Occult hepatitis B virus infection: a hidden menace?

Recovery from an acute hepatitis B virus (HBV) infection is associated with loss of HBV DNA from serum, hepatitis B e antigen seroconversion, hepatitis B surface antigen (HBsAg) seroconversion, and normalization of serum aminotransferases. These changes generally imply clearance of virus, but clinical observations have shown that reactivation of HBV infection can occur either spontaneously or after immunosuppression.1-3 Recent studies showed that immune response to HBV remains vigorous long after an acute infection. In addition, HBV DNA can be detected by polymerase chain reaction (PCR) assays in serum, liver, and peripheral blood mononuclear cells more than a decade after an apparent recovery from HBV infection.4-6 These findings suggest that recovery from acute hepatitis B may not result in complete virus elimination, but rather the immune system keeps the virus at very low levels. There is, however, no clear evidence that patients who have persistently low levels of HBV after recovery from acute hepatitis B develop progressive liver disease. The availability of PCR assays for HBV DNA allows the detection of 102 copies/mL compared with 106 copies/mL using hybridization assays. Using PCR assays, HBV DNA has been detected in some subjects who are HBsAg negative including those with no serologic markers of HBV infection. In this issue of the HEPATOLOGY, Bréchot et al. review the prevalence, virologic basis, and clinical significance of occult HBV infection.7 For the clinician, several issues regarding occult HBV infection are pertinent: Does it exist? How common is it? What is the risk of transmission? What is the risk of progressive liver disease? How can it be diagnosed? Is antiviral therapy indicated? Before these issues can be addressed, it must be recognized that there is currently no standardized definition or diagnostic criteria of occult HBV infection. A simple definition would be the detection of HBV DNA in HBsAg-negative subjects. However, more specific information must be provided, as occult HBV infection is a heterogeneous clinical entity. Bréchot et al. provide very strong evidence that occult HBV infection exists and that most cases are related to very low levels of HBV rather than to HBV mutants that do not express or produce aberrant surface proteins and therefore are undetected by standard testing.7 Because HBV-DNA detection is the key to diagnosis of occult HBV infection, the type of assay used and its sensitivity must be specified. The sensitivity of PCR assays for HBV DNA in studies on occult HBV infection varies from 101 to 103 copies/mL.8 However, most PCR assays including commercially available assays are not standardized.9 Other factors that may affect the detection rates of HBV DNA include the volume of sample used and the material tested. Thus, the limit of detection can be increased by using a larger volume of serum as in the case of the hybrid capture assay. Most studies on occult HBV infection have reported higher rates of HBV-DNA detection in liver or peripheral blood mononuclear cells compared with serum or plasma. In addition, snap-frozen liver tissue has a higher rate of HBVDNA detection than paraffin-embedded liver tissue. More importantly, specificity and reproducibility of assay results must be ensured. This requires meticulous steps to prevent contamination of samples, inclusion of negative controls, and performance of assays in duplicate using two independent sets of HBV primers. Occult HBV infection should also be reported in the context of other HBV serology markers. Broadly, individuals should be classified as being seropositive or seronegative. “Seropositive” subjects are positive for antibodies to hepatitis B core antigen (anti-HBc) and can be further divided into 2 subgroups: with and without anti-HBs. “Seronegative” subjects are negative for both anti-HBc and anti-HBs. As indicated in the review by Bréchot et al.,7 the HBV-DNA detection rate is highest in subjects who are anti-HBc positive/anti-HBs negative; some of these individuals probably have low-level HBV infection with subdetectable HBsAg. The HBV-DNA detection rate is intermediate in subjects who are positive for both antiHBc and anti-HBs. These individuals may have recovered from previous infection but may have persistent low levels of HBV. The HBV-DNA detection rate is lowest in seronegative subjects. These individuals have recovered from previous infection but lost all serologic markers of HBV infection. Rarely, they may be infected with HBV mutants that do not express HBV serologic markers. Geographic differences in the prevalence of occult HBV infection are most likely related to the endemicity of HBV infection. Thus, occult HBV infection is most commonly reported in high endemic areas where 70% to 90% of the population have been exposed to HBV and infrequently reported in low endemic areas where 5% to 20% of the population had prior infection with HBV.10-12 The prevalence of occult HBV infection also depends on the population studied, being more common in patients with chronic liver disease and less common among healthy blood or organ donors. Patients with fulminant hepatitis B may be misdiagnosed as occult HBV infection because of rapid virus clearance with undetectable HBsAg at the time of presentation. Transmission of HBV infection has been documented from HBsAg-negative, anti-HBc–positive blood and organ donors. The risk is variable (0.4%-90%)13-17; it is highest when livers Abbreviations: HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; PCR, polymerase chain reaction; anti-HBc, antibody to hepatitis B core antigen; HCC, hepatocellular carcinoma. From the Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI. Received March 14, 2001; accepted March 30, 2001. Address reprint requests to: Anna Lok, M.D., Division of Gastroenterology, University of Michigan Health System, 3912 Taubman Center, Box 0362, Ann Arbor, MI 481090362. E-mail: [email protected]; fax: 734-936-7392. Copyright © 2001 by the American Association for the Study of Liver Diseases. 0270-9139/01/3401-0028$35.00/0 doi:10.1053/jhep.2001.25225