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Occult HBV: Clinical Significance of Hepatitis B Core Antibody Positivity in HCV-Infected and HCV/HIV Coinfected Individuals
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Correspondence. Clinical Infectious Diseases May 2004;38:1335-1337
Curtis Cooper1 and Donald Kilby2
1The Ottawa Hospital Division of Infectious Diseases, University of Ottawa, Health Research Institute and 2University of Ottawa Health Services, Ottawa, Ontario, Canada
SIR- The combination of hepatitis B surface antigen (HBsAg) negativity and hepatitis B core antibody (anti-HBc) seropositivity is traditionally interpreted as indicative of prior hepatitis B virus (HBV) infection with clearance. More recently, it has become apparent that HBV DNA can be detected in serum or hepatic samples from at least some individuals who exhibit this combination. According to a recent publication, hepatitis B virus DNA surface and X regions of the hepatitis B virus genome, as well as covalently closed circular HBV DNA, were detected in 9 of 9 liver biopsy specimens obtained from HBsAg-negative individuals with histories of acute hepatitis B infection (median, 7.2 years before liver tissue analysis). Clinically apparent hepatitis caused by HBV has been reported in HBsAg-negative and anti-HBc seropositive individuals after immune reconstitution with human immunodeficiency virus (HIV) antiretroviral therapy and as a result of chemotherapy-induced immune suppression. This information demonstrates that, in at least some individuals, the phenomenon of occult chronic HBV infection may become clinically relevant.
The triad of hepatitis C virus (HCV) RNA positivity, HBsAg negativity, and anti-HBc seropositivity is frequently found in the clinical setting, given the shared risk factors for transmission of HBV and HCV infection. It is plausible that in individuals with chronic HCV infection, occult HBV persistence may contribute to higher transaminase levels, increased parenchymal inflammatory changes, and more-advanced stages of liver fibrosis. The quartet of HIV RNA positivity and the 3 markers mentioned above is commonly noted in the clinical setting, as well. It is unclear how HIV coinfection influences these complex interactions.
To address these questions, a cohort of 107 individuals who were positive for HCV by PCR and had results from HIV serological testing, anti-HBc and HBsAg testing, and liver biopsy was identified from among subjects followed-up at the Ottawa Hospital Viral Hepatitis Clinic and the University of Ottawa Health Service clinic. Biopsies were interpreted using the METAVIR system. Twenty-two (21%) subjects were HIV-seropositive, of which 15 (68%) were receiving antiretroviral therapy at the time of biopsy. Baseline transaminase levels, inflammation grade, fibrosis stage, and estimated fibrosis rates (defined as METAVIR fibrosis stage divided by the estimated number of years since onset of infection) were compared between anti-HBc seropositive and anti-HBc seronegative individuals. HCV RNA and aminotransferase levels were higher in anti-HBc seropositive subjects. Excessive alcohol consumption was not responsible for these differences, by our analysis. The mean fibrosis stage and proportion of subjects with advanced fibrosis was greater in anti-HBc seropositive subjects. However, the estimated fibrosis rates and inflammation grades were similar between these 2 groups. Of note, liver biopsy findings were consistent with chronic HCV infection and were not typical of the findings associated with chronic HBV infection.
HIV-seropositive individuals with chronic HBV infection (i.e., those who were HBsAg-positive) are known to progress more rapidly to cirrhosis and end-stage liver disease. We predicted that if HBV lingers in anti-HBc seropositive and HBsAg-negative subjects, then the manifestations of this occult infection would be most obvious in HCV/HIV coinfected individuals. The estimated fibrosis rate was higher for HIV-infected individuals than for HIV-seronegative subjects (mean rate [± SD], 0.161 [0.13] vs. 0.151 [0.31]). However, the grade, stage, and estimated fibrosis rate did not differ based on anti-HBc status in the 22 HCV/HIV coinfected subjects evaluated.
The objective of this evaluation was to determine whether markers of chronic HCV infection differed in patients routinely dismissed as chronically HBV infected (i.e., those who were anti-HBc seropositive and HBsAg-negative). Serum HBV DNA levels could not be measured in our cohort of subjects, because of the retrospective nature of this study. Although the inclusion of serum HBV DNA data would have been ideal, this information was not essential to the classification of our subjects or to the interpretation of our analysis. In reality, a negative serum HBV DNA result cannot be relied on to rule in or to rule out occult infection. The lower limit of detection of routinely used systems is insufficient to detect low-level HBV viremia occasionally present in occult HBV infection. Even with a lower threshold for detection, it is unlikely that many of these HCV-seropositive subjects with suspected occult HBV infection would have been HBV DNA positive. Furthermore, serum HBV DNA positivity is rare even among persons with occult HBV infection proven by liver tissue biopsy.
In conclusion, accumulating data raise questions as to whether HBV infection is ever truly cleared. Our analysis suggests that, in HBsAg-negative and anti-HBc seropositive individuals with chronic HCV, occult HBV infection may linger and contribute to increased HCV RNA and liver enzyme elevation. However, occult HBV infection likely does not produce a greater burden of end-stage liver disease, because the estimated liver fibrosis rate was not higher in HCV-monoinfected or in HCV/HIV coinfected individuals. The influence of this phenomenon on the efficacy of HCV and HIV drug therapies merits further evaluation.
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