Persistent HBsAg Research Articles

Prognostic significance of pre-S2 antigen and antibody in fulminant hepatitis B: Evidence for heterogeneous serological responses

Serial sera were collected prospectively and from early on in the clinical course of ten patients with fulminant hepatitis B. These were analysed for HBV DNA (dot-blot technique), HBsAg, HBeAg, pre-S2-Ag and their respective antibodies. Two patterns emerged in nine of the patients. The first and well-recognised pattern of rapid clearance of antigens and appearance of antibodies was seen in four patients, all of whom survived. The second pattern seen in five patients was one of persistence of HBsAg and pre-S2 antigen and failure to detect antibodies but only one patient survived. The first pattern may reflect a more rapid cessation of virus replication and this may favour liver cell regeneration and recovery. In contrast, the second pattern may indicate continuing virus replication and liver cell damage which could contribute to the high mortality in some patients with fulminant hepatitis B.

CHANGES IN THE LIVER HBV-DNA PATTERN EXPRESSION IN CHILDREN WITH HBV CHRONIC INFECTION

The antiviral effect of r-IFNa on HBV replication has been proven “in vivo”. However there is no information about the changes induced by the r-IFNa in the patterns of HBV-DNA, specially in children. The aim of this work was to study the effect of the r-IFNa over the liver HBV-DNA patterns in children with chronic hepatitis B.30 children with CAH histologically proved were included. All of them had HBeAg and serum HBV-DNA for at least 6 months prior to the beginning of the study. Two liver biopsies were obtained from all the patients, one just before the treatment and the second at the 15th month.HBV-DNA was tested in serum by dot blot and in liver by southern blot hybridization. In the first liver sample all children had replicative intermediates of the viral DNA and in one of them the HBV-DNA was also integrated in the host genome. In the second liver biopsy, in the children who did not respond to the therapy (HBV-DNA+ in serum) the replicative forms of the HBV-DNA remained in the liver and in 3 children inegrated HBV-DNA was detected simultaneously. Among the 9 patients who lost serum HBV-DNA at the end of the therapy, in 8 of them the viral DNA was undetectable in their liver, in the other child integrated and episomal forms non replicatives of the HBV-DNA were detected. None of the responder children lost the HBsAg in serum. To investigate this fact we looked for the presence of HBV-DNA in peripheral blood cells by dot-blot. None of these children showed viral DNA in these cells.In conclusion, HBV-DNA can be integrated in the host genome early in the natural history of the HBV- chronic infection. Our results suggest the antiviral effect of the r-IFNa of hepatic level. The persistence of HBsAg in the responder children is not maintained at expenses of HBV-DNA expression in mononuclear blood cells.

Prevalence of hepatitis B surface antigen in pregnant mothers and its perinatal transmission

1000 pairs of maternal and cord blood samples were collected simultaneously at the time of delivery. 23 (2·3%) of the maternal samples were positive for HBsAg by enzyme-linked immunosorbent assay. HBeAg was detected in 11 (47%) of the 23 HBsAg positive mothers and anti-HBeAg was detected in another 5 samples. HBsAg and HBeAg were detected in 7 (30%) of the 23 cord blood samples from HBsAg-positive mothers, and anti-HBeAg was detected in one of these samples. At follow-up (6–18 months), antigenaemia had persisted in 17 (85%) of the 20 HBsAg-positive mothers and in 9 (45%) of 20 babies born to HBsAg-positive mothers. Seven of the 10 babies (70%) born to mothers positive for both HBsAg and HBeAg had persistent HBsAg in their blood, in contrast to 2 of the 10 babies (20%) born to mothers positive for HBsAg only. However, none of these mothers or their babies were found to have anti-HBeAg at follow-up. We conclude that the presence of HBeAg in mothers' blood enhances vertical transmission of hepatitis B virus infection to their babies.

Serological assessment of HBcAg and HBV DNA: its prognostic relevance in acute hepatitis B.

