Occult and previous hepatitis B virus infection are not associated with hepatocellular carcinoma in United States patients with chronic hepatitis C

Previous studies have suggested that prior exposure to hepatitis B virus (HBV) infection may increase the risk of development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. The aim of this study was to compare the prevalence of previous or occult HBV infection in a cohort of hepatitis B surface antigen-negative patients with histologically advanced chronic hepatitis C in the United States who did or did not develop HCC. Stored sera from 91 patients with HCC and 182 matched controls who participated in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial were tested for hepatitis B core antibody (anti-HBc), hepatitis B surface antibody, and HBV DNA. Frozen liver samples from 28 HCC cases and 55 controls were tested for HBV DNA by way of real-time polymerase chain reaction. Anti-HBc (as a marker of previous HBV infection) was present in the serum of 41.8% HCC cases and 45.6% controls (P=0.54); anti-HBc alone was present in 16.5% of HCC cases and 24.7% of controls. HBV DNA was detected in the serum of only one control subject and no patients with HCC. HBV DNA (as a marker of occult HBV infection) was detected in the livers of 10.7% of HCC cases and 23.6% of controls (P=0.18). CONCLUSION: Although almost half the patients in the HALT-C Trial had serological evidence of previous HBV infection, there was no difference in prevalence of anti-HBc in serum or HBV DNA in liver between patients who did or did not develop HCC. In the United States, neither previous nor occult HBV infection is an important factor in HCC development among patients with advanced chronic hepatitis C.     

Occult hepatitis B virus and the risk for chronic liver disease: A meta-analysis

BackgroundThe role of occult hepatitis B virus infection as a cause of liver disease is still debated although many studies found a higher prevalence of this condition in subjects than those without liver disease compared. A recent meta-analysis showed an increased risk of hepatocellular carcinoma for occult hepatitis B virus infection.AimsWe carried out a meta-analysis of observational studies to summarize the existing evidence and assess quantitatively the association between occult hepatitis B virus infection and chronic liver disease.MethodsWe searched the available literature on this issue published up to May 2012 using PubMed and EMBASE. All articles that provided enough information to estimate the chronic liver disease risk associated with occult hepatitis B virus infection were selected. Fourteen studies were retrieved.ResultsA total of 1503 subjects with (cases) and 2052 without chronic liver disease (controls) were included. The summary odds ratio for chronic liver disease from all studies was 8.9 (95% confidence interval: 4.1–19.5). The meta-analysis restricted to 7 studies with more precise effect estimate (wt% > 8%) provided a lower odds ratio estimate (odds ratio = 3.9; 95% confidence interval: 1.7–9.0).ConclusionsThese findings suggest a relevant association between occult hepatitis B virus infection and chronic liver disease, confirming the hypothesis that hepatitis B virus may play a pathogenic role even in the “occult” status.     

Occult Hepatitis B Virus Infection in Hemodialysis Patients in Japan

Hepatitis B surface antigen is widely used in hepatitis B virus surveillance; patients who test negative for the antigen are judged to be uninfected. However, occult hepatitis B virus infection has been confirmed with hepatitis B virus DNA at low levels in the liver and peripheral blood in patients positive for hepatitis B core antibody or hepatitis B surface antibody, even if they test negative for hepatitis B surface antigen. To investigate the prevalence of occult hepatitis B virus in hemodialysis patients, we performed cross‐sectional analysis of 161 hemodialysis patients in two related institutions for hepatitis B surface antigen, hepatitis B core antibody, and hepatitis B surface antibody. Hepatitis B surface antigen, hepatitis B core antibody, or hepatitis B surface antibody was present in 45 patients (28.0%). Hepatitis B virus DNA was present in six patients (3.7%), all of whom also tested positive for hepatitis B core antibody. Hepatitis B surface antibody positivity was unrelated in only one of the six patients. Four of the six patients were positive for hepatitis B surface antigen; however, two (1.3%) of these with occult hepatitis B virus infection were found to be hepatitis B surface antigen negative. Occult hepatitis B virus infection may be missed in hepatitis B virus surveillance using hepatitis B surface antigen alone; therefore, routine hepatitis B core antibody screening is necessary. Patients who test positive for hepatitis B core antibody should undergo further hepatitis B virus DNA testing to enable accurate hepatitis B virus screening.     

