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.     

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.     

Interferon-α2b treatment in hepatitis B carriers. Effect on hepatitis B virus DNA levels in children infected with different genotypes

Eleven hepatitis B virus (HBV) carrier children, infected with genotypes A-D, were treated with interferon-α. Two children had a sustained loss of hepatitis B e-antigen and HBV DNA. They were infected with the non-Asian genotypes A and D, and had low HBV DNA and high ALT levels in serum before treatment. However, HBV DNA titres decreased during treatment also in children infected with the East-Asian genotypes B and C.     

Comparison of treatments of chronic hepatitis B in children with lamivudine and α-interferon combination and α-interferon alone

BACKGROUND: The aim of this study was to compare the efficacy of the alpha-interferon treatment with treatment using alpha-interferon and lamivudine in combination for cases of childhood chronic hepatitis B infection. METHODS: Patients were evaluated in two groups retrospectively. In group 1, 27 patients were simultaneously given alpha-interferon 2b 10 MU/m2, 3 days a week by s.c. injection plus lamivudine 4 mg/kg a day (maximum 100 mg) for 12 months. In group 2, there were 13 patients who only received the same dosage of alpha-interferon and no lamivudine over the same period of time. RESULTS: In group 1 the initial mean value of alanine aminotransferase (ALT) was 121 +/- 66 IU/L and decreased to 27.8 +/- 11.5 IU/L; in group 2, initial mean values of ALT was 129 +/- 46 IU/L and decreased to 60 +/- 6 IU/L at the end of the twelfth month of the therapy (P < 0.05). Hepatitis B virus DNA (HBV-DNA) clearance was obtained in all group 1 patients and six of 13 patients in group 2 at the end of the therapy (P < 0.001). The rates of hepatitis B early (HBe) antigen clearance and anti-HBe seroconversion were 59 and 37% in group 1 and 46 and 30.7% in group 2 (P > 0.05). The number of patients with complete response was found to be 10 out of 27 (37%) in group 1 and four out of 13 cases (30.7%) in group 2, 6 months after the end of the therapy. There was no statistically significant difference between both groups (P > 0.05). CONCLUSION: alpha-Interferon and lamivudine combination therapy had a more beneficial effect than alpha-interferon monotherapy in normalization of ALT and clearance of HBV-DNA; however, the complete response rate at 6 months after the end of the therapy was not statistically significantly different between both groups.     

Efficacy of interferon therapy on serum fibronectin levels in children with chronic hepatitis B infection

BACKGROUND: Fibronectin (FN) is a glycoprotein, the major sources of which are hepatocytes, Kupffer cells and endothelial cells. It has many biological functions including adhesion between cells, immunity, blood coagulation and platelet aggregation. Serum FN levels are generally decreased in pathological blood coagulation and inflammation. In the present study, we evaluated the serum levels of FN in patients with chronic hepatitis B virus (HBV) infection treated with interferon-alpha 2b. METHODS: We studied serum levels of FN in a prospective trial between October 1995 and May 1997. The study included 16 patients with chronic HBV infection before and after interferon therapy, in a period of 6 months, and 17 healthy controls. In total, we had 40 patients with chronic HBV infection. We studied these 16 patients (40%) who recovered with interferon therapy. We could not study the other 24 patients because we did not have enough of the reagents for studying FN. RESULTS: Chronic hepatitis B infection was diagnosed serologically and histopathologically. In mean age and sex, no statistically significant differences were found between patients and healthy subjects. The serum FN concentration before treatment with interferon therapy appeared significantly lower in HBV patients than in healthy control subjects (P = 0.026 using the Mann-Whitney confidence interval and test). After treatment with interferon, serum levels of FN were significantly higher than levels obtained before interferon therapy (P = 0.004 using the Wilcoxon Test). CONCLUSIONS: These results suggest that a decreased level of serum FN in patients with chronic hepatitis before interferon treatment is related to hepatic injury and inflammation. Because of inflammation, the serum FN level is decreased due to the consumption of FN. Increased levels of serum FN in patients having interferon therapy is important and is related to the effects of interferon including antiviral, antiproliferative, anti-inflammatory and immunoregulatory properties in patients with chronic HBV infection. A Japanese study showed a correlation between development of hepatic fibrosis and decrease of plasma FN concentration in adult patients with chronic liver disease. Therefore, the serum level of FN may be a useful marker of hepatic fibrosis in chronic liver disease and interferon may be an important drug for prevention of liver fibrosis. Fibronectin may be also a useful marker in predicting IFN response.     

