Serum hepatitis B surface antigen (HBsAg) kinetics in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B

Background

We investigated the differences in HBsAg kinetics at different levels of viremia in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB).

Methods

We compared HBsAg levels among HBeAg-negative CHB patients with persistently undetectable HBV DNA (≤20 IU/mL; Group A, n = 100), HBV DNA 20–2,000 IU/mL (Group B, n = 100), and HBV DNA >2,000 IU/mL (Group C, n = 100). HBsAg and HBV DNA levels were measured at three consecutive time points during follow-up (median 21.4 months).

Results

Median HBsAg levels were significantly lower in Group A than in Groups B and C at all time points (p < 0.001). HBV DNA and HBsAg levels were weakly correlated (r = 0.180 and 0.151 for Groups B and C, respectively). Among patients with HBsAg <100 IU/mL, Group A patients had the greatest median serum HBsAg reduction (0.341 log IU/mL/year; Group B, 0.122 log IU/mL/year; Group C, 0.057 log IU/mL/year; p = 0.002). Among Group A patients with HBsAg <100 IU/mL, baseline HBsAg achieved an AUROC of 0.876 in predicting >1 log annual HBsAg reduction; 10–100 IU/mL HBsAg was the optimal level for prediction (sensitivity 90 %; specificity 74.6 %). Serum HBsAg/HBV DNA ratios were significantly higher in Group B than in Groups A and C (p < 0.05).

Conclusions

HBV DNA and HBsAg were weakly correlated. Only patients with undetectable HBV DNA showed decline in HBsAg levels during follow-up. The greatest reduction in HBsAg levels occurred in patients with baseline HBsAg <100 IU/mL.     

Etiology of hepatitis B surface antigen (HBsAg)-negative chronic hepatitis.

A study was undertaken to elucidate the etiology of HBsAg-negative chronic hepatitis. Form 37 individuals with HBsAg-negative chronic hepatitis, 11 had liver membrane autoantibody (LMA) and were thus classified as autoimmune. 6 patients had anti-HBc, 1 of which was also positive for LMA. The majority of individuals with HBsAg-negative chronic hepatitis had antibodies to hepatitis A antigen (anti-HAV), in general at low titer. We conclude from our data that hepatitis A and hepatitis B virus infections are unlikely to play a significant role in inducing or maintaining HBs-Ag-negative chronic hepatitis. The etiological role of non-A non-B hepatitis agent(s) is difficult to estimate and must await the detection of appropriate markers for type non-A non-B hepatitis.     

Effects of vancomycin on platelets, plasma proteins and hepatitis B surface antigen.

The antibiotic vancomycin shares many similarities with ristocetin, an agent noted for its effects on platelets and plasma fibrinogen. Vancomycin did not aggregate platelets as ristocetin, but platelets were incorporated into precipitates induced by vancomycin. Fibrinogen and factor VIII were precipitated from plasma at low concentrations of vancomycin. The precipitated fibrinogen remained clottable. Hepatitis B surface antigen was selectively precipitated from serum and could be recovered from the precipitate. Rabbits receiving bolus intravenous injections of high doses of vancomycin developed hypofibrinogenemia and thrombocytopenia within minutes and often went on to die. Studies with 125I-vancomycin revealed little stable binding of the antibiotic to platelets or fibrinogen. A relationship is suggested between the potent protein precipitating effects and phlebitis at the infusion site commonly associated with vancomycin therapy.     

Chronic carriers of hepatitis B antigen (HBsAg)

Among 289 HBsAg carriers detected by the Montreal Red Cross Blood Transfusion Service and seen by our group, 31 submitted voluntarily to liver biopsy. These 31 carriers have now been followed for 10–33 months (mean: 23) and all remained positive for HBsAg. 15 of these 31 subjects had lived in institutions during infancy or childhood and none were drug users. Histological examinations revealed 24 cases of chronic persistent hepatitis (CPH), 2 cases of chronic aggressive hepatitis, 2 with steatosis, and 3 with normall liver. On repeated determination, 16 of the 31 subjects had at least one elevated transaminase level. Transaminases levels could not be correlated with the histological diagnosis. 4 cases had positive antinuclear antibodies, all in the CPH group, a finding that could not be correlated with any clinical, biological, or histological findings. The search for other autoantibodies and the immunoglobulin determinations were totally unrewarding. Thus, it appears that chronic HBsAg carriers in Montreal voluntary blood donors often have chronic hepatitis, usually persistent, occasionally aggressive; liver biopsy still remains the most useful approach in the evaluation of these HBsAg carriers. The HBsAg-carrier state seems to be well tolerated, but further long-term studies are needed to understand the natural history of this condition.     

