title: Delayed Reduction of Hepatitis B Viral Load and Dynamics of Adefovir-Resistant Variants during Adefovir plus Entecavir Combination Rescue Therapy.
abstract: OBJECTIVE
  Entecavir (ETV) added to adefovir (ADV) is recommended in the consensus for management of patients with ADV resistance. However, little attention has been focused on the delayed reduction of HBV DNA and dynamics of ADV-resistant variants during ADV-ETV combination rescue therapy in the clinical setting. We characterized the dynamics of viral load and resistant variants in nucleos(t)ide analogues (NAs)-naïve chronic hepatitis B (CHB) patients during antiviral treatment with ADV monotherapy followed by ADV-ETV combination therapy.
  
  
  METHODS
  A cohort of 55 CHB patients was enrolled in this study. Three NAs-naïve patients developed ADV-resistant variants during 24-33 months of ADV monotherapy, and then switched to ADV-ETV combination therapy. Thirty-five serial serum samples from these three patients were regularly collected during treatment. Ten mutants associated with commonly used antiviral drugs were detected by pyrosequencing.
  
  
  RESULTS
  HBV DNA decreased to the lowest level during ADV monotherapy at 6-18 months, with a decrease of 0.95-5.51 log10 copies/mL, whereas rtA181V or rtN236T gradually increased with extended therapy. HBV DNA decreased to below the detectable level during ADV-ETV combination therapy at 21-24 months, with a decrease of 4.19-4.65 log10 copies/mL. Resistant rtA181V and rtN236T were undetectable after 21-24 months of combination therapy. Moreover, no LAM-resistant rtM204I/V or ETV-resistant variants were detected during the 27-36 months of combination therapy.
  
  
  CONCLUSIONS
  Although ADV-resistant variants were suppressed, viral load reduction was delayed during ADV-ETV combination rescue therapy in patients with ADV-resistant HBV. The quantification of resistant variants by pyrosequencing may facilitate monitoring of antiviral therapy.
authors.affiliation: 1. Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1. Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.affiliation: 1. Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 1. Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Sujun
authors.initials: S
authors.lastname: Zheng
authors.affiliation: 1. Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: 2. Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing, China.
authors.forename: Fengmin
authors.initials: F
authors.lastname: Lu
authors.affiliation: 1. Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Duan
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000187:drug effects; D004359:Drug Therapy, Combination; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D063065:Organophosphonates / Q000494:pharmacology*; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; C413685:entecavir; D006147:Guanine; C053001:adefovir; D000225:Adenine
keywords: adefovir; entecavir; hepatitis B virus; rescue therapy; resistance