Review
Treatment of chronic hepatitis due to hepatitis B and hepatitis delta virus coinfection

https://doi.org/10.1016/j.ijantimicag.2019.09.012Get rights and content

Highlights

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    Hepatitis delta virus (HDV) infection rapidly evolves towards liver cirrhosis and hepatocellular carcinoma.

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    Interferon-based therapies have a modest impact on chronic HDV infection.

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    HDV offers no target for conventional antiviral agents.

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    Novel targets are virus entry, prenylation inhibition and HBsAg secretion.

ABSTRACT

An estimated 20–40 million individuals worldwide are infected with hepatitis delta virus (HDV), mostly with rapidly evolving liver disease. Therapy of chronic HDV infection remains an unmet need. To date, only interferon (IFN)-based therapy is recommended for HDV infection and response rates are unsatisfactory; in addition, many patients are intolerant to or ineligible for IFN treatment. In recent years, innovative approaches have been in development, including the following: targeting virus entry into hepatocytes; inhibition of the host enzyme farnesyltransferase by prenylation inhibitors, leading to inhibition of complete virion formation and release; blockade of hepatitis B surface antigen (HBsAg) secretion, inhibiting virus release; and IFN-lambda, which causes fewer adverse effects than IFN-alfa. Clinical trials are ongoing with encouraging preliminary results.

Introduction

Hepatitis delta virus (HDV) has an estimated global burden of 20–40 million chronically infected individuals; however, estimates are largely inaccurate due to the lack of systematic screening for HDV in hepatitis B surface antigen (HBsAg)-positive individuals [1,2]. Clusters of infection are still present in Eastern Europe, sub-Saharan Africa, South America and Asia [3,4]. In Western Europe, following a rapid decrease in prevalence over the period 1980–2000 [5], a re-emergence of chronic HDV infection has been noted, mostly due to immigration from endemic areas [6], [7], [8], [9]. Eight genotypes of HDV are known [10]; genotype 1 is ubiquitous and largely predominates in Europe, whilst the other genotypes have a typical geographical distribution. Superinfection by HDV in a chronic carrier of hepatitis B virus (HBV) generates a chronic infection in >80% of cases, which may evolve rapidly towards cirrhosis and hepatocellular carcinoma; simultaneous infection by the two viruses causes severe acute hepatitis that progresses towards chronic infection in <5% of cases [11]. HBV replication is suppressed in most chronically coinfected patients; in approximately 25% HBV may dominate or both viruses may fluctuate over time [12,13].

HDV is a unique human pathogen. Its small RNA (1.7 kb) encodes for only one protein, the hepatitis delta antigen (HDAg), in two forms, namely small (S-HDAg) and large (L-HDAg), whereas it lacks functional proteins that usually drive viral replication [14,15]. As such, HDV utilises human polymerase II and to some extent polymerase I to replicate and requires HBsAg to generate the complete virion, which uses the HBV cell receptor to enter hepatocytes. Further characteristics of HDV are: (i) the presence of ribozyme, a non-coding RNA typically present in plant virusoids and some viroids, that cleaves multimeric synthesised RNA into monomeric forms; and (ii) the use of host adenosine deaminase to convert adenosine to inosine on the antigenomic RNA; this causes a change of the UAG amber codon in the S-HDAg open reading frame (ORF) to a UGG tryptophan codon for the L-HDAg ORF [16]. Finally, prenylation at the CXXX box motif (where C represents cysteine and X any other amino acid) of L-HDAg by human farnesyltransferase is critical to promote its binding to HBsAg to generate the complete HDV virion (Fig. 1).

Due to its simple structure, HDV lacks the usual targets for most antiviral drugs, e.g. viral polymerase or other functional proteins. To date, the only drug registered for HDV infection is interferon (IFN) or pegylated interferon (peg-IFN). Innovative therapeutic approaches target non-replicative steps of the virus cycle, such as entry into hepatocytes or the prenylation process. In addition, some anti-HBV drugs that block HBsAg release have the potential to prevent the production of HDV virions. This brief review focuses on the results of IFN-based therapies and examines current data on new therapies.

