CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

Conclusions: Study treatments were generally well tolerated. LDV/SOF increases TFV exposure within RTV-boosted ATV- or DRV-based regimens. The safety of higher TFV concentrations in this setting has not been established. Consider alternative HCV or ARV therapy to avoid increases in TFV. Patients should be monitored for TFV-associated adverse reactions if coadministered. 83 Emtricitabine-Triphosphate in Dried Blood Spots (DBS) as a Marker of Recent Dosing Jose R. Castillo-Mancilla 1 ; Lane R. Bushman 1 ; Amie Meditz 2 ; Sharon M. Seifert 1 ; Jia-Hua Zheng 1 ; L Anthony Guida 1 ; Edward M. Gardner 3 ; DavidV. Glidden 4 ; Robert M. Grant 4 ; Peter L. Anderson 1 1 University of Colorado-AMC, Aurora, CO, US; 2 Beacon Center for Infectious Diseases, Boulder, CO, US; 3 Denver Health and Hospital Authority, Denver, CO, US; 4 University of California San Francisco, San Francisco, CA, US Background: Tenofovir diphosphate (TFV-DP) in red blood cells (measured in DBS) is a strong marker of cumulative adherence to tenofovir disoproxil fumarate/emtricitabine (TDF-FTC) and highly predictive of PrEP efficacy. However, because of its long half-life, TFV-DP does not discriminate recent vs. remote dosing. FTC is phosphorylated to FTC- triphosphate (FTC-TP) in red blood cells, which is simultaneously measured with TFV-DP in DBS, but the half-life and clinical utility of FTC-TP have not been elucidated. We aimed to determine the half-life of FTC-TP in DBS and to evaluate its utility as a marker of recent dosing. Methods: DBS were collected from 13 HIV-negative and 10 HIV-infected adults participating in an intensive pharmacokinetic (PK) study of daily TDF-FTC for 30 days in HIV- negative individuals and 60 days in HIV-infected subjects. DBS were obtained following dosing on days 1, 3, 7, 20, 30 and 60 in all participants and also on days 35 and 45 (off drug) in the HIV-negative group. FTC-TP was extracted from a 3mm punch and quantified using LC-MS/MS with a lower limit of quantification (LLOQ) of 0.1 pmol/punch. Plasma TFV-FTC was quantified using LC-MS/MS with a LLOQ of 10 ng/ml. The FTC-TP half-life was determined using one-compartment first-order PK. To assess the effectiveness of FTC-TP as a marker of recent dosing, the concordance of FTC-TP in DBS with TFV-FTC in plasma was determined by comparing paired plasma/DBS samples collected at various study visits from participants receiving daily TDF-FTC in the iPrEx Open Label Extension (iPrEx OLE). Data are presented as median (range). Results: Following dosing, FTC-TP reached Cmax at 4 (2-8) hours and exhibited a half-life of 31 (22-52) hours, with no difference according to HIV status (p=0.43). The FTC-TP average concentration at steady state was 0.25 (0.16-0.37) pmol/punch. A total of 482/515 (94%) paired plasma/DBS samples from iPrEX OLE were concordant for detection/non- detection of TFV/FTC in plasma vs. FTC-TP in DBS. When TFV/FTC were BLQ in plasma, FTC-TP was BLQ in DBS 98% of the time. When TFV/FTC were quantifiable in plasma, FTC-TP was quantifiable in DBS 90% of the time. Conclusions: FTC-TP has a 31 hour half-life in DBS (compared with 17 days for TFV-DP). Excellent concordance (94%) was observed between detection of FTC-TP in DBS with detection of TFV/FTC in plasma, demonstrating that FTC-TP informs recent TFV/FTC dosing, thereby complimenting the long-term cumulative adherence measure provided by TFV-DP. 84 Impact of EFV PK/PG on Neuropsychological Performance in Older HIV+ Patients Background: Despite being one of the most commonly prescribed first line antiretroviral agents, the pharmacokinetics (PK) and pharmacodynamics of efavirenz (EFV) and its 8-hydroxy metabolite (8-OH-EFV), have not been robustlyrobustly evaluated in older HIV-infected patients. Moreover, 8-OH-EFV has been shown to be more neurotoxic in vitro than EFV. We sought to investigate relationships between neuropsychological performance (NP) with EFV and 8-OH-EFV PK in HIV-infected individuals >50 yo. Methods: Cross sectional study of HIV-infected adults >50 yo, on EFV containing ART > 12 weeks. 12 h and 18 h post-dose plasma EFV and 8-OH-EFV were quantified via LC-MS-MS. CYP2B6 polymorphisms were investigated. NP battery assessed executive function, motor skills, verbal learning, memory, and speed of processing, CES-D depression scale and sleep quality index questionnaire were completed. Correlations of EFV and 8-OH-EFV plasma concentrations with NP performance, sleep, depression scores and CYP2B6 polymorphisms were assessed (Spearman’s correlation, and univariate logistic regression where appropriate). Results: 30 participants 24 men, 6 women with mean age 57 yrs (50-68)were enrolled. Mean CD4 was 736/mm 3 (range 145-2062); 26 participants had HIV RNA <20 c/mL and 4 < 100 c/mL. Median 12h and 18h EFV plasma concentrations were 1967 ng/mL (IQR 1476-2394) and 1676 ng/mL (IQR 1120-2062) respectively. Median 12hr and 18hr 8OH-EFV plasma concentrations were 378 ng/mL (IQR 223-589) and 384 ng/mL (IQR 216-621) respectively. EFV plasma concentrations did not correlate significantly with NP performance. Higher 8-OH-EFV plasma concentrations correlated with better learning (p=0.002), language (p=0.002) and total NPZ scores (p=0.005). Neither EFV nor 8OH-EFV plasma concentrations correlated with sleep disturbance or depression. The CYP2B6 516G>T polymorphismwas associated with significantly higher concentrations of EFV at 12h and 18 h (p=0.02) but not NP function. Uriel S. Sandkovsky 1 ; AnthonyT. Podany 1 ; Courtney Fletcher 1 ; Andrew Owen 2 ; Angela Felton-Coleman 1 ; Kevin Robertson 3 ; Susan Swindells 1 1 University of Nebraska Medical Center, Omaha, NE, US; 2 University of Liverpool, Liverpool, United Kingdom; 3 University of North Carolina, Chapel Hill, NC, US

Oral Abstracts

126

CROI 2015