α干扰素治疗HBeAg阳性慢性乙型肝炎疗效的荟萃分析

目的评价α干扰素治疗HBeAg阳性慢性乙肝病毒感染儿童的长期疗效及安全性。方法检索PubMed和CHKD期刊全文数据库,并追查所有纳入研究的参考文献,进行荟萃分析。纳入用英文或中文发表的比较α干扰素与非抗病毒药物（安慰剂或空白对照）治疗HBeAg阳性慢性乙肝病毒感染儿童的随机对照试验。结果共纳入10个随机对照试验,包括542个HBsAg和HBeAg阳性的慢性乙型肝炎患儿。结果显示,随访6个月～2年,α干扰素组HBeAg转阴率高于对照组[31．1％vs12．4％,OR3．17,95％CI（2．00,5．02）,P〈0．00001],HBV—DNA转阴率高于对照组[33．9％vs16．2％,OR2．59,95％CI（1．70,3．96）,P〈0．0001],HBsAg转阴率高于对照组[5．5％vs1．2％,OR3．44,95％CI（1．20,9．89）,P=0．02],丙氨酸氢基转移酶（ALT）复常率高于对照组[43．0％vs27．7％,OR1．99,95％CI（1．16,3．42）,P=0．01],HBeAg血清学转换率高于对照组[30．4％vs12．8％,OR2．90,95％CI（1．56,5．39）,P=0．0008],两组差异均有统计学意义,但HBsAg血清学转换率与对照组相比[1．9％vs0,95％CI（0．42,18．13）,P=0．29],差异无统计学意义。结论对HBeAg阳性的慢性乙肝病毒感染患儿,α干扰素可能有使HBeAg转阴、HBV-DNA转阴、HBsAg转阴、ALT复常及HBeAg血清学转换的效应,但未能实现HBsAg血清学转换。受原研究质量和不同研究干预措施差异的影响,α干扰素的效应尚需更多高质量足够样本量的随机对照试验予以证实。     

Lamivudine treatment in maternally transmitted chronic hepatitis B virus infection patients

BACKGROUND: Lamivudine treatment in chronic carriers who acquired hepatitis B virus through maternal transmission were investigated. METHODS: A total of 29 subjects (Male:Female, 24:5; mean age, 14.7 +/- 5.6 years) who were hepatitis B e antigen (HBeAg) seropositive for >6 months, alanine aminotransferase (ALT) was >1.3 times of upper limit of normal value, and receiving a 52 week-long treatment, received open-label lamivudine (3 mg/kg per day, maximum 100 mg/day). Another 29 subjects matched for gender, age, liver function, and HBeAg status followed up before the introduction of lamivudine served as the control group. The control group did not receive any treatment and were evaluated at week 52 after the onset of abnormal ALT. Mothers of all study subjects were hepatitis B surface antigen (HBsAg) carriers. A successful treatment response at week 52 was defined as: (i) undetectable hepatitis B virus DNA by real time polymerase chain reaction; (ii) normal ALT; and (iii) HBeAg/anti-HBe seroconversion. Lamivudine-resistant YMDD mutants were checked at week 52. RESULTS: The lamivudine group did not reach a better successful treatment response rate than the control group (17 vs 10%, P = 0.44), except in patients with a baseline ALT >5 times of the upper limit of normal value. YMDD mutants developed in 34% of patients in the lamivudine group. CONCLUSION: Lamivudine treatment is effective for maternally transmitted subjects with high ALT.     

Predictors of virologic response to Lamivudine treatment in children with chronic hepatitis B infection