Association of hepatitis Be antigen (HBeAg) with the core of the hepatitis B virus (HBcAg)

Three substances (pronase E, sodium dodecylsulfate (SDS) and guanidine hydrochloride) with different chemical actions partially convert HBcAg to HBeAg. This process retains the integrity of the HBcAg particle, which was not different between HBcAg subpopulations, and does not generate HBcAg or HBeAg sub-units. DNA polymerase activity was destroyed by SDS and guanidine hydrochloride, but not by pronase E. Serum HBeAg could not be converted into HBcAg, suggesting that this might be an irreversible process. The data are consistent with the assumption that HBcAg and HBeAg are coded for by the same gene (C gene of the HBV-DNA).     

delta Agent: association of delta antigen with hepatitis B surface antigen and RNA in serum of delta-infected chimpanzees.

The hepatitis B virus-associated beta antigen was found in the serum of experimentally infected chimpanzee as an internal component of a discrete subpopulation of hepatitis B surface antigen (HBsAg) particles. The 35- to 37-nm particles banded in CsCl at 1.24-1.25 g/cm3 and sedimented with a mobility intermediate between that of the hepatitis B virion and that of the 22-nm form of HBsAg. The particles contained only indistinct internal structure by electron microscopy and were not unique to delta agent infection, similar particles without delta-antigen activity being observed in the preinfection serum of HBsAg carrier chimpanzees. A small RNA (Mr, 5 X 10(5)) was temporally associated with delta antigen in the serum of infected chimpanzees and copurified with the delta-antigen-associated particles. This RNA is smaller than the genomes of known RNA viruses but larger than the viroids of higher plants.     

Hepatitis B surface antigen (Australia antigen) in mosquitoes collected in Senegal, West Africa.

During July and August of 1973, 9,198 mosquitoes were collected in the Republic of Senegal. Eight species of mosquitoes were found in the collections: Culex thalassius, Culex pipiens quinquefasciatus, Culex trigripes, Culex phillipi, Aedes irritans, Aedes aegypti, Anopheles gambiae, and Mansonia sp. Specimens were sorted by biological condition; those obviously engorged were designated as (E), females with swollen abdomens not conspicuously blooded were considered gravid (G), and those with normal or shrunken abdomens were considered neither blooded nor gravid (U). Representative samples of each species were tested by solid phase radioimmunoassay for hepatitis B surface antigen (HBSAg, Australia antigen). A total of 12 mosquitoes were found to be HBSAg positive out of 1,658 individuals tested. These were: 9 Culex thalassius, 1 (E), 5 (G), 3 (U); 2 Culex pipiens quinquefasciatus, 1 (E), 1 (U); and Aedes irritans, 1 (U).     

Differential distribution of hepatitis B surface antigen and hepatitis B core antigen in the liver of hepatitis B patients.

One hundred liver biopsies from 100 patients with clinical presumptive diagnosis of hepatitis were examined by immunofluorescence for the presence of hepatitis B surface antigen (HBSAg) and hepatitis B core antigen (HBcAg). Of the 60 HBsAg-positive livers, 51 were diagnosed as chronic hepatitis on histological grounds, 6 as acute hepatitis, and 3 as "near-normal liver." From the 60 tissue-positive cases, 3 subjects were HBsAg seronegative. HBcAg was detected in 44 livers, all of which also had HBcAg in the localized in the cytoplasm and the membranes of the hepatocytes, and HBcAg in the nuclei and in 4 cases also in the cytoplasm. Predominant HBsAg expression in the cytoplasm was observed in near-normal liver, chronic persistent hepatitis, and cirrhosis with little activity. This correlated with the amount of ground glass hepatocytes in the biopsies. HBcAg and membrane-localized HBsAg were minimal in those conditions. HBcAg was most prevalent in patients with chronic aggressive hepatitis and active cirrhosis treated with immunosuppressive drugs, whereas the amounts of HBsAg and HBcAg in nontreated patients of those two groups and in acute hepatitis with signs of transition to chronicity were almost equal. HBsAg expression in liver cell membranes was most prominent in active forms of chronic hepatitis (chronic aggressive hepatitis and in active cirrhosis) and in acute hepatitis with signs of transition to chronicity. This observation correlated in the presence of HBcAg in the biopsies of those patients. In acute hepatitis both HBsAg and HBcAg were detected rarely and no membrane expression of HBsAg was observed. The over-all results show a significant relationship between the different degrees of accumulation of HBsAg and HBcAg in the liver and the various histological types of hepatitis and further suggest an interplay of both hepatitis B virus and host immune response in the development and pathogenesis of hepatitis B.     

