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.     

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.     

Changes in hepatitis Be antigen/antibody system in children with chronic hepatitis B virus infection

The long-term changes in the HBeAg/anti-HBe system were examined in 55 children with chronic type B hepatitis (52 patients) or cirrhosis (three patients) during a follow-up period of two to 10 years. At the time of presentation, positive reactions to HBeAg were seen in 46 children, and to anti-HBe in nine. Spontaneous seroconversion from HBeAg to anti-HBe occurred in 13 of 38 patients (average annual rate 16%), mainly those with acute onset of hepatitis B or with features of active liver disease at presentation and with a focal distribution pattern of hepatitis B core antigen in the liver. Normalization of transaminase activity and disappearance of histologic features of activity were the rule in patients in whom seroconversion occurred, but the exception in those who maintained persistently HBeAg-positivity. In contrast to the favorable evolution of illness observed in children showing anti-HBe seroconversion, three of nine patients who had anti-HBe-positive reactions at presentation were found to have liver cirrhosis, and a fourth patient had features of active hepatitis throughout the observation period. Because delta antigen was detected in the liver in two of these patients, it is conceivable that etiologic cofactors could have influenced their course of chronic hepatitis.     

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     

Natural history of hepatitis B in perinatally infected carriers

OBJECTIVES: To establish natural seroconversion rates and incidence of hepatic pathology in perinatally infected hepatitis B carriers. METHODS: Seventy three perinatally infected hepatitis B carriers identified through maternal screening were evaluated. Fifty three were born to parents from the Indian subcontinent, nine were Oriental, six were Afro-Caribbean, and five were white. Median follow up was 10.24 (range 2.02-20.16) years. RESULTS: Only three of the children followed up had cleared hepatitis B surface antigen during this period, and 30% of the children had seroconverted to anti-HBe. Seroconversions to anti-HBe were observed in Asian (18/50) and white (4/5) children, but not in Oriental or Afro-Caribbean children. More girls (40%) than boys (23%) had seroconverted, but the difference was not significant. All children were asymptomatic with normal physical examination, growth, and development. Almost half (48%) of the hepatitis B e antigen (HBeAg) positive children had normal hepatic transaminases and liver function. Thirty five liver biopsies were performed in children with active virus replication (HBeAg or hepatitis B virus DNA positive) who were being considered for antiviral treatment as part of a clinical trial and were scored using the Ishak method. Two thirds (62%) of the children had mild hepatitis, 60% had mild fibrosis, and 18% had moderate to severe fibrosis. There was a weak correlation between histological evidence of hepatitis and hepatic transaminase activity, implying that biochemical monitoring of hepatic disease activity may be ineffective. CONCLUSIONS: These asymptomatic hepatitis B virus carrier children remain infectious in the medium to long term with notable liver pathology. They should receive antiviral treatment to reduce infectivity and to prevent further progression of liver disease. Hepatic transaminases alone are not a reliable marker of liver pathology, and liver histology is essential before consideration for antiviral treatment.     

Treatment results of chronic hepatitis B in children: a retrospective study

In this retrospective study, we aimed to share our experience with different treatment modalities for chronic hepatitis B in a series of children. The study included 126 children (mean: 9.5 +/- 3.8 years). Normalization of alanine aminotransferase (ALT), loss of hepatitis B virus (HBV)-DNA and hepatitis B e antigen (HBeAg), and development of antibody to HBeAg (anti-HBe) altogether at the end of the treatment was considered as end of therapy response (ETR). Seroconversion ongoing one year after the cessation of therapy was considered as sustained response. Of the total children, 90 (71.4%) were treated, whereas the remaining were just followed-up. High-dose interferon (IFN)-alpha (10 MU/m2) alone, standard-dose IFN-alpha (6 MU/m2) plus lamivudine (4 mg/kg/d), high-dose IFN-alpha plus lamivudine, or lamivudine alone was used, IFN-alpha thrice weekly for six months, and lamivudine daily for one year. Of children who had completed their treatment, 34 (37.8%) achieved ETR. Sustained response rate was 36.7%. Response rates were different in the different treatment groups (p: 0.01). The highest response rate was observed in those who received standard-dose IFN-alpha plus lamivudine treatment (61.5%). Of children without treatment, one (2.8%) had anti-HBe seroconversion. Standard-dose IFN-alpha plus lamivudine treatment was found superior to the other treatment modalities. Predictors of ETR were similar to those found in previous studies.     

