Long-term follow-up of antiviral combination therapy in chronic hepatitis B.

For patients with chronic hepatitis B e (HBe)-positive hepatitis, long-term results of pilot studies with lymphoblastoid interferon-alpha, acyclovir, or a combination, and of a randomized controlled trial of interferon/desciclovir combination therapy are presented. HBe seroconversion was observed in more than 40 percent of patients treated with combination therapy, 30 percent with interferon therapy, 18 percent with acyclovir, and 0 percent with no treatment. HBe reactivation occurred in two patients with cirrhosis. Hepatitis B surface seroconversion followed HBe seroconversion in 11 to 30 percent of treated patients. HBe seroconversion was significantly related to initial low levels of viral replication and to transient aminotransferase elevation during the second half of the interferon treatment of 16 weeks. Clinical improvement and persistent normalization of aspartate aminotransferase was observed in all patients with HBe seroconversion. Conversion to a state of virus latency (HBe negative) mostly occurred after therapy, suggesting that the specific immunologic host response had been brought about by the suppression of virus replication through antiviral agents. Recommendations for selection of patients for antiviral combination therapy are made on the basis of these long-term results.

Prevention of hepatitis B infection in newborns through mass screening and delayed vaccination of all infants of mothers with hepatitis B surface antigen.

Beginning in 1982 all pregnant women undergoing prenatal routine blood analysis in three large city hospitals and one large rural area were tested for hepatitis B surface antigen (HBsAg). Infants of all HBsAg-positive mothers received hepatitis B immunoglobulin (HBIg), 0.5 mL/kg of body weight within two hours of birth and, after randomization, 10 micrograms of hepatitis B vaccine either at 0, 1, 2, and 11 months of age (schedule A) or at 3, 4, 5, and 11 months of age (schedule B). A second injection of HBIg (1 mL) was given to infants on schedule B at 3 months of age. Blood samples were obtained at 3, 6, 11, 12, 24, and 36 months. In a two-year period, 28,412 pregnant women were tested for HBsAg; screening efficiency varied between 85% and 98%. The overall prevalence of HBsAg was 0.8%, with a marked variation between urban centers (2.2%) and the rural area (0.3%). Vaccinations were received by 180 of 193 infants of HBsAg-positive mothers (90 on schedule A and 90 on schedule B). Concentrations of hepatitis B surface antibody less than 10 IU/L were observed in nine instances in five children from group A and in seven instances in six children from group B. Four hepatitis B viral infections (two HBsAg carriers, two who underwent antihepatitis B core seroconversions) were recorded in group A v one infection (antihepatitis B core seroconversion) in group B. The protective efficacy of the program (screening plus passive immunization and delayed vaccination) was 94%. The estimated cost of preventing one cae of hepatitis B infection in neonates was $3,000 (US currency).(ABSTRACT TRUNCATED AT 250 WORDS)

Zidovudine inhibits hepatitis B virus replication.

Hepatitis B virus DNA polymerase is a viral enzyme that can use viral DNA as well as viral RNA as a template for DNA synthesis. Since both activities are essential for the production of new virus particles, blocking of this enzyme should reduce viral replication. In the present study the in vitro effect of zidovudine triphosphate on hepatitis B virus DNA polymerase activity and the in vivo effect of zidovudine on viral replication in chronic HBsAg-positive patients are investigated. Zidovudine triphosphate inhibited in vitro DNA polymerase activity by 50% at a concentration of 0.3 microM. Serum DNA polymerase activity was significantly reduced in 7 patients who received zidovudine (200 mg orally 4 times daily) for one week. A dose-response effect was suggested by the results found for 6 patients who received 100 mg, 200 mg and 300 mg orally 4 times daily for one week with 2 drug-free weeks between each course. We conclude that zidovudine may be of value for non-responders to alpha-interferon therapy or patients with high initial levels of viral replication prior to the start of interferon treatment.

Immune response after vaccination with recombinant hepatitis B vaccine as compared to that after plasma-derived vaccine.

Thirty-one individuals (health care workers) were vaccinated with recombinant hepatitis B vaccine (10 microgram dose) and their immune response (anti-HBs) was compared to that of twenty-five health care workers after vaccination with plasma-derived vaccine (20 microgram dose). Although the seroconversion rate and the percentage of anti-HBs/a antibodies at month 7 were comparable, the geometric mean titre of anti-HBs at month 7 was considerably lower for the recombinant vaccine group (857.4 vs. 6736.5 IU/l). However, vaccinees from the two groups showing seroconversion at month 1 had comparable titres at month 7. Raising the dose of HBsAg in the recombinant vaccine may favourably influence the seroconversion rate at month 1 and thereby the immune response after three injections.

