THE GORDON WILSON LECTURE: THE HEPATITIS C VIRUS: FROM HIPPOCRATES TO CURE.

The modern age of viral hepatitis began in the early 1960s with the serendipitous discovery of the Australia antigen, a protein that was later shown to represent the envelope of the hepatitis B virus leading to its designation as the hepatitis B surface antigen. This was the first marker for any hepatitis virus and became not only a diagnostic assay, but also a mandatory blood donor screening test and the basis for the first generation hepatitis B vaccine. Prospective studies of transfusion recipients then showed that hepatitis B virus accounted for only 25% of cases of post-transfusion hepatitis (PTH). Discovery of the hepatitis A virus in 1975 revealed that none of the non-B PTH cases were due to hepatitis A virus infection resulting in the designation of this predominant form of PTH as non-A, non-B hepatitis. Using pedigreed patient samples and the chimp model, it was shown even before the advent of molecular biology that the non-A, non-B agent was small and lipid enveloped suggesting it might be a flavivirus. This was confirmed when the agent was cloned by Houghton and colleagues at the Chiron Corporation in 1987 and renamed the hepatitis C virus (HCV). In 1990 a donor screening assay for HCV was introduced nationwide and by 1997 PTH had virtually disappeared with rates now mathematically estimated to be one case per 2 million transfusions, compared to a 30% incidence before 1970. Clinical and molecular studies of HCV have shown that it results in persistent infection in 75% to 85% of cases due to its high replication rate, its existence as a quasispecies with a high mutation rate and the ability of HCV proteins to blunt and ultimately exhaust the HCV immune response. Although HCV infection is clinically and histologically mild in most patients, it can lead to progressive fibrosis over the course of decades in 30% to 40% and culminate in cirrhosis and end-stage liver disease. HCV can also cause hepatocellular carcinoma, generally on the background of cirrhosis with an incidence of 1% to 3% per year in this setting. After 2 decades of difficult and prolonged treatments with interferon-based regimens that resulted in cure rates of less than 50%, successive generations of HCV specific direct-acting antivirals were introduced that now result in cure rates of 95% to 100% across all genotypes after only 8 to 12 weeks of nontoxic oral therapy. This unprecedented efficacy has led to speculation that HCV infection might be eradicated even in the absence of a vaccine, but there are many impediments to global eradication including ascertainment of silent carriers, access to medication, and high drug cost. Nonetheless, we are in a new era of HCV control and optimism abounds.

Chapter 6.1. Pediatric Chronic Hepatitis B and C: 30 Years of ESPGHAN Clinical Research and Recommendations.

The expression of hepatitis B and C virus infections in children differs from that in adults and requires specific paediatric expertise. The European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) has been a pioneer in this field, having stressed the need for straightforward recommendations since the mid-1980s. Following much observation, surveillance, and research, a panel of ESPGHAN experts was able to develop such recommendations on hepatitis B infection in children in 2009, which was then followed in June 2013 by proper guidelines. In the field of Chronic Hepatitis C, in 2011 ESPGHAN experts published also the Guidance for Clinical Trials for Children and Adolescents, and approved in 2012 the NASPGHAN guidelines for treatment. The ESPGHAN Society is to be commended for its pioneering work in furthering our understanding of chronic hepatitis B and C disease presentations in infants, children, and adolescents.

[Interferon in the treatment of viral hepatitis. The interferon was discovered 50 years ago]. / Interferon a vírushepatitis kezelésében. 50 éve fedezték fel az interferont.

The interferons are heterogenic glycoproteins which are produced on the effect of virus infection, as immune answer, by the living cells. They were discovered half a century ago. They have antineoplastic, antiviral and immunomodulator effect. The names of interferons used in the therapy are nominated with Greek letters. This nomination shows their origins: the interferon-alpha originates from leucocytes, the interferon-beta does from fibroblasts and the interferon-gamma is produced as immune interferon by lymphocytes. In human medicine both natural and recombinant interferons are applied. The connection of polyethyleneglycol to interferons ensures their sustained effect. Nowadays they are applied in the therapy of chronic hepatitis B or C as well as in oncology to inhibit the neoplasm progression.

Treatment of chronic hepatitis C infection: one step at a time.

Non-A, non-B hepatitis was recognised as an important cause of chronic liver disease long before the aetiological agent-hepatitis C virus-was identified in 1989. Recombinant interferons, initially developed as a treatment for malignancies, proved to be an effective treatment for this disease before the identification of the viral agent. Subsequent testing for hepatitis C virus RNA demonstrated that the virus appeared to be eradicated in a small proportion of treated patients. Treatment regimens have improved dramatically since 1989 with the addition of the oral nucleoside ribavirin and long-acting pegylated interferons to treatment regimens. Currently, more than half of treated patients can achieve durable viral clearance. This clearance is quite a remarkable feat; indeed, eradication is not possible in any other chronic viral infection. Considerable effort continues to be devoted to improving therapeutic regimens to make them more effective and tolerable. Drugs that directly act on the replicative machinery of the virus-protease and polymerase inhibitors-are under development and entering clinical trials in human beings.