Serological and histological follow up of chronic hepatitis B infection.

In order to study the clinical, serological, and morphological evolution of chronic hepatitis B virus infection in childhood, a prospective study has been carried out. A total of 90 children with a chronic infection were followed up for a mean (SD) of 3 (1.8) years. At the beginning of the study, 61 children were asymptomatic and 77 were household contacts of chronic carriers. Serologically 77 were hepatitis B e antigen (HBeAg) positive and 71 of them were positive to hepatitis B virus DNA. The mean alanine aminotransferase activities were higher among HBeAg positive patients than in antihepatitis B e (anti-HBe) positive ones. The most severe histological damage was also found among HBeAg positive patients. The annual seroconversion rate was 14%. A significant increase in the alanine aminotransferase activity was observed 13 (5.6) months before appearance of anti-HBe in the 85% of cases. Among anti-HBe positive patients, the alanine aminotransferase activities were normal in all except three (19%), two of whom had intrahepatic delta antigen. An increase in the histological activity was observed among patients who maintained HBeAg presence while an amelioration of liver damage was observed in anti-HBe carriers.     

Hepatitis B virus DNA in liver tissue of chronic HBsAg carriers in childhood and its relationship to other viral markers.

The aim of the study was to examine the state of hepatitis B virus (HBV) DNA in liver tissue of 103 children with chronic hepatitis B aged 0.5-18 years to detect free and integrated viral sequences by Southern blot hybridization. HBV DNA was found in 74 patients. Seventy-two were seropositive for hepatitis B e antigen (HBeAg) and two had anti-HBe antibodies. Integrated sequences could be demonstrated in two children. One of them had only integrated HBV DNA and was anti-HBe seropositive. The other one presented both free and integrated viral sequences and developed seroconversion from HBeAg to anti-HBe 5 months after biopsy. In 29 hepatitis B surface antigen (HBsAg) carriers, no HBV DNA could be detected in the liver. Ten were HBeAg and 19 anti-HBe seropositive. HBV DNA in serum was found in 65 of the 74 Southern blot-positive and only in two cases of the Southern blot-negative patients. In conclusion, most of the HBeAg-positive children had free HBV DNA in their liver tissue and all patients with anti-HBe except one were negative. According to our results, HBV DNA integration into the liver cell genome can occur at an early stage of chronic disease but is not a frequent event.     

The course and outcome of chronic hepatitis B in children]

Overall 98 children aged 1 to 14 years suffering from chronic hepatitis B (CHB) were followed up clinically for 1 to 6 years. CHB was diagnosed on the basis of the clinical and laboratory data. In the majority of the children, the diagnosis was verified by the results of a histological study of liver biopsy specimens. Chronic active hepatitis (CAH), was revealed in 27 children, chronic persistent hepatitis (CPH) in 31. CHB was marked by the presence of HBe-antigenemia in 89 patients (90.8%). The studies have demonstrated that CHB associated with HBe-antigenemia runs its course with insignificant clinical manifestations and enzymic exacerbations without jaundice. In the presence of persistent HBs-antigenemia, the natural course of CHB (in CAH and CPH) is characterized by seroconversion (from HBeAg to anti-HBe) with a simultaneous decrease and normalization of aminotransferase activity and a reduction of the pathological process activity in the liver (transformation of CAH to CPH). Seroconversion and clinico-biochemical amelioration supervene at different observation periods (after 1-6 years) and do not depend on the initial activity of hepatitis. As the observation period increases, the rate of anti-HBe appearance in the blood rises, amounting to 90% with the observation period exceeding 5 years. The conclusion is made that CHB patients do not need active drug therapy but require long and permanent observation.     

