Hepatitis C virus: from discovery to eradication in 40 years?

Abstract

Hepatitis C virus (HCV) was discovered in 1989 by Michael Houghton and coworkers. This discovery represented the first time that a new virus was identified using exclusively molecular biology techniques from the blood of an experimentally infected chimpanzee. The development and widespread use of a first-generation ELISA assay, and then of more sensitive enzyme immunoassays and of molecular biology-based techniques, for the detection of HCV RNA in body fluids revealed that HCV was highly prevalent worldwide and responsible for the vast majority of cases of so-called non-A, non-B and cryptogenetic chronic hepatitis. Twenty years later, where are we? In fact, very few medical fields have witnessed such rapid progress over such a short period, as eradication of HCV infection can now be foreseen within the next 20 years, at least in wealthy countries that will be able to afford the cost of modern therapies. Worldwide, almost 200 million individuals are infected with HCV. Although HCV is ubiquitous, the prevalence of infection varies from one area to another, as discussed by Lavanchy in this issue of the journal. HCV most likely originates from Africa or Asia, where the heterogeneity of HCV viral strains is greatest. Transmission in other areas of the world has occurred mostly through blood transfusion, intravenous drug use and unsafe medical or surgical procedures. Blood screening and prevention of viral transmission in intravenous drug users have considerably decreased, but not eradicated, HCV transmission. Therefore, acute cases are rarely seen nowadays, except in specific areas of very high endemicity, such as regions in rural Egypt. Before the discovery of HCV, Hoofnagle et al. had shown that interferon (IFN)-a was able to normalize alanine aminotransferase levels over the long term in patients with chronic non-A, non-B hepatitis. IFN-a was initially used at a dose of 3 million units three times per week for 6 months. Unfortunately, only 6% of patients receiving such treatment were able to achieve a sustained virological response (SVR), defined by undetectable HCV RNA 24 weeks after the end of therapy. The good news was that, in these patients, infection was definitively cured. Extending therapy for an additional 6 months led to an increase in overall SVR rates to 10%. A major advance in HCV therapy was the introduction of ribavirin, which, when given in combination with IFN-a, increases the SVR rates up to 40% overall. The rationale was that ribavirin is a nucleoside inhibitor that has antiviral activity against various DNA and RNA viruses. It is now known that this mechanism is unable to account for the anti-HCV effect of ribavarin. Ribavirin accelerates the clearance of infected cells, prevents relapses, and, in patients responding to IFN-a, transforms an IFN-based antiviral response into a cure, although the underlying mechanisms remain obscure. A further advance was the introduction of pegylated forms of IFN-a that could be administered once weekly, and increased the global SVR rates up to 50–60% when given in combination with ribavirin (40–50% SVR in patients infected with genotype 1, and 80% SVR in those infected with genotypes 2 and 3). In the past 10 years, the combination of pegylated IFN-a and ribavirin has remained the standard of care treatment for chronic hepatitis C. In addition, the development of sensitive and accurate molecular tools for the monitoring of HCV therapy, described by Chevaliez in this issue of the journal, has been particularly helpful in monitoring treatment efficacy and improving global results by tailoring treatment duration to the actual on-treatment virological response. Improvements in the management of side effects and optimization of adherence have also been beneficial. Nevertheless, approximately half of the treated patients still failed to eradicate HCV infection, and nothing could be offered to patients who were non-responsive to a first course of pegylated IFN-a and ribavirin. Basic research in the HCV field has been active and successful, thanks to generous funding in most industrialized countries when the magnitude of the public health problem became obvious. In vitro models have been developed, such as cell-free enzyme assays, pseudovirus particles, self-replicating replicon models and, ultimately, infectious cell culturebased systems. These models have been particularly useful in deciphering the molecular mechanisms of the HCV life cycle