Section snippets

Endpoints of treatment

Antiviral treatment in chronic HDV infection, as for other chronic viral hepatitis, is aimed at preventing the progression of liver disease and death. In clinical practice and in trials evaluating antiviral drugs, surrogate efficacy endpoints are measured. The ideal endpoint is sustained undetectability of HDV-RNA in plasma, which can be achieved following HBsAg clearance; a transient presence of HDV-RNA in plasma has been reported in a few cases following HBsAg clearance [17,18].

Interferon-alfa (IFN-α)-based therapies

Recombinant IFN-α was introduced for the therapy of chronic HDV infection in the mid-1980s. It was soon clear that the standard dose of 3 million units (MU) thrice weekly had poor efficacy and that 9 MU thrice weekly or 5 MU daily were required to reach some response in terms of viral suppression. Farci et al. showed that at higher doses, IFN-α resulted in long-term improvement of liver fibrosis in some patients [21]. Another cohort study demonstrated a long-term benefit in the rate of

Nucleos(t)ide analogues

Lamivudine, administered alone or in combination with IFN, was ineffective in inducing a decrease in HDV-RNA [46], [47], [48]. The same results were obtained with adefovir [33]. Current-generation analogues (entecavir, tenofovir) given alone for 24–96 weeks were also ineffective. In a well-designed randomised trial, tenofovir plus peg-IFNα for 96 weeks resulted in a better virological response at the end of treatment compared with peg-IFNα alone; however, the advantage was lost during the

Entry inhibitors

HBV enters hepatocytes through binding of the pre-S1 domain (S-HBsAg) of HBsAg with its receptor on the hepatocyte membrane, the sodium-taurocholate cotransporter peptide (NTCP), which drives the internalisation process [52]. HDV, being coated with HBsAg, utilises the same receptor (Fig. 1). Myrcludex B (MyrB; bulevirtide) is a synthetic N-acylated peptide derived from the pre-S1 domain that inhibits the HBV receptor on the hepatocyte surface and prevents the infection of healthy cells and

Prenylation inhibitors

These drugs target the host enzyme farnesyltransferase, which catalyses the farnesylation process at the carboxy edge of L-HDAg, thus making it able to bind HBsAg. Lonafarnib (LNF) was first introduced as an anti-leukaemia drug. Its use in chronic HDV infection was first assessed in vitro and in vivo in a mouse model [57,58]. In a phase 2A, randomised, proof-of-concept study, Koh et al. assigned 14 HDV patients to receive oral LNF at 100 mg (group 1) or 200 mg (group 2) twice a day or placebo

Blockade of hepatitis B surface antigen release/production

Nucleic acid polymers (NAPs) inhibit the release of HBV subviral particles; since HDV virions use the same secretion mechanism, a therapeutic effect on HDV infection was hypothesised. In vitro, these compounds blocked HDV infection in cultures of differentiated human hepatoma cells [61]. In a chronic duck HBV infection model in Pekin ducks, synergy with nucleos(t)ide analogues was noted [62].

Bazinet et al. treated 12 non-cirrhotic patients with chronic HDV infection (>6 months) with 500 mg of

Interferon-lambda (IFN-λ)

IFN-λ could be an alternative to IFN-α since it binds the type 1 IFN receptor that is prevalently expressed on hepatocytes; as a consequence, less systemic adverse effects are expected. In HBV/HDV-infected humanised mice, both IFN-α and IFN-λ reduced intrahepatic HDV infection markers [64]. In a phase 2 study, 33 patients with chronic HDV infection were randomised to receive peg-IFNλ at a dose of either 120 μg or 180 μg by weekly s.c. injection for 48 weeks; all patients also received daily

Conclusions

For decades, treatment for chronic HDV infection has been based on IFN-α, leading to unsatisfactory results. New therapeutic approaches provide some hope for the near future, since efficacy results surpassed those achieved with IFN and tolerability looked better than for IFN. Controlled trials are ongoing and will quantify the advantages. However, most studies still combine the new agents with peg-IFN, which involves the limitations of this treatment. IFN-λ could be an alternative since it

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