|Year : 2005 | Volume
| Issue : 1 | Page : 14-30
|Occult hepatitis B virus infection
Department of Haematology, University of Cambridge, Cambridge, United Kingdom
Click here for correspondence address and email
|How to cite this article:|
Allain JP. Occult hepatitis B virus infection. Hep B Annual 2005;2:14-30
| Introduction|| |
Occult hepatitis B infection (OBI) has been recognized for nearly 20 years. However, with the improvements in sensitivity of serological and genomic amplification assays, the frequency and attention given to this nearly silent form of the infection has been growing. Because low or very low viral load is part of the definition of OBI, molecular data are scarce, and, because most patients affected are asymptomatic, little clinical data, in particular histological, is available. In this short review, the biological background, diagnostic and clinical significance of this not so rare condition will be reviewed.
Occult hepatitis B virus infection is defined as the presence of viral DNA in circulating blood without detectable HBV surface antigen (HBsAg). The frequency of this condition is directly dependent on the sensitivity of either or both assays. The prevalence will be maximum with an insensitive HBsAg assay and very sensitive genomic amplification method. At present, the third generation of tests led by the Abbott PRISM can detect HBsAg levels less or equal to 0.1 ng/ml and the most sensitive NAT by transcription mediated amplification or real time PCR (QPCR) can detect 10 IU/ml or approximately 50 copies of viral genome/ml. In the past few years, several excellent reviews have been published on the topic.,,,
In addition to test sensitivity, there is a growing body of evidence suggesting that HBV genotype is a factor influencing the frequency of occult HBV. This difference is essentially related to the occurrence of anti-HBe seroconversion, which is well known to correlate with a dramatic decrease in viral load and viral replication. Fifty per cent seroconversions seem to occur in early childhood in infections with genotype E (before age 10), later when infected with genotypes A and D (before age 20), at around 30 with genotype B and at the oldest age of 40 with genotype C.,, The non-replicative phase following anti-HBe conversion can last for decades, during which the level of replication progressively declines resulting in extremely low levels of both HBsAg and viral DNA. However, in this particular phase of the HBV natural history, no correlation can be found between the levels of production of these two critical viral markers., Detectable HBsAg may correspond to HBV DNA below the lowest limit of detection in up to 20% of cases and viral DNA load below 500 IU/ml most of the time corresponds to undetectable HBsAg.,, Occult HBV during the non-replicative phase is therefore expected to be more frequent in areas where genotypes A, D and E are prevalent and less frequent in the far East predominantly infected with genotypes B and C.
Mechanisms leading to occult HBV infection [Table - 1]
- Four main mechanisms may lead to occult HBV infection. Three of them are operating in chronically infected individuals:
- Undetectable HBsAg at the tail end of chronic carriage during the above mentioned long term non-replicative phase following anti-HBe conversion,
- The occurrence of escape mutants interfering with HBsAg synthesis or detectability by various serological assays,
- The interference of other viruses in HBV replication, primarily the defective Delta virus, but possibly others.
The last type of situation occurs in individuals who have recovered from an acute infection in whom HBV persists mostly in sanctuaries such as the liver tissue but also occasionally in the circulation.
Each situation presents a number of features affecting the diagnosis. The mechanisms leading to the condition, which are reviewed below.
Occult HBV during this phase is characterized by the presence of two serological markers: anti-HBe and anti-HBc. However, over time, the titers of both the types of antibodies tend to decline and, after a few years, only anti-HBc remains detectable, becoming anti-HBc positive only (apart from the presence of HBV DNA). From a clinical point of view, this phase is typically asymptomatic with normal level of ALT. However, in some studies where a liver biopsy was obtained, liver fibrosis and signs of inflammation have been found. The difficulty at this stage is that a similar association of HBV markers can be found in another situation to be described later that is recovered HBV infection typically defined as the concomitant presence of anti-HBc and anti-HBs. Over several years, anti-HBs may become undetectable, leaving anti-HBc as sole serological markers. Low levels of HBV DNA may be detectable mimicking the previously described situation. Differential diagnosis between the two situations would be possible by studying the antibody response to natural exposure to the virus or vaccination with HBs antigen. In recovered infections, anti-HBs would reappear after approximately 7 days but not in chronic infections.,
Another potential differential tool might be the molecular detection of the pre-core stop codon typically associated with anti-HBe seroconversion in chronic infection. Irrespective of genotype, in viral strains carrying T-1858, >90% of samples with anti-HBe also carry the pre-core stop codon at position 1896. However due to the very low viral load seen in most occult HBV infection, it is technically difficult to obtain sequences. Nevertheless, in a group of 21 patients with non-B- non-C hepatitis without anti-HBc, HBV DNA was detected and sequenced, and in all cases, the 1896 stop codon was found.
