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• W2044218222 abstract "Chronic hepatitis B (CHB) infection is of global significance, affecting around 400 million persons worldwide and causing one million annual deaths from cirrhosis of the liver and hepatocellular carcinoma (HCC) [1]. The areas of high endemicity for CHB include Asia and sub-Saharan Africa. Over 70% of the CHB carriers of the world are Asians. What is much less well documented, especially in areas highly endemic for CHB, is the incidence and clinical effects of occult hepatitis B (OHB). HBsAg seroclearance in known CHB carriers has been documented in both patients who acquire the hepatitis B infection during adulthood (mostly white patients) and in patients who acquire the infection during early childhood (Asian and African patients). The annual incidence is estimated to be 0·4–2% for adult-acquired CHB and 0·1–0·8% for childhood-acquired CHB. CHB carriers who lose HBsAg are at one end of the spectrum of OHB, even though they have seldom been regarded as such. For subjects acquiring the infection during adulthood, loss of HBsAg is usually associated with an excellent prognosis and disease non-progression. However, for subjects who acquired the infection during early childhood (and this applies to the majority of the world’s CHB carriers), there is still evidence of continuing hepatitis B virus (HBV) replication and risk for the development of HCC. A study of 218 patients with spontaneous HBsAg seroclearance from Taiwan found the prognosis to be excellent in patients who had not developed cirrhosis, nor were co-infected with hepatitis C or D [2]. However, another study of 55 patients, also from Taiwan, showed that the cumulative probability of complications (mainly of HCC and cirrhosis) was 29·8% at 4 years after HBsAg seroclearance [3]. In a more recent series of 298 patients with HBsAg seroclearance from Hong Kong, 2·4% of patients subsequently developed HCC, the risk being significantly higher in patients with HBsAg seroclearance at age ≥50 years compared with those with seroclearance at age < 50 years (P = 0·004) [4]. Serum HBV DNA were detectable, using PCR assays, in 13·4, 6·1 and 3·7% patients within 1, 5–10 and > 10 years of HBsAg seroclearance. In 29 patients who had liver biopsies, 65·4% had no evidence of necroinflammation and fibrosis and the remaining 34·6% showed only mild necroinflammation and/or fibrosis. However, all patients (100%) had detectable intrahepatic HBV DNA and 79·3% had detectable covalently closed circular (ccc) DNA. (ccc HBV DNA is regarded as viral templates for HBV replication.) Apart from the low replicative state of the HBV in these patients, the transcriptional activity was also minimal. This was evidenced by the near absence of mRNA expressions for the core, surface and X genes of the HBV. Thus for subjects who acquire the HBV infection early in life, HBV persists at low replicative and transcriptional levels even after loss of HBsAg, presumably due to the prolonged period of infection. This has obvious bearing from the perspective of OHB infection. OHB is defined as the detection of HBV DNA, usually in low levels, in sera and/or livers of subjects who are negative for HBsAg. Most, though not all, of the studies have been based on transfusion services. Such a definition would include subjects who have an acute hepatitis B infection in the ‘s window’ phases (i.e. the period before the appearance of HBsAg, and the period between the loss of HBsAg and the detection of antibody against HBsAg [anti-HBs]), as well as CHB patients with HBsAg ‘escape’ mutants which are not detected by the standard HBsAg assays [5]. The HBV DNA levels in these two categories of subjects are often quite high and their blood products can be highly infectious. Fortunately, these two situations are relatively uncommon. The subsequent part of this article will deal exclusively with subjects with low-grade chronic hepatitis B and undetectable HBsAg. Among this group, there are three possibilities in relation to the presence or absence of other HBV markers. The subject may be positive for both anti-HBs and antibody against the hepatitis B core antigen (anti-HBc). Second, the subject may be positive for anti-HBc alone and negative for anti-HBs. Finally, both anti-HBc and anti-HBs may be negative. Although it has been suggested that OHB blood products containing anti-HBs do not transmit HBV [6], this is by no means proven. Organs from anti-HBs subjects have been shown to transmit HBV in the immunocompromised recipients [7]. All three categories of subjects mentioned above, whether anti-HBc and anti-HBs negative or positive, should be regarded as potentially infectious as well as possibly developing the sequelae of CHB infection. The detection of OHB has advanced with more sensitive assays for HBsAg detection allowing more CHB carriers to be detected, and with more sensitive assays for HBV DNA. The Artus HBV Rotor Gene assay (Qiagen, Hamburg, Germany, GmbH) has a lower limit of detection of 3·8 IU/ml. Individual donor nucleic acid testing (NAT) has been proven to be significantly more sensitive than mini-pool NAT [8]. However, it is uncertain whether individual donor NAT can replace HBsAg screening and whether it is cost effective in blood transfusion service [9]. The incidence of OHB from various countries are listed in Table 1. The incidence from the studies is affected by differences in sample collection, sensitivity of the tests and data analysis. Hence, it is difficult to form any firm conclusions for the geographical distribution of OHB. Most OHB subjects have HBV DNA levels at very