Comparative study between occult hepatitis C virus infection and chronic hepatitis C

We have recently described the presence of occult hepatitis C virus (HCV) infection (HCV-RNA in liver in the absence of anti-HCV and serum HCV-RNA) in patients with persistently abnormal liver function tests of unknown aetiology. The aim of this study was to compare the characteristics of patients with occult HCV infection vs those of patients with chronic hepatitis C. We compared clinical features of 68 patients with occult HCV infection and 69 untreated chronic HCV patients (anti-HCV and serum HCV-RNA positive), matched for age, gender, duration of abnormal liver function tests and body mass index. Aspartate aminotransferase and alanine aminotransferase were higher (P < 0.001) in chronic HCV, but cholesterol and triglycerides were significantly higher in patients with occult HCV infection (P < 0.001 and P = 0.002). Chronic HCV patients had higher gamma-globulin (P = 0.005), alpha-foetoprotein (P < 0.001) and iron (P < 0.001) levels. Percentage of patients with necroinflammatory activity and fibrosis was higher (P < 0.001) in chronic HCV than in occult HCV infection. Mean percentage of infected hepatocytes was higher (P = 0.001) in chronic HCV (10.1%) than in occult HCV infection (5.3%). This occult HCV infection is a milder disease than chronic HCV, and this could be related to the significantly lower number of infected hepatocytes observed in occult HCV.     

Hepatitis B and human immunodeficiency virus co-infection

Hepatitis B and human immunodeficiency virus (HBV and HIV) infection share transmission patterns and risk factors, which explains high prevalence of chronic HBV infection in HIV infected patients. The natural course of HBV disease is altered by the HIV infection with less chance to clear acute HBV infection, faster progression to cirrhosis and higher risk of liver-related death in HIV-HBV co-infected patients than in HBV mono-infected ones. HIV infected patients with chronic hepatitis B should be counseled for liver damage and surveillance of chronic hepatitis B should be performed to screen early hepatocellular carcinoma. Noninvasive tools are now available to evaluate liver fibrosis. Isolated hepatitis B core antibodies (anti-HBc) are a good predictive marker of occult HBV infection. Still the prevalence and significance of occult HBV infection is controversial, but its screening may be important in the management of antiretroviral therapy. Vaccination against HBV infection is recommended in non-immune HIV patients. The optimal treatment for almost all HIV-HBV co-infected patients should contain tenofovir plus lamivudine or emtricitabine and treatment should not be stopped to avoid HBV reactivation. Long term tenofovir therapy may lead to significant decline in hepatitis B surface Antigen. The emergence of resistant HBV strains may compromise the HBV therapy and vaccine therapy.     

Role of occult hepatitis B virus in chronic hepatitis C patients with flare of liver enzymes

Background

Occult HBV infection is defined by detection of HBV DNA in the serum or liver tissue of patients who test negative for HBsAg. The prevalence of occult HBV is higher in hepatitis C virus (HCV) positive patients than HCV negative patients and may have an impact on their clinical outcome. In this study, we evaluated the role of occult hepatitis B virus infection in chronic hepatitis C patients with ALT flare.

Methods

Sixty HBsAg negative patients with chronic hepatitis C virus infection were included. Patients were divided into 2 groups according to their ALT level: 30 patients with normal or slightly high ALT and 30 patients with ALT flare (≥ 5 times normal values). Patients in both groups were examined for the detection of anti-HBs, anti-HBc IgM, and anti-HBc IgG. HBV DNA was detected using semi-nested PCR technique.

Results

In patients with normal or slightly high ALT, HBV DNA was detected in 4 (13.3%) patients, while in those with ALT flare, HBV DNA was detected in 19 (63.3%) patients (p < 0.001). No association was found between the presence of HBV DNA and various serology markers of HBV infection.

Conclusion

Presence of occult hepatitis B, with its added deleterious effect, must always be considered in chronic hepatitis C patients especially those with flare in liver enzymes; HBsAg should not be used alone for the diagnosis of HBV infection.     

