HBsAg Seronegative Patients Research Articles

Occult infection with hepatitis B virus PreS variants synergistically promotes hepatocellular carcinoma development in a high-fat diet context by generating abnormal ceramides

BackgroundSome occult hepatitis B virus (HBV) infections are resulted from PreS mutations that reduce secretion of envelope protein (HBsAg). We investigated the ceramide amounts and species in hepatocytes infected with PreS variants that were isolated from HBsAg-seronegative patients with hepatocellular carcinoma (HCC) and the ceramide effects on autochthonous HCC development in murine models.MethodsHBV PreS/S regions from 35 HBsAg-seronegative HCC patients were sequenced. Hepatocyte cell lines and male C57BL/6J mouse livers were transfected with two PreS variant representatives. The ceramides with variated lengths of fatty acyl chains were quantified. Tumour development was examined in the HBV-transfected mice fed different diet types.ResultsIn HBsAg-seronegative HCC patients, nonneoplastic liver tissues harboured HBsAg and replication-competent HBV. The most frequently detected PreS/S variants carried mutations of altered amino acid properties in HBsAg compared with an isolate from one HBsAg-seronegative HCC patient. Hepatocyte infection with PreS variants caused HBsAg retention within the endoplasmic reticulum and generated more amounts of ceramides with C16:0 ceramide elevated the highest. Saturated fatty acids aggravated the PreS variant-infected hepatocytes to generate abnormal amounts and species of ceramides, which with HBV proteins synergistically activated NLRP3 inflammasome in liver inflammatory macrophages. Liver tumours were only detected in HBV-transfected mice fed high-fat diet, with higher tumour loads in the PreS variant-transfected, associated with abnormal ceramide generation.ConclusionsHBV PreS mutations which altered amino acid properties of envelope proteins inhibited HBsAg secretion. Hepatocyte infection with PreS variants generated abnormal ceramides which with HBV proteins coactivated NLRP3 inflammasome in liver macrophages to promote autochthonous HCC development.

Chronic hepatitis B virus infection is associated with a poorer prognosis in diffuse large B-cell lymphoma: a meta-analysis and systemic review.

Accumulating evidence from clinical trials indicates chronic hepatitis B virus (HBV) infection is associated with the incidence of diffuse large B-cell lymphoma (DLBCL) and may be associated with the prognosis of DLBCL, though this suggestion remains controversial. We performed a meta-analysis to assess whether HBV infection is associated with prognosis and response to chemotherapy in DLBCL. After a strict literature search strategy, a total of 809 HBV surface antigen (HBsAg) seropositive patients with DLBCL and 2849 HBsAg seronegative patients with DLBCL from twelve trials were included. DLBCL patients with chronic HBV infection had significantly poorer 2- and 5-year overall survival (OS) (HR 1.54, 95% CI 1.23-1.92, P<0.001 and 1.79, 1.48-2.17, P<0.001) and 2- and 5-year progression-free survival (PFS) (HR 1.44, 95% CI 1.14-1.81, P=0.002 and HR 1.34, 95% CI 1.02-1.75, P=0.03). HBsAg-seronegative patients also had a lower complete response (CR) rate (OR 0.48, 95% CI 0.34-0.68, P<0.001), higher progressive disease (PD) rate (OR 2.08, 95% CI 1.34-3.24, P=0.001), and more advanced clinical features. This meta-analysis indicates HBV infection leads to a poorer prognosis and poorer response to standard chemotherapy.

