Abstract and Introduction
Abstract
With more than 170 million individuals currently infected, HCV is a global pandemic, effecting approximately 3% of the entire world's population. HCV infection is a growing infectious disease pandemic with approximately 3-4 million new cases reported each year. Due to the persistent nature of the virus, 70-90% of infected individuals will develop chronic infection, which can lead to progressive liver disease including cirrhosis and hepatocellular carcinoma. Current standard treatment with a combination of IFN-α and ribavirin has improved the prognosis for many HCV sufferers; however, infection is very difficult to treat successfully and the protocol for treatment is neither simple, well tolerated nor economically favorable. Standard treatment can cost an average of US$22,000, and depending on genotype, as few as 42% of treated individuals will clear the infection. This collection of treatment issues combined with new concepts in immune therapy serve to underscore an urgent need for the development of improved immunotherapies, such as novel interferons, and support the possible development of therapeutic vaccines for the treatment of chronic HCV infection.
Introduction
HCV infection is a major health burden worldwide. The WHO estimates that 3% of the world's population is chronically infected with HCV, equaling approximately 170million individuals, with 3-4million new cases of HCV infection each year. HCV is one of five unrelated hepatotropic viruses, hepatitis A, B, C, D and E, so named for their pathology rather than their evolutionary relationship to one another. Each hepatitis virus belongs to a different viral family and, with the exception of hepatitis B, which is a DNA virus, the majority of hepatitis viruses are RNA viruses. Of the hepatitis viruses, HCV is the most persistent. While a small percentage of hepatitis B- and D-infected individuals develop chronic infection (hepatitis A and E have no chronic phase), HCV is able to persist in the livers of up to 70-90% of all infected individuals. Due to the persistent nature of the virus, up to 30% of infected individuals will develop progressive liver disease during their lifetime, including cirrhosis and hepatocellular carcinoma. In fact, in the developed world, HCV infection is responsible for up to 76% of all liver cancer cases and is the leading cause for liver transplantation.
Unlike other hepatitis viruses, it is the propensity of HCV to cause chronic infection, which makes the virus especially hard to treat. However, since its discovery in 1989, many strides have been made to improve the clinical outcome for individuals infected with HCV. Following the introduction of IFN-α monotherapy and more recently the current standard treatment protocol of pegylated (peg) IFN-α plus ribavirin, the number of infected individuals achieving sustained antiviral response has improved. Although the mechanisms behind the actions of IFN-α and ribavirin have yet to be completely understood, it is believed that IFN-α is able to interact with the hosts immune system and exert a direct antiviral effect while ribavirin is able to augment the effects of IFN-α and, therefore, this combination therapy decreases the likelihood of relapse.
However, even with new improvements in standard treatment protocols, HCV is extremely difficult and expensive to treat. The standard treatment protocol of pegIFN-α and ribavirin can cost in excess of US$22,000, which unfortunately contributes to the poor treatment rate among HCV infected individuals. In addition, response rates to treatment are highly dependent on the viral genotype. HCV is highly variable in sequence and is currently classified into six different genotypes with more than 50 subtypes. Genotype 1 represents the most prevalent genotype in North America and Europe and is by far the most difficult to treat. Genotypes2 and 3, however, are found more commonly in the Far East, while genotype 4 is prevalent in Africa and the Middle East and genotypes 5 and 6 are most commonly found in South Africa and South-East Asia, respectively. On average, as few as 42% of individuals infected with genotype 1 will respond to treatment and currently there is no approved treatment protocol for those individuals who have failed to clear the virus following initial treatment. Individuals infected with either genotype 2 or 3, however, are almost three-times more likely than genotype1-infected individuals to respond to treatment. Further complicating low response rates, current treatments have numerous side effects, including influenza-like symptoms, fever, fatigue, anemia, thrombocytopenia and depression. It is estimated that the intolerability of side effects is responsible for up to 20% of premature treatment discontinuations.
Therefore, the high prevalence of infection, expense of standard treatment protocols, low response rates and intolerability of side effects illustrates the urgent need for the development of new therapeutics to combat this disease.