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Hepatitis is an inflammation of the liver caused by toxic substances or – in the majority of cases – by viruses. To date, five viruses have been identified that target the liver and cause inflammatory infection. These viruses are referred to by the letters A, B, C, D and E, and vary according to their transmission mode (fecal-oral for A and E, parenteral for B and C) and their aggressive profile.
When hepatitis viruses attack the liver, they invade its cells, known as hepatocytes, where they multiply. The immune system, which provides the body's defense response, destroys the infected cells, causing inflammation of the liver. Contamination by this virus may result in characteristic symptoms of acute inflammation of the liver, and these can last several weeks. The symptoms include yellowing of the skin and eyes (jaundice), dark urine, pale stools, extreme fatigue, nausea, vomiting and abdominal pain. It is not possible to distinguish the various forms of hepatitis solely based on the symptoms of the acute phase of the disease.
In contrast to hepatitis A and hepatitis E, the hepatitis B and C viruses may lead to chronic infection, which means that the individual does not manage to eliminate the virus and, many years later, may develop serious complications of chronic hepatitis: cirrhosis and chances to develop cancer of the liver.
The hepatitis A and B viruses were identified in the 1960s and 1970s, while hepatitis C and E – formerly known as "non-A and non-B hepatitis" – were identified more recently, in 1989-90.
Hepatitis B is one of the most prevalent human diseases. It is estimated that 2 billion people have been infected by the virus, including over 370 million chronic carriers, able to transmit the virus over many years. Chronic carriers have a high risk of dying from cirrhosis or cancer of the liver. These diseases cause about a million deaths annually.
Acute hepatitis B is often asymptomatic, or causes flu-like symptoms (loss of appetite and digestive problems, nausea, vomiting, fatigue, fever). One in three infected people present characteristic symptoms of acute inflammation of the liver (jaundice, dark urine, pale stools). The incubation period for hepatitis B varies between 45 and 180 days, with an average of 60 to 90 days.
It should be stressed that almost one in ten people do not recover from hepatitis B, and it becomes a chronic infection. This figure is even higher in infants and young children. Most chronic carriers do not present obvious symptoms, despite showing signs of liver inflammation and being able to contaminate their immediate circle.
In most developing countries (sub-Saharan Africa, a large part of Asia and in the Pacific region), chronic carriers account for 8 to 15% of the population. In these regions, liver cancer caused by hepatitis B is among the three highest causes of cancer-induced death in humans. The Amazon region and Southeastern and Central Europe are also heavily affected. In the Middle East and the Indian subcontinent, chronic carriers account for about 5% of the population. Infection is less common in Western Europe and North America, where chronic carriers account for less than 1% of the population. In France, it is estimated that about 300,000 people are chronic carriers of the hepatitis B virus (HBV), of whom 9% are also infected with HIV.
The hepatitis B virus is transmitted via all biological fluids and secretions, usually via sexual contact and blood. Hepatitis B is deemed to be an extremely contagious infectious disease, and is between 50 and 100 times more infectious than the AIDS virus. The main transmission routes are sexual contact, high-risk injections (intravenous drug users) and transfusions, transmission from mother to child during labor and close contact with an infected person. Statistically, the most common transmission modes throughout the world are from mother to child, between children within the same family and the re-use of non-sterile syringes and needles.
In many developing countries, almost all children are infected by the virus. Hepatitis B cannot be transmitted by contaminated food or water, nor by casual contact in the workplace.
There is no drug treatment for acute hepatitis that improves the chances of recovery. The efficacy of so-called hepatoprotective products – in other words products to protect the liver – has not been proven. An infected person must wait until his or her own defense system naturally overcomes the virus. As long as recovery is not complete, the natural bodily fluids and secretions (blood, semen, vaginal secretions, saliva, etc.) remain contagious. Once recovery from hepatitis is complete, the liver returns to normal and there is lifelong protection against this disease.
In some people, chronic hepatitis B is treated with interferon-alpha and antiviral drugs such as Lamivudine, Adefovir or Entecavir. The cost of these treatments, however, amounts to thousands of euros, and keeps them out of reach for patients in developing countries. In addition, viruses are constantly developing resistance to these treatments. A liver transplant may be carried out in the case of cirrhosis.
