Virology, Natural History, and Treatment for HCV Genotype 3
Virology, Natural History, and Treatment for HCV Genotype 3
Affecting 2–3% of the world's population, hepatitis C is a common viral infection which is a significant cause of morbidity and mortality. Hepatitis C genotype 1 is the dominant viral genotype among Western patients. For the last 20 years, in the era of interferon-based therapy, it was far more difficult to treat relative to genotypes 2 and 3. Accordingly, a significant focus of research was on new antiviral agents for the dominant genotype 1 patient. Now, as promising specific treatments are being introduced for genotype 1, the attention of clinicians and researchers has turned back to the 50–70 million patients infected with a nongenotype 1 hepatitis C. Furthermore, after recent, larger randomized trials, we have realized that genotype 2 is truly interferon sensitive while genotype 3 patients are far less successful with therapy. In this fundamentally altered landscape, genotype 3 is now potentially the most difficult to treat genotype and an area of intense research for new drug development. Herein we review the virology, natural history and the treatment of genotype 3 hepatitis C.
Hepatitis C virus (HCV) affects an estimated 130–170 million persons (2–3% of the world's population). HCV is an important cause of liver-related morbidity and mortality including the complications of cirrhosis and liver cancer. One of first steps in the diagnosis and management of chronic HCV infection is genotype determination. Six major genotypes have been identified. The proportion of patients infected with a given genotype varies from country to country, with genotype 1 (HCV-1) dominant in the United States and Western Europe closely followed by genotype 3 (HCV-3).
Interferon (IFN) has been the major antiviral agent for the last 20 years, an era during which HCV-2 and HCV-3 were considered easy-to-treat genotypes with sustained virological response (SVR) rates approaching 70%. More recently with larger randomized trials of IFN and ribavirin (RBV) therapy, we have realized that HCV-2 is truly interferon sensitive with up to 80% SVR rates, whereas HCV-3 has an intermediate response at 65–70%. Because there was a belief that both HCV-2 and HCV-3 were easy to treat, a significant focus of research was on new antiviral agents for the dominant HCV-1 patient. Overall, HCV-1 response rates to PEG-IFN and RBV were between 40% and 50% and because 70% of patients in the United States are genotype 1, this represented a significant unmet need for new therapies. In 2011, new direct-acting antiviral agents (DAAs) against the NS3/4 protease were added to PEG-IFN and RBV and SVR rates reached 75%. In addition, newer DAA agents are being continuously introduced for HCV-1 disease with multiple different targets on the replication pathway and anticipated response rates are now between 80% and 90% and duration can be reduced to as little as 12 weeks of triple therapy. As these new HCV-1-specific treatments are being introduced, the attention of clinicians and researchers has turned back to the 50–70 million patients infected with a nongenotype 1 HCV. Herein, we will discuss how in this fundamentally altered landscape, HCV-3 is now potentially the most difficult to treat genotype and an area of intense research for new drug development.
Abstract and Introduction
Abstract
Affecting 2–3% of the world's population, hepatitis C is a common viral infection which is a significant cause of morbidity and mortality. Hepatitis C genotype 1 is the dominant viral genotype among Western patients. For the last 20 years, in the era of interferon-based therapy, it was far more difficult to treat relative to genotypes 2 and 3. Accordingly, a significant focus of research was on new antiviral agents for the dominant genotype 1 patient. Now, as promising specific treatments are being introduced for genotype 1, the attention of clinicians and researchers has turned back to the 50–70 million patients infected with a nongenotype 1 hepatitis C. Furthermore, after recent, larger randomized trials, we have realized that genotype 2 is truly interferon sensitive while genotype 3 patients are far less successful with therapy. In this fundamentally altered landscape, genotype 3 is now potentially the most difficult to treat genotype and an area of intense research for new drug development. Herein we review the virology, natural history and the treatment of genotype 3 hepatitis C.
Introduction
Hepatitis C virus (HCV) affects an estimated 130–170 million persons (2–3% of the world's population). HCV is an important cause of liver-related morbidity and mortality including the complications of cirrhosis and liver cancer. One of first steps in the diagnosis and management of chronic HCV infection is genotype determination. Six major genotypes have been identified. The proportion of patients infected with a given genotype varies from country to country, with genotype 1 (HCV-1) dominant in the United States and Western Europe closely followed by genotype 3 (HCV-3).
Interferon (IFN) has been the major antiviral agent for the last 20 years, an era during which HCV-2 and HCV-3 were considered easy-to-treat genotypes with sustained virological response (SVR) rates approaching 70%. More recently with larger randomized trials of IFN and ribavirin (RBV) therapy, we have realized that HCV-2 is truly interferon sensitive with up to 80% SVR rates, whereas HCV-3 has an intermediate response at 65–70%. Because there was a belief that both HCV-2 and HCV-3 were easy to treat, a significant focus of research was on new antiviral agents for the dominant HCV-1 patient. Overall, HCV-1 response rates to PEG-IFN and RBV were between 40% and 50% and because 70% of patients in the United States are genotype 1, this represented a significant unmet need for new therapies. In 2011, new direct-acting antiviral agents (DAAs) against the NS3/4 protease were added to PEG-IFN and RBV and SVR rates reached 75%. In addition, newer DAA agents are being continuously introduced for HCV-1 disease with multiple different targets on the replication pathway and anticipated response rates are now between 80% and 90% and duration can be reduced to as little as 12 weeks of triple therapy. As these new HCV-1-specific treatments are being introduced, the attention of clinicians and researchers has turned back to the 50–70 million patients infected with a nongenotype 1 HCV. Herein, we will discuss how in this fundamentally altered landscape, HCV-3 is now potentially the most difficult to treat genotype and an area of intense research for new drug development.
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