low levels (< 50 IU/ml), but occasionally the levels can reach to > 5000 IU/ml. A recent study from the University of Hong Kong and the Hong Kong Red Cross Transfusion Services consisted of a retrospective and a prospective cohort. In the retrospective cohort, 3044 donor sera, negative for HBsAg, hepatitis C virus (HCV) and human immunodeficiency virus (HIV), were individually tested with NAT. The serum HBV DNA levels of these specimens were then tested three times with the Artus assay. OHB in this study was defined as two or more of the three runs of Artus assays showing detectable HBV DNA. In the prospective cohort, 9990 donor specimens were tested individually with NAT initially. NAT-positive samples were then tested for HBsAg. NAT-positive HBsAg-negative samples were tested for HBV DNA using three runs of the Artus assay. The incidence of OHB in the retrospective cohort (with prior HBsAg screening) was 0·14%. The incidence of OHB in the prospective cohort (with NAT prior to HBsAg testing) was almost identical, 0·11%. It appears from this study that initial screening for HBsAg followed by individual donor NAT has the same efficacy in detecting OHB compared with first screening by NAT. The former may be a more cost-effective procedure for blood transfusion services in areas of high endemicity for CHB. The cost-effectiveness of NAT in areas of low endemicity for HBV has yet to be determined. However, in these areas, NAT should be important for the screening of HCV and HIV. Defining the infectivity of OHB blood components is a difficult task because of four reasons. First, nearly all the studies were, and probably will continue to be, retrospective in nature because known NAT-positive OHB components will not be transfused. Second, retrospective tracing of recipients is notoriously difficult. Third, the incidence of transfusion-transmitted hepatitis B infection in recipients is low, which would aggravate the problem of incomplete tracing. Finally, the hepatitis B serology of the recipients prior to transfusion is often not known. Given the difficulties outlined above in transfusion recipients, one possible method to study the infectivity of OHB blood component is in the laboratory. However, chimpanzee experiments are not easily available. Another possibility is the use of a chimeric mice model described by Tateno et al. [15] Severe combined immunodeficiency mice transgenic for the urokinase-type plasminogen activator gene can be successfully transplanted with human hepatocytes. The mice can then be tested with OHB sera. Such experiments are currently being performed. In the clinical studies, an early retrospective study suggests that OHB blood components which are anti-HBs positive are non-infectious [6]. This is confirmed by a more recent study from Japan, where 12 cases of transfusion-related hepatitis B infection with NAT-positive OHB blood components were identified from 1997–2004 [14]. Of these, the majority were caused by components negative for both anti-HBc and anti-HBs, presumed to be from donors in the ‘window’ phase of acute HBV infection. The infectivity of components positive for low-titre anti-HBc (i.e. probably OHB from previous infection) was 2·4–3%. No components positive for anti-HBs caused any transfusion-related hepatitis. The transmission of hepatitis B infection through OHB donors becomes a much greater problem in the liver transplant scenario where the recipients, who have not been previously exposed to HBV (i.e. both anti-HBs and anti-HBc negative) are immuno-suppressed. De novo hepatitis B infection occurs in 22–100% of liver transplant recipients irrespective of whether the donor is positive for anti-HBc only or positive for both anti-HBs and anti-HBc [16,17]. The natural course of de novo hepatitis B infection in the recipients is limited to relatively small series because of antiviral prophylaxis (either with nucleoside analogues and/or hepatitis B immunoglobulin [HBIG]) since the late 1990s. Although the course of the infection is less severe than in recurrent hepatitis B in known HBsAg-positive recipients, the mortality is significantly higher than in control transplant population [16]. The risk of de novo hepatitis B infection in other transplant recipients, including kidney, heart and bone marrow, is low presumably because HBV is present in negligible quantity in these other organs [18–20]. However, at least one kidney transplant recipient developed rapidly progressive liver failure and fibrosing cholestatic hepatitis due to de novo HBV infection [21].(The patient was treated successfully with lamivudine.) Because of its occult nature, the magnitude of the infection as well as the consequences cannot be truly assessed. In a study of 16 patients with acute self-limited hepatitis B 30 years earlier, all subjects were HBsAg-negative, anti-HBc positive and 11 were anti-HBs positive [22]. None had detectable HBV DNA in the sera. However, two of four patients who agreed to have liver biopsies had detectable HBV DNA in the liver, one of whom was anti-HBs positive. There was no evidence of mutations in the HBV sequences of these two patients to suggest changes in the viral genome for the establishment of latency of the hepatitis B infection. It has been shown in the woodchuck hepatitis virus (WHV) model that, among infected woodchucks which have cleared the WHV surface antigen and developed antibodies to the surface and viral capsid antigens, 15–20% still continue to develop HCC without concomitant cirrhosis [23]. Brechot et al. is the first group to detect HBV DNA sequences in the livers of French patients with alcoholic liver disease, 51 