A cure for the incurable: fighting chronic HBV
Dr Danny Ka Ho Wong is recognised as a pioneer in Hepatitis B Virus (HBV) research and is currently Assistant Professor at the Department of Medicine, The University of Hong Kong (HKU) located at Queen Mary Hospital. Despite preventative measures, there are an estimated 240 million sufferers of chronic HBV worldwide, the disease is responsible for over six hundred thousand deaths per year and there is no cure.
“Hepatitis C can be effectively cured but while we can control HBV and its replication, we are still some way from a cure,” says Wong.
He remembers that in high school he had a natural tendency to the science pathway. But it wasn’t until his undergraduate year that he took an interest in biochemistry and moved from Vancouver to Winnipeg to study at the microbiology-chemistry joint programme at the University of Manitoba.
“We were looking at molecular pathways and how they regulate each other- it was amazing and made me interested in biomedical research,” says Wong, who subsequently completed his MSc at the University of British Columbia (UBC) with a focus on photosynthetic bacteria and manipulating genes in that bacteria.
On completion of his MSc, Wong accepted a position at the Hong Kong University of Science and Technology (HKUST) as a research technician, studying Salmonella in the university’s bacterial lab. It was related to his MSc research in that his team manipulated genes within the bacteria and studied the variation in phenotypes.
“Professor James Hackett was my mentor at HKUST and I really enjoyed the stability of an interesting, secure job. But I was still young, and after about six years I thought, is this it for the rest of my career?” says Wong.
He wanted to be more engaged in medical research and HBV was a hot topic. It was less controlled in 2001 than now and he knew from general knowledge that it was regarded as “the Asian disease” and was particularly prevalent in Hong Kong. He decided to call HKU to enquire about research opportunities and by chance, Professor Ching-Lung Lai answered the phone.
It was a fortunate break because Lai is an internationally renowned expert in HBV whose studies and clinical trials have contributed significantly to advance the development of knowledge concerning the hepatitis B virus and its treatment. Lai took an interest in Wong and within two weeks he was enrolled on a PhD programme and was awarded a Croucher studentship in 2002 to support his studies.
“Prof Lai has been very influential in my work,” says Wong who explains that Lai was a key investigator in developing the first oral drug for HBV, Lamivudine, which was targeted to suppress HBV replication.
However, even now, no therapeutic agent can eliminate the HBV covalently closed-circular DNA (cccDNA). cccDNA is the indestructible chromosome of HBV, the persistence of which contributes to the chronicity of HBV infection. How best to control the viral replication of HBV and profiling the cccDNA levels during the natural history of chronic hepatitis B disease, as well as in patients receiving treatment and patients with hepatocellular carcinoma (HCC; a common form of liver cancer), became a central tenet of Wong’s research.
In a recent study, Wong’s research showed that in patients receiving long-term antiviral treatment, almost all of them had undetectable HBV DNA in the blood, and about 50% of patients had undetectable cccDNA in their liver. It was a key finding because it meant firstly, that cccDNA can be reduced by current treatment to an extremely low level undetectable by current detection assays and secondly, that even if the virus is not detected in the blood sample, it may still be present in the liver.
“In terms of controlling viral replication we are doing well - maybe 80% solved - but with eradicating cccDNA, we are not there yet,” says Wong, who reports that the WHO has set a target of control of hepatitis B by 2020 and a 90% reduction in new cases by 2030. Whether the total eradication of hepatitis B can be achieved is still debatable, but Wong thinks this goal may be within reach.
“At least, with the joint effort of academic and pharmaceutical research, we are much closer to this goal than 10 years ago,” he says.
Wong’s other research area is related to research into the phenomenon of occult HBV infection.
Occult HBV is defined as the detectable HBV DNA in blood or liver in the absence of detectable HBV surface antigen, the marker of chronic HBV. Wong discovered that over 70% of patients with an unknown cause of HCC in Hong Kong had occult HBV, highlighting the significance of occult HBV as a cause of liver cancer. In addition, his recent research also pointed to the importance of occult HBV as a cause of HBV reactivation in patients with immunosuppression.
“We are now looking for other markers that reflect HBV replication activity,” says Wong, explaining that while surface antigens and HBV DNA are the traditional markers, he is now looking at core related antigens.
“It’s another protein expressed by the virus in the blood stream but its level correlates with the level of cccDNA quite well,” says Wong and the medical implications could be profound. Traditionally cccDNA could only be identified via a liver biopsy, but this means it could be done so much more efficiently and harmlessly with a blood sample.
“The work is only just completed and we heard today that the paper has been accepted for publication,” says Wong, adding that close collaboration with clinical staff at the hospital is essential for the success of his work.
“We now want to look further at the importance of these markers to see if they can predict the development of liver cancer or other disease complications,” he says.
Dr Danny Wong is Assistant Professor in the Department of Medicine at The University of Hong Kong. He received his BSc in Biochemistry at The University of Manitoba and MSc in Microbiology at The University of British Columbia. With support from the Croucher Studentship in 2002, Wong received his PhD in Medicine at The University of Hong Kong. He was awarded the Dr KP Stephen Chang Gold Medal for the best PhD thesis in 2004.
To view Wong’s personal Croucher profile, please click here.