• HBV reactivation
• HBV reinfection
• HBsAg loss
• HBsAg recurrence
• cirrhosis
• hepatocellular carcinoma
• surveillance

• Humans
• Hepatitis B Surface Antigens/blood
• Hepatitis B, Chronic/immunology
• Hepatitis B, Chronic/drug therapy
• Hepatitis B, Chronic/virology
• Hepatitis B virus/immunology
• Carcinoma, Hepatocellular/virology
• Liver Neoplasms/virology
• Antiviral Agents/therapeutic use
• DNA, Viral
• Recurrence
• Liver Cirrhosis/virology

• 2018ZX10302204-001 National Science and Technology Major Project

• antiviral therapy
• cccDNA
• hepatitis B virus
• hepatitis cure
• hepatocellular carcinoma
• nucleoside analog

• HBV
• dsDNA repair
• early hepadnavirus–host DNA integration
• hepatocellular carcinoma
• oncogenesis
• retrotransposons
• virus-induced oxidative DNA damage
• woodchuck hepatitis virus

• Humans
• Hepatitis B virus/genetics
• Carcinoma, Hepatocellular/genetics
• Liver Neoplasms/genetics
• Hepatocytes
• Cell Transformation, Neoplastic
• Carcinogenesis/genetics
• Genomics
• DNA, Viral/genetics
• Hepatitis B/complications
• Hepatitis B/genetics
• X-ray Repair Cross Complementing Protein 1

• Marmota monax
• activation of T cells
• chronic hepatitis B
• immune cell subsets
• occult hepadnaviral infection
• programed cell death protein and ligand
• woodchuck model of hepatitis B

• HBV surface antigen
• covalently closed circular DNA
• hepatitis B virus
• occult HBV infection

• DNA, Viral/genetics
• Hepatitis B/diagnosis
• Hepatitis B/epidemiology
• Hepatitis B Surface Antigens
• Hepatitis B virus/physiology
• Hepatitis B, Chronic
• Humans
• Liver Neoplasms

Objective: The current study aimed to investigate the prognostic value of serological markers of hepatitis B virus (HBV) infection in squamous cell cervical cancer.

Methods: Squamous cell cervical cancer patients treated by concurrent chemoradiotherapy from January 2013 to December 2015 at Yunnan Cancer Hospital were retrospectively reviewed.

Results: Of a total of 277 patients, 12 (4.33%), 93 (33.57%), 2 (0.72%), 25 (9.02%), and 36 patients (13.00%) were seropositive for hepatitis B surface antigen (HBsAg), anti-hepatitis B surface antibodies (anti-HBs), hepatitis B envelope antigen (HBeAg), anti-hepatitis B envelope antibodies (anti-HBe), and anti-hepatitis B core antibodies (anti-HBc), respectively. No patients experienced more than mild hepatic adverse events during treatment. The five-year overall survival (OS) rates for patients with anti-HBs positive or negative status were 85.8% and 66.2% (p = 0.039), respectively. No statistically significant difference in the five-year OS rates was observed in HBsAg positive and negative, HBeAg positive and negative, anti-HBe positive and negative, anti-HBc positive and negative patients. The multivariable analysis revealed that anti-HBs positivity was an independent favorable prognostic factor for OS (HR= 0.279; 95%CI: 0.083-0.936; p = 0.039) in patients younger than 50 years.

Conclusions: The presence of anti-HBs predicts a superior OS for squamous cell cervical cancer patients aged younger than 50 years.

