| BackgroundHepatitis B virus (HBV) epidemic has regional difference, which is high in China.7.18%of Chinese people are carrying HBsAg (hepatitis B surface antigen), therefore there are about20million patients with chronic hepatitis B. Great majority of hepatitis B virus infections are acquired perinatally or during early childhood. The natural history of perinatal HBV infection is generally divided into three phases according to liver damage and the status of hepatitis B e antigen (HBeAg) and serum HBV DNA loads:immune tolerant phase, immune clearance phase, and inactive disease.Nucleoside (acid) analogues and interferon are usually used as anti-HBV drugs, which is the key to the treatment of chronic hepatitis B. Interferon has the dual role of immune regulation and antiviral, which is the first line drug for the treatment of chronic hepatitis B (CHB). There are two kinds of interferons used in the clinic, pegylated interferon (PEG-IFN) and standard interferon (IFN). One of the main side effect of interferon is myelosuppression. However, a few of studies on efficacy and myelosuppression between PEG-IFN and IFN are reported at present.The HBV serum markers include the surface antigen (HBsAg), the surface antibody (anti-HBs), the e antigen (HBeAg), the e antibody (anti-HBe) and the core antibody (anti-HBe). The pattern of these markers’ combination is associated with different clinical status, which is helpful for the diagnosis of CHB and antiviral treatment evaluation. One of the treatment goals in HBeAg positive patients is HBeAg loss as well as anti-HBe appear. Concurrence of HBeAg and anti-HBe was observed when we assessed the efficacy of PEG-IFN and IFN.When HBeAg positive patients received antiviral therapy, firstly, ALT dropped to normal, secondly, HBV DNA dropped to negative or limits of detection, lastly, HBeAg dropped to seroconversion. Concurrence of HBeAg and anti-HBe often happened when HBeAg was as low as its cutoff value.The C gene of HBV encodes the core nucleocapsid protein (HBeAg) and HBeAg. The synthesis of HBeAg is dually controlled at transcripation and translation levels. At the transcriptional level, mutations in the basal core promoter (BCP) at nt1762and nt1764were well defined. At the translation level, the mutation at ntl896caused a stop codon in the precore area and leaded to the cession of HBeAg expression. Mutations in precore or core often occurred before and after HBeAg seroconversion.Concurrence of HBeAg and anti-HBe is not only detected in the treatment of interferon, but also observed in the treatment of nucleoside (acid) analogues, as well as untreated patients who are in the immune clearance phase. However, little is known about the clinical characteristics and mechanisms elucidating this unique serological pattern of HBV e system.Objectives1.To find HBeAg and anti-HBe double-positive--a particular phenomenon discovered in the course of interferon therapy.2. To analyse the clinical characteristics of chronic hepatitis B with HBeAg and anti-HBe double positive3. To explore the possible mechanisms of HBeAg and anti-HBe concurrenceMethods1. A cohort of outpatients and inpatients who received interferon from March2007to November2010from the Hepatology Unit, Nanfang Hospital was collected. All patients follow:1) dignosed with CHB or HBsAg positive for at least6months.2) Continuous or intermittent increase of ALT levels before treatment.3) Did not receive antiviral and immunomodulatory therapy recent half a year.5) Received interferon treatment for at least24weeks. The exclusion standard was:1) Combined with nucleoside (acid) analogues.2) PEG-INF and IFN were used interchangeably.3) Coinfection with other hepatitis virus, human immunodeficiency virus, autoimmune hepatitis or alcoholic liver disease.4) Interferon contraindications. Compare the efficacy and bone marrow suppression of PEG-IFN with standard IFN in treating chronic hepatitis B patients.2. Analyse the clinical Characteristics of concurrence patients related to interferon after double-positive phenomenon was observed. The main objects were the317patients mentioned above who were HBeAg positive before treatment. We divided them into two groups:study group who had HBeAg and anti-HBe concurrence during the treatment and control group who hadn’t. We compared the clinical characteristics between the two groups, and observed the outcome of study group patients.3.418patients with concurrence of HBeAg and anti-HBe were collected from2010to2012. Clinical characteristics of three groups were compared. Using domestic ELISA kits detected concurrent serums to observe the double-positive rate.4.20patients were chose from the study group (mentioned above), who were divided into HBeAg seroconversion group and non-seroconversion group, and each group has10persons. Serums of the baseline, concurrence and outcome were found out from refrigeratory. Viral genotype, BCP and precore mutations were determined by direct sequencing.5. Compared anti-HBe relative affinity index between concurrent patients and anti-HBe sing-positive patients by using urea elution.Results1. In the423patients with interferon therapy, HBV DNA levels between PEG-IFN and IFN group were similar,(6.1±1.5) log10copies/ml vs.