Illustrates are representative of basins and location on highexchange manifold

Two types of OG-L002 hydrochloride mutations are associated with treatment failure to NA: primary mutations, which are directly responsible for drug resistance, and compensatory mutations enhancing replication ability. For example, resistance to lamivudine and telbivudine is conferred by mutation rtM204V or rtM204I in the YMDD motif, and this is often associated with compensatory mutations rtL180M and/or Farrerol rtV173L restoring a higher replication capacity. Qidong, China is the area that is most affected by HCC worldwide, with an age-standardized incidence rate of 77.7 per 100,000 for males and 24.3 per 100,000 for females. HCC is the leading cause of cancer mortality and accounts for almost half of the cancer occurrence in Qidong, and HBV infection poses a high level of risk for HCC in Qidong. Over the past few years, we defined that a high prevalence of the HBV C1 genotype, pre-S deletion and pre-S2 start codon mutation, C1653T, T1753A/ G, C1766T, and T1768A mutations in the BCP/EnhII region, and A2159G, A2189C, and G2203W in the core gene are associated with HCC in Qidong. Notably, using serial samples collected from a prospective cohort, we observed for the first time that mutations in the BCP/Enh II region occurred in a temporal order during the course of HCC development. In the present study, we extended our research to the HBV RT domain. After comparing the RT sequences from 231 HCC cases and 237 non- HCC controls, we identified three novel mutations significantly associated with HCC. Numerous studies have shown that mutations in the HBV pre- S, BCP/EnhII, and pre-C regions are associated with the risk of HCC. However, natural mutations in HBV RT and their relationship with HCC have rarely been explored before. In this study, we characterized spontaneous mutations in the HBV RT region and report, for the first time that the A799G, A987G, and T1055A mutations are independent risk factors for HCC. The association of these RT mutations with HCC is likely to be robust in genotype C-infected patients. Whether such mutations in other genotype of HBV have the similar association with HCC is an interesting issue for further study. HBV RT performs the primary enzymatic function of viral replication and is the main target of anti-HBV drug development.

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