• cervical cancer
• hepatitis B virus
• prognosis
• serologic markers

Since the discovery of hepatitis B virus (HBV) over five decades ago, there have been many independent studies showing presence of HBV genomes in cells of the immune system. However, the nature of HBV lymphotropism and its significance with respect to HBV biology, persistence and the pathogenesis of liver and extrahepatic disorders remains underappreciated. This is in contrast to studies of other viral pathogens in which the capability to infect immune cells is an area of active investigation. Indeed, in some viral infections, lymphotropism may be essential, and even a primary mechanism of viral persistence, and a major contributor to disease pathogenesis. Nevertheless, there are advances in understanding of HBV lymphotropism in recent years due to cumulative evidence showing that: (i) lymphoid cells are a reservoir of replicating HBV, (ii) are a site of HBV-host DNA integration and (iii) virus genomic diversification leading to pathogenic variants, and (iv) they play a role in HBV resistance to antiviral therapy and (v) likely contribute to reactivation of hepatitis B. Further support for HBV lymphotropic nature is provided by studies in a model infection with the closely related woodchuck hepatitis virus (WHV) naturally infecting susceptible marmots. This animal model faithfully reproduces many aspects of HBV biology, including its replication scheme, tissue tropism, and induction of both symptomatic and silent infections, immunological processes accompanying infection, and progressing liver disease culminating in hepatocellular carcinoma. The most robust evidence came from the ability of WHV to establish persistent infection of the immune system that may not engage the liver when small quantities of virus are experimentally administered or naturally transmitted into virus-naïve animals. Although the concept of HBV lymphotropism is not new, it remains controversial and not accepted by conventional HBV researchers. This review summarizes research advances on HBV and hepadnaviral lymphotropism including the role of immune cells infection in viral persistence and the pathogenesis of HBV-induced liver and extrahepatic diseases. Finally, we discuss the role of immune cells in HBV diagnosis and assessment of antiviral therapy efficacy.

• hepatitis B virus
• lymphotyropism
• virus genome integration
• virus variants
• woodchuck model of hepatitis B

This review describes woodchucks chronically infected with the woodchuck hepatitis virus (WHV) as an animal model for hepatocarcinogenesis and treatment of primary liver cancer or hepatocellular carcinoma (HCC) induced by the hepatitis B virus (HBV). Since laboratory animal models susceptible to HBV infection are limited, woodchucks experimentally infected with WHV, a hepatitis virus closely related to HBV, are increasingly used to enhance our understanding of virus-host interactions, immune response, and liver disease progression. A correlation of severe liver pathogenesis with high-level viral replication and deficient antiviral immunity has been established, which are present during chronic infection after WHV inoculation of neonatal woodchucks for modeling vertical HBV transmission in humans. HCC in chronic carrier woodchucks develops 17 to 36 mo after neonatal WHV infection and involves liver tumors that are comparable in size, morphology, and molecular gene signature to those of HBV-infected patients. Accordingly, woodchucks with WHV-induced liver tumors have been used for the improvement of imaging and ablation techniques of human HCC. In addition, drug efficacy studies in woodchucks with chronic WHV infection have revealed that prolonged treatment with nucleos(t)ide analogs, alone or in combination with other compounds, minimizes the risk of liver disease progression to HCC. More recently, woodchucks have been utilized in the delineation of mechanisms involved in innate and adaptive immune responses against WHV during acute, self-limited and chronic infections. Therapeutic interventions based on modulating the deficient host antiviral immunity have been explored in woodchucks for inducing functional cure in HBV-infected patients and for reducing or even delaying associated liver disease sequelae, including the onset of HCC. Therefore, woodchucks with chronic WHV infection constitute a well-characterized, fully immunocompetent animal model for HBV-induced liver cancer and for preclinical evaluation of the safety and efficacy of new modalities, which are based on chemo, gene, and immune therapy, for the prevention and treatment of HCC in patients for which current treatment options are dismal.

• Woodchuck
• Hepatitis B virus
• Chronic infection
• Liver disease
• Hepatocellular carcinoma
• Cancer treatment

• Hepatitis C
• Hepatocarcinogenesis
• Occult hepatitis B
• Pathogenesis
• Prevalence

