , Saye Khoo 2 , Marta Boffito 1 1 Chelsea and Westminster Hospital, London, UK, 2 University of Liverpool, Liverpool, UK Background: Dolutegravir (DTG) combined with boosted darunavir may be a promising NRTI sparing and/or salvage strategy for the treatment of HIV-1 infection. In patients undergoing drug monitoring, DTG trough concentrations doubled when switching from darunavir/ritonavir (DRV/r) to DRV/cobicistat (c), in contrast to a 38% decrease with darunavir/ritonavir (DRV/r) twice daily. However, no formal interaction studies between DTG and DRV/c have been published. Methods: This phase 1, open label, 57 day, cross over, pharmacokinetic (PK) study, enrolled healthy volunteers aged 18-65years, who were randomized to: i) group 1: DTG 50mg on days 1-14 followed by a 7 day wash out period, DTG+DRV/c 50mg+800/150mg on days 22-35 (co-administration period), which was followed by a 7 day wash out, and finally DRV/c 800/150mg on days 43-56 or ii) group 2: DRV/c 800/150mg on days 1-14 followed by a 7 day wash out period, DTG 50mg+DRV/c 800/150mg on days 22-35 (co-administration period), which was followed by a 7 day wash out and finally DTG 50mg on days 43-56. All doses were administered once daily. Each group underwent intensive PK sampling (0-24 hr post-dose) on days 14, 35 and 56 and DTG/DRV/c concentrations were measured by validated LC-MS methods. Results: To date, 13 healthy volunteers have been screened, 12 baselined and 9 have completed all PK phases (1 subject withdrew for personal reasons and 2

466 CYP2B6 VARIANTS ALTER ETONOGESTREL PHARMACOKINETICS WHEN COMBINED WITH EFAVIRENZ Megan Neary 1 , Catherine Chappell 2 , Kimberly K. Scarsi 3 , Shadia Nakalema 4 , Joshua Matovu 4 , Sharon L. Achilles 2 , Beatrice A. Chen 2 , Marco Siccardi 1 , Andrew Owen 1 , Mohammed Lamorde 4 1 University of Liverpool, Liverpool, UK, 2 University of Pittsburgh, Pittsburgh, PA, USA, 3 University of Maryland, Baltimore County, Baltimore, MD, USA, 4 Infectious Disease Institute, Kampala, Uganda Background: The etonogestrel (ENG) subdermal implant is an effective contraceptive method recommended by the WHO. Our group previously demonstrated ENG concentrations were 82% lower at week 24 in women receiving efavirenz (EFV) based antiretroviral therapy (ART) compared to women not receiving ART. We sought to investigate potential associations between single nucleotide polymorphisms (SNPs) involved in EFV and ENG metabolismwith the observed alteration in ENG pharmacokinetics (PK) in the same group of women. Methods: This study included 39 Ugandan women, 20 not yet receiving ART and 19 receiving EFV (600mg daily) based ART. ENG and mid-dose EFV plasma concentrations were quantified from plasma through week 24 post ENG implant placement, using HPLC/mass spectrometry for ENG and HPLC for EFV. Patient DNA was extracted fromwhole blood. Samples were genotyped for the following SNPs utilising TaqMan assays: CYP2B6 516G>T, 983T>C and 15582C>T, NR1I2 63396C>T, CYP3A4 293A>G, ABCB1 4036A>G and 3435C>T. Associations between patient genotype and ENG PK parameters were determined through univariate and multivariate linear regression. Results: Within the EFV group CYP2B6 516G>T was associated with a lower log 10 ENG Cmin (P=0.003, β=-0.102) and lower log 10 ENG AUC0-24 weeks (P=0.008, β=-0.106), which equates to a 43% difference in ENG Cmin and a 34% difference in ENG AUC0-24 weeks between homozygous G and homozygous T patients for CYP2B6 516G>T (see table). CYP2B6 983T>C was associated with lower log 10 ENG Cmax (P=0.003, β=-0.237) and lower log 10 ENG AUC0-24 weeks (P=0.016, β=-0.158), which equates to a 37% difference in ENG Cmax and a 20% difference in ENG AUC0-24 weeks between homozygous T and heterozygous CT patients for CYP2B6 983T>C (see table). EFV plasma concentration (C12-14hrs) was 76% higher in patients homozygous T for CYP2B6 516G>T compared to patients homozygous G and 69% higher in patients heterozygous CT for CYP2B6 983T>C compared to those homozygous T (see table). Conclusion: This group has previously described a genetic association between SNPs in CYP2B6 and a reduction in the PK of the levonorgestrel implant within patients receiving EFV. This study shows a similar relationship between CYP2B6 SNPs and ENG PK, which is likely mediated through an indirect effect on EFV. This further demonstrates the influence of patient genetics on the effectiveness of contraceptive implants when prescribed alongside efavirenz.

Poster Abstracts

CROI 2018 167