Letter: nucleos(t)ide analogues are good, but not sufficient for hepatitis B virus clearance

SIRS, In a recent issue of the Alimentary Pharmacology and Therapetics, we read with interest the article by Chen et al. In relation to this article, we wanted to emphasise the disadvantages of nucleos(t)ide analogues (NA), particularly the persistence of covalently closed circular deoxyribonucleic acid (cccDNA) as a novel target for hepatitis B virus (HBV) treatment in a summary. _ Indefinite therapy with NA is an important problem discussed by Chen et al. As stated in the article, it is also controversial in the different basic guidelines when and/or in which patients the therapy will be terminated. Basically, as a result of long-term use of NA, drug resistance may emerge or, on the other hand after the withdrawal of therapy, flare-ups of infection may occur. Lifelong threapy is also very expensive for especially developing countries. Patient compliance is another problem related to long-term use. Finally, with entecavir administration, while HBV DNA negative conversion rates were 55–96%, HBV surface antigen negative conversion rates were 0–5.1% and resistance mutant emergence rates were 0.2–1.2%. More importantly, although the efficient suppression of HBV DNA titres by these agents, the virus cannot be eradicated due to the accumulation and persistence of cccDNA in the hepatocyte nucleus. 4 It has been demonstrated that intrahepatic cccDNA levels were reduced slightly (only 1 log10) with entecavir, but did not differ statistically from the placebo group and cccDNA reduction were associated with improved necroinflammation and fibrosis. cccDNA has also crucial role in HBV persistence, reactivation after the cessation of therapy, improvement of occult infection and drug resistance. 5, 6 So, after the discontinuation of therapy, reactivation induced by especially drug resistance variants may occur due to the persistence of cccDNA. After all, it has been indicated that intrahepatic cccDNA suppression may be important to prevent HCC recurrence. For these reasons, targeting cccDNA is current and the key approach for HBV treatment. It has been reported that engineered nucleases, sequence-specific DNA cleavage enzymes, such as zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) may suppress viral replication in cell cultures and clustered regularly inter-spaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system can accurately and efficiently target cccDNA and inhibit viral replication in an animal model. By lymphotoxin b receptor (LT-bR) activation, apolipoprotein B messenger ribonucleic acid (RNA) editing enzyme catalytic polypeptide (APOBEC) A3 deaminases which play an important role in eradication of unknown DNA can be upregulated. Because of this, LTbR agonists can be the other option for targeting cccDNA. 9 Inhibiting HBV ribonuclease H (RNaseH) activity causes accumulation of long RNA:DNA heteroduplexes, blocks release of infectious virions and replacement of nuclear cccDNA. For this reason, HBV RNaseH inhibitors including some a-hydroxytropolones, b-thujaplinicol and ARC-520 (in phase II clinical trials) are promising other candidates for new HBV drugs. 10 HBV receptors on hepatocytes such as sodium taurocholate cotransporting polypeptide (NTCP), essential for viral entry into the cell represent a new target for antiHBV drug development to affect intrahepatic cccDNA levels. 9 Myrcludex-B (by binding to NTCP), Ro415253 which is a retinoic acid receptor selective antagonist (by inhibiting NTCP promoter activity) and IL-6 (by regulating NTCP expression) can block HBV entry.