Hepatitis B is one of the most serologically complex and heterogenous viral infections. It’s estimated that almost a quarter of a million Australians live with life-long chronic Hepatitis B, and more than 30 per cent of those are undiagnosed.1
Few people better understand the challenges posed by Hepatitis B than the experts at The Royal Melbourne Hospital's Victorian Infectious Diseases Reference Laboratory (VIDRL), at the Peter Doherty Institute for Infection and Immunity, who serve Victorian health services, the Commonwealth Department of Health and the region via their World Health Organization role.
Professor Peter Revill leads VIDRL's Hepatitis B Molecular Virology Group, with Kathy Jackson leading the laboratory's Molecular Microbiology Group. The pair have unique insights into the most pressing challenges presented by this virus, and the opportunities opened by improved assays.
"To really get in front of this virus, we need to fully understand its natural history, and the precise status of those infected, including measurement of viral load and replicative activity at very low levels" Revill says.
There are numerous complexities to the virus. One example is "silent" infections that cause no symptoms, allowing the infection to go unnoticed, but still creating a transmission risk. Improved awareness of risk factors and improved screening could capture these individuals.
While a large proportion of patients who are infected as an adult naturally rid themselves of the infection over several months, some progress to life-long chronic infection, which is generally only treated when liver damage is evident. However, the myth of the 'healthy carrier' who avoids liver damage has been busted by studies2 revealing increased risks of later progression to liver disease or cancer, regardless of symptomology.
"Here in Australia, only around 11 per cent of people with chronic Hepatitis B are receiving appropriate care. Indigenous Australians have around six to nine times the risk of not receiving care than non-indigenous Australians. We simply need to do better" says Jackson.
Abbott have recently launched the ARCHITECT HBsAg Next Qualitative Assay in Asia-Pacific, offering ultra-sensitive measurement of a key Hepatitis B biomarker, Hepatitis B Surface Antigen, at significantly lower levels than standard assays. This new assay will also offer improved detection of problematic mutant strains.3,4
More sophisticated assays that can detect very low levels of HBV DNA or HBsAg could be useful in a number of ways, suggests Revill.
"Knowing if there is a threshold of HBV DNA or HBsAg that may predict which chronic Hepatitis B patients will progress to liver disease or cancer, and/or would achieve functional cure on therapy, would be a major benefit and may allow us to personalise treatment and surveillance more.
Jackson sees other possible uses "It may also help particularly vulnerable cohorts among those with chronic disease, such as those facing compromised immunity from chemotherapy or co-infection with HIV. These situations are often accompanied by a sudden spike in viral activity, at the worst possible time. So, these tests may help us offer more sophisticated monitoring in those patients."
A high replication rate coupled with the involvement of error-prone reverse transcriptase drives the mutation rate in Hepatitis B far higher than those seen in many DNA viruses, to a level akin to that seen in RNA viruses. Threats posed by mutant strains include vaccination breakthrough infections, poorer clinical outcomes, evasion of detection via standard diagnostic assays, and impaired response to treatment.
Although the virus isn’t always replicating to detectable levels using current assays, its DNA is always present as a reservoir in liver cells, present as a circular form (cccDNA). Occult infections are defined as the presence of HBV DNA in the liver and/or viral DNA in the blood of people who test negative for HBsAg by standard assays. The ultra-sensitive assays could allow detection of these people, who are still at risk of liver disease or cancer and may unwittingly transmit the virus to others.
Revill and Jackson make the point that viewing hepatitis in terms of Australia and 'rest of world’ is not helpful.
"We have plenty of low- and middle- income countries on our doorstep where this virus is endemic, and who lack capacity to control spread through comprehensive diagnosis and treatment. Here at VIDRL, through our WHO role, we do what we can to help build that capacity. But with migration and human movement– 2020 notwithstanding – their issues around Hepatitis B spread are just as much our issues," says Jackson.
"It's simple - we just need to know everyone who has Hepatitis B so we can make sure they get the right treatment!"
3 Kuhns M, et al. Virology Journal. 2019;16:43
4 Lou S, et al., Journal of Clinical Virology. 105(2018)18-25.