title: GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees.
abstract: OBJECTIVE
  Direct-acting antiviral agents suppress hepatitis B virus (HBV) load, but they require life-long use. Stimulation of the innate immune system could increase its ability to control the virus and have long-lasting effects after a finite regimen. We investigated the effects of immune activation with GS-9620--a potent and selective orally active small molecule agonist of Toll-like receptor 7--in chimpanzees with chronic HBV infection.
  
  
  METHODS
  GS-9620 was administered to chimpanzees every other day (3 times each week) for 4 weeks at 1 mg/kg and, after a 1-week rest, for 4 weeks at 2 mg/kg. We measured viral load in plasma and liver samples, the pharmacokinetics of GS-9620, and the following pharmacodynamics parameters: interferon-stimulated gene expression, cytokine and chemokine levels, lymphocyte and natural killer cell activation, and viral antigen expression. Clinical pathology parameters were monitored to determine the safety and tolerability of GS-9620.
  
  
  RESULTS
  Short-term oral administration of GS-9620 provided long-term suppression of serum and liver HBV DNA. The mean maximum reduction of viral DNA was 2.2 logs, which occurred within 1 week of the end of GS-9620 administration; reductions of >1 log persisted for months. Serum levels of HBV surface antigen and HBV e antigen, and numbers of HBV antigen-positive hepatocytes, were reduced as hepatocyte apoptosis increased. GS-9620 administration induced production of interferon-α and other cytokines and chemokines, and activated interferon-stimulated genes, natural killer cells, and lymphocyte subsets.
  
  
  CONCLUSIONS
  The small molecule GS-9620 activates Toll-like receptor 7 signaling in immune cells of chimpanzees to induce clearance of HBV-infected cells. This reagent might be developed for treatment of patients with chronic HBV infection.
authors: Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, Texas 78227, USA. rlanford@txbiomed.org
authors: Robert E
authors: RE
authors: Lanford
authors: Bernadette
authors: B
authors: Guerra
authors: Deborah
authors: D
authors: Chavez
authors: Luis
authors: L
authors: Giavedoni
authors: Vida L
authors: VL
authors: Hodara
authors: Kathleen M
authors: KM
authors: Brasky
authors: Abigail
authors: A
authors: Fosdick
authors: Christian R
authors: CR
authors: Frey
authors: Jim
authors: J
authors: Zheng
authors: Grushenka
authors: G
authors: Wolfgang
authors: Randall L
authors: RL
authors: Halcomb
authors: Daniel B
authors: DB
authors: Tumas
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006515:Hepatitis B virus / Q000187:drug effects*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000276:immunology; D007113:Immunity, Innate; D007155:Immunologic Factors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002679:Pan troglodytes; D011621:Pteridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000276:immunology; D019562:Viral Load / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D007155:Immunologic Factors; D011621:Pteridines; D051199:Toll-Like Receptor 7; C582524:vesatolimod