title: Deep sequencing shows that HBV basal core promoter and precore variants reduce the likelihood of HBsAg loss following tenofovir disoproxil fumarate therapy in HBeAg-positive chronic hepatitis B.
abstract: Hepatitis B e antigen (HBeAg) seroconversion and hepatitis B surface antigen (HBsAg) loss are important clinical outcomes for patients with chronic hepatitis B (CHB) treated with antiviral therapy. To date, there have been few studies that have evaluated viral sequence markers predicting serological response to nucleos(t)ide analogue (NA) treatment.
  
  
  
  We used next-generation sequencing (NGS) and quantitative HBV serology (HBeAg and HBsAg) to identify viral sequence markers associated with serological response to long-term tenofovir disoproxil fumarate therapy among HBeAg-positive patients. In the GS-US-174-0103 study, approximately half the patients seroconverted to anti-HBe by week 192 and 11% of patients exhibited HBsAg loss, the closest outcome to functional cure. The frequency of HBV variants that have previously been associated with HBV clinical outcomes was evaluated. HBV viral diversity in baseline sequences generated by NGS was calculated using Shannon entropy.
  
  
  
  NGS analysis of HBV sequences from 157 patients infected with genotypes A to D showed the frequency of variants in the basal core promoter (BCP) and precore (PC) regions varied by genotype and that these mutations were associated with the absence of HBsAg loss. This was the case even when mutations were present at frequencies below the threshold of detection by population sequencing. Increased viral diversity across the HBV genome as determined by NGS was also associated with reduced likelihood of HBsAg loss.
  
  
  
  Patients with detectable BCP and/or PC variants and higher viral diversity have a lower probability of HBsAg loss during long-term NA therapy. Strategies to achieve functional cure of HBV infection through combination therapy should consider using NGS to stratify patients according to BCP/PC sequence. Consideration should also be given to earlier initiation of therapy prior to the emergence of BCP/PC variants.
  
  
  
  NCT00116805; Post result.
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Julianne
authors.initials: J
authors.lastname: Bayliss
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Lilly
authors.initials: L
authors.lastname: Yuen
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Gillian
authors.initials: G
authors.lastname: Rosenberg
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.|Department of Gastroenterology, St. Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: Darren
authors.initials: D
authors.lastname: Wong
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Margaret
authors.initials: M
authors.lastname: Littlejohn
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Jackson
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Anuj
authors.initials: A
authors.lastname: Gaggar
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kitrinos
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: G Mani
authors.initials: GM
authors.lastname: Subramanian
authors.affiliation: Hôpital Beaujon, University of Paris, Clichy, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.affiliation: Liver Unit, Valle d'Hebron (Ciberehd) University Hospital, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Buti
authors.affiliation: Toronto Center for Liver Diseases, Toronto Western and General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Harry L A
authors.initials: HLA
authors.lastname: Janssen
authors.affiliation: New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Ed
authors.initials: E
authors.lastname: Gane
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Vitina
authors.initials: V
authors.lastname: Sozzi
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Danni
authors.initials: D
authors.lastname: Colledge
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Rachel
authors.initials: R
authors.lastname: Hammond
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Edwards
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Locarnini
authors.affiliation: Department of Gastroenterology, St. Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Thompson
authors.affiliation: Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Revill
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D004279:DNA, Viral / Q000032:analysis; D004311:Double-Blind Method; D005260:Female; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics* / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D000069078:Seroconversion; D000068698:Tenofovir / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D000068698:Tenofovir
keywords: CHRONIC VIRAL HEPATITIS; HEPATITIS B