隐匿性乙型肝炎病毒感染者临床特点和肝组织病理学检查

目的了解血清肝炎病毒标志物阴性、肝功能反复异常患者中HBV隐匿性感染的比例及其临床和病理学特点。方法对27例血清肝炎病毒标志物阴性、肝功能反复异常患者采用免疫组化法检测肝组织HBsAg、HBcAg和HCVAg，并进行常规的病理学检查。结果肝组织HBsAg和（或）HBcAg阳性9例（33．3％）；HBsAg和（或）HBcAg及HCVAg阳性10例（37．0％）；全阴性8例（29．6％）。在HBV隐匿性感染的19例患者中，慢性肝炎8例，肝硬化11例。结论HBV和HCV感染为血清肝炎病毒标志物阴性患者肝功能反复异常的主要原因之一，尤其是HBV感染。这种HBV隐匿性感染与慢性肝炎、肝硬化的发生关系密切，应引起重视。     

Occult hepatitis B virus infection and its clinical implications

Occult hepatitis B virus (HBV) infection is characterized by presence of HBV infection with undetectable hepatitis B surface antigen (HBsAg). Serum HBV level is usually less than 10⁴ copies/mL in these patients. Diagnosis of occult HBV infection requires sensitive HBV-DNA PCR assay. Several possibilities have been hypothesized as the mechanisms of occult HBV infection. These include: (i) mutations of HBV-DNA sequence; (ii) integration of HBV-DNA into host's chromosomes; (iii) infection of peripheral blood mononuclear cells by HBV; (iv) formation of HBV-containing immune complex; (v) altered host immune response; and (vi) interference of HBV by other viruses. The precise prevalence of occult HBV infection remains to be defined. The clinical implications of occult HBV infection involve different clinical aspects. First of all, occult HBV infection harbours potential risk of HBV transmission through blood transfusion, haemodialysis, and organ transplantation. Second, it may serve as the cause of cryptogenic liver disease, contribute to acute exacerbation of chronic hepatitis B, or even fulminant hepatitis. Third, it is associated with development of hepatocellular carcinoma. Fourth, it may affect disease progression and treatment response of chronic hepatitis C. Most of the previous studies utilized retrospective observation without control groups, and lacked direct association of occult HBV infection with specific pathological changes and disease progression. Highly sensitive, quantitative, and functional molecular analyses of HBV, combined with a well-designed prospective clinical assessment will provide the best approach for the future study of occult HBV infection.     

Prevalence and clinical relevance of occult hepatitis B in the fibrosis progression and antiviral response to INF therapy in HIV-HCV-coinfected patients

Occult hepatitis B virus (HBV) infection is diagnosed when HBc antibodies (HBcAb) and HBV DNA are detectable in serum while hepatitis B surface antigen (HBsAg) is not. This situation has been frequently described in patients with chronic hepatitis C virus (HCV) infection. The objective of this study was to evaluate the prevalence of occult hepatitis B in HIV-HCV-coinfected patients and its clinical relevance in liver histology and viral response after interferon therapy for HCV. A total of 238 HIV-HCV-infected patients,negative for HBsAg, were included. Serum samples were analyzed for the presence of HBV DNA and HBcAb.HBV DNA quantification was determined with the Cobas TaqMan HBV Test (detection limit 6 IU/ml). Data from liver biopsy and laboratory tests were also analyzed. HBcAb resulted in 142 (60%) patients, being the independent associated factors: male gender, previous history of intravenous drug use, age, CD4 count,and HAV antibody presence. Among 90 HBcAb patients that we could analyze, HBV DNA was positive in 15 (16.7% of occult hepatitis B infection in this group, and 6.3% in the whole HIV-HCV cohort studied). No baseline factors, liver histology, or HCV therapy response were related to the presence of HBV DNA. We found that occult hepatitis B is a frequent condition present in at least 6.3% of our HCV-HIV patients and in more than 16% of those with HBcAb. Despite the high prevalence, this phenomenon does not seem to affect the clinical evolution of chronic hepatitis C or modify the viral response to interferon-based HCV therapies     

