Journal of Hepatology
Volume 46, Issue 1 , Pages 160-170, January 2007

Occult hepatitis B virus infection

Unit of Clinical and Molecular Hepatology, Department of Internal Medicine, University of Messina, 98124 Messina, Italy

published online 07 November 2006.

Article Outline

Abstract 

The persistence of hepatitis B virus (HBV) genomes in HBV surface antigen (HBsAg) negative individuals is termed occult HBV infection. Occult HBV status is associated in some cases with mutant viruses undetectable by HBsAg assays, but more frequently it is due to a strong suppression of viral replication and gene expression. Occult HBV infection is an entity with world-wide diffusion, although the available data of prevalence in various categories of individuals are often contrasting because of the different sensitivity and specificity of the methods used for its detection in many studies. Occult HBV may impact in several different clinical contexts, including the transmission of the infection by blood transfusion or organ transplantation and its acute reactivation when an immunosuppressive status occurs. Moreover, much evidence suggests that it can favour the progression of liver fibrosis and above all the development of hepatocellular carcinoma.

 

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1. Introduction 

Occult hepatitis B virus infection (HBV) can be defined as the long-lasting persistence of viral genomes in the liver tissue (and in some cases also in the serum) of individuals negative for the HBV surface antigen (HBsAg). Suspected to exist since the early ’80s, this peculiar form of chronic viral infection has been better identified during the past ten years, when the availability of highly sensitive molecular biology techniques made it possible to disclose several of its virological aspects, to show its worldwide diffusion and to reveal its possible implication in various clinical contexts.

The aim of this review is to re-examine the available data about occult HBV infection, pointing out the aspects that most need to be clarified.

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2. Virological aspects 

The molecular basis of the occult infection is strictly related to the peculiar life cycle of the HBV, which is graphically summarized in Fig. 1. In particular, a fundamental step is the conversion of the ∼3Kb relaxed circular genome into a covalently closed-circular DNA (cccDNA), a long lived HBV replicative intermediate that persists in the cell nuclei as a stable chromatinized episome and that serves as template for gene transcription [1], [2]. The stability and long-term persistence of viral cccDNA molecules [3], [4] together with the long half-life of hepatocytes imply that HBV infection, once it has occurred, may possibly continue for life [5].

Why the occult HBV carriers are HBsAg negative despite the presence in their liver of episomal, free HBV genomes remains an unresolved question. Some of these individuals are infected by viral variants either producing an antigenically modified HBV S protein undetectable by the available HBsAg assays [6], [7], [8], [9], [10], [11] (even when the most sensitive ones are used [12], [13], [14]), or carrying mutations capable of inhibiting the S gene expression and/or the viral replication [15], [16], [17]. However, much evidence indicates that the genomic heterogeneity of the virus does not account for the occult status in the majority of the cases [18], [19], [20]. This consideration clearly emerges from the studies that extensively examined HBV isolates from liver tissue of occult HBV carriers [21], [22]. Thus, the occult infection appears to be mostly due to a strong suppression of viral replication and gene expression affecting viruses whose genetic variability is comparable to that of HBV strains from individuals with “overt” chronic HBV infection [23]. Relevant though indirect confirmation on this assumption is provided by the observations that occult HBV may be transmitted (experimentally to chimpanzees and by blood transfusion or organ transplantation to humans) inducing classic acute hepatitis B in the recipients [24], [25], [26], [27], [28], [29] and that occult HBV carriers may show an acute reactivation of the infection with the reappearance of the typical hepatitis B serological profile [30], [31], [32], [33], [34]. The mechanisms responsible for the inhibition of HBV activities remain at present largely obscure, and all the hypotheses proposed are essentially based on indirect evidence. Schematically, the available data suggest that (a) the host’s immune response, (b) co-infection with other infectious agents, and (c) epigenetic factors may play important roles in inducing the occult status, as briefly discussed below.

