Viral hepatitis is an infection of the liver by one of several viruses. If it becomes a chronic illness it may lead to cancer or liver failure. The pharmaceutical industry is exploring many ways to find new medicines and vaccines to tackle this serious worldwide health problem.
Viral hepatitis is an infection of the liver caused by one of several viruses. Three such viruses cause severe disease: hepatitis A (HAV), transmitted by contaminated water, food or smear infection, is generally an acute disease that is only occasionally fatal, but hepatitis B (HBV) and hepatitis C (HCV), both transmitted through blood and body fluids, can lead to chronic infections that gravely affect a person’s health. Vaccines are available for the prevention of HAV and HBV, but so far not for HCV.
Throughout Europe, there is a considerable underestimate of the true incidence of HAV, as many cases, especially in young children (more than 70 per cent), show no symptoms. Contrary to these findings, more than 75 per cent of patients infected with HBV or HCV are in the age range 15-44. More than 400 million people around the world have HBV and approximately 170 million people suffer from HCV. Several strains of HCV are seen and these differ in their resistance to treatment.
Adults infected by HBV mostly develop an acute infection and subsequently recover, but about ten per cent develop chronic infection, which can progress to cirrhosis or to hepatoma, a form of liver cancer. Most of the patients suffering from chronic HBV worldwide have acquired the virus at birth or in early childhood. The poorest prognosis of the disease goes along with genetic mutations to the core promoter and/or pre-core region of the virus genome. This occurs 10-20 years after the onset of the infection and is characterised by loss of the HBe antigen. For this reason doctors differentiate two forms of chronic HBV: HBeAG-positive and HBeAG-negative infection.
HBeAG-negative chronic HBV – also known as “variant” or “pre-core mutant” disease – has so far been less responsive to therapy and progresses faster towards cirrhosis. In the past ten years, there has been a dramatic increase in the prevalence of this form of the disease. It is estimated that in Southern Europe HBeAG-negative chronic HBV accounts for 80 per cent of cases.
Persistent infection with HCV is one of the main causes of liver-related mortality and the main reason for liver transplantations in Europe. The number of those chronically infected with HBV or HCV in Europe is not accurately known, but is estimated at three per 10,000 of the population, with a somewhat higher prevalence of HCV in Southern Europe. Altogether, this would equal nearly 1.5 million people.
To prevent HAV and HBV, there is a combined HAV+HBV vaccine, and two infant combination vaccines that include HBV along with other childhood vaccines are also available.
The aim of chronic HBV therapy is to suppress replication of the virus and prevent disease progression. The ideal aim is sustained clearance of the HBV surface antigen (HBs-AG), as this is associated with improved long-term outcomes. Two medicine classes, with different mechanisms of action, are used in HBV management: nucleoside/nucleotide analogues and interferons.
The five nucleoside/nucleotide analogue compounds currently available act by blocking HBV DNA polymerase, an enzyme involved in the replication of HBV. The agents are usually administered for extended periods of time, because they effectively suppress and maintain undetectable levels of HBV DNA. However, the rate of HBs-AG clearance is low and resistance may develop with prolonged therapy. Treatment with conventional interferon, pegylated interferon alfa-2a and pegylated interferon alfa-2b has a dual mode of action. In addition to inhibiting HBV DNA replication, the compounds have an immunomodulatory effect which supports the body’s own immune system in attacking the virus.
The current standard of care for chronic HCV infection is the combination of pegylated interferon plus the nucleoside analogue compound ribavirin. The goal of therapy is eradication of HCV, as indicated by sustained virological response (SVR), which is defined as undetectable HCV RNA by polymerase-chain-reaction (PCR) assay in serum 24 weeks after the end of therapy. The vast majority of patients with an SVR remain virus free for several years.
Though it is possible to eradicate HCV, SVR rates vary widely – from excellent: 80 per cent, to less than satisfactory: 20 per cent - depending on HCV genotype and patient characteristics. Thus there is a need for new therapeutic agents to increase response rates in difficult-to-cure patients and potentially to shorten treatment durations as well as decreasing side effects of the therapy.
There are Phase 3 trials in progress to extend the use of nucleotide analogues in HBV to children in the age range 2-16 who may have contracted the disease as a result of transmission from their mother. Another antiviral blocking HBV DNA polymerase is in Phase 3 trial for the treatment of patients who do not respond to other nucleotide analogues. The new compounds may also reduce the overall treatment period from 48 to 24 weeks. It is also hoped that the development of new compounds will result in an all-oral combination therapy.
Direct Acting Antiviral (DAA) Therapies designed to inhibit the HCV serine protease and the RNA dependent RNA polymerase have recently entered clinical development. Initial trials of DAAs have shown promising results, but when used alone, some of these agents have been associated with the rapid development of viral resistance.
Patients treated with a combination of pegylated interferon plus nucleoside analogue without achieving undetectable serum levels of HCV RNA may benefit from the accompanying therapy with a newly-found inosine monophosphate dehydrogenase inhibitor. In a Phase 2 clinical trial, a compound of this type gave a dose-dependent antiviral response when used in combination with pegylated interferon plus a nucleoside analogue after six months. Patients had previously been treated for at least 12 weeks without achieving undetectable levels of HCV RNA.
Other new investigational strategies include targeted delivery to the liver. Also, an oral form of caspase enzyme inhibitor is in Phase 3 clinical trial. Caspase enzymes have been shown to mediate apoptosis (programmed cell death) and to be implicated in liver diseases.
Interesting projects are underway in the vaccine area: one is a DNA-based vaccine for the prevention of HBV. It is believed that vaccinating with DNA coding for HBV antigens will be an efficient alternative to the more usual vaccines that employ recombinant protein and may induce cellular, as well as antibody-based, immunity. Two vaccines for the treatment of established HBV infections are under investigation. Another two DNA vaccines encoding genetically modified proteins from the surface of HCV have entered Phase 1 clinical trials. They are supposed to elicit an immune response to prevent infection with HCV.
Some approaches at an early stage of exploration include the pre-clinical development of an inhibitor of a key HCV enzyme called helicase. In addition, an antisense compound is being explored that may inhibit viral replication; this is undergoing early clinical investigation in patients with chronic HCV.
Research also is pursuing the development of new thiophene-2-carboxylic acid derivatives to inhibit the HCV-NS5B protein. This is the primary catalytic enzyme of the HCV replicase complex, an RNA-dependent RNA polymerase which is believed to be responsible for the genome replication of HCV.
Recent research findings on how HCV hides itself from the human immune system may open new avenues for medical treatment of persistent infection: Apparently, the virus uses a protease called NS3/4A to neutralise human enzyme interferon-regulatory-factor 3 (IRF-3), which would orchestrate the spectrum of countermeasures mounted by the human body against viral infections.
Development of an effective and affordable vaccine against HCV is highly desirable. Like HIV, the virus is known to undergo continual rapid mutation and so far the development of a therapeutic vaccine remains a challenging project.
The development of medicines to treat HCV has been slowed by the absence of a cell culture system for studying viral replication. Research groups have succeeded in constructing a full-length HCV genome using sequences from two different viral strains. The scientists found that the newly combined (chimeric) virus could replicate to high titres in cultured human liver cells. This finding may open another new avenue for the research and development of new treatments against HCV.