Darwish Murad, S; Pattynama, PMT; van Buuren, HR; Frerichs, SJGC; Janssen, HLA Author Information

Abstract: Background: The effect of pegylated interferon or its combination with lamivudine on liver histology of patients with chronic hepatitis B (CHB) is unknown. In a double‐blinded, randomized, multi‐center study we assessed histological changes in 110 hepatitis B e‐antigen (HBeAg)‐positive CHB patients treated for 52 weeks with Pegylated interferon α‐2b (PEG‐IFN) in combination with either lamivudine or placebo. Liver biopsies were taken before and at the end of treatment. All biopsies were blinded and scored according to the Ishak system.

Patients with hepatocellular carcinoma (HCC) are characterized by a weak T-cell response to their tumor, and chronic carriers of hepatitis B virus or hepatitis C virus have a poor T-cell response against the virus. These inadequate T-cell responses may be due to insufficient activation of the T cells by dendritic cells (DCs). Because lymph nodes (LNs) are the primary site of antigen-specific T-cell activation, we hypothesized that hepatic LNs of patients with HCC and/or chronic viral hepatitis might have aberrant compositions of their DC populations. To address this hypothesis, we enumerated mature myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in hepatic LNs by quantitative immunohistochemistry. Patients with HCC and chronic viral hepatitis and patients with chronic viral hepatitis without HCC were compared with patients with liver inflammation of nonviral etiology and with organ donors with healthy livers. The numbers of PDCs and mature MDCs in hepatic LNs of patients with chronic viral hepatitis did not differ from those of patients with liver inflammation of nonviral etiology nor from individuals with healthy livers. However, hepatic LNs of patients with HBV or HCV infection complicated by HCC showed a 1.5-fold reduction in numbers of mature MDCs and a 4-fold increase in numbers of PDCs in their T-cell areas compared with those of patients with viral hepatitis only (P <.01). In conclusion, patients with HCC have an aberrant composition of the DC population in their hepatic LNs. This may be one of the causes of the inadequate T-cell response against HCC in these patients.

In chronic hepatitis B transition from active replication to viral latency (HBeAg seroconversion) usually leads to remission of the disease. alpha-Interferon (IFN) therapy induces HBeAg seroconversion in about one-third of the patients, thus leaving the majority of patients with persistent disease. Eighteen chronic hepatitis B patients who did not respond (HBeAg seroconversion and clearance of HBV-DNA) to an initial 16-week course of IFN subsequently received IFN again after at least 6 months of no therapy. The repeated therapy consisted of 1.5-5 MU lymphoblastoid IFN daily for 16 weeks. Treatment effects were monitored by quantitative measurement of HBeAg and HBV-DNA. To analyze whether the results were related to patient characteristics known to affect the response to initial treatment, a predicted response rate, based on pre-treatment factors, was determined. After a follow-up of 52 weeks, 2 of the 18 patients (11%) had responded to therapy. Two additional patients became HBV-DNA-negative with sustained HBeAg positivity. All patients remained HBsAg-positive. According to the pre-treatment parameters, a response was predicted for 9 of the 18 patients (50%). This predicted response rate was significantly higher than the actual response rate (p = 0.03). In conclusion, this pilot study with moderate dosages of IFN suggests that the HBeAg seroconversion rate after repeated IFN treatment is low for previous non-responders and probably is not related to important clinical characteristics that influence the response to initial IFN treatment. A large controlled trial with higher doses of IFN is desirable to further evaluate the benefits of retreatment.

Alfa-interferon (alpha-IFN) has now proven to be an effective treatment for HBeAg-positive patients with chronic hepatitis B. In approximately one third of the patients alpha-IFN induces a transition to viral latency (HBeAg seroconversion) which is almost always followed by a disappearance of inflammatory activity. Progression of the disease is then arrested. Patients should preferably be monitored in regional centers since a severe exacerbation of the liver disease con occur and neuropsychiatric side effects of alpha-IFN calls for expertise in management. For chronic hepatitis B patients with decompensated liver disease or co-infection with the hepatitis delta virus the benefit-risk ratio of alpha-IFN still needs to be established.