BACKGROUND: Some children with chronic hepatitis B develop advanced liver disease. Lamivudine, an oral nucleoside, is a therapeutic option. A recent large, multicenter study demonstrated that lamivudine was superior to placebo in eliciting loss of hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA from serum in children (2 to 17 years) treated for 52 weeks. OBJECTIVE: To identify pretreatment factors that predict the likelihood of response to lamivudine in children with chronic hepatitis B infection. STUDY DESIGN: Data from the multicenter trial in 297 children (191 lamivudine, 96 placebo) were analyzed for the effects of baseline factors on the likelihood of responses. These responses included virologic response, defined as loss of HBeAg and HBV DNA, and HBeAg seroconversion, defined as loss of HBeAg and development of antibody to HBeAg. Univariate and multivariate analyses examined the effects of lamivudine treatment, age, gender, race, body weight, body mass index, previous interferon treatment and baseline alanine aminotransferase (ALT), histologic activity index (HAI) score and HBV DNA on the virologic responses. RESULTS: In the univariate analysis higher baseline ALT, higher HAI score and lower HBV DNA level predicted a greater likelihood of virologic responses to lamivudine. In the multivariate model only baseline ALT and HAI score were predictive of responses. There was no effect of age or ethnicity on response. CONCLUSIONS: Children with higher pretreatment ALT and HAI scores are most likely to respond to lamivudine. Age, ethnicity and other factors do not significantly influence the frequency of virologic responses in children with chronic hepatitis B infection.     

Efficacy of combined interferon alpha and long-term lamivudine therapy in children with chronic hepatitis B

The aim of this study was to evaluate the efficacy of interferon alpha (IFN-alpha) and long-term lamivudine therapy in children with chronic hepatitis B and to determine the optimal duration of lamivudine therapy. Thirty-eight HBeAg-positive children simultaneously received IFN-alpha2a 5 MU/m2 to 10 MU/m2 for six months and lamivudine (4 mg/kg/day). Lamivudine was administered until anti-HBe seroconversion and was continued for six months in responders. During the five-year study period, we evaluated the efficacy of treatment, occurrence of YMDD mutants and adverse effects. During the study period, alanine aminotransferase (ALT) normalization, clearance of hepatitis B virus (HBV) DNA, HBeAg/anti-HBeAb, HBsAg/anti-HBsAb seroconversion, and histological response were noted in 27 (71.1%), 14 (36.8%), 13 (34.2%), 2 (5.2%) and 10 (47.9%) patients, respectively. Complete response was determined in 34.2% (13/38), and in 69.2% of these responders, response was achieved within 18 months. Breakthrough and YMDD mutant rates were 65.8% and 55.2%, respectively. Breakthrough time was a median 24 months and was associated with low baseline ALT level (p < 0.01). In conclusion, although lamivudine was used for a longer period, the response rate was not higher than in previous reports. We suggest that 18 months' duration of lamivudine treatment is sufficient for combination therapy.     

Chronic hepatitis B. Treatment in childhood with alpha-interferon]

BACKGROUND: In adults several trials of successful therapy for chronic hepatitis B using alpha-interferon with rates of seroconversion from HBeAg to anti-HBe of 30-40% have been reported. Despite the experiences in children are limited, alpha-interferon seems to be a promising drug in this age group as well. We report on our results in the treatment of chronic hepatitis B virus carrier using the recombination interferon alpha-2b. METHODS: 24 children aged 0.6-16 years with chronic active or chronic persistent hepatitis B were included in the study. 12 children received 9 million units of alpha-interferon/m2 body surface area three times a week during four months. 12 control patients were not treated. The follow-up period was 9-12 months after the beginning of therapy. HBsAg, anti-HBs, anti-HBe and Hepatitis-B-Virus-DNA were assessed during this time on a regular basis. RESULTS: Only seroconversion of HBe-Ag to anti-HBe was considered as response to interferon treatment. During the follow-up period anti-HBe could be detected in 5 (41.6%) of the treated and in one (8.3%) of the untreated children. In one case additional seroconversion of HBsAg to anti-HBs due to virus elimination was observed. In all children a marked reduction of viral replication could be shown. 9 patients cleared Hepatitis-B-Virus-DNA at least for one time during therapy. Alpha-interferon was well tolerated and no severe side effects were observed. CONCLUSION: Our results demonstrate that alpha-interferon can be successfully applied to a considerable number of children with chronic hepatitis B. In patients responding to alpha-interferon usually serum transaminases become normal and infectivity of the disease is markedly reduced. alpha-Interferon treatment should be primarily recommended for children with chronic active inflammation.     

