Abstract
High rate of viral replication and lacking of proofreading activity in hepatitis B virus (HBV) polymerase lead to the generation of mutations in HBV virus. Mutations in the reverse transcriptase (RT) region of HBV polymerase are demonstrated to be strongly associated with drug resistance during antiviral treatment. However, the presence of mutations as well as its clinical significance in treatment-naïve hepatitis patients (defined as pre-existing mutations) need to be further investigated. In the present study, a total of 168 serum samples from treatment-naive chronic hepatitis B (CHB) patients were collected, and the RT region of HBV polymerase was sequenced. The results showed that pre-existing mutations in the RT region of HBV polymerase were detected in 43 of 168 (25.6%) treatment-naive CHB patients within which there were no well-characterized primary nucleotide analogs (NAs) resistance sites. Three dominant sites at rt191, rt207 and rt226 were found mutant in 7(16.28%), 8(18.60%), and 14(32.56%) samples respectively among these 43 patients. No significant correlation was found between pre-existing mutations and gender, age, HBV genotype, ALT, HBeAg or HBV DNA loads. However, patients with pre-existing RT mutations under HBeAg sero-negative status exhibited decreased HBV DNA loads, which contributed to the decreased HBV DNA loads in the total HBeAg sero-negative patients. The above investigation indicated that there was a prevalence of pre-existing mutations in RT region of HBV polymerase which might affect the serum HBV DNA level in treatment-naive CHB patients. Its effects on the occurrence of NAs resistance and the prognosis after treatment need to be further investigated.
Highlights
Chronic hepatitis B virus (HBV) infection, a major cause of cirrhosis and hepatocellualr carcinoma, afflicts approximately 350 million people worldwide[1] and 93 millions of Chinese population[2]
Samples from 168 treatment-naive chronic hepatitis B (CHB) patients were enrolled in this retrospective study
The existence of pre-existing mutations in reverse transcriptase (RT) region of HBV polymerase was reported in previous literatures, for instance, secondary/compensatory but not primary mutations were found in treatment-naïve Italian population[23], while there were 8.8% Indian treatment-naïve CHB patients carrying primary drug resistant mutations[24]
Summary
Chronic hepatitis B virus (HBV) infection, a major cause of cirrhosis and hepatocellualr carcinoma, afflicts approximately 350 million people worldwide[1] and 93 millions of Chinese population[2]. HBV is a partially double-stranded DNA virus containing 3200 nucleotides with four open reading frames (ORFs), encoding pre-S/S, pre-C/C, HBX and polymerase. It replicates DNA genome through RNA intermediate during viral life cycle using reverse transcriptase encoded by DNA-P region[3]. Lacking of proof reading ability of reverse transcriptase, the error rate after the replication of viral genome has been mounted as 10−7 per nucleotide which is 10-fold higher than other DNA virus[4]. High rate of mutations in HBV genome compromises the antiviral therapy of nucleotide analogs (NA), leading to the generation of drug resistant viral strains and disease progression
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