Chronic hepatitis B (HBV) remains one of the world's major public health challenges, and finding a functional cure for the infection is one of the toughest goals in virology today. More than 250 million people live with a chronic infection, at risk of developing cirrhosis, liver failure and hepatocellular carcinoma (HCC), conditions that cause roughly one million deaths every year.
A safe, highly effective vaccine has been available for more than thirty years, and antiviral therapies are well established. Yet nearly one million new infections are still recorded each year. This gap shows that current vaccination coverage, together with existing treatment options, is not yet enough to substantially reduce the global burden of the disease and its clinical consequences.
For World Hepatitis Day, marked every year on 28 July, we spoke with Professor Luca Guidotti, Full Professor of Pathology at Vita-Salute San Raffaele University and Deputy Scientific Director of San Raffaele Hospital (IRCCS), and Professor Matteo Iannacone, Full Professor of Pathology at Vita-Salute San Raffaele University and Director of the Institute of Immunology and Infectious Diseases at San Raffaele Hospital (IRCCS).
Today's standard treatment for chronic hepatitis B relies on nucleos(t)ide analogues (NUCs), drugs that effectively suppress viral replication, reduce liver inflammation, and significantly lower the risk of progression to cirrhosis and hepatocellular carcinoma. These treatments, however, require daily administration and, in most patients, must continue for life. Suppression of viral replication is also not always complete: a proportion of patients retain residual viral replication (viral leakiness), which carries a significantly higher risk of developing hepatocellular carcinoma than in patients who achieve full HBV suppression.
Over the past decade, research has focused mainly on strategies to achieve a functional cure, defined as the persistent loss of surface antigen (HBsAg) after treatment is stopped. Despite substantial investment and extensive clinical research, results have fallen short of expectations: response rates generally remain below 20% and are limited to specific patient subgroups, while several development programmes, including some run by major pharmaceutical companies, have been discontinued or scaled back. The main obstacles stem from the high biological heterogeneity of chronic HBV infection, the lack of fully validated biomarkers to monitor the intrahepatic viral reservoir, the complexity of the immune response, and particularly stringent regulatory requirements.
The current standard of care for chronic hepatitis B is represented by nucleos(t)ide analogues (NUCs). These oral antiviral agents effectively suppress viral replication and reduce the risk of disease progression, cirrhosis, liver failure, and hepatocellular carcinoma (HCC). However, they require daily administration, often for life, and only rarely lead to elimination of the infection.
There is therefore a pressing need to develop therapies that are more effective and sustainable over the long term. To address this challenge, the research teams led by Professors Luca Guidotti and Romano Di Fabio (Professor of Medicinal Chemistry at Vita-Salute San Raffaele University), in collaboration with Professor Raffaele Di Francesco (Professor of Microbiology at the University of Milan) and Professor Matteo Iannacone, are pursuing a complementary therapeutic strategy. Their goal is to develop a new generation of suppressive antiviral agents capable of delivering meaningful clinical benefit while remaining readily translatable into clinical practice.
Rather than aiming for a functional cure, their objective is to develop drugs that achieve faster, deeper, and more durable suppression of viral replication than current NUCs. Such therapies could further reduce the risk of disease progression and hepatocellular carcinoma while offering a significantly more predictable clinical development and regulatory pathway. Unlike functional cure programs, this strategy is based on well-established clinical endpoints already recognized by regulatory authorities, enabling faster, less costly development with a lower translational risk.
Chronic Hepatitis B Research at UniSR and San Raffaele Hospital
At Vita-Salute San Raffaele University and San Raffaele Hospital, these two strategies are being developed through complementary, closely integrated research programmes.
One research line, led by Professor Luca Guidotti and Professor Romano Di Fabio (Full Professor of Pharmaceutical Chemistry at Vita-Salute San Raffaele University), in collaboration with Professor Raffaele Di Francesco (Full Professor of Microbiology at the University of Milan) and Professor Matteo Iannacone, is developing a new generation of antivirals. The group has designed an innovative Capsid Assembly Modulator (CAM) intended for subcutaneous administration and long-acting antiviral activity. Preclinical results with this molecule are promising and were presented at the EASL Congress 2026, one of the leading international conferences on liver disease. The goal is a faster, deeper and more durable suppression of viral replication than current therapies allow, while reducing dosing frequency and improving treatment adherence.
In parallel, Professor Matteo Iannacone's laboratory, working with Professor Luca Guidotti, studies how the liver's immune microenvironment shapes the immune system's ability to control HBV infection. The group's research has helped clarify how the virus exploits the liver's distinctive immunological features to persist in the body over the long term, and how chronic exposure to viral antigens progressively weakens the immune response.
Building on this knowledge, the laboratory is developing new immunotherapy strategies designed to restore an effective antiviral response and combine it rationally with next-generation antivirals, with the aim of helping the immune system maintain control of the infection even after treatment ends.
Together, these research lines reflect a broader paradigm shift now underway in hepatitis B research. Until a few years ago, the main goal was blocking viral replication. Today the ambition is greater: pairing increasingly effective antivirals with strategies that restore a protective immune response. Developed in parallel at UniSR and San Raffaele Hospital, these two approaches could bring therapies that move a growing number of patients closer to a functional cure for hepatitis B.