In another study, among 10 patients with HCV infection and HBV markers, three were anti-HBc positive only and seven had anti-HBs. Contrary to the previous study, only one had the 1896 stop codon and none had core promoter mutations. The contrasting picture between these two groups of patients suggests that the first group had occult chronic infection and the second persistent infection after recovery. The 1896 mutation might indicate chronic infection and wild type persistent HBV after recovery.
Mutations [Table - 2]
The development of HBV mutations interfering with viral replication or antibody recognition of HBsAg in serological assays has been known for many years. However, when viral DNA is detected and HBsAg is not, several types of mutations can explain this discrepancy.
First, there might be mutations interfering with viral replication in the pre-core (PC) region such as the classical 1896 stop codon already mentioned or mutations might occur in the Basic Core Promoter (BCP) pseudo TATA box region which initiates the synthesis of pregenomic RNA. For both types of mutations, there is conflicting evidence regarding their impact on viral replication. The PC 1896 G-A mutation correlates with the occurrence of anti-HBe and the rapid decline of HBV DNA load but experimental evidence of a direct effect on replication is unclear. Similarly, the BCP mutations at position 1762 and 1764 or deletions in the same region do not clearly correlate with a lower viral load. In vitro systems to determine the impact on replication provided variable results of decrease, increase or no effect, depending upon the reports.,,, Considering the differences in sensitivity between the assays detecting HBsAg and HBV DNA, it is possible that very low levels of viral replication might produce detectable DNA and undetectable HBsAg in relation to these mutations. However, no clear evidence that this mechanism might be involved in OBI has been provided.
The second type of mutation is occurs in the pre-S region. pre-S1 codes for the translation of the long S protein where the putative viral ligand binding to target cells is located. In the absence of pre-S1 transcription caused by a stop codon or a major deletion, viral replication can be seriously impaired and/or the production of HBsAg considerably decreased. A recent article by Chaudhuri et al reported the frequent presence of a pre-S1 single nucleotide mutation or deletions of 9-15 nucleotides at position 58-95 or pre-S1/pre-S2 deletions (95-23 or 78-9) in cases of occult HBV infections detected in patients with chronic liver disease. In these cases, premature termination or absence of translation was predicted. In these samples of genotype A or D, the viral load was low in 8 (10E3-10E4 copies/ml) and higher in the last sample (10E7 copies/ml). Another report has described 40 and 60 nucleotide deletions in pre-S2. The interpretation of the data in this situation is that pre-S1/pre-S2 variants may not only limit viral replication by interfering with viral attachment to target cells but may also limit HBsAg production to the small molecular form of the envelope protein.
The third type of mutations affecting the amino acid sequence of the antigenic 'a' region of the S gene has been extensively studied. Mutations in the third or fourth loop (aa 124-147) affected the conformation of the epitopes and their recognition by assay capture and/or detection antibodies, particularly when monoclonal. The most frequent mutation is a substitution of amino acid in position 145 from glycine to alanine and the most disrupting were substitution of the cysteines in positions 121 124, 137 or 147. In occult HBV, such substitutions of Cysteines at positions 121, 147 by and G/A at position 145, as well as several other substitutions in loops 3 and 4 have been described.,,, In such cases, the viral load would be expected to be high if the cause of occult HBV was duek lack of HBsAg detection. However, in two articles where viral load was indicated, it tended to be low (<10E4 copies/ml) suggesting that the 'a' region mutations did not play a major role in HBsAg detection and the diagnosis of occult infection.,
The interference by the delta virus (HDV) in HBV replication has been known for many years. In the presence of anti-HDV, the HBV load in patients with chronic liver disease is significantly lower than in those without anti-HDV. In these patients, HBsAg detection can be very difficult with the relatively insensitive tests. Although this mechanism has not been specifically implicated in the occurrence of occult HBV, it might occasionally be involved.
