Journal of Hepatology
Volume 49, Issue 4 , Pages 652-657, October 2008

Statements from the Taormina expert meeting on occult hepatitis B virus infection☆

  • Giovanni Raimondo

      Affiliations

    • Unit of Clinical and Molecular Hepatology, Department of Internal Medicine, Messina University Hospital, Messina, Italy
    • Corresponding Author InformationCorresponding author. Tel.: +39 0 90 2212392; fax: +39 0 90 935162.
    • ,
  • Jean-Pierre Allain

      Affiliations

    • Department of Haematology, Division of Transfusion Medicine, Cambridge Blood Centre, University of Cambridge, Cambridge, UK
    • ,
  • Maurizia R. Brunetto

      Affiliations

    • Gastroenterology and Hepatology Unit, University Hospital of Pisa, Pisa, Italy
    • ,
  • Marie-Annick Buendia

      Affiliations

    • Unité d’Oncogenèse et Virologie Moléculaire and PT Puce à ADN, Institut Pasteur, Paris, France
    • ,
  • Ding-Shinn Chen

      Affiliations

    • Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
    • ,
  • Massimo Colombo

      Affiliations

    • First Division of Gastroenterology, A.M.& A. Migliavacca Center for Liver Diseases, IRCCS Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Milan, Italy
    • ,
  • Antonio Craxì

      Affiliations

    • Gastroenterology and Hepatology, Di.Bi.M.I.S., University of Palermo, Palermo, Italy
    • ,
  • Francesco Donato

      Affiliations

    • Institute of Hygiene, Epidemiology and Public Health, University of Brescia, Brescia, Italy
    • ,
  • Carlo Ferrari

      Affiliations

    • Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
    • ,
  • Giovanni B. Gaeta

      Affiliations

    • Department of Infectious Diseases, Second University of Naples, Naples, Italy
    • ,
  • Wolfram H. Gerlich

      Affiliations

    • Institute of Medical Virology, Justus Liebig University, Giessen, Germany
    • ,
  • Massimo Levrero

      Affiliations

    • Department of Internal Medicine and Laboratory of Gene Expression, Fondazione Andrea Cesalpino, University of Rome “La Sapienza”, Rome, Italy
    • ,
  • Stephen Locarnini

      Affiliations

    • Research and Molecular Development,Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
    • ,
  • Thomas Michalak

      Affiliations

    • Molecular Virology and Hepatology Research Group, Division of BioMedical Science, and Discipline of Laboratory Medicine, Faculty of Medicine, Health Science Centre, Memorial University, St. John’s, Newfoundland, Canada
    • ,
  • Mario U. Mondelli

      Affiliations

    • Area Infettivologica,Fondazione IRCCS Policlinico S. Matteo and Dipartimento di Malattie Infettive, University of Pavia, Pavia, Italy
    • ,
  • Jean-Michel Pawlotsky

      Affiliations

    • Department of Virology, French National Reference Center for Viral Hepatitis B, C and delta, and INSERM U841, Hôpital Henri Mondor, Université Paris XII, Créteil, Paris, France
    • ,
  • Teresa Pollicino

      Affiliations

    • Unit of Clinical and Molecular Hepatology, Department of Internal Medicine, Messina University Hospital, Messina, Italy
    • ,
  • Daniele Prati

      Affiliations

    • First Division of Gastroenterology, A.M.& A. Migliavacca Center for Liver Diseases, IRCCS Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Milan, Italy
    • Department of Transfusion Medicine and Hematology, A. Manzoni Hospital, Lecco, Italy
    • ,
  • Massimo Puoti

      Affiliations

    • Institute of Hygiene, Epidemiology and Public Health, University of Brescia, Brescia, Italy
    • ,
  • Didier Samuel

      Affiliations

    • Hôpital Paul Brousse, Centre Hépato-Biliaire, Université Paris-Sud, UMR-S 785, INSERM U785, Villejuif, France
    • ,
  • Daniel Shouval

      Affiliations

    • Liver Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel
    • ,
  • Antonina Smedile

      Affiliations

    • Department of Gastro-Hepatology, San Giovanni Battista (Molinette) Hospital, Turin, Italy
    • ,
  • Giovanni Squadrito

      Affiliations

    • Unit of Clinical and Molecular Hepatology, Department of Internal Medicine, Messina University Hospital, Messina, Italy
    • ,
  • Christian Trépo

      Affiliations

    • INSERM, U871, 26 Université Claude Bernard Lyon 1, Lyon, Hospices Civils de Lyon, Hôtel Dieu, Service d’Hépatologie, Lyon, France
    • ,
  • Erica Villa