Safety and efficacy of interferon retreatment in children with chronic hepatitis B

More than 50% of children with chronic hepatitis B do not respond to treatment with alpha-interferon. Since these patients continue to display high viral replication and progressive liver disease, retreatment should be considered. To date it has not been well evaluated whether a second course of treatment could increase the response rate. In two alpha-interferon retreatment trials in adult patients the response rate, defined by seroconversion from HBeAg to anti-HBe, ranged between 11% and 44%. One beta-interferon retreatment study in children reported a seroconversion rate of 32%. Regrettably, none of the studies included a control group observing the `spontaneous' seroconversion rate after a first interferon cycle. Thus, a nonrandomized alpha-interferon retreatment study in children including control patients was performed. Alpha-interferon for retreatment was administered 3 times a week for 16–24 weeks in 15 children (5–16 years) at least 6 months after ceasing the first cycle. Four children received 5 MU/m² of a natural alpha-interferon and 11 children 9 MU/m² recombinant alpha-interferon 2b. Follow up was 18–47 months after initial treatment. In parallel, a control group of 19 un-retreated children with comparable clinical and demographic data was followed for 12–39 months. HBeAg seroconversion was observed in 5 (33%) of the retreated children and in 5 (26%) of the control patients during follow up. The difference is not significant. In the initially nonresponding children, those with high ALT levels before the first treatment showed late HBeAg seroconversion more frequently than those with low ALT levels (P = 0.017) irrespective of retreatment. The ALT level before retreatment was not a predictor for response. Conclusions A second cycle of alpha-interferon during the 3 years following the first treatment in nonresponding children with chronic hepatitis B can be safely performed but did not increase HBeAg/anti-HBe seroconversion compared with the spontaneous seroconversion rate of patients without retreatment. Received: 29 July 1997 / Accepted in revised form: 23 October 1997     

Interferon treatment for chronic hepatitis B: enhanced response in children 5 years old or younger

OBJECTIVE: To test the hypothesis that there is an improved response to interferon in children with chronic hepatitis B (HBV) who are < or =5 years of age. STUDY DESIGN: Retrospective chart review of 22 consecutive children with chronic HBV (ages 17 months to 17 years; median, 83.9 months; 14 male, 8 female) treated with interferon-alpha2b. RESULTS: Ten patients (48%) responded to treatment [HBeAg (-), Anti-HBe (+), HBV DNA (-), HBsAg (+) and normal alanine aminotransferase/aspartate aminotransferase (ALT/AST) at 6 months after treatment], and 5 seroconverted HBsAg [above plus HBsAg negative and anti-HBs (+)]. Seven of 9 patients (78%) < or =5 years of age responded (5 cleared HBsAg). Three of 13 patients (23%) >5 years of age responded. Patient age at treatment was significantly lower in responders (63 +/- 70 months) versus nonresponders (104 +/- 55 months, P =.005). AST, ALT, and HBV DNA at the start of treatment were not different between responders and nonresponders or between patients < or =5 and >5 years old. CONCLUSIONS: Interferon treatment may be more effective in younger children with chronic hepatitis B.     

Lamivudine Facilitates Optimal Chemotherapy in Hepatitis B Virus-Infected Children with Hematological Malignancies: A Preliminary Report

Hepatitis B virus (HBV) reactivation is well documented in infected patients who have hematologic malignancies, precluding appropriate chemotherapy courses and, therefore, increasing the possibility of relapse of malignancies. The objective of this study was to evaluate lamivudine treatment to prevent hepatitis B reactivation in children with cancer who acquired infection with HBV and so allow completion of optimal chemotherapy. Ten children (7:3 M:F; median age: 9.8 years), undergoing chemotherapy for hematological malignancies and suffering from immunosuppressive-induced hepatitis B virus reactivation, were treated concurrently with lamivudine (3 mg/kg bw,od) for up to 18 months. All were HBsAg+ve, HBsAb?ve, HBV-DNA+ve. Serology markers (HBsAg/Ab, HBeAg/Ab, HBV-DNA) and ALT were tested 3 monthly. Histological assessments were performed pre- and 18 months post-lamivudine therapy. During lamivudine therapy chemotherapy courses were completed for all children, and none of the patients suffered reactivation of hepatitis. After a median follow-up of 10 months, remission of malignancy was maintained in 7/10 patients while 3 patients relapsed. HBeAg+ve seroconversion occurred in 4/9 HBeAg+ve children within 3 months. After 9 months of therapy, 8/10 were HBV-DNA?ve. Six out of 7 children with histological evidence of chronic hepatitis showed marked improvement post-therapy. Lamivudine therapy for up to 18 months in children receiving chemotherapy helped prevent recurrence of hepatitis B exacerbations and improved the underlying chronic hepatitis, while facilitating completion of appropriate chemotherapy regimens without compromise.     

