Histological severity, clinical outcomes and impact of antiviral treatment in indeterminate phase of chronic hepatitis B: A systematic review and meta-analysis.

Background & Aims: Current international guidelines recommend close monitoring and evaluation of patients with chronic hepatitis B (CHB) in the indeterminate phase, and treatment of patients at high risk of adverse outcomes. Clinical outcomes and the effect of antiviral therapy on the indeterminate phase remain unclear. We performed a systematic review and meta-analysis to study the incidence of adverse clinical outcomes including hepatocellular carcinoma (HCC), cirrhosis, and hepatic decompensation, and the effect of antiviral therapy, in the indeterminate phase.

Methods: Two investigators independently searched Embase, MEDLINE, Web of Science and China National Knowledge Infrastructure from 1/1/2007 to 31/12/2023. Three investigators independently assessed study eligibility and quality. We included cohort studies and a randomised-controlled trial, allowing for calculation of the incidence rate of adverse clinical outcomes, and cross-sectional studies that reported the prevalence of moderate-to-severe inflammation and different degrees of fibrosis. Incidence rates and prevalence were pooled using generalised linear mixed-effects models and random-effects models, respectively.

Results: One hundred and three studies (70 case-control studies [18,739 patients], 32 cohort studies [15,118 patients], and one RCT [160 patients]) were included. The annual incidence rate of HCC in patients in the indeterminate phase was 0.32% (95% CI 0.21-0.48%, I = 85.7%), and those of cirrhosis and hepatic decompensation were 0.67% (95% CI 0.30-1.49%, I = 94.3%) and 0.34% (95% CI 0.17-0.69%, I = 51.8%), respectively. The pooled prevalence of moderate-to-severe liver inflammation, significant fibrosis, advanced fibrosis, and cirrhosis was 40.7%, 39.7%, 17.9%, and 7.2%, respectively. Use of antiviral therapy was associated with a lower risk of HCC in patients in the indeterminate phase (adjusted incidence rate ratio 0.38, 95% CI 0.18-0.79, p = 0.009).

Conclusions: Patients in the indeterminate phase are at risk of developing advanced liver disease and HCC. Although inherent heterogeneity across studies limited the evidence to support expanding treatment to all patients in the indeterminate phase, antiviral therapy may reduce the risk of HCC development in high-risk subgroups.

Impact And Implications: Current international guidelines recommend close monitoring and evaluation of patients with chronic hepatitis B (CHB) in the indeterminate phase, in whom antiviral treatment is not always indicated. Based on the systematic review and meta-analysis with significant heterogeneity across studies, patients in the indeterminate phase are at risk of developing hepatocellular carcinoma, cirrhosis, and hepatic decompensation. Meta-regression findings on platelet count, positive HBeAg, and age highlighted the importance of liver fibrosis assessment, accurate phase classification, and timely detection of phase transition to identify antiviral treatment indications, supporting current guideline recommendations. Antiviral treatment may reduce the risk of hepatocellular carcinoma in the high-risk subgroups of patients in the indeterminate phase.

Prospero Registration Number: CRD42024537095.