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Background: About 20% of on-treatment patients with chronic hepatitis B (CHB) experienced low-level viraemia (LLV), which is associated with persistent low-grade inflammation, fibrosis progression, and increased risk of hepatocellular carcinoma. We aimed to investigate the high-risk factors related to LLV., Methods: In this retrospective study, patients receiving entecavir (ETV) treatment from January 2018 to January 2023 were enrolled, and were divided into a LLV (HBV DNA 20-2000 IU/mL) cohort and a complete virological response (CVR) (HBV DNA < 20 IU/mL) cohort according to the virological response at week 48 posttreatment. Treatment baseline characteristics were retrieved from electronic medical records. Multivariate logistic regression was performed., Results: Totally, 1653 patients were enrolled, male patients accounted for 73.0%; the median age was 44 years; the mean HBV DNA level was 5.9 Log 10 IU/ml. Among them, 472 (28.6%) experienced LLV. Multivariate analysis showed that HBeAg positivity (OR = 2.650, 95% CI: 2.000-3.511, p < 0.001), HBV DNA ≥ 6.0 Log 10 IU/mL (OR = 1.370, 95% CI: 1.054-1.780, p = 0.019), qHBsAg ≥ 9000 IU/mL (OR = 4.472, 95% CI: 3.410-5.866, p < 0.001), cirrhosis (OR = 1.650, 95% CI: 1.234-2.207, P = 0.001), LSM ≥ 13.0 kPa (OR = 1.644, 95% CI: 1.203-2.246, p = 0.002), and PLT < 100×10 9 /L (OR = 1.450, 95% CI: 1.094-1.922, p = 0.010) at baseline were related to the development of LLV., Conclusions: High HBV DNA/HBsAg quantification/LSM, low PLT, HBeAg positivity, and liver cirrhosis were high-risk factors associated with LLV in patients receiving entecavir treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Chen, Jia, He, Cui, Du, Kang, Feng, He, Jin, Chen, Wang, Ji, Lau and Wu.)

Fibroblast growth factor 21 (FGF21), a stress-induced hormone in the liver, has been shown the protective functions in pathological conditions. The study investigated the association of circulating FGF21 with hepatitis B virus (HBV) infection and its related diseases. Serum FGF21 levels were measured in 33 acute hepatitis B (AHB), 75 chronic hepatitis B (CHB) and 66 CHB patients with advanced liver diseases including liver cirrhosis, acute-on-chronic liver failure (ALCF) and hepatocellular carcinoma (HCC) together with 200 age- and BMI-matched healthy controls. FGF21 levels were significantly increased in AHB patients and rapidly returned to normal levels after treatment. FGF21 levels reflected the degree of liver injury caused by AHB. However, serum FGF21 levels were decreased in CHB patients especially in those who developed cirrhosis and were associated with hepatic protein synthesis capacity. Serum FGF21 in CHB patients were increased with the occurrence of ACLF. Notably, in CHB patients who developed HCC, serum FGF21 exhibited a dramatic increase, which may provide important information on monitoring tumorigenesis in CHB patients. In conclusion, we revealed the diverse changes of circulating FGF21 in HBV-related diseases. FGF21 may be a useful biomarker in monitoring the tumorigenesis in patients with CHB.

Background & Aims: Little is known about the benefit of antiviral therapy for hepatitis B e antigen (HBeAg)-positive patients with high viral load and normal levels of alanine aminotransferase. We evaluated the effects of single and combination therapies in immune-tolerant patients with chronic hepatitis B., Methods: In a double-blind study, nucleos(t)ide-naïve patients with high levels of hepatitis B virus (HBV) DNA who were positive for HBeAg and had normal levels of alanine aminotransferase were randomly assigned to groups given either oral tenofovir disoproxil fumarate (TDF, 300 mg) and placebo (n = 64) or a combination of TDF (300 mg) and emtricitabine (200 mg, n = 62) for 192 weeks. The primary end point was proportion of patients with serum levels of HBV DNA <69 IU/mL at week 192., Results: The study population (mean age was 33 years; 89% were Asian) was predominantly infected with HBV genotypes B and C (93%), 99% were HBeAg positive with a mean baseline level of HBV DNA of 8.41 log10 IU/mL. At week 192, 55% of patients (35 of 64) in the TDF+placebo group and 76% of patients (47 of 62) in the TDF+emtricitabine group had levels of HBV DNA <69 IU/mL (P = .016). No patients were found to have viral resistance to therapy. HBeAg seroconversion occurred in 3 patients (5%), all in the TDF+placebo group; no patient had loss of hepatitis B surface antigen. In multivariate analysis, female sex (odds ratio = 7.05; P = .002) and TDF+emtricitabine treatment (odds ratio = 3.9; P = .01) were associated with a favorable response. Both regimens were well tolerated., Conclusions: In HBeAg-positive patients with chronic HBV infection, high viral loads, normal levels of alanine aminotransferase, and therapy with the combination of TDF and emtricitabine provided better viral suppression than TDF alone, although rates of HBeAg seroconversion and hepatitis B surface antigen loss were low., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