Anti-pre-S(2) analysis after hepatitis B vaccination in haemodialysis patients.

We investigated the development of anti-pre-S(2) antibodies by enzyme immunoassay and by Western blot analysis in a vaccination study in haemodialysis patients; both the Pasteur plasma vaccine retaining the pre-S(2) epitopes and the Merck, Sharp and Dohme (MSD) plasma vaccine containing only HBsAg were used. By enzyme immunoassay (EIA), one anti-pre-S(2) response at month 7 was registered in 23 patients after 5 injections with the 5 micrograms dose of Pasteur vaccine (PS group), whereas 6 responses were seen in 20 patients after 4 injections with the 10 micrograms dose (PD group). None of the 22 vaccines injected with MSD vaccine (40 micrograms) (4 injections, MD group) showed an anti-pre-S(2) response at month 7. In the Western blot an anti-pre-S(2) response was seen in 12 PS patients, in 8 PD patients and in none of the MD patients. Anti-pre-S(2) responses were predominantly observed in patients with a high anti-HBs response but exceptions occurred. Prevaccination anti-pre-S(2) positivity, in the absence of anti-HBc and anti-HBs, was detected in dialysis patients with EIA as well as Western blot, in 10.8 and 21.6%, respectively; similar findings were made in health care personnel. The possible nature of this phenomenon is discussed. In this study the Western blot technique has been shown to be a suitable test system for qualitative and semi-quantitative analysis of anti-pre-S(2) antibodies after hepatitis B vaccination with a higher sensitivity, but probably also a different specificity than the EIA.

Detection of HBV-DNA in liver biopsy and serum: its significance in the selection of hepatitis B patients for antiviral therapy.

We have characterized the hepatitis B virus state in liver and serum of 38 HBsAg-positive chronic hepatitis patients (chronic active hepatitis (CAH), 19; chronic persistent hepatitis (CPH), 7; cirrhosis, 11; 'normal' carrier, 1) and 21 HBsAg-negative patients. Episomal HBV-DNA in liver, without detectable integrated HBV-DNA sequences, concomitant with HBV-DNA in serum was found in 19 HBeAg-positive patients (CAH, 16; CPH, 1; cirrhosis, 2). Integrated sequences were detected in 13 HBsAg-positive HBeAg-negative patients (CAH, 1; CPH, 5; cirrhosis, 7) and in 1 HBsAg-negative patient. Episomal HBV-DNA and integrated HBV-DNA sequences were observed simultaneously in 1 HBsAg-positive HBeAg-negative CPH patient and in 4 HBsAg-positive cirrhosis patients (2 HBeAg-positive, 2 HBeAg-negative). The presence of HBcAg immunofluorescence corresponded well with that of episomal HBV-DNA. Antiviral therapy is advised for HBsAg-positive chronic hepatitis patients with episomal HBV-DNA, irrespective of the presence of integrated sequences. Since the presence of episomal HBV-DNA in liver is not always accompanied by the presence of serum HBV-DNA, procedures for the selection and evaluation of patients for antiviral therapy should be extended by characterization of the HBV-DNA state in liver biopsies.

Measurement of HBsAg to monitor hepatitis B viral replication in patients on alpha-interferon therapy.

HBsAg was measured quantitatively in serum samples collected serially before and after the HBeAg seroconversion date from 69 patients with HBeAg seroconversion and 17 patients with both HBeAg and HBsAg seroconversion. In patients with only HBeAg seroconversion the median HBsAg level decreased from 8.39 micrograms/ml (range 0.01-57.51) before HBeAg seroconversion to 3.53 micrograms/ml (range 0.002-68.66) after seroconversion (P < 0.001). No significant drop in HBsAg was found for the control group (18 HBeAg-positive patients without seroconversion). From 12 other patients on alpha-interferon therapy HBsAg was quantitatively assayed monthly during and after therapy; HBsAg levels were compared to the levels of HBV-DNA and HBeAg. We observed a good correlation between the HBsAg level and both the HBV-DNA (r = 0.76; P < 0.001) and the HBeAg (r = 0.70; P < 0.001) level, irrespective of the response to alpha-interferon. Quantified assessment of HBsAg appears promising as a simple and cheap method for monitoring viral replication in chronic hepatitis B in patients undergoing interferon therapy.