Anti-hepatitis a virus seroprevalence and seroconversion in a cohort of patients with chronic viral hepatitis

BACKGROUND: Patients with chronic hepatitis C infected by hepatitis A virus have a substantial risk of fulminant hepatitis or death, while the course of hepatitis A virus is uncomplicated in most subjects with chronic hepatitis B. AIM: To evaluate the prevalence of anti-hepatitis A virus antibodies and the incidence of hepatitis A virus seroconversion in a nationwide sample of 530 patients with chronic hepatitis B and/or hepatitis C infection initially susceptible to this infection after a follow-up of some years. RESULTS: The overall anti-hepatitis A virus prevalence was 85.7%, with no difference between males and females. By the age of 50 years, almost all patients were found to have been exposed to hepatitis A virus. After a mean follow-up period of 76 months the overall anti-hepatitis A virus seroconversion rate in the 76 initially susceptible individuals was 1.2 per 100 person/years. However, it was 0.3 per 100 person/years in those hepatitis B surface antigen positive but 3.36 per 100 person/years in those anti-hepatitis C virus positive. None of the seroconverters was affected by a clinically evident disease or showed deterioration of underlying chronic liver disease. CONCLUSIONS: The present study shows that Italian patients >50 years of age with chronic liver disease have already been exposed to hepatitis A virus suggesting that anti-hepatitis A virus screening is not advisable in these subjects.     

Molecular characteristics of non‐cancerous liver tissue in non‐B non‐C hepatocellular carcinoma

Although chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) are the most important risk factors for the development of hepatocellular carcinoma (HCC) worldwide, the proportion of HCC patients negative for the hepatitis B surface antigen and hepatitis C antibody, so‐called “non‐B non‐C HCC”, is rapidly increasing, especially in Japan. The background liver diseases of non‐B non‐C HCC patients can be multifactorial, including occult HBV infection and non‐alcoholic steatohepatitis. It is reasonable to investigate the non‐cancerous liver tissues to identify the potential molecular mechanisms responsible for the processes of hepatocarcinogenesis of non‐B non‐C HCC. However, to date, only a few studies have focused on this research concept based on the idea of “field cancerization”. This review highlights the potential importance of the molecular analysis of non‐cancerous liver tissues to clarify the molecular characteristics in patients with non‐B non‐C HCC. A better understanding of the molecular mechanisms underlying the individual predisposition to non‐B non‐C HCC will lead to improvements in the prevention, early diagnosis and treatment of this neoplastic disease.     

Hepatitis B virus and lymphomagenesis: novel insights into an occult relationship

BackgroundIncreasing evidence shows that Hepatitis B virus infection associates with B-cell but not T-cell malignancies. It remains unclear (a) whether this association is restricted to discrete subtypes of B-cell neoplasms and (b) if occult hepatitis B virus infection can impact on the risk of B-cell malignancy.MethodsWe analysed the prevalence of occult hepatitis B virus infection in three age and sex matched groups: patients with multiple myeloma, chronic lymphocytic leukaemia and healthy volunteers (N = 80 each group). Hepatitis B virus sequences were detected by PCR in blood mononuclear cells isolated prior to treatment.ResultsFifteen subjects tested positive for occult hepatitis B virus infection and its distribution significantly favoured chronic lymphocytic leukaemia (p < 0.02) over the other groups. No difference in age, gender and proportion of anti-HBc seropositivity was noted according to occult hepatitis B virus infection status. Chronic lymphocytic leukaemia had an odds ratio of 4.6 (95% CI 1.5–13.9) for the presence of occult hepatitis B virus infection in comparison to multiple myeloma and controls. Most occult hepatitis B virus infection cases (10/15, 67%) were detected in completely hepatitis B virus seronegative subjects.ConclusionsOur data support a potentially causal relationship for hepatitis B virus in chronic lymphocytic leukaemia but not in multiple myeloma. HBsAg seropositivity alone may bias the study of this association, potentially leading to underestimation. Primary occult hepatitis B virus infection appears the most frequent setting in our patients, extending the clinical relevance of hepatitis B virus vaccination to a preventative measure for B-cell neoplasms.     

