1. Academic Validation
  2. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees

GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees

  • Gastroenterology. 2013 Jun;144(7):1508-17, 1517.e1-10. doi: 10.1053/j.gastro.2013.02.003.
Robert E Lanford 1 Bernadette Guerra Deborah Chavez Luis Giavedoni Vida L Hodara Kathleen M Brasky Abigail Fosdick Christian R Frey Jim Zheng Grushenka Wolfgang Randall L Halcomb Daniel B Tumas
Affiliations

Affiliation

  • 1 Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, Texas 78227, USA. [email protected]
Abstract

Background & aims: 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.

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