Entecavir Resistance-Associated Mutations in Chronic HBV Patients in Turkey (STREAM Study)

Hypothesis

• Entecavir resistance-associated mutations are detectable in both naïve and lamivudine-experienced patients.
• Prevalence is higher in lamivudine-experienced patients compared to treatment-naïve patients.
• Longer lamivudine exposure and higher HBV-DNA are associated with resistance.
• Nanopore sequencing detects minor resistance variants not captured by conventional methods.

Sample size: 700 estimated participants

Pre-existing lamivudine-induced resistance mutations create a genetic background that facilitates the emergence of secondary entecavir resistance mutations, even in patients currently receiving tenofovir-based therapy.

Investigators further hypothesize that peripheral blood-derived cccDNA sequencing can serve as a minimally invasive method to characterize transmitted and acquired resistance mutation profiles in chronic HBV infection.

Clinical Significance Chronic hepatitis B management relies on long-term antiviral therapy, and resistance-associated mutations significantly influence treatment success and future therapeutic strategies.

Although entecavir has a high genetic barrier, prior lamivudine exposure may predispose patients to secondary resistance mutations, potentially compromising antiviral efficacy. However, the prevalence and distribution of such mutations in the Turkish HBV population remain insufficiently characterized

This study will provide:

• National-level data on entecavir resistance-associated mutations
• Comparative analysis between treatment-naïve and lamivudine-experienced patients
• Insight into the clinical relevance of minor resistance variants detected by long-read sequencing Peripheral blood-derived cccDNA sequencing may represent a minimally invasive resistance monitoring tool.

The findings may contribute to optimizing antiviral selection strategies, guiding individualized treatment decisions, and informing national hepatitis B management policies.

This study will provide national-level data on entecavir resistance mutations in Turkey.

It may support individualized antiviral selection and contribute to national HBV management strategies.

Inclusion criteria

• Age ≥18 years
• HBsAg positive
• Group 1: Either treatment-naïve participants with HBV DNA>2000 IU/ml
• Group 2: Prior lamivudine therapy ≥6 months with switch to ADVor TDF or TAF
• Ability to provide informed consent

Exclusion criteria

• Prior entecavir exposure
• Prior telbivudine exposure
• Age <18 years
• Inability to provide informed consent Note: Previous adefovir or (pegylated) interferon use is not an exclusion criterion.

Patients with insufficient sample volume or inadequate DNA quality for sequencing will be excluded from final analysis.