CROI 2017 Abstract e-Book

Abstract eBook

Oral Abstracts

40 CLINICAL PHARMACOLOGY OF THE HIV INTEGRASE STRAND TRANSFER INHIBITOR BICTEGRAVIR Heather Zhang, Joseph M. Custodio , Xuelian Wei, Hui Wang, Amanda Vu, John Ling, Hal Martin, Erin Quirk, Brian P. Kearney Gilead Sci, Foster city, CA

Background: Bictegravir (BIC) is an investigational, once-daily, unboosted HIV integrase strand transfer inhibitor (INSTI) with potent in vitro activity against most INSTI- resistant variants. BIC is currently in development as a single tablet regimen (STR) coformulated with FTC/TAF for treatment of HIV-1 infection in adults and adolescents. Clinical pharmacology assessments of the PK, ADME and DDI potential were performed. Methods: A single- (SD) and multiple-dose (MD) randomized, double-blind, placebo-controlled (6 active; 2 placebo/cohort) of staggered dose-escalation evaluated SD BIC 5, 25, 50, 100, 300 or 600 mg; or once-daily MD 5, 25, 50, 100 or 300 mg for 14 days (fasted) in healthy volunteers. An ADME/ mass balance study included 8 healthy male subjects dosed with a SD 100 mg plus 100 µCi [14C]-labeled BIC. Blood, urine and feces samples were analyzed for total radioactivity and pooled plasma and excreta samples were radio-profiled. An open-label, six cohort (n=15/cohort), fixed sequence and cross-over study assessed the DDI liability of BIC as a victim through utilization of CYP3A4, UGT1A1, and/or P-gp inhibitors and inducers. Safety was assessed throughout each study. Results: BIC exposure was dose proportional following SD of 25-100mg. Accumulation at steady-state was approximately 1.6x, consistent with the observed half-life of approximately 18 hours. Following a SD of [14C]-labeled BIC, the total recovery of radioactivity was 95%± 1.5%, with 60%± 5.5% from feces and 35%± 5.0% from urine. Balanced glucuronidation and oxidation contributed to the major clearance pathways of BIC. The DDI study (Table 1) showed increased BIC AUC (61-74%) by CYP3A4 inhibitors voriconazole and DRV/COBI, but showed a greater increase (~4x) by potent dual inhibitors of UGT1A1 and CYP3A4, ATV and ATV+COBI. Coadministration of BIC with a potent CYP3A4/UGT1A1/P gp inducer, rifampin resulted in a 75% decrease of BIC AUC; in contrast, a lesser reduction (38%) was associated with the moderate CYP3A4/P gp inducer, rifabutin. Overall, BIC was well tolerated at all doses studied. No deaths, SAEs, or Grade 3 or 4 AEs were reported. The safety profile for BIC did not differ with increasing doses of SD or MD. Conclusion: The favorable BIC PK profile supports once daily dosing. The DDI results of BIC are consistent with its ADME profile, in which both CYP3A4 and UGT1A1contributed to BIC elimination. BIC was safe and well tolerated in healthy volunteers.

Oral Abstracts

41 RANDOMIZED TRIAL OF BICTEGRAVIR OR DOLUTEGRAVIR WITH FTC/TAF FOR INITIAL HIV THERAPY Paul E. Sax 1 , Edwin DeJesus 2 , Gordon Crofoot 3 , Douglas Ward 4 , Paul Benson 5 , Xuelian Wei 6 , Kirsten L. White 6 , Hal Martin 6 , Andrew Cheng 6 , Erin Quirk 6 1 Brigham and Women’s Hosp, Boston, MA, USA, 2 Orlando Immunol Cntr, Orlando, FL, USA, 3 The Crofoot Rsr Cntr, Houston, TX, USA, 4 Dupont Circle Physicians Group, Washington, DC, USA, 5 Be Well Med Cntr, Berkley, MI, USA, 6 Gilead Scis, Inc, Foster City, CA, USA Background: Because of their potency and safety, integrase strand transfer inhibitors (INSTIs) are widely recommended initial HIV-1 treatments in most major treatment guidelines. Bictegravir (BIC, GS-9883) is a novel, unboosted, once-daily INSTI that demonstrated potent activity in a 10-day monotherapy study and has in vitro activity against most INSTI-resistant viruses. Methods: Treatment naïve, HIV-infected adults were randomized 2:1 to receive blinded treatment once daily with BIC 75 mg or dolutegravir (DTG) 50 mg; both were given with open label emtricitabine 200 mg/tenofovir alafenamide 25 mg (FTC/TAF). Treatments were administered without regard for food for 48 weeks. The primary endpoint was the proportion with HIV RNA <50 copies/mL (c/mL) at Week (W) 24 using snapshot analysis. Noninferiority was assessed through 95% confidence intervals (CI) at W24 and W48. Safety (adverse events [AEs] and laboratory results through Week 48) was a secondary endpoint. Results: Of 98 patients enrolled, 65 were randomized to BIC+FTC/TAF and 33 to DTG+FTC/TAF. Most subjects were male, had asymptomatic HIV infection, with median HIV-1 RNA 4.4-4.5 log10; baseline characteristics were balanced between arms. Virologic success (HIV-1 RNA <50 c/mL) at W24 was 97% for the BIC arm and 94% for the DTG arm, and at W48 was 97% and 91%, respectively (Table). One subject in the DTG arm had HIV-1 RNA >50 c/mL at W48. No viral resistance was detected in the BIC+FTC/TAF arm. Mean CD4 count increases at W48 were 258 cells/µL in the BIC arm and 192 cells/µL in the DTG arm. There were no treatment-related serious adverse events and no deaths. The most commonly reported adverse events were diarrhea (12% in each arm) and nausea (8% BIC, 12% DTG). One subject in the BIC arm discontinued due to an adverse event of urticaria following the W24 visit. Median changes in estimated glomerular filtration by Cockcroft-Gault (GFRCG) at W48 were -7.0 mL/min for BIC and -11.3 mL/min for DTG, with no discontinuations due to renal adverse events. Conclusion: Bictegravir+FTC/TAF and DTG+FTC/TAF both demonstrated high virologic response rates at W24 that were maintained at W48. No treatment-emergent resistance was detected in the BIC+FTC/TAF arm through W48. Both treatments were well tolerated, and no significant safety signal was detected in either arm. Estimated GFRCG changes were consistent with known inhibition of tubular creatinine transport by BIC and DTG. Further evaluation of BIC for the treatment of HIV infection is warranted.

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CROI 2017