Hepatitis B virus pregenomic RNA status can reveal the long‐term prognoses of chronic hepatitis B patients treated with nucleos(t)ide analogues

Abstract

We examined whether the hepatitis B virus (HBV) pregenomic RNA (pgRNA) status after nucleos(t)ide (NA) treatment can predict the long‐time prognoses of chronic hepatitis B patients. Patients with chronic hepatitis B (98) who were treatment‐naïve and had begun a 7‐year NA therapy regimen were enrolled in this study. Biochemical indicators and serological markers of HBV infection were performed during therapy. HBV pgRNA was quantified by real‐time quantitative PCR with specific primers. During treatment, HBV DNA undetectable rates increased. The aminotransferase (ALT) normalization (ALT < 50 IU/L) and HBeAg‐negative rates also increased. After 48 weeks’ NA treatment, 48.28% (28/58) of HBV DNA undetectable patients still had HBV pgRNA‐positive. After 7 years of treatment, more HBV pgRNA‐negative patients (n = 35) achieved HBeAg clearance than the patients who were HBV pgRNA‐positive (n = 63) (19/23 vs 19/56, P < .00). HBV pgRNA‐positive patients also had an increased risk of failing to achieve HBeAg clearance (OR = 9.25, 95% CI: 2.75‐31.08). The median time to HBeAg clearance in the HBV pgRNA‐positive patients was longer than that of the HBV pgRNA‐negative patients (152 weeks vs 72 weeks). The HBV pgRNA‐positive patients also required more time to achieve HBV DNA undetectable (124 weeks, 95% CI: 103.33‐144.67 vs 48 weeks, 95% CI: 34.80‐61.20). The HBV pgRNA status after NA treatment can predict the long‐term prognoses of patients with chronic HBV. Patients who remain HBV pgRNA‐positive after 48 weeks of NA treatment have an increased risk of not achieving HBeAg clearance, need more time to achieve HBeAg clearance and undetectable HBV DNA load.

Single hepatocytes show persistence and transcriptional inactivity of hepatitis B

“…Plasma HBV RNA levels have been shown to predict response to pegylated interferon ( 8 , 11 , 23 ) and to NUC interruption ( 6 , 7 , 9 , 10 ): persons with suppressed plasma HBV DNA and RNA levels are less likely to develop HBV reactivation after NUC interruption than persons with suppressed HBV DNA levels but detectable HBV RNA levels. One potential explanation for this finding is that persons with suppressed HBV RNA levels might have infected cells that are transcriptionally inactive, and thus less likely to reactivate.…”

Serum HBV RNA Correlated with Intrahepatic cccDNA More Strongly than other HBV Markers During Peg-Interferon Treatment

“…In previous studies, both serum HBV RNA and HBcrAg were reported to be potential surrogate biomarkers of cccDNA in predicting the outcomes of peg-IFN or NAs treatments [4,20,21]. The correlation of cccDNA with HBV RNA has also been studied before and after nucleos(t)ide analog treatment [5,21,22]. However, it is still unclear whether serum HBV RNA or HBcrAg is better as the surrogate marker of intrahepatic cccDNA.…”

Hepatitis B virus RNA decline without concomitant viral antigen decrease is associated with a low probability of sustained response and hepatitis B surface antigen loss

“…On the other hand, among the few patients experiencing significant HBV RNA declines during treatment with nucleo(s)tide analogues or PEG-IFN, HBV RNA decline was associated with higher rates of off-treatment sustained response. 18,20,21,24,33 Interestingly, two preliminary reports of recent studies in patients treated with novel capsid assembly modifiers have demonstrated superior HBV RNA declines. 13,25 Whether these declines also translate to higher rates of off- Until now, it has been unclear how such a response, i.e.…”

“…[15][16][17][18] Recent studies suggest that a decline in serum HBV RNA levels during treatment with nucleo(s)tide analogues or PEG-IFN is associated with treatment response, although overall declines during treatment were limited. [19][20][21][22][23][24] Interestingly, recent phase 1 studies of novel capsid assembly modifiers have shown substantially stronger HBV RNA declines, which has been interpreted as a possible sign of a more potent effect on the intrahepatic HBV reservoir. 25 However, besides the observed decline in serum HBV RNA during capsid assembly modifiers therapy, little changes in hepatitis B surface antigen (HBsAg) and hepatitis B core-related antigen (HBcrAg) concentrations were observed in these patients.…”

“…Recently, hepatitis B virus (HBV) RNA has emerged as a potential prognostic biomarker for treatment response, as it correlates with transcriptional activity of cccDNA and therefore may reflect intrahepatic replication activity 15‐18 . Recent studies suggest that a decline in serum HBV RNA levels during treatment with nucleo(s)tide analogues or PEG‐IFN is associated with treatment response, although overall declines during treatment were limited 19‐24 . Interestingly, recent phase 1 studies of novel capsid assembly modifiers have shown substantially stronger HBV RNA declines, which has been interpreted as a possible sign of a more potent effect on the intrahepatic HBV reservoir 25 …”