HIV infection has a significant impact on the natural progression of hepatitis B virus (HBV) related liver disease. In HIV-HBV co-infected patients, little is known about mutations in the HBV genome, which can influence severity of liver disease. The aim of this study was to characterize and to determine the frequency of known clinically significant mutations in the HBV genomes from HIV-HBV co-infected patients and from HBV mono-infected patients. To accomplish this, genomic length HBV sequencing was performed in highly-active anti-retroviral therapy (HAART)-naïve HIV-HBV co-infected patients (n=74) and in anti-HBV therapy-naïve HBV mono-infected patients (n=55). The frequency of HBV mutations differed between the co-infected and mono-infected patients when comparing patients with the same genotype. BCP mutations A1762T and G1764A were significantly more frequent in HBV genotype C mono-infection and the -1G frameshift was significantly more frequent in co-infection and was only observed in HBV genotype A co-infection. PreS2 deletions were observed more frequently in the setting of co-infection. Further work is needed to determine if these mutational patterns influence the differences in liver disease progression in HIV-HBV co-infected and HBV mono-infected patients., (Copyright 2010 Elsevier Inc. All rights reserved.)

It remains uncertain whether hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and pregenomic RNA (pgRNA) can be detected in the serum or peripheral blood mononuclear cells (PBMC) of patients with chronic hepatitis B (CHB) infection. We examined HBV cccDNA and pgRNA in the serum and PBMC, and investigated the effect of lamivudine therapy on the viral loads in the PBMC of CHB patients. Paired serum and PBMC samples from 50 treatment-naïve CHB patients [25 hepatitis B e antigen (HBeAg) positive and 25 HBeAg negative] were quantified for total HBV DNA, cccDNA and pgRNA by real time polymerase chain reaction. HBV cccDNA and pgRNA were below the lower detection limit in all serum samples, and in 84% of PBMC. HBV DNA (r = 0.889, P < 0.001) and pgRNA (r = 0.696, P < 0.001) in PBMC correlated with the HBV DNA in serum. In the longitudinal study, 30 patients treated with lamivudine therapy for a median duration of 34 weeks (range 12-48 weeks) were examined. The median HBV DNA reduction in PBMC before and after treatment was 1.318 (range -0.471 to 3.846) log units, which was significantly lower than serum HBV DNA reduction [3.371 (range -0.883 to 9.454) log units, P < 0.05]. HBV cccDNA and pgRNA were undetectable in the serum of CHB patients. HBV viral loads in PBMC correlated with serum HBV DNA. Lamivudine therapy had less effect on the HBV viral loads in PBMC compared with the serum viral loads.

Unlabelled: Defective hepatitis B virus DNA (dDNA) is reverse-transcribed from spliced hepatitis B virus (HBV) pregenomic messenger RNA (pgRNA) and has been identified in patients with chronic HBV (CH-B). The major 2.2-kb spliced pgRNA encodes a novel HBV gene product, the hepatitis B splice protein (HBSP) via a deletion and frame shift within the polymerase. Although spliced RNA and HBSP expression have been associated with increased HBV DNA levels and liver fibrosis, the role of dDNA in HBV-associated disease is largely undefined. Our aims were to (1) compare the relative proportions of dDNA (% dDNA) in a range of HBV-infected serum samples, including patients with human immunodeficiency virus (HIV)/HBV coinfection and HBV-monoinfected persons with differing severities of liver disease, and (2) determine the effect of mutations associated with drug resistance on defective DNA production. Defective DNA was detected in 90% of persons with CH-B. There was no significant difference in the relative abundance of dDNA between the monoinfected and HIV/HBV-coinfected groups. We also found no association between the % dDNA and alanine aminotransferase, hepatitis B e antigen status, HBV DNA levels, fibrosis levels, compensated or decompensated liver cirrhosis, genotype, or drug treatment. However, the % dDNA was significantly lower in individuals infected with lamivudine-resistant (LMV-R) HBV compared with wild-type HBV (P < 0.0001), indicating that antiviral drug resistance alters the balance between defective and genomic length DNA in circulation. Experiments in vitro using HBV encoding LMV-R mutations confirmed these results., Conclusion: Our results identified no association between dDNA and parameters associated with disease status and suggested that the relative abundance of dDNA is largely dependent on the integrity of the HBV polymerase and is unrelated to the severity of liver disease.

