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.