(a) The host’s immune-surveillance probably has a critical role in the development of the occult HBV infection, as suggested by at least two main arguments: first, there is evidence showing that a vigorous memory T-cell response against HBV antigens is still present many years after clinical recovery from acute B hepatitis, probably because the long-lasting persistence of the occult infection produces a minute (and undetectable) amount of antigens able to maintain an efficient anti-viral T-cell response [35], [36]; second, all the conditions inducing immunosuppression may provoke the reactivation of the occult HBV infection with the reappearance of the typical serological profile of the productive infection [30], [31], [32], [33], [34]. These occurrences strongly support the hypothesis that during occult infection a kind of balancing between the virus and the host’s immune system is established, and, besides the cytotoxic T lymphocytes, the cytokines synthesized in the liver might also exert a control on HBV replication. In fact, there is evidence indicating that cytokines like tumor necrosis factor α and interferon γ may strongly inhibit the HBV gene expression at post-transcriptional level [37], [38].

(b) The virus interference has been taken into account as an additional factor that might negatively influence HBV replication and gene expression. Co-infection with other agents may be of relevance in inducing HBV inhibition. Of note, the highest prevalence of occult HBV has been found in patients with hepatitis C virus (HCV) infection, and in vitro studies have clearly demonstrated that the HCV “core” protein strongly inhibits HBV replication [39], [40], [41]. Moreover, it cannot be excluded that also non-viral infectious agents might potentially induce a suppression of HBV activities. In this context, it has recently been shown that schistosoma mansoni infection is capable of strongly inhibiting HBV replication in a transgenic mice model [42].

(c) Recent evidence demonstrates that epigenetic mechanisms have an important role in the regulation of HBV replication and transcription. In fact, nuclear HBV cccDNA molecules – organized as viral minichromosomes, as mentioned above – seem to be subjected to the same enzymatic activities involved in chromatin remodelling [43]. According to this scenario, one might theoretically suppose that suppression of viral replication is achieved by active mechanisms of repression of the viral transcription mediated by deacetylases and methylases that, cooperating with other enzymatic activities and signalling pathways, establish posttranslational modifications of cccDNA-bound histones. Since several liver-enriched and ubiquitous host factors are involved in the regulation of HBV transcriptional program, we might hypothesize that HBV suppression is the result of functional (and potentially reversible) modifications of the intracellular environment that can be due to co-infection by other pathogens or chemical agents or cytokines. In this context, it has been reported that DNA damaging agents are able to suppress HBV replication through transcriptional repression of the virus mediated by the tumor suppressor protein p53 [44].

The strong suppression of HBV activity is responsible not only for the HBsAg negativity but also for the very low or even undetectable levels of serum HBV DNA characterizing most of the cases with occult infection [19], [45], [46], [47]. In fact, the studies evaluating the presence of occult HBV both in liver and in serum samples have shown that a relevant percentage of subjects who are negative for HBV DNA in the serum prove to be positive at liver tissue level [21], [48], [49], [50]. However, the fact that occult HBV carriers have very low viremia levels does not necessarily imply that the amount of viral genomes present in the liver is also very low. In fact, the quantification of intra-hepatic viral DNA in different sets of chronic HBV infected individuals demonstrated that the amount of HBV DNA in the liver of occult HBV infected patients is often comparable to that detected in HBsAg positive individuals [51].

Another relevant aspect to be discussed is that, although occult HBV infection is significantly associated with the presence of anti-HBV antibodies (namely, anti-HBc and anti-HBs antibodies directed against the viral core antigen and the HBsAg, respectively), it must be stressed that more than 20% of the occult carriers are negative for all serum markers of HBV infection, as evaluated by a recent review [46]. At present, it is unknown whether the complete HBV seronegativity is dependent on a progressive disappearance of all viral markers developing in the years after the resolution of an acute infection, whether it occurs from the beginning of the infection or whether both these two conditions may occur in the various cases. What is clear is that the comprehension of the “biological reasons” underlying the existence of the two categories of subjects with cryptic infection (individuals positive for anti-HBV antibodies and individuals negative for all serum HBV markers) as well as the identification of hypothetical clinical differences between them constitute, at present, a major challenge in the occult HBV field of research.