Inhibitory effect of 9-(2-phosphonylmethoxyethyl)-adenine (PMEA) on human and duck hepatitis B virus infection.

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) was evaluated for its inhibitory effect on hepadnavirus replication in three different cell systems, i.e., human hepatoma cell lines HepG2 2.2.15 and HB611 (transfected with human hepatitis B virus (HBV)) and primary cultures of duck hepatocytes infected with duck hepatitis B virus (DHBV). PMEA inhibited HBV release from HepG2 2.2.15 cells and HB611 cells at a 50% inhibitory concentration (IC50) of 0.7 and 1.2 microM, respectively. Intracellular viral DNA synthesis was inhibited at concentrations equivalent to those required to inhibit virus release from the cells. DHBV secretion from duck hepatocytes was inhibited by PMEA at an IC50 of 0.2 microM. HBsAg secretion was inhibited by PMEA in a concentration-dependent manner in HB611 cells and DHBV-infected duck hepatocytes but not HepG2 2.2.15 cells. The 50% cytotoxic concentration, as measured by inhibition of [3H-methyl]deoxythymidine incorporation was 150 microM for the two human hepatoma cell lines and 40 microM for the duck hepatocyte cultures. In a pilot experiment PMEA was found to reduce the amounts of DHBV DNA in the serum of Pekin ducks.

Immune response to HBsAg differently interpreted by RIA and EIA.

In the first part of this study anti-HBs developed after vaccination (three different vaccines, sampling at four time intervals after the first injection) or infection (n = 342) was simultaneously tested by Ausab-RIA and Ausab-EIA (Abbot Laboratories). For each vaccination subgroup (vaccine, time) the geometric mean level (GML) of anti-HBs, expressed in IU/l using the Abbott reference panel, was calculated. The ratio GML-RIA/GML-EIA ranged from 1.4 to 2.2. Differences between the vaccine subgroups were found at months 2/3 and month 7, but not at months 12 and 24. The results obtained in convalescent sera by RIA and EIA were similar (ratio GML 1.1). It is concluded that the behaviour of anti-HBs based on the Abbott reference panel differs from that of anti-HBs obtained after vaccination. In the second part of this study, we compared RIA (Abbott Laboratories) with two other EIAs (Organon Teknika): Hepanostika anti-HBs monoclonal (HM) and Hepanostika anti-HBs 'new' (HN). The suitability of these EIAs for detecting anti-HBs greater than 10 IU/l was investigated in sera obtained after vaccination and infection (n = 538). On the first screening, all samples with anti-HBs greater than 10 IU/l (n = 109) in the RIA were detected by HM, whereas 5-7%, dependent on the time of the first incubation step, were negative by HN. The functional sensitivity of HN was 3.9 IU/l (short incubation) or 1.5 IU/l (overnight incubation) and 16.1 IU/l for HM as determined with the Organon reference panel. Sera from three reference panels, as in-house panel, an Abbott panel and an Organon panel were tested in Ausab-RIA, HM and HN. For a serum with the arbitrarily chosen level of 50 IU/l anti-HBs (in-house panel) the results of the in-house panel, the Abbott panel and the Organon panel deviated less by the Ausab-RIA. Since in the Organon-EIAs extreme values of 77 and 35 IU/l were calculated with the Abbott and the Organon panel, respectively, the need for reference sera, the use of which is not related to any particular test system, is stressed once again.

Evaluation of a semi-automatic radioimmunoassay for hepatitis B surface antigen (HBsAg).

The recently developed semi-automatic Hepatube system was evaluated in comparison to another radioimmunoassay for the detection of hepatitis B surface antigen (HBsAg), the manual Ausria II-125 test. After incubation of serum in anti-HBs coated tubes, the Hepatube system uses a machine to wash the tubes and to add tracer. After a second incubation, tubes are washed again in the machine and are manually transferred to the gamma counter. Two machines were used. Machine 1 had an undefined defect. Of 1490 samples tested, 69 (4.6%) gave false-positive results versus 11 (0.7%) in the Ausria II-125 test. Machine 2 had one false-positive result among 920 samples versus 5 in the Ausria II-125 test. The sensitivity was measured with reference panels from Wellcome and Abbott as well as in titration series. The Hepatube system was found to be a factor three less sensitive than the Ausria II-125 test. The Hepatube processor is easy to handle; radioactive material can be held at a distance during the whole procedure; waste material is limited and less voluminous than in the Ausria II-125 test.