without HCC and 20 with HCC. In the 51 patients without HCC, eight patients had integrated HBV DNA in the livers (3 were HBsAg-positive). In the 20 patients with HCC, none was positive for serum HBsAg, but all (100%) had integrated HBV DNA in the neoplastic liver cells [24]. The same group subsequently studied the livers of 134 HBsAg-negative patients with chronic liver disease, including 20 with HCC [25]. Fifty-nine percent of 88 liver samples (including 17 of 20 HCC samples) showed HBV DNA sequences. These two studies by Brechot et al. demonstrate the high frequency of OHB in causing chronic liver disease, especially in HCC, even in areas of low endemicity for HBV infection. Similar to the WHV model, HCC can develop in OHB patients without cirrhosis. The direct oncogenic role of HBV in these patients may be related to mutations and truncations in the HBV X gene [26]. The role of HBV in HCC development in CHB patients with seroclearance of HBsAg has already been discussed in the first section [3]. The other major consequence for OHB patients is the possibility of HBV reactivation on receiving chemotherapy and bone marrow transplantation (BMT). The reversion to HBsAg positivity occurs mainly in patients with haematological malignancies and lymphomas. The severity of the reactivation appears to be related to the type of treatment. For conventional chemotherapy, the reactivation rate is reported to be 4–30% [27,28]. Most reactivations are mild. For allogenic BMT, the reactivation rate is 14–50%. Most of the reported series are small [29–32], with a delay of reactivation from 6–52 months after BMT. This delay in reactivation may be related to (1) the slow decline in the recipient memory B cell immunity; (2) the resulting reactivation of HBV replication; and (3) lack of protective immunity from the donor marrow cells [33]. Although most reactivations are mild, non-fatal fulminant reactivation has been reported. The most frequent and severe reactivation is associated with the recent use of monoclonal antibodies against B and T lymphocytes, namely rituximab (monoclonal antibody against CD20+ malignant lymphoid cells) and alemtuzumab (monoclonal antibody against CD52+ malignant lymphoid cells). Both drugs give rise to profound depletion of T and B cells. CD8+ cytotoxic T-cell immunity responsible for hepatocyte killing in HBV infection can be primed with B cells acting as antigen-presenting cells. Delayed HBV reactivation may occur with progressive depletion of B cells after repeated cycles of therapy. In the only systematic review of HBV reactivation following the use of rituximab in patients with diffuse B cell lymphoma, 80 HBsAg-negative patients were studied [34]. HBV-related reactivation was not observed in anti-HBc-negative subjects (n = 34). Among the 46 anti-HBc-positive patients, HBV reactivation only occurred in patients who (1) were negative for anti-HBs and (2) received rituximab in addition to the conventional anti-lymphoma chemotherapy. The incidence was high (25%), the occurrence delayed (median of 98 days after rituximab therapy) and the reactivation often severe with one fatality. Another retrospective review of 394 anti-HBc positive patients with lymphoma showed the incidence of hepatitis B reactivation to be 2·7% in patients treated with rituximab compared with 0·8% in patients treated with other forms of treatment (P < 0·05) [35]. Preemptive treatment with nucleoside/nucleotide analogues for anti-HBc-positive subjects undergoing chemotherapy, especially for regimes including monoclonal antibodies such as rituximab or alemtuzumab, is strongly recommended, though most treatment guidelines mainly concentrate on patients with known CHB infection. HBV DNA levels should be monitored before, during and after the chemotherapy. Such preemptive treatment has been proven to significantly reduce the incidence and severity of possible hepatitis B reactivation. The recommended duration of treatment is 3–6 months after cessation of chemotherapy, the longer duration of 6 months being necessary for the monoclonal antibodies with their prolonged suppressive effects on B and T lymphocytes. However, if the patient’s prechemotherapy HBV DNA is high, the antiviral treatment should be extended for a longer period of time since viral rebound with hepatitis flares may occur with cessation of the antiviral therapy. The global magnitude of OHB is difficult to determine by the very nature of its being occult. Known CHB patients have been documented to clear HBsAg with time. Patients with acute self-limiting HBV infection have also been shown to harbour HBV in their liver 30 years after apparent recovery. Blood components of OHB blood donors have low infectivity, especially if the donors are also positive for anti-HBs. However, recipients of anti-HBc-positive liver donors (and possibly kidney donors) are at high risk of developing de novo hepatitis B infection and should be prophylactically treated with antiviral therapy. OHB subjects, especially those who are previously HBsAg-positive, can develop HCC even without concomitant cirrhosis. They are also at risk of hepatitis B reactivation when they receive chemotherapy, especially if monoclonal antibodies against B and T lymphocytes are also given. Such reactivation should be preemptively prevented by antiviral therapy." @default.
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• W2044218222 date "2009-10-14" @default.
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• W2044218222 title "Occult hepatitis B infection: Incidence, detection and clinical implications" @default.
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