title: Antiviral Activity, Safety, and Exposure-Response Relationships of GSK3532795, a Second-Generation Human Immunodeficiency Virus Type 1 Maturation Inhibitor, Administered as Monotherapy or in Combination With Atazanavir With or Without Ritonavir in a Phase 2a Randomized, Dose-Ranging, Controlled Trial (AI468002).
abstract: BACKGROUND
  GSK3532795 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor that targets HIV-1 Gag, inhibiting the final protease cleavage between capsid protein p24 and spacer protein-1, producing immature, noninfectious virions.
  
  
  METHODS
  This was a phase 2a, randomized, dose-ranging multipart trial. In part A, subtype B-infected subjects received 5-120 mg GSK3532795 (or placebo) once daily for 10 days. In part B, subtype B-infected subjects received 40 mg or 80 mg GSK3532795 once daily with atazanavir (ATV) with or without (±) ritonavir (RTV) or standard of care (SOC) (tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and ATV/RTV 300 mg/100 mg) for 28 days. In part C, subtype C-infected subjects received 40 mg or 120 mg GSK3532795 once daily (or placebo) for 10 days. Endpoints included change in HIV-1 RNA from baseline on day 11 (parts A/C) or day 29 (part B).
  
  
  RESULTS
  A >1 log10 median decline in HIV-1 RNA was achieved by day 11 in parts A and C and day 29 in part B at GSK3532795 doses ≥40 mg; part B subjects receiving GSK3532795 and ATV ± RTV achieved similar declines to those receiving SOC. Median of the maximum declines in HIV-1 RNA were similar for the 40-120 mg once-daily dose groups regardless of baseline Gag polymorphisms. There were no deaths, adverse events leading to discontinuation, or serious adverse events.
  
  
  CONCLUSIONS
  GSK3532795 demonstrated potent antiviral activity against subtype B (monotherapy or with ATV ± RTV) and subtype C, and was generally well tolerated, which supported continued development of GSK3532795 in subjects with HIV-1 subtype B or subtype C.
  
  
  BACKGROUND
  NCT01803074.
authors.affiliation: Research and Development, Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Carey
authors.initials: C
authors.lastname: Hwang
authors.affiliation: Charité Research Organisation GmbH.|Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schürmann
authors.affiliation: Charité Research Organisation GmbH.
authors.forename: Christian
authors.initials: C
authors.lastname: Sobotha
authors.affiliation: St Stephen's Centre, Chelsea and Westminster Hospital, London, United Kingdom.
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
authors.affiliation: Research and Development, Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Heather
authors.initials: H
authors.lastname: Sevinsky
authors.affiliation: Research and Development, Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Neelanjana
authors.initials: N
authors.lastname: Ray
authors.affiliation: Research and Development, Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Palanikumar
authors.initials: P
authors.lastname: Ravindran
authors.affiliation: Research and Development, Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Hong
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Charité Research Organisation GmbH.
authors.forename: Christian
authors.initials: C
authors.lastname: Keicher
authors.affiliation: Charité Research Organisation GmbH.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hüser
authors.affiliation: Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
authors.affiliation: Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Ira B
authors.initials: IB
authors.lastname: Dicker
authors.affiliation: Research and Development, Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Dennis
authors.initials: D
authors.lastname: Grasela
authors.affiliation: Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: Max
authors.initials: M
authors.lastname: Lataillade
mesh_terms: D000328:Adult; D000069446:Atazanavir Sulfate / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D000069446:Atazanavir Sulfate; D019438:Ritonavir
keywords: GSK3532795; HIV-1 infection; dose-ranging; maturation inhibitor; phase 2a study