The Potential Role of Simeprevir for the Treatment of Hepatitis C

Cristina del Barrio Gascón; Maria Buti

Disclosures

Future Virology. 2015;10(2):67-75. 

In This Article

Abstract and Introduction

Abstract

Simeprevir is an HCV NS3/4A protease inhibitor with antiviral activity against HCV genotypes 1, 2, 4, 5 and 6. Simeprevir (SMV) has been approved for the treatment of genotype 1 and 4 patients in combination with PEGylated interferon (PEG-IFN) and ribavirin (RBV) or other direct antiviral agents. SMV plus PEG-IFN/RBV for 12 weeks in naive patients and prior relapsers with chronic hepatitis C genotype 1 or 4, followed by 12 additional weeks of PEG-IFN/RBV has yielded high efficacy rates. In IFN-free therapy, SMV combined with other antiviral drugs such as sofosbuvir achieved highly sustained virologic response rates in treatment-naive and experienced patients with HCV genotype 1 infection. SMV is generally well tolerated. SMV represents an important advance in the treatment of hepatitis C.

Introduction

Infection with HCV is a leading cause of liver disease worldwide.[1] An estimated 130–210 million people (3% of the global population) are currently infected, with an annual incidence of 2–4 million. Between 70 and 90% of acute infections become chronic and may lead to liver cirrhosis, chronic liver failure, hepatocellular carcinoma and death. Death related to the complications of cirrhosis in this population occurs at an annual rate of approximately 4%, whereas hepatocellular carcinoma occurs at a rate of 1–5%. Complications of chronic HCV infection have become the most common indication for liver transplantation.[2]

HCV is classified into at least six major genotypes (designated 1–6) and many subtypes (a, b, c, and so on). Genotypes 1 to 3 have a worldwide distribution, and genotypes 1a and 1b are the most common, accounting for approximately 60% of all HCV infections, mainly in the USA, Europe and Japan. Genotype 3 is primarily endemic in Southeast Asia. Genotype 4 is most prevalent in the Middle East, North Africa and sub-Saharan Africa, but has recently spread to Europe and other parts of the world through immigration and injection drug use. Genotype 4 is responsible for more than 90% of HCV infections in Egypt, where it is associated with reuse of needles during mass administration of parenteral antischistosomal therapy up to the 1980s. Approximately 20% of people infected with HCV worldwide have HCV genotype 4. Genotype 5 is mainly found in South Africa and genotype 6 mainly in Asia.[3]

About 30% of HIV-positive patients have HCV coinfection. The presence of HIV has been shown to accelerate the natural history of chronic hepatitis C in terms of progression to cirrhosis and end-stage liver disease. While morbidity and mortality secondary to opportunistic infections have decreased dramatically in this patient population with the introduction of highly active antiretroviral therapy, liver-related deaths have increased; hence, treatment of HCV has become a priority.[4]

The combination of PEGylated inteferon (PEG-IFN) and ribavirin (RBV) has been the mainstay HCV treatment for many years. Nonetheless, the efficacy of PEG-IFN/RBV is unsatisfactory in some HCV genotypes or subpopulations (e.g., patients with cirrhosis) and the treatment is associated with considerable side effects, such as fatigue, influenza-like symptoms, gastrointestinal disturbances, neuropsychiatric symptoms and hematologic abnormalities.[5]

In 2011, two direct-acting antiviral agents, telaprevir (TPV) and boceprevir, each administered in combination with PEG-IFN/RBV, were approved for the treatment of chronic HCV genotype 1 infection.[6] TPV and boceprevir are inhibitors of the HCV-encoded NS3/4A protease, which is an essential enzyme for viral replication, and in combination with PEG-IFN/RBV have demonstrated higher sustained virologic response (SVR) rates in treatment-naive and treatment-experienced populations than with PEG-IFN/RBV alone.[7] In addition, these combinations have been found to shorten overall treatment duration (from 48 weeks to 24–28 weeks) in a significant percentage of patients.[8]

Nevertheless, SVR rates with TPV or boceprevir-containing regimens remain low in difficult-to-cure populations, such as patients with a null response to previous PEG-IFN/RBV therapy and those with advanced liver disease, and the activity against HCV genotypes other than type 1 is very limited.[9] Furthermore, coadministration of TPV or boceprevir with PEG-IFN/RBV is associated with a greater frequency and severity of adverse events, such as anemia and rash, than with PEG-IFN/RBV alone, especially in cases of more advanced liver disease.[10] Management of these adverse events adds to the costs and complexity of treatment.[11] In addition, TPV (two-times to three-times daily) and boceprevir (three-times daily) currently require multiple daily dosing, which may have a negative impact on adherence.[12]

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