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Occult HBV Seen in 26% of HCV+
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"Occult hepatitis B virus infection in Greek patients with chronic hepatitis C and in patients with diverse nonviral hepatic diseases"
Journal of Viral Hepatitis
Volume 11 Issue 4 - July 2004
S. P. Georgiadou 1 , K. Zachou 1 , E. Rigopoulou 2 , C. Liaskos 1 , P. Mina 1 , F. Gerovasilis 3 , E. Makri 2 and G. N. Dalekos 1,2
1Research Laboratory of Internal Medicine, 2Academic Liver Unit, Department of Internal Medicine, Medical School, University of Thessaly Larissa, Thessaly; and 3Gastroenterology Division at General Hospital of Volos, Magnesia, Greece
"...HBV-DNA was detected in 26.2% of HCV-infected patients who were Hepatitis B surface antigen (-)
"...no serologic marker of HBV infection should be used as a surrogate indicator of occult HBV infection in HCV-infected patients and in patients with nonviral hepatic diseases.
"...Occult HBV infection does not seem to affect the clinical features and the histologic progression of liver disease in both Greek patients' groups. However, additional studies of long-term clinical and laboratory follow-up with repeated PCR investigations are rather needed in order to better clarify and understand the pathobiological basis and significance of occult hepatitis B
Summary. Occult hepatitis B virus (HBV) infection has been reported in patients with chronic hepatitis C who are negative for HBV surface antigen (HBsAg). However, the significance of 'silent' HBV in hepatitis C virus (HCV) infection is unknown.
We investigated 540 subjects for the presence of occult HBV in Greek HCV patients, patients with nonviral liver diseases and healthy donors in an attempt to determine the frequency and importance of this phenomenon. One hundred and eighty-seven anti-HCV(+)/HBsAg(-) patients' sera were investigated for the presence of HBV-DNA by polymerase chain reaction.
Two hundred and eighty-two selected blood donors (positive for antibodies to HBV core antigen) and 71 patients with various nonviral hepatic diseases consisted the control groups [both controls were anti-HCV()/HBsAg(-)]. HBV-DNA was detected in 26.2% of HCV-infected patients vs 8.5% of patients with nonviral diseases (P = 0.003) and 0/282 of donors (P = 0.0000).
HBV-DNA was neither associated with HBV markers, nor with the clinical status of HCV and nonHCV patients. Neither epidemiological, histologic and virologic data nor the response to therapy were associated with the HBV-DNA detection. Hence one quarter of HCV-infected patients had occult HBV infection. Similar findings were not found in both control groups.
Occult HBV infection in Greek patients with chronic hepatitis C does not seem to modify the progression of chronic liver disease. Further studies of longer duration are needed in order to clarify the role of 'silent' HBV infection in HCV-infected patients.
INTRODUCTION
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are considered to be the most common causes of liver disease worldwide. Both viruses are transmitted parenterally and they share similar risk factors for transmission. As a consequence combined HBV and HCV infection is quite frequent, especially in HBV endemic areas.
Overt HBV and HCV coinfection has been reported to be associated with a more severe liver disease, increased frequency of hepatocellular carcinoma and resistance to -interferon (a-IFN) therapy. Several studies have also demonstrated the presence of HBV-DNA in the sera and/or liver of patients who lack serologic markers for HBV and HCV, and patients with and/or cryptogenic hepatitis, cirrhosis or hepatocellular carcinoma with an incidence ranging from 14 to 85%. Furthermore, the reported detection rate of HBV-DNA by polymerase chain reaction (PCR) in the sera and/or liver of patients with hepatitis C who were negative for hepatitis B surface antigen (HBsAg) varies widely (0-90%).