Woodchuck infected with woodchuck hepatitis virus (WHV) represents the pathogenically nearest model of hepatitis B and associated hepatocellular carcinoma (HCC). This naturally occurring animal model also is highly valuable for development and preclinical evaluation of new anti-HBV agents and immunotherapies against chronic hepatitis (CH) B and HCC. Studies in this system uncovered a number of molecular and immunological processes which contribute or likely contribute to the immunopathogenesis of liver disease and modulation of the systemic and intrahepatic innate and adaptive immune responses during hepadnaviral infection. Among them, inhibition of presentation of the class I major histocompatibility complex on chronically infected hepatocytes and a role of WHV envelope proteins in this process, as well as augmented hepatocyte cytotoxicity mediated by constitutively expressed components of CD95 (Fas) ligand- and perforin-dependent pathways, capable of eliminating cells brought to contact with hepatocyte surface, including activated T lymphocytes, were uncovered. Other findings pointed to a role of autoimmune response against hepatocyte asialoglycoprotein receptor in augmenting severity of liver damage in hepadnaviral CH. It was also documented that WHV in the first few hours activates intrahepatic innate immunity that transiently decreases hepatic virus load. However, this activation is not translated in a timely manner to induction of virus-specific T cell response which appears to be hindered by defective activation of antigen presenting cells and presentation of viral epitopes to T cells. The early WHV infection also induces generalized polyclonal activation of T cells that precedes emergence of virus-specific T lymphocyte reactivity. The combination of these mechanisms hinder recognition of virus allowing its dissemination in the initial, asymptomatic stages of infection before adaptive cellular response became apparent. This review will highlight a range of diverse mechanisms uncovered in the woodchuck model which affect effectiveness of the anti-viral systemic and intrahepatic immune responses, and modify liver disease outcomes. Further exploration of these and other mechanisms, either already discovered or yet unknown, and their interactions should bring more comprehensive understanding of HBV pathogenesis and help to identify novel targets for therapeutic and preventive interventions. The woodchuck model is uniquely positioned to further contribute to these advances.

• asialoglycoprotein receptor
• hepatocyte as cytotoxic immune effector
• intrahepatic innate and adaptive immune responses
• major histocompatibility complex presentation
• pre-acute infection
• toll-like receptors
• virus-hepatocyte interaction
• woodchuck model of hepatitis B

• HBV S variants
• HBV cccDNA
• HBV reactivation
• HBV transmission
• Hepatocellular carcinoma
• OBI
• Occult HBV infection

• Carcinoma, Hepatocellular/etiology
• DNA, Viral/blood
• Hepatitis B/complications
• Hepatitis B/diagnosis
• Hepatitis B/epidemiology
• Hepatitis B/virology
• Hepatitis B Antibodies/blood
• Hepatitis B Surface Antigens/immunology
• Hepatitis B virus/genetics
• Hepatitis B virus/immunology
• Humans
• Liver/pathology
• Liver/virology
• Liver Neoplasms/etiology
• Risk Factors

Woodchucks infected with woodchuck hepatitis virus (WHV) represent a highly valuable model of human hepatitis B virus (HBV) infection, chronic hepatitis (CH), and virus induced-primary liver cancer. Toll-like receptors (TLRs) are important mediators of immune responses playing pivotal roles in the pathogenesis of viral diseases; however, their expression profiles in different forms of infection and stages of hepatitis, and in healthy animals remain essentially unknown. In this study, woodchuck TLRs 1–10 exon fragments were identified and TLR genes transcription quantified in livers, primary hepatocytes, peripheral blood mononuclear cells (PBMC), and in selected organs during experimental WHV infection. Among others, liver biopsies from acute hepatitis (AH) and CH showed significantly augmented expression of the majority of TLRs when compared to healthy and woodchucks prior to AH, with resolved AH or primary occult infection. In contrast to the liver tissue, significant upregulation of TLR3, TLR4, and TLR10, but downregulation of TLR7, characterized hepatocytes derived from livers of animals with resolved AH accompanied by secondary occult infection. Hepatocytes from CH showed significantly lower expression or a trend toward suppression of several TLRs when compared to hepatocytes from healthy animals and woodchucks with other forms of infection or hepatitis, suggesting that hepatocyte innate immune response is downregulated during CH. Contrastingly, upregulated transcription of some TLRs characterized PBMC throughout CH. Our study uncovered that TLR expression significantly varies between different forms of hepadnaviral infection and whether infection is accompanied or not by hepatitis. The results showed that the profiles of TLRs’ expression in circulating lymphomononuclear cells do not mirror accurately those of livers and hepatocytes from infected animals. These findings are of importance to the understanding of immune process operating at different sites targeted by virus in the course of hepadnaviral infection and evaluation of future therapies modifying antiviral innate responses in the woodchuck model.

