Although the development mechanism of chronic viral hepatitis B(CVH-B), which is the most important etiologic factor in liver cirrhosis(LC) and hepatocellular carcinoma (HCC) in Korea, has not been fully understood until now, immune mechanism of the host(especially cellular immunity) seems to play a major role in this area¹⁾.

Hepatitis B virus (HBV) by itself does not appear to induce hepatic lesion directly, and lysis of infected hepatocytes depends on the immune response of the host²⁾. In these circumstance, IFN induces the recognition of cytotoxic T cells to infected hepatocytes and lysis of the infected hepatocyte^1–5).

Immune system abnormality of the host accompanies incomplete removal of the infected hepatocytes and persistent replication of HBV introduces the development of CVH-B^{6, 7)}. Several studies^8–10) reported that decrease of the IFN concentration, CD4/CD8 ratio and value of CD4, and increase of the value of CD8 were discovered in patients with CVH-B. These results suggested that the defective immune system of the host participated in the pathogenesis of CVH-B^11–15).

According to the above results, one hypothesis^{18, 19)} was that therapeutic agents (which improve the host immunity and prevent the proliferation of HBV) prevent the progression of CVH-B to LC or HCC and, therefore, many antiviral and immunosuppressive agents were tried and variable therapeutic effects were observed^18–22) Among these, IFN may be the most valuable and effective treatment modality^15–22).

Therefore, the authors have undertaken a controlled study to determine the effectiveness of combination treatment with prednisolone withdrawal and IFN α-2b to find out the abnormalities of cellular immunity on patients with CAH-B, and compared the effectiveness of combination treatment with IFN α-2b with prednisolone withdrawal to IFN alone.

CAH-B is one of the most important causes of the development of LC and HCC. Its clear pathogenesis was not proven until now, but defective cellular immunity of the host has been suggested as playing an important role in the development of CVH-B^1–5).

With HBV infection to the hepatocytes, HBeAg and HBeAg were expressed on the surface of the hepatocyte²⁴⁾, and major histocompatability antigen complex-I(MHC-I) was expressed concomittently⁴⁾. These MHC-I and HBeAg or HBeAg interact synergically and induce cytolysis of the infected liver cells by the cytotoxic T cell⁵⁾.

IFN is released by activated lymphocytes and activates the intracellular enzyme(2,5-oligoadenylate synthetase) and this enzyme induces the release of ribonuclease which destroys viral mRNA, and eventually prevents viral translation and propagation to the adjacent tissue⁵⁾. IFN increases the expression of MHC-I on the hepatocytes also, and induces the cytolysis of the infected hepatocytes by cytotoxic T cell⁵⁾.

Several studies reported that reduced serum IFN level and qualitative or quantitative abnormalities of cellular immunity of the host were discovered in patients with CVH-B^8–10).

Many reports for T cell subsets in CVH-B showed variable results, but usually many authors^{10, 11, 24, 25)} agree that decreased ratio of CD4 to CD8 cells is largely dependent on significantly decreased CD4 cells in patients with CVH-B. Barnaba et al²⁶⁾ had demonstrated that the ratio of CD4 to CD8 cells was decreased during acute viral hepatitis B and that it resulted from increased CD8 cells or decreased CD4 cells or both. Thomas et al¹²⁾ also reported similiar results in chronic liver disease and that it resulted from decreased CD4 cells mostly.

In this report, increase of CD8 cells appeared but was statistically insignificant. In our study, decreased CD4 cells and increased CD8 cells were also significantly noted(Table 4).

Similiarly as in previous reports^{11, 12, 24–26)}, the ratio of CD4 to CD8 cells was decreased in patients with CAH-B as compared with normal control in our study too, but was statistically insignificant(p>0.05, Table 4). These results may be due to both an decrease of CD4 cells and an increase of CD8 cells. In our study, CD4 cells of patients were lower significantly in the responder group compared with that of the normal control group, but insignificant in the non-responder group(Table 5). It is suggested that decrease of CD4 cells may be used as a potential prognostic factor to predict the course of CVH-B, but further studies can be assessed to confirm this suggestion.

In our study, a larger decrease of CD4 cells and a larger increase of CD8 cells also appeared in the responder group than in the non-responder group at the pre-treatment period. It is interesting that CD4 cells have increased significantly from 35.2±6.8% to 40.0±9.3% (P<0.05) and that CD8 cells have decreased from 31.6±9.6% to 30.2±8.8%(P>0.05) in the responder group, but were insignificant in the non-responder group in our study(Table 6).

Many authors agree that persistent proliferation of HBV may play an essential role in the progression of CVH to LC or HCC^{6, 7)}. In our study, all of the patients with CVH-B had HBeAg and HBV DNA which were serologic markers for proliferation of HBV(Table 3). Loss of these markers was accompanied by improvement of symptoms and laboratory data^27–29). These findings propose that various antiviral therapies will prevent the progression of CVH-B to LC or HCC.

In various reports, Immunosuppressants(prednisolone, azathioprine etc) and several antiviral or immunomodulating agents(adenosine arabinoside, adenosine arabinoside monophosphate, IFN, and interleukin-2 etc) had been studied and many authors agree that IFN is the most effective agent among these^{15–22, 30)}.

Yasushi et al³⁰⁾ reported that loss of HBV DNA occurred in 42% with treatment of IFN α for 12 to 24 months, and 54% in Lok et al¹⁷⁾ and 52% in Thomas et al¹⁸⁾. In Korea, Choi et al¹⁵⁾ and Choi et al¹⁶⁾ reported that seroconversion rates of HBeAg were 25% and 17.6% apart. These results were superior to the spontaneous conversion rate of HBeAg in Korea reported by Yoon et al³¹⁾, but inferior to those in western countries^16–18).

However, the reason why these results were worse than western countries is suspected as follow; first, transmaternal transmission of HBV was more common in Korea and patients with CVH-B occurred in this manner were more resistent to IFN treatment and, second, we commonly used a lower dose than western countries^16–18). Therefore, if the dose of IFN is increased, a better response will be acquired.

Recently, several studies^{32, 33)} reported that IFN therapy with prednisolone withdrawal may be more effective for the seroconversion of HBeAg than in IFN therapy alone. In Korea, Kim et al³⁴⁾ reported that combined therapy with IFN and short-term prednisolone withdrawal was more effective(50% rate of seroconversion) than single IFN therapy. It has been demonstrated that seroconversion of HBeAg occurred in 12 cases(37.5%) of 32 patients with interferon treatment, and it is significantly higher than in the control patient group(7 Of 30 cases, 23.3%, p<0.05) in our study(Table 3) and this result was inferior to Kim et al³⁴⁾, but superior to Choi et al¹⁵⁾(17.6%) and Choi et al¹⁶⁾(25.0%). Therefore it may be suggested that combination therapy of IFN with prednisolone withdrawal is more effective than IFN alone.

Disappearance of HBV DNA occurred in 21 cases(65.6%) of 32 patients and these results were similiar to those of other previous reports. The above results were significantly better than the control patients. Loss of HBV DNA occurred faster than seroconversion of HBeAg and similiar results were reported by other authors^37–39).

The good responder group for the IFN treatment includes the patients with recently acquired infection, higher levels of serum aminotransferases, lower serum level of HBV DNA and active hepatitis on liver biopsy. Heterosexuals and women respond better than homosexuals and men³⁵⁾. However, in our study, the levels of aminotransferase and sex difference did not influence the prognosis of IFN treatment(p>0.05).