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.     

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.     

Hepatitis B und C im Kindesalter

The development of new medications and therapy regimes has expanded the therapy of hepatitis B and C during the last years. In childhood therapy of chronic hepatitis B is indicated during the high viral phase if transaminase levels are increased on several occasions or if liver fibrosis above grade 2 is present or if social conditions necessitate hepatitis B virus suppression. Treatment with α-interferon is the therapy of choice and leads to seroconversion of anti-HBe in 26–38% of patients. In non-responders or contraindications against the use of interferon lamivudin can be used. After a period of 12 months these therapies lead to seroconversion of anti-HBe in 20–25% of patients and subsequently to the loss of HBeAg and a dramatic decrease of HBV-DNA and mostly also transaminases. Nowadays, therapy with nucleoside and nucleotide analogues should be given until seroconversion to anti-HBe has been achieved but in most cases this involves a long term therapy lasting several years. Therefore, exact knowledge of the characteristics of the currently available nucleosides is crucial. Chronic hepatitis C can be cured in 50–90% of children through combined treatment with alpha-interferon and ribavirin. If treatment is unsuccessful the therapy can be repeated. Medications such as protease and polymerase inhibitors are currently being tested in clinical studies on adults and in some years could be an extension to the clinical therapy.     

Detection of hepatitis B virus DNA by polymerase chain reaction in serum and liver of children with chronic hepatitis B negative for hepatitis B virus DNA by conventional hybridization tests.

Hepatitis B virus (HBV) DNA was detected by polymerase chain reaction in the serum of 87 and liver tissue of 40 children with chronic hepatitis B, negative for HBV DNA by dot blot and Southern blot hybridization, respectively. In sera HBV DNA could be detected in 73 hepatitis B surface antigen carriers; 14 were hepatitis B e antigen (HBeAg), 56 were anti-HBe-seropositive and 3 had neither HBeAg nor positive anti-HBe. In 14 anti-HBe-positive patients no HBV DNA could be found. Viral sequences in liver tissue were present in 33 specimens; 20 were HBeAg and 13 were anti-HBe-seropositive. All of the 7 negative children had anti-HBe. Our results confirm polymerase chain reaction to be a more sensitive method to detect HBV DNA in the liver compared with conventional hybridization techniques. Every HBeAg-positive carrier as well as the majority of anti-HBe-positive patients show ongoing viral replication. This is of special clinical relevance, because these children must be considered infectious.     

HLA typing associated with hepatitis B E antigen seroconversion in children with chronic hepatitis B virus infection: a long-term prospective sibling cohort study in Taiwan

OBJECTIVE: To conduct a prospective cohort study to clarify the relationship between human leukocyte antigen (HLA) polymorphisms and the seroconversion of hepatitis B e antigen (HBeAg). STUDY DESIGN: In the prospective cohort study, 81 HBeAg-positive children with chronic hepatitis B virus (HBV) infection from 40 unrelated families were recruited and followed-up regularly for a mean period of 17.70 +/- 3.23 years. The association between HLA antigen and the age at HBeAg seroconversion was analyzed using Cox regression model with shared frailties under left truncation and right censorship. RESULTS: HLA-B61 and HLA-DQB1*0503 antigens predicted a higher HBeAg seroconversion rate (relative incidence = 6.17 and 3.22, P = .024 and .017, respectively). Within-family frailty in our sibling cohort study demonstrated a negligible or a low degree of within-family correlation with spontaneous HBeAg seroconversion in each HLA antigen. CONCLUSIONS: HLA class I antigen B61 and class II antigen DQB1*0503 are associated with earlier HBeAg seroconversion in Taiwanese children with chronic HBV infection.     

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.     

Retreatment with higher dose interferon alpha in children with chronic hepatitis B infection.

