CROI 2019 Abstract eBook

Abstract eBook

Oral Abstracts

RNA <50 c/mL (LA 93.6% vs CAR 93.3%). Four LA recipients (1.4%) had CVF; 3 had mutations in the NNRTI + INSTI domains (K101K/E/Q + G140R, E138K + Q148R, and E138E/A/K/T + Q148R, respectively) and 1 was not tested (PO only). The CAR arm had 3 CVFs with no INSTI resistance. Adverse events (AE) leading to withdrawal and serious AE were infrequent in both arms. The most common drug-related AE was injection site reactions (ISRs; 82% of participants in the LA arm); frequency decreased over time. 99% of ISRs were Grade 1 or 2; the median duration was 3 days. Of 263 LA participants completing HIVTSQc at W48, 99% were more satisfied with CAB+RPV compared with their prior daily oral CAR. Conclusion: The regimen of monthly injections of CAB+RPV was noninferior to DTG/ABC/3TC at W48. The LA regimen was generally well tolerated with few CVFs. Overall, these results demonstrated the therapeutic potential of CAB+RPV injections, following short initial induction with oral DTG/ABC/3TC to achieve viral suppression.

weeks, to date (Cohorts 1 and 2). The increase in exposure (C max and AUC) between 30 and 100 mg GS-6207 was approximately dose proportional. To date, there have been no deaths, serious adverse events, or Grade 3 or 4 adverse events (AEs). Most AEs were mild (Grade 1) and resolved. Conclusion: Based on the interim data, GS-6207 was safe and well tolerated following single SC doses of up to 450 mg in healthy subjects. Sustained delivery supports a dosing interval of at least 3 months. The safety and PK of GS-6207 supports evaluation of its antiviral activity in HIV-infected participants. 142 A PHASE IIA STUDY OF NOVEL MATURATION INHIBITOR GSK2838232 IN HIV PATIENTS Edwin DeJesus 1 , Sara Harward 2 , Roxanne C. Jewell 2 , Mark Johnson 2 , Etienne Dumont 3 , Viviana Wilches 3 , Fiona Halliday 4 , Christine Talarico 2 , Jerry Jeffrey 2 , Kevin Gan 3 , Franco B. Felizarta 5 , Anita Scribner 6 , Moti Ramgopal 7 , Paul Benson 8 , Brian A. Johns 2 1 Orlando Immunology Center, Orlando, FL, USA, 2 GlaxoSmithKline, Research Triangle Park, NC, USA, 3 GlaxoSmithKline, Collegeville, PA, USA, 4 GlaxoSmithKline, Uxbridge, UK, 5 Private Practice, Bakersfield, CA, USA, 6 DCOL Center for Clinical Research, Longview, TX, USA, 7 Midway Immunology and Research Center, Fort Pierce, FL, USA, 8 Be Well Medical Center, Berkley, MI, USA Background: GSK2838232 is a second-generation HIV maturation inhibitor with a distinct preclinical virologic profile and well-defined pharmacokinetics (PK), safety, and tolerability in non-HIV-infected subjects that suggests potential to overcome hurdles met by prior drugs in this class. This profile provided rationale for investigation of GSK2838232 co-administered with cobicistat in HIV-1-infected adults. Methods: This proof of concept Phase IIa study assessed GSK2838232 antiviral activity, PK, safety, and tolerability in HIV infected adults currently off antiretroviral therapy. The dose-ranging two-part study evaluated 4 dose levels of once daily GSK2838232 monotherapy administered with 150 mg cobicistat for 10 days. PK samples were collected at Days 1 and 10, and safety assessments were performed throughout the study. Subjects were followed for 11 days after the end of treatment (Day 21). Results: A total of 33 subjects were enrolled across 4 cohorts (200 mg n=8, 100 mg n=10, 50 mg n=8 and 20 mg n=7) of GSK2838232. Following completion of the 100 mg cohort, an interim safety and PK analysis was performed, then remaining cohorts enrolled. Dose-proportional increases in drug exposure were seen. There was moderate-to-high PK variability, with steady state by Day 8 and a geometric mean plasma t½ on Day 10 of 16-19 h across the dose levels. GSK2838232 monotherapy showed a reduction in plasma HIV-1 RNA from baseline to Day 11, with a mean maximum decrease of 1.70, 1.32, 1.56 and 0.67 log10 copies/mL at the 200, 100, 50 and 20 mg dose levels respectively. The population viral genotype was assessed pre- and post-GSK2838232 dosing. Of the 28 subjects with reported genotype data, 2 subjects had treatment- emergent A364A/V mixtures associated with in vitro GSK2838232 resistance. Of these 2 subjects, 1 subject had phenotypic resistance to GSK2838232. Study drug was well-tolerated with no clinically relevant trends in laboratory values, vital signs, or cardiac signals. There were no serious adverse events and all adverse events (AEs) were mild to moderate. There were 5 subjects assessed as experiencing 6 possible drug-related AEs: headache (n=2), somnolence (n=1), skin rash (n=1), abnormal dream (n=1) and pruritus (n=1). Conclusion: GSK2838232 demonstrated short-term tolerability and antiviral activity, with the maximal response observed in the highest dose cohort. Preliminary evidence of clinical activity observed in HIV patients provides a positive proof of concept for further exploration of GSK2838232. 143 SYSTEMATIC DETERMINATION OF IN VITRO HIV-1 INTEGRASE RESISTANCE FROM CLINICAL SAMPLES Aniqa Shahid 1 , Vincent Montoya 1 , Wendy W. Zhang 1 , Conan K. Woods 1 , Natalia S. Oliveira 1 , Sarina Barnes 1 , Rob Hollebakken 1 , Chanson J. Brumme 1 , Peter Cheung 1 , P. Richard Harrigan 2 Background: Resistance phenotype data is relatively sparse for the newest HIV integrase inhibitors, dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB). Here, we report the phenotypic susceptibility of a large panel of oligo- clonal patient-derived subtype B recombinant viruses selected to maximize in vivo sequence variation. 1 British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada, 2 University of British Columbia, Vancouver, BC, Canada