Given the low efficacy of the available treatments, vaccination against hepatitis B is the primary reliable, large-scale measure to protect people against this disease. Highly effective hepatitis B vaccines have been available since 1981, including one developed by the Institut Pasteur (GenHevac B). Three injections with this vaccine convey protection against the hepatitis B virus in 98% of vaccinated individuals. Protection lasts at least ten years – and probably for life – in 90% of vaccinated individuals. This vaccine also prevents the serious complications of acute fulminant hepatitis, cirrhosis and liver cancers.
At the Institut Pasteur
The Pathogenesis of Hepatitis B Virus Laboratory (Institut Pasteur/Inserm 845), led by Marie-Louise Michel, is studying the immune response to various viral proteins in infected individuals. Scientists have designed a therapeutic vaccine candidate for chronic carriers of the virus, a combination vaccine associating DNA and antivirals. It is currently undergoing phase II clinical trials under the aegis of the French National Agency for AIDS Research (ANRS). Another of the team's key lines of research focuses on the mechanisms involved in inflammation and regeneration of the liver in animal models.
As part of the Epidemiology of Emerging Diseases Unit, Muriel Vray is coordinating a study on vaccine coverage of children under five in Senegal and the Central African Republic.
Working within the Hepacivirus and Innate Immunity Unit, Christine Neuveut is establishing the identification of cell effectors involved in the replication and pathogenesis of HBV.
The hepatitis C virus (HCV) was identified in 1989 as the major cause of post-transfusion hepatitis. It was formerly known as "non-A, non-B hepatitis".
HCV is classified as a separate genus (hepacivirus) within the large Flaviviridae family. This family includes many other major viruses seen in the medical or veterinary fields, such as those responsible for yellow fever, dengue, West Nile virus (flavivirus genus) or bovine virus diarrhea (pestivirus genus). Humans and chimpanzees are apparently the only species susceptible to infection by the hepatitis C virus.
Replication of the viral genome gives rise to numerous errors, resulting in the circulation of a great many viral molecular species in the human population. The viral variants identified to date are grouped into 7 genotypes, which have variable susceptibility to treatments.
Acute hepatitis C develops after an incubation period averaging between six and ten weeks. It is largely asymptomatic. Symptoms that do occur are similar to those of other forms of viral hepatitis (fatigue, nausea, pains followed by dark urine and jaundice). Measurement of concentrations of transaminases in the blood shows that the liver is relatively unaffected at this stage. Occasionally, HCV infection may trigger acute liver failure, known as fulminant hepatitis.
Full recovery is confirmed by tests showing absence of the virus in the blood for more than six months following acute infection, as well as the presence of HCV antibodies. It is acknowledged that only 15 to 35% of cases of acute hepatitis C end in recovery, irrespective of whether or not they are symptomatic, while 65 to 85% of infected patients go on to develop chronic infection. This can lead to progressive deterioration of the liver, and subsequently to cirrhosis. In Europe and North America, the risk of this development is estimated at 20% ten to twenty years after infection. The percentage is reportedly higher in Japan.
Three main factors influence the risk of cirrhosis: the duration of the chronic viral infection, age when first infected and level of alcohol consumption, with high intake an exacerbating factor. From the cirrhosis stage, there is a high risk of development of hepatocellular carcinoma, the rate being between 1 and 4% per year. Cirrhosis resulting from hepatitis C is a major indication for liver transplant. The development of effective anti-HCV therapies for transplant patients is currently in progress, and is based on inhibiting reinfection of the healthy donor liver by the patient's HCV virus. This is expected to increase the overall survival rate of transplant patients with cirrhosis C (currently in the order of 70% five years after the transplant).
Current epidemiological data places the figure for chronic carriers of the hepatitis C virus at between 130 and 170 million people worldwide, with an average seroprevalence of around 2.2 %. This prevalence varies depending on the country: it is very low in Northern Europe, but higher in Southeast Asia and Africa, with over 20% in Egypt. The World Health Organization estimates theannual number of deaths from hepatitis C infections at nearly 350,000.
In France, the number of HCV seropositive cases is estimated at about 400,000, of which 65% involve chronic infection. There are 4,000 new cases annually. It is estimated that 24% of patients infected with human immunodeficiency virus (HIV) are also infected with HCV.
The silent advance of the disease and high incidence of chronic infection explain why there is such a large reservoir of infected individuals.
The hepatitis C virus is mainly transmitted through blood (transfusion, intravenous drug use, organ transplant).
Transmission via blood transfusion is now under control in developed countries, but was the most common transmission mode prior to the introduction of screening systems for donated blood in 1991. It is estimated that high-risk injections (particularly among drug users) using non-sterile equipment and the transfusion of contaminated blood products cause two million new cases of hepatitis C virus infection each year worldwide.