Treatment of serum precipitates with sodium thiocyanate in patients with hepatitis B virus (HBV) replication results in liberation of circulating hepatitis core antigen (HBcAg) which can be demonstrated radioimmunologically. Follow-up investigations were performed in 80 patients with acute hepatitis B. Sera were examined for HBcAg. HBV DNA and conventional HBV markers. At the time of admission to hospital 34 of 80 (42%) patients were HBeAg positive. Twenty-six (76%) of the 34 HBcAg positive patients were HBV DNA positive, and circulating HBcAg was detectable in 25 of 34 (73%) HBcAg positive cases. In patients with uncomplicated courses of acute hepatitis B the serological HBcAg assay and HBV DNA became negative 1 to 8 weeks before elimination of HBeAg and up to 12 weeks earlier than the sera became negative for HBsAg. Five patients (6%) showed transition to chronic hepatitis B with persistence of HBsAg, HBeAg, HBV DNA and HBcAg in serum. One patient with acute hepatitis B and development of chronic hepatitis suffered from acquired immunodeficiency syndrome and showed delayed formation of anti-HBc. In this case uncomplexed HBcAg was demonstrable during the acute phase of hepatitis B. With the appearance of anti-HBc HBcAg circulated in a complexed form. The data indicate that serological determinations of HBcAg and HBV DNA can serve as prognostic markers in the early phase of acute hepatitis B. The demonstration of uncomplexed HBcAg in serum of a patient with inadequate formation of anti-HBc supports the hypothesis that circulating HBcAg is usually complexed by specific antibodies.

Blood donors positive for HBsAg and negative for anti-HBc antibody.

From January 1980 to December 1983, 989,907 blood donations were screened for HBsAg. A total of 1,345 was found HBsAg positive; 33 of whom were negative for anti-HBc (2.45%); in 10 cases HBeAg was present at a low level along with HBsAg. 2 of the 33 subjects were lost to follow-up. Late serum samples were available for 28 blood donors, and clinical and biological data only were known for the 3 others. An evolution of HBV markers was observed in each case; anti-HBc antibody became positive in 24 subjects (the 4 remaining subjects had a very short follow-up); HBeAg was positive at a high titer in 18 subjects and seroconversion to anti-HBe was observed in 7 individuals; HBsAg concentration increased in 21 subjects from 2 to 4,000 times and decreased in the 7 others. Seroconversion to anti-HBs was observed in 8 individuals. According to these serological, biological and clinical findings, different outcomes were observed: in 6 subjects too short a follow-up was available to allow appropriate classification, but there was evidence to suggest all probably developed clinical hepatitis; in 6 subjects asymptomatic hepatitis with rapid loss of HBsAg occurred; in 2 subjects asymptomatic hepatitis with the persistence of HBsAg at a low level and seroconversion to anti-HBe occurred; and in 17 subjects clinical hepatitis developed. These observations establish that most of the 33 blood donors were infectious at the time of their blood donation, and that anti-HBc antibody screening must not replace HBsAg screening for blood donations.

Blood Donors Positive for HBsAg and Negative for Anti-HBc Antibody

From January 1980 to December 1983, 989,907 blood donations were screened for HBsAg. A total of 1,345 was found HBsAg positive; 33 of whom were negative for anti-HBc (2.45%); in 10 cases HBeAg was present at a low level along with HBsAg. 2 of the 33 subjects were lost to follow-up. Late serum samples were available for 28 blood donors, and clinical and biological data only were known for the 3 others. An evolution of HBV markers was observed in each case; anti-HBc antibody became positive in 24 subjects (the 4 remaining subjects had a very short follow-up) ; HBeAg was positive at a high titer in 18 subjects and seroconversion to anti-HBe was observed in 7 individuals; HBsAg concentration increased in 21 subjects from 2 to 4,000 times and decreased in the 7 others. Seroconversion to anti-HBs was observed in 8 individuals. According to these serological, biological and clinical findings, different outcomes were observed: in 6 subjects too short a follow-up was available to allow appropriate classification, but there was evidence to suggest all probably developed clinical hepatitis; in 6 subjects asymptomatic hepatitis with rapid loss of HBsAg occurred; in 2 subjects asymptomatic hepatitis with the persistence of HBsAg at a low level and seroconversion to anti-HBe occurred; and in 17 subjects clinical hepatitis developed. These observations establish that most of the 33 blood donors were infectious at the time of their blood donation, and that anti-HBc antibody screening must not replace HBsAg screening for blood donations.

