Hepatitis Undercover

First identified in the 1960s, the hepatitis B virus (HBV) has a relationship with humans that goes back many millenia (1). However, despite this long history and advancements in both science and technology, HBV remains a transfusion-transmissible infection (TTI).

William Irving, Academic Clinical Virologist at the University of Nottingham, UK, spoke at ESCMID Global 2024 about the challenges surrounding occult HBV infected donors. We caught up with Irving after the conference to hear more about the current situation and what the future holds for diagnosis and screening of HBV.

Please tell us about the importance of improving diagnosis and screening of HBV
 

The standard diagnostic test for HBV is to look for the presence of surface antigen (sAg) in a patient’s peripheral blood. Now, we know some patients are HBsAg negative but have replicating viruses in their livers, which can spill over into the bloodstream. This means that screening for surface antigen can bring up a negative result when the patient is actually infected with a risk of liver disease and a risk of passing the infection to others. 

With these conflicting results, occult donors are patients that want to donate blood presenting negative for HBV but could still cause infection in the recipient of their transfused blood. Though rare, this is still a life threatening concern. I believe the latest instance of a patient dying as a result of blood transfusion infection was in 2018 in the UK (2). Of course, blood transfusion services remain concerned and improving screening and diagnosis is key in preventing HBV TTIs. 

How high is the HBV TTI risk?
 

For a long time, the general consensus was that TTIs weren’t a real condition. Of course, now the evidence has been built, we can confirm that it is. In the UK, The Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) set up a working party in 2018 to assess the risk to recipients and discuss ways to reduce the risk of infection (3). As far as blood-borne agents are concerned, there is always a risk of infection via blood transfusion. Of course, the ones we know about (HIV and HBV) we can screen for, but these tests aren’t 100 percent accurate. The chances of transmission therefore may be less than one in a million, but it isn’t zero. 

What are the main challenges in tackling HBV TTIs?
 

As noted, the main challenge lies in identifying occult HBV donors and diagnosing them. Until 2022, we screened blood donors for the surface antigen individually and pooled 24 donors for nucleic acid testing. This type of testing is extremely sensitive but if one individual out of 24 has the virus, the testing is diluted enough that sometimes the PCR cannot pick up the DNA.

To tackle this issue, there are two solutions. The first is to conduct individual PCR tests and remove the pools of 24; the second is to introduce a completely new test – the anti-HB Core test. The latter is a marker that detects antibodies to the core protein of the virus – a marker of having had HBV infection sometime in the past. Almost all occult-infected individuals will be anti-HBc positive.

The SaBTO working party conducted extensive assessments of both strategies. An individual nucleic acid test approach proved extremely expensive and still does not guarantee that you will identify an occult HBV positive patient. Alternatively, anti-HB Core screening is much cheaper and proves successful in almost all cases. With this result, ministers approved rollout of the anti-HB Core test across UK blood transfusion services in 2022. 

What might account for false negative HB sAg test results – and what could be done about it?
 

Some of these patients have mutations in their surface antigen that show up as false negatives, so even with surface antigen in the peripheral blood, the test cannot pick it up. There’s also possibilities that surface antigen is below the limit of detection. 

If we had more sensitive surface antigen tests, we could detect lower levels of antigens and identify patients who are currently missed. These more sensitive tests, which are ten to a hundred times better than current ones, will likely become commercially available and eventually be used by blood transfusion services. This might help identify more cases, however, the biology of occult HBV is complex, and there are still many unknowns.

Could you tell us about the models available for estimating residual risk?
 

SaBTO working group uses two models: Australian and South African. The Australian model extrapolates from the rates of known OBI detection compared to previous missed donations from the same donors. The South African model estimates the distribution of viral loads in OBI donors and factors in the known sensitivity of the PCR test.

Both models have been in literature for around 10 years and the SaBTO working group determined that there was no evidence of one method being better than the other. As such, we’ve used both to calculate residual risk, with results indicating the risk was 10-50 per million donations.

What’s next for your work in this area?
 

We’re in the process of setting up a study of chronic hepatitis B patients with colds to see if there’s increased risk of long-term liver damage. If the funding is granted, we would look at the immune responses in these individuals over the years. This work would increase our understanding of the virus replication, whether it's continuous or intermittent, perhaps offering new options in future prevention.

These studies would start in the UK, but the goal is to do a pan European study and reach collaborators in other countries. The more varied the data, the more we can learn about this disease and improve future outcomes.