2.1. Detection of occult HBV infection 

Considering what is reported above, there is no doubt that the analysis of liver DNA extracts is the most correct methodological approach for occult HBV detection. However, it must be considered that the availability of liver tissue specimens depends on the execution of a needle liver biopsy that, as is obvious, cannot be performed in the great majority of the subjects. In fact, most of the available data on occult HBV infection come from studies performed by analysing blood samples. Moreover, the technical procedures used so far have differed greatly from one study to another in terms both of specificity and sensitivity and, as a consequence, the results obtained have frequently been contradictory. Commercial, standardized and valid assays for studying the cryptic infection are not yet available. Therefore, at present, the gold standard to test for occult HBV is still the “home made” analysis of DNA extracts – from liver as well as from blood samples – performed by a “nested”-PCR technique and the use of oligonucletide primers specific for at least three different HBV genomic regions. With this approach, only the cases in which HBV DNA is detected using at least two different sets of primers may be considered positive for the cryptic infection [19], [21], [22], [46], [52].

2.2. Animal models 

The occurrence of an occult infection has also been demonstrated both in ground squirrels and in woodchucks infected, respectively, by the ground squirrel hepatitis virus (GSHV) and the woodchuck hepatitis virus (WHV), two viruses of the Hepadnaviridae family closely related to HBV [53], [54]. In particular, interesting findings have recently been obtained with the woodchuck model. In fact, it has been shown that the lifelong silent persistence of WHV is an invariable consequence of resolved acute viral hepatitis [55], and that this virus is transmittable from mothers to newborns where it induces an asymptomatic long-term infection [56] Moreover, this model revealed that the virus, when inoculated at doses containing less than 103 virions, may establish an infection that initially engages the lymphatic system – and only later on may involve the liver too – and persists in the absence of all the virus serological markers [57]. This “primary” occult infection does not protect against re-infection with a large WHV dose in contrast to the “secondary” (residual) silent WHV persistence, which normally endures after the resolution of viral hepatitis and is positive for antibodies to the virus antigens [57].

2.3. Prevalence 

Occult HBV infection is a world-wide diffused entity, although its distribution may reflect the general prevalence of the HBV in the various geographic areas and in the various populations.

There is a fairly general agreement in considering HCV infected patients as the category of individuals with the highest prevalence of occult HBV [18], [19], [45], [46], [47]. In particular, HBV DNA is detectable in about one-third of HBsAg negative HCV carriers in the Mediterranean basin, and this prevalence is even higher in Far East Asian countries [21], [22], [58], [59], [60], [61]. Patients with HCV-negative chronic liver disease have been less investigated than HCV infected ones, and variable prevalence has been reported in subjects with cryptogenic liver disease [15], [18], [21], [62], [63], [64].

Besides the patients with liver disease, the categories of individuals at high risk of parenteral-transmitted infections have also been widely investigated for occult HBV. In general, a high prevalence has been reported, with 45% in intravenous drug addicts in Baltimore [65] and 51% in hemophiliacs in Japan [66]. On the contrary, the studies performed up to now on hemodialysis patients provide widely divergent results, reporting a prevalence of occult HBV that ranges from 0% to 36% in the most recent reports [67], [68], [69], [70], [71], [72]. As mentioned above, however, these discrepancies appear to be mainly dependent on the different sensitivity and specificity of the assays utilized in the various studies (Table 1). In this context, it is of note that several authors consider occult HBV as a possible source of virus spread in hemodialysis units (thus representing a risk of infection for both patients and staff), and suggest some precautions including HBV DNA screening for all hemodialysis patients [71].

Table 1. Reported prevalence of occult HBV infection in haemodialysis patients
StudyCountryNo. of patientsOccult HBV No. (%)Methods
Siagris et al. (2006) [67]Greece49a10 (20.4)Single step PCR
Kanbay et al. (2006) [68]Turkey13821 (15.2)Real time PCR
Goral et al. (2006) [69]Turkey50a0Single step PCR
Fabrizi et al. (2005) [70]Italy2130Single step PCR
Minuk et al. (2004) [71]Canada2399 (3.8)Real time PCR
Besisik et al. (2003) [72]Turkey33a12 (36.4)Double step (“nested”) PCR

aAll patients were anti-HCV positive.

