Clinical significance of occult hepatitis B virus infection

Occult hepatitis B virus(HBV) infection(OBI) is defined as the presence of HBV DNA in the liver(with or without detectable HBV DNA in serum) for individuals testing HBV surface antigen negative.Until recently,the clinical effect of OBI was unclear on the progression of liver disease;on the development of hepatocellular carcinoma;and on the risk for reactivation or transmission of HBV infection.Several studies suggest a high prevalence of OBI among patients with cryptogenic chronic liver disease,but its role...     

Occult hepatitis B virus and hepatocellular carcinoma

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.     

Occult Hepatitis B Virus Infection in Hemodialysis Patients: A Concept for Consideration

Hemodialysis patients potentially have an increased risk of infection with parenterally transmitted viral agents due to an impaired host immune response and multiple transfusion requirements. Viral hepatitis is considered as a problem for hemodialysis patients because 1.9% of all deaths among this population are related to the consequence of viral hepatitis. Hepatitis B virus (HBV) is one of the most important causes of transmitted infections by the parenteral route in hemodialysis patients. Occult HBV infection is characterized by presence of HBV infection without detectable hepatitis B surface antigen (HBsAg), which harbors potential risk of HBV transmission through hemodialysis. There are conflicting reports on the prevalence of occult HBV infection (OBI) in hemodialysis patients. Considering the importance of occult HBV infection in hemodialysis patients and the growing evidence on this subject, the purpose of this review is to provide comprehensive information on OBI prevalence in hemodialysis patients and highlight the most important points in this issue.     

Occult hepatitis B virus infection is not associated with disease progression of chronic hepatitis C virus infection

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

Chemotherapy-related reactivation of hepatitis B infection: Updates in 2013

Hepatitis B reactivation is a potentially serious complication of anticancer chemotherapy, which occurs during and after therapy. This condition affects primarily hepatitis B surface antigen (HBsAg)-positive patients, but sometimes HBsAg-negative patients can be at risk, based only on evidence of past infection or occult infection with a low titer of detectable hepatitis B virus (HBV) DNA. The clinical outcomes vary with the different degrees of virologic and biochemical rebound, ranging from asymptomatic elevations in liver enzymes to hepatic failure and even death. Despite the remarkable advancement in the treatment of chronic hepatitis B over the past decade, proper strategies for the prevention and management of HBV reactivation remain elusive. Moreover, with the increasing use of rituximab in patients with lymphoma, HBV reactivation in occult or past infections has become increasingly problematic, especially in HBV-endemic regions. This review addresses the current knowledge on the clinical aspects and management of chemotherapy-related HBV reactivation, updates from recent reports, several unresolved issues and future perspectives.     

Occult hepatitis B virus infection

Occult hepatitis B virus(HBV)infection(OBI)refers to the presence of HBV DNA in the absence of detectable hepatitis B surface antigen.Since OBI was first described in the late 1970s,there has been increasing interest in this topic.The prevalence of OBI varies according to the different endemicity of HBV infection,cohort characteristics,and sensitivity and specificity of the methods used for detection.Although the exact mechanism of OBI has not been proved,intrahepatic persistence of viral covalently closed circular DNA under the host’s strong immune suppression of HBV replication and gene expression seems to be a cause.OBI has important clinical significance in several conditions.First,OBI can be transmitted through transfusion,organ transplantation including orthotopic liver transplantation,or hemodialysis.Donor screening before blood transfusion,prophylaxis for high-risk organ transplantation recipients,and dialysis-specific infection-control programs should be considered to reduce the risk of transmission.Second,OBI may reactivate and cause acute hepatitis in immunocompromised patients or those receiving chemotherapy.Close HBV DNA monitoring and timely antiviral treatment canprevent HBV reactivation and consequent clinical deterioration.Third,OBI may contribute to the progression of hepatic fibrosis in patients with chronic liver disease including hepatitis C.Finally,OBI seems to be a risk factor for hepatocellular carcinoma by its direct protooncogenic effect and by indirectly causing persistent hepatic inflammation and fibrosis.However,this needs further investigation.We review published reports in the literature to gain an overview of the status of OBI and emphasize the clinical importance of OBI.     