A series of reports were recently published indicating that in chronic HCV infection with liver disease, occult HBV infection was relatively frequent.,,,, In such cases, anti-HBc was present and in up to 20% of patients HBV DNA was found. In one study, 15/21 patients had low levels of HBV DNA detectable in the liver tissue and only 4/21 had HBV DNA in circulation, with a viral load below 2500 copies/ml. There is preliminary data suggesting that the HCV core protein might inhibit the replication of HBV. Conversely, there is some evidence that HBV replication might interfere with HCV viral load. However, there is no clear evidence that the association of these infections has a significant impact on the severity of liver disease, including on the occurrence of hepatocellular carcinoma (HCC).
Persistence after recovery
Long-term follow-up of adult patients after HBV acute infection for 2-13 years has shown that, contrary to previous interpretation, HBV remains detectable in a substantial number of recovered infections. Viral genome was present in circulation in 9/17 patients in one study at a level close to the threshold of sensitivity of the nested PCR as no more than two of four repeats yielded a positive result. Another study from the same laboratory showed that the detected viral DNA was indeed originating mostly, but probably not exclusively from complete viral particles circulating as immune complexes., When samples were available, viral DNA was also detectable in peripheral blood mononuclear cells but more frequently in the liver tissue. In this last study of 14 patients, three had viral DNA in serum below 3x10E4 copies/ml but it was present in nine in the liver at concentrations below 5x10E4 copies/mg of tissue. Cellular cytotoxic and proliferative responses to capsid and envelope viral antigens was present in 25 to 50% of patients.
In a group of 14 donors with anti-HBs, 12 (86%) had detectable HBV DNA in the liver tissue and the sequence results of 6 of 7 were of wild type. These limited data suggest that in adults after recovery from acute HBV infection, some if not most retain viral DNA or low level of viral replication that may occasionally in some individuals, be sufficiently important to be detectable in circulation. Such hypothesis is strongly supported by the occurrence of HBV reactivation in patients positive for either anti-HBc and anti-HBs or anti-HBc alone when they are submitted to severe immunosuppressive regime for bone marrow transplantation, solid tumor chemotherapy or organ transplantation.,,, The percentage of reactivation ranges between 0 and 5% in different studies.
Persistence and ability to replicate in occult HBV was further demonstrated in 570 HBsAg negative patients receiving liver transplantation; 8 presented with reactivation of HBV infection. Prior to transplantation, all were viremic but three had anti-HBs, and two anti-HBc as the only serological marker of HBV infection while three had no serological marker. Unfortunately, the prevalence of HBV markers in the whole population was not provided. Despite small numbers, this study clearly indicates that occult HBV is kept under control by the immune system and that when immune surveillance relaxes under immunosuppressive treatment, high level of viral replication resumes. Another similar scenario is the transplantation of liver from a donor with OBI where despite the presence of anti-HBs or anti-HBc only, transmission of HBV takes place in a substantial number of cases.,,,
Epidemiology of occult HBV
Several studies have approached the issue of HBV persistence albeit differently by screening for HBV DNA in different populations of individuals, often blood donors, carrying either anti-HBs or anti-HBc only.,,, In blood donors carrying anti-HBc only, 0.3-15% have detectable HBV DNA. This percentage depends on the sensitivity of the NAT assay, the genotype(s) prevalent in the population and the specificity of the anti-HBc assay., In two unpublished populations from high and low prevalence areas, 7% and 1% of blood donors were found to be viremic respectively (Allain, personal data). To a large extent, the frequency of occult HBV depends on the epidemiology. The mode of transmission is critical as vertical transmission and horizontal transmission before age five results in frequent chronic infections which, after varying periods of time according to the genotype (see above), reach the non-replicative stage that leads to occult infection. In contrast, in areas where the epidemiology is dominated by transmission by sexual or intravenous drug use, in adults, most infections will recover and occult infection will be found in persistent recovered cases. Although substantial data from both high and low prevalence areas have been published on anti-HBc positive symptomatic and asymptomatic individuals, very little is available on the prevalence of HBV DNA in recovered infection.
