Hepatitis Delta Virus: Replication Strategy and Upcoming Therapeutic Options for a Neglected Human Pathogen

Abstract

The human Hepatitis Delta Virus (HDV) is unique among all viral pathogens. Encoding only one protein (Hepatitis Delta Antigen; HDAg) within its viroid-like self-complementary RNA, HDV constitutes the smallest known virus in the animal kingdom. To disseminate in its host, HDV depends on a helper virus, the human Hepatitis B virus (HBV), which provides the envelope proteins required for HDV assembly. HDV affects an estimated 15–20 million out of the 240 million chronic HBV-carriers and disperses unequally in disparate geographical regions of the world. The disease it causes (chronic Hepatitis D) presents as the most severe form of viral hepatitis, leading to accelerated progression of liver dysfunction including cirrhosis and hepatocellular carcinoma and a high mortality rate. The lack of approved drugs interfering with specific steps of HDV replication poses a high burden for gaining insights into the molecular biology of the virus and, consequently, the development of specific novel medications that resiliently control HDV replication or, in the best case, functionally cure HDV infection or HBV/HDV co-infection. This review summarizes our current knowledge of HBV molecular biology, presents an update on novel cell culture and animal models to study the virus and provides updates on the clinical development of the three developmental drugs Lonafarnib, REP2139-Ca and Myrcludex B.

Towards curative therapy of chronic viral hepatitis

“…1, ▶ Table 2). The only viral factor that could be therapeutically addressed is the HDAg or the two ribozymes, which are essential for HDV RNA replication [77]. Unfortunately, no such antiviral drug has been developed so far.…”

Abstracts

“…Blank et al 2 found that the concentration of Myr that blocks HDV entry is 100 times lower than that inhibiting bile acid transport. The drug is well tolerated with no dose limiting toxicity.…”

“…Although modest and transient increases of amylase and lipase occur, they are clinically uneventful and spontaneously resolved. Bogomolov et al 2 treated seven patients with Myr at a dose of 2 mg daily subcutaneously for 24 weeks. Therapy was accompanied by more than a 1 log 10 reduction in serum HDV RNA in four patients and by its clearance in two.…”

Targeting Hepatitis D

“…19 The HBsAg binds to the NTCP via the myristoylated Nterminal receptor site of the viral preS1 domain; 20 the binding is blocked in cell culture and in a humanized mouse model by synthetic lipopeptides that mimic the receptor site within the preS1 domain. [21][22][23] The first block-entry drug used in CHD is Myrcludex B (MyrB), a myristoylated synthetic N-acylated peptide of the preS1 domain of the HBV.…”

“…Further combination studies are currently in progress, with MyrB administered at three different doses (2-5-10 mg) together with tenofovir versus tenofovir alone for 24 weeks and together with IFN-α versus IFN-α alone for 48 weeks. 23 Studies in progress with LNF were also designed in combination with Peg IFN. In the LOWR HDV-2, patients are given low doses of LNF (75 mg, 50 mg or 25 mg twice a day) together with ritonavir, with or without Peg IFN for 12 to 24 weeks; 36 at week 24 of therapy, 25 mg LNF (plus 100 mg ritonavir) and Peg IFN had reduced serum HDV-RNA below the limit of quantification in five of five treated patients.…”