Lamivudine facilitates optimal chemotherapy in hepatitis B virus-infected children with hematological malignancies: a preliminary report

Hepatitis B virus (HBV) reactivation is well documented in infected patients who have hematologic malignancies, precluding appropriate chemotherapy courses and, therefore, increasing the possibility of relapse of malignancies. The objective of this study was to evaluate lamivudine treatment to prevent hepatitis B reactivation in children with cancer who acquired infection with HBV and so allow completion of optimal chemotherapy. Ten children (7:3 M:F; median age: 9.8 years), undergoing chemotherapy for hematological malignancies and suffering from immunosuppressive-induced hepatitis B virus reactivation, were treated concurrently with lamivudine (3 mg/kg bw,od) for up to 18 months. All were HBsAg+ve, HBsAb-ve, HBV-DNA+ve. Serology markers (HBsAg/Ab, HBeAg/Ab, HBV-DNA) and ALT were tested 3 monthly. Histological assessments were performed pre- and 18 months post-lamivudine therapy. During lamivudine therapy chemotherapy courses were completed for all children, and none of the patients suffered reactivation of hepatitis. After a median follow-up of 10 months, remission of malignancy was maintained in 7/10 patients while 3 patients relapsed. HBeAg+ve seroconversion occurred in 4/9 HBeAg+ve children within 3 months. After 9 months of therapy, 8/10 were HBV-DNA-ve. Six out of 7 children with histological evidence of chronic hepatitis showed marked improvement post-therapy. Lamivudine therapy for up to 18 months in children receiving chemotherapy helped prevent recurrence of hepatitis B exacerbations and improved the underlying chronic hepatitis, while facilitating completion of appropriate chemotherapy regimens without compromise.     

Therapeutic efficacy of sequential and simultaneous treatments with interferon-α and lamivudine in children with chronic hepatitis B

BACKGROUND: Interferon (IFN)-alpha and lamivudine (LAM), a nucleoside analog, are frequently used drugs for the treatment of chronic hepatitis B (CHB), and their combined therapy has been shown to be effective. The purpose of the present study was to examine the therapeutic efficacy of sequential and simultaneous combination therapies of IFN-alpha and LAM in children with CHB. METHODS: A total of 45 children with CHB, whose antibody status was positive for hepatitis B surface antigen (HBsAg), hepatitis B envelope antigen (HBeAg), and HBV-DNA at least for 6 months; who had alanine aminotransferase (ALT) levels 1.5-fold higher than normal and hepatic activity index scores higher than 6, were allocated to two groups. The first group included 24 children who were given standard dose IFN-alpha (5 MU/m(2) s.c., thrice weekly) for 6 months, followed by LAM (4 mg/kg per day per oral, maximum 100 mg/day) for an additional 6 months (sequential therapy group). The second group included 21 children who were given IFN-alpha and LAM therapy simultaneously for 6 months and who continued with LAM alone for another 6 months (simultaneous therapy group). Partial response was defined as normalization of ALT and eradication of HBV-DNA. Complete response was defined as normalization of ALT, eradication of HBV-DNA and e seroconversion. Non-responders were defined as having positive HBV-DNA and abnormal ALT levels. Sustained response was defined as absence of HBsAg and presence of hepatitis B surface antibody (anti-HBs). RESULTS: The mean age of the sequential therapy group was 12.7 +/- 4.1 years, and 16 (66.7%) of the patients were male. The mean age of the simultaneous therapy group was 14.8 +/- 4.6 years, and 15 (71.4%) were male. In the first group, 13 patients (54.2%) were non-responders; partial response was observed in five patients (20.8%), and complete response was seen in six patients (25%). Despite the occurrence of e seroconversion, normalization of ALT was not achieved in one case. In the second group, which consisted of 21 patients, 11 subjects (52.4%) were non-responders; partial response was observed in one case (4.8%), and complete response was seen in seven (33.3%). Sustained response was found in two patients (9.5%). There were no significant differences between the groups (P > 0.05). CONCLUSION: When the therapeutic efficiency of two different treatment regimens applied for 1 year was evaluated in childhood CHB therapy, it was remarkable that there was a sustained response and a higher complete response in group 2, although there was no considerable difference between the therapy results of both groups.     

