国际肝病采访F. Blaine Hollinger教授

Hepatology Digest: We are quite interested in your investigation of occult hepatitis B and transfusion infection. Can you define occult hepatitis B and its prevalence in populations around the world?

Prof. Hollinger: The consensus definition for occult hepatitis B is an individual who is HBsAg negative but HBV DNA positive. The HBV DNA is usually detected in the blood but sometimes may only be found in the liver. A certain percentage of patients with occult hepatitis B will also have anti-HBc and/or anti-HBs but approximately 20% of them will display no serologic markers except for the HBV DNA. That makes this disorder somewhat difficult to diagnose if the physician fails to order virus-specific nucleic acid testing. The classic occult hepatitis B case is a person in the pre-seroconversion window period of an acute hepatitis B infection prior to the development of HBsAg.

In order to make a proper diagnosis of occult hepatitis B， you will need to order the most sensitive HBsAg test available that has a lower limit of detection of less than 0.1 nanogram/mL of HBsAg. In addition， a sensitive HBV DNA test that will detect less than 10 IU/mL is required since most available HBV DNA tests detect from 40-100 IU/mL and these assays will miss almost 90% of the patients with occult hepatitis B.

Hepatology Digest: Is the inaccessibility of these highly sensitive tests a barrier to detecting occult hepatitis B?

Prof. Hollinger: I think that it is. In the United States， we have to search for laboratories that have the capability of detecting HBV DNA at the optimal lower level of detection when we suspect occult hepatitis B. Our level of suspicion for occult hepatitis B is particularly raised in patients with hepatitis C infection because 30~60% of them may be coinfected with occult hepatitis B.  The unsuspected HBV infection may first show up in a person whose hepatitis C infection has been successfully treated but the enzymes remain elevated at the end of therapy.  Or there may be a rise in the liver enzymes during the first 4-12 weeks of therapy， an observation that frequently occurs when treating hepatitis B with interferon， but rarely occurs in a monoinfected hepatitis C patient.

Hepatology Digest: So the clinician needs to have an awareness of when to look for occult hepatitis B?

Prof. Hollinger: That is the key issue. They need to have a sensitive enough test to detect HBV DNA at the lowest level， to be aware that a hepatitis C infected patient may be coinfected with occult hepatitis B， and to recognize that patients who are going to receive chemotherapy may have an underlying occult hepatitis B infection that could become reactivated following immunosuppression.

Hepatology Digest: What is the potential for disease progression to cirrhosis or hepatocellular carcinoma in occult hepatitis B patients?

Prof. Hollinger: Part of this goes back to the prevalence of HBV infection in patients with advanced fibrosis or cirrhosis because HCC is more likely to occur in those patients. A percentage of patients with HCC may have HBV only in the liver and not in the blood. HBV DNA may not be detected in liver tissue following a liver biopsy unless the tissue is processed correctly. Dr. Care?o and colleagues in Madrid have stipulated that successful detection of virus in the liver requires snap-freezing the specimen in liquid nitrogen within 30 seconds of collection to avoid loss of virus-specific nucleic acid.

Hepatology Digest: Is the blood from occult hepatitis B patients with both anti-HBs and anti-HBc safer for transfusion to recipients than donor blood without the presence of anti-HBs?

Prof. Hollinger. The number of occult hepatitis B pre-seroconversion window period donors in the United States is about 1 out of approximately 410，000 donations. Recently， the American Red Cross reviewed the demographics， epidemiology and molecular virology of several of these occult hepatitis B donors and found that about half of them were individuals who had already been vaccinated against hepatitis B but subsequently acquired their HBV infection from a sexual partner who was a chronic carrier of hepatitis B. Although they never got sick and had what appears to be a subclinical infection， HBV DNA was detected in their blood and sometimes persisted for more than 75 days in the presence of measureable anti-HBs. The real issue is whether or not blood collected during that time period is infectious especially when concurrent antibody is present. One study in Japan showed that such blood may not be infectious. Investigators in that country looked at recipients of blood from donors with occult hepatitis B. There were two groups of donors. One group had HBV DNA positive blood containing anti-HBs and another group of donors were HBV DNA positive in the absence of anti-HBs. Only the latter group was associated with the transmission of HBV infection to recipients. Individuals that were transfused with blood containing anti-HBs failed to develop HBV infection. We are now faced with the issue of some donors who are vaccinated but still capable of acquiring hepatitis B， and the issue is whether or not that blood is infectious.

Hepatology Digest: How can we improve diagnostic techniques to detect hepatitis B infection during the window period， especially in blood donations?

Prof. Hollinger: It is through the availability of highly sensitive nucleic acid tests. In the United States， the American Red Cross， which tests over half of the blood collected in the country， is already testing donors with nucleic acid tests for hepatitis B. There are at least two licensed nucleic acid tests that can detect nucleic acid for HIV， HBV， and HCV at the same time. They are sufficiently sensitive (<10 IU/mL for HBV DNA) so that pools of 6 to 16 donations can be initially tested with these very sensitive assays. Once a minipool is found to be positive， the individual donations can be tested with individual assays to determine if they have HIV， HBV， or HCV. The introduction of HBV DNA testing in blood banks will further reduce transfusion-associated hepatitis B. This will be of great benefit especially in countries where HBV is endemic precluding the need to test blood for anti-HBc which would lead to an unacceptable loss of donors. Of greatest importance， however， is the availability of an all volunteer donor population that repeatedly donates blood.