Concurrent and reactivation of hepatitis B virus infection in diffuse large B-cell lymphoma: risk factors and survival outcome

ObjectiveTo determine the clinical features and survival difference of HBV related and Non-HBV related diffuse large B-cell lymphoma (DLBCL) and to evaluate the occurrence of HBV reactivation in DLBCL patients and related risk factors for HBV reactivation after R-CHOP therapy.MethodsA total of 246 patients diagnosed with CD20+ DLBCL were enrolled from June 2010 to June 2015. The medical records and survival data were analysed. Multivariate logistic regression analysis was used to identify predictors of HBV reactivation. Survival curves were performed by the Kaplan–Meier method.ResultsAmong patients enrolled, 80 patients were HBsAg sero-positive and 166 patients were HBsAg sero-negative. Findings showed that HBsAg sero-negative patients were significantly older than that of patients with HBsAg sero-positive (P < 0.001). Proportion of B symptom positive patients in HBsAg sero-positive were higher (p = 0.002). Higher LDH level (P = 0.019) and late Ann Arbor stage (P = 0.010) were more often observed in patients with HBsAg sero-positive. The rate of complete response, partial response, stable disease and progress disease in HBsAg sero-negative group were 63.9, 16.9, 1.1 and 18.1%, respective, which is significantly higher than that in HBsAg sero-positive group (36.2, 18.8, 1.2 and 43.8%). Kaplan-Meier analysis showed that DLBCL patients with HBsAg sero-negative had better prognosis. In total, 17 patients showed HBV reactivation among 166 patients (10.2%) with HBsAg sero-negative after R-CHOP treatment, while a significant higher HBV reactivation 18.75% (9/48) in HBsAb negative group were observed, with 8.25% (8/97) patients in HBsAb level 10–100 U/mL group, and 0% patients in HBsAb level higher than 100 U/mL group. Multivariable analysis showed that serum HBsAb and serum HBcAb were independent risk factors for HBV reactivation in DLBCL patients.ConclusionOur data revealed that characteristics and prognosis were significantly different between HBV related DLBCL than non-HBV related DLBCL patients. DLBCL patients with resolved hepatitis B are at a higher risk of developing HBV reactivation after R-CHOP chemotherapy compared with HBsAg-negative/HBcAb negative patients.

Viral immunochemical status of HBeAg, HBeAb, Anti-HIV, and Anti-HCV in hepatitis B surface antigen-seronegative anicteric malaise patients

Introduction: Malaise involves general discomfort, uneasiness, or pain which could indicate microbial infection or other diseases which could be as a result of immune response. Methods: The study population was 200 malaise anicteric hepatitis B surface antigen (HBsAg)-seronegative patients (females – 100; males – 100) aged 5–76, and 111 apparently healthy anicteric nonmalaise age-matched subjects who were HBsAg-seronegative (females – 56 and males – 55) were recruited as test and control subjects, respectively. Immunochemical assay of anti-HBe, anti-HCV, HBsAg, and HBeAg was carried out in all the participants by enzyme-linked immunosorbent assay, while anti-HIV was determined in the participants by immunochromatographic and Western blot assay. Results: The results obtained in HBsAg-seronegative anicteric malaise patients revealed the frequency of occurrence of 3% (6) HBeAg; 9.5% (19) HBeAb; 3.5% (7) anti-HIV; 6.5% (13) anti-HCV; 1% (2) anti-HIV + HBeAg; 0.5% (1) anti-HIV + HBeAb; 0.5% (1) anti-HIV + anti-HCV; and 0.5% (1) anti-HIV + anti-HCV + HBeAg, with 9.5% (19) HBeAb found to be most frequent followed by 6.5% (13) anti-HCV; 3.5% (7) anti-HIV and 3% (6) HBeAg were more in female than male. About 25% (50/200) malaise HBsAg-seronegative patients expressed at least one of the HIV, HCV, and HBV serologic markers compared with 9.9% (11/111) in the control subjects. There was a low frequency of coexpression of viral biomarkers (0.5%–1%). Conclusion: Malaise in HBsAg-seronegative patients could be associated with the expression of serologic biomarkers of HCV, HIV, and HBV.

THU0291 Forward to Good Practice in Vaccination against Hepatitis B in Rheumatic Patients with Biological Therapies

BackgroundThe increasingly frequent use of biologic agents in rheumatic diseases implies the existence of a large number of patients at risk of reactivation of hepatitis B virus (HBV). Rheumatic patients...

