Fulminant Hepatitis B Virus Infection Research Articles

Human genomics of acute liver failure due to hepatitis B virus infection: An exome sequencing study in liver transplant recipients.

Acute liver failure (ALF) or fulminant hepatitis is a rare, yet severe outcome of infection with hepatitis B virus (HBV) that carries a high mortality rate. The occurrence of a life-threatening condition upon infection with a prevalent virus in individuals without known risk factors is suggestive of pathogen-specific immune dysregulation. In the absence of established differences in HBV virulence, we hypothesized that ALF upon primary infection with HBV could be due to rare deleterious variants in the human genome. To search for such variants, we performed exome sequencing in 21 previously healthy adults who required liver transplantation upon fulminant HBV infection and 172 controls that were positive for anti-HBc and anti-HBs but had no clinical history of jaundice or liver disease. After a series of hypothesis-driven filtering steps, we searched for putatively pathogenic variants that were significantly associated with case-control status. We did not find any causal variant or gene, a result that does not support the hypothesis of a shared monogenic basis for human susceptibility to HBV-related ALF in adults. This study represents a first attempt at deciphering the human genetic contribution to the most severe clinical presentation of acute HBV infection in previously healthy individuals.

Pharmacological interventions for acute hepatitis B infection: an attempted network meta-analysis.

Pharmacological interventions for acute hepatitis B infection: an attempted network meta-analysis.

Genomic Diversity of Hepatitis B Virus Infection Associated With Fulminant Hepatitis B Development.

Context:After five decades of Hepatitis B Virus (HBV) vaccine discovery, HBV is still a major public health problem. Due to the high genetic diversity of HBV and selective pressure of the host immune system, intra-host evolution of this virus in different clinical manifestations is a hot topic of research. HBV infection causes a range of clinical manifestations from acute to chronic infection, cirrhosis and hepatocellular carcinoma. Among all forms of HBV infection manifestations, fulminant hepatitis B infection possesses the highest fatality rate. Almost 1% of the acutely infected patients develop fulminant hepatitis B, in which the mortality rate is around 70%.Evidence Acquisition:All published papers deposited in Genbank, on the topic of fulminant hepatitis were reviewed and their virological aspects were investigated. In this review, we highlight the genomic diversity of HBV reported from patients with fulminant HBV infection.Results:The most commonly detected diversities affect regulatory motifs of HBV in the core and S region, indicating that these alterations may convert the virus to an aggressive strain. Moreover, mutations at T-cell and B-cell epitopes located in pre-S1 and pre-S2 proteins may lead to an immune evasion of the virus, likely favoring a more severe clinical course of infection. Furthermore, point and frame shift mutations in the core region increase the viral replication of HBV and help virus to evade from immune system and guarantee its persistence.Conclusions:Fulminant hepatitis B is associated with distinct mutational patterns of HBV, underlining that genomic diversity of the virus is an important factor determining its pathogenicity.

Current Information Concerning Association of IL-12 and Hepatitis B Infection

Hepatitis B is one of the most prevalent infectious diseases and is induced by hepatitis B virus (HBV). The chronic, asymptomatic, and occult forms of hepatitis B are long-term infections that can lead to various hepatic cancers and cirrhosis in the carrier. IL-12 is one of the main cytokines involved in inducing appropriate immune responses against viral infections, especially HBV. Therefore, the aim of the present review was to address the most recent information within the database regarding the status and association between IL-12 and hepatitis B infection and its complications including cirrhosis and hepatocellular carcinoma. The data presented was collected by searching the following keywords in the Pubmed and Scopous databases: Hepatitis B, occult HBV infection, chronic HBV infection, asymptomathic HBV infection, acute HBV infection, fulminant HBV infection, IL-12, and all the papers regarding the relation between IL-12 and hepatitis B were used. These data were presented in the current review article. Results showed that IL-12 plays important roles in Hepatitis B infection and patients infected with the long-term form of hepatitis B are unable to produce sufficient amount of this cytokine. Our research provided mechanistic insights into the immunoprotective roles of IL-12 and proposed that it can be considered as an important molecule for immunotherapy of HBV infected infection.