Efficacy of vitamin E in children with immunotolerant-phase chronic hepatitis B infection

BACKGROUND: The purpose of the present paper was to investigate the efficacy of vitamin E in children with immunotolerant-phase chronic hepatitis B virus (CHB) infection. METHODS: Fifty-eight immunotolerant children were prospectively and randomly recruited into two groups. Group 1 (study group) included 30 patients who received vitamin E at a dose of 100 mg/day throughout 3 months; group 2 (control group) contained 28 patients who did not receive any medication. Comparison of serological, virologic, and biochemical response ratios were done at the end of the therapy and after 6 months of vitamin E discontinuation. RESULTS: Mean alanine transaminase (ALT) values in group 1 at the beginning of the therapy, 3 months after the therapy initiation and 6 months after discontinuation were 30.4 +/- 7.3 IU/L, 31.3 +/- 7.8 IU/L and 32.1 +/- 8.5 IU/L, respectively. The mean hepatitis B virus (HBV)-DNA load of group 1 at onset, and at the third and ninth months of the treatment were 3106 +/- 718 pg/mL, 3530 +/- 137 pg/mL and 3364 +/- 1246 pg/mL, respectively. These changes in both ALT and HBV-DNA values did not reach significant levels (P > 0.05). In group 2, mean ALT values at the beginning of therapy, and at the third and ninth months were 28.0 +/- 1.8 IU/L, 34.6 +/- 8.1 IU/L, and 34.1 +/- 7.0 IU/L, respectively (P > 0.05), and mean viral load of HBV-DNA was 4227 +/- 1435 pg/mL, 3368 +/- 2673 pg/mL, and 3018 +/- 2814 pg/mL, respectively (P > 0.05). There was no statistically significant difference between group 1 and group 2 at the third and ninth months in the mean ALT values and viral load of HBV-DNA (P > 0.05). Hepatitis B s antigen and hepatitis B e antigen clearance or hepatitis B s antibody and hepatitis B e antibody seroconversion were not observed in either group. CONCLUSION: As a first study investigating the effect of vitamin E in children with immunotolerant CHB infection, no beneficial effect could be demonstrated. Different immunomodulator protocols should be considered for future investigations.     

Alpha interferon and lamivudine combination therapy for chronic hepatitis B in children

BACKGROUND: Lamivudine is a new alternative therapeutic agent for chronic hepatitis B, in which alpha interferon (IFN-alpha) monotherapy is not successful enough. Published reports have revealed no satisfactory data on IFN-alpha and lamivudine combination therapy in children. The aim of this study is to investigate the efficacy and safety of this combination therapy in children with chronic hepatitis B. METHODS: Children with chronic hepatitis B were given either IFN-alpha and lamuvidine (group 1, n = 47) or IFN-alpha alone (group 2, n = 30). Alpha interferon was administered as 5 million U/m2 s.c., thrice a week for 6 months and lamivudine 4 mg/kg per day p.o., maximum 100 mg, for 1 year. Clinical examination was performed; blood cell counts and serum alanine aminotransferase (ALT) and amylase were studied at each visit. At the third, sixth and twelfth month, serological markers were determined. RESULTS: End of therapy response was achieved in 19 (40.4%) patients in group 1 and in 14 (46.7%) children in group 2 (P > 0.05). In group 1, pretreatment serum ALT and hepatic activity index (HAI) were statistically higher in children who responded to therapy (P < 0.005). In group 2, mean serum ALT was higher and hepatitis B virus (HBV) DNA was lower in responders. Sustained response rate was 40.4 versus 43.3% in two groups. CONCLUSION: The response rate of IFN-alpha and lamivudine combination therapy in children with chronic hepatitis B was similar to that of IFN-alpha monotherapy. High ALT level and HAI, rather than low HBV-DNA level were found to be important predictors of response.     

HBsAg阳性母亲的婴儿接种乙肝疫苗后慢性HBV感染相关因素探讨

为探讨HBsAg阳性母亲的婴儿接种乙肝疫苗后慢性HBV感染相关因素及机制,对624名儿童随访了(6.34±1.71)年。结果发现慢性HBV感染89例,其中82.0％始于6月龄前。HBeAg同时阳性母亲的婴儿慢性HBV感染率高于单阳性母亲的婴儿(单用疫苗,P<0.005;HBIG+疫苗,P<0.05),且在6月龄内出现HBsAg阳性时,慢性化率也高(单用疫苗,P<0.025)。联合使用HBIG和疫苗可进一步减少慢性HBV感染率(单阳性组,P<0.025,双阳性组,P<0.005)及在1月～6月HBsAg阳性婴儿慢性化率(双阳性组,P<0.025)。提示HBsAg阳性母亲的婴儿接种乙肝疫苗后慢性HBV感染主要发生于宫内或产程中。双阳性母亲的婴儿更易形成慢性HBV感染,HBIG联合疫苗的预防效果优于单用疫苗。     

