CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

Conclusions: ABT‐493 and ABT‐530 exposure were not affected by rilpivirine or raltegravir. ABT‐493 + ABT‐530 increased rilpivirine and raltegravir exposures. Consistent with rilpivirine and raltegravir label recommendations for other drugs with similar magnitude of exposure increase, no dose adjustment is needed when ABT‐493 and ABT‐530 are coadministered with rilpivirine or raltegravir.

454 Pharmacokinetics of Dolutegravir and Rilpivirine in CombinationWith SMV and SOF Marco Merli 1 ; Laura Galli 2 ; Letizia Marinaro 3 ; Alexandra Ariaudo 3 ; Emanuela Messina 4 ; Caterina Uberti Foppa 2 ; Antonella Castagna 2 ; Adriano Lazzarin 4 ; Stefano Bonora 3 ; Hamid Hasson 4 1 Vita-Salute San Raffaele Univ, Milan, Italy; 2 San Raffaele Scientific Inst, Milan, Italy; 3 Univ of Turin, Turin, Italy; 4 Vita-Salute Univ, San Raffaele Scientific Inst, Milan, Italy Background: Anti-HCV treatment with direct-acting antivirals (DAAs)-based regimens is a priority in HIV/HCV co-infected patients (pts) with advanced liver disease. We evaluated plasma through concentration of dolutegravir and rilpivirine (DTG-RPV) used in combination with simeprevir plus sofosbuvir (SMV-SOF) in HIV/HCV co-infected pts with advanced liver disease. Methods: Pts infected with HCV and HIV-1, with advanced liver disease (Metavir F3-F4), on antiretroviral therapy (ART), HIV-RNA<50 cps/mL at the start of anti-HCV treatment, treated for HCV with SMV plus SOF for 12 weeks and on treatment for HIV with DTG-RPV-including regimens were considered. Immuno-virological data were recorded at DAAs start (baseline, BL), week 4, week 12 and at post-treatment (PT) week 4, PT week 12. Plasma DTG, RPV, SOF, SMV trough concentrations were evaluated with a HPLC validated method at BL (only DTG, RPV were tested) and week 4. Results were reported as median (IQR) or frequency (%). Geometric means were also calculated to summarize through concentration values. Wilcoxon signed rank test applied to assess significant changes in plasma through concentration since BL. Results: Eleven pts evaluated: 73%males, age 53 (52-54) yrs, duration of HIV infection 23 (22-25) yrs, nadir CD4+ 181 (109-326) cells/µL, CD4+ 515 (357-722) cells/µL, HCV-RNA 6.1 (5.6-6.4) log10 cps/mL; HCV genotype (GT) was: 9 (82%) GT1a, 1 (9%) GT1b, 1 (9%) GT4a; 10 (91%) pts had Child-Pugh (CTP) A, 1 (9%) had CTP B; liver stiffness was 18.9 (12.2- 33.8) KPa. Ribavirin was used in 8 (73%) pts. Main(>10%) ART regimens were: 5 (45%) DTG/RPV, 4 (36%) DTG/RPV/3TC. All pts completed anti-HCV treatment: 7 (64%) achieved HCV-RNA <12 UI/ml by week 4 and 11 (100%) at the end of treatment. Geometric means (95%CI) of Ctrough at BL and w4 were: for DTG 1148 (550-2455) vs 1413 (776-2630) ng/mL (p=0.301), for RPV 115 (63-209) vs 141 (85-240) ng/mL (p=0.203). Geometric means (95%CI) of SOF and SMV Ctrough at w4 were 380 (191-741) ng/ml and 2570 (1445-4571) ng/ml, respectively. Conclusions: This is the first study evaluating pharmacokinetics of DTG and RPV-based antiretroviral regimen in patients treated with SOF plus SMV. DTG and RPV plasma exposure was not affected by concomitant DAAs and SOF and SMV plasma concentration were in the expected range. This antiretroviral regimen deserves further evaluations in larger samples of HIV/HCV co-infected subjects treated with DAAs. 455 Effect of Direct Acting Antivirals on the Pharmacokinetics of Calcineurin Inhibitors Thibaut Gelé 1 ; Aurélie Barrail-Tran 2 ; Audrey Coilly 3 ; Claire Laforest 4 ; Rodolph Anty 5 ; Georges-Philipp Pageaux 6 ; Jean-Charles Duclos-Vallée 3 ; Anne-Marie Taburet 1 ; for the ANRS CO23 CUPILT StudyTeam 1 Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France; 2 Hosp Bicêtre, Kremlin Bicêtre, France; 3 Hosp Paul Brousse, Villejuif, France; 4 Hosp Pontchaillou, Rennes, France; 5 Hosp Nice, Nice, France; 6 Hosp Montpellier, Montpellier, France Background: Severe hepatitis C virus (HCV) recurrence affects post-transplant survival in HCV infected patients. We describe the effect of sofosbuvir-based anti-HCV therapy on disposition of anti-calcineurin immunosuppressive drugs. Methods: Liver transplant patients (pts) with severe HCV recurrence who signed the informed consent were included in the ANRS CO23 CUPILT cohort and their characteristics recorded. Immunosuppressive therapy backbone was either tacrolimus (TAC) or cyclosporine (CyA). They were treated according to HCV genotype with 2 nd generation direct acting antivirals (DAA) including sofosbuvir (SOF) with either daclatasvir (DCV) +/- ribavirine (RBV) or simeprevir (SMV) at standard dosing. Predose blood samples were drawn before DAA initiation (D0) and at week4 (W4) after DAA initiation. Trough concentrations (Ct) of TAC or CyA at steady state were measured by quality controls validated assays (immunoassay or LC-MS/MS). Apparent clearance (Cl/F) of TAC or CyA was estimated from the ratio of the dose per intake over the trough concentration (as a surrogate of average concentration at steady state) times the time interval between 2 doses Cl/F= D/(DDt*Ct). W4/D0 geometric mean ratio (GMR) and 2-sided 90% CIs (CI90) were calculated for Cl/F and compared to the 0.80-1.25 bioequivalence range. Unless otherwise indicated, results are medians and ranges. Results: Twenty three pts were on TAC and 12 on CyA. Characteristics at inclusion were age 57years (43, 81), weight 72kg (45, 106) and MELD score 9 (0, 26). HCV genotypes were G1 (25 pts), G2 (2 pts) and G4 (8 pts). On the 3 pts on antiretrovirals, one was on efavirenz (EFV) and 2 on raltegravir-based regimen combined with 2 nucleoside analogs. Pt on EFV has the highest TAC Cl/F. Creatinine clearance (MDRD equation) remained unchanged at W4 compared to D0. Cl/F of TAC and CyA at D0 and W4 are shown in the table below. Conclusions: Despite wide interindividual variability on TAC or CyA Cl/F, our data show that most liver transplant pts have an increased Cl/F on DAAs, statistically significant for TAC, leading to a decrease in concentrations and likely warranting an increased dosing. All these liver transplant pts should be monitored closely at the time of DAA initiation and during follow-up. These results need to be confirmed in a larger cohort of pts as well as the identification of factors explaining such drug-drug interaction.

Poster Abstracts

175

CROI 2016