Immuno disc assay for screening duck hepatitis B surface antigen in serum, liver tissue and cultured hepatocytes.

An immuno disc assay (IDA) for semi-quantitative analysis of the surface antigen (DHBsAg) of duck hepatitis B virus (DHBV) is described. Unpurified antigen preparations were adsorbed onto punched-out nitrocellulose membrane discs. Rabbit antiserum raised against serum-derived gradient-purified DHBsAg was used for detecting the antigen. Cross-reacting antibodies in the rabbit antiserum were removed using normal duck serum and normal duck hepatocytes. The sensitivity of the IDA was compared with that of the Western blot analysis and was observed to be of the same order, but differed slightly for DHBsAg in liver and sera. In contrast to Western blot analysis, antigen specificity for the IDA included the S-protein. Immunodetection was carried out in microtitre plates, but the procedure was accelerated by attaching the antigen-adsorbed discs to an adhesive plate sealer. The IDA was exemplified for measuring DHBsAg in duck serum, duck liver homogenates and viral protein synthesis in cultures of DHBV-infected hepatocytes.

Comparison of two techniques for detecting antibody to HBsAg during a hepatitis B vaccine study.

Two assays for the detection of antibody against hepatitis B surface antigen (anti-HBs) were compared. The first was a direct sandwich radioimmunoassay (RIA) which detects, in principle, antibody against any epitope of hepatitis B surface antigen (HBsAg). The second assay was an inhibition enzyme-linked immunosorbent assay (ELISA). In this assay a fixed amount of HBsAg which can be blocked by anti-HBs is measured in a direct sandwich test. Prevaccination screening sera (n = 191) and follow-up sera obtained from high risk groups (n1 = 85; n2 = 41) during two hepatitis B vaccine studies were compared in RIA and ELISA. In prevaccination sera either HBsAg or anti-HBs were detected by ELISA. Full agreement between the results of RIA and ELISA for anti-HBs was obtained in sera containing more than 10 IU/l anti-HBs. Both tests showed variable results at low titres. Experiments with monoclonal anti-HBs indicated that ELISA is less sensitive for subtype specific antibodies (anti-d, anti-y), which may explain that there were consistent differences between RIA and ELISA in a minority of cases.

Influence of perceived psychological stress and distress on antibody response to low dose rDNA hepatitis B vaccine.

The present study focused on the relationship between psychological stress and immune reaction to a novel antigen. Participants completed questionnaires on daily hassles, psychoneurotic complaints, coping style, and loneliness, 2 and 6 months after the first of a series injections with a low dose recombinant DNA hepatitis B vaccine. Antibody response was determined 7 months after the first vaccination. Based on the psychological questionnaires two different stress measures were calculated: a Stress Index score-month-2 and a Stress Index score-month-6 indicating stress levels experienced at the beginning and at the end of the study respectively. Antibody levels were found to be negatively related with the Stress Index score-month-2. Although the influence of psychological stress reported on month 6 tended to be in the same direction, this effect was not significant. Coping styles and loneliness were not associated with antibody formation. These results suggest that antibody formation to rDNA hepatitis B vaccine is negatively influenced by psychological stress.

Long-term application of human polyclonal hepatitis-B immunoglobulin to prevent hepatic allograft infection. A review of the literature and presentation of five cases.

Liver transplantation has evolved as the therapy of choice in end-stage liver disease. However, liver transplantation for viral liver disease is associated with recurrence of viral hepatitis in the graft. In this paper we discuss the mechanisms of liver cell damage, the clinical impact of recurrent infection and the use of hepatitis-B-specific immunoglobulin (HBIg) to prevent recurrent infection in the allograft. In addition, we propose an HBIg schedule tailored to each individual patient. Based on the excellent survival results published for acute hepatic failure and chronic liver failure with latent hepatitis B virus (HBV) or hepatitis delta infection, we think that no contraindication exists for liver transplantation in these cases. For patients with active viral replication, liver transplantation should only be considered within a scientific frame to prevent reinfection of the allograft.

Immune response to hepatitis B vaccine in pregnant women receiving post-exposure prophylaxis.

