| BackgroundHepatitis B virus (HBV) infection is a global public health problem.In China, HBV infection is highly endemic.There were an estimated93millon HBV carriers, and among them30million were patients with chronic hepatitis B. Immune mechanisms of chronic HBV infection are not fully elucidared. However, more and more studies suggested that innate immunity played an important role in the process. Dentritic cell (DC) and monocyte (MO),which represent important innate immune cells, may be involved in the immunity of the patients with chronic HBV infection.The initial response to viral infection is the rapid release of type I interferons (IFNs), IFNa and IFNβ, which was observed for most viruses studied.Therefore, it has vital clinical significance to investigate IFN-a producing in patients with chronic hepatitis B infection.Plasmacytoid dendric cells (pDCs) are principal IFN-α producing cells and they contribute to more than95%of the IFN-a production among peripheral blood mononuclear cell (PBMC). But monocytes also represent a competing IFN-a source in total PBMC due to their high frequency, although pDCs produced highest IFN-a levels per cell. No researches were reported about the IFN-a producing of monocyte in patients with chronic hepatitis B infection.There were few new treatment options until the mid1990’s when nucleos(t)ide analogue (NUCs) was attempted in the treatment of CHB. Use of agents with a high genetic barrier to resistance as first-line of therapy is vital to improving outcomes in patients with CHB. In China, there needs more long follow-up data of antiviral treatment about lamivudine(LAM), telbivudine(LdT) and entecavir(ETV) in clinical practice. Objective Part one:To investigate the features of peripheral blood mononuclear cell secreting interferon-alfa(IFN-a) and evaluate the function of pDC and monocyte to produce IFN-a in patients with chronic hepatitis B virus infection. Part two: To observe the long-term outcomes of nucleos(t)ide therapy in patients with chronic hepatitis B(CHB) in clinical practice, and compare the virological and biochemical response and drug-resistance between lamivudine (LAM) group, telbivudine(LdT) group, and entecavir (ETV) group.MethodPart one:The fresh blood samples were collected from16patients with chronic hepatitis B,16age matched patients with HBV carrier,18age matched healthy individuals as controls from July in2012to March in2013in peking Union Medical College Hospital. PBMCs were isolated and then stimulated by in vitro CPG oligodeoxynucleotides (CPG ODN)2216or Polyinosinic-Polycytidylic acid (poly Ⅰ:C) as stimulators and measured by enzyme linked immunosorbent assay (Elisa) for IFN-a production. Part two:87patients with CHB were included from June in2008to April in2013in peking Union Medical College Hospital, with follow-up of192weeks.The virological response, biochemical response, HBeAg/HBsAg seroconversion and drug-resistance were detected every3month.ResultsPart one:With CPG ODN2216stimulation, the level of IFN-a production was31.20(7.33-44.04) pg/ml in CHB group,109.91(13.74-240.27) pg/ml in HBV carrier group,107.95(48.59-227.33) pg/ml in healthy control group, respectively. Lower levels of IFN-a production in CHB group were observed comparing with the counterparts in healthy control(P=0.007), and with in HBV carrier group (P=0.027).With poly(I:C) stimulation, the level of IFN-a production was10.44(3.46-36.08) pg/ml in CHB group,37.50(4.40-44.45) pg/ml in HBV carrier group,7.06(2.89-22.80) pg/ml in healthy control group, respectively.There were no different significance between three groups (P=0.427). Part two:1. At week24,48,96,144, the rates of undetectable HBV DNA were68.8%,63.2%,80.0%,81.8%in LAM group. The rates of ALT normalization were72.2%,80.0%,90.9%,83.3%. The rates of HBeAg seroconversion were11.1%,18.2%,33.3%,37.5%.2. At week24,48,96,144, the rates of undetectable HBV DNA were90.9%,90.9%,66.7%,80.0%in LdT group. The rates of ALT normalization were63.6%,88.9%, 100.0%,80.0%. The rates of HBeAg seroconversion were12.5%,14.3%,40.0%,50.0%.3. At week24,48,96,144, the rates of undetectable HBV DNA were84.8%,83.3%,100%,85.7%in ETV group. The rates of ALT normalization were80.6%,88.9%,70.0%,75.0%. The rates of HBeAg seroconversion were0%,10.0%,22.2%,42.9%.4. Virological breakthrough occurred in nine patients (40.9%) in LAM group, as compared in two patients(15.4%) in LdT group, and in two patients (5.0%) in ETV group, respectively.ConclusionsPart one:1. PBMCs pulsed with CPG ODN2216produced markedly higher levels of IFN-α than the counterparts pulsed with poly (I:C) both in HBV carrier group and healthy control group.2. There is no significant difference in IFN-a production from PBMCs pulsed with CPG ODN2216between HBV carrier group and healthy control group.3. Impaired function of plasmacytoid dendritic cells secreting IFN-a was found in the patients with chronic Hepatitis B infection, while no significant difference in monocyte secreting. It suggested patients with chronic hepatitis B present immune suppression.Part two:1. At week144, it achieved the best virological response in ETV group, and the lowest in LdT group, but there were no different significance in three groups.2. At week144, it achieved the best biochemical response in LAM group, and the lowest in ETV group, but there were no different significance in three groups.3. At week144, it achieved a higer HBeAg seroconversion in LdT group, and the lowest in LAM group, but there were no different significance in three groups.4. At the end of follow-up, ETV was superior to LdT and LAM in developing drug resistance. |
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