Clinical significance of occult hepatitis B virus infection

Abstract

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 in the progression to cirrhosis remains unclear. Although OBI has been well documented in human immunodeficiency virus (HIV)-positive patients, especially among those coinfected with hepatitis C virus, further studies are needed to determine its current clinical impact in HIV setting.

Key Words: Occult hepatitis B virus infection; Liver disease; Cryptogenic cirrosis; Hepatitis B virus coinfection; Human immunodeficiency virus

CLINICAL SIGNIFICANCE OF OCCULT HEPATITIS B VIRUS INFECTION

Occult hepatitis B virus (HBV) infection (OBI) was redefined by international experts, meeting in Italy in 2008, as the presence of HBV DNA in the liver (with or without detectable HBV DNA in serum) for individuals testing HBV surface antigen (HBsAg) negative[1]. These experts also introduced a cut-off value for HBV DNA of < 200 IU/mL. A serum concentration greater than 200 IU/mL should be interpreted as an infection caused by escape mutants, not an OBI. Nevertheless, other experts prefer the traditional definition of OBI: the presence of HBV DNA in blood or liver tissues in patients negative for HBsAg, with or without any HBV antibodies.

Patients with OBI were further classified as either seronegative, when both antiHBs and antiHBc are negative, or seropositive when antiHBc is present[2]. These patients are also found to be positive for antiHBcs plus antiHBs or only positive for antiHBc but without antiHBs. For both of these latter patients, the HBV viral load is greater[3]. Moreover, viral replication seems to be controlled by different mechanisms: for antiHBc positive patients by a T-cell response of protective memory; whereas antiHBc negative individuals have no HBV-specific T-cell expansion, suggesting that low level infection is insufficient for protective memory to mature.

There are scant data for the molecular mechanisms that explain the lack of detection of HBsAg in the presence of HBV DNA. One possible explanation is defective transcription control of both the HBV-polymerase and HBsAg coding regions that can lead to a significant decrease of the viral replication levels and the circulating HBsAg titres. The presence of HBsAg/anti-HBs immune-complex, especially in those patients with low titres of surface antigen may interfere in the detection of circulating HBsAg.

Until recently, the clinical effect of OBI was unclear in the following contexts: for its influence on the progression of liver disease; on the development of hepatocellular carcinoma; and on the risk for reactivation or transmission of HBV infection[4].

OBI IN OTHERWISE HEALTHY INDIVIDUALS

For patients with OBI but who are otherwise healthy, the key issues are HBV prognosis and transmission. From the 5 blood donors with OBI and the 55 recipients of their blood studied by Gerlich et al[5], 22 probable cases of HBV transmission were identified, but these patients remained healthy. Nevertheless, fulminant hepatitis B was found in 3 of these blood recipients that were immunosuppressed. Although transmission is possible, this risk appears to be negligible when concurrent antiHBs is present (> 100 mIU/mL)[6]. In addition, HBV transmission was not found by Satake et al[7] for OBI blood donors that were antiHBs positive, whereas 27% of antiHBs negative donors transmitted HBV infection. These results were confirmed by other studies[8,9]. While HBV transmission by OBI donors is possible transmission risk is negligible when antiHBs titres are present (even at low levels).

After transplantation, organs, particularly livers from antiHBc positive donors, may transmit HBV infection. Cholongitas et al[10] reviewed 39 studies that included 903 recipients of antiHBc positive donors. De novo HBV infection developed in 19% of HBsAg-negative recipients, but was less frequent for antiHBc and antiHBs positive recipients than for HBV naïve recipients. Adequate prophylaxis with lamivudine or specific gammaglobulin, or both in combination, reduced de novo infections in these two groups.

A second issue is patients with OBI developing complications. Mild necrosis and inflammation can be present in liver biopsies of humans after acute hepatitis and in woodchucks infected by woodchuck hepatitis virus (WHV). This mild inflammation probably has no repercussion if the patient has no other cause of liver disease[1]. For 18 patients with OBI who underwent liver transient elastometry[11], the median liver stiffness was 4.2 kPa (healthy people 4.6 kPa), showing absence of fibrosis for them. Additionally, no significant mortality was found caused by hepatocellular carcinoma in patients developing unapparent hepatitis B[6]. Therefore, immune individuals with only OBI but no other concomitant liver disease usually show no clinical evidence of hepatic damage.