Late HBsAg seroreversion of mutated hepatitis B virus after bone marrow transplantation

BackgroundAbout ninety percent of immunocompetent adults recover from hepatitis B virus (HBV) infection within 6 months after transmission. The infection is considered to be terminated if the antibodies (HBsAb) to the hepatitis B surface antigen (HBsAg) become detectable and the HBsAg and Hepatitis B virus DNA (HBV DNA,) are no longer perceptible. After recovery from an acute infection, the detection of HBsAb is assumed to indicate lifelong immunity. However, after initiation of severe immunosuppression, HBV reactivation, as detected by HBsAg seroreversion may be observed in patients with previously resolved HBV infections.Case presentationWe present an unusual case of a 64-year-old Caucasian woman showing clinically apparent HBV seroreversion more than 45 months after hematopoietic stem cell transplantation (HSCT). Despite living without immunosuppressive agents for more than 40 months, she developed a fulminant HBV infection with detection of a mutated hepatitis B virus carrying two immune escape mutations (D144E/G145R) in the HBsAg (HBsIE mutation).ConclusionAfter HSCT, the absence of risk factors such as strong immunosuppression and graft-versus-host disease decreases the risk of HBV seroreversion but may rearward seroreversion to a later time. Therefore, when monitoring HSCT, patients with serological markers of a resolved HBV infection [HBcAb + (hepatitis B core antibody), HBsAb+, and HBsAg−], the follow up has to be extended over several years to exclude HBV reactivation with HBsAg seroreversion. Furthermore, this case demonstrates the complexity of virus evolution after HBsAg seroreversion as a result of immunosuppression after HSCT.

Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience

Acute hepatitis B progresses to liver failure with the need of liver transplantation in about 1% of cases. We treated patients with severe acute or fulminant hepatitis B with lamivudine in an attempt to prevent hepatitis B virus (HBV) reinfection after potential liver transplantation. Since September 2000, 17 patients with severe acute or fulminant HBV infection were treated with 100 or 150 mg lamivudine daily once we had evidence for a severe course as indicated by an INR >2.0. These were compared to a historic control from our unit and to external patients. Fourteen of the 17 patients (82.4%) survived with full recovery without liver transplantation. All these 14 individuals cleared HBsAg on lamivudine within less than 6 months. Twelve patients recovered quickly as indicated by a normalized prothrombin time within 1 week while two patients had a more prolonged course. None of the patients showed an adverse event. Three patients requiring transplantation despite lamivudine therapy had more advanced disease on admission, of whom one had additionally ingested paracetamol (acetaminophen) while the second was already HBV-DNA negative by polymerase chain reaction on admission. The lamivudine treated patients had significant higher frequency of survival without liver transplantation 82.4 vs 20% (4/20) in the historic control (P < 0.001). Similar data were derived from external centres using lamivudine (15/20, 75%). Lamivudine is safe in patients with severe acute or fulminant hepatitis B, leading to fast recovery with the potential to prevent liver failure and liver transplantation when administered early enough.

Orthotopic liver transplantation in patients with hepatitis B-related liver disease

ACUTE AND CHRONIC liver disease related to hepatitis viruses are the main indications for orthotopic liver transplantation (OLT) worldwide. The outcome for patients liver-transplanted for hepatitis B virus (HBV) infection is tampered by the risk of reinfection. Patients with a chronic HBV disease who are positive for HBVDNA and/or HBeAg carry the highest risk of reinfection, whereas those with a hepatitis D virus infection superimposed upon chronic HBV infection or with an acute fulminant HBV infection have a better prognosis. If the patient at the time of transplantation has developed hepatocellular carcinoma (HCC), he or she also carries a risk of recurrence of the malignant disease. With the introduction of immunoprophylaxis and antiviral drugs the risk of reinfection has been reduced. Between 1985 and the end of 1999, 469 OLT have been performed in 425 patients in our institution. Twenty-two patients had HBV-related liver disease as the primary indication. The aim of this study was to review our results over a time period of 15 years.

Hepatitis B virus sequence changes evolving in liver transplant recipients with fulminant hepatitis

Background/Aims: Patients undergoing liver transplantation for hepatitis B virus (HBV) related liver cirrhosis are at major risk of developing HBV recurrence, and occasionally fulminant hepatitis. Here we tested in a longitudinal study whether specific viral variants are associated with fulminant HBV infection in the graft. Methods: The complete HBV genomes isolated from the sera of three patients with HBV and HBV and hepatitis delta virus (HDV) coinfection during chronic infection before and during fulminant reinfection after transplantation were amplified and directly sequenced. Results: Twenty, 25 and 19 mutations, distributed over the entire genome, were identified which differed between the HBV genomes isolated from each patient during chronic and fulminant infection, respectively. This reflects a much higher rate of nucleotide sequence changes than expected from the natural variation of HBV. No common HBV mutation emerged in any of the three cases during fulminant infection. However, precore defective viruses were found to be present in all three patients at the time of fulminant infection and in two of the patients before fulminant infection. Two of the patients had preS2-defective HBVs both before and after transplantation. A point mutation in the ‘a”-determinant of the surface protein emerged in one case after transplantation under treatment with polyclonal HBV specific immunoglobulins. Conclusions: Many new, but no specific common mutations emerged during fulminant HBV reinfection. Although HBeAg defective variants were found in all cases studied, the presence of these variants also during chronic infection in two cases demonstrates that they are not sufficient to cause fulminant hepatitis. Thus, other factors than the emergence of a specific viral strain seem to contribute to the development of fulminant reinfection in a liver graft.

