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)

Clin Infect Dis. 2017 Aug 1;65(3):442-452. doi: 10.1093/cid/cix239.

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.

Clinical trials registration: NCT01803074.

Keywords: GSK3532795; HIV-1 infection; dose-ranging; maturation inhibitor; phase 2a study.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Atazanavir Sulfate* / administration & dosage
  • Atazanavir Sulfate* / adverse effects
  • Atazanavir Sulfate* / therapeutic use
  • Female
  • HIV Infections / drug therapy*
  • HIV Protease Inhibitors* / administration & dosage
  • HIV Protease Inhibitors* / adverse effects
  • HIV Protease Inhibitors* / therapeutic use
  • Humans
  • Male
  • Middle Aged
  • RNA, Viral / blood
  • Ritonavir* / administration & dosage
  • Ritonavir* / adverse effects
  • Ritonavir* / therapeutic use
  • Young Adult

Substances

  • HIV Protease Inhibitors
  • RNA, Viral
  • Atazanavir Sulfate
  • Ritonavir

Associated data

  • ClinicalTrials.gov/NCT01803074