Evolution of hepatitis B viral load and viral genome sequence during adefovir dipivoxil therapy.
Phase II and III clinical trials of adefovir dipivoxil (ADV) for the treatment of chronic hepatitis B have shown that this hepadnavirus polymerase inhibitor is well tolerated and effectively suppresses hepatitis B virus (HBV) replication. We therefore analysed the evolution of viral load and the emergence of HBV polymerase mutants in a 22-patient subgroup from a phase III clinical trial of ADV for the treatment of HBeAg-positive chronic hepatitis B. HBV DNA serum titres were quantified using a real-time polymerase chain reaction (PCR) assay with molecular hybridization probes. Emergence of polymerase mutants was assessed by direct sequencing of the viral reverse transcriptase domain after PCR amplification of HBV DNA isolated from serum. Our results indicated that ADV therapy effectively suppressed HBV replication in these patients (median serum HBV decrease at week 48 of treatment = 4.3 log10 copies/mL). The initial drop of HBV DNA titres in serum at week 12 of ADV therapy seemed to be predictive of subsequent HBe seroconversion (P = 0.059). Neither viral breakthrough nor the selection of drug resistant mutants were observed during the study period. Our results showed that ADV administration for 48-72 weeks effectively suppresses HBV replication without the emergence of resistant viral mutants.
Werle
B
B
INSERM Unit 271, Albert Thomas, Lyon, France.
Cinquin
K
K
Marcellin
P
P
Pol
S
S
Maynard
M
M
Trépo
C
C
Zoulim
F
F
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D000410:Alanine Transaminase / Q000097:blood; D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000097:blood; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001706:Biopsy; D004279:DNA, Viral / Q000737:chemistry / Q000302:isolation & purification; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000235:genetics; D019143:Evolution, Molecular; D005814:Genes, Viral; D006509:Hepatitis B / Q000188:drug therapy* / Q000821:virology*; D006510:Hepatitis B Antibodies / Q000097:blood; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000276:immunology; D006801:Humans; D008099:Liver / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D063065:Organophosphonates; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics; D017422:Sequence Analysis, DNA; D019562:Viral Load
D000956:Antigens, Viral; D000998:Antiviral Agents; D004279:DNA, Viral; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D063065:Organophosphonates; D000410:Alanine Transaminase; D012194:RNA-Directed DNA Polymerase; D004259:DNA-Directed DNA Polymerase; D000225:Adenine; C106812:adefovir dipivoxil