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Hepatitis B virus (HBV) infection remains a major global public health problem with 240 million chronic carriers. Current treatments for chronic HBV infection are unable to achieve a functional cure, defined by the loss of the HBsAg and allowing the treatment cessation as well as a decreased risk of liver complications. Several new therapeutic molecules that target the cccDNA, the nuclear replicative intermediate that act as template for the transcription of all viral mRNAs, with the aim of silencing or reducing the pool of cccDNA to achieve a functional cure with a finite treatment duration, are at the preclinical or early clinical stage of evaluation. A persistent suppression of serum HBV DNA and loss of HBsAg are considered the most important primary efficacy endpoints for novel molecular entities in clinical development. However, the suppression of HBV DNA in serum is not an appropriate efficacy endpoint to evaluate new HBV treatments in patients treated with DNA-decreasing nucleotide analogues. In addition, although HBsAg levels may predict HBsAg loss, the kinetic of HBsAg decline is too slow in most patients to be useful to predict functional cure within the short duration of early clinical trials. Finally, HBsAg antigens may origin from HBV sequences integrated into the host genome and do not reflect the number of cccDNA molecules and their transcriptional activity. Circulating HBV RNA reflects the transcriptional activity of cccDNA in the liver and would thus be a good non-invasive biomarker for the inactivation of cccDNA or the reduction of the cccDNA reservoir. The quantification of circulating HBV RNAs may contribute to monitor the disease, to a personalized therapeutic management, and to the evaluation of new therapeutic molecules. The establishment of an HBV RNA standard remains a challenge and is crucial for the development of all circulating HBV RNA quantification assays. To this aim we have generated several clonal cell lines carrying mutated HBV genomes. A clonal cell line (Huh7-3D29) secreting ...
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