Exploration of nucleos(t)ide analogs cessation in chronic hepatitis B patients with hepatitis B e antigen loss

BACKGROUNDNucleos(t)ide analogs (NAs) cessation in chronic hepatitis B (CHB) patients remains a matter of debate in clinical practice. Current guidelines recommend that patients with hepatitis B e antigen (HBeAg) seroconversion discontinue NAs after relatively long-term consolidation therapy. However, many patients fail to achieve HBeAg seroconversion after the long-term loss of HBeAg, even if hepatitis B surface antigen (HBsAg) loss occurs. It remains unclear whether NAs can be discontinued in this subset of patients.AIMTo investigate the outcomes and factors associated with HBeAg-positive CHB patients with HBeAg loss (without hepatitis B e antibody) after cessation of NAs.METHODSWe studied patients who discontinued NAs after achieving HBeAg loss. The Cox proportional hazards model was used to identify predictors for virological relapse after cessation of NAs. The cut-off value of the consolidation period was confirmed using receiver operating characteristic curves; we confirmed the cut-off value of HBsAg according to a previous study. The log-rank test was used to compare cumulative relapse rates among groups. We also studied patients with CHB who achieved HBeAg seroconversion and compared their cumulative relapse rates. Propensity score matching analysis (PSM) was used to balance baseline characteristics between the groups.RESULTSWe included 83 patients with HBeAg loss. The mean age of these patients was 32.1 ± 9.5 years, and the majority was male (67.5%). Thirty-eight patients relapsed, and the cumulative relapse rate at months 3, 6, 12, 24, 36, 60, 120, and 180 were 22.9%, 36.1%, 41.0%, 43.5%, 45.0%, 45.0%, 45.0%, and 52.8%, respectively. Twenty-six (68.4%) patients relapsed in the first 3 mo after NAs cessation, and 35 patients (92.1%) relapsed in the first year after NAs cessation. Consolidation period (≥ 24 mo vs < 24 mo) (HR 0.506, P = 0.043) and HBsAg at cessation (≥ 100 IU/mL vs < 100 IU/mL) (HR 14.869, P = 0.008) were significant predictors in multivariate Cox regression. In the PSM cohort, which included 144 patients, there were lower cumulative relapse rates in patients with HBeAg seroconversion (P = 0.036).CONCLUSIONHBeAg-positive CHB patients with HBeAg loss may be able to discontinue NAs therapy after long-term consolidation, especially in patients with HBsAg at cessation < 100 IU/mL. Careful monitoring, especially in the early stages after cessation, may ensure a favorable outcome.     

Fulminant hepatitis in infants in Taiwan: Strong association with hepatitis B e antigen-negative but antibody-positive maternal hepatitis B surface antigen carriage

This study examined the virologic profiles and pathologic features in 10 infants with fulminant hepatitis and aged 2–7 months. Nine male infants were related to hepatitis B virus infection: as evidenced by positive anti-HBc IgM (4 cases); positive serum HBsAg, and/or liver HBcAg (4 cases); or born to an HBsAg carrier mother (1 case). Only one female infant had presumed non-A non-B fulminant hepatitis, but none had hepatitis A. The mothers of eight infants with HBV-ralated fulminant hepatitis were all positive for serum HBsAg, and most (5/6) were negative for HBeAg but positive for anti-HBe. These findings suggest that infants born to HBsAg carrier mothers, particularly those who are negative for HBeAg, may contract fulminant hepatitis B in infancy in Taiwan. Six infants studied had massive hepatic necrosis and all died, whereas four had submassive or bridging hepatic necrosis and all survived, suggesting a close correlation between the extent of liver necrosis and the patient's outcome. None of the infants had hepatocyte HBsAg, although four had cytoplasmic HBcAg. Anti-HBc IgM was commonly detected (4/6), in sharp contrast to the constant negativity in infants who had contracted an asymptomatic HBV infection. These findings suggest that cytoplasmic HBcAg and anti-HBc IgM may be related to the occurrence of severe liver disease.     

Viral factors correlate with hepatitis B e antigen seroconverson in patients with chronic hepatitis B.

BACKGROUND/AIMS: Seroconversion (SC) from hepatitis B envelope antigen (HBeAg) to anti-HBe usually indicates lower viral loads, resolved hepatitis activity and improved long-term outcomes. However, the role of viral factors in the development of SC remains largely unknown. We thus comprehensively studied these factors in 25 patients with sustained HBeAg SC and seven control patients with sustained loss of HBeAg. METHODS: We determined viral factors in serum samples obtained 1 year before, 6 months before, 3 months before, at the time of, 6 months after and 1 year after HBeAg SC or HBeAg loss. Precore A1896 and basal core promoter T1762/A1764 mutants were determined by polymerase chain reaction (PCR)-based assays. Serum HBV levels were determined by a real-time PCR assay. RESULTS: We found that decline of serum viral load, frequently accompanied by hepatitis exacerbation, occurred within 1 year before HBeAg SC. The proportions of precore and BCP mutations also increased gradually throughout the process of HBeAg SC. The virologic features were similar between HBeAg SC group and HBeAg loss group. Before HBeAg SC or loss, genotype B patients had higher serum viral loads and lower proportions of BCP mutation compared with genotype C patients. CONCLUSION: Our findings suggested that viral factors correlate with the development of sustained HBeAg SC or loss.