• PBMC
• hepadnaviral infection
• hepatocytes
• liver
• lymphatic organs
• toll-like receptors
• woodchuck model of hepatitis B

Occult hepatitis B infection (OBI) is recognized as a risk factor for cirrhosis and hepato-cellular carcinoma. However, OBI brings together a large spectrum of patients who might harbor different characteristics and prognosis.

We analyzed the databases of a university hospital in Paris to identify OBI among patients (n = 3966) concomitantly tested for hepatitis B virus (HBV) DNA and serology during a 7-year period. OBI patients were gathered into clinical entities according to their clinical records.

Forty-seven OBIs were identified (1.2%). All patients had detectable anti-HBc, isolated (n = 26) or associated with anti-HBs (n = 21). The proportion of OBIs was 3.4% for patients with isolated anti-HBc and 4.2% for patients with both anti-HBc and anti-HBs. Four clinical categories of OBI patients were identified: patients with a passed HBV infection with HBs Ag clearance (group A, 23.4%); HBV-exposed patients receiving immunosuppressive therapy (group B, 29.8%); HIV/HBV-coinfected patients with therapy discontinuation (group C, 17%); HBV-exposed patients with severe liver conditions (group D, 29.8%). Significant follow-up was available for 32 patients, showing a more deleterious prognosis in group D patients, associated more with their underlying condition than the OBI status.

OBI is a heterogeneous condition with various clinical implications.

• hepatitis B virus
• immunosuppression
• occult B infection

Chronic hepatitis B (CHB) is a major global health problem affecting an estimated 350 million people with more than 786000 individuals dying annually due to complications, such as cirrhosis, liver failure and hepatocellular carcinoma (HCC). Liver transplantation (LT) is considered gold standard for treatment of hepatitis B virus (HBV)-related liver failure and HCC. However, post-transplant viral reactivation can be detrimental to allograft function, leading to poor survival. Prophylaxis with high-dose hepatitis B immunoglobulin (HBIG) and anti-viral drugs have achieved remarkable progress in LT by suppressing viral replication and improving long-term survival. The combination of lamivudine (LAM) plus HBIG has been for many years the most widely used. However, life-long HBIG use is both cumbersome and costly, whereas long-term use of LAM results in resistant virus. Recently, in an effort to develop HBIG-free protocols, high potency nucleos(t)ide analogues, such as Entecavir or Tenofovir, have been tried either as monotherapy or in combination with low-dose HBIG with excellent results. Current focus is on novel antiviral targets, especially for covalently closed circular DNA (cccDNA), in an effort to eradicate HBV infection instead of viral suppression. However, there are several other molecular mechanisms through which HBV may reactivate and need equal attention. The purpose of this review is to address post-LT HBV reactivation, its risk factors, underlying molecular mechanisms, and recent advancements and future of anti-viral therapy.

• Hepatitis B virus
• Liver transplantation
• Reactivation
• Hepatitis B immunoglobulin
• Recurrence
• Prophylaxis
• Antivirals

Hepatitis B virus (HBV) and the closely related woodchuck hepatitis virus (WHV) are potent carcinogens that trigger development of primary hepatocellular carcinoma (HCC). The initial sites of hepadnavirus–host genome integration, their diversity and kinetics of formation can be central to virus persistence and the initiation and progression of HCC. To recognize the nature of the very early virus–host interactions, we explored de novo infection of human hepatocyte-like HepaRG cells with authentic HBV and naive woodchucks with WHV. HepaRG were analyzed from several minutes post exposure to HBV onwards, whereas woodchuck liver biopsies at 1 or 3 h and 6 weeks post infection with WHV. Inverse PCR and clonal sequencing of the amplicons were applied to identify virus–host genomic junctions. HBV and WHV DNA and their replication intermediates became detectable in one hour after virus exposure. Concomitantly, HBV DNA integration into various host genes was detected. Notably, junctions of HBV X gene with retrotransposon sequences, such as LINE1 and LINE2, became prominent shortly after infection. In woodchucks, insertion of WHV X and preS sequences into host genome was evident at 1 and 3 h post infection (h.p.i.), confirming that hepadnavirus under natural conditions integrates into hepatocyte DNA soon after invasion. The HBV and WHV X gene enhancer II/core promotor sequence most often formed initial junctions with host DNA. Moreover, multiple virus–virus DNA fusions appeared from 1 h.p.i. onwards in both infected hepatocytes and woodchuck livers. In summary, HBV DNA integrates almost immediately after infection with a variety of host’s sequences, among which tandemly repeating non-coding DNAs are common. This study revealed that HBV can engage mobile genetic elements from the beginning of infection to induce pro-oncogenic perturbations throughout the host genome. Such swift virus insertion was also evident in natural hepadnaviral infection in woodchucks.