OBI AND CRYPTOGENIC CHRONIC LIVER DISEASE

For a cohort of 159 patients with cryptogenic chronic liver disease, the prevalence of OBI investigated by Fang et al[12] was 28% for serum HBV DNA positivity, but for antiHBc positive individuals the prevalence reached 100%. Similar results for patients with cryptogenic cirrhosis were reported by Chan et al[13]: 32% had OBI, most of them with antiHBc and/or antiHBs. By contrast, Kaviani et al[14] only found OBI in 1.9% of patients with cryptogenic hepatitis. These results, however, may be explained by both the variation in methods for the measurement of HBV DNA and differences in endemicity for the geographic areas studied. In the paper by Kaviani et al[14], OBI was found in patients with cryptogenic hepatitis by qualitative polymerase chain reaction (PCR) with a sensitivity of 150 × 10³ copies/L. Therefore, it is very important to use the most sensitive tools to measure HBV viral load, such as “real-time” PCR methods (lower detection limit 10-15 IU/mL) in order to define OBI. Yet, it is nevertheless unclear if OBI was the main cause of this liver disease and its role in the progression to cirrhosis.

OBI AND DIALYSIS PATIENTS

In a study including 366 patients from six dialysis units in Central Greece, an OBI prevalence of 0.9% was recently reported by Mina et al[15]: 15 patients were HBV DNA positive, 12 had overt HBV infection (one HBeAg positive, 10 antiHBe positive and 1 antiHBc plus antiHBs positive) and OBI was diagnosed in 3 patients (two had no serological markers of HBV infection and one was antiHBc and antiHBs positive). For both groups the HBV DNA levels were low. Additionally, there was no association with HCV infection. In the setting of continuous ambulatory peritoneal dialysis and hemodialysis (71 patients in each group), another study[16] reported a higher prevalence of OBI than the Greek study (17% in peritoneal dialysis and 10% in hemodialysis). Similarly, HBV viral loads were low and HCV positivity was not a contributing factor to OBI. These low HBV DNA titres may be explained by both the transfer of HBV DNA from serum to the dialysate compartment and also the destruction of the HBV genome during the haemodialysis session[15].

OBI AND HUMAN IMMUNODEFICIENCY VIRUS-INFECTED PATIENTS

Human immunodeficiency virus (HIV) infection modifies the natural history of hepatitis B disease. Coinfected patients have higher HBV DNA levels and are more likely to have accelerated loss of protective anti-HBs and an increased risk for liver morbidity and mortality. The increasing survival of patients with HIV-HBV treated with HAART allows a longer time for liver cirrhosis to develop, with some patients experiencing accelerated progression to clinically significant liver disease.

The prevalence of OBI for patients with HIV has been estimated by several studies with controversial results[17-20]: from a Brazilian group’s[19] estimate of 5% to one in India[18] of nearly 25%. The Indian group described the presence of detectable HBV DNA in 21% of antiHBc positive patients. Additionally, HIV patients are at a higher risk for HCV coinfection[18]. Morsica et al[17] reported that OBI is more frequent in HCV-coinfected patients. However, other studies[18,19] did not confirm these results.

Because most HIV-infected patients currently on HAART receive drugs with anti-HBV activity, recognition of OBI in these patients may be difficult. Although reactivation of HBV infection in HIV-positive/HBsAg-negative is rare, it would be possible after withdrawal of antivirals against HBV, such as lamivudine or tenofovir[21]. Recently, Bloquel et al[20] described reactivation for two HIV patients with anti-HBc after withdrawal of HAART with anti-HBV activity. Consequently, it would be very important to know the HBV virological status of these patients before starting antiretroviral therapies in order to avoid reactivations if treatment is stopped. Further studies are needed to determine the current clinical impact of OBI for HIV setting.

OBI AND HCV INFECTED PATIENTS: REACTIVATION AFTER IMMUNOSUPRESSION THERAPY

These issues will be reviewed in other chapters. Although the presence of OBI in HCV infected patients has been well established, its significance is currently under investigation. Some studies have shown higher fibrosis stages in patients with OBI compared with individuals without it. Nevertheless, others have failed to show this finding. Central questions include the implication of OBIs on hepatic carcinogenesis and their effect on response to HCV treatment.

Patients positive for HBsAg have a high risk of reactivation of hepatitis B after cytotoxic or immunosuppressive therapy. In this regard, OBI patients under immunosuppressant conditions may show a reactivation of viral replication when immunological reconstitution is achieved with a consequently CTL-mediated hepatocyte injury[1]. Therefore, reactivation more often appears after end of treatment. Hui et al[22] studied 244 patients who received rituximab plus steroids. All were HBsAg-negative and 8 patients developed HBV reactivation. Thus, for these patients starting antivirals early, close monitoring of HBV DNA is mandatory before the occurrence of de novo hepatitis.

CONCLUSION

Although the clinical significance of OBI remains unclear, the more recent data suggest an important role in reactivation of hepatitis B in immunosuppressed patient (especially after treatment with cytotoxic drugs and biologic therapies) and in HBV transmission in liver transplantation, particularly livers from antiHBc positive donors. Other issues such as cryptogenic liver disease, or the relevance in “healthy” patients should be clarified with more studies.