title: Higher efficacy of sequential therapy with interferon-alpha and lamivudine combination compared to lamivudine monotherapy in HBeAg positive chronic hepatitis B patients.
abstract: BACKGROUND
  Monotherapy with interferon (IFN) or lamivudine is effective in a limited proportion of chronic hepatitis B (CHB) patients. A sequential combination may have better therapeutic effects by sustained viral suppression combined with immunomodulation.
  
  
  OBJECTIVE
  To compare the efficacy of sequential lamivudine and IFN therapy versus lamivudine monotherapy in HBeAg positive CHB patients.
  
  
  METHODS
  Seventy-five treatment naïve HBeAg positive patients with histologically proven CHB and alanine aminotransferase (ALT) >1.5 x ULN received lamivudine 100 mg per day for 52 wks with IFN 5 MIU per day added for 16 wks after the first 8 wks (group A, n = 38; age 30 +/- 12 yr; M:F = 35:3) or lamivudine 100 mg per day for 52 wks (group B, n = 37; age 30 +/- 16 yr; M:F = 31:6). Biochemical and virologic responses were assessed at weeks 52 and 76 and analysis was done on intention-to-treat. Serial samples were studied for the emergence of lamivudine-resistant YM552I/VDD mutations by direct sequencing.
  
  
  RESULTS
  At week 52, HBeAg loss occurred in 15 (39.5%) in group A and 14 (37.8%) in group B (p= 1.00). HBeAg loss, anti-HBe appearance, and undetectable DNA levels were seen in 26.3% and 13.5% (p= 0.249), respectively. Nine of 10 (90%) patients in group A and 1 of 5 (20%) in group B maintained the response through week 76 (p= 0.017). At week 76, 5 additional patients in group A and 3 in group B further achieved the primary end point and the overall HBeAg loss was observed in 44.7% and 18.9% (p= 0.025) and HBeAg loss, anti-HBe appearance, and undetectable hepatitis B virus (HBV) DNA levels in 36.8% and 10.8% in group A and group B, respectively (p= 0.026). At week 76, undetectable HBV DNA was seen in 39.5% and 16.2% in groups A and B, respectively (p= 0.039). Normal ALT was seen in 47.7% and 40.5% at week 52 (p= 0.489) and ALT was normal in 39.5% and 13.5% at week 76 (p= 0.018) in groups A and B, respectively. YM552I/VDD-resistant mutants emerged in 6 of 38 (15.5%) patients in group A, and 3 of 37 (8.1%) in group B (p= ns). The rate of histological improvement was comparable in the two groups.
  
  
  CONCLUSIONS
  Our results demonstrate that sequential therapy is superior to lamivudine monotherapy in achieving sustained seroconversion, ALT normalization, and HBV DNA loss. Compared to 80% with sequential therapy, only 20% Indian patients with CHB did not relapse after stopping lamivudine monotherapy.
authors.affiliation: Department of Gastroenterology, G.B. Pant Hospital, Affiliated to the University of Delhi, India.
authors.forename: Shiv Kumar
authors.initials: SK
authors.lastname: Sarin
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Syed Naqui
authors.initials: SN
authors.lastname: Kazim
authors.forename: Rajkumar Chander
authors.initials: RC
authors.lastname: Guptan
authors.forename: Puja
authors.initials: P
authors.lastname: Sakhuja
authors.forename: Barjesh Chander
authors.initials: BC
authors.lastname: Sharma
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006510:Hepatitis B Antibodies / Q000097:blood; D006513:Hepatitis B e Antigens / Q000097:blood*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D019259:Lamivudine / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006510:Hepatitis B Antibodies; D006513:Hepatitis B e Antigens; D016898:Interferon-alpha; D019259:Lamivudine; D000410:Alanine Transaminase