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Occult hepatitis B: A major challenge in blood screening

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Dr Sangeeta Agarwal, Senior Consultant, Department of Transfusion Medicine, Fortis Memorial Research Institute, Gurugram gives an insight into how occult HBV infection is closely related to endemicity of HBV infection

Hepatitis B virus (HBV) remains a major public health problem worldwide. Among its various transmission routes, transfusion is the one that should be worked upon to prevent it. Implementation of hepatitis B surface antigen (HBsAg) in routine screening of blood donors has greatly enhanced transfusion safety and has reduced the incidence of transfusion-transmitted hepatitis B over the last few years. But, it has been seen that HBV transmission by blood components negative for HBsAg can still occur and HBV transmission remains the most frequent transfusion-transmitted viral infection; thus, the term occult hepatitis B virus infection (OBI) was introduced.

Occult hepatitis B virus infection (OBI), is a challenging clinical entity. It is recognised by two main characteristics: absence of HBsAg and low viral replication. Sensitive HBV DNA amplification assay is the gold standard assay for detection of OBI. Viral as well as host factors are implicated in the pathogenesis of OBI. Several possible mechanisms have been hypothesised for the pathogenesis of OBI and the condition is probably multifactorial.

Studies have shown that the prevalence of occult HBV infection is closely related to the endemicity of HBV infection. Patients from countries highly endemic for HBV are more likely to develop occult HBV infections. As in highly endemic countries, the majority of infections are contracted perinatally or in early childhood; a higher proportion of the infected adults have late chronic HBV with undetectable HBsAg.

Evaluation of Occult hepatitis B infection

Most OBIs are asymptomatic and would only be detected by systematic screening. Investigations should be considered in the following situations: (1) HCV-infected patients with flares in viral replication and liver damage; (2) infected patients becoming immune deficient mainly by receiving immunosuppressive regimens for various clinical conditions; (3) screening of blood donations for immunocompromised recipients; and (4) subjects with unexplained liver diseases.

Liver biopsy: Detection of HBV DNA in liver biopsy is the best way for diagnosis of OBI. However, liver biopsy tissue is not always available.

HBsAg Testing: Presently HBsAg screening assays used are enzyme immunoassays (EIAs)- enzyme-linked immunosorbent assays (ELISAs) and chemiluminescence immunoassays (CLIAs).

Anti-HBc testing: HBV DNA detection rate is highest in subjects who are anti-HBc-positive but anti-HBs-negative, and these individuals are more likely to be infectious.

HBV nucleic acid (DNA) testing: The gold standard test for detection of OBI is the amplification of HBV DNA. Nucleic acid testing (NAT) for HBV DNA detection that combines simultaneous detection of human immunodeficiency virus (HIV) RNA, HCV RNA, and HBV DNA and use of an automated testing platform have made HBV NAT blood screening feasible. Studies have shown that pooled-sample NAT would reduce the window period (WP) by 9 – 11 days; and single-sample NAT or individual donor NAT (ID-NAT) would reduce the WP by 25 – 36 days. This leaves WPs of 40 – 50 days with mini-pool (MP) and 15 – 34 days with individual donor (ID) HBV NAT. It has been emphasised by few studies that the ability of NAT to reduce the WP depends not only on the sensitivity of both the molecular and serological tests but also on the sample volume (200 or 500 μL) as well as the dilution factor introduced by pooling samples, the prevalent HBV genotype at the location and the level of HBV endemicity. Beyond shortening the WP, NAT screening, particularly in individual units, has uncovered a relatively large number of HBsAg-negative ‘‘occult” HBV infection or carriage.

Most HBV infections spontaneously resolve in immunocompetent adults, whereas they become chronic in most neonates and infants who are at great risk of developing complications such as cirrhosis, chronic liver disease (CLD) and HCC. Those with chronic HBV infection may present in one of the four phases of infection: immune tolerance, immune clearance (HBeAg-positive chronic hepatitis B), inactive carrier state, and reactivation (HBeAg-negative chronic hepatitis B).

OBI infectivity by transfusion

Studies have examined the infectivity of HBV-containing blood products according to the immune status of recipients. It was seen that WP and anti-HBs-positive and negative OBI units can transmit HBV and viral transmission can be associated with extremely low levels of HBV DNA in anti-HBc-positive only units (< 20 IU/mL) or blood collected during the very early phase of acute infection.

OBI status in India

Risk of OBI in India is unknown because of lack of data on the subject. Though HBV screening is mandatory by HBsAg in India, but it still continues to be transmitted by blood and blood components, maybe due to presence of OBI among donors as well as WP donations.

HBsAg screening alone is not sufficient to detect HBV in all phases of the infection. A combination of screening with HBsAg and antibody to core antigen or NAT preferably ID NAT is desirable.

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