      Affiliations

    • Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy
    • ,
  • Hans Will

      Affiliations

    • Heinrich-Pette-Institut für experimentelle Virologie und Immunologie an der Universität Hamburg, Hamburg, Germany
    • ,
  • Alessandro R. Zanetti

      Affiliations

    • First Division of Gastroenterology, A.M.& A. Migliavacca Center for Liver Diseases, IRCCS Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Milan, Italy
    • ,
  • Fabien Zoulim

      Affiliations

    • INSERM, U871, 26 Université Claude Bernard Lyon 1, Lyon, Hospices Civils de Lyon, Hôtel Dieu, Service d’Hépatologie, Lyon, France

published online 31 July 2008.

Associate Editor: M. Colombo

Article Outline

 

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1. Introduction 

Occult hepatitis B virus (HBV) infection is one of the most challenging topics in the field of viral hepatitis with its virological and clinical relevance being debated for more than 30years. Initially described in the late 1970s, this form of hepatitis B infection has now been further characterised. In particular, in the last 10years the application of highly sensitive molecular biology techniques has resulted in the elucidation of its virological features and possible clinical implications. It is noteworthy that there has been a steady and continuous increase in the number of publications on occult HBV infection, with many reviews, editorials and commentaries recently being published by journals covering different areas of bio-medical interest [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. However, several aspects of occult HBV infection are still not resolved, even including the definition itself as well as a standardised approach for laboratory-based detection.

An EASL endorsed international workshop on occult HBV infection was held in Taormina (Italy) on March 7–8, 2008. Invited presentations by experts and subsequent extensive discussions reviewed the virology and immunology of occult HBV infection as well as its diagnosis and epidemiology, risk of transmission by blood transfusion or liver transplantation, risk of reactivation in conditions of immune suppression, its potential significance in promoting the progression of chronic hepatitis and thereby possible intervention strategies, and finally its possible role in the development of hepatocellular carcinoma (HCC). The final session of the meeting focused on discussion among the members of the faculty that produced a number of statements and recommendations that are the subject of this report.

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2. Occult hepatitis B virus infection (OBI) 


•Definition: Presence of HBV DNA in the liver (with detectable or undetectable HBV DNA in the serum) of individuals testing HBsAg negative by currently available assays.When detectable, the amount of HBV DNA in the serum is usually very low (<200IU/ml).On the basis of the HBV antibody profile, OBI may be distinguished as:
Seropositive-OBI (anti-HBc and/or anti-HBs positive).

Seronegative-OBI (anti-HBc and anti-HBs negative).

In seropositive-OBI subjects, serum HBsAg may become negative either following the resolution of acute hepatitis B (thus, after a few months of HBsAg carriage) or after years of chronic HBsAg positive infection [33], [34], [35], [36], [37], [38], [39] (Fig. 1). The seronegative-OBI cases might have either progressively lost the hepatitis B specific antibodies or theoretically, the individual may have been hepatitis B specific antibody negative from the beginning of the infection (Fig. 1), similar to what has been observed in the woodchuck model of hepadnavirus infection with the woodchuck hepatitis virus (WHV) [40].

•“False” OBI: Cases with serum HBV DNA levels comparable to those usually detected in the different phases of serologically evident (overt) HBV infection have to be considered as “false” OBI and are usually due to infection by HBV variants with mutations in the S gene (escape mutants) producing a modified HBsAg that is not recognized by some or all commercially available detection assays [4], [7], [9], [15], [18], [20], [26], [29] (Fig. 1). Considering that the identification of these S-gene variants is essential for a correct diagnosis and for the possible clinical implications, the use of multivalent anti-HBs antibodies in the HBsAg assays is strongly recommended for optimal detection of these variants.

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3. Virological and immunological aspects 


•The molecular basis of persistent OBI is related to the long-lasting persistence of HBV cccDNA in the nuclei of hepatocytes [4], [26], [41], [42], [43], [44], [45].

•Almost all OBI cases are infected with replication-competent HBV showing strong suppression of overall replication activity and gene expression resulting in a significant reduced yield of HBV [4], [7], [9], [26], [46], [47].A small number of cases of OBI are due to infection with HBV mutants with defective replication activity or synthesis of S proteins respectively due to mutations in the Pol gene or in the S promoter genomic region [48], [49].

•HBV DNA may also be integrated in the OBI host’s genome [4], [14].

