{"id":1336,"date":"2013-02-01T00:00:12","date_gmt":"2013-02-01T05:00:12","guid":{"rendered":"http:\/\/rhochistj.org\/RhoChiPost\/?p=1336"},"modified":"2014-02-24T16:25:44","modified_gmt":"2014-02-24T21:25:44","slug":"emerging-pathways-treating-hepatitis-c-virus","status":"publish","type":"post","link":"https:\/\/rhochistj.org\/RhoChiPost\/emerging-pathways-treating-hepatitis-c-virus\/","title":{"rendered":"Emerging Pathways For Treating Hepatitis C Virus"},"content":{"rendered":"

By:\u00a0 Maria Sorbera, PharmD Candidate c\/o 2013, AMSCOP, LIU<\/span><\/p>\n

–<\/p>\n

Hepatitis C is the leading cause of chronic liver disease and cirrhosis, presenting a global health challenge.\u00a0 Approximately 170 million people worldwide, 3% of the population, are infected with the Hepatitis C Virus (HCV), roughly 3.2 million of whom reside in the United States.\u00a0 The virus can present as an acute or chronic infection. Acute infections occur within six months of exposure, and an estimated 75\u201385% of patients will eventually develop a chronic infection.\u00a0 HCV can also be asymptomatic, with many patients being unaware that they are infected, allowing the infection to progress potentially causing liver disease, cirrhosis, and hepatocellular carcinoma.\u00a0 Although it is not known who will develop these complications, each patient\u2019s risk factors need to be assessed.\u00a0 Standard therapy consists of interferon (IFN) and ribavirin (RBV) for 24-48 weeks; however, not every patient is a candidate for or can tolerate treatment.<\/p>\n

HCV is an RNA virus consisting of six genotypes, which replicate within the hepatocytes. Genotype 1, the most common in the US, is the most challenging to treat.\u00a0 Individuals infected with genotypes 2 and 3 are more likely to respond to therapy than those infected with genotype 1.\u00a0 The primary goal of therapy is to eradicate the infection.\u00a0 Secondary goals include decreasing inflammation, reducing the risk of cancer, and slowing the progression to liver disease.\u00a0 Disease eradication is determined by achieving a sustained viral response (SVR), defined as the absence of HCV RNA six months after the completion of treatment.\u00a0 There are predictors to estimate who will achieve an SVR such as being negative for HCV RNA at 12 weeks of therapy.\u00a0 This is referred to as a complete early virologic response (EVR).\u00a0 A 2 log(10) or greater reduction in HCV RNA at 12 weeks of treatment defines a partial EVR.\u00a0 Patients who do not achieve an EVR have less than a 2% chance of reaching a SVR.\u00a0 Also, patients who have undetectable HCV RNA at week 4 of therapy, known as a rapid virologic response (RVR), have greater than a 90% chance of achieving a SVR.\u00a0 From the development of IFN to the current advances of direct acting antivirals (DAAs), improving SVR rates has been the primary efficacy measurement of therapy.<\/p>\n

During the 1980s, it was observed\u00a0that IFN improves liver enzymes.\u00a0 Soon RBV, which inhibits RNA viral replication, was added to interferon therapy to improve SVR.\u00a0 Subsequently, the pegylated formulation of interferon (PEG-IFN), was manufactured.\u00a0 Chronically infected patients achieve a SVR 54-56% of the time when treated with PEG-IFN\/RBV.\u00a0 IFN is only available in an injectable form, has an extensive side effect profile, and has incidences of relapses\u2014many challenges to patient compliance.\u00a0 Side effects include, but are not limited to, nausea, flu-like symptoms, hematological effects, ophthalmologic disorders, respiratory symptoms, and thyroid dysfunction.\u00a0 For many reasons, it is difficult for patients to complete the full 24-48 weeks of therapy presenting the need for newer treatment regimens that can be taken orally, with less toxicity and lower relapse rates.<\/p>\n

Advancements in treating hepatitis C do not end with INF and RBV.\u00a0 Developments are underway that present major changes to HCV treatment. Two Direct Acting Antivirals (DAA), telaprevir and boceprevir, are NS3\/4A serine protease inhibitors, recently approved by the FDA to be used with PEG-IFN and RBV. According to the American Association for the Study of Liver Disease (AASLD), these two agents should only be considered as an adjunctive therapy if a patient is infected with genotype 1.\u00a0 Gilead Sciences\u2019 GS-7977, GS-5885 and GS-938, are currently undergoing Phase II and III clinical trials for interferon-free HCV regimens.\u00a0 Meanwhile, in November 2012, Abbott announced that the results from their Phase 2b Interferon-free Hepatitis C\u00a0trial studying a triple-DAA regimen (ABT-450, ABT-267, ABT-333) plus ribavirin will be presented at the Annual Meeting of the AASLD in Boston.\u00a0 GS-7977, GS 5885, GS-938, ABT450\/ritonavir, ABT-267, and ABT-333 are all promising investigational DAAs.<\/p>\n

