title: Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial.
abstract: Chronic liver injury can result in fibrosis that may progress over years to end-stage liver disease. The most effective anti-fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed.
  
  
  
  The aim of this study was to study the safety and tolerability of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2 (LOXL2) enzyme, in subjects with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or HCV-HIV co-infection and advanced liver disease.
  
  
  
  Eighteen subjects with advanced liver fibrosis received simtuzumab 700 mg intravenously every 2 weeks for 22 weeks. Transjugular liver biopsies were performed during screening and at the end of treatment to measure hepatic venous pressure gradient (HVPG) and to stage fibrosis.
  
  
  
  Treatment was well-tolerated with no discontinuations due to adverse events. No significant changes were seen in HVPG or liver biopsy fibrosis score after treatment. Exploratory transcriptional and protein profiling using paired pre- and post-treatment liver biopsy and serum samples suggested up-regulation of TGF-β3 and IL-10 pathways with treatment.
  
  
  
  In this open-label, pilot clinical trial, simtuzumab treatment was well-tolerated in HCV- and HIV-infected subjects with advanced liver disease. Putative modulation of TGF-β3 and IL-10 pathways during simtuzumab treatment merits investigation in future trials.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.|Division of Infectious Diseases, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.|Critical Care Medicine Department, AIDS Section, NIH Clinical Center, Bethesda, MD, USA.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Meissner
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: McLaughlin
authors.affiliation: Critical Care Medicine Department, AIDS Section, NIH Clinical Center, Bethesda, MD, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Matthews
authors.affiliation: Biomedical and Metabolic Imaging Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Gharib
authors.affiliation: Radiology and Imaging Sciences, NIH Clinical Center, Bethesda, MD, USA.
authors.forename: Bradford J
authors.initials: BJ
authors.lastname: Wood
authors.affiliation: Radiology and Imaging Sciences, NIH Clinical Center, Bethesda, MD, USA.
authors.forename: Elliot
authors.initials: E
authors.lastname: Levy
authors.affiliation: Biomedical Engineering, Imaging Sciences and Biomedical Engineering Division, Kings College, London, UK.
authors.forename: Ralph
authors.initials: R
authors.lastname: Sinkus
authors.affiliation: Genomics Unit, Research Technology Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT, USA.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Virtaneva
authors.affiliation: Genomics Unit, Research Technology Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Sturdevant
authors.affiliation: Genomics Unit, Research Technology Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Martens
authors.affiliation: Genomics Unit, Research Technology Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Porcella
authors.affiliation: Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA, USA.
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Goodman
authors.affiliation: Gilead Sciences Inc., Foster City, CA, USA.
authors.forename: Bittoo
authors.initials: B
authors.lastname: Kanwar
authors.affiliation: Gilead Sciences Inc., Foster City, CA, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Myers
authors.affiliation: Gilead Sciences Inc., Foster City, CA, USA.
authors.forename: Mani
authors.initials: M
authors.lastname: Subramanian
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Hadigan
authors.affiliation: Critical Care Medicine Department, AIDS Section, NIH Clinical Center, Bethesda, MD, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Masur
authors.affiliation: Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
authors.affiliation: Critical Care Medicine Department, AIDS Section, NIH Clinical Center, Bethesda, MD, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kovacs
authors.affiliation: Critical Care Medicine Department, AIDS Section, NIH Clinical Center, Bethesda, MD, USA.
authors.forename: Caryn G
authors.initials: CG
authors.lastname: Morse
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D060085:Coinfection / Q000150:complications* / Q000821:virology; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000150:complications*; D019698:Hepatitis C, Chronic / Q000150:complications*; D006801:Humans; D016753:Interleukin-10 / Q000097:blood; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000821:virology; D008297:Male; D008396:Maryland; D008875:Middle Aged; D017082:Portal Pressure / Q000187:drug effects; D053782:Transforming Growth Factor beta3 / Q000097:blood; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C508609:IL10 protein, human; C509044:TGFB3 protein, human; D053782:Transforming Growth Factor beta3; C000613471:simtuzumab; D016753:Interleukin-10
keywords: hepatic venous pressure gradient; lysyl oxidases; magnetic resonance elastography; transforming growth factor beta-3