By:  Maria Sorbera, PharmD Candidate c/o 2013, AMSCOP, LIU

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Hepatitis C is the leading cause of chronic liver disease and cirrhosis, presenting a global health challenge.  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.  The virus can present as an acute or chronic infection. Acute infections occur within six months of exposure, and an estimated 75–85% of patients will eventually develop a chronic infection.  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.  Although it is not known who will develop these complications, each patient’s risk factors need to be assessed.  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.

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.  Individuals infected with genotypes 2 and 3 are more likely to respond to therapy than those infected with genotype 1.  The primary goal of therapy is to eradicate the infection.  Secondary goals include decreasing inflammation, reducing the risk of cancer, and slowing the progression to liver disease.  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.  There are predictors to estimate who will achieve an SVR such as being negative for HCV RNA at 12 weeks of therapy.  This is referred to as a complete early virologic response (EVR).  A 2 log(10) or greater reduction in HCV RNA at 12 weeks of treatment defines a partial EVR.  Patients who do not achieve an EVR have less than a 2% chance of reaching a SVR.  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.  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.

During the 1980s, it was observed that IFN improves liver enzymes.  Soon RBV, which inhibits RNA viral replication, was added to interferon therapy to improve SVR.  Subsequently, the pegylated formulation of interferon (PEG-IFN), was manufactured.  Chronically infected patients achieve a SVR 54-56% of the time when treated with PEG-IFN/RBV.  IFN is only available in an injectable form, has an extensive side effect profile, and has incidences of relapses—many challenges to patient compliance.  Side effects include, but are not limited to, nausea, flu-like symptoms, hematological effects, ophthalmologic disorders, respiratory symptoms, and thyroid dysfunction.  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.

Advancements in treating hepatitis C do not end with INF and RBV.  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.  Gilead Sciences’ GS-7977, GS-5885 and GS-938, are currently undergoing Phase II and III clinical trials for interferon-free HCV regimens.  Meanwhile, in November 2012, Abbott announced that the results from their Phase 2b Interferon-free Hepatitis C trial 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.  GS-7977, GS 5885, GS-938, ABT450/ritonavir, ABT-267, and ABT-333 are all promising investigational DAAs.

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

After HCV enters the hepatocyte and its genome is translated, the virus can then encode proteases.  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.  The RNA polymerase first makes a negative strand of RNA serving as a template for the production of a positive strand.  Inhibiting NS5B prevents the initiation of RNA replication, making this a targeted mechanism for drug discovery.  From the Phase 2 trials, ELECTRON and QUANTUM, GS-7977 combined with RBV displays potential in increasing SVR rates and decreasing relapse rates.  Currently undergoing the phase III clinical trial, FISSION, GS 7977 seems promising.

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.  The interferon sensitivity determining region (ISDR) of NS5A appears to determine the sensitivity of the virus to interferon.  Mutations in this region may correlate with low response rates to interferon therapy.  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.

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.  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’t this potentially result in resistance?’ Pharmasset designed these two agents to work synergistically, with GS-7977 being a pyrimidine analog and GS-352938 a purine analog.  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.

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.  HCV is translated into a polyprotein once it enters the host cell. The polyprotein is converted into structural proteins and NS proteins.  Structural proteins, such as E1, E2, and P7, are involved in the virus’ 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.  When the protein NS3/4A is inhibited, the virus cannot replicate.

Similar to GS-5885, ABT-267 is also an NS5A inhibitor.  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.  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.  This drug also inhibits RNA replication by blocking the enzyme that synthesizes RNA from an RNA template.  The interferon-free regimen of ABT-450/r + ABT-267 + ABT-333 has produced promising results in the Aviator trial.  With or without RBV, the regimen resulted in high SVR 12 weeks post-treatment in all arms.  This study included non-cirrhotic patients who were treatment-naïve as well as null responders who have failed PEG-IFN/RBV therapy.  Of note, there was an SVR of 93.3% 12 weeks post treatment in null responders taking the triple-DAA regimen + RBV.  This is important because there are few treatment options once patients fail the standard PEG-IFN + RBV therapy.  Although there has been great emphasis on interferon-free regimens, a new interferon therapy is in phase 2 and 3 clinical trials.

Pegylated Interferon-Lambda (PEG-IFN-Lambda), being developed by Bristol-Myers Squibb, is in the pipeline for becoming a “first-in-class” interferon.  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.  As the result is the same, the two pathways do have common ground and converge at some point.  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).

IFN is usually a side-effect limiting therapy, in which many patients simply cannot tolerate the medication.  Binding mainly to epithelial cells, IFN-lambda is a more specific IFN therapy.  IFN-alpha receptors are present on numerous cells including leukocytes.  The receptors of IFN-lambda create a much more tolerable and safe treatment.  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.  With time, this newer agent can become an alternative to or even replace standard interferon therapy.

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.  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.  HCV is a growing health concern in which current therapies produce a SVR only 54-56% of the time.  Furthermore, there is a risk for relapse in which treatment options become fewer and treatments less effective.  The new therapies present great potential in treating HCV for naïve and null responders, possibly making the mainstay of treatment of PEG-IFN plus RBV a thing of the past.  It is safe to say that a new page has been turned for the treatment of HCV.

Acknowledgements:  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.

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