Advances in Hepatitis C Treatment: At the Crossroads
Advances in Hepatitis C Treatment: At the Crossroads
Chronic hepatitis C virus (HCV) infection is a serious public health problem. Globally, over 170 million persons are infected and suffer from HCV infection, cirrhosis, and hepatocellular carcinoma. HCV infection is among the leading causes of death in the United States. Recently, there have been newer, direct-acting antiviral agents approved by the US Food and Drug Administration for treatment of HCV for genotypes 1–4. The aim of this study is to evaluate the clinical efficacy, pharmacologic properties, and safety profiles from clinical trials and the costs associated with the new antiviral regimens, including sofosbuvir, simeprevir, and ledipasvir/sofosbuvir.
Chronic hepatitis C virus (HCV) infection is a serious public health problem. Over 170 million people worldwide are estimated to be infected and suffer from chronic hepatitis C (CHC), high rates of cirrhosis, and end-stage liver disease, and have an increased risk for hepatocellular carcinoma (HCC). In the United States, approximately 4 million people are infected with CHC, which is the leading reason for liver transplantation. The prevalence of people living with CHC does not include individuals who are institutionalized, incarcerated, or homeless in the US, because the estimates are derived from the National Health and Nutrition Examination Survey. Therefore, the statistics may underestimate the actual number of infected Americans. An expanded prevalence study reported between 5 and 7 million persons are actually infected in the US.
Early treatment of HCV using pegylated interferon alfa (PegIFN) and ribavirin (RBV) showed limited efficacy with a side effect profile that was intolerable to many infected patients on treatment in addition to a long treatment duration of 48 weeks. The real revolution in the HCV treatment arsenal occurred in 2011 with the introduction of boceprevir and telaprevir, which were the first oral direct-acting antiviral (DAAs) agents and were used as adjunctive therapy with PegIFN and RBV. Triple therapy with the first-generation protease inhibitors demonstrated better efficacy than dual treatment for genotype 1–infected persons, but their use against hepatitis C was hampered by a cumbersome response-guided therapy, increased pill burden, drug-drug interactions, low barriers to resistance, and significant adverse effects. Over the past 5 years, the development of additional oral DAAs that target viral enzymes and proteins across the virus life cycle has ushered in a new era for more tolerable and effective IFN-sparing treatments.
Sofosbuvir (SOF) is the first uridine nucleotide analog inhibitor of the NS5B polymerase. Simeprevir (SMV) is a second-generation inhibitor of the NS3/4A protease. Both agents were approved by the US Food and Drug Administration (FDA) in December 2013. More recently, ledipasvir/sofosbuvir (LDV/SOF) was approved in October 2014. These 3 DAAs have higher barriers to resistance, better tolerability and safety profiles, shorter durations of treatment, and significantly improved sustained virologic response (SVR) or cure rates. SVR became the benchmark for successful therapy and is still defined as HCV becoming undetectable in the blood during treatment and remaining so 24 weeks after the end of treatment. Historically, SVR at 24 weeks after completion of HCV treatment (SVR24) was used as a key response measure in clinical trials. However, recent trials investigating the efficacy of new DAAs used SVR at 12 weeks after treatment (SVR12) because of their higher efficacy rates within a shorter treatment duration. The chance of relapse after achieving SVR12 is < 1%. Recent phase 3 trials data showed that undetectable HCV RNA at 12 weeks after treatment is highly reliable for prediction of overall SVR.
Abstract and Introduction
Abstract
Chronic hepatitis C virus (HCV) infection is a serious public health problem. Globally, over 170 million persons are infected and suffer from HCV infection, cirrhosis, and hepatocellular carcinoma. HCV infection is among the leading causes of death in the United States. Recently, there have been newer, direct-acting antiviral agents approved by the US Food and Drug Administration for treatment of HCV for genotypes 1–4. The aim of this study is to evaluate the clinical efficacy, pharmacologic properties, and safety profiles from clinical trials and the costs associated with the new antiviral regimens, including sofosbuvir, simeprevir, and ledipasvir/sofosbuvir.
Introduction
Chronic hepatitis C virus (HCV) infection is a serious public health problem. Over 170 million people worldwide are estimated to be infected and suffer from chronic hepatitis C (CHC), high rates of cirrhosis, and end-stage liver disease, and have an increased risk for hepatocellular carcinoma (HCC). In the United States, approximately 4 million people are infected with CHC, which is the leading reason for liver transplantation. The prevalence of people living with CHC does not include individuals who are institutionalized, incarcerated, or homeless in the US, because the estimates are derived from the National Health and Nutrition Examination Survey. Therefore, the statistics may underestimate the actual number of infected Americans. An expanded prevalence study reported between 5 and 7 million persons are actually infected in the US.
Early treatment of HCV using pegylated interferon alfa (PegIFN) and ribavirin (RBV) showed limited efficacy with a side effect profile that was intolerable to many infected patients on treatment in addition to a long treatment duration of 48 weeks. The real revolution in the HCV treatment arsenal occurred in 2011 with the introduction of boceprevir and telaprevir, which were the first oral direct-acting antiviral (DAAs) agents and were used as adjunctive therapy with PegIFN and RBV. Triple therapy with the first-generation protease inhibitors demonstrated better efficacy than dual treatment for genotype 1–infected persons, but their use against hepatitis C was hampered by a cumbersome response-guided therapy, increased pill burden, drug-drug interactions, low barriers to resistance, and significant adverse effects. Over the past 5 years, the development of additional oral DAAs that target viral enzymes and proteins across the virus life cycle has ushered in a new era for more tolerable and effective IFN-sparing treatments.
Sofosbuvir (SOF) is the first uridine nucleotide analog inhibitor of the NS5B polymerase. Simeprevir (SMV) is a second-generation inhibitor of the NS3/4A protease. Both agents were approved by the US Food and Drug Administration (FDA) in December 2013. More recently, ledipasvir/sofosbuvir (LDV/SOF) was approved in October 2014. These 3 DAAs have higher barriers to resistance, better tolerability and safety profiles, shorter durations of treatment, and significantly improved sustained virologic response (SVR) or cure rates. SVR became the benchmark for successful therapy and is still defined as HCV becoming undetectable in the blood during treatment and remaining so 24 weeks after the end of treatment. Historically, SVR at 24 weeks after completion of HCV treatment (SVR24) was used as a key response measure in clinical trials. However, recent trials investigating the efficacy of new DAAs used SVR at 12 weeks after treatment (SVR12) because of their higher efficacy rates within a shorter treatment duration. The chance of relapse after achieving SVR12 is < 1%. Recent phase 3 trials data showed that undetectable HCV RNA at 12 weeks after treatment is highly reliable for prediction of overall SVR.
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