To clarify the prevalence of occult hepatitis B virus (HBV) infection (OBI) and the association between OBI and liver disease progression, defined as development of liver cirrhosis or hepatocellular carcinoma (HCC), worsening of Child-Pugh class, or mortality in cases of chronic hepatitis C virus (HCV) infection.

This prospective cohort study enrolled 174 patients with chronic HCV infection (chronic hepatitis, n = 83; cirrhosis, n = 47; HCC, n = 44), and evaluated disease progression during a mean follow-up of 38.7 mo. OBI was defined as HBV DNA positivity in 2 or more different viral genomic regions by nested polymerase chain reaction using 4 sets of primers in the S, C, P and X open reading frame of the HBV genome.

The overall OBI prevalence in chronic HCV patients at enrollment was 18.4%, with 16.9%, 25.5% and 13.6% in the chronic hepatitis C, liver cirrhosis and HCC groups, respectively (P = 0.845). During follow-up, 52 patients showed disease progression, which was independently associated with aspartate aminotransferase > 40 IU/L, Child-Pugh score and sustained virologic response (SVR), but not with OBI positivity. In 136 patients who were not in the SVR state during the study period, OBI positivity was associated with neither disease progression, nor HCC development.

The prevalence of OBI in chronic HCV patients was 18.4%, and OBI was not associated with disease progression in South Koreans.

• Hepatitis B virus
• Hepatitis C virus
• Disease control
• Oncogenesis

• Aged
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/virology
• Coinfection
• DNA, Viral/genetics
• Disease Progression
• Female
• Genotype
• Hepacivirus/genetics
• Hepatitis B/diagnosis
• Hepatitis B/epidemiology
• Hepatitis B Surface Antigens/genetics
• Hepatitis B virus/genetics
• Hepatitis C, Chronic/diagnosis
• Hepatitis C, Chronic/epidemiology
• Hepatitis C, Chronic/mortality
• Humans
• Liver Cirrhosis/diagnosis
• Liver Cirrhosis/epidemiology
• Liver Cirrhosis/virology
• Liver Neoplasms/diagnosis
• Liver Neoplasms/epidemiology
• Liver Neoplasms/virology
• Male
• Middle Aged
• Open Reading Frames
• Prevalence
• Prospective Studies
• Republic of Korea/epidemiology
• Risk Factors
• Viral Load

• Consequences of occult hepadnaviral infection
• Hepatitis B
• Hepatocellular carcinoma
• Occult hepatitis B virus infection
• Primary occult infection
• Secondary occult infection
• Woodchuck hepatitis virus
• Woodchuck model of hepatitis B

Hepatitis B virus (HBV) is classically considered to be hepatotropic, but accumulating evidences strongly support its extra-hepatotropic nature too. HBV nucleic acids and proteins have long been reported in a variety of extra-hepatic tissues. Of these, HBV has been studied in details in the peripheral blood mononuclear cells (PBMCs), due to its accessibility. From these studies, it is now well established that PBMCs are permissive to HBV infection, replication, transcription and production of infective virions. Furthermore, molecular evolutionary studies have provided definite evidences towards evolution of HBV genome in PBMCs, which is independent of evolution occurring in the liver, leading to the emergence and selection of compartment specific escape variants or drug resistant strains. These variants/resistant strains of HBV remain restricted within the PBMCs and are rarely detected in the serum/plasma. In addition, HBV infected PBMCs have been reported to be directly transmitted through intrauterine modes, and this infection does not correlate significantly with serum HBV surface antigen or HBV DNA markers. This editorial briefly reviews the current knowledge on this topic, emphasizes and delineates the gaps that are required to be filled to properly understand the biological and clinical relevance of extrahepatic tropism of HBV.