It is uncertain whether occult hepatitis B virus co-infection will hasten progressive liver disease in chronic hepatitis C patients after liver transplantation. This study evaluated fibrosis progression and severe fibrosis in 118 consecutive hepatitis B surface antigen-negative patients with virological and histological evidence of recurrent chronic hepatitis C infection co-infected with occult hepatitis B virus after liver transplantation. HBV DNA was detected from serum at the time of recurrent chronic hepatitis C infection by polymerase chain reaction. Each subject underwent a repeat liver biopsy 5 years post-liver transplantation. Occult hepatitis B virus co-infection was present in 41 of the 118 (34.7%) patients. At 5 years post-liver transplantation, 13 of the 41 occult hepatitis B virus co-infected patients compared with 16 of the 77 patients without occult hepatitis B virus co-infection developed fibrosis progression (31.7% vs. 20.8%, respectively, p = 0.39). Eight of 41 the occult hepatitis B virus co-infected patients compared with 13 of the 77 patients without occult hepatitis B virus co-infection had severe fibrosis (19.5% vs. 16.9%, respectively, p = 0.97). In conclusion, occult hepatitis B virus co-infection in patients with recurrent chronic hepatitis C infection was not associated with accelerated fibrosis progression or severe fibrosis after liver transplantation.

Background: The hepatic outcome of hepatitis B surface antigen (HBsAg) positive patients undergoing chemotherapy after withdrawal of pre-emptive lamivudine is unknown., Aims: To examine the occurrence of hepatitis B virus (HBV) reactivation after withdrawal of pre-emptive lamivudine., Methods: Pre-emptive lamivudine was started one week before initiation of chemotherapy in 46 consecutive HBsAg positive patients and continued for the entire duration of chemotherapy. Pre-emptive lamivudine was stopped at a median 3.1 (range 3.0-3.4) months after completion of chemotherapy. Patients were longitudinally followed up after withdrawal of pre-emptive lamivudine., Results: Median time of follow up after withdrawal of lamivudine was 25.7 (range 5.7-75.7) months. Eleven of the 46 patients (23.9%) developed HBV reactivation after withdrawal of pre-emptive lamivudine. Eight of the 16 patients with high pre-chemotherapy HBV DNA (> or =10(4) copies/ml) compared with three of the 30 patients with low pre-chemotherapy HBV DNA (<10(4) copies/ml) developed HBV reactivation (50.0% v 10.0%, respectively; p<0.001). Hepatitis B e antigen positive patients were also more likely to develop HBV reactivation (5/11 (45.5%) v 6/35 (17.1%), respectively; p = 0.041). A high pre-chemotherapy HBV DNA (> or =10(4) copies/ml) was the most important risk factor for HBV reactivation after withdrawal of pre-emptive lamivudine on Cox proportional hazards analysis (relative risk 16.13, (95% confidence interval 2.99-87.01; p = 0.001)., Conclusions: HBV reactivation is more likely to occur in patients with high pre-chemotherapy HBV DNA after withdrawal of pre-emptive lamivudine. A more prolonged course of antiviral therapy may be necessary in these patients after completion of chemotherapy in order to reduce post-chemotherapy HBV reactivation.