\u00a0 \u00a0 \u00a0 Sofosbuvir (GS-7977), previously PSI-7977, was discovered by Pharmasset, which has become a subsidiary of Gilead Sciences.\u00a0 The prodrug, GS-7977, is a nucleotide analogue NS5B-polymerase inhibitor.\u00a0 The figure in the previous page depicts the HCV genome showing the structural and nonstructural (NS) proteins.\u00a0 NS5B protein is an RNA-dependent RNA polymerase.<\/span><\/p>\n

After HCV enters the hepatocyte and its genome is translated, the virus can then encode proteases.\u00a0 Following the NS protein formation of an RNA Replication Complex comprising viral proteins, replicating RNA, and altered cell membranes, RNA is replicated by RNA polymerase NS5B.\u00a0 The RNA polymerase first makes a negative strand of RNA serving as a template for the production of a positive strand. \u00a0Inhibiting NS5B prevents the initiation of RNA replication, making this a targeted mechanism for drug discovery.\u00a0 From the Phase 2 trials, ELECTRON and QUANTUM, GS-7977 combined with RBV displays potential in increasing SVR rates and decreasing relapse rates.\u00a0 Currently undergoing the phase III clinical trial, FISSION, GS 7977 seems promising.<\/p>\n

GS-5885 is an NS5A inhibitor. Like NS5B, NS5A is a nonstructural protein component of the RNA Replication Complex that aids RNA replication. NS5A can also mount a host-cell interferon response, making it an increasingly popular focus of pharmacotherapy.\u00a0 The interferon sensitivity determining region (ISDR) of NS5A appears to determine the sensitivity of the virus to interferon.\u00a0 Mutations in this region may correlate with low response rates to interferon therapy.\u00a0 GS-5885\/GS-7977 plus RBV are in phase III of clinical trials in the hopes of potentially changing the main stay of HCV treatment.<\/p>\n

The prodrug, GS-352938, is metabolized to GI-352666 (PSI-352666), which is an inhibitor of NS5B RNA-dependent RNA polymerase similar to GS-7977.\u00a0 The question arises : why would Gilead conduct a trial using GS-7977 + GS-352938 + RBV, if both the polymerase inhibitors are nucleotide analogs that share the same mechanism of action? Can\u2019t this potentially result in resistance?\u2019 Pharmasset designed these two agents to work synergistically, with GS-7977 being a pyrimidine analog and GS-352938 a purine analog.\u00a0 According to the December issue of the Journal of Virology, no cross-resistance was found between GS-352938 and other HCV-polymerase inhibitors including GS-7977. Gilead is in the midst of the first interferon-free HCV treatment regimen, with various new drugs; however, Abbott, is also on their way after promising results with ABT-450, ABT-267, and ABT-333 in the Phase 2 AVIATOR study.<\/p>\n

Like telaprevir and boceprevir, ABT-450 is a protease inhibitor that exhibits its effects on the HCV protein NS3\/4A. Similar to HIV therapy, optimum drug levels of ABT-450 are maintained by combining the medication with ritonavir, which is used as a pharmacokinectic boost.\u00a0 HCV is translated into a polyprotein once it enters the host cell. The polyprotein is converted into structural proteins and NS proteins.\u00a0 Structural proteins, such as E1, E2, and P7, are involved in the virus\u2019 ability to affect other cells, while NS proteins, such as NS3, NS4A, NS4B and NS5B aid the replication of the HCV. NS4A is a cofactor protein that is needed for NS3 to properly carry out protease and helicase activity.\u00a0 When the protein NS3\/4A is inhibited, the virus cannot replicate.<\/p>\n

Similar to GS-5885, ABT-267 is also an NS5A inhibitor.\u00a0 Both NS5A and NS5B interact and act as targets for DAA development. Along with DNA replication, NS5A also stimulates NS5B, which, as stated before, contains RNA-dependent RNA polymerase.\u00a0 By inhibiting NS5A, HCV replication is suppressed, and stimulatory effects on NS5B are arrested, possibly decreasing polymerase activity. Another Abbott investigational drug is ABT-333, a non-nucleoside HCV NS5B polymerase inhibitor.\u00a0 This drug also inhibits RNA replication by blocking the enzyme that synthesizes RNA from an RNA template.\u00a0 The interferon-free regimen of ABT-450\/r + ABT-267 + ABT-333 has produced promising results in the Aviator trial.\u00a0 With or without RBV, the regimen resulted in high SVR 12 weeks post-treatment in all arms.\u00a0 This study included non-cirrhotic patients who were treatment-na\u00efve as well as null responders who have failed PEG-IFN\/RBV therapy.\u00a0 Of note, there was an SVR of 93.3% 12 weeks post treatment in null responders taking the triple-DAA regimen + RBV.\u00a0 This is important because there are few treatment options once patients fail the standard PEG-IFN + RBV therapy.\u00a0 Although there has been great emphasis on interferon-free regimens, a new interferon therapy is in phase 2 and 3 clinical trials.<\/p>\n