PREVENTION OF THE HBsAg CARRIER STATE IN NEWBORN INFANTS OF MOTHERS WHO ARE CHRONIC CARRIERS OF HBsAg AND HBeAg BY ADMINISTRATION OF HEPATITIS-B VACCINE AND HEPATITIS-B IMMUNOGLOBULIN: Double-blind Randomised Placebo-controlled study

Newborn infants of Chinese HBeAg-carrier mothers in Hong Kong were randomly assigned to one of four study groups. Group I was treated with 3 μg heat-inactivated hepatitis B (HB) vaccine at birth and at 1, 2, and 6 months thereafter, in conjunction with seven monthly HBIg injections; group II was treated according to the same vaccine schedule but received only one HBIg injection at birth; group III received only the vaccine, at months 0, 1, 2, and 6; and group IV received placebos for both vaccine and HBIg. The first set of injections was given within 1 h after birth. Comparisons were made in the 140 children who were at least six months old at the close of the trial (495 days). In all three treatment groups development of the persistent carrier state was significantly (p0·0001) less frequent than in controls (2·9%, 6·8%, and 21·0% versus 73·2%). Although vaccination alone was significantly less protective than vaccination plus multiple HBIg injections (p=0·03), the degree of protection was still remarkable. 12 months after the first set of injections 96-100% of the infants in the three treatment groups were anti-HBs positive; the geometric mean titres of anti-HBs in the three groups did not differ significantly. This indicates that even high doses of HBIg do not interfere with the anti-HBs response to the vaccine. Probable intra-uterine HB infections were observed in 3 infants. No serious side-effects were observed from the interventions, even in the babies with intra-uterine infections who had received HBIg and HB-vaccine at birth. To prevent development of the persistent HBsAg carrier state, and thereby the consequent chronic liver disease and/or primary carcinoma of the liver, HB vaccine and HBIg should be administered as soon as possible after birth to all newborn infants at risk of perinatal hepatitis B infection.

Immune electron microscopic study of hepatitis B virus associated antigens in hepatocytes

In order to elucidate the localization of HBV-associated antigens including nonstructural forms, immune electron microscopic study was carried out in liver tissues obtained from 96 cases of chronic liver diseases with persistent HBs antigenemia and asymptomatic HBsAg carriers. The results obtained were as follows. 1) HBsAg was localized in the cytoplasm with two different patterns: an intracytoplasmic localization and a diffuse membranous localization. 2) Most cases showing membranous localization of HBsAg were associated with HBeAg in serum and the existence of core and Dane particles in the hepatocytes. 3) Antigenicity of HBsAg was found on the outer coat of Dane particles and cisternal membrane of dilated endoplasmic reticulum (ER) in addition to the plasma membrane. Some of the antigen positive ER were detected close to the plasma membrane, suggesting that the membranous localization of HBsAg was presumably resulted from the exocytosis of the antigen positive ER. These findings suggest that HBsAg expressed on the plasma membrane is a very likely target antigen in the course of cytolysis mediated by immunological mechanism. 4) HBcAg and HBeAg were localized in the cytosol of the hepatocyte in addition to the nucleus, but never found on the plasma membrane.

Incidence of hepatitis B virus infections in preschool children in Taiwan.