A category of patients where the available data of occult HBV prevalence are wildly divergent is that of HIV positive individuals. In fact, the published prevalence ranges from 0% to 89% [73], [74], with a considerable number of other studies reporting results between those two extremes [75], [76], [77], [78], [79], [80], [81], [82], [83] (Table 2). The great difference in sensitivity and specificity of the assays used in these various studies has already been denounced in a previous review [84]. For this purpose, it is of note that the study finding the highest prevalence of occult HBV both used a very sensitive HBV DNA amplification procedure and examined serial serum samples from each individual [74]. Indeed, since serum HBV DNA levels seem to fluctuate even in cryptic HBV carriers, it is becoming clear that repeating the HBV test over time is a useful tool in identifying the occult HBV status [76], [85].

Table 2. Reported prevalence of occult HBV infection in HIV positive patients
StudyCountryNo. of patientsOccult HBV No. (%)Methods
Hofer et al. (1998) [74]Switzerland5751 (89)Double step (“nested”) PCRb
Torres-Baranda et al. (2006) [75]Mexico357 (20)Double step (“nested”) PCR
Filippini et al. (2006) [76]Italy8617 (20)Single step PCRb,c
Mphahlele et al. (2006) [77]South Africa14031 (22)Double step (“nested”) PCR
Pogany et al. (2005) [78]Netherlands93a4 (4)Single step PCRd
Neau et al. (2005) [79]France160a1 (0.6)Single step PCRd,e
Santos et al. (2003) [80]Brazil101a16 (16)Single step PCRc
Wagner et al. (2004) [81]France30a11 (37)Double step (“nested”) PCR
Goncales et al. (2003) [82]Brazil1598 (5)Double step (“nested”) PCR
Nunez et al. (2002) [73]Spain850Single step PCRd
Piroth et al. (2000) [83]France3713 (35)Single step PCRb,c

aAll patients were positive for anti-HBV antibodies.

bAmplification test performed in serially collected serum samples.

cAmplification test performed with the use of multiple sets of primers.

dAmplification test performed with the use of single set of primers.

eFifty-two patients tested at two different time points.

Concerning the populations of apparently healthy individuals, occult HBV has been quite extensively explored in blood donors and much less in the general population. Again, the available data provide incomplete information. Among the blood donors, this cryptic infection appears to be a rare occurrence in the western world, whereas it is frequently detected in the developing countries [86]. As far as the general population is concerned, in a recent study evaluating the occult HBV prevalence in HBsAg negative residents of a Canadian Inuit community, Minuk et al. detected HBV DNA in 18% of anti-HBc positive subjects and in 8% of HBV seronegative individuals, respectively [87], whereas Kim et al. found occult HBV in 31 of 195 (16%) Korean HBV/HCV negative healthy subjects with normal transaminase values [88], and Hui et al. detected occult HBV genomes in 19 out of 124 (15.3%) healthy hematopoietic stem cell donors from Hong Kong [89].

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3. Clinical relevance 

The emerging evidence of the potential, considerable clinical relevance of the occult HBV infection is the main reason for the growing interest in this topic. Occult HBV may impact in several different clinical contexts that we have schematically grouped into four main points which are briefly discussed below.

3.1. Transmission of occult HBV infection 

Carriers of occult infection may be a source of HBV transmission in the case of blood transfusion [27], [90], [91] with the consequent development of a typical type B hepatitis in the recipients. This possible occurrence was first reported in the late 1970s [26], [92] and experimentally confirmed in chimpanzees some years later [93]. At present, post-transfusional hepatitis B is a rare event in the western world [94] (although the residual risk of transmission of the HBV by transfusion is surely higher than HCV or HIV [86]) and occult HBV infection of the donors appears to be the main factor responsible for the residual cases [95]. Interestingly, occult HBV is the major cause of transfusionally transmitted HBV infection also in countries like Taiwan and India where the incidence of post-transfusional hepatitis B is still anything but negligible [96], [97]. After HIV and HCV, nucleic acid amplification techniques (NAT) are now commercially available also for HBV testing. Obviously, it is not the task of this review to enter in the debate about the appropriateness of introducing this assay in blood donor screenings. What is clear, however, is that all the discussion regarding the use of NAT for HBV detection concerns its ability to identify occult HBV.