Background: The expression of the hepatitis Be antigen (HBeAg) is one of several strategies used by hepatitis B virus (HBV) to ensure persistence. The HBeAg may function as a toleragen in utero and has been shown to regulate the host's immune response., Aim: The aim of this study was to examine the effect of the HBV precore and core protein on cellular gene expression in the hepatoma cell line Huh-7., Study Design: Huh-7 cells with tight regulated expression of the HBV core or precore protein were produced using the Tet-Off tetracycline gene expression system. Changes in cellular gene expression in response to core/precore expression compared to Huh-7 cells not expressing the proteins were determined using a commercial high-density oligonucleotide array (Affymetrix Hu95A GeneChip) containing probes for 12,626 full-length human genes., Results: Analysis of differential mRNA gene expression profiles at 7 days post precore and core expression revealed 45 and 5 genes, respectively, with mRNA changes greater than three-fold. The most striking feature was in Huh-7 cells expressing the precore protein in which 43/45 genes were downregulated 3-11-fold. These included genes that encoded products that regulate transcription/DNA binding proteins, cell surface receptors, cell-cycle/nucleic acid biosynthesis and intracellular signalling and trafficking. The only known gene, which was upregulated encoded a cytoskeletal protein. For the core cell line, 4/5 genes were downregulated 3-15-fold upon core induction and included genes that encoded products that affect intermediary metabolism, cell surface receptors and intracellular signalling. The one gene, which was upregulated was a cytokine gene., Conclusion: The results of this study show that HBV precore protein has a much greater effect on cellular gene expression in comparison to the core protein, suggesting that core and precore proteins may have diverse effects on cellular functions and equally different roles in modulating HBV pathogenesis.

Background & Aims: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is a unique episomal replicative intermediate responsible for persistent infection of hepatocytes. Technical constraints have hampered the direct study of cccDNA maintenance and clearance mechanisms in patients. The aim of this study was to develop a sensitive and specific assay for quantifying cccDNA in biopsy samples from chronic hepatitis B patients during different natural history phases and in patients undergoing antiviral therapy., Methods: Intrahepatic cccDNA levels were quantified by a specific real-time PCR assay. Ninety-eight liver biopsy samples from patients in the major phases of the natural history of chronic hepatitis B and 32 pairs of samples from patients receiving adefovir dipivoxil (ADV) therapy were assessed., Results: cccDNA was detected, at levels ranging over 3 orders of magnitude, in patients in different phases of the natural history of chronic hepatitis B. cccDNA levels were strongly correlated with levels of total intracellular HBV DNA and serum HBV DNA. Forty-eight weeks of ADV therapy resulted in a significant 0.8 log decrease in cccDNA copies/cell. Changes in cccDNA were correlated with a similar reduction in serum HBsAg titer but not with a decrease in the number of HBV antigen-positive cells during ADV treatment., Conclusions: cccDNA persists throughout the natural history of chronic hepatitis B, even in patients with serologic evidence of viral clearance. Long-term ADV therapy significantly decreased cccDNA levels by a primarily noncytolytic mechanism.

Background: Lamivudine (LMV) is the only nucleoside analogue approved for the treatment of chronic hepatitis B (CHB). LMV, as with other nucleoside analogues including Famciclovir (FCV), suppresses the replication of hepatitis B virus (HBV) by targeting the viral polymerase. However, prolonged antiviral therapy results in the emergence of drug resistance HBV which can contribute to virological breakthroughs and recurrent hepatitis flares., Objectives: A 38-year-old hepatitis B e antigen (HBeAg) positive Chinese female infected with genotype B HBV commenced treatment with FCV and LMV combination therapy but was later maintained on LMV monotherapy. The patient remained HBeAg positive throughout treatment. Virological breakthrough occurred with the emergence of drug resistant HBV. This coincided with worsening liver function and the patient died of subacute fulminant hepatitis. This study evaluated the virological factors that contributed to the clinical decline of the patient., Study Design: Biochemical analysis and full-length HBV genomic sequencing were performed on serial serum samples collected from the patient before and during antiviral therapy., Results: Virological analysis revealed that the pre-treatment dominant HBV quasispecies in the patient had a number of non-consensus genotype B mutations which were located in the basal core promoter (BCP), polymerase, X, core and S genes. Subsequent to the instigation of antiviral therapy, the dominant drug resistant HBV which caused virological breakthrough and was associated with hepatic failure displayed a series of unique mutations particularly in the BCP (A1762T and G1764A) and in the polymerase (rtL180M, rtM204V, rtA222T and rtL336V), core (cP5T, cS26A, cV85I and cP135A), surface (sI195M and sM213I) and X (xK95Q, xN118T, xK130M and xV131I) proteins., Conclusions: Monitoring for the accumulation of unique mutations within the genome of drug resistant HBV mutants isolated during long term antiviral therapy appears warranted in the clinical management of patients with CHB.

