PMID- 19302908
OWN - NLM
STAT- MEDLINE
DCOM- 20090512
LR  - 20221207
IS  - 0149-2918 (Print)
IS  - 0149-2918 (Linking)
VI  - 31
IP  - 2
DP  - 2009 Feb
TI  - Evolution of hepatitis B virus polymerase mutations in a patient with 
      HBeAg-positive chronic hepatitis B virus treated with sequential monotherapy and 
      add-on nucleoside/nucleotide analogues.
PG  - 360-6
LID - 10.1016/j.clinthera.2009.02.016 [doi]
AB  - BACKGROUND: Nucleoside/nucleotide analogues are a fundamental tool for the 
      treatment of chronic hepatitis B virus (HBV). Sequential anti-HBV treatment might 
      lead to the selection of mutations. OBJECTIVE: This report aimed to analyze the 
      genetic evolution of the reverse-transcriptase (RT) gene of viral quasispecies in 
      a patient with hepatitis B e antigen (HBeAg)-positive chronic HBV who received, 
      sequentially, lamivudine (LAM), adefovir dipivoxil (ADV), and ADV + telbivudine 
      (LDT) combination treatment over a total of 108 weeks. METHODS: A 20-year-old 
      Chinese man presented to Huashan Hospital, Fudan University, Shanghai, People's 
      Republic of China, with hepatitis B surface antigen-positive and HBeAg-positive 
      chronic HBV and was sequentially treated with LAM 100 mg/d for 18weeks,ADV 10mg/d 
      for 68weeks, and ADV 10mg/d + LDT 600 mg/d combination treatment for 22 weeks. 
      Compliance was monitored every 4 weeks using a pill count. For genotypic 
      analysis, the RT region of the polymerase gene from the serum of this patient was 
      amplified, cloned, and sequenced. Fifty clones with HBV insert were selected for 
      sequencing at weeks 0 (baseline), 18, 22, 60, 70, 86, and 108. RESULTS: The 
      rtM204V/L LAM-resistance mutation was detected in 4.4% (2/45) of clones prior to 
      LAM treatment. At week 18 during LAM treatment, the rtM204I mutation became 
      predominant, being present in 79.5% (35/44) of clones. The rtM204I mutation was 
      associated with compensatory mutations (rtL180M and rtT184L). A total of 9.1% 
      (4/44) of the clones harbored the rtL180M + rtT184L + rtM204I mutations. Two new 
      mutations, rtL229V and rtV191I, were detected in 75.0% (33/44) and 11.4% (5/44) 
      of clones, respectively. At week 22 during ADV treatment, LAM-resistance 
      mutations (rtL180M, rtT184L, rtM204I, rtV191I, and rtL229V) were not detected. At 
      week 86 during ADV therapy, the rtN236T ADV-resistance mutation was detected in 
      58.8% (20/34) of clones. A total of 20.6% (7/34) of the clones harbored the 
      rtK212T + rtM250L mutation, and rtA181V was found in 2.9% (1/34) of the clones. 
      At week 108, after the patient had been receiving ADV + LDT combination therapy 
      for 22 weeks, rtS202G and rtI269T had emerged, representing 28.9% (13/45) and 
      8.9% (4/45), respectively, of the viral population during ADV + LDT combination 
      treatment. We also detected several polymorphic sites,including rtF221Y, rtS223A, 
      rtI224V, rtN238H, rtL267Q, and rtQ271M, during the sequential treatment. After 22 
      weeks of combination treatment, HBV DNA count was decreased to less than the 
      lower limit of quantitation (<200 copies/mL). CONCLUSIONS: This report identified 
      HBV mutations that escaped the antiviral pressure of LAM, ADV, and ADV + LDT in 
      this patient and provided insight into the process of mutation selection through 
      genotypic analysis during antiviral treatment. Mutations selected under 
      sequential treatments of LAM, ADV, and ADV + LDT can lead to a series of 
      compensatory mutations, which partially restore the level of viral replication. 
      ADV administered in combination with LDT appeared to be effective in this 
      selected case with clinical or virologic resistance to sequential treatment with 
      LAM and ADV.
FAU - Wang, Feifei
AU  - Wang F
AD  - Department of Infectious Disease, Huashan Hospital, Fudan University, Shanghai, 
      People's Republic of China.
FAU - Wang, Honghai
AU  - Wang H
FAU - Shen, Hongbo
AU  - Shen H
FAU - Meng, Chengyan
AU  - Meng C
FAU - Weng, Xinhua
AU  - Weng X
FAU - Zhang, Wenhong
AU  - Zhang W
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Ther
JT  - Clinical therapeutics
JID - 7706726
RN  - 0 (Antiviral Agents)
RN  - 0 (Hepatitis B e Antigens)
RN  - 0 (Reverse Transcriptase Inhibitors)
RN  - EC 2.7.7.49 (RNA-Directed DNA Polymerase)
SB  - IM
MH  - Antiviral Agents/*administration & dosage
MH  - Asian People
MH  - China
MH  - Chronic Disease
MH  - Hepatitis B e Antigens/blood
MH  - Hepatitis B virus/drug effects/genetics
MH  - Hepatitis B, Chronic/drug therapy/*genetics
MH  - Humans
MH  - Male
MH  - Mutation
MH  - RNA-Directed DNA Polymerase/drug effects/*genetics
MH  - Reverse Transcriptase Inhibitors/administration & dosage
MH  - Young Adult
EDAT- 2009/03/24 09:00
MHDA- 2009/05/13 09:00
CRDT- 2009/03/24 09:00
PHST- 2008/10/31 00:00 [accepted]
PHST- 2009/03/24 09:00 [entrez]
PHST- 2009/03/24 09:00 [pubmed]
PHST- 2009/05/13 09:00 [medline]
AID - S0149-2918(09)00059-9 [pii]
AID - 10.1016/j.clinthera.2009.02.016 [doi]
PST - ppublish
SO  - Clin Ther. 2009 Feb;31(2):360-6. doi: 10.1016/j.clinthera.2009.02.016.