Finally sofosbuvir: an oral anti-HCV drug with wide performance capability

Pharmacogenomics and Personalized Medicine Dovepress open access to scientific and medical research Review Pharmacogenomics and Personalized Medicine downloaded from https://www.dovepress.com/ by 54.37.117.73 on 13-Jul-2018 For personal use only. Open Access Full Text Article Finally sofosbuvir: an oral anti-HCV drug with wide performance capability This article was published in the following Dove Press journal: Pharmacogenomics and Personalized Medicine 8 December 2014 Number of times this article has been viewed Zeid Kayali 1 Warren N Schmidt 2,3 Division of Gastroenterology and Hepatology, University of Southern California, Los Angeles, CA, USA; 2 Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA, USA; 3 Roy G and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, USA 1 The clinical problem Correspondence: Warren N Schmidt Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 4553 JCP Iowa City, IA 52242, USA Tel +1 (319) 353 7048 Fax +1 (319) 356 7918 Email Chronic Hepatitis C virus (HCV) infection is a serious major global health problem. Worldwide, over 170 million patients are estimated to be infected1 and suffer from chronic hepatitis, high rates of cirrhosis, end-stage liver disease, and increased risk for hepatocellular carcinoma.2 A smaller but significant number of infected patients also show extrahepatic complications such as mixed cryoglobulinemia, glomerulonephritis, arthritis, and some varieties of B-cell lymphoma.3 Following exposure to HCV, only a minority of patients clear the acute infection, whereas 80% persist with life-long chronic viremia if not successfully treated.4 The natural history of liver disease due to HCV is highly variable and profoundly influenced by patient cofactors such as type II diabetes, nontemperate alcohol consumption, fatty liver disease, and human immunodeficiency virus (HIV) coinfection.5 Since discovery of the virus, α-interferon (IFN) by injection has been the backbone drug for antiviral protocols, which have achieved only limited success. Regardless of the IFN preparation, the drug has been plagued with excessive toxicity, therapeutic limitations, and restricted patient availability. Recently, sofosbuvir (SOF), an oral antiviral agent with low toxicity and wide performance capability, has been approved by the US Food and Drug Administration (FDA) and European Union for treatment of 387 submit your manuscript | www.dovepress.com Pharmacogenomics and Personalized Medicine 2014:7 387–398 Dovepress © 2014 Kayali and Schmidt. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/PGPM.S52629 Powered by TCPDF (www.tcpdf.org) Abstract: Chronic Hepatitis C virus (HCV) infection is the leading cause of advanced liver disease worldwide. The virus successfully evades host immune detection and for many years has hampered efforts to find a safe, uncomplicated, and reliable oral antiviral therapy. Initially, interferon and ribavirin therapy was the treatment standard of care, but it offered limited performance across the wide spectrum of HCV disease and was fraught with excessive and often limiting side effects. Sofosbuvir (SOF) is a potent first-in-class nucleoside inhibitor that has recently been approved for treatment of HCV. The drug has low toxicity, a high resistance barrier, and minimal drug interactions with other HCV direct-acting antiviral agents such as protease inhibitors or anti-NS5A agents. SOF is safe and can be used across different viral genotypes, disease stages, and special patient groups, such as those coinfected with human immunodeficiency virus. When used in combination with ribavirin or another direct-acting antiviral agent, SOF has revolutionized the HCV treatment spectrum and set the stage for nearly universal HCV antiviral therapy. More so than any other anti-HCV drug developed to date, SOF offers the widest applicability for all infected patients, and new regimens will be tailored to maximize performance. Keywords: Hepatitis C virus, sofosbuvir, polymerase inhibitors, interferon-free treatment Dovepress Kayali and Schmidt Pharmacogenomics and Personalized Medicine downloaded from https://www.dovepress.com/ by 54.37.117.73 on 13-Jul-2018 For personal use only. chronic HCV infection. Because of the drug’s versatility, low side effect profile, and antiviral efficacy, it clearly is emerging as a first-in-class “breakthrough” drug that will replace IFN and become the new foundation for HCV therapy. susceptibility to antiviral therapy, a fact that individualizes specific treatment paradigms depending on patient genotype. Cloning and sequencing of patient isolates also established that HCV circulates as a swarm of viruses, with small changes in gene sequences termed quasispecies, which arise naturally because of host innate antiviral pressures and the high replicative capacity of the error-prone RdRp.11 Development of effective antiviral therapies for HCV was initially challenging due to the failure of early attempts to pass the virus in cell culture or small animal models.8 Finally, the introduction of replicon systems and permissive cell types in 1999 greatly facilitated in vitro replication assays and boosted drug development.12–14 Replicon constructs enabled highthroughput in vitro testing for a wide variety of prototypical direct-acting antiviral agents (DAAs) that established the proof of concept that specific compounds could target viral proteins such as the NS3/4A protease and serve as antiviral drugs in vivo.15 Description of the virus and structure HCV is a small, 9,500-nucleotide, plus-stranded ribonucleic acid (RNA) virus that replicates in the cytoplasm with a single open-reading frame (Figure 1). The genome contains three major structural proteins and at least six nonstructural (NS) proteins that provide the protease, helicase, and RNAdependent RNA polymerase (RdRp) activities of the virus.6,7 The plus-stranded viral RNA is first translated into a large polyprotein that is then cleaved by host and viral proteases into structural and enzymatic proteins, respectively.8,9 The small, error-prone RdRp is a major factor accounting for the high mutability and rapid acquisition of viral resistance to designer drugs that target viral sites such as the NS3/4A protease. Early sequencing studies in patient populations established at (...truncated)