Occult HBV infection is characterized by undetectable serum HBsAg but detectable HBV-DNA in serum or liver. In addition, some studies have shown that HBV-DNA can often be detected in liver tissue samples even when it is not detectable in the serum, suggesting an even higher prevalence of occult HBV infection among HCV positive patients. So far, data on the prevalence and clinical significance of occult HBV infection in patients with chronic hepatitis C are missing in our country. In addition, the clinical impact of occult HBV on HCV-related disease remains controversial. For these reasons, we conducted a large study to determine the prevalence and clinical significance of occult HBV infection in 187 consecutive HCV-positive/HBsAg-negative patients from Central Greece, an area with intermediate endemicity for HBV infection. As control groups we investigated 71 patients with diverse nonviral chronic liver diseases (disease control group) and 282 HBsAg-negative/antibodies to HBV core antigen (anti-HBc)-positive healthy blood donors (healthy control group). In order to explore the possible clinical impact of occult HBV infection on HCV-related disease, the presence or absence of HBV-DNA was associated with epidemiological, clinical, laboratory, virologic, histologic data and HBV serologic markers as well as with the response to antiviral therapy.
RESULTS
The detection of HBV-DNA was significantly more frequent in patients with HCV infection (49/187; 26.2%; 95% CI: 22.9-29.4%) compared with the disease control group (6/71; 8.5%; 95% CI: 5.2-11.8%) (P = 0.003) as well as with the healthy control group (0/282; 0%) (P = 0.0000). The mean ± SD titre of HBV-DNA was 3122 ± 5546 copies/mL (range: 205-32 000 copies/mL) in HCV-infected and 1196 ± 1825 copies/mL (range: 259-4870 copies/mL) in the disease control group (not statistically significant difference). HBV-DNA seropositivity was associated neither with age, sex, the source and the duration of HCV infection nor with certain epidemiological and demographic factors (operations, conduction of tattoos, traditional practices, etc.). In addition, the detection of HBV-DNA both in HCV-infected patients and in the disease control group was not associated with several clinical and laboratory parameters studied. Among the six HBV-DNA positive patients of the disease control group three patients had autoimmune liver disease, one Budd-Chiari syndrome, one alcoholic liver disease and the last one undifferentiated cholestatic syndrome. Only one of them had cirrhosis at the time of the study.
Negativity for all HBV markers was recorded in 94 of 187 HCV-infected patients (50.3%; 95% CI: 46.6-53.9%) and in 41 of 71 patients of the disease control group (57.7%; 95% CI: 51.8-63.5%) (not statistically significant difference). Anti-HBc positivity was found in 64 of 187 patients with HCV infection (34.2%; 95% CI: 30.7-37.6%) and in 29.6% of the disease control group (95% CI: 24.2-35.1%), while anti-HBs positive had 32.6% (95% CI: 29.1-36%) and 28.2% (95% CI: 19.4-36.9%), respectively (not statistically significant differences). None of the anti-HBc positive patients had a known history of acute or chronic HBV infection. The detection of HBV-DNA was not found to be associated with each of the specific markers of HBV infection both in HCV-infected patients and the disease control group. Moreover, the presence of at least one positive HBV marker in HCV-infected patients was not associated with the detection of HBV-DNA [23/93; 24.7%; 95% CI: 20.2-29.2% in HCV (+)/at least one HBV marker (+) vs 26/94; 27.7%; 95% CI: 23.1-32.3% in HCV (+)/all HBV markers (), P > 0.05]. Similar findings were recorded in the disease control group [3/6; 50% in patients with at least one HBV marker (+) vs 3/6; 50% in patients with all HBV markers (-), P > 0.05]. Furthermore, HBV-DNA positivity was not associated with virologic parameters of HCV such as, the HCV genotype and HCV-RNA levels.
In the 101 HCV-infected patients who had undergone liver biopsy, HBV-DNA positivity was not associated with liver histology. In addition, fibrosis was not associated with the detection of HBV-DNA even if all patients with normal levels of aminotransferases and cirrhosis were included - irrespective of the presence of liver biopsy - in the none/mild and moderate/severe groups of fibrosis, respectively (data not shown). During the follow up, three HCV-infected patients developed hepatocellular carcinoma. Only one of them had detectable HBV-DNA in serum.