Occult HBV infection may also be transmitted in the event of organ transplantation, and in particular in the cases of orthotopic liver transplantation (OLT) as obvious consequence of the fact that the hepatocytes are the reservoir of the viral strains [25], [29], [98], [99]. Indeed, occult HBV transmission appears to be a very low risk occurrence in cases of kidney or heart [28], [100], and it is uncommon also in bone marrow transplantation [101]. In cases of OLT, from 17% to 94% of HBsAg negative/anti-HBc positive donors may transmit HBV infection to the recipients (reviewed in [102]), while the transmission of the occult infection from HBV seronegative individuals is uncertain (and also difficult to recognize).

3.2. Reactivation of occult HBV infection 

As mentioned above, the state of suppression of viral replication and gene expression typical of the occult HBV status may be discontinued, leading to the development of a typical hepatitis B that often has a severe – and sometimes even fulminant – clinical course. This event is usually observed in patients under condition of immunosuppression induced by therapies and/or related to diseases that involve the immune system [24], [30], [31], [32], [33], [34], [103], [104], [105], [106], [107], [108]. In fact, an occult HBV carrier becoming immunocompromised may show a reactivation of the viral replication because of the fault of the immunological control, and, once recovery is achieved and immune surveillance re-constituted, the CTL-mediated hepatocyte injury may occur leading to the development of hepatitis. The virological and clinical reactivation of the occult HBV infection has been repeatedly observed in several different clinical conditions including hematological malignancies, HIV infection, hematopoietic stem cell transplantation, and organ transplantation (Table 3). In this context, it is of note that occult HBV infected patients undergoing OLT may present re-infection of the new liver [109], and occasionally this event may be followed by virological and clinical re-activation [110]. Moreover, the availability of new, potent immunosuppressive drugs – like the anti-CD20, the anti-CD52 and the anti-TNF monoclonal antibodies, recently introduced in the therapeutic schedules of various clinical settings – seems to have further increased the risk of HBV reactivation in cryptically infected individuals that may present very severe clinical sequels [111], [112], [113], [114], [115].

Table 3. Categories of occult HBV carriers known to be prone to viral reactivation
Patients with
Haematological malignancies
HIV infection
Patients underwent
Bone marrow transplantation
Liver transplantation
Kidney transplantation
Chemotherapy
Treatment with anti-CD20 (Rituximab)
Treatment with anti-CD52 (Alemtuzumab)
Treatment with anti-TNF (Infliximab)

Finally, an aspect that is still unclear is the frequency of occult HBV reactivation. For this purpose, Onozawa et al. recently reported an interesting study performed on 14 anti-HBs/anti-HBc positive patients who underwent allogenic hematopoietic stem cell transplantation [116]. Twelve individuals experienced the progressive and persistent disappearance of anti-HBs and 7 HBsAg re-seconvertion. Of these last 7 cases, only one developed symptomatic acute hepatitis and needed hospitalisation. This article thus suggests that occult HBV reactivation is quite a frequent event in immunocompromised patients, but, since it is usually investigated only in the case of development of acute hepatitis, its recognition might be missed in most of the cases. All these data clearly justify the recommendation to monitor all patients undergoing immunosuppressive therapy very carefully for HBV serology and/or viremia – particularly if they are antibody to viral antigen(s) positive – and to continue this monitoring for months (or even years) after stopping treatment. In fact, the precocious identification of a virological reactivation makes it possible to begin specific antiviral therapy early, which may prevent the occurrence of hepatitis B that appears to be very dangerous in this subset of patients [117].

