Hepatitis B Virus RNA as Early Predictor for Response to Pegylated Interferon Alpha in HBeAg-Negative Chronic Hepatitis B

Abstract

Background Hepatitis B virus RNA (HBV-RNA) is a novel serum biomarker that correlates with transcription of intrahepatic covalently closed circular (cccDNA), which is an important target for pegylated interferon (PEG-IFN) and novel therapies for functional cure. We studied HBV-RNA kinetics following PEG-IFN treatment and its potential role as a predictor to response in HBeAg-negative chronic hepatitis B (CHB) patients. Methods HBV-RNA levels were measured in 133 HBeAg-negative CHB patients treated in an international randomized controlled trial (PARC study). Patients received PEG-IFN α-2a for 48 weeks. HBV-RNA was measured from baseline through week 144. Response was defined as HBV-DNA <2000 IU/mL and ALT normalization at week 72. Kinetics of HBV-RNA were compared with HBV-DNA, HBsAg, and HBcrAg. Results Mean HBV-RNA at baseline was 4.4 (standard deviation [SD] 1.2) log10 c/mL. At week 12, HBV-RNA declined by −1.6 (1.1) log10 c/mL. HBV-RNA showed a greater decline in responders compared to nonresponders early at week 12 (−2.0 [1.2] vs −1.5 [1.1] log10 c/mL, P = .04). HBV-RNA level above 1700 c/mL (3.2 log10 c/mL) had a negative predictive value of 91% at week 12 and 93% at week 24 (P = .01) for response. Overall, HBV-RNA showed a stronger correlation with HBV-DNA and HBcrAg (.82 and .80, P < .001) and a weak correlation with HBsAg (.25). At week 12, HBV-RNA was significantly lower among patients with lower HBsAg (<100 IU/mL) or HBsAg loss at week 144. Conclusions During PEG-IFN treatment for HBeAg-negative CHB, HBV-RNA showed a fast and significant decline that correlates with treatment response and HBsAg loss at long-term follow-up. Clinical Trials Registration NCT00114361

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.…”

Factors associated with the biphasic kinetics of serum HBV RNA in patients with HBeAg‐positive chronic hepatitis B treated with nucleos(t)ide analogues

“…In recent years, serum HBV RNA has been applied to predict the treatment efficacy of NAs and Peg‐IFN 18‐21 . Several studies have reported that the early kinetics of serum HBV RNA provide good predictive ability for hepatitis B e antigen (HBeAg) seroconversion induced by NAs or Peg‐IFN therapies in HBeAg‐positive CHB patients 18‐20 .…”

<p>Serum Hepatitis B Virus RNA Levels Predict HBeAg Seroconversion and Virological Response in Chronic Hepatitis B Patients with High Viral Load Treated with Nucleos(t)ide Analog</p>

“…Several studies have demonstrated that the serum HBV RNA level is correlated significantly with HBV markers, such as HBV DNA and HBsAg, 11,19,24,25 which supports the notion that the serum level of HBV RNA could be a marker to reflect the intrahepatic activity of HBV replication. We found a correlation between the total serum level of HBV RNA and total serum level of HBV DNA, with a correlation coefficient of 0.653.…”