RNA Interference Therapy for Chronic Hepatitis B Predicts the Importance of Addressing Viral Integration When Developing Novel Cure Strategies

Abstract

Chronic hepatitis B infection remains a globally important cause of morbidity and mortality and has recently undergone a renaissance in therapeutic interest with increased pre-clinical and clinical testing of new drug classes. One of the first new classes in the clinic was RNA interference agents, which have the potential to impact the entire viral life cycle by reducing all virus-produced mRNA. Early clinical testing with the first of these agents in the clinic, ARC-520, demonstrated that rapid and deep reductions in viral proteins, RNA and DNA could be produced with this approach, but also the surprising insight that HBsAg production from incomplete HBV DNA integrated into the host genome appears to play a heretofore unappreciated and important role in maintaining circulating HBsAg, thought to play a fundamental role in preventing host clearance of the virus. Thus, accounting for viral DNA integration in novel HBV treatment approaches may prove to be essential to achieving successful finite therapies of this difficult to treat chronic infection.

Integrated hepatitis B virus DNA maintains surface antigen production during antiviral treatment

“…NUCs inhibit HBV replication by interrupting HBV polymerase, a reverse transcriptase that converts viral pregenomic RNA (pgRNA) to relaxed circular DNA (rcDNA), the infectious genome detected in plasma. Importantly, NUCs do not directly affect the covalently closed circular DNA (cccDNA) present in the nucleus of every infected cell, and thus cannot, on their own, result in HBV eradication (6)(7)(8). Furthermore, although NUCs are the mainstay of antiviral treatment in CHB, their suppressive effect on HBV viremia belies their limited impact on plasma HBsAg levels (1,9,10).…”

Discovery of Novel cccDNA Reducers toward the Cure of Hepatitis B Virus Infection

“…Although the carboxylic acid analogue (25) could significantly improve metabolic stability, its activity was, unfortunately, completely lost. At the 3′-position of the pyrrolidine ring, several polar and charged groups, including hydroxyl (26), amino (27), and carboxylic acid (28) moieties, were explored. Hydroxyl analogue 26 showed the best HepDes19 potency (IC 50 = 0.43 μM), and the most gratifying discovery was the identification of carboxylic acid analogue 28.…”

Functional cure of hepatitis B requires silencing covalently closed circular and integrated hepatitis B virus DNA

“…The findings from Grudda et al ( 15 ) and other studies showing that iDNA can be a predominant source of HBsAg in some patients, particularly those who are HBeAg-negative ( 12 ), and the low rates of HBsAg loss achieved in ongoing trials of emerging therapies that specifically target HBsAg ( 17 ), have raised the question whether HBsAg loss is a valid definition of functional HBV cure and if it is achievable. These findings imply that attainment of a high rate of HBsAg loss after a finite course of therapy would require not only sustained silencing of cccDNA transcription but also silencing of iDNA transcription or elimination of hepatocytes with iDNA.…”