We examined whether combination therapy with thymosin-alpha1 and famciclovir would induce hepatitis B e antigen seroconversion in patients with chronic hepatitis B infection in the immune-tolerant phase without inducing significant hepatic necro-inflammation. We studied 32 hepatitis B e antigen positive patients in the immune-tolerant phase of infection, treated with 26-weeks combination therapy of famciclovir and thymosin-alpha1 (group 1). Thirty-two patients who received 26-weeks famciclovir monotherapy (group 2) and another 32 patients who received no treatment (group 3), served as controls. Peripheral blood mononuclear cell proliferation and cytokine secretion in response to recombinant HBV core and surface antigen and serial serum HBV-DNA, were assayed. No significant difference in adverse events were observed among the three groups. By week 26, the median reduction in group 1 (0.94 log10 copies/mL) was greater than group 2 (0.70 log10 copies/mL, P < 0.001). Five (15.6%) patients in group 1 at 52 weeks (median range 13-78 weeks) and none in group 2 or 3 experienced hepatitis B e antigen seroconversion (P = 0.053). Sustained serological clearance of hepatitis B e antigen was associated with activation of CD4 positive HBV-specific T-cell reactivity and were of T-helper 1. Hence combination therapy with immunomodulatory agents and nucleoside analogues should be explored.

Previous studies have suggested that hepatitis B virus (HBV) variants may account for the presence of HBV DNA in hepatitis B surface antigen (HBsAg)-negative patients (occult HBV infection). However, it is not known how widespread these variants are and how they influence the course of liver disease. To determine the prevalence of variants within the major hydrophilic region (MHR) of HBsAg, we investigated 2,565 subjects, including subjects with chronic hepatitis, cryptogenic cirrhosis, hemodialysis patients, and blood donors. Fifty-one of them had occult HBV infection. The entire S gene from 46 of these patients was sequenced from amplified serum HBV DNA. Forty-three percent (20 of 46) had mutations in the MHR of HBsAg. Thirty-two amino acid substitutions between positions 100-160 of the MHR of HBsAg were detected in 18 patients, and these ranged from 1 to 4 per patient. These changes involved 11 positions inside and 5 outside of the historical first and second loops of the "a" determinant, and included the following: Q101K, T115A, K122N, T123A, T126N, Q129N, G130R, T131I, M133T, F134L, C138Y, K141E, P142S, G145R, N146S, and C147F/R. Combinations of mutations were detected in 9 patients, and 7 of these have not been described before. Two further patients had insertion mutations immediately before the "a" determinant. Monoclonal antibody binding tests with the Royal Free hepatitis B surface (RFHBs) panel of antibodies revealed decreased immunoreactivity in 6 novel variants of HBsAg. The existence of patients with occult HBV infection caused by HBsAg variants, therefore, has implications for their possible transmission through sexual contact and by blood transfusion.

In an endemic area for chronic hepatitis B infection, reactivation of this virus is a serious cause of morbidity and mortality in patients undergoing cytotoxic or immunosuppressive therapy. Careful prospective serological testing has shown that hepatitis B virus reactivation is a two-staged process. The initial stage occurs during intense cytotoxic or immunosuppressive therapy and is characterised by enhanced viral replication, as reflected by increases in the serum levels of hepatitis B virus DNA, hepatitis B e antigen, hepatitis B virus DNA polymerase and infection of naïve hepatocytes with hepatitis B virus. The second stage is related to restoration of immune function following withdrawal of cytotoxic or immunosuppressive therapy, which causes rapid immune-mediated destruction of infected hepatocytes. Clinically, this can lead to hepatitis, hepatic failure and even death. The occurrence and severity of hepatitis B virus reactivation after various cytotoxic or immunosuppressive therapy is unpredictable and treatment has been disappointing, largely due to the late administration of therapy. Recently, pre-emptive treatment of chronic hepatitis B patients undergoing cytotoxic or immunosuppressive therapy, with potent nucleoside analogues has shown some promising results. Further controlled studies are needed to define the incidence and risk factors of hepatitis B reactivation so that pre-emptive treatment with nucleoside analogues could be administered to those patients at high risk of disease., (Copyright 2001 John Wiley & Sons, Ltd.)