Association of CYP1A2 genetic polymorphisms with hepatocellular carcinoma susceptibility: a case–control study in a high-risk region of China

Aflatoxin B1 exposure is one of the major risk factors for hepatocellular carcinoma (HCC). CYP1A2 is a cytochrome P450 isoenzyme that plays an important role in the bioactivation of AFB1 to its carcinogenic metabolite. The study was designed to assess whether genetic polymorphisms in CYP1A2 are associated with HCC susceptibility in a high-risk region. A case-control study of 431 HCC cases and 550 cancer-free controls recruited from an HCC endemic region in China was carried out. Three single nucleotide polymorphisms, namely -3860G > A (CYP1A2*1C), -3113G > A, and 5347T > C (CYP1A2*1B) were genotyped by polymerase chain reaction-restriction fragment length polymorphism methods. Homozygous carriers of the major haplotype -3860G/-3113G/5347C were associated with increased HCC susceptibility in the overall population (odds ratio [OR] = 1.65, 95% confidence interval [CI]: 1.11-2.46, P = 0.014), in HBsAg seronegative individuals (OR = 2.69, 95% CI: 1.43-5.06, P = 0.002), and in heavy smokers (OR = 2.14, 95% CI: 1.21-3.80, P=0.009). In addition, individuals carrying at least one CYP1A2*1C allele showed significantly decreased HCC risk (OR = 0.49, 95% CI: Q0.27-0.86, P = 0.013) in the HBsAg seronegative subpopulation. Furthermore, as compared with HBsAg seropositive patients, wild-type homozygotes of the CYP1A2*1C polymorphism were significantly over-represented in HBsAg seronegative patients (P = 0.024). No significant association between CYP1A2 genetic polymorphisms and HCC risk was observed in either HBsAg seropositive individuals or non-smokers. CYP1A2 genetic polymorphisms are associated with HCC susceptibility in smokers and HBsAg seronegative individuals in the Fusui endemic region.

Identification of hepatitis B virus integration in hepatitis C virus-infected hepatocellular carcinoma tissues

Background/Aims: The integration of HBV DNA is thought to be involved in the initial stage of hepatocarcinogenesis, and it has been reported that transactivating factors encoded by the X and preS2/S genes stimulate transcription of multiple viral and cellular genes. We assessed the possible contributions of hepatitis B virus integration to the occurrence of hepatocellular carcinoma in hepatitis C virus-infected as well as in hepatitis B virus-infected patients by identifying the integrated HBV DNA sequence, and the X and preS2/S regions were further investigated in HBV DNA-integrated cases. Methods: Southern blot hybridization for detecting HBV DNA in tumor tissues from 28 hepatocellular carcinoma patients was carried out with full-length HBV DNA, and then with X and preS2/S regions as probes. We also carried out reverse transcription-polymerase chain reaction for detecting HCV RNA to confirm hepatitis C virus-infection in liver tissues. Results: Clonally integrated HBV DNA sequences were demonstrated in 16 of 28 patients (57.1%), including five HBsAg seropositive and 11 HBsAg sero-negative patients. Of these 11 HBsAg seronegative patients, 10 were also positive for anti-HCV in their sera, and all nine examined cases had HCV RNA in liver. Furthermore, the X region was identified in 14 of 16 HBV DNA integrated cases (87.5%), and the preS2/S region in 6 16 (37.5%). Conclusions: The present Southern blot analysis demonstrates that clonally integrated HBV DNA sequences were identified even in hepatitis C virus-infected hepatocellular carcinoma patients at a high rate ( 10 18 , 55.6%), and suggests that integrated hepatitis B virus, whose major component is the X gene, may play an important role in hepatocarcinogenesis in hepatitis B virus-integrated cases with and without hepatitis C virus infection.

