Prevalence and Distribution of Naturally Occurring Antiviral Resistance-Associated Mutations in Treatment-Naïve Chronic Hepatitis B: A Systematic Review and Meta-Analysis

Background: Chronic hepatitis B virus (HBV) infection remains a major global public-health problem and an important cause of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Although nucleos(t)ide analogue therapy has substantially improved management, antiviral resistance-associated mutations may occasionally be detected before treatment exposure. Objective: To systematically determine the prevalence and distribution of established primary antiviral resistance-associated mutations among treatment-naïve patients with chronic HBV infection and to estimate the pooled prevalence of patients carrying at least one established primary resistance mutation. Methods: A systematic review and meta-analysis were conducted using a patient-level endpoint defined as the presence of at least one established primary antiviral resistance-associated mutation in a unique treatment-naïve patient. Secondary or compensatory mutations were not counted as primary resistance when occurring alone. Studies using highly sensitive assays, including mutation-specific PCR and next-generation sequencing, were considered separately where appropriate. The review was structured according to PRISMA 2020. Results: The current primary quantitative dataset comprised 42 cohorts involving 9,811 evaluable treatment-naïve participants, of whom 417 carried at least one qualifying primary resistance-associated mutation, giving a crude prevalence of 4.25%. The current random-effects synthesis estimated an overall pooled prevalence of 1.80% (95% CI, 1.04–3.09%). Between-study heterogeneity was very high (I²=93.3%; τ²=2.541; Q=616.02). The approximate 95% prediction interval was 0.08–30.41%. Conclusion: Naturally occurring primary antiviral resistance-associated mutations are detectable in a minority of treatment-naïve patients with chronic HBV infection, but reported prevalence varies substantially according to population, geography, genotype, study design, and assay sensitivity. The pooled estimate should therefore not be interpreted as a universal prevalence applicable to every clinical setting.