Clinical significance of TT virus infection in children with chronic hepatitis B

BACKGROUND: The pathogenic role of TT virus (TTV) is not clear in patients with chronic hepatitis B. The aims of the present study were to determine the frequency of TTV positivity in serum and saliva samples and the possible role of TTV in children with chronic hepatitis B. METHODS: Sera and saliva from 29 healthy children and 25 children with chronic hepatitis B were tested for TTV-DNA by means of real-time polymerase chain reaction (PCR). RESULTS: Fifty-two percent (13/25) of the serum samples and 32% (8/25) of the saliva samples were positive for TTV-DNA in children with chronic hepatitis B. In healthy non-transfused children, TTV-DNA was detected in 58% (17/29) of the serum samples and 41% (12/29) of the saliva samples. Six (46%) of 13 children with chronic hepatitis and 10 (59%) of 17 healthy children had TTV-DNA positivity both in serum and saliva samples. Two serum samples were negative for TTV-DNA while the saliva samples were positive for TTV-DNA in chronic hepatitis B and control groups. Mean age, sex, serum alanine aminotransferase levels, hepatitis B virus (HBV)-DNA values were similar in TTV-positive and -negative children with chronic hepatitis B. However, total histologic activity index (HAI), periportal necrosis and portal inflammation scores were significantly higher in children with HBV-DNA and TTV-DNA viremia (P = 0.013, P = 0.008, P = 0.015, respectively). CONCLUSIONS: Because total HAI, periportal necrosis and portal inflammation scores were higher in children with TTV coinfection, TTV infection may contribute to the progression of liver damage in children with chronic hepatitis B.     

粒细胞-巨噬细胞集落刺激因子联合乙肝疫苗对宫内感染HBV携带儿童治疗机制初探

目的从细胞因子水平初步探讨粒细胞一巨噬细胞集落刺激因子(GM—CSF)联合乙肝疫苗对宫内HBV感染携带儿童的疗效机制。方法采用ELISA和半定量逆转录-聚合酶链反应(RT—PCR)，对12例GM—CSF联合乙肝疫苗治疗后儿童、6例乙肝免疫球蛋白(HBIG)联合乙肝疫苗治疗后儿童及9例未治疗的宫内感染儿童外周血单个核细胞在PHA LPS、HBsAg及无刺激物时γ-干扰素、白细胞介素(IL)-4分泌及mRNA表达水平进行检测。结果与对照组比较，GM-CSF联合乙肝疫苗治疗儿童γ-干扰素自发分泌显著增加(P=0．017)，HBIG联合乙肝疫苗治疗儿童IL-4 mRNA转录显著降低(P=0．002)。结论GM—CSF联合乙肝疫苗治疗宫内感染HBV慢性携带儿童时HBV受抑制可能与γ-干扰素产生增多有关，HBIG联合乙肝疫苗治疗时IL-4转录受抑不影响HBV复制，提示慢性HBV感染治疗应以增强Th1应答为主。     

Antiviral treatment of chronic hepatitis B with lamivudine in pediatric renal transplantation

Renal transplantation in patients with chronic hepatitis B virus (HBV) infection is known to be associated with an increased risk for exacerbation of liver dysfunction. Lamivudine has been proven to be a potent inhibitor of hepatitis B virus replication in adults after kidney transplantation. Little is known about its efficacy and safety in pediatric renal transplant recipients. Three cases serve for the discussion to demonstrate the complexity of the clinical course and effective treatment of chronic hepatitis B in pediatric patients awaiting renal transplantation. Two patients on dialysis with a high HBV replication rate were treated with lamivudine before transplantation. After the viral load had decreased below the detection limit, they underwent transplantation successfully. Despite intensified immunosuppression to treat a rejection episode in one and a relapse of the nephrotic syndrome in the other patient, the viral load remained <2.5 pg/mL. Both patients developed a mutation in the YMDD motif of the HBV genome associated with an increase in the HBV replication rate >10,000 pg/mL without deterioration of the liver function. In a third patient with a chronic HBV infection with a low replication rate, lamivudine was started about nine months after kidney transplantation due to an increasing viral load after treatment of an acute rejection episode. Six months later, the HBV DNA was no longer detectable. The patient had no signs of liver dysfunction. Lamivudine in the treatment of chronic HBV infection in pediatric renal recipients seems to be safe and effective in preventing acute liver deterioration. Three clinical cases are discussed with regard to current options in monitoring and antiviral treatment of chronic HBV in pediatric renal transplant recipients.     