BACKGROUND: More than 50% of children with chronic hepatitis B infection do not respond to interferon-alpha (IFN-alpha) treatment and are prone to have progressive liver disease. The best treatment modality is unknown in these children. The aim of this study was to evaluate the possible benefit of a second higher dose IFN-alpha therapy for children with chronic hepatitis B diseases who failed previous therapy. METHODS: Twenty-four children with chronic hepatitis B infection who had not responded to previous IFN-alpha treatment were enrolled into the study. All were hepatitis B virus DNA- and hepatitis B e antigen-positive for >6 months after initial treatment. They received 10 megaunits (MU)/m2 of IFN-alpha 2a three times a week for 24 weeks. Liver function tests, hepatitis B virus markers and hepatitis B virus DNA were determined regularly during treatment and follow-up. A complete response was defined as clearance of both hepatitis B virus DNA and hepatitis B e antigen (HBeAg). RESULTS: At the end of therapy 8 (33.3%) patients cleared hepatitis B virus DNA and seroconverted to anti-HBeAg. Patients were followed for an average period of 12.2 +/- 4.7 months after retreatment. During follow-up an additional 4 patients cleared hepatitis B virus DNA and seroconverted to anti-HBe, whereas one seroconverted patient became HBeAg-positive again. Thus 11 patients (45.8%) had complete response at the end of the follow-up period. Alanine aminotransferase normalized in 11 responder patients and in 5 nonresponders. Positive predictive factors were low baseline titers of hepatitis B virus DNA and elevated transaminase values (> 100 IU/l). CONCLUSIONS: IFN-alpha retreatment with a higher dose may be an alternative modality for treatment of children with chronic hepatitis B infections who failed previous IFN-alpha, especially in those with favorable predictive factors.     

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     

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.     

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.     

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. Detection with polymerase chain reaction in liver tissue of children with chronic hepatitis B]

BACKGROUND: Detection of hepatitis B virus DNA is a reliable evidence of the presence of the viral agent and its replication. Conventional hybridization techniques are limited to detect about 30,000 virions. With the polymerase chain reaction it became possible to extend the sensitivity by amplification of viral sequences. In our study we intended to test whether viral sequences could be found in liver tissue specimens negative for hepatitis B virus DNA by conventional hybridization techniques. METHODS: Hepatitis B virus DNA was detected by PCR in liver tissue of 37 children with chronic hepatitis B, negative for hepatitis B virus DNA by Southern blot hybridization. PCR was performed in a thermal cycler using Taq-polymerase and oligonucleotide primers within the hepatitis B core region. Hepatitis B virus DNA was visualized by ethidium bromide staining and subsequent Southern blot hybridization. RESULTS: 20 patients were HBeAg- and 17 anti-HBe-seropositive. Viral sequences were present in each of the 20 HBeAg positive HBsAg carriers and in 10 patients with anti-HBe. No hepatitis B virus DNA could be found in 7 children, all of them positive for anti-HBe. CONCLUSIONS: Our results confirm polymerase chain reaction to be a more sensitive method to detect hepatitis B virus DNA in the liver compared with conventional hybridization techniques. Every HBeAg positive carrier as well as the majority of anti-HBe positive patients present viral DNA in their liver. Polymerase chain reaction will be suitable to monitor viral replication in spontaneous course and treated patients.     

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     

Hepatitis B virus perinatal transmission among Arab women

One thousand five hundred and fifty-four Arab women were screened at delivery for the presence of hepatitis B virus (HBV) antigenaemia in their sera. Forty-five or 2.9% were found to be positive. Only three of 41 (7.3%) of these hepatitis B surface antigen-positive (HbsAg) mothers were found to be positive for the presence of hepatitis B e antigen (HBeAg), 27 (65.8%) had anti-HBe and the remaining 11 (26.8%) had neither HBeAg nor its corresponding antibody. These results, therefore, predicted a low rate of transmission of virus from mother to newborn. Follow-up for 4-13 months after delivery on 14 of these HBsAG-positive mothers and their infants indicated that in only one infant born to an HBeAg-positive mother did HBV antigenaemia develop. Another infant died from undetermined causes. Therefore, HBV perinatal transmission among Arabs, unlike that among populations in Southeast Asia, does not appear to contribute in an important way to the pool of carriers in this population.     

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.     