Occult hepatitis B virus co-infection in human immunodeficiency virus-positive patients: A review of prevalence,diagnosis and clinical significance

The prevalence of human immunodeficiency virus(HIV) and hepatitis B virus(HBV) co-infection is high as they share similar mechanisms of transmission. The development and widespread use of highly sensitive tests for HBV diagnosis has demonstrated that a significant proportion of apparently healthy individuals with evidence of exposure to HBV continue to carry fully functional HBV DNA in their hepatocytes, a situation that predisposes them to the development of progressive liver disease and hepatocellular carcinoma. The presence of co-infections frequently influences the natural evolution of each of the participating infections present by either facilitating their virulence or competing for resources. Furthermore, the drugs used to treat these infections may also contribute to changes in the natural course of these infections, making the analysis of the impact of co-infection more difficult. The majority of studies has examined the impact of HIV on overt chronic hepatitis B, finding that co-infection carries an increased risk of progressive liver disease and the development of hepatocellular carcinoma. Although the effect of HIV on the natural history of occult hepatitis B infection(OBI) has not been fully assessed, all available data suggest a persisting risk of repeated flares of hepatitis and progressive liver disease. We describe studies regarding the diagnosis, prevalence and clinical significance of OBI in HIVpositive patients in this short review. Discrepancies in worldwide prevalence show the urgent need for the standardization of diagnostic criteria, as established by the Taormina statements. Ideally, standardized protocols for testing should be employed to enable the comparison of data from different groups. Additional studies are needed to define the differences in risk for OBI without HIV and in HIV-HBV co-infected patients with or without overt disease.     

Clinical impact of occult hepatitis B virus infection in immunosuppressed patients

Occult hepatitis B infection(OBI), is characterized by low level hepatitis B virus(HBV) DNA in circulating blood and/or liver tissue. In clinical practice the presence of antibody to hepatitis B core antigen in hepatitis B surface antigen(HBsAg)-/anti-HBs-negative subjects is considered indicative of OBI. OBI is mostly observed in the window period of acute HBV infection in blood donors and in recipients of blood and blood products, in hepatitis C virus chronic carriers, in patients under pharmacological immunosuppression, and in those with immunodepression due to HIV infection or cancer. Reactivation of OBI mostly occurs in anti-HIV-positive subjects, in patients treated with immunosuppressive therapy in onco-hematological settings, in patients who undergo hematopoietic stem cell transplantation, in those treated with anti-CD20 or anti-CD52 monoclonal antibody, or anti-tumor necrosis factors antibody for rheumatological diseases, or chemotherapy for solid tumors. Under these conditions the mortality rate for hepatic failure or progression of the underlying disease due to discontinuation of specific treatment can reach 20%. For patients with OBI, prophylaxis with nucleot(s)ide analogues should be based on the HBV serological markers, the underlying diseases and the type of immunosuppressive treatment. Lamivudine prophylaxis is indicated in hemopoietic stem cell transplantation and in onco-hematological diseases when high dose corticosteroids and rituximab are used; monitoring may be indicated when rituximab-sparing schedules are used, but early treatment should be applied as soon as HBsAg becomes detectable. This review article presents an up-to-date evaluation of the current knowledge on OBI.     

