CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

427 EVALUATION OF RPV/FTC/TAF EXPOSURE-EFFICACY AND EXPOSURE-SAFETY RELATIONSHIPS Sophia R. Majeed 1 , Kavitha Bhasi 1 , Yongwu Shao 1 , William Garner 1 , Jenna Scott 1 , Carlos P. Ruixo 2 , Devi SenGupta 1 , Huyen Cao 1 , Brian P. Kearney 1 , Joseph M. Custodio 1 1 Gilead Scis, Foster City, CA, USA, 2 Janssen Rsr and Development, Beerse, Belgium Background: Tenofovir alafenamide (TAF) is a tenofovir (TFV) prodrug that achieves markedly lower plasma TFV exposures compared to tenofovir disoproxil furmarate (TDF), reducing risks of renal and bone toxicities. Efficacy and safety of switching from TDF-based single-tablet regimens (STRs), rilpivirine (RPV)/emtricitabine (FTC)/TDF or efavirenz (EFV)/FTC/TDF to the TAF-based STR, RPV/FTC/TAF, was evaluated in 2 randomized, double-blind, active-controlled Phase 3 studies in virologically suppressed HIV-1 infected adults. Methods: Area under the curve over 24 hours (AUCtau), maximum concentration (Cmax) and/or concentration at 24 hours (Ctau) were estimated from sparsely sampled pharmacokinetic (PK) data from the RPV/FTC/TAF arm of both studies for RPV (4 visits), TAF (1 visit), and its metabolite TFV (4 visits) using established population PK models. The PK-pharmacodynamic (PKPD) efficacy endpoint, proportion of subjects with HIV-1 RNA <50 copies/mL at Week 48 (FDA snapshot algorithm), was assessed by RPV and TAF exposure quartiles. Logistic regression was performed on log-transformed PK exposures of subjects with HIV-1 RNA <50 copies/mL. Exposures of subjects with HIV-1 RNA >=50 copies/mL and HIV-1 RNA <50 copies/mL were compared by a one-way analysis of variance. PKPD safety endpoints for RPV, TAF and TFV included most frequently reported AEs of upper respiratory tract infection (URI), nasopharyngitis, diarrhea, and headache, and were evaluated by quartiles of RPV, TAF and TFV exposures. Results: 754 subjects were treated with RPV/FTC/TAF. RPV, TAF and TFV PK parameters were available for 749, 545 and 748 RPV/FTC/TAF-treated subjects, respectively. Mean (% coefficient of variation) RPV AUCtau was 2551 (33.7), with a range of 502.0 to 5824 ng*h/mL and TAF AUCtau was 173.9 (28.2), with a range of 91.7 to 413.1 ng*h/mL. Virologic success was high across RPV and TAF exposure quartiles (Table 1). No exposure-efficacy trend was seen for TAF. A significant trend was noted with virologic success and RPV exposure, driven by higher frequency of subjects lost to follow up and missing data in the lowest quartile. This was not considered clinically relevant as RPV exposures were similar irrespective of virologic outcome. No clinically relevant relationships with AEs were observed across wide ranges of RPV, TAF and TFV exposures (Table 1). Conclusion: RPV/FTC/TAF was safe and efficacious, with no clinically relevant relationships between exposure and efficacy or safety noted across RPV, TAF and TFV exposures.

Poster and Themed Discussion Abstracts

CROI 2017 178