Chronic HBV infection is a serious health threat in the Asian-Pacific region. The introduction of lamivudine has greatly improved the hope of these patients and is undoubtly a milestone in the management of chronic HBV infection. The combination of lamivudine with another nucleotide or nucleoside analogue or immunomodulatory agent to improve its therapeutic efficacy further must be investigated. Also, the use of lamivudine to prevent HBV reactivation on withdrawal of immunosuppressive therapy should be explored.

Background: A double variant in the basal core promoter, converting nucleotide 1762 from A to T (T1762) and nucleotide 1764 from G to A (A[764), has been described in patients with chronic hepatitis B infection. Its prevalence and significance in Chinese chronic HBV carriers are unknown., Methods: We studied 177 Chinese patients with chronic HBV infection (chronic hepatitis/asymptomatic: 89/88; hepatitis B e antigen positive/negative: 84/93). The double variant was detected by mismatched polymerase chain reaction and restriction fragment length polymorphism analysis. The reliability of this method was verified by sequencing in 41 serum samples with 100% matching., Results: The double variant T1762/ A1764 was found in 52 of 89 patients with chronic hepatitis, but in only 6 of 59 asymptomatic carriers (p<0.001). The prevalence was significantly lower in hepatitis B e antigen positive patients (23/84) than in hepatitis B e antigen negative patients (35/64) (p<0.005). Precore variant, A1896 was detected in 40 individuals; 31 of them suffered from chronic hepatitis and 9 were asymptomatic (p<0.001). A combination of both variants T1762/A1764 and A1896 was seen in 3 of 59 asymptomatic and 22 of 89 patients with chronic hepatitis (p<0.005)., Conclusions: Mismatched polymerase chain reaction with restriction fragment length polymorphism provides a reliable, easy and fast method for detection of the presence of the T1762/A1764 variant. In Chinese chronic hepatitis B carriers, T1762/A1764 variant was associated with both active liver disease and hepatitis B e antigen negativity.

A 26-year-old female bone marrow transplant (BMT) recipient was hepatitis B surface antigen (HBsAg) and hepatitis B e antibody (HBeAb) positive. The donor, her human leucocyte antigen (HLA)-compatible sister, was HBsAg negative but hepatitis B surface antibody (HBsAb) and hepatitis B core antibody (HBcAb) positive. Twelve weeks post-BMT the patient became HBsAg negative, as determined using a monoclonal antibody-based assay. At 16 weeks post-BMT, HBsAg became undetectable by monoclonal and polyclonal immunoassay with seroconversion to HBsAb; however, at 24 weeks post-BMT the patient again became HBsAg positive. Both the recipient and the donor were retrospectively tested by hepatitis B virus (HBV) polymerase chain reaction (PCR) and found to be positive. The recipient displayed variants at amino acids 4 and 47 of the surface (S) gene prior to BMT. These mutations were not detected 32 weeks post-BMT when the S gene sequence was identical to that of an adr prototype. The donor was found to have four unique amino acid substitutions at positions 30, 98, 101 and 210 of the S gene. However, in vitro-expressed HBsAg from the donor was detected by commercial kits and an immunofluorescence assay, indicating that antigenic alteration did not explain HBsAg negativity. This donor highlights the value of PCR as the gold standard test for current HBV infection. It also demonstrates that discordance between two commercial HBsAg assays may not always be caused by antigenic variants. The second episode of hepatitis may theoretically have been caused by reactivation, selection of an escape mutant by HBsAb, reinfection or recombination. We suggest it was reactivation because none of the donor variants was seen in the recipient post-BMT.