Diagnosis of occult HBV infection
As explained above, the diagnosis of occult HBV relies on the differential sensitivity between HBsAg and HBV DNA assays. Since OBI is characterized by a viral load in circulation generally below 2x10E3 IU/ml or 1x10E4 copies/ml, nested PCR , TMA or QPCR are the detection methods of choice.,,, Contrary to what is currently implemented in the donated blood screening, tests need to be applied to individual samples instead of plasma pools. We have shown that when tested in pools of 10 plasmas, approximately 50% of OBIs remain undetected. The amount of plasma used for nucleic acid extraction is also critical and increasing the standard 200 µl extraction volume to 0.5 ml as with the TMA assay or 1 ml improves sensitivity. Some investigators prefer to repeat extraction and testing under the assumption that according to Poisson distribution, repeating testing increases the chances of detecting a low number of template sequences. In the QPCR method, samples are generally tested in duplicate and a signal observed in one replicate can be considered positive but cannot be utilized for accurate quantification. However, with this last method, it is often difficult to differentiate between genuine positivity and low level of probe degradation observed beyond 38 or 40 cycles of amplification. The determination of a cut-off number of cycles is then required which might limit sensitivity. At low levels of viremia, confirmation of a positive amplification result is critical and requires utilizing an alternative confirmatory assay such as nested PCR when using TMA or QPCR assays.
As in all genomic amplification methods, taking draconian precautions to avoid contamination is even more critical when attempting to identify very low levels of viral genome. Discriminating between true low positive and contamination can be very challenging since the variability of HBV genome, even in the most variable pre-S/S region is not very high. In addition, sequencing, which might be informative in such circumstances, becomes very difficult to perform at levels of viremia below 200 IU/ml.
Clinical significance of OBI
The clinical significance of this condition remains largely unknown. OBI was initially detected in patients with HCC or unclassified chronic liver disease., There is therefore a clear association of OBI and liver disease in the absence of other causes such as HCV infection or excessive alcohol intake. However, it is likely that most OBI are asymptomatic and would only be detected by systematic screening of large populations.
All cases of OBI in the presence of anti-HBs have normal ALT levels. However, in one study, follow up of adult patients who had recovered from the infection revealed that only 1/9 patients had normal liver histology. The others had either inflammation or some degree of fibrosis.
In blood donors with positive anti-HBc only, most reports do not mention ALT levels, and because they are asymptomatic, few liver disease related investigations were conducted, and in particular, no liver biopsies were performed. In a study of 20 blood donors with OBI and either anti-HBs or anti-HBc positivity only, there was no indication of biological or anatomical liver disease. In another study of 19 donors, all but one had normal ALT levels, and after discontinuation of excessive alcohol intake, ALT level returned to normal in the only case with elevated ALT. In a series of over 1,000 patients referred for chronically elevated ALT levels, 19 carried detectable HBV DNA only and one of them was a blood donor.
As mentioned above, the clinical significance of OBI is considerable in cases of infected patients becoming immunodeficient mainly by receiving immunosuppressive regimens for various clinical conditions. However, the severity of the immunosuppression and its duration plays a considerable role in triggering reactivation of the infection. Reactivation during relatively mild and short-term immunosuppression for homologous bone marrow transplantation or solid tumor chemotherapy elicits lower frequency of reactivation than more severe regimen such as employed in allogenic bone marrow or organ transplantation. Little data is available that includes a pre-treatment sample where HBV DNA has been detected with highly sensitive methods.
| Conclusions|| |
Occult HBV infection is still poorly characterized because of the technical problems arising from extremely low viral load. However advanced techniques are now available that should help considerably. Identification of OBI prior to treatments causing immunodeficiency should pave the way for a specific management strategy and prevention of reactivation which in some cases can be fatal. This diagnosis may also have some prognostic utility for the long-term outcome of HBV infection whether chronic or recovered.
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Department of Haematology, University of Cambridge, Cambridge
[Table - 1], [Table - 2]
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