• Lymphotropism
• Compartmentalization
• Hepatitis B virus
• Peripheral blood mononuclear cell
• Genotype

• chronic hepatitis B
• clonal sequencing
• genotype
• lymphoid
• quasispecies

Hepadnavirus at very low doses establishes in woodchucks asymptomatic, serologically undetectable but molecularly evident persistent infection. This primary occult infection (POI) preferentially engages the immune system and initiates virus-specific T cell response in the absence of antiviral antibody induction. The current study aimed to determine whether POI with time may culminate in serologically identifiable infection and hepatitis, and what are, if any, its pathological consequences. Juvenile woodchucks were intravenously injected with inocula containing 10 or 100 virions of woodchuck hepatitis virus (WHV) to induce POI and followed for life or up to 5.5 years thereafter. All 10 animals established molecularly detectable infection with virus DNA in serum (<100–200 copies/mL) and in circulating lymphoid cells, but serum WHV surface antigen and antibodies to WHV core antigen remained undetectable for life. By approximately 2.5–3.5 years post-infection, circulating virus transiently increased to 10³ copies/mL and virus replication became detectable in the livers, but serological markers of infection and biochemical or histological evidence of hepatitis remained undetectable. Nonetheless, typical hepatocellular carcinoma (HCC) developed in 2/10 animals. WHV DNA integration into hepatic and lymphatic system genomes was identified in 9/10 animals. Virus recovered from the liver virus-negative or virus-positive phases of POI displayed the wild-type sequence and transmitted infection to healthy woodchucks causing hepatitis and HCC. In summary, for the first time, our data demonstrate that an asymptomatic hepadnaviral persistence initiated by very small amounts of otherwise pathogenic virus, advancing in the absence of traditional serological markers of infection and hepatitis, coincides with virus DNA integration into the host's hepatic and immune system genomes, retains liver pro-oncogenic potency and is capable of transmitting liver pathogenic infection. This emphasizes the role for primary occult hepatitis B virus infection in the development of seemingly cyptogenic HCC in seronegative but virus DNA reactive patients.

Introduction of highly sensitive molecular assays for detection of hepatitis B virus (HBV) identified the existence of persistent occult HBV infection years after recovery from an episode of hepatitis B and in individuals exposed to HBV but without symptoms and classical markers of infection. Because HBV integrates into human DNA and is a potent human carcinogen, it is postulated that occult HBV infection can be a cause of hepatic cancer in many individuals in which the tumor origin remains currently unknown. A causative relation between occult HBV infection and hepatocarcinoma is highly challenging to investigate in humans since occult HBV persistence is rarely diagnosed with current clinical assays and cancer development takes 15–30 years. However, we have established excellent models of occult HBV infection in the eastern North American woodchucks which are naturally susceptible to a virus closely related to HBV and in which chronic infection advances to liver cancer. In the current study, exploring experimental primary occult infection in woodchucks, we proved that the silently progressing infection, which is not detectable by serological markers, can culminate in hepatocellular carcinoma and that the persisting virus remains infectious, and causes hepatitis and liver cancer when transmitted to virus-naïve hosts.