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目的 探讨乙型肝炎病毒携带产妇所生新生儿血清乙型肝炎病毒标志物(HBV-M)转归.方法 2001年3月至2006年3月在暨南大学附属第一医院进行产前检查的500例HBsAg阳性产妇所生新生儿,根据母亲HBeAg状态分为HBeAg阳性组144例,HBeAg阴性组356例.两组新生儿在出生12 h内均注射乙型肝炎免疫球蛋白100 IU,并按常规0、1、6方案分别在出生时、1月龄和6月龄注射基因重组乙型肝炎疫苗5μg,注射主被动免疫前分别抽取外周静脉血检测HBV-M.结果 两组新生儿出生时外周血HBsAg、HBeAg均阳性者分别为24例和9例,追踪至6月龄时HBsAg阳性例数分别为10例和5例,HBsAg阴转率差异无统计学意义.两组新生儿出生时HBsAg阳性、HBeAg阴性者分别为4例和21例,追踪至6月龄时,HBsAg阴转率分别为100%和85.7%.出生时HBsAg阴性、HBeAg阳性者,HBeAg阳性组为29例,占20.1%,显著高于HBeAg阴性组比例(P＜0.01),其6月龄HBsAg阳转率为6.9%,明显低于HBeAg阴性组(P＜0.01).在接受全程主被动免疫的情况下,HBeAg阳性组新生儿6月龄HBsAg和HBsAb阳性率分别为9.7%和67.4%,HBeAg阴性组分别为3.1%和78.1%,两组比较差异有统计学意义(P＜0.05).结论 新生儿出生时外周血HBsAg阳性不能作为判断宫内感染的指标,HBeAg阳性新生儿预后与母亲HBeAg状态密切相关,母亲HBeAg阳性会抑制新生儿对乙型肝炎疫苗的反应.     

Lamivudine treatment for chronic hepatitis B infection in children unresponsive to interferon

BACKGROUND/AIMS: Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication. This prospective open study reports the results of lamivudine treatment in children with chronic hepatitis B infection who did not respond to previous interferon treatment. PATIENTS AND METHODS: Lamivudine, 3 mg/kg/day (maximum, 100 mg/day), was given for 52 weeks to 20 children and adolescents, ages 8.5 to 19 years, with chronic hepatitis B infection who had been treated with interferon 2 to 5 years earlier. We evaluated virologic and biochemical responses, the occurrence of YMDD mutants and adverse effects. RESULTS: All children were HBV DNA+, hepatitis B e antigen (HBeAg) /anti-hepatitis B e antibody- at start of treatment. At the end of 1 year, HBV DNA declined by 95% in all patients, and 8 of 18 (44%) had sustained undetectable HBV DNA by hybridization assay. Median pretreatment alanine aminotransferase (ALT) x1.5 upper limit of normal decreased to ALT x0.9 upper limit of normal after 1 year. One child became HBeAg-negative. YMDD mutants were detected in 11 of 17 (65%) children after 1 year of lamivudine treatment. Among children with YMDD mutant variants, 54% maintained normal ALT values and 45% had undetectable HBV DNA by hybridization assay. No adverse effects were observed. CONCLUSIONS: Children with chronic hepatitis B infection treated with lamivudine after failure of interferon therapy had decreased HBV replication and improved ALT values. However, lamivudine treatment resulted in an exceptionally high rate of lamivudine-resistant mutants and low HBeAg seroconversion rate.     

Effects of Short-Term Prednisolone Therapy (So-Called Steroid Rebound Therapy) in Children With HBeAg-Positive Chronic Hepatitis B