The risk of materno-fetal transmission for HCV is around 5% if the virus is detectable in the mother's blood at the time of birth. Although sexual transmission remains controversial, it has never been excluded. HCV/HIV co-infection is an increasing problem in countries with HIV epidemics and among intravenous drug users. Approximately 10% of hepatitis C cases are classified as "sporadic", since there are no discernible associated risk factors.
The current treatment combines pegylated interferon-alpha and ribavirin. This treatment, which sometimes produces serious adverse effects, is used only in 15 to 30% of cases, and is not recommended in the acute phase of the disease, which generally resolves spontaneously. Treatment is administered for chronic infections, when hepatic fibrosis becomes significant. The duration of treatment (6 to 12 months) depends on several different factors, including the nature of the viral genotype. Treatment is considered successful when viremia (the presence of the virus in the blood stream) is not detectable and transaminases are persistently normal for at least six months following the end of treatment (sustained virological response). Overall treatment efficacy is 80% in cases of infection by genotypes 2 or 3, but is around 45% in cases of infection by the viruses most resistant to treatment (genotype 1).
New therapeutic approaches that specifically target the virus have been developed over the last few years as a result of improved understanding of the structure and function of viral proteins. Recent clinical trials combining interferon-alpha and ribavirin with various, chemically synthesized small molecules, aiming to block a specific viral enzyme (in particular the major protease) have shown a clear 20% increase in recovery rate in patients infected with genotype 1 HCV. This represents a sustained virological response of around 60-70%. Anti-HCV triple therapy is now available, combining interferon-alpha, ribavirin and a chemical inhibitor targeting the major HCV protease. However, the cost of this triple therapy being very high (about €40,000) it is out of reach for patients in developing countries. Various other anti-HCV molecules, which target polymerase or other non-structural viral proteins, are continually undergoing clinical trials in an effort to expand the therapeutic arsenal against this infection. In addition, there are efforts to develop the production of certain natural products that have proved effective against HCV, and research on therapeutic and preventive vaccines continues.
There is currently no vaccine against hepatitis C. The most effective means of fighting the disease is based on controlling the risk of nosocomial HCV transmission (blood transfusions, high-risk injections, etc.) and a risk reduction policy for intravenous drug users. Screening of high-risk groups, in particular people who received blood products before 1992, is also an important factor in the fight against this infection.
At the Institut Pasteur
The Hepacivirus and Innate Immunity Unit, led by Eliane Meurs, is studying the modes of interaction of HCV and HBV with their common host (hepatocytes), with the aim of developing new approaches to inhibit their replication, propagation and persistence in the host. Key projects include the characterization of interactions of the hepatitis C virus with components of the cellular innate immune response pathway (group led by Eliane Meurs), characterization of the mechanisms involved in HCV cell entry and its intracellular transport (group led by Agata Budkowska) and characterization of cellular effectors involved in HBV replication and pathogenesis (group led by de Christine Neuveut).
The Epidemiology of Emerging Diseases Unit, led by Arnaud Fontanet, is conducting a study of the epidemiology and treatment of HCV in Egypt, which has the world's highest prevalence of HCV infection, affecting 45% of people over 40 in rural areas. The team is coordinating the ANRS research site on viral hepatitis in Egypt. The Dendritic Cell Immunobiology Unit, led by Matthew Albert, is participating in this project, and is particularly focusing on biomarkers involved in spontaneous recovery from acute hepatitis C (SPHINX project, funded by the European Community).
In addition, an international research program on HCV, initiated by the Institut Pasteur International Network management, is being coordinated at the Institut Pasteur by Pascal Pineau, of the Nuclear Organization and Oncogenesis Research Unit, and by Vincenzo Barnaba, Angela Santoni (University of Rome), Penelope Mavromara (Hellenic Institut Pasteur, Athens, Greece) and Sergei Mukomolov (Institut Pasteur in Saint Petersburg). These various groups and Institut Pasteur units are brought together in a consortium entitled DHEVIRT (Decoding HEpatitis VIrus-Related Tumors). The consortium is studying the interactions between HBV or HCV and their tissue microenvironment (liver, lymphoid tissue) in order to characterize the elements that trigger the process of tumorigenesis and identify tools that could be used in a clinical setting.
Illustration – Copyright Institut Pasteur
Caption – Hepatitis B virus (HBV) under electron microscopy. Chronic hepatitis B can cause cancer and cirrhosis of the liver.