Hepatitis B immunoglobulin and vaccine were given as post-exposure prophylaxis to 73 women after an outbreak of hepatitis B due to in vitro fertilization treatment. The immunization schedule consisted of 5 ml of hepatitis B immunoglobulin (125 IU/ml) at months 0 and 1 and recombinant hepatitis B vaccine (10 micrograms of HBvaxDNA) at months 0, 1, 2 and 6. The safety and immunogenicity of hepatitis B vaccine were studied in 16 women who became pregnant after in vitro fertilization; 57 non-pregnant women receiving the same treatment served as controls. Blood samples were drawn at 0, 1, 2, 6 and 7 months. One patient had a clinical abortion 2 days after initial immunization; other side effects of vaccination were not found in vaccinees or in their offspring. All vaccinees exhibited antibodies against hepatitis B surface antigen after vaccination but relatively low peak geometric mean titers of 258 IU/l and 684 IU/l were attained in pregnant and non-pregnant women, respectively. There were no significant differences in seroconversion rates and geometric mean titers between the two groups although the immune response to hepatitis B vaccine was slower and lower in pregnant women at all times. Our results suggest that when post-exposure prophylaxis for hepatitis B infection is indicated, passive active immunization can be started safely during pregnancy. The relative weak response to the vaccine calls for monitoring of the anti-HBs 1 month after the initial series of vaccinations.

A family infected with hepatitis B and with concurrently circulating HBsAg and heterotypic anti-HBs.

A family is described, of whom all members were found to be infected with the adw2 subtype hepatitis B virus. The mother and both the children were positive for anti-HBs (anti-y). The usual explanation for the co-occurrence of HBsAg and anti-HBs ("two infections hypothesis") was clinically highly unlikely. HLA typing was performed to investigate the possibility that genetically determined host dependent factors are involved. However, no relationship between the simultaneous presence of HBsAg and anti-HBs and a particular haplotype was observed.

Proposal for routine antenatal screening at 14 weeks for hepatitis B surface antigen. Dutch Study Group on Prevention of Neonatal Hepatitis.

OBJECTIVE: To develop a low cost, high compliance screening programme for identification of carriers of hepatitis B surface antigen in the obstetric population of the Netherlands. DESIGN: A seven year open, descriptive study of screening for hepatitis B surface antigen as part of routine prenatal laboratory testing at 14 weeks of gestation. Compliance with programme evaluated by checking delivery records (hospitals) or registration of births in the 30 participating municipalities (rural area). SETTING: Three large city hospitals (two tertiary referral centres) and one rural area with a large number of home deliveries. SUBJECTS: 99,706 pregnant women applying for prenatal care for the first time. MAIN OUTCOME MEASURES: Proportion of pregnant women routinely screened; prevalence of hepatitis B surface antigen in large cities and rural area. RESULTS: Uptake of screening reached 97% in the hospitals after inclusion of 10% screened at delivery; the estimated uptake in the rural area was > 95%. Prevalence of hepatitis B surface antigen was 1.6% in the large cities and 0.3% in the rural area. For screening at delivery the prevalence was 2.5 times higher (4%, P < 0.01) than for screening at week 14 of gestation. CONCLUSION: Incorporation of universal testing for hepatitis B surface antigen into routine prenatal laboratory testing is practical; high compliance is achieved when screening is supplemented with rapid screening at delivery for those who escaped routine prenatal care.

[Vaccination against hepatitis B possibly indicated for elderly institutionalized mentally handicapped persons with isolated anti-HBc positivity of the prevaccination serum]. / Vaccinatie tegen hepatitis B mogelijk aangewezen bij geïnstitutionaliseerde oudere verstandelijk gehandicapten met geïsoleerde anti-HBc-positiviteit van het prevaccinatieserum.