We have studied the effect of short-term prednisolone therapy on seroconversion from HBeAg to anti-HBe, transaminase levels and hepatitis B virus markers in twelve children with HBeAg-positive chronic hepatitis B. They were followed up for more than two years after the discontinuation of prednisolone. On discontinuation, 11 of the children (91.6%) showed disappearance of HBeAg. In eight of them (66.6%), seroconversion from HBeAg to anti-HBe occurred, concurrently with a gradual fall in serum transaminase level. The seronegative reaction occurred within two to 11 months, and seroconversion occurred within five to 15 months after withdrawal of prednisolone. Transaminase activities fell to normal and have remained normal during two to three years in all 11 patients, with disappearance of HBeAg. Hepatitis B virus-DNA polymerase activities were markedly elevated during prednisolone treatment, and then gradually declined along with or before seroconversion from HBeAg to anti-HBe. The patients seroconverted from HBeAg to anti-HBe showed DNA polymerase negativity throughtout the period of observation. It is thought that rapid withdrawal of prednisolone in children with HBsAg- and HBeAg-positive chronic hepatitis will result in a reduction or elimination of HB virus. In our follow-up study, HBsAg disappeared in only one patient. No severe symptoms were encountered during the period of this short-term steroid therapy.     

Longitudinal study on mutation profiles of core promoter and precore regions of the hepatitis B virus genome in children

Precore nucleotide 1896 and core promoter mutations may account for hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B virus (HBV) infection, yet the mutational profiles of the core promoter are largely unknown in children. An age-matched, case-control study enrolled 110 chronic HBV-infected children, including 55 HBeAg seroconverters and 55 nonseroconverters. Precore and core promoter genes of HBV were sequenced and the serum viral genomes were genotyped from three serial serum samples of the seroconverters and from one serum sample of the nonseroconverters. Higher frequency of A1775G and G1799C mutation rates and lower frequency of A1752G mutation rate were found in the seroconverters. Precore 1896 mutation appeared more in seroconverters than in nonseroconverters (45.5% versus 10.9%; p < 0.001). 1762 + 1764 mutation rates were not different between the seroconverters (9.1%) and the nonseroconverters (5.5%). Genotype B was the major type. Genotype C was associated with core promoter 1762 + 1764 mutations in the seroconverter group (p = 0.023). The conclusions of this study include the following: 1) mutations of core promoter at nucleotide position 1752, 1775, and 1799 have significant correlations with HBeAg seroconversion; 2) core promoter 1762 + 1764 mutations play a minimal role in HBeAg seroconversion; 3) precore 1896 mutant accounted for half of childhood HBeAg seroconversion; 4) genotype C is associated with 1762 + 1764 mutations during the process of HBeAg seroconversion.     

Tolerance of interferon-alpha therapy in children with chronic hepatitis B

OBJECTIVE: To assess the side-effects of interferon-alpha (IFN-alpha) therapy in children with chronic hepatitis B. METHODS: This prospective study was performed on one hundred children by interviewing the patients and their parents; clinical examinations and laboratory investigations were performed during and after therapy. RESULTS: The most frequent side-effects of IFN-alpha therapy were fever, flu-like symptoms, and headaches. Lowering of the mean haemoglobin level, leukocyte and platelet count was significant, but transient during INF-alpha treatment. No increase in autoantibody titres or significant alterations in thyroid function was observed. Twelve months after treatment, hepatitis Be antigen (HBeAg) elimination and alanine aminotransferase (ALT) normalization was achieved in 46% of the children; HBeAg and hepatatis B surface antigen (HBsAg) elimination, together with ALT normalization, was achieved in 14% of the cases. CONCLUSION: The side-effects of the IFN-alpha therapy in children such as fever, flu-like symptoms and bone marrow suppression are common, but transient and mild.     

Natural History of Hepatitis B Virus Carriers Born to Hepatitis B Virus Carrier Mothers

Ninety-five infants born to hepatitis B virus (HBV) carrier women were followed without hepatitis B immune globulin injections over five months. Twenty-one infants (22%) became HBV carriers. These 21 HBV carrier children were followed and the mean follow-up period is six years and nine months. Eighteen mothers (85.7%) of these HBV carrier children were HBeAg positive in perinatal period. One was both HBeAg and anti-HBe negative and the status of the other two was unknown. The mean appearance time of HBsAg is 2.0 ± 1.2 months. Nine carrier children (42.9%) became HBeAg negative in the observation period. In seven cases (33.3%), seroconversion from HBeAg to anti-HBe was observed. In six of seven seroconverted cases, liver dysfunction was observed from the HBeAg positive phase and the liver function normalized within one year after the appearance of anti-HBe except in one case. The mean values of AST (Aspartate aminotransferase or SGOT) and ALT (Alanine aminotransferase or SGPT) of the seroconverted group during the whole observation period were significantly higher than those of the persistent HBeAg positive group. The HBeAg positive rate decreases year by year and inversely the anti-HBe positive rate increases. At 8 years old, the former rate is 55.6%, and the latter rate is 33.3%. The mean annual disappearance rate of HBeAg under eight years is 10.1 ± 5.8% and the mean annual appearance rate of anti-HBe under eight years is 6.1 ± 5.8%. The higher the mean annual disappearance rate of HBeAg, the lower the positive rate of HBeAg in pregnant women. This may contribute to the decrease in the appearance of new HBV carriers.     

