The pathogenesis of CHB shows that persistent replication of HBV is closely related to the disease process. So using effective drugs in time to inhibit HBV amplification is very important to interrupt the disease process. Interferon has been considered effective while treating CHB. It was effective only in some patients, but ineffective when treating other patients. In this study, as to SVR in the 62 patients who received standard IFN treatment for six months, the complete response rate was 21.0% (13/62), partial response rate was 43.5% (27/62) and non-response rate was 35.5% (22/62). After a six-month treatment, as to SIR the rate of HBeAg, HBV DNA and HBsAg loss was 43.4% (23/53), 30.2%(16/53), 1.9%(1/53) respectively in HBeAg positive patients. The rate of HBV DNA and HBsAg loss was 44.4% (4/9), 11.1% (1/9) respectively in HBeAg negative patients. The rates in present study were higher as compared to some other clinical studies , which may correlated to the definition of therapeutic effect evaluation (complete response, partial response and non-response). Additionally, limited samples, short course of treatment and short follow-up survey also may be correlated to this high response rates.
Anti-HBV effect of IFN is thought to act through JAK-STAT signaling pathway [18, 19]. In this pathway STAT1, STAT2 and IRF9 formed trimer complex called the gene factor of the Interferon-stimulated 3 (ISGF3). The ISGF3 combines with the Interferon- stimulated response element (ISRE) sequence after transporting to the cell nucleus, then activates the expression of Interferon Stimulated Genes (ISG) such as the Interferon Regulatory Factor 7 (IRF7), the Interferon Regulatory Factor 1 (IRF1) and the Interferon Regulatory Factor 2 (IRF2) etc, thus inhibit viral replication and gene expression. Therefore, the anti-HBV effects of IFN are affected by both the host and virus. According to current knowledge, the host factors may include the degree of liver inflammation, the level of transaminase, IL-12 variation during IFN therapy, the basic status of DCs, the expression of α/β receptor of the PBMCs and the levels of HLA-DRB1 DT before and after the therapy. The virus factors include the initiation level of HBV DNA, the decrease amplitude after one month treatment, genotypes and the mutations of DNA .
Recently, several studies showed that HBV gene mutation may affect IFN therapy [17, 21]. A study with 48 HBeAg positive CHB patients who received IFN treatment for more than 24 weeks showed that the patients with nt1762 and nt1764 mutation had a poorer response to IFN with lower HBV DNA decrease and HBeAg conversion . In addition the loss of HBeAg was related not only to nt1762 and nt1764 mutation (69.5%) but also closely to nt1896 (100%) and nt1814 mutation (65.2%). When these mutations occurred the antiviral efficacy of IFN was not ideal and the other antiviral strategies should be adopted. Another study showed that the T1762-A1764 mutation of HBV DNA might affect the clearance of the virus . It suggested that virus with T1762- A1764 mutation had strong response to IFN therapy. IFN was not only able to clear HBV directly but also can eliminate HBV by activating or strengthening immune system.
It has been reported that there was a functional IRE in HBV enhancerI/X promoter region , which can mediate the regulation of gene transcription by IFN α, gene factor of the IFN-stimulated 3, IFN regulatory factor 1 (IRF1) and IFN regulatory factor 7 (IRF7). It suggested that IFN probably regulated HBV gene transcription directly by IRE. Therefore it is possible that the mutation of IRE may partially block or reduce the inhibition of IFN to HBV, causing no response occurring. In this study we found that there were six kinds of HBV IRE sequences TTTCACTTTC, TTTtACTTTC, TTTCAtTTTC, TTTtAtTTTC, TTTtACTTTt and cTTtACcTTC in the CHB patents included in our study. Comparing sequence of IRE of wild strains, we found that there were 35 cases (56.6%) among 62 patients in our study. There were five kinds of point mutation sequences. Except for the forth base C→T mutation, the other four kinds of point mutation, including the sixth base C→T mutation (2 cases), the tenth base C→T mutation (2 cases), the first base T→C mutation(1 case) and the seventh base T→C mutation(1 case), only accounted for 8% of total sample. These events may relate to random mutation or errors occurring during transcription.
In summary, the forth base C→T mutation in IRE element of HBV may partially influence the response of Interferon treatment in CHB patients. We will carry on in vitro test in order to confirm whether the forth base C→T mutation was specific mutation related to the anti-HBV effect of interferon. In addition, we still collect serum specimen of patients with no response to interferon in the hope of confirm the correlation between the HBV IRE mutation and no response to interferon with larger sample size.