Hepatitis B virus infection

Hepatitis B virus (HBV) infection is a worldwide health problem and may cause acute, fulminant, chronic hepatitis, liver cirrhosis, or hepatocelullar carcinoma (HCC). Infection with HBV in infancy or early childhood may lead to a high rate of persistent infection (25-90%), while the rates are lower if infection occurs during adulthood (5-10%). In most endemic areas, infection occurs mainly during early childhood and mother-to-infant transmission accounts for approximately 50% of the chronic infection cases. Hepatitis B during pregnancy does not increase maternal mortality or morbidity or the risk of fetal complications. Approximately 90% of the infants of HBsAg carrier mothers with positive hepatitis B e-antigen (HBeAg) will become carriers if no immunoprophylaxis is given. Transplacental HBeAg may induce a specific non-responsiveness of helper T cells and HBcAg. Spontaneous HBeAg seroconversion to anti-HBe may develop with time but liver damage may occur during the process of the immune clearance of HBV and HBeAg. Mother-to-infant transmission of HBV from HBeAg negative but HBsAg positive mothers is the most important cause of acute or fulminant hepatitis B in infancy. Although antiviral agents are available to treat and avoid the complications of chronic hepatitis B, prevention of HBV infection is the best way for control. Screening for maternal HBsAg with/without HBeAg, followed by three to four doses of HBV vaccine in infancy and hepatitis B immunoglobulin (HBIG) within 24h of birth is the most effective way to prevent HBV infection. In areas with a low prevalence of HBV infection or with limited resources, omitting maternal screening but giving three doses of HBV vaccine universally in infancy can also produce good protective efficacy. The first universal HBV immunisation programme in the world was launched in Taiwan 22 years ago. HBV infection rates, chronicity rates, incidence of HCC and incidence of fulminant hepatitis in children have been effectively reduced.     

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     

Long-term outcome of chronic hepatitis B in adolescents or young adults in follow-up from childhood

BACKGROUND: It has not yet been defined whether children with chronic hepatitis B are likely to develop severe liver disease in the future. The purpose of this study was to evaluate the evolution of chronic hepatitis B acquired in childhood. METHOD: Fifty-two children in the age range of 0 to 15 years who were positive for hepatitis B surface antigen and hepatitis B e antigen in serum for at least 6 months were enrolled in this study. In the majority of the 52 children, hepatitis B virus infection was acquired by perinatal transmission. All 52 showed abnormal liver function test findings for more than 6 months before enrollment, and the subjects were followed up longitudinally for 3 to 22 years (mean, 11 years). They are now more than 15 years of age (15-27 years old). RESULTS: During the follow-up period, 26 (50%) children had spontaneous seroconversion to anti-hepatitis B e. Serum levels of alanine aminotransferase normalized in these 26 children. In one child of these children, hepatocellular carcinoma developed at the age of 21 years, 16 years after seroconversion, although his liver function profiles remained normal. The other 26 children remained hepatitis B e antigen positive, most with unchanged biochemical features. Sixteen (62%) children among these 26 children were treated with interferon-alpha. Eleven (69%) children had seroconversion to anti-hepatitis B e within the first year after the cessation of therapy. Hepatocellular carcinoma developed in 1 of these 11 children at the age of 16 years, 6 years after interferon therapy. Thus, hepatocellular carcinoma developed in two children in an anti-hepatitis B e positive phase. CONCLUSION: All children carrying hepatitis B surface antigen should be observed carefully to monitor the possible development of hepatocellular carcinoma, especially in the antihepatitis B e-positive phase after spontaneous seroconversion or even after interferon treatment.     

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.     

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.     