OBJECTIVE: To determine whether vaccination against hepatitis B may be omitted in persons with isolated positive anti-HBc. DESIGN: Prospective study using control groups. SETTING'S: Heeren Loo-Lozenoord, Ermelo, the Netherlands. METHOD: Twenty-six older residents (group P) with isolated anti-HBc positivity (HBsAg negative and anti-HBs < 10 IU/l) were given hepatitis B vaccine (3 doses); 16 matched controls (group C1) lacking hepatitis B markers, received a primary vaccination (3 doses), 8 controls (group C2) with a immune status based on infection in the past received vaccination (3 doses) and 27 controls (group C3) were given a booster vaccination (1 dose) after vaccination 7 years earlier. The anti-HBs response was measured 0, 1 and 7 months after the first vaccine dose. An anamnestic response was defined as a fourfold rise of anti-HBs after one dose of vaccine or--in the absence of an anti-HBs titer in the prevaccination serum--a response > or = 10 IU/l after one dose of vaccine. A primary response was defined as an anti-HBs response > or = 10 IU/l after giving 3 vaccines, while the criteria for an anamnestic response were not met. RESULTS: In the isolated anti-HBc group (P) and in the corresponding control group (C2) 15 and 12.5%, respectively, showed an anamnestic response; the majority reacted with a primary response or did not respond at all. The subjects given a primary vaccination (C1) responded in 62.5% with a primary response while those vaccinated earlier (C3) responded in 92.6% with a fourfold rise of anti-HBs. CONCLUSIONS: The anti-HBs response to vaccination in older mentally handicapped persons is delayed and there is a reduced chance of development of a protective anti-HBs titer. The majority of individuals with isolated anti-HBc showed a primary response. In these persons vaccination should not be omitted, especially if there is a risk of hepatitis B.

[Alpha-interferon antiviral treatment in 100 patients with chronic hepatitis B]. / Antivirale behandeling met alpha-interferon bij 100 patiënten met chronische hepatitis B.

In a retrospective study we investigated the antiviral effect of alpha-interferon in 100 patients with chronic hepatitis B who were treated in controlled trials conducted in Rotterdam (1985-1990). The aim of the treatment was to induce viral latency as indicated by HBeAg seroconversion. Alpha-interferon was administered in a dose of 5 mega-units per day subcutaneously. Sixty-two patients received alpha-interferon for 16 weeks combined with a second antiviral agent (acyclovir or descyclovir) while the other 38 patients were treated with alpha-interferon monotherapy during 20 to 34 weeks. Follow-up continued until 1 year after the start of therapy. Thirty-eight per cent of the patients exhibited an HBeAg seroconversion and 9% exhibited an HBsAg seroconversion indicating a complete eradication of the virus. After 1 year transaminase levels were normalised in 70% of the patients with HBeAg seroconversion compared with 22% in those without seroconversion (p less than 0.05). The combination therapy for 16 weeks and the alpha-interferon monotherapy of longer duration resulted in HBeAg seroconversion rates of 29% and 53%, respectively (p less than 0.05). The predominant adverse effects were fatigue, flue-like illness and leukopenia. Serious side effects such as seizures, psychosis and peripheral neuropathy occurred in seven patients. Side effects led to a dose reduction in 26% of the patients. Alpha-interferon is effective in terminating the virus replication in chronic hepatitis B. However, both the common mild and the uncommon major side effects necessitate intensive patient monitoring during alpha-interferon treatment.

[The course of hepatitis B in 9 children who became positive for viral surface antigen HBsAg in spite of vaccination]. / Het beloop van hepatitis B bij 9 kinderen die ondanks vaccinatie positief werden voor het virale oppervlakteantigeen HBsAg.

OBJECTIVE: To describe the viral, clinical and biochemical course of infants, who, in spite of passive-active hepatitis B immunisation, became infected with hepatitis B. DESIGN: Prospective cohort study. SETTING: The Netherlands. MATERIAL AND METHOD: As part of the research programme of the Dutch study group 'Prevention neonatal hepatitis B', 705 newborns of HBsAg-positive mothers received passive and active immunisation. Despite passive-active immunisation, 9 children became positive for HBsAg. These children were analysed clinically and their HBsAg, anti-HBs, HBeAg, anti-HBc and anti HD were measured. RESULTS: Median follow up was 5 years (range 3-8 years). Of the 9 HBsAg-positive infants 8 also tested positive for HBeAg. At the end of the follow-up 1 child had lost HBsAg and 2 children had lost HBeAg. Only 1 child experienced a symptomatic hepatitis B infection with raised aminotransferase levels. The other 8 infants with chronic hepatitis B had no clinical symptoms. Aminotransferase levels were normal throughout in 7 infants. CONCLUSION: Most of the infants who, in spite of passive-active hepatitis B immunisation, became HBsAg positive developed a chronic hepatitis B infection without clinical or biochemical dysfunctions. On the basis of these findings and considering possible therapy, guidelines are given for the follow up of children with chronic hepatitis B.