• Animals
• Carcinoma, Hepatocellular/virology
• DNA, Viral/blood
• Disease Models, Animal
• Hepatitis B/complications
• Hepatitis B/virology
• Hepatitis B Virus, Woodchuck
• Liver Neoplasms/virology
• Marmota
• Reverse Transcriptase Polymerase Chain Reaction
• Viral Load

• MOP-14818 Canadian Institutes of Health Research

Occult hepatitis B virus (HBV) infection (OBI) is a challenging pathobiological and clinical issue that has been widely debated for several decades. By definition, OBI is characterized by the persistence of HBV DNA in the liver tissue (and in some cases also in the serum) in the absence of circulating HBV surface antigen (HBsAg). Many epidemiological and molecular studies have indicated that OBI is an important risk factor for hepatocellular carcinoma (HCC) development. OBI may exert direct pro-oncogenic effects through the activation of the same oncogenic mechanisms that are activated in the course of an HBsAg-positive infection. Indeed, in OBI as in HBV-positive infection, HBV DNA can persist in the hepatocytes both integrated into the host genome as well as free episome, and may maintain the capacity to produce proteins-mainly X protein and truncated preS-S protein - provided with potential transforming properties. Furthermore, OBI may indirectly favor HCC development. It has been shown that the persistence of very low viral replicative activity during OBI may induce mild liver necro-inflammation continuing for life, and substantial clinical evidence indicates that OBI can accelerate the progression of liver disease towards cirrhosis that is considered the most important risk factor for HCC development.

• Hepatitis B virus
• Hepatitis B virus surface antigen
• Hepatitis B virus DNA
• HBx protein
• Hepatocellular carcinoma
• Occult hepatitis B virus infection

• Animals
• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/virology
• DNA, Viral/analysis
• Disease Progression
• Genome, Viral
• Hepatitis B Surface Antigens/blood
• Hepatitis B virus
• Hepatitis B, Chronic/complications
• Hepatitis B, Chronic/diagnosis
• Hepatitis B, Chronic/pathology
• Hepatocytes/virology
• Humans
• Inflammation
• Liver/pathology
• Liver Neoplasms/complications
• Liver Neoplasms/diagnosis
• Liver Neoplasms/virology
• Risk Factors
• Treatment Outcome

Resolution of chronic hepatitis C is considered when serum HCV RNA becomes repeatedly undetectable and liver enzymes normalize. However, long-term persistence of HCV following therapy with pegylated interferon-α/ribavirin (PegIFN/R) was reported when more sensitive assays and testing of serial plasma, lymphoid cells (PBMC) and/or liver biopsies was applied. Our aim was to reassess plasma and PBMCs collected during and after standard PegIFN/R therapy from individuals who became HCV RNA nonreactive by clinical testing. Of particular interest was to determine if HCV genome and its replication remain detectable during ongoing treatment with PegIFN/R when evaluated by more sensitive detection approaches. Plasma acquired before (n = 11), during (n = 25) and up to 12–88 weeks post-treatment (n = 20) from 9 patients and PBMC (n = 23) from 3 of them were reanalyzed for HCV RNA with sensitivity <2 IU/mL. Clone sequencing of the HCV 5′-untranslated region from plasma and PBMCs was done in 2 patients. HCV RNA was detected in 17/25 (68%) plasma and 8/10 (80%) PBMC samples collected from 8 of 9 patients during therapy, although only 5.4% plasma samples were positive by clinical assays. Among post-treatment HCV RNA-negative plasma samples, 9 of 20 (45.3%) were HCV reactive for up to 59 weeks post-treatment. Molecularly evident replication was found in 6/12 (50%) among PBMC reactive for virus RNA positive strand collected during or after treatment. Pre-treatment point mutations persisted in plasma and/or PBMC throughout therapy and follow-up. Therefore, HCV is not completely cleared during ongoing administration of PegIFN/R otherwise capable of ceasing progression of CHC and virus commonly persists at levels not detectable by the current clinical testing. The findings suggest the need for continued evaluation even after patients achieve undetectable HCV RNA post-treatment.

