Author(s): Gregor Ebert [*] aff1 , Marc Pellegrini aff1
apoptosis; cancer drugs; HBV; immune modulation
HBV infection & its consequences
Currently, persistent chronic HBV infection is an incurable disease. The infection specifically targets the liver and it has affected an estimated 2 billion people worldwide. HBV infection is associated with an increased risk for patients of developing liver cirrhosis and hepatocellular carcinoma (HCC) [1 ]. The majority of people infected with HBV are able to control and suppress viral replication, but nonetheless they are still at higher risk of developing HCC compared with the general population. A proportion of patients develop a persistent active infection and associated hepatitis that can progress, if left untreated, to cirrhosis and HCC. HBV infection is responsible for 50 and 33% of deaths related to liver cancer and cirrhosis, respectively [2 ]. As a result, HCC is now one of the leading causes of cancer-related deaths worldwide.
Current antiviral therapies for chronic HBV infection
Despite the fact that a safe and very effective preventative vaccine against HBV infection was introduced in 1982, about 360 million people worldwide remain chronic carriers of the virus [1 ]. The vaccine has no efficacy in treating people that have already acquired infection. Approved therapies for chronic HBV infection include pegylated IFN-[alpha], which is an immunomodulatory drug, as well as nucleotide or nucleoside analogs (NUCs) that act as reverse transcriptase inhibitors blocking viral replication. IFN-[alpha] therapy is associated with low response rates and its use is associated with several side effects. Although NUCs are potent drugs that are well tolerated and show excellent efficacy in suppressing viremia, they are not capable of inhibiting hepatitis B s-antigen or e-antigen (HBsAg, HBeAg) production. Treatment with some NUCs, such as lamivudine, is often associated with the development of drug-resistant HBV mutants. Fortunately, resistance has not yet developed to the latest generation of NUCs.
Nevertheless, none of the present therapies are capable of eliminating all HBV genome from the liver and consequently viral rebound can occur following cessation of treatment. Even in people that suppress viremia, spontaneously or following drug treatment, viral rebound can occur if patients become immunosuppressed. Covalently cccDNA, an episomal replicative form of HBV-DNA, persists in the nucleus of infected hepatocytes, triggering relapses in the aforementioned situations. Therefore, lifelong daily treatment with NUCs is the current recommendation [3 ].
The ultimate goal of HBV treatment is the elimination of cccDNA, the replicative template and main driver of persistent active infection. There is an urgent and unmet need for new therapies that eliminate all persistent HBV genome capable of reactivating viremia. Such treatments would mitigate the morbidity and mortality associated with chronic HBV infection.
Progress in defining novel therapeutic for chronic HBV infection
Novel antiviral drug approaches include the attempt to inhibit HBV entry into hepatocytes and hence abrogate the spread of HBV throughout the liver. A very promising study is a Phase IIa clinical trial using a recombinant myristoylated form of the HBV pre-S peptide (Myrcludex B). In preclinical models this...