Chronic hepatitis C is a persistent, potentially progressive inflammatory liver disease caused by chronic infection with the hepatitis C virus (HCV). Worldwide there are an estimated 170 to 200 million persons with chronic HCV infection. Patients with advanced hepatitis C can potentially experience fatal liver failure or liver cancer, and hepatitis C is estimated to account for over 350,000 deaths per year worldwide (WHO estimate). HCV associated deaths and severe liver disease are increasing in the U.S. and worldwide. New public health initiatives are underway in many countries to detect HCV infection and, where appropriate, allow early treatment of HCV infection before patients have developed advanced liver disease.
HCV is an enveloped, positive-stranded RNA virus and member of the Flaviviridae family. There are 7 major genotypes (strains) of HCV, which have differing geographic distributions. Globally, about 40-60% of patients are infected with HCV genotype 1, with the remaining patients infected with HCV genotypes 2 through 7. The geographical distribution of patients infected with various genotypes of HCV is reported as follows: genotypes 1 and 2 are common in the Far East, North and South America, Europe, Australia/New Zealand, and parts of Africa; genotype 3 is common in Europe, North America, Thailand and India, and Australia/New Zealand; genotype 4 is common in Egypt and the Middle East, Central and North Africa; genotype 5 is common only in South Africa; genotype 6 is common only in a small region of Southeast Asia, including Hong Kong, Macau and Vietnam; and genotype 7 has been reported in central Africa.
HCV infection is a highly dynamic process, with a viral half-life of two hours or less and an average viral production and clearance rate of one trillion (1012) viral particles per day. The lack of a proof-reading function of the HCV RNA polymerase provides the basis for the genetic variability of individual viral particles and strains observed in cell culture and in hepatitis C patients. The rapid spontaneous mutability of HCV during natural infection provides a rationale for the development and implementation of multi-drug antiviral combination therapies. There is an urgent need for novel combination therapies employing potent, small molecule inhibitors that inhibit different steps in the HCV life cycle and that can be administered orally. The 9.6-kb RNA genome of HCV encodes one large polyprotein, cleaved by viral and cellular proteases into ten viral proteins inside HCV-infected cells, including structural and non-structural proteins. The HCV non-structural protein 5A (NS5A) is a multi-functional protein essential for HCV replication. Similarly, the viral polymerase (NS5B) is a critical enzyme responsible for generation of viral transcription and replication of the viral genome RNA. Both have proven to be excellent targets for developing small molecule inhibitors against HCV.
HCV treatment is evolving rapidly with the development of interferon-free, oral direct-acting antiviral (DAA) combination therapies that enable high sustained virologic response (SVR) rates, reduced duration of treatment and enhanced convenience for patients. However, recently approved therapies are too expensive to be used in many developing In countries, where pegylated interferon-alfa plus ribavirin remains the current treatment available. HCV DAA combinations, alone or with pegylated interferon-alfa plus ribavirin (peg-IFN/RBV), are not yet regulatory-approved, standard treatment is peg-IFN/RBV, which requires weekly injections and is only partially effective, with many side effects that are sometimes severe and treatment-limiting. As a result, there is a continuing need for all oral, efficacious and cost effective regimens. more consistently effective and better tolerated antiviral combinations for HCV infection, regardless of HCV genotype, patient genetic factors, or disease stage.