CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

1 NIH Clinical Center, Bethesda, MD, 2 National Institute of Allergy and Infectious Diseases, Bethesda, MD, 3 Leidos Biomedical Research, Inc., Bethesda, MD Background: Once-weekly isoniazid (INH) and rifapentine (RPT) (wHP) for 3 months is a recommended regimen for latent tuberculosis infection (LTBI). Limited drug interaction data exist on the use of this regimen with antiretroviral agents. This study sought to characterize the effects of wHP on the steady-state pharmacokinetics (PK) of dolutegravir (DTG). Methods: This was an open-label, intrasubject drug interaction study in HIV-negative healthy volunteers comprised of 2 phases: (1) DTG once daily alone and (2) DTG once daily with wHP. The study design is detailed in Figure 1. DTG levels were measured at all PK visits, and RPT and INH levels on Day 19. DTG, RPT, and INH PK parameters were determined by non-compartmental methods (Phoenix WinNonlin, v6.4). Geometric mean ratios with 90% confidence intervals [CI] were compared between PK days. Adverse events (AEs) were graded via the DAIDS AE Toxicity Table (v2.0). Results: Of 4 enrolled subjects (3 males, 1 female, age 22-46 years), 3 completed the study and 1 withdrew prior to the 3rd dose of HP. The study was stopped prematurely due to the development of multiple AEs in 2 subjects. In both subjects, flu-like syndrome with symptoms of nausea, vomiting, and fever (Grades 2 and 3) began ~8 hours after the last doses of DTG, RPT, and INH and lasted 24-48 hours. One subject required a 24-hour hospitalization for management of orthostatic hypotension (Grade 3). Transaminase elevations (Grades 2-4) occurred in both subjects. Following wHP initiation, DTG exposure was decreased by 46% on Day 14 vs. 4 (p=0.134, 90% CI [0.27-1.10]) and Cmin was decreased by 74% on Day 15 (p=0.017) (n=4). The Cmin was 5.3x DTG’s protein-adjusted IC90 (0.064 μg/mL) at this time point (range 0.9-11.0). One subject had multiple Cmin values <0.3 μg/ mL following wHP initiation, a level associated with higher rates of DTG treatment failure. Day 19 exposure to RPT and its active metabolite were similar to reference PK data, but INH exposure was 67-92% higher than expected in the 2 subjects who developed AEs. Conclusion: Serious toxicities, possibly related to high INH exposure, were observed in 2 of 3 subjects receiving 3 doses of wHP with once daily DTG, leading to early termination of our study. Limited PK data from these subjects showed decreased DTG exposure and Cmin values with wHP co-administration. Given that flu-like syndrome was reported in <4% of subjects in studies of the efficacy of wHP alone, these data suggest that co-administration of DTG and wHP should be avoided.

Poster and Themed Discussion Abstracts

410 INCREASED DOLUTEGRAVIR EXPOSURE IN HIV PATIENTS SWITCHED FROM RITONAVIR TO COBICISTAT Cristina Gervasoni , Agostino Riva, Amedeo Capetti, Valeria Cozzi, Giuliano Rizzardini, Massimo Galli, Emilio Clementi, Dario Cattaneo Luigi Sacco Univ Hosp, Milan, Italy

Background: Cobicistat is a new pharmacoenhancer which is now replacing ritonavir thanks to its more selective inhibition on cytochrome P450-mediated hepatic metabolism. Here we carried out a pharmacokinetic survey in HIV-infected patients switching from darunavir/ritonavir (800/100 mg/daily) to darunavir/cobicistat (800/150 mg/daily) and given dolutegravir (50 mg/daily) as part of their antiretroviral therapy Methods: A consecutive series of HIV-infected patients undergoing therapeutic drug monitoring (TDM) of dolutegravir and darunavir plasma trough concentrations before (visit 1) and after (visit 2) the switch from ritonavir to cobicistat were considered. Collected blood samples had to be taken 24 hours after the last drug intake (a time window of ±20 min was considered acceptable), immediately before drug administration. Drug concentrations were assessed by high performance liquid chromatography method with UV detection previously developed in our lab. Comparisons between the two visits were performed by paired t-tests Results: Patients (n=10) were all Caucasians, highly pretreated, mainly males (80%), with mean age of 54±6 years and with good immunological status (CD4 cell count: 650±399 cells/mL, viral load <37 copies/mL). As shown in Figure 1, the switch from ritonavir to cobicistat resulted in a 100% increase of dolutegravir trough concentrations (from 591±373 to 1130±634 ng/mL, p<0.01), whereas no difference on darunavir trough concentrations were observed (from 2249±989 to 2122±1032 ng/mL, p=0.602). The second visit was performed at 79±64 days after the fist TDM assessment. During this period no significant increment in serum creatinine concentrations was recorded (visit 1: 1.14±0.33 mg/dL, visit 2: 1.22±0.29 mg/dL, p=0.655) Conclusion: We confirmed in a real-life setting that the switch from ritonavir to cobicistat resulted in a comparable boosting effect on darunavir exposure. We also documented for the first time that cobicistat significantly increased dolutegravir trough concentrations. It is likely that such pharmacokinetic interaction may be the result of a higher degree of inhibition of cobicistat than ritonavir on intestinal efflux transporters P-glycoprotein and breast cancer resistance protein, ultimately resulting in increased dolutegravir absorption. Interestingly, concomitant administration of dolutegravir and cobicistat – both drugs reported to potentially affect kidney function – has no effect on serum creatinine concentrations

CROI 2017 168