Research summary: Accelerating change in the management of Chronic Hepatitis B

15 March 2021

Whole exome HBV DNA integration is independent of the intrahepatic HBV reservoir in HBeAg negative Chronic Hepatitis B, Gut 2021

In this work, conceived by Professor Kennedy and international collaborators (Svicher & Salpini; Tor Vergata, Rome, Italy), they report on novel findings which challenge the concept that patients in the ‘quiescent’ phase of chronic hepatitis B (CHB) do not require treatment for prevention of disease progression. Blood and liver tissue from a cohort of Hepatitis B ‘e’ antigen (HBeAg) negative patients at the Royal London Hospital were analysed, to study the integration of HBV into the host genome and generate these new data. Current national and international treatment guidelines exclude certain HBeAg negative CHB patients from treatment, but these latest results challenge this approach.

In line with their previous data, (Kennedy et al., Gastroenterology 2012 and Mason et al., Gastroenterology 2016) the team observed that patients currently excluded from treatment in fact have evidence of immunopathology, by means of integrated HBV DNA as a precursor for the development of liver cancer and the potential for progressive disease. In short, their latest work highlights the complexity of CHB and the need to consider broadening treatment candidacy to offer antiviral therapy to those previously excluded based on national and international guidelines.

What is new about the study?

• Chronic Hepatitis B (CHB), progresses through disease phases; with distinct disease states, HBeAg positive and negative phases. The majority of patients seen in secondary care clinics comprise of HBeAg negative disease.
• Many patients with HBeAg negative disease have low levels of circulating virus (HBV DNA) and normal liver enzymes and are thought to be in a quiescent disease phase and thus not considered treatment candidates.
• In keeping with their previous work, (Mason et al., Gastroenterology 2016) where the group showed that young patients considered to be in a benign disease state had evidence of HBV DNA integration, their latest study demonstrates evidence of HBV DNA integration in HBeAg negative CHB patients (with low level viraemia) and thus highlighting that these patients remain at risk for the development of liver cancer.
• They show that HBV DNA integrations occur in regions crucial for human gene expression and involve genes regulating cell proliferation, carcinogenesis in addition to antiviral immunity and hepatocyte metabolism.
• High levels of HBsAg (>5,000IU/ml), a commercially available assay, can predict the presence of HBV DNA integration events in HBeAg negative CHB patients and may represent a tool to be adopted more widely in the risk stratification of CHB patients.

How did you carry out the study?

• The study was carried out using serum and plasma blood samples in addition to liver biopsy tissue specimens from patients managed in The Royal London Hospital Viral Hepatitis Service.
• Using blood and liver material, viral markers were analysed by conventional and digital droplet PCR and whole exome along with transcriptome sequencing was used to analyse the presence of HBV DNA integration events in the liver.
• Viral markers from the blood and liver were then correlated and associations sought with HBV DNA integration events.

Is there anything surprising about the results?

• Data on HBV DNA integration and intrahepatic viral markers in CHB are limited, yet this information could impact treatment decisions for patients.
• The demonstration that HBV DNA integration in CHB patients perceived as low-risk, mandates a re-evaluation of current treatment candidacy.
• Historically, these patients have been considered to have mild disease and have been excluded from treatment consideration. However, these latest data are at odds with this perception and in fact demonstrates that these patients (some of whom are older) may have progressive disease, and therefore are already at increased risk of advanced liver disease and liver cancer.

Why is the study important?

• CHB is the leading cause of primary liver cancer worldwide.
• Events associated with the development of liver cancer in low viraemic patients are present, but are not considered in current management guidelines.
• This study makes a compelling case that HBeAg negative CHB patients with low viraemia should be considered for treatment and therefore challenges the current treatment paradigm based around disease phase.

What are the wider implications?

• Additional work in delineating the HBV transcriptome is critical to further understand the pathogenesis of HBV as DNA integrations are not restricted to hepatocarcinogenesis, but also have roles in antiviral immunity, inflammation and metabolism.
• These results provide the impetus for larger studies to evaluate the potential therapeutic benefits of widening treatment candidacy in CHB at a time of major change in the HBV treatment landscape.
• Early treatment in CHB can prevent liver disease progression and has the potential to prevent liver cancer complicating chronic infection.
• The new terminology for CHB (EASL 2017) has improved the classification and management of patients, but further work is required to broaden treatment candidacy.

More information

Research paper: Svicher V, Salpini R, Piermatteo L, Carioti L, Battisti A, Colagrossi L, Scutari R, Surdo M, Cacciafesta V, Nuccitelli A, Hansi N, Ceccherini Silberstein F, Perno CF, Gill US, Kennedy PTF. Whole exome HBV DNA integration is independent of the intrahepatic HBV reservoir in HBeAg-negative chronic hepatitis B. Gut. 2020 Dec 21:gutjnl-2020-323300. doi: 10.1136/gutjnl-2020-323300. Epub ahead of print. PMID: 33402415.