Molecular targets of HBV replication present possibility of cure
Functional cure of hepatitis B virus (HBV) infection could be possible in the near future with the development of drugs that inhibit HBV replication, recent early-phase clinical studies have shown.
“As HBV molecular entry and replication mechanisms continue to be elucidated and agents targeting different steps in HBV replication at the molecular level are being developed, existing therapies could be used concomitantly with newer immunomodulators to prevent drug resistance or even achieve functional cure of the chronic disease,” said Professor Rakesh Aggarwal of the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, who spoke at the Asian Pacific Digestive Week 2017 held recently in Hong Kong.
Current treatment strategies for HBV, namely the nucleos(t)ide analogues (NAs, which inhibit HBV DNA polymerase) and interferon-based regimens, result in potent HBV suppression but do not eradicate the virus. As such, long-term treatment is required, which often leads to drug resistance. Although these treatments can reverse liver inflammation and fibrosis, prevent progression to cirrhosis and reduce the risk of hepatocellular carcinoma (HCC), the risk of HCC remains.
“Patients who have supposedly had ‘full recovery’ from acute HBV infection and are hepatitis B surface antibody-positive after treatment with NAs have persistent covalently closed circular DNA [cccDNA] in their hepatocytes. They can thus experience HBV reactivation when immunosuppressed,” Aggarwal pointed out.
“Inhibiting viral entry and preventing HBV DNA integration with hepatocytes is a promising strategy. Myrcludex B, a synthetic lipopeptide derived from HBV large surface protein which binds to the HBV entry receptor, sodium taurocholate co-transport peptide [NTCP], has been shown effective in reducing HBV DNA levels by >1.0 log10 at the end of 24 weeks in 75 percent of patients given 10 mg daily of the drug in a phase II clinical trial,” said Aggarwal. [Nat Rev Gastroenterol Hepatol 2015;12:70-72; Urban S, et al, AASLD 2014, abstract LB-20]
“Agents targeting cccDNA are of greatest interest currently,” he highlighted. “Agents being developed act by inhibiting cytoplasmic release of relaxed circular (rc)DNA, inhibiting conversion of rcDNA to cccDNA through host-DNA repair mechanisms , and preventing mRNA formation from cccDNA by epigenetic silencing such as with HBV X protein antagonists. cccDNA-targeted endonucleases are also being developed.” [Gut 2015;64:1314-1326]
“RNA interference-based therapies, such as those delivered by the ARC-520 system, have also demonstrated promising results. The siRNA acts directly to reduce levels of the targeted viral transcripts, leading to rapid reduction in viral protein production with resultant reduction in hepatitis B surface antigen [HBsAg] levels and reversal of immune suppression, ultimately leading to HBsAg seroconversion and possibly functional cure,” said Aggarwal. “This is in contrast to NAs, which directly inhibit the polymerase-reverse transcriptase to reduce viral DNA synthesis but do not directly affect the production of viral proteins, and thus can only gradually reduce HBV protein levels.”
“HBV core protein modulators and nucleic acid polymers that block HBsAg subviral particle release are among other potential and useful agents in the development pipeline,” added Aggarwal.