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Indeterminate Phase/Grey Zone of Chronic Hepatitis B: Clinical Features, Outcomes and Molecular Insights
Maria Stella Franzè1,2,3, Teresa Pollicino3, Jean-Michel Pawlotsky1,2,4
1Team "Viruses, Hepatology, Cancer", Institut Mondor de Recherche Biomédicale, INSERM Unit U955, Créteil, France.
Insights
Chronic hepatitis B virus (HBV) infection poses global health risks. Patients in the indeterminate or "grey zone" require further research for optimal antiviral treatment strategies and long-term outcome evaluation.
Area of Science:
- Hepatology
- Virology
- Public Health
Background:
- Chronic hepatitis B virus (HBV) infection is a significant global health concern, leading to severe liver disease complications like cirrhosis and hepatocellular carcinoma (HCC).
- Current antiviral therapies aim to prevent disease progression and transmission, but treatment rates remain suboptimal.
- The natural history of chronic HBV infection is dynamic, with a substantial proportion of patients falling into an 'indeterminate' or 'grey zone' that complicates treatment decisions.
Purpose of the Study:
- To review current knowledge on the clinical features, management, and outcomes of chronic HBV infection in the indeterminate phase.
- To highlight the challenges in managing patients within this 'grey zone' who are at risk of disease progression despite not meeting current treatment criteria.
- To discuss emerging data on the potential benefits of antiviral therapy in selected 'grey zone' patients and the need for refined management strategies.
Main Methods:
- Literature review of clinical features, management approaches, and outcomes for chronic HBV infection in the indeterminate phase.
- Analysis of current international guidelines and the shift towards personalized, risk-based treatment decisions.
- Synthesis of emerging data on antiviral therapy efficacy in previously ineligible patient groups.
Main Results:
- A significant percentage of chronic HBV patients (28-55%) do not fit neatly into defined clinical phases, forming a 'grey zone'.
- Patients in the 'grey zone' are at risk for liver fibrosis, cirrhosis, and HCC, yet often lack a clear indication for antiviral treatment.
- Emerging evidence suggests potential long-term benefits of antiviral therapy in selected 'grey zone' patients, though outcomes are variable.
Conclusions:
- The 'grey zone' in chronic HBV infection represents a heterogeneous group requiring further research for optimized management.
- Personalized, risk-based approaches are increasingly important, moving beyond rigid phase classifications.
- Further investigation is crucial to refine treatment strategies and evaluate long-term benefits of antiviral therapy in this challenging patient population.
Abstract:
Chronic hepatitis B virus (HBV) infection remains a global public health challenge, with a high risk of complications such as cirrhosis, hepatocellular carcinoma (HCC) and death. As outlined in current international society guidelines, antiviral therapies are aimed at preventing progression of liver disease to life-threatening complications and viral transmission. However, the proportion of patients currently treated remains low. Four phases have been identified in the natural history of chronic HBV infection. Because these phases evolve dynamically, serial assessments of alanine aminotransferase (ALT), HBV DNA and liver histology are crucial to optimise treatment strategies. However, 28% to 55% of patients with chronic HBV infection do not fit into any of the four clinical phases precisely defined by international guidelines. These patients fall into the so-called indeterminate phase or grey zone. Patients in the grey zone generally have no indication for treatment, despite being at risk for progression to liver fibrosis, cirrhosis and HCC. The latest EASL Clinical Practice Guidelines have moved away from rigid phase-based classifications for therapeutic decisions, adopting instead a personalised, risk-based approach that integrates HBV DNA, ALT, liver fibrosis, age, family history of HCC and comorbidities. Nevertheless, the concept of the grey zone remains relevant in research, as it highlights a heterogeneous group of patients whose prognosis and management remain challenging. Emerging data suggest that antiviral therapy can improve long-term outcomes in selected patients previously considered ineligible for treatment, but clinical outcomes are variable and influenced by factors such as age, gender, viral load and histological findings. Further research is needed to refine the management strategies for these patients with grey zone HBV infection and to evaluate the long-term benefits of antiviral treatment indications. This review article summarises the current knowledge on the clinical features, management approaches and outcomes of patients with chronic HBV infection in the indeterminate phase/grey zone.
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