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Molecular targets of HBV replication present possibility of cure

Elaine Tan
04 Oct 2017

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.

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Most Read Articles
Roshini Claire Anthony, 16 Oct 2017

Treatment failure in osteoporosis remains a problem, even among patients who are treatment-adherent, according to a presentation at the recent meeting of the Asian Federation of Osteoporosis Societies (AFOS 2017), held in Kuala Lumpur, Malaysia. 

Elvira Manzano, 6 days ago
Bisphosphonates have proven antifracture efficacy and remain to be the cornerstone of osteoporosis treatment. However, a drug holiday is of particular importance with bisphosphonates due to some signals with long-term use of the drug, including rare incidence of atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ), says a leading endocrinologist at AFOS 2017.
Yesterday
Drinking coffee, whether caffeinated or decaffeinated, is associated with a reduced risk of cardiovascular disease (CVD) and ischaemic heart disease (IHD) mortality in patients with a prior myocardial infarction (MI), according to a recent study.
2 days ago
Breast cancer patients have notably different microbiomes in the local breast tissue and urinary tract, a recent study reveals. Particularly, species in the Methylobacterium genus are reduced in the local breast tissue while the urinary tract is enriched in gram-positive bacteria.