Occult hepatitis B

Worldwide, chronic hepatitis B virus (HBV) infection is the primary cause of cirrhosis and hepatocellular carcinoma and is one of the ten leading causes of death. Traditionally, people with chronic HBV infection have been identified with blood tests for HBV antigens and antibodies. Recently, another group of patients with chronic HBV infection has been identified by sensitive, molecular testing for HBV DNA. Members of this group are often referred to as having occult hepatitis B because they are HBV-DNA positive, but hepatitis B surface antigen negative. Occult hepatitis B occurs in a number of clinical settings. In this review, we examine occult hepatitis B in people co-infected with hepatitis C, in whom occult hepatitis B has been associated with advanced fibrosis and diminished response to interferon alpha. Although much more research is needed, existing reports justify a heightened awareness of the medical importance and means of testing for occult hepatitis B.     

Dual chronic hepatitis B virus and hepatitis C virus infection

Dual hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are common in HBV or HCV endemic areas. However, several clinical and pathogenetic issues remain unresolved. First, clinical and in vitro studies suggest the interactions between two viruses. The dynamics of the interaction in untreated setting versus treated setting and its influence on the long-term outcomes await further studies. A key issue regarding viral interactions is whether modulation of infection occurs in the same dually infected individual hepatocyte of the liver. Clarifying this issue may help to understand the reciprocal interference between HCV and HBV and provide clues for future immunopathogenetic studies. Second, the prevalence and clinical significance of coexisting occult HBV infection in patients with chronic HCV infection need further investigations. Third, combination therapy of peginterferon alfa-2a and ribavirin appears to be just as effective and safe for the treatment of hepatitis B surface antigen (HBsAg)-positive patients chronically infected with active chronic hepatitis C as it is in patients with HCV monoinfection. Nevertheless, one-third of dually infected patients with nondetectable serum HBV DNA-level pretreatment developed HBV reactivation posttreatment. How to prevent and treat this reactivation should be clarified. Furthermore, about 10% of the dually infected patients lost HBsAg. Underlying mechanisms await further investigations. Finally, the optimal treatment strategies for dually infected patients with hepatitis B e antigen-positive chronic hepatitis B should be identified in future clinical trials.     

慢性乙型肝炎病毒感染者家族隐匿性乙型肝炎病毒感染的调查

目的 了解慢性HBV感染者家族隐匿性HBV感染的发生率及其与HBV标志物、年龄和性别等的关系.方法 ELISA方法检测慢性HBV感染者家族成员的HBV血清学标志物,套式PCR法检测136例HBsAg阴性家族成员的血清HBV DNA,并将隐匿性HBV感染者和HBsAg、HBV DNA均阴性者分别作为试验组和对照组进行HBV标志物、年龄、性别和生物化学检测结果的比较.两组均数比较采用t检验.率的比较采用χ~2检验或Fisher确切概率法检验.结果 在52个慢性HBV感染者家族中共检测到92例HBsAg阳性者和136例HBsAg阴性者,其中15例为隐匿性HBV感染者,慢性HBV感染者家族HBsAg阳性率和隐匿性HBV感染的发生率分别为40.4%和11.0%,15例隐匿性HBV感染者中有7例抗-HBc阳性(χ~2=5.341,P=0.02),但隐匿性HBV感染的存在与年龄、性别等无关.结论 HBV感染存在家庭聚集现象,且在其家族中存在隐匿性HBV感染,并在抗-HBc阳性者中发生率较高.     

