A systematic review and meta-analysis of hepatitis B virus drug resistance and escape mutations in low- and middle-income countries

Background: Hepatitis B virus (HBV) remains highly endemic in many low- and middle-income countries (LMICs), where challenges such as antiviral resistance and immune/vaccine-escape mutations complicate disease management. Objective: This review synthesizes current data on HBV drug resistance, including the prevalence and distribution of resistance-associated mutations (RAMs), vaccine-escape mutations (VEMs), and immune-escape mutations (IEMs) in LMICs. Design: Systematic review and meta-analysis. Data sources: PubMed, Scopus, and Web of Science. Methods: A systematic search was conducted from 2014 to 2025 (last search date: August 04, 2025), and data were extracted from eligible studies. A random-effects meta-analysis was conducted to estimate pooled resistance rates and prevalences. Results: A total of 43,834 participants from 47 studies conducted in 28 LMICs were included. The overall antiviral resistance rate was 7.87% (95% CI (5.13–11.11)), with very high heterogeneity ( I 2 = 99.7%). Lamivudine (3TC) and telbivudine (LdT) had the highest resistance rates. Asia consistently reported the greatest resistance, with rates of 32.45% for 3TC and 51.92% for LdT. In a subgroup analysis on economic regions, Lower-middle-income countries showed the highest pooled resistance rate at 10.61% (95% CI (5.21–17.51); I 2 = 96.9%). The most frequently detected RAMs were rtM204V/I, rtV173L, and rtL180M. The pooled prevalence of vaccine-escape mutations was 8.92% (95% CI (5.02–13.64); I 2 = 78.4%). Immune-escape mutations were much more common, with a pooled prevalence of 55.66% (95% CI (28.10–81.53); I 2 = 98.1%). The most prevalent mutations were sG145R/A/K, sQ129H/R, sD144E/A, sS143L/T, and sP120S/T. The pooled estimates in this study are reported and interpreted descriptively, given the substantial heterogeneity observed. Conclusion: The remarkably high drug resistance rates and prevalence of immune and vaccine-escape mutations suggest notable burdens of resistance, especially for drugs with low genetic barriers such as lamivudine and telbivudine, underscoring the growing challenges in achieving the WHO 2030 reduction goals, and highlighting the need for enhanced surveillance, adoption of potent antiviral regimens such as tenofovir disoproxil fumarate, and continuous vaccine efficacy monitoring. However, the results should be interpreted with caution due to the very high heterogeneity observed in the study. Trial registration: International prospective register of systematic reviews (PROSPERO) under the ID: CRD420251030302.