Superinfection therapy

Curing chronic hepatitis B virus (HBV) infection by viral superinfection therapy (SIT) without life-long treatment

Global morbidity and mortality from hepatitis B virus (HBV) infection remain a major public health burden

Viral hepatitis deaths from acute infection, cirrhosis, and liver cancer have risen from the tenth to the seventh leading cause of death worldwide between 1990 and 2013. About 250 million individuals are chronically infected with hepatitis B virus (HBV) and close to 700 thousand people die every year due to complications of hepatitis B, including cirrhosis and liver cancer. Complete cure of chronic HBV infections with currently available therapies cannot be achieved for most patients, only permanent immune control meaning cessation or decrease of replication of the virus, which results in slower progression or no progression of the hepatic disease. Patients need long-term, continuous treatment. The treatment is costly and even a short-term suspension may result in progression or worsening of the hepatitis. A compounding problem is that approximately 1 in every 3 individuals worldwide may have been exposed to HBV infection. Importantly, after recovery from HBV infection, a covalently closed circular DNA (cccDNA) episome can persist in a latent state for decades in infected cells as a reservoir for HBV reactivation in any individuals who have been infected with the virus. Current anti-HBV treatment cannot eliminate the viral cccDNA and emergence of resistance remains a problem. HBV reactivation may occur from latent episomal cccDNA reservoirs following cessation of therapy, patient non-compliance, the development of escape mutants, during hepatitis C virus (HCV) DAA therapy, cancer chemotherapy, immunosuppressive therapies for the management of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions, solid-organ or bone marrow transplantation. Therefore, despite effective HBV vaccines and HBV therapies, HBV will remain a major public health burden in terms of global morbidity and possibly mortality for decades to come.

Systemic recombinant interferon alpha (IFN-α) is the only therapy that can eliminate cccDNA of HBV but has severe side effects

Host directed therapy (HDT) is an emerging anti-infective approach. HDT interferes with host cell factors that are required by a pathogen for replication or persistence, in order to enhance protective immune responses. HDTs administering interferons have been well established for the treatment of chronic viral hepatitis. In fact, administration of recombinant interferon alpha (IFN-α) or its pegylated derivatives remains the only HDT drugs licensed for management of chronic HBV infection because it can eliminate cccDNA of HBV. Unfortunately, the severe side effects of systemic IFN treatment, which include influenza-like symptoms with fever and fatigue, depression, bone marrow suppression, exacerbated autoimmunity and, mainly due to ribavirin, hemolytic anemia, represent a major shortcoming of this therapy.

Gene-based therapies to disable cccDNA directly

Gene therapy enables the durable expression of immune modulators to attenuate cccDNA. Expression of IFN-α-encoding sequences in the liver has been explored as a means of improving anti-HBV efficacy and reducing side effects of conventional IFN-α treatment. An alternative quasi gene therapy strategy is using double stranded RNA (dsRNA) viruses, which are efficient inducer of endogenous IFN-α/β via a signaling cascade that leads to the activation of several hundred IFN-stimulated genes (ISGs).

Consistent with this, it was recently proposed that the activation of endogenous innate immune response by viral vectors via TLRs could be a HDT strategy for the functional cure of persistent viral infections such as HBV and for the development of broad-spectrum antivirals against emerging viruses. This strategy exploits one of the outstanding characteristics of viruses that they have very restricted cellular and host tropism. Actually, the Infectious Bursal Disease Virus (IBDV) superinfection therapy is a clinically validated HDT, which does not require life-long therapy in HBV patients.

Superinfection therapy is based on clinical observations that unrelated viruses might interact in co-infected patients

Viral Superinfection therapy (SIT) exploits viral competition for the treatment of acute and persistent viral infections. SIT is an innovative HDT, which boosts the interferon-dependent antiviral gene program by an attenuated IBDV, a non-pathogenic avian double-stranded (ds) RNA virus. The idea is based on clinical observations that unrelated viruses might interact in co-infected patients. Hepatitis infection, for example, by one type of virus (e.g. HBV) is often abolished following accidental infection by a second hepatitis virus (e.g. HCV). The dominant virus interferes with the replication of the other virus. Nevertheless, in cases when both viruses are pathogenic the disease persists and hepatitis remains. However, the patient may benefit from superinfection with a non-pathogenic dsRNA virus such as the IBDV. IBDV interacts with appropriate cells such that its dsRNA is recognized by specific receptors (e.g. TLR3). These activate several gene families from within. This is a major difference between systemic IFN-based and superinfection therapy. Fortunately, even the wild type IBDV is not known to be a hazard in transmitting to species other than poultry despite its worldwide distribution in the domestic fowl. The scientific rationale of this project proposal has been published (Bakacs, et al., 2018) (Kovesdi and Bakacs, 2019).

HepC develops a new IBDV drug candidate (R903/78) for a broad-spectrum post-infection oral antiviral therapy

A conventionally produced IBDV vector (V903/78) was already shown to be safe and effective in patients infected with two completely different viruses, the hepatitis B (DNA) and hepatitis C (RNA) viruses (HBV/HCV). The proof of SIT concept was demonstrated in a preliminary clinical trial that included 42 acute HBV and HCV patients. Most importantly, SIT was also safe and effective in two HBV and two HCV patients suffering from parenchymally decompensated chronic hepatitis with various life threatening complications, e.g. portal hypertension, diuretic resistant ascites, progressive jaundice, generalized edema, hepatic encephalopathy, etc. During IBDV treatment, all four patients went into long lasting remission with spectacular clinical improvement, while conventional therapy were unable to stabilize the conditions of these patients. A striking feature of SIT was the regeneration of the cirrhotic liver over several years of follow up. Since reproducible manufacture of homogeneous IBDV drug substance that satisfies both FDA and EMA regulatory requirements could not be met by conventional virus production, a new viral drug candidate, R903/78, was created by using reverse genetics. Therefore, all preclinical studies had to be repeated.

Based on recommendation of The National Institute of Pharmacy and Nutrition (OGYÉI) HepC Inc focuses on superinfection therapy of chronic HBV infection

We had already a meeting with the experts of The National Institute of Pharmacy and Nutrition (OGYÉI), who support the SIT program.

Based on their recommendations we will complete the preclinical studies including the study of the mechanism of action of viral interference in vitro and in vivo (developing animal models). We will measure the activation of IFN-stimulated genes (ISGs) by our R903/78 drug candidate. We will demonstrate that our attenuated R903/78 drug candidate does not cause disease in chickens. Following the completion of the preclinical studies we will prepare an Investigational Medicinal Product Dossiers for the EMA Innovation Task Force Meeting in order to obtain permission for a Phase I clinical trial. We wish to develop an animal model for the study of the mechanism of action of viral interference between our viral R903/78 drug candidate and other viruses. We wish to make a Vero cell line Master Cell Bank (MCB) and Working Cell Bank (WCB), and then start virus production by fully GMP run. Quality control will be performed as required by testing the drug candidate for contaminants. A preclinical dossier for Phase I clinical trial will be prepared. To this end, we will be advised by a regulatory consultant and OGYÉI. We plan a Phase I safety and efficacy study of Infectious Bursal Disease Virus Antiviral Biologic Product (R903/78) for the host-directed superinfection therapy of patients with HBeAg negative chronic hepatitis B as add-on therapy combined with standard NA treatment. We will recruit 10-15 HBV patients in clinically good condition.


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