New perspectives in occult hepatitis C virus infection

Occult hepatitis C virus (HCV) infection, defined as the presence of HCV RNA in liver and in peripheral blood mononuclear cells (PBMCs) in the absence of detectable viral RNA in serum by standard assays, can be found in anti-HCV positive patients with normal serum levels of liver enzymes and in anti-HCV negative patients with persistently elevated liver enzymes of unknown etiology. Occult HCV infection is distributed worldwide and all HCV genotypes seem to be involved in this infection. Occult hepatitis C has been found not only in anti-HCV positive subjects with normal values of liver enzymes or in chronic hepatitis of unknown origin but also in several groups at risk for HCV infection such as hemodialysis patients or family members of patients with occult HCV. This occult infection has been reported also in healthy populations without evidence of liver disease. Occult HCV infection seems to be less aggressive than chronic hepatitis C although patients affected by occult HCV may develop liver cirrhosis and even hepatocellular carcinoma. Thus, anti-HCV negative patients with occult HCV may benefit from antiviral therapy with pegylated-interferon plus ribavirin. The persistence of very low levels of HCV RNA in serum and in PBMCs, along with the maintenance of specific T-cell responses against HCV-antigens observed during a long-term follow-up of patients with occult hepatitis C, indicate that occult HCV is a persistent infection that is not spontaneously eradicated. This is an updated report on diagnosis, epidemiology and clinical implications of occult HCV with special emphasis on anti-HCV negative cases.     

Hepatitis B virus infection:defective surface antigen expression and pathogenesis

Hepatitis B virus(HBV) infection is a global public health concern. HBV causes chronic infection in patients and can lead to liver cirrhosis, hepatocellular carcinoma, and other severe liver diseases. Thus, understanding HBV-related pathogenesis is of particular importance for prevention and clinical intervention. HBV surface antigens are indispensable for HBV virion formation and are useful viral markers for diagnosis and clinical assessment. During chronic HBV infection, HBV genomes may acquire and accumulate mutations and deletions, leading to the expression of defective HBV surface antigens. These defective HBV surface antigens have been found to play important roles in the progression of HBV-associated liver diseases. In this review, we focus our discussion on the nature of defective HBV surface antigen mutations and their contribution to the pathogenesis of fulminant hepatitis B. The relationship between defective surface antigens and occult HBV infection are also discussed.     

Occult hepatitis B in patients on hemodialysis: a review

The hepatitis B virus (HBV) is one of the most frequently transmitted agents in dialysis units. Occult hepatitis B is characterized by HBV infection without detectable surface antigen (HBsAg) in the patient’s serum, a positive or negative HBV DNA marker result in the serum and a positive result in the liver tissue, which leads to the potential risk of transmission during renal replacement therapy service. There is variation in occult hepatitis B prevalence rates in this population across various studies that may be related to numerous factors. The presence of occult hepatitis B in individuals undergoing renal replacement therapy is important with regard to both the possibility of transmission and the consequences for the patient, especially the development of chronic liver disease and reactivation of the disease after renal transplantation.     

Antibody to hepatitis B core antigen as a screening test for occult hepatitis B virus infection in Egyptian chronic hepatitis C patients

Purpose  The presence of hepatitis B virus (HBV) DNA in liver tissue and/or in serum in the absence of detectable hepatitis B surface antigen (HBsAg) is called occult HBV infection. This pattern was identified in patients with chronic hepatitis C virus (HCV) infection. The aim of this study was to determine the role of antibodies to hepatitis B core antigen (anti-HBc) as a screening test for occult HBV infection in Egyptian chronic HCV patients. Methods  One hundred chronic HCV patients negative for HBsAg were included and subdivided into two groups according to anti-HBc-IgG seroreactivity. Group A included 71 patients positive for anti-HBc (53 men and 18 women, mean age ± SD 48.8 ± 9.6 years), and group B included 29 patients negative for anti-HBc (18 men and 11 women, mean age ± SD 46.6 ± 11.7 years). All patients were subjected to full clinical assessment, routine laboratory investigations, abdominal ultrasonography and quantification of HBV-DNA by real-time PCR. Results  Chronic HCV patients positive for anti-HBc have more severe liver disease compared with anti-HBc negative patients. Although HBV-DNA in the serum was detected in 22.5% of anti-HBc-positive chronic HCV patients, it was not detected in any of anti-HBc-negative chronic HCV patients. There was no significant difference in any of the clinical and laboratory data tested between anti-HBc-positive patients with and without HBV-DNA in the serum. Conclusion  A significant number of patients with anti-HBc had detectable levels of HBV-DNA in the serum. Egyptian chronic HCV patients have a high prevalence of occult HBV infection.