IgM antibody to hepatitis B core antigen in children with chronic type B hepatitis

IgM antibody to hepatitis B core antigen (anti-HBc IgM) was investigated by an antibody-capture radioimmunoassay (serum dilution 14000) in serum samples from 31 untreated children with chronic hepatitis B who were followed prospectively for 1–7 years. At the start, all patients were positive for hepatitis B e antigen (HBeAg), and anti-HBc IgM was detected in 23 cases, including 15 out of 16 with chronic active hepatitis and 7 out of 14 with chronic persistent hepatitis. A significant positive correlation was found between anti-HBc IgM levels and severity of liver damage (P<0.05), while an inverse relationship was found between anti-HBc IgM levels and distribution of hepatitis B core (HBcAg) antigen in the liver as detected by immunofluorescence. In fact 75% of anti-HBc IgM positive patients showed a focal HBcAg pattern (less than 40% positive nuclei), whereas 87% of antibody negative cases exhibited a diffuse HBcAg expression (more than 60% stained nuclei). During follow-up, seroconversion from HBeAg to anti-HBe with subsequent remission of liver disease occurred in 82% of patients presenting with detectable levels of anti-HBc, including three out of seven cases with chronic persistent hepatitis, but in none of the cases that were initially negative (P<0.01). These results indicate that during the natural course of chronic hepatitis B in children, anti-HBc IgM levels in serum reflect the degree of host immune response to infected hepatocytes. The close correlation between anti-HBc IgM seropositivity and seroconversion from HBeAg to anti-HBe suggests that anti HBc IgM may have a prognostic value during the follow-up of children with chronic HBeAg positive hepatitis B.Abbreviations anti-HBc IgM IgM antibody to hepatitis B core antigen - HBeAg hepatitis B antigen - HBcAg hepatitis B core antigen - HBV hepatitis B virus - ALT alanine aminotransferase - CAH chronic active hepatitis - CPH chronic persistent hepatitis     

Therapeutic vaccination in the immunotolerant phase of children with chronic hepatitis B infection

AIM: Hepatitis B virus (HBV) infection is a major global health concern and is the most common cause of chronic liver disease worldwide. Our aim was to investigate the efficacy of specific HBV vaccination as active immunotherapy in treating chronic hepatitis B (CHB) infection during the immunotolerant phase of children with normal aminotransferase values and high viral load. MATERIALS AND METHODS: Seventy-four patients never vaccinated before were randomly and prospectively recruited into two groups. Group 1 included 43 patients vaccinated with three standard injections of the GenHevac B vaccine at 30-day intervals. Group 2 contained 31 patients who did not receive any medication or vaccination (control group). Postvaccination serologic and virologic evaluation was performed 6 months after the first injection and at the end of the 12th month. Response to therapy was defined as loss of HBV DNA in serum and hepatitis B e antigen (HBeAg) seroconversion (loss of HBeAg), development of hepatitis B e antibody (anti-HBe). RESULTS: The mean baseline alanine aminotransferase (ALT) value in Group 1 was 33.0 +/- 9.6 IU/l, 34.6 +/- 13.9 IU/l at 6 months after first injection and 34.3 +/- 17.1 IU/l at end of 12 months (P > 0.05). In Group 1 the HBV DNA load at the start of immunization was 3571 +/- 1292 pg/ml; this value was 3220 +/- 1217 pg/ml at the 6th month and 2931 +/- 1292 pg/ml at the 12th month (P > 0.05). In Group 2 the mean ALT values at the beginning of therapy and at the 6th and 12th months were 32.6 +/- 7.8, 32.3 +/- 8.0 and 30.3 +/- 7.3 IU/l, respectively (P > 0.05), and the mean viral load HBV DNA values were 3909 +/- 1378, 3546 +/- 869 and 3106 +/- 718 pg/ml, respectively (P > 0.05). There was no statistically significant difference between Group 1 and Group 2 at the end of the 6th and 12th months in the mean ALT values and mean viral load of HBV DNA (P > 0.05). Except for one patient in each group, hepatitis B surface antigen and HBeAg clearance or hepatitis B surface antibody and anti-HBe seroconversion were not observed during follow-up (P > 0.05). CONCLUSION: In this multicentered study comparison of vaccinated and unvaccinated groups of immunotolerant children with CHB infection showed no difference in the clearance of HBV DNA or seroconversion from HBeAg to anti-HBe. Different immunization protocols should be considered for future investigations in the immunotolerant phase of children with CHB infection.     

