Early reduction of infected hepatocytes by activated immunity at the time of interferon withdrawal hepatitis followed by lamivudine administration resulted in higher seroconversion in hepatitis Be antigen-positive patients with chronic hepatitis B.
BACKGROUND
It has been found that the efficacy of lamivudine (LAM) therapy can be improved by preceding administration with a short course of corticosteroid that induces a flare of the disease upon its withdrawal. Because of the side effects of corticosteroid, we tested the effect of a short course of interferon (IFN) as the primer instead of prednisolone, which was followed by LAM when the hepatitis flare occurred. The incidence of LAM resistance mutations and the effect of core promoter and precore mutations on the durability of the responses were also studied.


METHODS
Patients treated with interferon (IFN)-LAM therapy (n=73) were compared to those treated with IFN alone (n=117). The IFN-LAM group received IFN-alpha MU/day, t.i.w. for a 3-month period. LAM (10mg/day during 1 year) was started when IFN withdrawal hepatitis occurred during 2-10 months after stopping IFN. The LAM-resistant, core promoter, and precore mutations were examined by sequencing.


RESULTS
(1) The IFN-LAM group developed exacerbated hepatitis following IFN withdrawal in 63 patients before starting LAM therapy. The seroconversion (SC) rate was significantly higher in the IFN-LAM group than in the IFN-alone group (61% vs 26%, P=0.0001). (2) The LAM resistance mutation rate was 31% at 1 year after initiating LAM therapy. (3) In a stepwise discriminant-function analysis, decreased level of HBeAg determined at 4 weeks after LAM administration and increased level of HBeAb before the start of LAM administration contributed significantly on seroconversion to anti-HBe (P = 0.0073 and 0.004, respectively). (4) The reappearance rate of HBeAg within 6 months after the therapy (relapse) was 33% in the IFN-LAM group and 10% in the IFN-alone group. The prevalence of core promoter and precore mutations did not change before and after the therapy, nor did these mutations correlate with the relapse after stopping IFN-LAM therapy.


CONCLUSIONS
(1) Our findings suggest that early reduction of infected hepatocytes expressed by HBeAg by LAM may contribute to a high SC rate of IFN-LAM therapy. (2) The emergence of LAM-resistant mutations was similar to the previously reported rate, and neither core promoter nor precore mutations correlated with relapse of seroconverters after IFN-LAM withdrawal.
Liver Diseases Section, Akashi Municipal Hospital, 1-33 Takashoumachi, Akashi 673-8501, Japan.
Michiko
M
Shindo
Kazushige
K
Hamada
Akira
A
Muramatsu
Teruhisa
T
Morikawa
Tadao
T
Okuno
D000328:Adult; D004351:Drug Resistance / Q000276:immunology; D005260:Female; D006513:Hepatitis B e Antigens / Q000032:analysis*; D006515:Hepatitis B virus / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000276:immunology*; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D007372:Interferons / Q000008:administration & dosage*; D019259:Lamivudine / Q000008:administration & dosage*; D008297:Male; D009154:Mutation; D012008:Recurrence; D013375:Substance Withdrawal Syndrome / Q000276:immunology*
D006513:Hepatitis B e Antigens; D019259:Lamivudine; D007372:Interferons