(6.3±1.4) log10copies/ml, P=0.274. However, HBV DNA levels in the PEG-IFN group were significantly lower than IFN group at week12,24,48, and all P value were less than0.05. As of July2011, there were16(3.8%) patients occurred HBsAg loss and12(2.8%) occurred HBsAg seroconversion. HBsAg loss rate and seroconversion rate in the PEG-IFN group were much higher than IFN group,7.2%(13/180) vs.1.2%(3/204), P=0.005;5.0%(9/180) vs.1.2%(3/204),P=0.048.2. Of the317patients with HBeAg positive before treatment, HBV DNA loss rates in PEG-IFN group were higher than the IFN group at week24(35.0%vs.23.2%, P=0.023) and48(69.6%vs.51.9%,P=0.011).There were no significant difference for HBeAg loss rates and seroconversion rates between the two groups at week12,24,48.1n PEG-IFN group, medians of white blood cells, neutrophils at week24,48and platelets at week24were significantly lower than that of IFN group.3. There were no significant difference for HBV DNA loss rate, HBsAg loss rate and seroconversion rate between PEG-IFN group and IFN group. Only the medians of white blood cells (3.3×109/L vs.4.6×109/L, P=0.003) and neutrophils (1.8×109/L vs.2.4×109/L, P=0.009) at week24in the PEG-IFN group were lower than IFN group.4. In the PEG-IFN group, HBV DNA loss rate in patients≥27years of age was higher than the IFN group, as well as HBsAg loss rate and seroconversion rate in patients<27years of age.5. In the course of interferon therapy, we watched a particular phenomenon:HBeAg and anti-HBe double-positive.There were80patients with HBeAg-positive at baseline, who were observed this phenomenon.6. In317patients with HBeAg positive, there were male227and femal90whose average age was (28.6±8.1) years old. They were divided into study group (80cases) and control group (237cases). HBeAg level of study group before treatment was much lower than that of control group,187.5(1.1-1206.4) S/CO vs.321.9(1.0-3111.2)S/CO, P=0.003.7. When patients in the study group were detected concurrence of HBeAg and anti-HBe for the first time, HBV DNA average level was (3.8±1.2)log10copies/ml, and the median (range) of ALT was1.0(0.2-4.0)ULN. HBeAg and anti-HBe titers (median and range) in the study group were3.4(1.0～187.5) S/CO and0.5(0.03-0.99)S/CO, which were much close to their respective cutoff values.8. Whether to HBeAg and anti-HBe concurrent as the dependent variable, and the patients’age, gender, interferon type and HBV DNA before treatment as the independent variable, Binary Logistic regression was used to analyse which was the factor influencing HBeAg and anti-HBe concurrence. The result showed that men were more prone to HBeAg and anti-HBe double-positive, and OR value was1.9(95%CI:1.013～3.518,P=0.046).9. HBV DNA loss rate, HBeAg loss rate and seroconversion rate in the study group were76.2%(61/80),62.5%(50/80),61.2%(49/80), which were much higher than control group [49.8%(118/237),35.9%(85/237),29.1%(69/237)].10.20patients chosen from study were sequenced and analysed. Mutations of nucleotide in precore and BCP and mutations of amino acid in core were similar among the baseline, concurrence and outcome.11.418patients with concurrent HBeAg and anti-HBe were divided into interferon group (148cases), nucleoside group (105cases) and spontaneous group (165cases). For the HBV DNA, ALT, TBIL levels and anti-HBe titers, there were significant differences among the three groups. HBV DNA, ALT, TBIL levels in the spontaneous group were the highest among the three groups, but anti-HBe titers of the nucleoside group were the lowest among the three groups.12. Anti-HBe relative affinity index in the concurrence of HBeAg and anti-HBe patients was significantly lower than patients with anti-HBe single-positive,92.6(39.4～240.7)%vs.104.7(39.6-252.4)%,P=0.001.Conclusions1. Pegylated interferon was better significantly than standard interferon in HBV DNA loss and HBsAg loss and seroconversion rate, but more pronounced bone marrow suppression.2. About a quarter of HBeAg positive patients (25.2%) showed HBeAg and anti-HBe double-positive during interferon treatment, and most of whom were male patients.3. Patinets with concurrent HBeAg and anti-HBe during interferon treatment shown more possibility to get HBeAg seroconversion.4. Clinical characteristics of concurrent HBeAg and anti-HBe were different among interferon group, nucleoside group and spontaneous group. HBV DNA, ALT, TBIL levels in the spontaneous group were the highest among the three groups, but anti-HBe titers of the nucleoside group were the lowest among the three groups.5. Concurrent HBeAg and anti-HBe during interferon treatment had no relationship with nucleotide mutations in BCP and precore and amino acid mutations in core area. 6. Relative affinity index of anti-HBe in the concurrence of HBeAg and anti-HBe patients was significantly lower than that in patients with anti-HBe single-positive, which might be one of the reasons why HBeAg and anti-HBe were concurrent. |
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