Emerging Therapies in Hepatitis C: Dawn of the Era of the Direct-Acting Antivirals

Infection with hepatitis C virus (HCV) is a worldwide epidemic affecting up to 3% of the world’s population. Approximately 80% of people infected with HCV will go on to develop chronic disease. Of these individuals, approximately 25% develop cirrhosis and are vulnerable to its complications, including hepatocellular carcinoma. Treatment for HCV can be curative, and successful treatment improves the quality of life of HCV infected individuals as well as prevents progression of liver disease and its associated morbidity and mortality.

For the last decade, the standard of care treatment for HCV has been pegylated interferon-α (pegIFNα) plus ribavirin (RBV) for 24 to 48 weeks depending on viral genotype. Therapy is expensive, difficult to tolerate, and associated with a variety of quality-of-life–limiting side effects. Furthermore, the response rates to treatment are not optimal; only about 40% of genotype 1–infected patients respond to treatment. Patients infected with genotypes 2 and 3 have a higher rate of treatment response, which approximates 80%.

A major goal within the fields of hepatology and infectious diseases is to improve the rate of response to HCV treatment. Novel discoveries over the past few years, such as the finding of a polymorphism near the IL28B gene, have helped identify those patients that are most likely to respond to HCV treatment with pegIFNα and RBV. Additionally, new therapies have been developed, and some of the most promising new drugs are those that act to directly inhibit the virus. These direct-acting antiviral (DAA) drugs are currently in various stages of development, and are described in detail in this review.

Viral Structure and Life Cycle

A basic understanding of the viral structure and life cycle ( Fig. 1 ) is important to understand the targets of the new drugs in development. The HCV is a positive single-strand RNA virus with 9.5 kilobases. The virus enters the hepatocyte via a variety of receptors (including glycosaminoglycans, CD81, SR-BI, Claudin-1) by receptor mediated endocytosis. Once in the hepatocyte, the virus is translated into a single long polypeptide on the ribosome then cleaved by both host and viral proteases into 10 functional proteins. A replication complex is formed using viral and host proteins and results in a double-stranded RNA intermediate that includes a positive-strand RNA and a negative-strand RNA. The negative strand serves as a template for the synthesis of positive-strand RNA, which is then packaged and released from the hepatocyte. The synthesis of positive-strand RNA is disproportionate to the negative strand and is transcribed in a 5- to 10-fold excess of negative-strand RNA.