Authors: Raymond T. Chung, MD; Esperance Anne Kreek Schaefer, MD, MPH (More Info)
Editors In Chief: Nezam H. Afdhal, MD, FRCPI; Stefan Zeuzem, MD
Last Reviewed: 8/6/14 (What's New)
Therapeutic Targets
Summary
Therapy for HBV infection currently includes interferon and nucleos(t)ide analogues that inhibit HBV polymerase
Peginterferon alfa-2a is administered for 1 year and leads to a 27% chance of HBeAg seroconversion and a 3% chance of HBsAg loss[Dienstag 2008]
A subset of patients will require retreatment
5 nucleos(t)ide analogues are currently approved for HBV treatment: lamivudine, telbivudine, adefovir, entecavir, and tenofovir.
Targeting other steps in the viral life cycle (eg, encapsidation and viral entry), stimulating the innate immune response, and therapeutic vaccination, as well as RNA interference–based strategies are currently under investigation
Two major classes of therapies are currently used for the treatment of chronic hepatitis B virus (HBV) infection: interferon and nucleos(t)ide analogues (NAs) that are HBV polymerase inhibitors.
Therapy with peginterferon alfa 2a is administered for 1 year and leads to a 27% chance of hepatitis B e antigen (HBeAg) seroconversion and a 3% chance of hepatitis B surface antigen (HBsAg) loss.[Dienstag 2008] A subset of these patients will have persistently high HBV DNA levels after HBeAg seroconversion, meaning they will progress to HBeAg-negative chronic HBV infection, and will require retreatment.[Buster 2008; Wong 2010]
There are 5 NAs approved for HBV to date: lamivudine, telbivudine, adefovir, entecavir, and tenofovir. The NAs are integrated into the HBV DNA during replication, leading to chain termination and inhibition of replication. Treatment with the NAs is generally indefinite in duration and leads to high rates of viral inhibition with the most potent agents but carries a risk of developing resistance that varies substantially, depending on the NA agent.
New potential therapeutic strategies that may lead to less risk of developing resistance include stimulation of the innate immune response via toll-like receptors, RNA interference–based strategies, therapeutic vaccination, and targeting viral entry. Treatment with the toll-like receptor 7 agonist, GS-9620, has been investigated in 2 animal models of chronic HBV infection, and resulted in sustained reduction of serum S antigen and seroconversion in the woodchuck model[Menne 2011] and sustained suppression of serum and liver HBV DNA and serum HBsAg and HBeAg in chimpanzees.[Lanford 2013] Two phase I clinical trials investigating the effects of GS-9620 treatment in patients with chronic HBV infection have recently been completed and a phase II trial is currently under way (Clinical Trial: NCT02166047). Therapeutic vaccination is also an active area of investigation using yeast or adenovirus-based approaches, and immunization with yeast expressing HBx, HBsAg, and HBcAg elicited antigen specific CD4 and CD8 T-cell responses in peripheral blood mononuclear cells from healthy individuals and in mice.[Kemmler 2012; Guo 2012]
Short-interfering RNA (siRNA) targeting HBV DNA or pregenomic RNA represents a therapeutic option that reduces viral load, allowing the immune system to more effectively clear the virus. Several proof-of-concept studies have shown that siRNA delivered to either HepG2 cells or mice models of HBV infection results in reduced viral antigen expression, viral transcripts, or viral DNA.[Li 2014a; Li 2014b; Giladi 2003; Huang 2014; Thongthae 2014] One promising system demonstrated successful targeting of siRNAs to hepatocytes in mice by coinjection of an N-acetylgalactosamine-conjugated melittin-like peptide with liver-tropic cholesterol-conjugated siRNAs targeted to conserved HBV gene sequences. In mouse models of chronic HBV infection, silencing of HBV transcripts reduced viral RNA, protein and DNA production.[Wooddell 2013] This RNAi system, termed ARC-520, is currently being evaluated in a phase II trial of patients with chronic HBV infection (Clinical Trial: NCT02065336).
The bile acid transporter Na+/taurocholate cotransporting polypeptide (NTCP) has recently been identified as an HBV entry receptor in hepatocytes and provides an attractive therapeutic target to block the initial stages of HBV infection.[Yan 2012] Several NTCP inhibitors are effective in inhibiting HBV infection including cyclosporine A,[Watashi 2014a; Nkongolo 2014] progesterone, propranolol, bosentan, ezetimibe,[Watashi 2014b; Lucifora 2013] and Myrcludex-B, a synthetic lipopeptide of the myristoylated region of preS1.[Petersen 2008] Following the success of Myrcludex-B’s demonstrated ability to inhibit NTCP transporter activity in the nanomolar range in cultured hepatocytes[Ni 2014] and prevent HBV infection in mice,[Petersen 2008] it is now being investigated in a phase II trial in Russia. Since it is likely that, even with NAs, new hepatocytes can still become infected, by combining virus entry inhibitors with NAs, a more effective way to eliminate the virus may be achieved in patients with chronic disease, especially in the case of blocking reoccurrence in patients receiving liver transplantation.[Urban 2014]