Dynamics of Serum Pregenome RNA in Chronic Hepatitis B Patients Receiving 96-Month Nucleos(t)ide Analog Therapy

Abstract

BackgroundTissue covalently closed circular DNA (cccDNA) can reflect the activity of HBV replication. However, it is impractical to assess intrahepatic cccDNA in every outpatient. Serum pregenome RNA (pgRNA) is transcribed from intrahepatic cccDNA and may reflect the activity of intrahepatic cccDNA. We explored the dynamics and the potential role of serum pgRNA in patients receiving long-term NAs treatment.MethodsSerum pgRNA, HBV DNA, HBsAg, HBeAg, and ALT levels were quantified, and the relationships between serum pgRNA and these common clinical indicators before and after the treatment were investigated.ResultsSerum pgRNA showed dynamic change during the 96-month NAs therapy, and serum pgRNA levels were positive and detectable in 19 patients with undetectable serum HBV DNA. Serum pgRNA showed strong and positive correlation with serum HBV DNA (r = 0.693, p < 0.001) and serum HBsAg levels (r = 0.621, p < 0.001) at baseline. Patients with HBeAg seroconversion had lower baseline serum pgRNA levels (p = 0.002). The area under the curve (AUC) of baseline serum pgRNA for predicting HBeAg seroconversion was 0.742 (95% CI: 0.606–0.850) with 63.16% sensitivity and 80.56% specificity. The cumulative HBeAg seroconversion rate was higher in patients with low serum pgRNA (p = 0.001).ConclusionSerum pgRNA of low level at baseline or great decline at month 6 may independently predict the high incidence of undetectable serum pgRNA at year 4 following NAs therapy, and the baseline serum pgRNA may serve as a novel predictor for HBeAg seroconversion during NAs therapy.

Biogenesis of serum HBV RNA and clinical phenomena of serum HBV RNA in chronic hepatitis B patients before and after receiving nucleos(t)ide analogues therapy

“…64 Baseline HBV RNA levels were considerably lower in patients who experienced HBeAg seroconversion during NAs treatment compared to those without HBeAg seroconversion. 69,78,80,83,109,111,112 Likewise, serum HBV RNA level was much lower at different time points under NAs therapy among patients achieving HBeAg seroconversion. 74,82,109,113 Hence, serum HBV RNA levels at baseline and different time points after NAs therapy were strong predictors of HBeAg seroconversion, which displayed better prediction performance than HBV DNA and HBsAg.…”

“…Considerable declines of serum HBV RNA were observed under long-term NAs treatment in the vast majority of current studies, and HBV RNA showed a much slower decline than serum HBV DNA, 8,57,59,65,69-83 which could be observed as early as 1 week after treatment. 8 gradually exceeded HBV DNA concentration during treatment, 69,71,72 and HBV RNA could remain detectable despite HBV DNA becoming undetectable in patients under persistent NAs therapy, 65,69,[76][77][78]80,[84][85][86] even in some patients achieving HBsAg clearance. 76,87,88 Contrary to the mainstream findings, it was observed that serum HBV RNA level showed a rise within 4 weeks after NA therapy and began to decline afterward.…”

“…Monitoring transcriptional activity of cccDNA [58,66,67,[72][73][74]79,104,105] Predicting HBeAg loss/seroconversion [69,71,74,78,80,82,83,109,[111][112][113][114] Predicting HBsAg loss [81,115] Predicting relapses after NAs discontinuation [19,76,115,[117][118][119][120] TA B L E 3 Main clinical applications of serum HBV RNA.…”

“…HBeAg status Positive [59,61,65,67,69,73,78,[96][97][98][99] Liver injury Positive [61,62,68,72,96,98] Th1 immunity Negative [98] Th2 immunity Positive [98] Age Negative [61,96,97] HBV Genotype B Positive [68,[96][97][98] HBV Genotype D Negative [68,96] HBV BCP/PC mutation Negative [96][97][98] TA B L E 2 Influencing factors of serum HBV RNA levels.…”

“…HBeAg status is a crucial factor associated with serum HBV RNA which was considerably higher in HBeAg-positive patients than in HBeAg-negative patients regardless of whether these patients received antiviral therapy or not. 59,61,65,67,69,73,78,[96][97][98][99] HBeAg is considered to have immunomodulatory activities and promote viral persistence. 100 The reduction in serum HBV RNA after HBeAg clearance may be attributed to decline of cccDNA load and decreased cccDNA transcriptional activity.…”