title: Clinical course and predictive factors of virological response in long-term lamivudine plus adefovir dipivoxil combination therapy for lamivudine-resistant chronic hepatitis B patients.
abstract: The aims of this study were to assess the long-term efficacy of lamivudine (LAM) plus adefovir dipivoxil (ADV) combination therapy in patients with chronic hepatitis B resistant to LAM, to identify predictive factors of complete viral response (HBV-DNA <2.6  log  copies/ml at 12 months of combination therapy), and to analyze amino acid substitutions associated with treatment resistance in the hepatitis B virus (HBV) genome. Seventy-two patients who received ADV in addition to LAM for breakthrough hepatitis were enrolled. Undetectable HBV-DNA was observed in 61%, 74%, 81%, 84%, and 85% at 12, 24, 36, 48, and 60 months of combination therapy, respectively. On multivariate analysis, undetectable HBV-DNA during the preceding LAM monotherapy (P < 0.0001), alanine aminotransferase value  ≥  the upper limit of normal × 6 (P = 0.006) and HBV-DNA level < 6.0 log copies/ml at the initiation of combination therapy (P = 0.007) were independent significant predictors of complete viral response. The cumulative rate of undetectable HBV-DNA was significantly higher in patients with response to the preceding LAM monotherapy than in those with poor response to it. Breakthrough hepatitis occurred in three patients without complete viral response and with poor response to the preceding LAM monotherapy, and rtA181A/V substitution was detected in one of the three patients. In conclusion, undetectable HBV-DNA during the LAM monotherapy was the strongest independent predictor of complete viral response to the following combination therapy. The efficacy of LAM plus ADV combination therapy may be determined by viral response to the preceding LAM monotherapy.
authors.affiliation: Department of Gastroenterology and Hepatology, Kashiwa Hospital, Jikei University School of Medicine, Chiba, Japan. mashu0914@hotmail.co.jp
authors.forename: Mashu
authors.initials: M
authors.lastname: Aizawa
authors.forename: Akihito
authors.initials: A
authors.lastname: Tsubota
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Fujise
authors.forename: Keiko
authors.initials: K
authors.lastname: Tatsuzawa
authors.forename: Midori
authors.initials: M
authors.lastname: Kono
authors.forename: Sadayori
authors.initials: S
authors.lastname: Hoshina
authors.forename: Hisao
authors.initials: H
authors.lastname: Tajiri
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000187:drug effects; D004279:DNA, Viral / Q000097:blood; D024882:Drug Resistance, Viral / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D015684:Gene Products, pol / Q000235:genetics; D006510:Hepatitis B Antibodies / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007564:Japan / Q000453:epidemiology; D019259:Lamivudine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D063065:Organophosphonates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011379:Prognosis; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects; D055815:Young Adult
chemical_list: D004279:DNA, Viral; D015684:Gene Products, pol; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D063065:Organophosphonates; C066027:P protein, Hepatitis B virus; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D000225:Adenine; C106812:adefovir dipivoxil