Role of occult hepatitis B virus infection in chronic hepatitis C

The development of sensitive assays to detect small amounts of hepatitis B virus(HBV) DNA has favored the identification of occult hepatitis B infection(OBI), a virological condition characterized by a low level of HBV replication with detectable levels of HBV DNA in liver tissue but an absence of detectable surface antigen of HBV(HBs Ag) in serum. The gold standard to diagnose OBI is the detection of HBV DNA in the hepatocytes by highly sensitive and specific techniques, a diagnostic procedure requiring liver tissue to be tested and the use of non-standardized non-commercially available techniques. Consequently, in everyday clinical practice, the detection of anti-hepatitis B core antibody(antiHBc) in serum of HBs Ag-negative subjects is used as a surrogate marker to identify patients with OBI. In patients with chronic hepatitis C(CHC), OBI has been identified in nearly one-third of these cases. Considerable data suggest that OBI favors the increase of liver damage and the development of hepatocellular carcinoma(HCC) in patients with CHC. The data from other studies, however, indicate no influence of OBI on the natural history of CHC, particularly regarding the risk of developing HCC.     

Current hepatitis B virus infection situation in Indonesia and its genetic diversity

Indonesia has a moderate to high endemicity of hepatitis B virus(HBV) infection. The risk for chronic HBV infection is highest among those infected during infancy. Since 1997, hepatitis B(Hep B) vaccination of newborns has been fully integrated into the National Immunization Program. Al though HBV infection has been reduced by the universal newborn Hep B immunization program, it continues to occur in Indonesia. The low birth dose coverage and the presence of vaccine escape mutants might contribute to this endemicity among children. Although limited information is available for an analysis of occult HBV infection(OBI), several variations and substitutions in the pre-S/S region have been detected in Indonesian HBV strains. Additionally, persistent infection and disease progression of chronic hepatitis B are related to not only viral factors but also the host genome. Indonesia is one of the most ethnically heterogeneous nations, with Javanese and Sundanese as the two highest ethnic groups. This multi-ethnicity makes genomic research in Indonesia difficult. In this article, we focused on and reviewed the following aspects: the current hepatitis B immunization program and its efficacy, OBI, HBV infection among high-risk patients, such as hemodialysis patients, and research regarding the host genome in Indonesia.     

Updates on the treatment and outcomes of dual chronic hepatitis C and B virus infection

Dual hepatitis C virus(HCV)/hepatitis B virus(HBV)infection is found in HBV or HCV endemic areas,and in specific populations exhibiting a high risk of parenteral viral transmission.Clinical observations have revealed that HCV/HBV dually infected patients demonstrate a higher risk of liver disease progression compared with HBV or HCV monoinfected patients.The viral activity responsible for liver disease progression can be determined by examining the viral loads of HCV and HBV and by conducting liver biopsy examinations.Recent trials have confirmed that the combination therapy of peginterferon alpha-2a or 2b and ribavirin for dual hepatitis patients with HCV dominance appears to be as effective and safe as it is in patients with HCV monoinfections.Strikingly,approximately 60% of dually infected patients with inactive hepatitis B before treatment develop HBV reactivation after the clearance of the HCV.The clinical significance of this HBV reactivation and the strategy to prevent and treat this event should be determined.Furthermore,approximately 30%of dually infected patients lost hepatitis B surface antigen(HBsAg)within 5 years after the start of peginterferonbased therapy,and 40%of them harbored occult HBV infection.The underlying mechanisms of their accelerating HBsAg seroclearance and the development of occult HBV await further investigations.Moreover,the optimal treatment strategies for dually infected patients who are seropositive for the hepatitis B e antigen must be explored.Finally,the advent of new direct-acting antiviral-based anti-HCV therapy may change the optimal therapies for patients with dual hepatitis in the near future,which warrants further clinical trials.     

Prevalence of occult hepatitis B virus infection

Occult hepatitis B virus(HBV) infection(OBI) is characterized by the persistence of HBV DNA in the liver tissue in individuals negative for the HBV surface antigen.The prevalence of OBI is quite variable depending on the level of endemic disease in different parts of the world,the different assays utilized in the studies,and the different populations studied.Many studies have been carried out on OBI prevalence in different areas of the world and categories of individuals.The studies show that OBI prevalence...     