Oral Abstracts

141 SAFETY AND PK OF SUBCUTANEOUS GS-6207, A NOVEL HIV-1 CAPSID INHIBITOR Jennifer E. Sager , Rebecca Begley, Martin Rhee, Steve K. West, John Ling, Scott D. Schroeder, Winston C. Tse, Anita Mathias Gilead Sciences, Inc, Foster City, CA, USA Background: GS-6207, a selective, multi-stage inhibitor of HIV-1 capsid function, is in development for the treatment of HIV-1 infection. GS-6207 is characterized by potent antiviral activity, low predicted human clearance, and low aqueous solubility, making it well suited for an extended-release parenteral formulation. This Phase 1 study evaluated the safety, tolerability and pharmacokinetics (PK) of a subcutaneous (SC) suspension of GS-6207 in healthy volunteers. Methods: This is a randomized, blinded, placebo-controlled healthy volunteer study with staggered single dose escalation cohorts. Within each cohort, subjects were randomized (4:1) to receive single SC doses of GS-6207 (n=8/ cohort) or placebo (N=2/cohort), at 30, 100, 300 or 450 mg. PK parameters will be estimated and summarized by dose and dose proportionality will be assessed. Safety, tolerability and PK will be evaluated for at least 24 weeks post-dose. Results: 40 subjects received a single SC dose of GS-6207 (N=32) or placebo (N=8). The study is ongoing with interim safety and PK data available through at least 20 weeks (Cohort 1, 30 mg), 16 weeks (Cohort 2, 100 mg), 8 weeks (Cohort 3, 300 mg) and 4 weeks (Cohort 4, 450 mg). PK parameters for Cohorts 1 and 2 have been estimated. Analysis for Cohorts 3 and 4 is ongoing. The PK profile of SC GS-6207 is consistent with sustained delivery. T max values ranged from 21 to 35 days (Cohorts 1 and 2). The median apparent terminal t 1/2 was between 30 to 38 days and concentrations are measureable for at least 16

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CROI 2019