Serum HBV RNA as a possible marker of HBV replication in the liver during nucleot(s)ide analogue therapy

Abstract

We read with interest the article by Tsuge et al. [1] published in the recent issue of the Journal of Gastroenterology. Treatment with nucleot(s)ide analogue (NUC) strongly suppresses the replication of hepatitis B virus (HBV) leading to a high rate of serum HBV DNA negativity. However, the incidence of relapse after the cessation of NUCs is high. Criterion for safe discontinuation of NUC therapy after long term therapy is not established to date. In HBe antigen positive patients, seroconversion, HBV DNA negativity and consolidation therapy of[6 months may be a consensus criteria but 30–50 % of patients fulfilling this criteria experience a relapse. In HBe antigen negative patients, NUC therapy is generally recommended until HBs antigen becomes undetected. Tsuge et al. [1] measured serum HBV RNA plus DNA by real time PCR and showed that the serum HBV DNA ? RNA titer following 3 months of NUC treatment was a significant predictor of early (within 24 weeks) HBV DNA rebound after discontinuation of NUC. The serum HBV DNA ? RNA titer was also associated with ALT rebound in HBe antigen positive patients. The results of the study by Tsuge et al. indicate that serum HBV DNA ? RNA titer may serve as predictor of relapse after discontinuation of NUC. The high rate of relapse after discontinuation of NUC is due to the persistence of HBV replication in the liver even during the NUC therapy. The replicative intermediate form of HBV, covalently closed circular DNA (cccDNA), may not be eliminated by NUC therapy and serves as a template for viral pre-genomic messenger RNA [2]. This concept was proved by a study showing that quantification of intrahepatic HBV cccDNA had a high accuracy of predicting sustained virological response after NUC discontinuation [3]. Still, we need a non-invasive and clinically usable marker for the assessment of HBV replication in the liver during NUC therapy. The measurement of HBV core related antigen may be an alternative [4]. The rationale of measuring HBV RNA in serum was that immature HBV particles including HBV RNA are released from hepatocytes during NUC treatment under the circumstances that pre-genomic HBV RNA are transcribed from HBV cccDNA, packaged into HBV core particles, but not reverse transcribed into plus-strand HBV DNA due to strong interference by NUC, and the excessive amounts of these immature particles are accumulated in hepatocytes [5, 6]. Tsuge et al. showed that serum HBV DNA ? RNA titer following 3 months of NUC treatment was significantly lower in patients with no rebound of HBV DNA. By using a cut-off value of 4.8 log copies/mL, the cumulative incidence of HBV DNA rebound was significantly lower in patients with serum HBV DNA ? RNA titer \ 4.8 log at 3 months of NUC treatment. The same groups previously showed that HBV RNA levels at 3 months of lamivudine treatment were predictor of early emergence of resistant mutations [7]. Taken together, serum HBV DNA ? RNA titer may be linked to the level of HBV replication in the liver during NUC therapy. Monitoring of serum HBV DNA ? RNA response may be utilized in various decision makings in treatment of HBV patients with NUC therapy. Based on these important findings, several questions may remain for future elucidation. Commercially available transcription-mediated amplification and hybridization assay An answer to this letter to the editor is available at doi:10.1007/s00535-013-0801-6.