Clinical improvement and normalized Th1 cytokine profile in early and long-term interferon-α treatment in a suspected case of hyper-IgE syndrome

We are reporting on a 7-months-old boy with suspected hyper-IgE syndrome, presenting with a therapy resistant severe eczema and an overall reduction of in vitro cytokine production. Interferon-α (IFN-α) treatment resulted in a marked and stable clinical improvement and normalization of in vitro T-cell cytokine production, indicating a valid therapeutic potential of IFN-α as immunomodulating drug.     

小儿慢性乙型肝炎干扰素治疗引起的抗纤维化效应

目的观察儿童慢性乙型肝炎(CHB)应用α-干扰素(IFN-α)治疗引起的抗纤维化效应。方法30例小儿CHB应用IFN-α治疗24周以上,且停药后随访36周,其中5例治疗前后均行肝活体组织检查。所有患儿均在治疗前、治疗后24周和36周,应用放射免疫法检测患儿血清肝纤维化标志物:透明质酸(HA)、层连蛋白(LN)、Ⅳ型胶原(Ⅳ-C)。结果应用IFN-α治疗前(0周)、治疗后24周和36周,小儿CHB血清肝纤维化标志物HA值分别为(243.6±70.5)ng/mL、(145.2±51.6)ng/mL、(85.1±40.3)ng/mL;LN值分别为(180.5±61.3)ng/mL、(102.7±40.6)ng/mL、(62.8±32.6)ng/mL;Ⅳ-C值分别为(137.1±48.6)ng/mL、(108.9±40.3)ng/mL、(70.5±30.7)ng/mL,治疗后血清肝纤维化标志物较治疗前显著下降(P<0.05)。肝活体组织病理检查显示,治疗后肝组织纤维化分期比治疗前有明显降低(P<0.01)。结论IFN-α在治疗小儿CHB时,不仅有抗病毒作用,在改善肝纤维化方面,也具有一定疗效。     

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     

��ͯ���͸��ײ������������ٴ��ֶ�������о�

目的了解儿童乙型肝炎病毒(HBV)基因型与临床分度的关系。方法选择甘肃省人民医院儿科和兰州大学第一医院感染科2008年4月至2010年4月门诊和住院患儿中HBV-DNA阳性的124例乙型肝炎患儿,其中男84例,女40例。HBV携带者65例,慢性乙型肝炎59例(轻度31例、中度18例、重度10例),对以上患儿进行基因分型、同时检测肝功、术前出凝血、HBV-DNA载量。结果 124例肝病患儿中,C基因型62例(50.0%),B基因型48例(38.7%),B/C混合型9例(7.3%),非B/C型5例(4.0%);HBV携带者和轻度组中,以B基因型为主,分别为47.7%和45.2%;中度和重度组中,以C基因型为主,分别为72.2%和80%;在C、B基因型分布方面,HBV携带者和轻度组与中度和重度组比较差异有统计学意义;C基因型患者的HBV-DNA载量、丙氨酸转氨酶(ALT)、天冬氨酸转移酶(AST)、总胆红素(TBIL)均高于B基因型;C基因型患者与B基因型比较,凝血酶原时间(PT)延长、凝血酶原活动度(PTA)下降、纤维蛋白原(FIB)减少。B、C型通过母婴传播的比例差异无统计学意义。结论甘肃省儿童乙型肝炎病毒基因...     

Hepatitis B precore mutant in children with chronic hepatitis B virus infection

BACKGROUND: In adults, hepatitis B virus (HBV) with a G to A point mutation at nucleotide 83 in the precore region (mutant HBV 83), is commonly found in HB e antibody positive HBV carriers. It has been reported that this mutant is not able to produce HB e antigen. The exact prevalence of mutant HBV 83 in patients with chronic HBV infection is not fully understood, especially in children. METHODS: To investigate the role of mutant HBV 83 in children with chronic HBV infection, sera were tested for the presence of mutant HBV 83 using a mutation site-specific assay. RESULTS: Mutant HBV 83 was detected in 15 of 22 children (68%). Seven children were followed longitudinally, of which three were asymptomatic carriers and the other four had chronic hepatitis B on entry. There was no clear relationship between the disease activity and the presence of mutant HBV 83. CONCLUSIONS: It was concluded that mutant HBV 83 is commonly present in children with chronic HBV infection and this mutant is not necessarily associated with activation of hepatitis.