To determine the incidence of infections with hepatitis B virus (HBV) among Chinese preschool children, 1,510 children (mean age, 29 months) were tested for HBV markers; 15.9% were infected with HBV (7.8% positive for hepatitis B surface antigen [HBsAg] and 8.1% positive for antibody to HBsAg) and 84.1% were susceptible when the children were enrolled in the study. The average length of follow-up was 2.1 years among 1,110 children. Among the 924 susceptible children who were followed up, 10.6% had seroconversions for HBV markers, none of which was associated with clinical illness; the annual incidence of HBV infections was 5.0%. Among the 98 children who experienced HBV infections during the study, 23% became HBsAg carriers, and HBsAg persistence was age-related, with most carriers being among the youngest children infected. In contrast, among the children with HBV markers at the time of enrollment, 118 (49.2%) were HBsAg-positive and 86% were still positive on follow-up. The incidence of HBV infections was significantly associated with the frequency of previous injections.

Anti‐HBc of IgM‐class, HBeAg and anti‐HBe in acute and chronic hepatitis B

The presence and persistence of IgM antibody against hepatitis B core antigen (anti-HBc IgM) and the correlation with other HBV markers were studied in 42 patients, all of whom had acute HBsAg-positive hepatitis but whose subsequent diseases differed. All patients initially had anti-HBc IgM. In 13 out of 15 patients with uncomplicated acute hepatitis, anti-HBc IgM disappeared within 6 months after onset of the disease. In five out of 12 patients, who in spite of transient HBsAg developed chronic liver disease, the anti-HBc IgM persisted for more than 2 years. Among 15 patients with persistent HBsAg, anti-HBc IgM was present from 7 months to more than 8 years. Seroconversion from HBeAg to anti-HBe was observed in seven patients and in five of these anti-HBc IgM disappeared during the follow-up period. These results indicate that anti-HBc IgM can be used as a serological marker of recent or ongoing HBV infection.

Radioimmunoassay for detection of hepatitis B e antigen and its antibody. Results of clinical evaluation.

The performance of a solid phase radioimmunoassay (ABBOTT-HBe) for the detection of hepatitis B e antigen (HBeAg) and its antibody anti-HBe was evaluated in clinical studies. The reagents and procedure were found to be reproducible by seven investigators, and lab-to-lab variations were minimal. In HBsAg positive sera, ABBOTT-HBe detected HBeAg or anti-HBe in 90% of the specimens compared to 50% tested by immunodiffusion. During the early acute stage of viral infection, serum HBeAg coincided with the rise and decline of HBsAg and seroconversion to anti-HBe occurred most often prior to loss of HBsAg. Patients with clinical evidence of chronic liver disease showed persistence of HBsAg and HBeAg. Vertical transmission studies of hepatitis B virus infection from mother to newborns, showed that mothers whose sera were positive for both HBsAg and HBeAg resulted in a greater incidence of transmission of hepatitis B virus to their offspring than mothers whose sera were HBsAg positive but HBeAg negative.

Prevalence of type B and non-A, non-B hepatitis in hemophilia: Relationship to chronic liver disease