3.3. Occult HBV infection and chronic liver disease 

Individuals who have recovered from self-limited acute hepatitis may persistently carry HBV genomes for decades without showing any clinical or biochemical sign of liver damage [35], [36], [118], [119]. However, when the liver tissue of this kind of subjects has been examined, the histological patterns of a mild necroinflammation have been revealed up to 30 years after the resolution of the acute hepatitis [50], [120]. Very similar results were observed in woodchucks convalescent from acute WHV hepatitis: these animals show the lifelong persistence of small amounts of replicating virus associated with a mild liver necroinflammation continuing for life [55].

These data tempted us to speculate that – at least in conditions of immunocompetence – the occult infection is inoffensive in itself, but when other important causes of liver damage co-exist, the minimal lesions produced by the immune response to the occult virus might contribute to making the course of the liver disease worse over time [121]. This hypothesis is consistent with the evidence that occult HBV infection might favour or accelerate the progression of chronic liver disease in HCV infected individuals, as most of the studies on this topic – although not all of them – suggest [21], [61], [122], [123], [124], [125], [126], [127] (Table 4). The possible negative influence of cryptic HBV on the clinical outcome of chronic hepatitis C is, obviously, one of the most important issues of the entire chapter of occult HBV infection, and definitive clarification of this matter should be of fundamental importance. In this context, considering that only cross-sectional evaluations have been performed so far, it is hopeful that a methodologically correct (also from the diagnostic point of view) prospective study will be performed in the near future.

Table 4. Studies describing the association of occult HBV infection with severe chronic liver disease and/or HCC
StudyGeographic areaAetiology
Occult HBV and chronic liver disease
Sagnelli et al. (2001) [124]ItalyHCV
De Maria et al. (2000) [125]USAHCV
Cacciola et al. (1999) [21]ItalyHCV
Villa et al. (1995) [61]ItalyHCV
Squadrito et al. (2006) [126]ItalyHCV
Zhang et al. (1993) [64]ChinaCryptogenic
Chemin et al. (2001) [62]FranceCryptogenic
Berasain et al. (2000) [63]SpainHCV/cryptogenic
Chen et al. (2002) [123]TaiwanHCV/cryptogenic
Fukuda et al. (1996) [130]JapanCryptogenic
Jilg et al. (1995) [122]GermanyHCV/Cryptogenic
Liang et al. (1991) [48]IsraelCryptogenic
Occult HBV and HCC
Shafritz et al. (1981) [133]South AfricaUnknown
Brechot et al. (1981) [134]FranceUnknown
Paterlini et al. (1990) [135]South Africa, Italy, France, and JapanUnknown
Paterlini et al. (1993) [136]FranceHCV/cryptogenic
Sheu et al. (1992) [138]TaiwanHCV/cryptogenic
Yu et al. (1997) [139]USAHCV/cryptogenic
Koike et al. (1998) [59]JapanHCV
Kubo et al. (1998) [140]JapanHCV
Huo et al. (1998) [141]TaiwanHCV/cryptogenic
Pollicino et al. (2004) [22]ItalyHCV/cryptogenic
Donato et al. (2006) [132]ItalyHCV/Alcoholic
Yotsuyanagi et al. (2004) [142]JapanAlcoholic
Squadrito et al. (2006) [126]ItalyHCV

As a note, we have to report that several studies performed in the 1990s suggested that occult HBV may exert its negative influence on chronic hepatitis C also in terms of a reduced response to IFN therapy [21], [58], [125], [128], [129]. The mechanisms by which the occult HBV may help HCV to resist IFN are at present totally unknown. Although this topic is intriguing and potentially very relevant, from a practical point of view we must point out that all the cited reports concerned treatment schedules using the conventional IFN therapy, whereas there are no reliable studies evaluating whether occult HBV infection may interfere with the response to PEG-IFN plus Ribavirin (the present gold-standard therapy for the chronic hepatitis C treatment). This particular aspect of the possible interaction between the two viruses must be completely re-evaluated once more valid data are available.