Hepatitis B virus genomes of patients with fulminant hepatitis do not share a specific mutation

The pathogenesis of fulminant hepatitis B virus (HBV) infection is not well understood. The aim of this study was to investigate whether there is an association between specific viral variants and a fulminant disease course. The entire HBV genomes from the serum of eight patients with fulminant HBV infection and one patient with fulminant hepatitis during reinfection after liver transplantation were investigated. After isolation and amplification of viral DNA by polymerase chain reaction (PCR), plus and minus strands were directly sequenced. Sequence data were analyzed by comparative sequence alignments with 35 and 2 complete HBV genome sequences from patients without and with fulminant hepatitis, respectively. Several point mutations were present in all regions of the genomes. Many nucleotide changes had never or rarely been found in the reported HBV isolates from patients without fulminant hepatitis. A distinct mutation present in all genomes was not identified. Clusters of rare and unique mutations were observed in the enhancer II core promoter region. Mutations previously suggested to be associated with fulminant HBV infection were not consistently found. A precore stop codon mutation at nucleotide position 1896 or an A-to-T mutation at nucleotide position 1762 and a G-to-A mutation at nucleotide position 1764 in the core promoter region were present in four and three cases, respectively. Fulminant HBV infection does not appear to be caused by a specific genomic mutation. However, various mutations clustering in the enhancer II core promoter region may contribute to a fulminant disease course. (Hepatology 1996 Aug;24(2):300-6)

Hepatitis B Virus Genomes of Patients With Fulminant Hepatitis Do Not Share A Specific Mutation

The pathogenesis of fulminant hepatitis B virus (HBV) infection is not well understood. The aim of this study was to investigate whether there is an association between specific viral variants and a fulminant disease course. The entire HBV genomes from the serum of eight patients with fulminant HBV infection and one patient with fulminant hepatitis during reinfection after liver transplantation were investigated. After isolation and amplification of viral DNA by polymerase chain reaction (PCR), plus and minus strands were directly sequenced. Sequence data were analyzed by comparative sequence alignments with 35 and 2 complete HBV genome sequences from patients without and with fulminant hepatitis, respectively. Several point mutations were present in all regions of the genomes. Many nucleotide changes had never or rarely been found in the reported HBV isolates from patients without fulminant hepatitis. A distinct mutation present in all genomes was not identified. Clusters of rare and unique mutations were observed in the enhancer II core promoter region. Mutations previously suggested to be associated with fulminant HBV infection were not consistently found. A precore stop codon mutation at nucleotide position 1896 or an A-to-T mutation at nucleotide position 1762 and a G-to-A mutation at nucleotide position 1764 in the core promoter region were present in four and three cases, respectively. Fulminant HBV infection does not appear to be caused by a specific genomic mutation. However, various mutations clustering in the enhancer II core promoter region may contribute to a fulminant disease course.

Is hepatitis B infection an indication for orthotopic liver transplantation? the answer, my friend, is Blowin' in the wind