To assess the relationship of liver dysfunction and hepatitis markers in hemophilic patients treated with factor VIII or IX concentrates, we studied 103 patients with hemophilia A and B for 6–36 mo. Elevated serum alanine aminotransferase was noted in 79% of the patients, with 51% of the patients showing persistent elevation for longer than 6 mo. Thirteen patients (12%) were HBsAg-positive, with 8 patients showing persistence of HBsAg and abnormal serum alanine aminotransferase for more than 6 mo. Overall, anti-HBs was detected in 77% of patients. Twelve episodes of acute hepatitis were documented in 10 patients during 36 mo. Six episodes were due to hepatitis B virus. The remaining 6 episodes were due to non-A, non-B hepatitis with negative HBsAg and absence of seroconversion to hepatitis B virus, hepatitis A virus, cytomegalovirus, and Epstein-Barr virus. In the six episodes of non-A, non-B hepatitis, the incubation period was less than 10 days in 3 patients and 30 days in 2 patients. In all cases with non-A, non-B hepatitis, the illness was symptomatic, but mild. Serum alanine aminotransferase returned to normal within 4 mo in 2 patients, but in 3 patients serum alanine aminotransferase persisted longer than 6 mo. One patient developed an acute B hepatitis 40 wk after non-A, non-B hepatitis. Thus, infection with the hepatitis B virus still remains prevalent as a cause of acute hepatitis in hemophiliacs receiving commercial factor concentrates, and accounts for chronic liver dysfunction in patients with persistent HBs antigenemia. In addition, acute non-A, non-B hepatitis appears to be relatively common in hemophiliacs, and non-A, non-B virus may account for many cases of persistent liver dysfunction in these patients.

“Triple infections” (fungal, bacterial and viral) in immunosuppressed renal transplant recipients

In a period of 5 years, 8 out of 77 renal transplant patients showed simultaneous fungal, bacterial and viral infections. Candida albicans was found in all cases. The most severe bacterial complications were infections with Klebsiella, Pseudomonas and Staphylococcus aureus. Cytomegalovirus, persistent HBsAg positive hepatitis, herpes zoster, and herpes simplex infections were also found. Seven patients died of bacterial superinfection and miliary tuberculosis. The data presented show that "triple infections" are associated with high mortality and that miliary tuberculosis occurred frequently in immunosuppressed renal transplant recipients.

Determination of HBeAg by Radioimmunoassay: Prognostic Implications in Hepatitis B

A radioimmunoassay was used to determine the presence of the hepatitis B e antigen (HBeAg) and anti-HBe in the serum of 12 hepatitis B patients, who were follofed from an early phase of the illness into convalescence. The duration of detectable HBeAg in serum from these patients, in all ow whom the disease ran a normal course, was compared with the persistence of HBeAg in serum of nine patients with a protracted course and persistence of HBsAg in serum for more than 1 year. None of the hepatitis B patients with a normal course of the disease had HBeAg demonstrable for more than 9 weeks after the onset of illness (mean 5.4 weeks), whereas all patients developing chronic hepatitis had HBeAg in serum for more than 1 year after the onset of illness. These findings indicate that the detection of HBeAg in serum by radioimmunoassay for 10 weeks or more after the onset of illness implies a great risk of progression of the hepatitis B infection to chronic liver disease.

Hepatitis B in hemodialysis patients: Significance of HBeAg

Twenty-four HBsAg-positive (HBsAg+) hemodialysis patients were prospectively studied to assess (1) the prognostic value of HBeAg and its HBe1Ag and HBe2Ag components and (2) whether a difference in cellular immune status between HBeAg+ and HBeAg-negative (HBeAg−) patients could be defined. Sixteen patients were HBeAg+ and 8 were HBeAg− initially. After a mean follow-up period of 23.7 months, it was concluded that the initial presence of HBeAg correlated with the persistence of HBsAg because 15 of the 16 HBeAg+ patients were still HBsAg+ at death or last follow-up, whereas 7 of the 8 HBeAg− patients had become HBsAg− at a mean period of 3.8 months. HBe1Ag was consistently present in 15 of the 16 patients when HBeAg was detectable, whereas HBe2Ag fluctuated widely in individual patients over time. No difference in cellular immune status between HBeAg+ and HBeAg− patients could be defined; although both HBeAg+ and HBeAg− patients had a similar decrease in peripheral blood T cells and poor responsiveness to purified HBsAg, both groups of patients had stimulation indices to nonspecific mitogens within the normal range.