Concerning patients with HCV infection who completed antiviral treatment 14 of 44 (31.8%) were HBV-DNA positive. However, HBV-DNA seropositivity was not associated with the response to therapy (biochemical, virologic or histologic) either at the end of treatment or 6 months after completion of therapy (data not shown). Actually, response rates either at the end of treatment or 6 months after the completion of therapy were 73.3 and 68.4% respectively in the HCV(+)/HBV-DNA(-) patients vs 58.3 and 33.3% in the HCV(+)/HBV-DNA(+) patient group (not statistically significant difference).
AUTHOR DISCUSSION
The detection of HBV-DNA was significantly more frequent in patients with HCV infection (49/187; 26.2%; 95% CI: 22.9-29.4%) compared with the disease control group (6/71; 8.5%; 95% CI: 5.2-11.8%) (P = 0.003) as well as with the healthy control group (0/282; 0%) (P = 0.0000). The mean ± SD titre of HBV-DNA was 3122 ± 5546 copies/mL (range: 205-32 000 copies/mL) in HCV-infected and 1196 ± 1825 copies/mL (range: 259-4870 copies/mL) in the disease control group (not statistically significant difference). HBV-DNA seropositivity was associated neither with age, sex, the source and the duration of HCV infection nor with certain epidemiological and demographic factors (operations, conduction of tattoos, traditional practices, etc.). In addition, the detection of HBV-DNA both in HCV-infected patients and in the disease control group was not associated with several clinical and laboratory parameters studied. Among the six HBV-DNA positive patients of the disease control group three patients had autoimmune liver disease, one Budd-Chiari syndrome, one alcoholic liver disease and the last one undifferentiated cholestatic syndrome. Only one of them had cirrhosis at the time of the study.
Negativity for all HBV markers was recorded in 94 of 187 HCV-infected patients (50.3%; 95% CI: 46.6-53.9%) and in 41 of 71 patients of the disease control group (57.7%; 95% CI: 51.8-63.5%) (not statistically significant difference). Anti-HBc positivity was found in 64 of 187 patients with HCV infection (34.2%; 95% CI: 30.7-37.6%) and in 29.6% of the disease control group (95% CI: 24.2-35.1%), while anti-HBs positive had 32.6% (95% CI: 29.1-36%) and 28.2% (95% CI: 19.4-36.9%), respectively (not statistically significant differences). None of the anti-HBc positive patients had a known history of acute or chronic HBV infection. The detection of HBV-DNA was not found to be associated with each of the specific markers of HBV infection both in HCV-infected patients and the disease control group. Moreover, the presence of at least one positive HBV marker in HCV-infected patients was not associated with the detection of HBV-DNA [23/93; 24.7%; 95% CI: 20.2-29.2% in HCV (+)/at least one HBV marker (+) vs 26/94; 27.7%; 95% CI: 23.1-32.3% in HCV (+)/all HBV markers (), P > 0.05]. Similar findings were recorded in the disease control group [3/6; 50% in patients with at least one HBV marker (+) vs 3/6; 50% in patients with all HBV markers (), P > 0.05]. Furthermore, HBV-DNA positivity was not associated with virologic parameters of HCV such as, the HCV genotype and HCV-RNA levels.
In the 101 HCV-infected patients who had undergone liver biopsy, HBV-DNA positivity was not associated with liver histology. In addition, fibrosis was not associated with the detection of HBV-DNA even if all patients with normal levels of aminotransferases and cirrhosis were included - irrespective of the presence of liver biopsy - in the none/mild and moderate/severe groups of fibrosis, respectively (data not shown). During the follow up, three HCV-infected patients developed hepatocellular carcinoma. Only one of them had detectable HBV-DNA in serum.
Concerning patients with HCV infection who completed antiviral treatment 14 of 44 (31.8%) were HBV-DNA positive. However, HBV-DNA seropositivity was not associated with the response to therapy (biochemical, virologic or histologic) either at the end of treatment or 6 months after completion of therapy (data not shown). Actually, response rates either at the end of treatment or 6 months after the completion of therapy were 73.3 and 68.4% respectively in the HCV(+)/HBV-DNA() patients vs 58.3 and 33.3% in the HCV(+)/HBV-DNA(+) patient group (not statistically significant difference).
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