Background/aims: Reactivation of chronic hepatitis B viral infection causes significant morbidity and mortality after bone marrow transplantation. Recently, nucleoside analogues, such as famciclovir, were found to have a direct suppressive effect on hepatitis B virus replication in both in vitro and in vivo studies. We have studied the effect of famciclovir on the incidence of hepatitis B virus reactivation and hepatitis after allogeneic bone marrow transplantation., Methods: Eight hepatitis B surface antigen (HBsAg)-positive patients who received allogeneic bone marrow transplantation were given oral famciclovir 250 mg three times daily, starting at least 1 week prior to bone marrow transplantation and continuing for 24 weeks after transplantation. Clinical and serological outcomes in these patients were compared with 24 HBsAg-positive recipients of allogeneic bone marrow transplantation who did not receive famciclovir (historical controls)., Results: After bone marrow transplantation, there were five patients with hepatitis B virus reactivation among those who received famciclovir 250 mg three times daily. Four of these patients responded to increased dosages of 500 mg three times daily and did not develop hepatitis. The remaining patient suffered from hepatitis related to hepatitis B virus reactivation. Compared to historical controls, there were fewer cases of hepatitis due to hepatitis B virus reactivation and veno-occlusive disease. The median follow-up was 701.6 days (range: 50-2346 days) with ten deaths (three due to hepatic failure related to HBV reactivation) in those who did not receive famciclovir and one death (due to hepatic failure related to graft-versus-host disease) in those who received famciclovir., Conclusions: Use of famciclovir significantly reduced hepatitis due to hepatitis B virus reactivation in HBsAg-positive recipients after allogeneic bone marrow transplantation.

In chimpanzees and in vitro cell culture studies, hepatitis C infection has been shown to suppress hepatitis B virus expression. In addition, hepatitis C infection can cause much more severe liver disease in patients chronically infected with hepatitis B virus. The aims of the present study were to determine the prevalence of hepatitis C infection in asymptomatic chronic hepatitis B Hong Kong Chinese patients and the histological changes and hepatic expression of hepatitis B virus and hepatitis C virus. Five hundred and seventy-one Hong Kong Chinese asymptomatic chronic hepatitis B patients were studied. Only four (0.7%) were hepatitis C virus antibody positive; they were also all positive for hepatitis C viral RNA in serum by reverse transcription-polymerase chain reaction (RT-PCR). Portal lymphoid aggregates and bile duct damage was noted in the liver sections of three of the four patients. Hepatic expression of hepatitis B surface antigen was detected in three patients; none had detectable hepatitis B core antigen. By branched DNA assay, serum hepatitis B DNA could not be detected in any of the four patients, but three had hepatitis C RNA. By in situ RT-PCR, hepatitis C RNA was detected in the cytoplasm of three of the four patients. These findings suggest that hepatitis C coinfection in asymptomatic chronic hepatitis B patients is uncommon in Hong Kong Chinese and active hepatitis B viral replication is absent in these patients.

Delayed clearance of hepatitis B surface antigen was previously reported in a 38 year old woman after high dose chemotherapy with autologous peripheral blood stem cell rescue. Sixteen months later, this patient remained hepatitis B surface antigen negative, hepatitis B surface antibody positive, and serum hepatitis B DNA negative by polymerase chain reaction. Serial liver biopsies (one at hepatitis B e antigen positive stage, one at hepatitis B e antibody positive stage, and one at hepatitis B surface antigen negative and hepatitis B surface antibody positive stage) showed a gradual resolution of the inflammatory activity with loss of hepatitis B e antigen and then hepatitis B surface antigen in the serum. However, the degree of fibrosis, though mild, remained the same. With the serological clearance of hepatitis B surface antigen, a small amount of hepatitis B virus DNA was still detectable in the nuclei of liver cells.

Background: Hepatitis B virus (HBV) DNA has been detected in the peripheral blood leukocytes (PBL) during acute and chronic HBV infection. Possible pathobiologic significance includes infectivity and altered immunity. There are few data relating PBL HBV-DNA with severity of the liver disease, in particular with hepatocellular carcinoma (HCC)., Methods: HBV-DNA was detected by dot-spot hybridization technique in PBL separated from venous blood samples of 209 hepatitis B surface antigen-positive patients (28 healthy carriers and 95 chronic hepatitis, 29 cirrhotic, and 57 HCC patients). Serum HBV-DNA and hepatitis B e-antigen (HBeAg) were also measured., Results: Thirty percent of HCC patients were hepatitis e-antigen-positive compared to 50%, 84% (P < 0.0001), and 69% (P < 0.00001) of healthy carriers and chronic hepatitis and cirrhotic patients, respectively. Furthermore, only 11% of HCC patients had detectable serum HBV-DNA compared to 39% (P < 0.001), 58% (P < 0.001), and 31% (P < 0.05) of these respective patient groups. despite low viral replication among HCC patients, 58% had PBL HBV-DNA. Corresponding figures for healthy carriers and for chronic hepatitis and cirrhotic patients were 39%, 58%, and 56%. Fifty-two percent of HCC patients had positive PBL HBV-DNA in the absence of serum HBV-DNA, compared with 25% in healthy carriers (P < 0.05) and 22% in chronic hepatitis (P < 0.001) and 35% in cirrhotic patients (P = NS)., Conclusion: The high detection rate of PBL HBV-DNA among HCC patients may reflect certain pathogenetic processes of HBV infection and indicate a higher risk of development of HCC.