ANTIGEN IN CHILDREN UNDERGOING DIALYSIS AND TRANS-PLANTATION: A SERIAL STUDY

Between June 1970 and July 1976, all patients entering the Dialysis and Transplantation Program were tested serially for hepatitis B surface antigen (HBsag). 36 patients became HBsag positive (+). e antigen (e) testing was performed by rheophoresis on sera at the time of : 1) initial HBsag + (only 29 sera available); 2) highest HBsag titre; 3) highest transaminase enzyme abnormalities; 4) the latest HBsag + sera. Of 36 patients, 28 (75%) had at least one e+ serum. e+ sera were found in 41% of patients at initial HBsag titre; in 68% coincident with the highest HBsag titre; in 62% coincident with the highest transaminase levels; and in 72% at their most recent determination. Of 12 patients identified as e+ at initial HBsag testing, 8 remained e+ and 2 were intermittently e+. Of 17, initially e negative (-), 10 became consistently e+, 4 remained e- and 3 became intermittently e+. 31 patients were persistently HBsag + for 4 to 51 months; 28 were e+ at least once. None of the 5 patients transiently HBsag + were e+ (P<0.0001). Mean transaminase values at the time of each e determination were not significantly different when e+ and e- serums were compared. The data indicate that persistence of HBsag correlates with the presence of e in children undergoing dialysis and transplantation; hepatic enzyme abnormalities are not similarly correlated. Conversion to e+ often occurs after e- and may account for persistent transmissability of HBsag noted in these patients.

Histocompatibility-(HLA) antigens in patients with HBsAg positive and negative hepatitis and healthy carriers of HBsAg and anti-HBs. (author's transl)

New own data and a survey of published data concerning the frequencies of 23 HLA antigens in patients with HBsAg positive and negative chronic active hepatitis (CAH) and healthy carriers of Hepatitis-surface antigen (HBsAg) and high titers of antibodies to HBaAg (Anti-HBs) allow to conclude as follows: 1. Patients with CAH and persistence of HBsAg show a normal frequency of HLA-B8. 2. There is no increased frequency of HLA-B8 in HBsAg negative CAH without autoimmune antibodies. 3. Only in patients with HBsAg negative CAH with autoimmune antibodies is the frequency of HLA-B8 is statistically significantly increased (p less than 0.01 after correction for the number of antigens and different groups of patients compared). These are patients with the autoimmune form of CAH. 4. There exist no significant differences in the frequencies of the HLA antigens tested in patients with HBsAg positive CAH and healthy carriers of HBsAg and Anti-HBs. Thus no indications could be found for HLA-associated factors in the different behaviour to the hepatitis-B virus.

The long-term outcome of hepatitis B.

Among 466 hospitalized patients with serologically verified acute hepatitis B, 440 individuals (94.4%) could be followed up until normalization of liver function had occured, or for at least one year. In 90.2% of the patients followed-up liver function including galactose tolerance) returned to normal within four months after onset of illness. Chronic persistent hepatitis B surface antigen (HB Ag) for at least one year in 14 patients (50%). Liver biopsy was performed in consistent with CPH in all cases. Histological signs of chronic aggressive hepatitis developed in 15 patients (3.4%) and persistence of HB Ag was observed in 11 of these patients (73%). No histological follow-up was performed in patients with normal liver function within four months after onset of illness. Cprticosteroid treatment in 56 patients with prolonged symptoms did not seem to predispose to persistence of HbsaG in the serum.

Susceptibility to persistence of Australia antigen

To test the hypothesis that liver function is different in populations with inherited susceptibility to persistent Australia antigen (hepatitis B surface antigen [HBsAg]), Sardinians living in Turin, Italy, were compared with their native Turinese neighbors. The study was controlled for age, sex, place of birth, and presence or absence of persistent HBsAg. Slight differences in liver function were found in the Sardinians compared with the Turinese. Their values were in the direction of abnormality. Sardinians also had considerably higher serum gamma-globulin levels than the Turinese. The levels of alpha2-globulin by electrophoresis correlated with the presence of HBsAg.