Hepatitis B virus mutation in children

Due to the lack of proof reading activity of hepatitis B virus (HBV) polymerase, mutation/variation of the viral sequence is frequently found during long term follow-ups. In the majority of children with chronic HBV infection, wild type HBV is the dominant viral strain during the natural course of chronic HBV infection. During long-term follow-up, HBV precore mutants developed spontaneously in approximately 10 to 24% of children before HBeAg seroconversion, and in around 50% of children after HBeAg seroconversion mutants. Occasionally, children may be infected primarily by mutant strains of HBV. Approximately 36% of children with fulminant hepatitis and 30% of children with acute hepatitis B were infected by precore mutants of HBV transmitted by their mothers or blood donors. In addition, after universal HBV vaccination, HBV surface gene variants emerge or are selected under the immune pressure generated by the host or by administration of hepatitis B immune globulin and hepatitis B vaccination. In HBV DNA positive children from four sequential surveys in Taiwan, the prevalence of hepatitis B surface gene a determinant mutants increased from 7.8% before the vaccination program, to 19.6%, 28.1%, and 23.1% at 5, 10, and 15 years after the program. Nucleoside analogue may also induce mutant strains, which reduces the antiviral effects. The most common example is the YMDD mutation of the HBV polymerase gene after antiviral therapy with lamivudine. It developed in 19% of the treated children. In conclusion, children may be infected primarily by mutant strains of HBV either naturally during acute HBV infection. Those infected with wild type HBV initially may develop mutant strains gradually during the course of chronic infection under the host immune pressure. Vaccine escape mutants may develop after immunoprophylaxis. In addition, antiviral therapy with nucleoside anlogues may also induce drug resistant mutant strains. Understanding the viral mutation status will help to design accurate strategies of immunoprophylaxis and antiviral therapy against HBV infection.     

Vertical hepatitis B transmission by anti-HBe positive hepatitis B carrier mothers

5 infants (3 boys and 2 girls) were infected vertically with hepatitis B virus by their healthy anti-HBe positive HBsAg carrier mothers. First sign of infection in the infants occurred 1 to 6 months after birth. The course of the disease was as follows: subclinical hepatitis B (1 case), acute hepatitis B with complete resolution (1 case), fatal fulminant hepatitis B (1 case), chronic persistent hepatitis B (1 case), and chronic active hepatitis with rapid progression to cirrhosis. We conclude that anti-HBe positive hepatitis B carrier mothers may be infective and thus may cause serious, eventually fatal disease in their infants. Passive-active immunization must be given to infants of all hepatitis B carrier mothers irrespective if they are anti-HBe positive or not.     

Delta infection in children with chronic viral hepatitis B

The incidence and clinical features of chronic viral hepatitis B associated with the delta infection were studied in 300 children between one and 14 years in age. Anti-delta was found in 42 (14%) of 300 children with chronic viral hepatitis B, predominantly in patients with chronic active hepatitis who had anti-HBe; exacerbations were found in 11 of 12 children with anti-delta, but in only four of 12 children without these antibodies. These findings confirm the assumption that the process of exacerbation in patients with chronic active hepatitis and anti-HBe may be related to super-infection induced by the delta virus.     

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。     

Clinical relevance of precore and basal core promoter variants of hepatitis B virus during natural hepatitis B e antigen seroconversion may be overstated

BACKGROUND: Clinical relevance of nucleotide changes in precore and basal core promoters in the hepatitis B virus genome during hepatitis B e antigen seroconversion may be overstated. The authors investigated the existence and changes in the relative proportion of variants to wild virus that occur with seroconversion. METHODS: Sera from 30 school-aged long-term hepatitis B virus carriers, including 11 tested before and after seroconversion during 1 to 8 years of follow-up, were evaluated for variations in nucleotide sequences of the basal core promoter (T1762 and A1764), precore region (A1869), and carboxyl-terminus of the X region of the hepatitis B virus genome using an amplification refractory mutation detection system with mutant-specific primers. RESULTS: All variants were found to already exist before seroconversion at various wild-type/mutant ratios. The positive rates of these variants were not changed with loss of hepatitis B e antigen. Although there was a relative increase in the concentration of these mutants in wild-type/mutant mixed populations, most patients with only a wild-type population maintained the same pattern after loss of hepatitis B e antigen. CONCLUSIONS: Our results indicate that hepatitis B virus exists as a quasi species, and correlations of nucleotide sequences with clinical and serologic findings must be done with caution.