Objective: In a trial of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B, 24 week post-treatment biochemical and virological response rates with peginterferon α-2a with or without lamivudine were significantly higher than with lamivudine alone. The effect of pre-treatment factors on post-treatment responses was investigated. Methods: Multivariate analyses were performed using available data from 518 patients treated with peginterferon α-2a with or without lamivudine, or with lamivudine alone. A post-treatment response was defined as alanine aminotransferase (ALT) normalisation and hepatitis B virus (HBV) DNA level of <20 000 copies/ml. Results: In logistic regression analyses across all treatment arms, peginterferon α-2a (with or without lamivudine) therapy, younger age, female gender, high baseline ALT, low baseline HBV DNA and HBV genotype were identified as significant predictors of combined response at 24 weeks post-treatment. In the peginterferon α-2a and lamivudine monotherapy arms, patients with genotypes B or C had a higher chance of response than genotype D infected patients (p<0.001), the latter responding better to the combination than to peginterferon α-2a monotherapy (p = 0.015). At 1 year post-treatment, response rates by intention-to-treat analysis were 19.2% for the peginterferon α-2a, 19.0% for the combination, and 10.0% for the lamivudine groups, with genotypes B or C associated with a sustained combined response to peginterferon α-2a with or without lamivudine therapy. Conclusions: Baseline ALT and HBV DNA levels, patient age, gender, and infecting HBV genotype significantly influenced combined response at 24 weeks post-treatment, in patients treated with peginterferon α-2a and/or lamivudine. At 1 year post-treatment HBV genotype was significantly predictive of efficacy for patients treated with peginterferon α-2a with or without lamivudine. [ABSTRACT FROM AUTHOR]

Background: The hepatic outcome of hepatitis B surface antigen (HBsAg) positive patients undergoing chemotherapy after withdrawal of pre-emptive lamivudine is unknown. Aims: To examine the occurrence of hepatitis B virus (HBV) reactivation after withdrawal of pre-emptive lamivudine. Methods: Pre-emptive lamivudine was started one week before initiation of chemotherapy in 46 consecutive HBsAg positive patients and continued for the entire duration of chemotherapy. Pre-emptive lamivudine was stopped at a median 3.1 (range 3.0-3.4) months after completion of chemotherapy. Patients were longitudinally followed up after withdrawal of pre-emptive lamivudine. Results: Median time of follow up after withdrawal of lamivudine was 25.7 (range 5.7-75.7) months. 1 Eleven of the 46 patients (23.9%) developed HBV reactivation after withdrawal of pre-emptive lamivudine. Eight of the 16 patients with high pre-chemotherapy HBV DNA (⩾104 copies/ml) compared with three of the 30 patients with low pre-chemotherapy HBV DNA (<104 copies/ml) developed HBV reactivation (50.0% v 10.0%, respectively; p<0.001). Hepatitis B e antigen positive patients were also more likely to develop HBV reactivation (5/11 (45.5%) v 6/35 (17.1%), respectively; p = 0.041). A high pre-chemotherapy HBV DNA (⩾104 copies/ml) was the most important risk factor for HBV reactivation after withdrawal of pre-emptive lamivudine on Cox proportional hazards analysis (relative risk 16.13, (95% confidence interval 2.99-87.01; p=0.001). Conclusions: HBV reactivation is more likely to occur in patients with high pre-chemotherapy HBV DNA after withdrawal of pre-emptive lamivudine. A more prolonged course of antiviral therapy may be necessary in these patients after completion of chemotherapy in order to reduce post-chemotherapy HBV reactivation. [ABSTRACT FROM AUTHOR]