HBV再激活相关肝衰竭的研究进展

HBV感染是全球重大公共问题。当前的抗病毒治疗药物能够有效的控制病毒复制,但无法清除HBV,在停用了抗HBV药物之后病毒仍然有再激活的可能。实验研究及临床研究表明在感染HBV以后,虽然95%的成人能够自发达到临床痊愈,但病毒基因组仍在宿主的肝细胞内持续存在,当使用免疫抑制剂或肿瘤化疗等药物治疗实体和血液系统恶性肿瘤、风湿免疫疾病、HCV感染等基础疾病时,HBV复制可能重新激活。HBV再激活可能导致严重的临床结局,部分患者可出现肝衰竭,甚至死亡。我国的回顾性研究表明有9%~30%乙型肝炎相关慢加急性肝衰竭是由HBV再激活引起。因此,识别HBV再激活的风险人群并制订合理的预防措施对于减少乙型肝炎相关慢加急肝衰竭的发生有着非常重要的意义。简述了HBV再激活的定义、发生基础,同时论述了HBV再激活引起肝衰竭的诱因及机理,最后总结了需预防人群及措施。     

Prevalence and clinical significance of occult hepatitis B virus infection among renal transplant recipients in Korea

Abstract Background: Occult hepatitis B infection (OBI) is the presence of hepatitis B virus (HBV) DNA in serum or hepatic tissue without detectable hepatitis B surface antigen (HBsAg) in serum. Kidney disease patients in the post-renal transplantation period are in a specific situation as a result of the high pre-transplantational risk of HBV infection and post-transplantational immunosuppression. We studied the pre-transplantational prevalence and post-transplantational influence of OBI on kidney transplantation patients. Methods: We investigated pre-transplantational serum samples of 217 HBsAg-negative patients of post-renal transplant status for the presence of HBV DNA by real-time quantitative polymerase chain reaction. Serologic markers for HBV and hepatitis C virus (HCV) infection as well as liver enzymes were analyzed. Results: We detected HBV DNA in 2.3% (5/217) of HBsAg-negative patients, and the median HBV DNA titer was 33.15 copies/ml (range 30.6-144.6 copies/ml). Among the 5 OBI patients, 2 had hepatitis B surface antibodies (anti-HBs) and 1 had hepatitis B core antibodies (anti-HBc IgG). None of the patients with OBI were co-infected with HCV. There was no evidence of reactivation of OBI during the 36-month (range 27-63 months) follow-up monitoring period after transplantation, in spite of immune suppression to prevent rejection. Conclusions: The prevalence of occult HBV in the setting of renal transplantation was higher than that in the general population of Korea, and no reactivation of hepatitis B was observed in patients with OBI in the post-renal transplantation period.     

Occult Hepatitis B and Other Unexplored Risk Factors for Hepatocellular Carcinoma in Latin America

Occult hepatitis B infection (OBI) is the presence of hepatitis B virus (HBV) DNA in the liver and/or serum (< 200 IU/mL) in HBsAg-negative patients with or without serologic markers of previous viral exposure. The clinical significance of OBI is of concern in post-transfusional hepatitis B infection, hepatitis B reactivation, chronic liver disease and hepatocellular carcinoma (HCC). The diagnosis of OBI relays on the use of highly sensitive and specific laboratory techniques. Herein, comments derived from a study analyzing the frequency and characteristics of OBI in HCC Japanese patients are stated. While OBI and other causes of HCC have been highly studied in Asia and Europe, research in Latin America in these topics is limited. Several findings such as population risk groups with high prevalence of overt and OBI infection, HBV genotype F in Argentinean HCC patients, and the clinical impact of the foreign A-D genotypes suggest the need of further investigation. Additionally, alcoholism, obesity, NASH and type 2 diabetes may override the presence of OBI. Therefore, OBI diagnosis is essential. It is known that anti-HBc alone is a predictive signal of potential OBI and given the fluctuations of the HBV infection markers, testing for HBsAg and anti-HBc at baseline and follow-up is recommended. In conclusion, OBI and other causes involved in the epidemiology of HCC in Latin America are unexplored risk factors. Genome-based research is required to decipher the role of gene-environmental interactions associated with chronic liver disease. Novel algorithms to detect OBI supported by basic/applied/clinical research are also needed.     

