In this research summary of two new studies from Blizard Institute researchers, we hear about new ways to boost the innate immune function of Hepatitis B patients that could shorten treatments, and serious questions are raised on current treatment decisions for young patients.

1) Interferon alpha induces sustained changes in NK cell responsiveness to hepatitis B viral load suppression in vivo. PLoS Pathog. (2016)

In this work, supervised by Dr Patrick Kennedy (Reader in Hepatology & Honorary Consultant, QMUL) and Professor Mala Maini (Wellcome Trust Senior Investigator & Professor of Viral Immunology at UCL), the research team observed novel responses to hepatitis B treatment.

As first author, Dr Upkar Gill, funded by a Wellcome Trust Clinical Research Training Fellowship, performed the experimental work using carefully selected samples from patients treated at The Royal London Hospital.

What is new about the study?

  • The current treatments for hepatitis B, interferon and oral antivirals, act differentially on the immune response.
  • The team shows that oral antivirals given in sequence, after interferon (sequential therapy) maintains boosting of the innate immune response (NK cell function).
  • Loss of HBsAg (the surface antigen of the hepatitis B virus) is the ideal curative outcome. HBsAg level reduction is greater with sequential therapy than other therapies alone, highlighting the potential benefit of interferon priming.
  • This sustained boosting of the innate immune response following interferon priming has not previously been described.

How was the study carried out?

  • The study was carried out using peripheral blood samples from patients undergoing treatment at The Royal London Hospital.
  • Immune cells from the blood were analysed to determine their composition and function and these were correlated with the clinical outcomes for the treated patients.

Is there anything surprising about the results?

  • There is limited data on immune cell function in patients treated for hepatitis B.
  • The continued boosting of NK cells is surprising as they are thought to be ‘short lived’ cells, but the data show they may have the potential of maintaining a ‘long lived’ population with antiviral function, important for hepatitis B clearance.

Why is the study important?

  • The findings in this study provide a mechanistic rationale for using interferon/oral antivirals in sequence or in combination to improve treatment outcomes in hepatitis B.
  • The improved reduction of HBsAg with this treatment strategy could reduce the duration of treatments, which is an important endpoint in hepatitis B therapy.

 

What are the wider implications?

  • The results from this study provide a springboard for larger clinical trials to explore the value of shorter courses of interferon, to prime the immune response.
  • Definitive treatment endpoints and reductions in HBsAg, ultimately leading to a cure have wide implications to reduce complications of chronic liver disease and liver cancer on a global scale.
  • The potential of shorter treatment durations would mean that younger patients could be treated, without the burden of life long therapy thus increasing the pool of patients for treatment candidacy.

 

 

2) HBV DNA Integration and Clonal Hepatocyte Expansion in Chronic Hepatitis B Patients Considered Immune Tolerant, Gastroenterology (2016)

In this work, conceived by Dr Patrick Kennedy and international collaborators Professor Mason (Philadelphia, USA) and Professor Bertoletti (Singapore) novel findings challenging the concept of ‘immune tolerant’ chronic hepatitis B (CHB) are presented, which challenge the premise on which current treatment decisions are made. Drs Upkar Gill and Patrick Kennedy, have been studying the evolution of CHB in children and young adults from the dedicated clinics at The Royal London Hospital. Using valuable blood and liver tissue samples from these patients, collaborating with other key leaders in the field, this work has led to the generation of novel findings in the management of the disease in young people. Current national and international treatment guidelines exclude young patients (believed to be in this immune tolerant phase) from treatment, but the new results raise serious questions about this approach.

In line with previous data, (http://www.gastrojournal.org/article/S0016-5085(12)00840-2/fulltext) the team observed that young patients considered to have “immune tolerant” CHB, in fact have evidence of immunopathology and the potential for progressive disease, no different to their peers with “active” disease.

What is new about the study?

  • Chronic Hepatitis B (CHB), progresses through disease phases; the first of which, the ‘immune tolerant’ phase is thought to be a disease-free state and thus patients are not considered for therapy.
  • In keeping with previous work, (http://www.gastrojournal.org/article/S0016-5085(12)00840-2/fulltext) the team shows that there is evidence of immunopathology in young patients considered immune tolerant.
  • Importantly, they also demonstrate these young patients have evidence of HBV DNA integration and clonal expansion of hepatocytes; events which could lead to the development of liver cancer over time.

How did you carry out the study?

  • The study was carried out using peripheral blood samples and liver biopsy tissue specimens from children and adults managed in The Royal London Hospital Viral Hepatitis Service.
  • Immune cells from the blood were analysed to determine T cell function and liver tissue was analysed for DNA integration, clonal expansion of liver cells and expression of viral proteins in liver tissue.

Is there anything surprising about the results?

  • Data on immune function in CHB patients considered immune tolerant is limited.
  • Historically, these young patients were considered to have mild disease, devoid of disease progression. Conversely, our data is at odds with this perception and in fact demonstrates that these patients already have progressive disease and therefore are already at risk for the development of advanced liver disease and liver cancer.

Why is the study important?

  • CHB is the leading cause of primary liver cancer worldwide
  • This study makes a compelling case that historical terms, such as “immune tolerance”, are misleading and challenges the clinical categorisations on which treatment decisions are made.
  • Events leading to the development of liver cancer may already be present in young CHB patients.
  • Young patients, previously excluded from treatment, may benefit from early antiviral therapy, which potentially could prevent disease progression and the development of liver cancer.

What are the wider implications?

  • The term immune tolerant CHB should not be used to define the early phase of CHB infection as it is both inaccurate and out-dated. Treating physicians should now describe this phenotype as the “high replication, low inflammation stage” and importantly, should be more circumspect about treatment and management of these patients.
  • These results should provide a springboard for larger studies to evaluate the potential therapeutic benefits of early treatment in CHB at a time of major change in the HBV treatment landscape.
  • Adjusting the bar for treatment candidacy may mean that these patients would be treated earlier to prevent advanced liver disease and liver cancer complicating CHB infection.