Background. The role of liver transplantation in patients positive for the hepatitis B surface antigen (HBsAg) is controversial because of the high rate of recurrent hepatitis B virus (HBV) infection. It has not been determined whether this risk is greater for certain patients and whether the administration of anti-hepatitis B surface antigen (anti-HBe) immune globulin is beneficial. Methods. We conducted a retrospective study at 17 European centers of 372 consecutive HBsAg-positive patients who underwent liver transplantation between 1977 and 1990. Recurrence of HBV infection was defined as the reappearance of HBsAg in serum. Results. For all 334 patients with follow-up data, the mean (± SE) three-year actuarial risk of recurrence of HBV was 50 ± 3 percent. The risk was 87 ± 4 percent among 163 patients with HBV-related cirrhosis. 32 ± 5 percent among 110 patients with cirrhosis related to hepatitis delta virus, 40 ± 16 percent among 14 patients with fulminant hepatitis delta infection, and 17 ± 7 percent among 39 patients with fulminant HBV infection (P<0.001). Among the patients with HBV-related cirrhosis, the risk of HBV recurrence was greatest (83 ± 8 percent) in those who were seropositive for HBV DNA at the time of transplantation and lowest (56 ± 7 percent) in those with neither HBV DNA nor hepatitis B e antigen detectable in serum. With respect to the use of passive prophylaxis with anti-HBs immune globulin, the risk of HBV recurrence was 75 ± 5 percent among the 67 patients given no immunoprophylaxis, 74 ± 5 percent among the 83 treated for two months, and 36 ± 4 percent among the 209 treated for six months or longer (P<0.001). In a multivariate analysis the predictors of a lower risk of HBV recurrence were the long-term administration of the immune globulin, hepatitis delta virus superinfection, and acute liver disease. For the entire study cohort, survival was 75 percent at one year and 63 percent at three years, but for those in whom HBV infection recurred, survival was 68 percent at one year and 44 percent at three years. Conclusions. In this retrospective study of HBsAg-positive patients, liver transplantation had better results in those who had fulminant hepatitis or delta virus superinfection. An absence of viral replication at the time of transplantation and long-term immunoprophylaxis were associated with a reduced risk of recurrent HBV infection and reduced mortality.

Liver transplantation in European patients with the hepatitis B surface antigen.

The role of liver transplantation in patients positive for the hepatitis B surface antigen (HBsAg) is controversial because of the high rate of recurrent hepatitis B virus (HBV) infection. It has not been determined whether this risk is greater for certain patients and whether the administration of anti-hepatitis B surface antigen (anti-HBs) immune globulin is beneficial. We conducted a retrospective study at 17 European centers of 372 consecutive HBsAg-positive patients who underwent liver transplantation between 1977 and 1990. Recurrence of HBV infection was defined as the reappearance of HBsAg in serum. For all 334 patients with follow-up data, the mean (+/- SE) three-year actuarial risk of recurrence of HBV was 50 +/- 3 percent. The risk was 67 +/- 4 percent among 163 patients with HBV-related cirrhosis, 32 +/- 5 percent among 110 patients with cirrhosis related to hepatitis delta virus, 40 +/- 16 percent among 14 patients with fulminant hepatitis delta infection, and 17 +/- 7 percent among 39 patients with fulminant HBV infection (P < 0.001). Among the patients with HBV-related cirrhosis, the risk of HBV recurrence was greatest (83 +/- 6 percent) in those who were seropositive for HBV DNA at the transplantation and lowest (58 +/- 7 percent) in those with neither HBV DNA nor hepatitis B e antigen detectable in serum. With respect to the use of passive prophylaxis with anti-HBs immune globulin, the risk of HBV recurrence was 75 +/- 6 percent among the 67 patients given no immunoprophylaxis, 74 +/- 5 percent among the 83 treated for two months, and 36 +/- 4 percent among the 209 treated for six months or longer (P < 0.001). In a multivariate analysis the predictors of a lower risk of HBV recurrence were the long-term administration of the immune globulin, hepatitis delta virus superinfection, and acute liver disease. For the entire study cohort, survival was 75 percent at one year and 63 percent at three years, but for those in whom HBV infection recurred, survival was 68 percent at one year and 44 percent at three years. In this retrospective study of HBsAg-positive patients, liver transplantation had better results in those who had fulminant hepatitis or delta virus superinfection. An absence of viral replication at the time of transplantation and long-term immunoprophylaxis were associated with a reduced risk of recurrent HBV infection and reduced mortality.

Elevation of serum sex hormone-binding globulin in females with fulminant hepatitis B virus infection.

Amongst adults exposed to the hepatitis B virus (HBV), the infection pursues a fulminant course more frequently in females, while conversely a chronic carrier state is more frequent in males. Because of these differences in sex ratio, we investigated the relationship between the outcome of HBV infection and serum concentrations of sex hormone-binding globulin (SHBG), a circulating glycoprotein that exerts an important influence on the balance of free sex hormones. SHBG levels were significantly elevated in females with fulminant HBV infection compared to females with either uncomplicated acute or chronic HBV infection (P less than .05 and P less than .001, respectively). That this was not a nonspecific effect of fulminant hepatitis was confirmed by the significantly higher levels in this group than in age-matched females with fulminant hepatitis unrelated to HBV (P less than .05). In contrast, four of 15 female HBsAg carriers had SHBG values in the male range, and these included three of four patients who had acquired HBV as adults. SHBG levels were normal in all male groups. These results suggested that for adults the hormonal environment may be important in determining the course of HBV infection.