What are the priorities for a research gap meta-analysis on hepatitis B?

Research Gap Meta-Analysis Priorities for Hepatitis B

The most critical research gaps in hepatitis B requiring meta-analysis focus on developing better predictive models for treatment selection that incorporate age, gender, and genotype, as current guidelines fail to factor these clinically relevant variables into treatment decisions. 1

Priority Research Gaps Requiring Meta-Analysis

Patient Selection and Risk Stratification

• High-quality studies are urgently needed to develop predictive models that identify high-risk individuals for treatment, as current guidelines do not adequately incorporate clinically relevant factors such as age, gender, and genotype into the treatment decision-making process 1
• Meta-analyses should focus on defining optimal treatment thresholds for patients in the immune tolerant phase, where current evidence remains limited to intermediate outcomes rather than clinical endpoints 2
• Research is needed to establish evidence-based criteria for treatment discontinuation in HBeAg-negative patients, as only noncomparative and indirect evidence currently exists 2

Treatment Endpoints and Functional Cure

• Meta-analyses should prioritize studies examining HBsAg loss (functional cure) as an endpoint, which has been associated with improved clinical outcomes including reduced HCC and improved survival, but remains difficult to achieve with current antiviral therapies 1
• Research gaps exist in understanding when and how to achieve sustained viral suppression versus immune control, as the endpoint of functional cure is unlikely in most chronic hepatitis B patients 1

Diagnostic Test Optimization

• Meta-analyses are needed to validate non-invasive fibrosis test cutoffs across diverse populations, particularly in low- and middle-income countries where the 2024 WHO guidelines recommend APRI >0.5 or FibroScan >7.0 kPa for significant fibrosis 1
• Research should examine the performance of non-invasive tests in specific subgroups, including children, pregnant women, and patients with comorbidities, as current evidence predominantly focuses on adult populations 1

Treatment Strategy Gaps

• Very low-quality evidence exists comparing the safety of entecavir versus tenofovir, representing a critical gap requiring high-quality comparative effectiveness research 2
• Meta-analyses should address the effectiveness of continuing versus discontinuing antiviral therapy in HBeAg-positive patients who achieve seroconversion from HBeAg to anti-HBe, as only very low-quality evidence currently informs this decision 2
• Research is needed on monotherapy versus adding a second agent in patients with persistent viremia during treatment, where only indirect evidence is available 2

Special Populations

• Meta-analyses should focus on compensated cirrhosis patients with low-level viremia, as current evidence for antiviral effectiveness in this population relies on indirect evidence 2
• Research gaps exist for patients with decompensated liver disease and HBV-HIV coinfection, despite these being high-risk populations 3

Long-term Clinical Outcomes

• Moderate-quality evidence supports that antiviral therapy reduces cirrhosis, decompensated liver disease, and hepatocellular carcinoma in immune-active chronic HBV infection, but meta-analyses are needed to quantify these benefits across different patient subgroups and treatment durations 2
• Research should examine whether interferon therapy's documented reduction in cirrhosis (RR 0.65,95% CI: 0.47-0.91) and HCC (RR 0.59,95% CI: 0.43-0.81) translates to nucleos(t)ide analogue therapy 4

Global Health Implementation

• Meta-analyses should address the diagnostic and treatment cascade gaps, particularly in low- and middle-income countries where only 13% of the 254 million people with chronic hepatitis B are diagnosed and less than 3% receive antiviral therapy 1, 5
• Research is needed on simplified clinical algorithms that can be implemented in resource-limited settings, as complex heterogeneous algorithms remain difficult to implement in endemic countries 1

Critical Methodological Considerations

• Future meta-analyses must prioritize systematic reviews as the highest level of evidence using the GRADE framework, which provides transparent methodology for rating evidence quality and explicitly balances benefits and harms 1
• Research should focus on clinical outcomes (mortality, cirrhosis, HCC) rather than surrogate markers alone, as the natural history of chronic hepatitis B includes dynamic phases requiring lifelong monitoring 1