Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Universidad de Sevilla on 06/15/15 For personal use only.
Review
Chronic hepatitis B virus in young adults: the need for new approaches to management Expert Rev. Anti Infect. Ther. 12(9), 1045–1053 (2014)
Upkar S Gill and Patrick TF Kennedy* Hepatology Unit, Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK *Author for correspondence: Tel.: +44 0 207 882 2383 Fax: +44 0 207 882 2187 [email protected]
One in four patients infected with hepatitis B virus (HBV) at birth or in early childhood will develop cirrhosis or hepatocellular carcinoma. Historically, guidelines have overlooked treatment in young people, as the immune tolerant disease phase is considered synonymous with chronic infection in the young. Current treatment aims to suppress HBV replication through long-term nucleos(t)ide therapy with little emphasis on virus eradication. To achieve HBsAg loss, it is accepted that effective immune control of virus is required, mimicking that seen in those who resolve acute HBV infection. We have recently challenged the accuracy of a generic immune tolerant state in young people, thus raising a potential role for earlier treatment. Here we report on our immunological analysis of HBV in young people and the role of a dedicated clinic; we make the case for earlier intervention to achieve effective immune control leading to better outcomes. KEYWORDS: exhaustion • HBV-specific T cells • hepatitis B virus • immune tolerance • nucleos(t)ide analogue • pegylated-interferon • young adult
The WHO estimates that approximately 400 million people are chronically infected with hepatitis B virus (HBV) worldwide representing a major global healthcare challenge [1–3]. Despite the existence of an effective vaccine for more than 40 years, the prevalence of the virus in addition to morbidity and mortality related to chronic hepatitis B (CHB) continue to increase. Cirrhosis and hepatocellular carcinoma (HCC) complicate chronic infection and together account for more than 600,000 deaths per year [4]. Historically, the UK is considered a low prevalence country; however, migrants make up the majority of those chronically infected in the UK and frequently prevalence rates among migrant communities is more in keeping with prevalence rates in their country of origin. Thus, the impact of changing migration patterns is increasing the UK prevalence rate of CHB, which is expected to increase further over the next 5 years in line with net migration [3]. Recently, the NICE reported that approximately 500,000 people in the UK are thought
informahealthcare.com
10.1586/14787210.2014.940899
to have CHB and an even greater number of people remain undiagnosed [5]. Indeed, HBVrelated mortality is believed to contribute to the estimated 20% increase in liver-related deaths in the UK, while there is a concurrent decline in all-cause mortality [6]. Although CHB is a disease which affects all ages, it is believed to run a benign course in children and young adults [7]. Recent data, however, are challenging this perception. This is a critical shift in the debate around CHB and how it should be managed. We have recently shown that a proportion of young patients considered to be ‘immune tolerant,’ in fact had demonstrable immune activity with a more robust HBV-specific immune response than that seen in their adult counterparts [8]. This observation is a first step in the reevaluation of disease categorization in CHB and we believe that these findings may act as a springboard for a broader debate around earlier treatment in young patients with chronic infection. In this review, we reexamine the natural history of CHB, review current treatment
2014 Informa UK Ltd
ISSN 1478-7210
1045
Review
Gill & Kennedy
recommendations and consider the case for earlier treatment. Furthermore, we discuss the merits of a dedicated young adult clinic with greater focus on the individual patient at this relatively early stage of the patient journey and we discuss the novel treatment strategies and the potential new therapies that will improve clinical outcomes in these young patients in the future.
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Universidad de Sevilla on 06/15/15 For personal use only.
Natural course of HBV
Our understanding of hepatitis B immunopathogenesis and virology has improved dramatically in recent years, despite this the natural history of CHB remains unpredictable [9]. The course and natural history of HBV infection depends largely on age at the time of exposure to the virus [10]. CHB is a dynamic disease and classically progresses through four distinct phases: immune tolerant (IT), immune active (IA), inactive carrier (IC) and in a proportion of patients a reactivation phase [11]. Immune tolerance is characteristically associated with perinatal infection or infection in early childhood, thus this phase of disease is thought to be synonymous with infection in childhood or early adulthood [7]. The hallmarks of immune tolerance are hepatitis B e antigen (HBeAg) positivity, high levels of HBV DNA and normal serum alanine aminotransferase (ALT) levels. True immune tolerance should be associated with minimal or no liver fibrosis on biopsy and this phase of disease is believed to last from a few years to several decades [12]. The IA phase (or immune clearance phase) is characterized by the presence of HBeAg positivity at the outset. ALT levels are typically elevated reflecting immune activity against the virus, consequently HBV DNA levels fluctuate, but are usually >20,000 IU/ml. Patients may then progress to develop HBeAgnegative disease, where DNA levels are lower (>2000 IU/ml) [13]. This phase of CHB is thought to represent an awakening or activation of the immune response and is therefore associated with immune-mediated liver injury leading to liver damage, progressive disease and the development of fibrosis [14]. The IC phase of the disease classically follows this period of immune activity and reflects immune control of the virus. This demonstrates the host’s ability to control the virus and therefore transition from the IA to the IC phase is not a definite sequence of events. The IC phase of the disease is characterized by loss of HBeAg and the presence of anti-HBe. ALT levels are stable and remain within the normal range, HBV DNA is