• Antiviral Agents/administration & dosage
• Antiviral Agents/therapeutic use
• Female
• Hepacivirus/genetics
• Hepacivirus/isolation & purification
• Hepacivirus/physiology
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/virology
• Humans
• Interferon-alpha/administration & dosage
• Interferon-alpha/therapeutic use
• Limit of Detection
• Male
• Polyethylene Glycols/administration & dosage
• Polyethylene Glycols/therapeutic use
• RNA, Viral/blood
• Recombinant Proteins/administration & dosage
• Recombinant Proteins/therapeutic use
• Ribavirin/administration & dosage
• Ribavirin/therapeutic use
• Virus Replication

• MOP-126056 Canadian Institutes of Health Research

• Coinfection
• Hepatitis B
• Hepatitis B Surface Antigens

• occult hepatitis b
• hepatitis c
• pegylated interferon
• lamivudine

• Antiviral Agents/administration & dosage
• Antiviral Agents/therapeutic use
• Coinfection
• Drug Therapy, Combination
• Hepatitis B, Chronic/drug therapy
• Hepatitis B, Chronic/virology
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/virology
• Humans
• Interferon-alpha/administration & dosage
• Interferon-alpha/therapeutic use
• Lamivudine/administration & dosage
• Lamivudine/therapeutic use
• Male
• Polyethylene Glycols/administration & dosage
• Polyethylene Glycols/therapeutic use
• Recombinant Proteins/administration & dosage
• Recombinant Proteins/therapeutic use
• Ribavirin/administration & dosage
• Ribavirin/therapeutic use
• Viral Load
• Virus Activation
• Young Adult

• Carcinoma, Hepatocellular/virology
• Female
• Hepatitis B/complications
• Hepatitis B virus/physiology
• Hepatitis B, Chronic/complications
• Hepatitis C, Chronic/complications
• Humans
• Liver Neoplasms/virology
• Male
• Virus Replication

• hbv dna
• hepatitis b core antibody
• cirrhosis

• antiviral resistance
• diversity
• hbv
• peripheral blood mononuclear cells
• quasispecies
• reservoirs

• Adaptive Immunity
• Animals
• Annexins
• Apoptosis
• Cell Proliferation
• Cell Separation
• Disease Models, Animal
• Flow Cytometry
• Hepatitis B/immunology
• Hepatitis B/pathology
• Hepatitis B/physiopathology
• Hepatitis B/virology
• Hepatitis B Virus, Woodchuck/physiology
• Humans
• Marmota
• T-Lymphocytes/immunology
• T-Lymphocytes/metabolism
• T-Lymphocytes/pathology
• T-Lymphocytes/virology
• Virus Replication

• MOP-14818 Canadian Institutes of Health Research

Epidemiological studies have provided overwhelming evidence for a causal role of chronic HBV infection in the development of hepatocellular carcinoma (HCC), but the molecular mechanisms underlying virally-induced tumorigenesis remain largely debated. In the absence of a dominant oncogene encoded by the HBV genome, indirect roles have been proposed, including insertional activation of cellular oncogenes by HBV DNA integration, induction of genetic instability by viral integration or by the regulatory protein HBx, and long term effects of viral proteins in enhancing immune-mediated liver disease. In this chapter, we discuss different models of HBV-mediated liver cell transformation based on animal systems of hepadnavirus infection as well as functional studies in hepatocyte and hepatoma cell lines. These studies might help identifying the cellular effectors connecting HBV infection and liver cell transformation.

• HBx
• hepatitis B virus
• hepatocellular carcinoma
• pathogenesis
• transformation

• Animals
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/virology
• Hepatitis B virus/isolation & purification
• Hepatitis B virus/metabolism
• Humans
• Liver Neoplasms/diagnosis
• Liver Neoplasms/virology
• Molecular Biology/methods
• Viral Proteins/analysis

• Acute Disease
• Animals
• DNA, Viral/analysis
• Disease Progression
• Gene Expression Regulation, Viral
• Genes, Viral
• Hepadnaviridae Infections/immunology
• Hepadnaviridae Infections/metabolism
• Hepadnaviridae Infections/pathology
• Hepatitis B/immunology
• Hepatitis B Virus, Woodchuck/immunology
• Immunity, Cellular
• Immunity, Innate
• Liver/metabolism
• Liver/pathology
• Marmota
• Random Allocation

• Adaptation, Biological
• Animals
• Cell Line
• Cells, Cultured
• Hepatitis B Virus, Woodchuck/genetics
• Hepatitis B Virus, Woodchuck/growth & development
• Hepatocytes/virology
• Lymphocytes/virology
• Marmota
• Serial Passage