title: Baseline interpatient hepatitis B viral diversity differentiates HBsAg outcomes in patients treated with tenofovir disoproxil fumarate.
abstract: OBJECTIVE
  HBsAg loss is a desired, but rare, treatment-induced clinical endpoint in chronic hepatitis B (CHB). Few studies have evaluated viral factors contributing to HBsAg loss.
  
  
  METHODS
  This study evaluated baseline interpatient sequence diversity across the HBV genome in tenofovir disoproxil fumarate-treated patients who lost HBsAg and compared it to that of control patients with high HBsAg levels throughout therapy. Twenty-one HBeAg+ patients (14 genotype (GT) A and 7 GT D) who achieved HBsAg loss and 27 controls (17 GT A and 10 GT D), were analyzed. Population sequencing was performed on baseline samples and pairwise genetic distances were calculated for 17 overlapping regions across the HBV genome as a measure of interpatient viral diversity.
  
  
  RESULTS
  Overall, viral diversity was up to 10-fold higher across GT D patients compared to GT A patients throughout the HBV genome. Within the pol/RT and HBs genes, interpatient viral diversity was significantly lower among HBsAg loss patients for both GT A and D, with the difference driven largely by a reduction in diversity in the small S gene. Conversely, interpatient viral diversity was generally higher in HBsAg loss patients across the HBx gene regulatory elements and precore region.
  
  
  CONCLUSIONS
  In HBsAg loss patients, less interpatient viral diversity was observed within structural-coding regions while specific regions across the HBx and precore genes encoding nonstructural regulatory elements generally displayed higher interpatient viral diversity. These distinct patterns may reflect different responses to adaptive pressure for HBV genomic structural and nonstructural elements.
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, USA. Electronic address: pcharuworn@gmail.com.
authors.forename: Prista
authors.initials: P
authors.lastname: Charuworn
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, USA.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Hengen
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Aguilar Schall
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Dinh
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, USA.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ge
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, USA.
authors.forename: Amoreena
authors.initials: A
authors.lastname: Corsa
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: Reesink
authors.affiliation: INSERM U1052, Hospices Civils de Lyon, Lyon University, Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: Gilead Sciences, Inc, Foster City, CA, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kitrinos
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology; D004279:DNA, Viral / Q000235:genetics*; D018562:Disease Transmission, Infectious; D005260:Female; D014644:Genetic Variation / Q000187:drug effects*; D006514:Hepatitis B Surface Antigens / Q000235:genetics*; D006513:Hepatitis B e Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000276:immunology / Q000635:transmission / Q000821:virology; D006801:Humans; D008297:Male; D000068698:Tenofovir / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D000068698:Tenofovir
keywords: Genetic distance; HBV coding regions; HBV genotype differences; HBsAg loss; Nucleotide treatment outcome