Review
Chronic hepatitis B virus in young adults: the need for new approaches to management Expert Rev. Anti Infect. Ther. 12(9), 1045–1053 (2014)
Upkar S Gill and Patrick TF Kennedy* Hepatology Unit, Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK *Author for correspondence: Tel.: +44 0 207 882 2383 Fax: +44 0 207 882 2187 [email protected]
One in four patients infected with hepatitis B virus (HBV) at birth or in early childhood will develop cirrhosis or hepatocellular carcinoma. Historically, guidelines have overlooked treatment in young people, as the immune tolerant disease phase is considered synonymous with chronic infection in the young. Current treatment aims to suppress HBV replication through long-term nucleos(t)ide therapy with little emphasis on virus eradication. To achieve HBsAg loss, it is accepted that effective immune control of virus is required, mimicking that seen in those who resolve acute HBV infection. We have recently challenged the accuracy of a generic immune tolerant state in young people, thus raising a potential role for earlier treatment. Here we report on our immunological analysis of HBV in young people and the role of a dedicated clinic; we make the case for earlier intervention to achieve effective immune control leading to better outcomes. KEYWORDS: exhaustion • HBV-specific T cells • hepatitis B virus • immune tolerance • nucleos(t)ide analogue • pegylated-interferon • young adult
The WHO estimates that approximately 400 million people are chronically infected with hepatitis B virus (HBV) worldwide representing a major global healthcare challenge [1–3]. Despite the existence of an effective vaccine for more than 40 years, the prevalence of the virus in addition to morbidity and mortality related to chronic hepatitis B (CHB) continue to increase. Cirrhosis and hepatocellular carcinoma (HCC) complicate chronic infection and together account for more than 600,000 deaths per year [4]. Historically, the UK is considered a low prevalence country; however, migrants make up the majority of those chronically infected in the UK and frequently prevalence rates among migrant communities is more in keeping with prevalence rates in their country of origin. Thus, the impact of changing migration patterns is increasing the UK prevalence rate of CHB, which is expected to increase further over the next 5 years in line with net migration [3]. Recently, the NICE reported that approximately 500,000 people in the UK are thought
informahealthcare.com
10.1586/14787210.2014.940899
to have CHB and an even greater number of people remain undiagnosed [5]. Indeed, HBVrelated mortality is believed to contribute to the estimated 20% increase in liver-related deaths in the UK, while there is a concurrent decline in all-cause mortality [6]. Although CHB is a disease which affects all ages, it is believed to run a benign course in children and young adults [7]. Recent data, however, are challenging this perception. This is a critical shift in the debate around CHB and how it should be managed. We have recently shown that a proportion of young patients considered to be ‘immune tolerant,’ in fact had demonstrable immune activity with a more robust HBV-specific immune response than that seen in their adult counterparts [8]. This observation is a first step in the reevaluation of disease categorization in CHB and we believe that these findings may act as a springboard for a broader debate around earlier treatment in young patients with chronic infection. In this review, we reexamine the natural history of CHB, review current treatment
2014 Informa UK Ltd
ISSN 1478-7210
1045
Review
Gill & Kennedy
recommendations and consider the case for earlier treatment. Furthermore, we discuss the merits of a dedicated young adult clinic with greater focus on the individual patient at this relatively early stage of the patient journey and we discuss the novel treatment strategies and the potential new therapies that will improve clinical outcomes in these young patients in the future.
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Universidad de Sevilla on 06/15/15 For personal use only.
Natural course of HBV
Our understanding of hepatitis B immunopathogenesis and virology has improved dramatically in recent years, despite this the natural history of CHB remains unpredictable [9]. The course and natural history of HBV infection depends largely on age at the time of exposure to the virus [10]. CHB is a dynamic disease and classically progresses through four distinct phases: immune tolerant (IT), immune active (IA), inactive carrier (IC) and in a proportion of patients a reactivation phase [11]. Immune tolerance is characteristically associated with perinatal infection or infection in early childhood, thus this phase of disease is thought to be synonymous with infection in childhood or early adulthood [7]. The hallmarks of immune tolerance are hepatitis B e antigen (HBeAg) positivity, high levels of HBV DNA and normal serum alanine aminotransferase (ALT) levels. True immune tolerance should be associated with minimal or no liver fibrosis on biopsy and this phase of disease is believed to last from a few years to several decades [12]. The IA phase (or immune clearance phase) is characterized by the presence of HBeAg positivity at the outset. ALT levels are typically elevated reflecting immune activity against the virus, consequently HBV DNA levels fluctuate, but are usually >20,000 IU/ml. Patients may then progress to develop HBeAgnegative disease, where DNA levels are lower (>2000 IU/ml) [13]. This phase of CHB is thought to represent an awakening or activation of the immune response and is therefore associated with immune-mediated liver injury leading to liver damage, progressive disease and the development of fibrosis [14]. The IC phase of the disease classically follows this period of immune activity and reflects immune control of the virus. This demonstrates the host’s ability to control the virus and therefore transition from the IA to the IC phase is not a definite sequence of events. The IC phase of the disease is characterized by loss of HBeAg and the presence of anti-HBe. ALT levels are stable and remain within the normal range, HBV DNA is