Detection of Hepatitis B Virus DNA Sequences in Liver in HBsAg Seronegative Patients with Liver Disease with and without Anti-HBc Antibodies&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/xref&gt;

Excluding studies from Brechot and co-workers, little support has been found for a role of the hepatitis B virus in the pathogenesis of HBsAg seronegative patients with predominantly chronic liver diseases, including primary liver cancer. In this study liver DNA from 59 predominantly British patients (four cases with paired biopsies, 6-12 months apart) with different, mostly chronic, liver diseases was analysed by molecular hybridization. All were seronegative for HBsAg and serum hepatitis B virus DNA (dot blot hybridization) and their liver diseases were believed to be unrelated to hepatitis B virus infection. Hepatitis B virus DNA was detected in liver of 11 (18.6 per cent) patients; nine had episomal (3.2 Kb) DNA and eight had higher molecular weight bands suggesting integrated forms. Six patients were also seronegative for anti-HBc. Patients of UK and non-UK origin were equally represented. Hepatitis B virus DNA was detected in serum of six of nine patients tested using the polymerase chain reaction. The detection of hepatitis B virus DNA in liver and in serum by this assay in a significant proportion of patients with chronic liver disease, hitherto unsuspected of being hepatitis B virus-related, suggests a possible role for this virus in low- as well as high-prevalence countries.

Polymerase chain reaction for detection of hepatitis B virus DNA in HBsAg seronegative patients with hepatocellular carcinoma from Mozambique.

(1991). Polymerase chain reaction for detection of hepatitis B virus DNA in HBsAg seronegative patients with hepatocellular carcinoma from Mozambique. Annals of Tropical Medicine & Parasitology: Vol. 85, No. 2, pp. 277-279.

Identification and characterization of intrahepatic hepatitis b virus dna in hbsag-seronegative patients with chronic liver disease and hepatocellular carcinoma in Taiwan

To clarify the role of hepatitis B virus infection in HBsAg-seronegative patients with chronic liver disease and hepatocellular carcinoma in Taiwan, we examined the hepatitis B virus DNA in liver biopsy tissues of 112 patients by Southern blot analysis. The patients studied included 43 patients with nonalcoholic chronic liver disease, 21 patients with hepatocellular carcinoma and 48 control patients with other hepatobiliary and gastrointestinal diseases. To confirm the specificity of the intrahepatic hepatitis B virus DNA signal and to understand the structure of the integrated viral sequences, molecular cloning and DNA sequencing of an integrated hepatitis B virus DNA were done in one patient. Among 13 patients without serological evidence of previous hepatitis B virus infection, no hepatitis B virus sequences were found in the liver. In other HBsAg-negative patients with evidence of previous hepatitis B virus exposure, a substantial positive rate of intrahepatic hepatitis B virus DNA was found (7%). The intrahepatic hepatitis B virus DNA was all in integrated form. The positive rate among patients with nonalcoholic chronic hepatitis and cirrhosis (2%) was not different from that of the control group with other hepatobiliary and gastrointestinal diseases (4%). However, the positive rate of integrated hepatitis B virus DNA between hepatocellular carcinoma patients and nonhepatocellular carcinoma patients was statistically significant (19% vs. 3%, p less than 0.05). Molecular cloning and sequencing of a 3.0 kb EcoRI fragment of an integrated hepatitis B virus DNA from an anti-HBs-positive patient revealed that it was a partial copy of the hepatitis B virus genome.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies. to Hepatitis B Core Antigen in Hepatitis B Surface Antigen-Positive and -Negative Chronic Hepatitis

Antibody to hepatitis B core antigen (anti-HBc) is a sensitive indicator of hepatitis B virus (HBV) infection. However, anti-HBc has been found in only a few patients with chronic hepatitis. Therefore, we tested for anti-HBc in 124 sera from 67 patients with histologically proven chronic hepatitis by the indirect fluorescent antibody technique. All patients, except for one with chronic hepatitis who was seropositive for hepatitis B surface antigen (HBs Ag), had anti-HBc that persisted throughout the follow-up period (three months to three years). Of 33 HBs Ag-seronegative patients, anti-HBc was detected in seven patients and persisted for six months to two years. These findings suggest that in this study 21% of patients with chronic hepatitis with undetectable amounts of HBs Ag in the serum had evidence of recent or continued HBV replication.