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Quest for HBV functional cure: what have we learnt from silencing RNAs?
  1. Norah Terrault1,
  2. Anna S Lok2
  1. 1University of Southern California, Los Angeles, California, USA
  2. 2University of Michigan, Ann Arbor, Michigan, USA
  1. Correspondence to Professor Norah Terrault, University of Southern California, Los Angeles, California, USA; terrault{at}usc.edu

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The remarkable success of direct-acting antivirals in curing hepatitis C led to concerted efforts in developing a cure for hepatitis B. Unlike hepatitis C, it is accepted that a sterilising cure is not feasible in the foreseeable future. Instead, functional cure defined as hepatitis B surface antigen (HBsAg) loss (below detection) and HBV DNA suppression (below quantification) sustained for at least 24 weeks after completion of treatment has been embraced.1 Nucleos(t)ide analogues (NA) currently in use, entecavir and tenofovir, are highly effective in maintaining suppression of HBV DNA replication and yields substantial clinical benefits including reduced rates of cirrhosis and hepatocellular carcinoma, but HBsAg loss remains elusive. Yet, if a functional cure is achieved, the benefits are multiple, with further reductions in the risk for liver-related outcomes,2 elimination of the need for long-term monitoring and NA treatment and addressing the stigma associated with HBsAg-positivity.

Strategies to increase rates of HBsAg loss among persons on long-term NA therapy included NA withdrawal and peginterferon add-on or switch. It should be noted that such studies focus on the population who are HBeAg-negative and on NA therapy with suppressed HBV DNA for years. Studies show that NA withdrawal can increase the rate of HBsAg loss compared with continued treatment with NA but the rates of HBsAg loss are modest at best (10–20% at 3–5 years after NA discontinuation) and lower in persons of Asian origin (<5%) and can be associated with hepatitis flares and hepatic decompensation.3 Furthermore, half the patients require resumption of treatment within 4 years of NA withdrawal. Peginterferon add-on therapy to NA similarly increases rates of HBsAg loss to~10% but has more limited applicability due to the side effect profile of peginterferon.4 Clearly, these results are underwhelming, but they provide a useful benchmark …

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Footnotes

  • Contributors Both authors contributed equally to the work and NT is the guarantor.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests NT has received research grant support from GlaxoSmithKline and Eiger Pharmaceuticals and served as unpaid consultant for GlaxoSmithKline, Vir Biotechnology and Gilead Sciences. AL has served as a consultant for Chroma, GlaxoSmithKline, Grifols, Moderna, Precision, Pfizer, Virion and Zenasbio; and received research grant support from TARGET.

  • Provenance and peer review Commissioned; internally peer reviewed.

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