Pegylated Interferon-Lambda (PEG-IFN-Lambda), being developed by Bristol-Myers Squibb, is in the pipeline for becoming a \u201cfirst-in-class\u201d interferon.\u00a0 When HCV enters the body, interferon lambda proteins are generated by the immune response. The mechanisms by which IFN-Lambda proteins are released differ from IFN-alpha in that different receptors are utilized; however, both IFNs prevent the assembly of viral capsids.\u00a0 As the result is the same, the two pathways do have common ground and converge at some point.\u00a0 The figure below shows that although different receptors are bound to initially, there is a common pathway that activates the interferon-stimulating response element (ISRE), and then subsequently, the interferon-stimulating gene factors (ISGF).<\/p>\n

IFN is usually a side-effect limiting therapy, in which many patients simply cannot tolerate the medication.\u00a0 Binding mainly to epithelial cells, IFN-lambda is a more specific IFN therapy.\u00a0 IFN-alpha receptors are present on numerous cells including leukocytes.\u00a0 The receptors of IFN-lambda create a much more tolerable and safe treatment.\u00a0 The efficacy and safety of PEG IFN-lambda plus RBV in comparison to PEG IFN-alpha plus RBV is being evaluated; however, the duration of therapy is the same, unlike the DAAs.\u00a0 With time, this newer agent can become an alternative to or even replace standard interferon therapy.<\/p>\n

With the development of new direct-acting antivirals and PEG IFN-lambda, treatment of the Hepatitis C Virus is undergoing a groundbreaking transformation that can increase compliance, increase SVR rates, and reduce relapse rates.\u00a0 Two main contributors to this transformation are the pharmaceutical companies, Gilead Sciences and Abbott, which appear to be racing toward the first interferon-free HCV treatment.\u00a0 HCV is a growing health concern in which current therapies produce a SVR only 54-56% of the time.\u00a0 Furthermore, there is a risk for relapse in which treatment options become fewer and treatments less effective.\u00a0 The new therapies present great potential in treating HCV for na\u00efve and null responders, possibly making the mainstay of treatment of PEG-IFN plus RBV a thing of the past.\u00a0 It is safe to say that a new page has been turned for the treatment of HCV.<\/p>\n

Acknowledgements:\u00a0 Special thanks to Ivy Cohen, the Assistant Director of Pharmacy and Clinical Trial Coordinator, and to the Investigational Pharmacists, Giuseppe Difiore and Alla Khodzhayeve, at the Mt. Sinai Medical Center for their input and help with this article.<\/em><\/p>\n

SOURCES:<\/span><\/strong><\/span><\/p>\n

    \n
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  12. Pagliaccetti N, Chu E, Bolen C, Kleinstein S, Robek M. Lambda and Alpha Interferons Inhibit Hepatitis B Virus Replication Through a Common Molecular Mechanism but with Different In Vivo Activities.\u00a0 Virology. 06\/05\/2010:Vol 401(2);197-206.<\/li>\n
  13. Donnelly RP, Kotenko SV. Interferon-lambda: A New Addition to an Old Family. J Interferon Cytokine Res. 08\/30\/2010(8):555-64.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    By:\u00a0 Maria Sorbera, PharmD Candidate c\/o 2013, AMSCOP, LIU – Hepatitis C is the leading cause of chronic liver disease and cirrhosis, presenting a global health challenge.\u00a0 Approximately 170 million people worldwide, 3% of the population, are infected with the Hepatitis C Virus (HCV), roughly 3.2 million of whom reside in the United States.\u00a0 The…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[7,4],"tags":[1825,2237,343,193,49,2060,40,2243,1566,1218,1160,102,15,13,2229,2227,1819,2232,94,132,314,1647,62,20,18,2233,2247,23,137,139,601,315,542,2236,203,14,210,101,363,1625,19,1560,2230,11,1195,42,671,1820,169,447,31,1736,1695,36,21,2252,1161,16,17,51,48],"class_list":["post-1336","post","type-post","status-publish","format-standard","hentry","category-clinical","category-featured","tag-agents","tag-aids","tag-and","tag-annual","tag-antiviral","tag-boceprevir","tag-cancer","tag-cdc","tag-complete","tag-complex","tag-control","tag-december","tag-disease","tag-drug","tag-drugs","tag-ebola-virus-disease","tag-exposure","tag-fda","tag-february","tag-flu","tag-for","tag-formulation","tag-gene","tag-health","tag-hepatitis","tag-hepatitis-b","tag-hepatitis-c","tag-hiv","tag-infection","tag-inflammation","tag-inhibitor","tag-injectable","tag-interferon","tag-liver","tag-log","tag-medication","tag-note","tag-november","tag-of","tag-or","tag-patient","tag-peginterferon","tag-pharmaceutical","tag-pharmacy","tag-plus","tag-public","tag-r","tag-reduction","tag-relapse","tag-release","tag-research","tag-respiratory","tag-ribavirin","tag-risk","tag-study","tag-symptoms","tag-therapy","tag-treatment","tag-trial","tag-vaccine","tag-virus"],"views":584,"_links":{"self":[{"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/posts\/1336","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/comments?post=1336"}],"version-history":[{"count":0,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/posts\/1336\/revisions"}],"wp:attachment":[{"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/media?parent=1336"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/categories?post=1336"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/tags?post=1336"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}