Virus genotype 1b and long-term response to interferon alpha monotherapy in children with chronic hepatitis C

Interferon alpha (IFN-) remains the basic modality in the treatment of chronic hepatitis C in children, but the effects of therapy are still unsatisfactory. The aim of this study was to evaluate parameters linked to IFN- response within a 2-year period. Human C virus (HCV) infected children (n=34) were subdivided into IFN-treated (n=20) and IFN-untreated (n=14 control) groups. The IFN-treated group received a dosage 3 MU of IFN- three times a week for 24 weeks. Liver biopsy was performed in all IFN-treated children and the HCV genotype was determined before the start of the study. Patients were sequentially screened for alanine transaminase (ALT) activity and tested for the presence of HCV-RNA in serum. All patients had either mild persistent or moderate active hepatitis, which was diagnosed from the liver biopsy. In the IFN-treated group ALT normalisation was observed by the end of treatment in 9/20 patients, but after 6 months 10 patients (50%) had sustained ALT normalisation and in 4 of them the virus was eliminated. They continued to show these features up to the end of the observation period (2 years). Eighteen out of 24 children tested had 1b genotype of virus. Out of 10 responders, all patients who were clear of HCV had the 1b genotype. The median age of responders (6.0, range 3.8–16) was significantly lower than non-responders (14.0, range 4–15) In the control group none of the children were clear of HCV-RNA. Conclusion: The negative predictive effect of HCV genotype 1b in the course of IFN- treatment may be not valid in children and other features have to be taken into account in the assessment of the efficacy of therapy.Abbreviations HCV human C virus - RNA ribonucleic acid - PCR polymerase chain reaction - ALT alanine aminotransferase - RBC red blood cells - HBsAg hepatitis B surface antigen - ELISA enzyme linked immunosorbent assay - CMV cytomegaly virus - IFN interferon - MU mega units - ETR end of treatment response - SR ALT sustained biochemical (ALT) response - HAI histological activity index - R responders - NR non-responders - U/l units per litter - CPH chronic persistent hepatitis - CAH chronic active hepatitis - APC antigen presenting cells - MHC major histocompatibility complex - ALL acute lymphoblastic leukaemia - CML chronic myelogenous leukaemia     

Factors affecting clearance of hepatitis B e antigen in hepatitis B surface antigen carrier children

To understand the natural history of chronic hepatitis B virus infection in children, we studied factors affecting the clearance of hepatitis B e antigen (HBeAg). One hundred sixty-nine apparently healthy children whose sera were positive for HBeAg and hepatitis B surface antigen (HBsAg) and who were recruited by screening were followed prospectively to delineate the HBeAg clearance rate. Another 59 carrier children visiting the outpatient clinic because of symptoms or abnormal liver function were studied for comparison. The annual HBeAg clearance rate was low (less than 2%) during the first 3 years of life but increased with age. The HBeAg clearance rate in children older than 6 years of age was lower in those whose mothers had HBsAg positivity (14.3%) than in those whose mothers had no detectable HBsAg (35.3%). Children who were brought for medical care had higher HBeAg clearance rates (42.4%) than those who were recruited by screening (14.6%) because immune clearance of hepatitis B virus and hence HBeAg often led to hepatocellular damage manifested by abnormal liver function profiles or by symptoms that had caused the parents to seek medical care for their children. We conclude that age, source of subject recruitment, and maternal HBsAg status are important factors affecting HBeAg clearance rate in HBsAg carriers.