Interferon-alpha plus lamivudine vs lamivudine reduces breakthroughs, but does not affect sustained response in HBeAg negative chronic hepatitis B.
OBJECTIVE
The HBeAg negative form of chronic hepatitis B (CHB) predominates in the Mediterranean area and has a rising frequency in Europe and North America. At present there are three approved therapies for patients with CHB: interferon-alpha (IFN-alpha), lamivudine and adefovir dipivoxil. Unfortunately, none of these drugs are effective in achieving a sustained response in patients with HBeAg negative CHB. Therefore, new therapeutic approaches have been examined. Our aim was to investigate the efficacy of combination treatment of IFN-alpha and lamivudine compared to lamivudine monotherapy, after 24 mo of administration in HBeAg-negative hepatitis B patients.


METHODS
Fifty consecutive patients were randomly assigned to receive IFN-alpha-2b (5 MU thrice per week, n = 24) plus lamivudine (100 mg daily) or lamivudine only (n = 26) for 24 mo. Patients were followed up for further 6 mo. The primary outcome was the proportion with sustained virological response (undetectable serum HBV DNA concentrations) and or sustained biochemical response (transaminase levels within normal range) at 30 mo (6 mo after the end of therapy). Secondary end-points were timed from initial virological (biochemical) response to VBR (BBR, respectively) and the emergence of YMDD mutants across the two arms.


RESULTS
Five of twenty-four (21%) patients in the combination arm vs 3/26 (12%) in the lamivudine arm had sustained response (i.e., normal serum transaminase levels and undetectable HBV DNA by PCR assay) 6 mo after treatment discontinuation. A reduction in the emergence of YMDD mutants and in the development of virological breakthroughs was observed in patients receiving combination treatment (10% vs 46%, P = 0.01 and 14% vs 46%, P = 0.03, respectively). Time from initial virologic response to virologic breakthrough (VBR) was greater among initial responders receiving combination treatment compared to those receiving lamivudine (22.9 mo vs 15.9 mo, respectively; P = 0.005).


CONCLUSIONS
Our results demonstrate that IFN-alpha plus lamivudine combination therapy did not increase the sustained response, compared to lamivudine. However, combination therapy reduces the likelihood of VBR due to YMDD mutants and prolongs the time period until the breakthrough development.
Economou
Michalis
M
Department of Gastroenterology, Polyclinic General Hospital, Athens, Greece. meconom@cc.uoi.gr
Manolakopoulos
Spilios
S
Trikalinos
Thomas-A
TA
Filis
Spyros
S
Bethanis
Sotiris
S
Tzourmakliotis
Dimitrios
D
Avgerinos
Alec
A
Raptis
Sotiris
S
Tsianos
Epameinondas-V
EV
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000378:metabolism / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood; D004359:Drug Therapy, Combination; D005838:Genotype; D006513:Hepatitis B e Antigens / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D019259:Lamivudine / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D016896:Treatment Outcome
D000998:Antiviral Agents; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D016898:Interferon-alpha; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D000410:Alanine Transaminase