•OBI shows long-lasting specific T-cell immune-response against HBV epitopes with a profile that is different between OBI-seropositive and OBI-seronegative individuals. While ex vivo responses are similarly weak, in vitro T cell expansion following specific peptide stimulation is generally more efficient among seropositive OBI [50].

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4. Diagnosis of OBI and epidemiological aspects 


•HBV DNA is the only reliable diagnostic marker of OBI.

•Key recommendation: OBI tests must be performed only on samples collected and stored under the most appropriate conditions for polymerase chain reaction (PCR) procedures, paying particular attention to avoid cross-contamination.

•If highly sensitive HBV DNA testing is not feasible, anti-HBc should be used as a less than ideal surrogate marker for identifying potential seropositive OBI individuals in cases of blood, tissue or organ donation and when immune suppressive therapy has to be administered.In this context, it has to be stressed that not all anti-HBc positive individuals are found to be HBV DNA positive and that anti-HBc tests may provide false-positive results [7], [12], [24], [26], [29], [32].

•Standardized and valid assays for detection of OBI in liver tissue are not yet available. On the contrary, commercially available real time PCR-based assays for serum (or plasma) HBV DNA detection are sufficiently sensitive to detect many (but not all) OBI cases.

•The gold standard for occult HBV testing is the analysis of DNA extracts – from liver as well as from blood samples – amplified in two subsequent rounds of PCR (“nested” PCR) or by a “real time” PCR technique (detection limits of less than 10 copies of HBV DNA per reaction) and the use of oligonucleotide primers specific for different HBV genomic regions and complementary to highly conserved (genotype shared) nucleotide sequences [4], [5], [7], [26]. A set of primers that have been used by several investigators is shown in Table 1.
Table 1. Oligonucleotide primers for detection of occult HBV DNA through “nested” PCR amplification
HBV genomic regionsNucleotide positiona
S Region
S1-F: 5′-CATCAGGATTCCTAGGACCCCT-3′[168–189]
S2-F: 5′-CTTGTTGACAAGAATCCTCACA-3′[214–235]
S3-R: 5′-AGGACAAACGGGCAACATAC-3′[478–458]
S4-R: 5′-CCAACAAGAAGATGAGGCATA-3′[442–420]

Pre-core/core region
C5-F: 5′-TCACCTCTGCCTAATCATC-3′[1825–1843]
C6-F: 5′-TTCAAGCCTCCAAGCTGTGCC-3′[1862–1882]
C7-R: 5′-GAGGGAGTTCTTCTTCTAGG-3′[2391–2371]
C8-R: 5′-AGGAGTGCGAATCCACACTCC-3′[2277–2267]

Pol region
P9-F: 5′-CGTCGCAGAAGATCTCAATC-3′[2420–2439]
P10-F: 5′-CCTTGGACTCATAAGGT-3′[2463–2479]
P11-R: 5′-TCTTGTTCCCAAGAATATGGT-3′[2845–2825]
P12-R: 5′-TCCCAAGAATATGGTGACCC-3′[2839–2820]

X Region
X13-F: 5′-CGCCAACTTACAAGGCCTTTC-3′[1100–1120]
X14-F: 5′-CCATACTGCGGAACTCCTAG-3′[1266–1685]
X15-R: 5′-GGCGTTCACGGTGGTCTCCAT-3′[1628–1608]
X16-R: 5′-CGTAAAGAGAGGTGCGCCCC-3′[1540–1521]

aNucleotide positions of the primers are numbered from the unique EcoRI site and the nomenclature is according to Galibert et al. (Nature 1979;281:646–650.)

DNA should be isolated using the most efficient extraction procedure. It is mandatory to include appropriate controls of specificity and sensitivity and for contamination in each assay run. Moreover, sequencing analysis of amplicons is recommended.Considering that the OBI status is dependent on the long-lasting persistence of viral genomes in the hepatocytes, the analysis of liver DNA extracts (better from frozen tissues than formalin fixed ones) is the most appropriate for occult HBV detection. In order to minimize variations in the amount of input material used in the PCR, accurate spectrophotometric quantification of the cellular DNA or – in the case of real time PCR procedure – normalization by the use of a host cell gene (i.e. beta-globin) should always be performed.Since liver specimens are available only in a minority of cases, analysis of serum samples is the most common approach to identify cases of OBI. In this context, to improve the sensitivity of the test it is strongly suggested that DNA should be extracted from at least 1ml of serum and that serially collected samples be tested.In the woodchuck model, there is clear evidence that occult WHV may persist in peripheral blood mononuclear cells (PBMC) [2], [30]. However, for human HBV the available data on the possible presence of HBV DNA in PBMC of humans with OBI are presently inconclusive. Considering the potential clinical and diagnostic implications, well-designed clinical studies are clearly warranted to promptly resolve this issue.