Several reports indicate that occult HBV infection is associated with the progression of liver fibrosis and cirrhosis development also in patients with cryptogenic liver disease [18], [48], [62], [63], [64], [122], [123], [130]. This observation is not easy to explain, also in consideration of the above-mentioned hypothesis that occult HBV might be unable to produce severe hepatic injury by itself. A plausible explanation is that some of the patients with productive HBV infection may present a progressive reduction of viral replication and serum HBsAg amount. The HBsAg may even disappear over time despite the presence of severe liver disease that had been provoked by the overt B hepatitis and then maintained once the occult HBV status occurs [123].

3.4. Occult HBV infection and HCC 

A great deal of solid evidence indicates that occult HBV infection is a risk factor for HCC development (reviewed in [19], [46], [131], [132]). The association between occult HBV and liver cancer was suggested by the first epidemiological and molecular studies performed in the 1980s, and subsequently widely confirmed also when the most sensitive and specific molecular techniques became available [22], [59], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142] (Table 4). Moreover, our very recent observational cohort study showed that, among HBsAg negative patients with chronic hepatitis, HCC mostly develops in carriers of occult HBV [126]. Finally, experiments in animal models demonstrated that both woodchucks and ground squirrels, once infected by WHV and GSHV, respectively, are at high risk of developing HCC also after the apparent clearance of the virus [53], [54]. The cryptic infection appears to exert its pro-oncogenic role in HCV infected patients as well as in alcoholics and in individuals with cryptogenic liver disease [22], [132], [142]. Initially, the transforming capacity of the occult HBV was considered the consequence of the integration of viral DNA into the host’s genome. However, the subsequent observations that (a) the occult strains usually persist as free episomal forms [143] (that can be detected also in tumor liver tissues [22]) maintaining the capacities to transcribe and replicate; (b) the lifelong persistence of these replicating viruses may induce a mild liver necroinflammation continuing for life; (c) cirrhosis is the most important risk factor for HCC development and, as mentioned above, occult HBV infection is believed to contribute to progression toward cirrhosis in HBsAg-negative chronic liver disease, suggesting that occult HBV might contribute to hepatocellular transformation through the same mechanisms traditionally considered the basis of the tumorigenic properties of the HBV, which – it should not be forgotten – has been classified as a Group 1 human carcinogen and is considered the second most important oncogenic agent after smoking tobacco [144], [145].

In conclusion, occult HBV infection is a phenomenon mainly related to the intrahepatic persistence of viral cccDNA and to a strong suppression of viral replication and gene expression. In consideration of the very low levels of serum HBV DNA, its detection requires the use of highly sensitive and specific molecular biology techniques. The inhibition of HBV replication may be reversible and the occult infection may reactivate leading to acute and severe forms of classical hepatitis B, which may also occur after transmission of occult HBV by blood transfusion or organ transplantation. The long-lasting persistence of the virus in the liver may provoke a very mild but continuing necroinflammation that – if other causes of liver damage co-exist – may contribute over time to the progression of the chronic liver damage toward cirrhosis. Moreover, occult HBV seems to maintain the pro-oncogenic properties typical of the overt infection, and in fact it is an important risk factor for HCC development. Considering what is summarized above, we believe that the clinicians should take into account the presence of occult HBV infection in several categories of patients, such as immunosuppressed subjects and cirrhotic individuals who, when they carry this peculiar infection, are at the highest risk of developing viral reactivation and liver cancer, respectively.

Several additional arguments (i.e. possible extrahepatic sites of the occult HBV reservoir; occult HBV and HBsAg-negative fulminant hepatitis; influence of occult HBV on the liver disease of particular populations such as HIV infected patients, etc.) have not been discussed in this review, since we considered the available data still too incomplete. Occult HBV infection is a complex entity comprising many conditions and situations that may be widely different from each other both from the biological point of view and in terms of clinical consequences. These considerations imply the need for a critical re-evaluation of the large amount of available information by experts who should also establish a common definition and the best ways of increasing our knowledge on this fascinating field of bio-medical research.

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PII: S0168-8278(06)00577-0

doi:10.1016/j.jhep.2006.10.007

Journal of Hepatology
Volume 46, Issue 1 , Pages 160-170, January 2007

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