Diagnostic strategy for occult hepatitis B virus infection

In 2008,the European Association for the study of the liver(EASL) defined occult hepatitis B virus infection (OBI) as thepresence of hepatitis B virus(HBV) DNA in the liver(with detectable or undetectable HBV DNA in the serum) of individuals testing hepatitis B surface antigen(HBsAg) negative by currently available assays.Several aspects of occult HBV infection are still poorly understood,including the definition itself and a standardized approach for laboratory-based detection,which is the purpose of this ...     

Genetic variation of occult hepatitis B virus infection

Occult hepatitis B virus infection(OBI), characterized as the persistence of hepatitis B virus(HBV) surface antigen(HBs Ag) seronegativity and low viral load in blood or liver, is a special form of HBV infection. OBI may be related mainly to mutations in the HBV genome, although the underlying mechanism of it remains to be clarified. Mutations especially within the immunodominant "α" determinant of S protein are "hot spots" that could contribute to the occurrence of OBI via affecting antigenicity and immunogenicity of HBs Ag or replication and secretion of virion. Clinical reports account for a large proportion of previous studies on OBI, while functional analyses, especially those based on full-length HBV genome, are rare.     

慢性乙型肝炎患者中庚型肝炎病毒检测

目的了解慢性乙型肝炎中庚型肝炎病毒（ＨＧＶ）的感染率及其对病变程度和ＨＢＶ复制的影响。方法逆转录聚合酶链反应（ＲＴＰＣＲ）检测６５例经肝活检证实的慢性乙型肝炎患者血清中ＨＧＶＲＮＡ。结果有８例（１２．３％）慢性乙型肝炎患者合并ＨＧＶ感染,轻度、中度和重度患者中的ＨＧＶ检出率统计学处理差异无显著性,ＨＧＶ混合感染与其临床表现无相关性,ＨＧＶ阳性组与阴性组患者的肝功能改变相近。ＨＢｅＡｇ阳性组和ＨＢｅＡｇ阴性组患者的ＨＧＶ检出率亦相当。结论在慢性乙型肝炎患者中,ＨＧＶ混合感染对慢性乙型肝炎的病变程度及病毒复制无明显影响     

Post-transfusion occult hepatitis B (OBI): a global challenge for blood recipients and health authorities

Hepatitis B is one of the most frequent post-transfusion infections. Occult hepatitis B infection (OBI) is a form of hepatitis B infection in which, despite the presence of HBV-DNA in the serum and hepatocytes of the carrier, HBsAg is absent. In addition to the risk of transmission through the transfusion of infected blood, reactivation of hepatitis B in OBI patients and recipients of their blood can lead to cirrhosis, hepatic cancer, and reactivation of viral replication in the carrier. Therefore, effective assays to assess and screen for OBI in blood donors are of paramount importance and require urgent attention. Recently, several investigations in various regions of Iran have reported OBI in blood donors. In response, there has been a drive to apply more specific, sensitive, and accurate methods for the detection of HBV, which should become an obligatory screening process for all blood transfusion services. In this review, we address the progression of occult hepatitis B and the common problems associated with occult hepatitis B worldwide. Finally, we reflect on the research and screening that is being performed in Iran to deal with this problem.     

Management of occult hepatitis B virus infection: an update for the clinician

Occult hepatitis B virus(HBV) infection(OBI) is defined by the presence of HBV DNA in the liver tissue of individuals who test negative for hepatitis B surface antigen(HBsAg).Patients who have recovered from acute hepatitis B can carry HBV genomes for a long time and show histological patterns of mild necro-inflammation,even fibrosis,years after the resolution of acute hepatitis,without showing any clinical or biochemical evidence of liver disease.At least in conditions of immunocompetence,OBI is inoffensiv...