CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Results: RBC were obtained from 186 individuals [60%male, 63%white/29% African American, median (range) age and weight of 53 (21, 78) years and 85 (45, 153) kg] receiving RBV for a median (range) of 84 (19, 336) days. RBV TP was significantly different between ITPA phenotypes (figure, p<0.0001), with RBV-TP in the 30% and 5-10% activity phenotypes being approximately 2-fold higher than wild-type (100%).

Conclusions: ITPA variant phenotypes have higher RBV TP concentrations in RBC despite having less RBV-induced hemolytic anemia. A potential mechanism for this observation is that ITPA may degrade RBV TP in RBC and thus phosphorylated RBV levels are higher in subjects with ITPA variant phenotypes. Prospective studies are needed to confirm and extend these findings, to establish the mechanism, and to evaluate additional cell types other than RBC.

TUESDAY, FEBRUARY 24, 2015 Session P-H3 Poster Session

Poster Hall

2:30 pm– 4:00 pm Drug-Drug Interactions 519 Interactions of Antiretroviral Drugs With the SLC22A1 (OCT1) Drug Transporter Darren M. Moss ; Neill Liptrott; Marco Siccardi; Andrew Owen University of Liverpool, Liverpool, United Kingdom

Background: SLC22A1 is expressed on the basolateral membrane of hepatic liver cells and is involved in the excretion of numerous cationic drugs into the bile. The inhibition of SLC22A1 by several antiretrovirals, such as the protease inhibitor darunavir, has not previously been determined. In order to better understand and predict drug-SLC22A1 interactions, a range of antiretrovirals were screened for SLC22A1-associated inhibition and transport. Methods: Stable SLC22A1-expressing KCL22 cells were produced previously by nucleofection and neomycin selection. Control KCL22 cells were transfected with the empty vector pcDNA3.1. Accumulation of 14C radiolabelled tetraethylammonium (TEA; 5.4 m M, 0.3 m Ci/mL, 30 min) was determined in SLC22A1-expressing and mock-transfected cells with and without 50 m M of control SLC22A1 inhibitors prazosin or cepharanthine, or 50 m M of each antiretroviral drug. Following the experiment, SLC22A1 IC 50 values for efavirenz, darunavir and prazosin were determined (inhibitor range 0-100 m M). Cellular accumulation of efavirenz and darunavir (1 m M) was also assessed in SLC22A1-expressing KCL22 cells and reversibility was assessed using the SLC22A1-inhibitor, prazosin (200 m M). Results: TEA accumulation was higher in SLC22A1-expressing cells compared to mock-transfected cells (10.5 ± 0.6 m M versus 0.3 ± 0.004 m M, p<0.001) and was significantly reduced in SLC22A1-expressing cells when co-incubated with all antiretrovirals tested except atazanavir, lamivudine, tenofovir, zidovudine and raltegravir (Table). SLC22A1 IC 50 values in the presence of 10% FBS for efavirenz, darunavir and prazosin were 21.8, 46.2 and 2.8 m M, respectively. Efavirenz accumulation was higher in SLC22A1-expressing cells compared to mock-transfected cells (16.3% higher, p<0.05) which was reversed using prazosin, whereas no difference was observed for darunavir (p=0.45).

Poster Abstracts

340

CROI 2015