Abstract
Hepatitis B virus (HBV) is known to cause severe liver diseases such as acute or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis B (CHB) infection is a major health problem with nearly 300 million individuals infected worldwide. Currently, nucleos(t)ide analogs (NAs) and interferon alpha are clinically approved treatments for HBV infection. NAs are potent antiviral agents that bind to HBV polymerase and block viral reverse transcription and replication. Besifovir dipivoxil maleate (BSV) is a newly developed NA against HBV in the form of acyclic nucleotide phosphonate that is available for oral administration similar to adefovir and tenofovir. Until now, resistance to BSV treatment has not been reported. In this study, we found a CHB patient who showed viral breakthrough after long-term treatment with BSV. The isolated HBV DNA from patient’s serum were cloned into the replication-competent HBV 1.2 mer and the sequence of reverse transcriptase (RT) domain of HBV polymerase were analyzed. We also examined the drug susceptibility of generated clones in vitro. Several mutations were identified in HBV RT domain. A particular mutant harboring ten RT mutations showed resistance to BSV treatment in vitro. The ten mutations include rtV23I (I), rtH55R (R), rtY124H (H), rtD134E (E), rtN139K (K), rtL180M (M), rtM204V (V), rtQ267L (L), rtL269I (I) and rtL336M (M). To further identify the responsible mutations for BSV resistance, we performed in vitro drug susceptibility assay on several artificial clones. As a result, our study revealed that rtL180M (M) and rtM204V (V) mutations, already known as lamivudine-resistant mutations, confer resistance to BSV in the CHB patient.
Highlights
Mutation Profile of Hepatitis B virus (HBV) reverse transcriptase (RT) Domain Isolated from a Patient Treated with Besifovir dipivoxil maleate (BSV)
We identified a double BSV-resistant mutation in HBV isolated from one Chronic hepatitis B (CHB) patient with clinical resistance to BSV treatment and confirmed in vitro BSV resistance
To the best of our knowledge, this is the first report of HBV mutants with both clinical and in vitro resistance to BSV treatment
Summary
HBV is a major cause of chronic liver diseases with estimated 1.5 million new infections each year (WHO 2019). Liver cirrhosis and hepatocellular carcinoma (HCC) are associated with more than 800,000 annual deaths worldwide [1]. HBV polymerase has different functions such as pgRNA packaging, protein priming, and DNA synthesis. HBV replication process initiates after pgRNA encapsidation and recognition of epsilon in the 5’ end of pgRNA by Pol (polymerase or reverse transcriptase)
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