Efficacy of interferon-α2b treatment in children with chronic hepatitis B who have previously undergone therapy for cancer

BACKGROUND: The aim of the present study was to evaluate the efficacy of treatment with recombinant interferon (IFN)-alpha2b in 12 children with chronic hepatitis B who had previously undergone therapy for cancer. METHODS: Nine children had acute leukemias and the other three children had solid tumors. The mean (+/-SD) age of the children was 8.4+/-3.8 years (range 4-16 years). All cases were hepatitis B virus (HBV)-DNA positive and 11 were hepatitis B e antigen (HBeAg) positive. One was anti-HBe positive (mutant strain). Four cases were anti-delta IgG positive. Liver biopsy revealed chronic hepatitis B in 11 patients and cirrhosis in one patient. Interferon-alpha2b was given at a dose of 5 MU/m2 three times a week, subcutaneously, for 12 months. RESULTS: Elimination of serum HBV-DNA was obtained in three cases, but a further three patients demonstrated a marked decrease in HBV-DNA levels after therapy. Three of 11 patients seroconverted from HBeAg to anti-HBe. Alanine aminotransferase (ALT) levels returned to normal in three of nine cases in whom the ALT levels were high before treatment. At the end of therapy, the mean histologic activity index score was significantly diminished (P = 0.0039). CONCLUSIONS: In conclusion, a 12 month course of IFN-alpha2b induces some beneficial effects on virologic, biochemical and histologic indices in children with chronic hepatitis B who have previously undergone therapy for cancer.     

Clinical importance of hepatitis B virus DNA detection in serum of children with chronic hepatitis B]

206 sera from 172 children with chronic hepatitis B infection were tested for HBV DNA by dot blot hybridization. 111 were positive and 95 negative for HBV DNA. 103 (78.6%) of the positive patients had HBeAg and 5 (7.7%) anti-HBe. In 60 (92.3%) of the anti-HBe positive sera no HBV DNA could be detected. Children with elevated liver enzymes had HBV DNA in 80.1%, whereas in 71.6% of the chronic HBsAg carriers with normal liver enzymes no HBV DNA was found. In 87 of the 95 dot blot negative patients polymerase chain reaction was performed. 73 (83.9%) children of this group were HBV DNA positive. All HBeAg positive patients and those with elevated aminotransferases had HBV DNA in their serum. 56 anti-HBe-positive HBsAg carriers were also positive; 14 were negative for HBV DNA. Our results demonstrate that viral sequences can be found in all HBeAg positive and in most of the anti-HBe positive children. Patients with ongoing virus replication have to be considered infectious and recommendation for vaccination of close relatives of these patients must be stressed.     

Chronic viral hepatitis B in childhood

The results of immunological studies in serum and liver tissue from 26 patients with chronic HBsAg-positive hepatitis (15 CPH, 9 CAH, 2 MinH) are presented.Determination of serum immunoglobulins showed no significant differences between the three categories of HBsAg-positive CH. AGF, ANA and AMA were not demonstrable in our patients.HBsAg and anti-HBc were demonstrated in all patients, HBeAg in 16, anti-HBe in 6 patients. 2 children had anti-HBs antibodies.Elevated DNA polymerase activity was found in 8 of 12 HBeAg-seropositive and 0 of 9 HBeAg-sero-negative patients.HBcAg was present in liver tissue from 9 of 10 HBeAg-seropositive and 1 of 9 HBeAg-seronegative children. In some cases the classification of viral antigen expression patterns according to the studies of Bianchi and Gudat did not correspond to the histological diagnosis and the presence of serum HBeAg.Studies in 51 family members of 23 children showed a high incidence of HBsAg carriers among the siblings and frequent evidence of anti-HBs in the mothers. Altogether, contact with HBV was demonstrated in 28 of the relatives studied.Abbreviations used HBV hepatitis B virus - CH chronic hepatitis - CPH chronic persistent hepatitis - CAH chronic aggressive hepatitis - MinH minimal hepatitis - HBsAg hepatitis B surface antigen - HBcAg hepatitis B core antigen - HBeAg hepatitis B e antigen - anti-HBs antibody to HBsAg - anti-HBc antibody to HBcAg - anti-HBe antibody to HBeAg - AGF anti-gamma-globulin factors - ANA antinuclear antibodies - AMA antimitochondrial antibodies - SMA smooth muscle antibodies - LMA liver membrane antibodies - DNA desoxyribonucleic acid