•Although many studies have been carried out on OBI prevalence in different areas of the world and categories of individuals, the lack of standardization of laboratory techniques and differences in selection criteria of subjects do not allow meaningful comparisons. However, OBI prevalence seems to be higher among subjects at high risk for HBV infection and with liver disease than among individuals at low risk of infection and without liver disease [4], [9], [15], [26], [51].

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5. Clinical impact 


•HBsAg unreactive blood donations containing HBV DNA have to be considered infectious. As discussed above, the use of multivalent anti-HBs antibodies in the HBsAg detection kits is strongly recommended.The ability of HBV nucleic acid amplification testing (NAT) in detecting potentially infectious blood units before donation is clear nowadays. However, the real risk of transmission to recipients and the “cost/benefit ratio” of testing the blood of donors for OBI in terms of avoided morbidity and mortality still requires further evaluation [12], [25].

•There is a risk of transmission of occult HBV in cases of orthotopic liver transplantation (OLT) from an OBI-seropositive donor, in particular if the recipient is negative for all HBV serum markers.Prophylaxis with antiviral agents such as lamivudine prevents hepatitis B of the recipient in most (but not all) of these cases [8], [19].Although theoretically possible, there is no evidence of HBV transmission from occult HBV-seronegative organ donors, even if this may have been underestimated by a systematic assignment to de novo HBV infection after transplantation.

•Any patient with occult HBV receiving systemic chemo- radio- or immuno-therapy is potentially at risk of HBV reactivation [4], [7], [9], [15], [26], [27], [28].

•The risk of HBV reactivation is well documented in HBsAg positive hemato-oncologic patients who require pre-emptive antiviral therapy. However, the risk of HBV reactivation in OBI, with or without a low viral load, is still undefined and requires further study.All patients receiving chemo and immuno therapy should be tested at least once for anti-HBc antibodies before starting therapy and monitored periodically for ALT elevations. In case of ALT elevation, further diagnostic work-up is required pending initiation of antiviral therapy upon establishing the diagnosis of HBV reactivation [27].

•The risk of severe HBV reactivation is well documented in HIV-infected individuals, and it should particularly be taken into account after withdrawal of antiretrovirals active against HBV [22].The possible influence of OBI on chronic liver disease of HIV patients must be explored.

•Studies in the woodchuck model of hepadnavirus infection have clearly demonstrated that silently persisting WHV is infectious, and can be associated with liver pathology and play a role in oncogenesis [2], [30].

•The possible role of OBI in favouring or accelerating the development of cirrhosis (both in HCV co-infected and non-infected patients) is still unresolved [9], [15], [26].Prospective studies using standardized laboratory techniques and well-defined selection criteria of patients are needed on this critical issue.

•The available data does not allow any conclusion regarding the possible negative influence of OBI on the response to antiviral therapy in chronic hepatitis C, due to the heterogeneity of the patients studied so far, and to the lack of data with the current standard of treatment, i.e. PEG IFNs plus ribavirin.

•Many molecular-oncology and molecular-epidemiology studies suggest that occult HBV may be a risk factor for HCC development. In this context, OBI maintains several of the oncogenic mechanisms of HBV such as the capacity to be integrated in the host’s genome and production of transforming proteins [4], [7], [9], [13], [14], [23], [31], [52], [53]. However, to reach the conclusion that OBI plays a major role in hepatocellular transformation, further studies of molecular pathogenesis and prospective molecular epidemiological studies will still be required.

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6. Conclusions 

Occult HBV infection is a complex biological entity with possible relevant clinical implications.

There are discordant data sets on several aspects of OBI, mainly reflecting the lack of methodological uniformity among the different studies, and varied technical approaches employed for the diagnosis of OBI. The goal of the Taormina meeting was to review the present knowledge on occult HBV and to identify the most appropriate ways that should be followed in future studies. Hopefully, these statements may represent the basis for uniform methodological approaches that will be essential for resolving the current controversies that still exist with regard to this virologically important and clinically relevant topic.

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☆ The participants at this meeting declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this meeting report.

PII: S0168-8278(08)00479-0

doi:10.1016/j.jhep.2008.07.014

Journal of Hepatology
Volume 49, Issue 4 , Pages 652-657, October 2008

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