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Solving the HCV Enigma: Current and Future Drug Therapy for Hepatitis C

By: Tamara Yunusova, Senior Staff Editor

Approximately 3.2 million Americans have chronic hepatitis C infection.1 While acute cases are not common, rates of chronic hepatitis C continue to surge due to the recent discovery of the virus in 1989 and consequently, the establishment of a test screening for HCV antibodies in 1992.1 HCV has spawned much attention over the years and as a result, numerous therapies have been developed. An understanding of HCV structure, replication, and assembly has revealed a vast array of targets for drug therapy. Apart from the viral RNA which is cleaved into 10 distinct polypeptide units, over 11 proteins assemble to form a replication complex. Current therapy, which consists of a combination of Peg-Interferon and Ribavirin for genotype 2 or 3 patients and triple therapy for patients with genotype 1, is efficacious but the adverse side effects and complex dosing regimens continue to present a great challenge. With the recent development of protein inhibitors, misense oligonucleotides, polymerase inhibitors, and interferon-free drug cocktails, the pharmaceutical industry has made great strides in hepatitis C drug therapy.

HCV is a positive single-strand RNA virus that replicates in the liver. Replication is rapid, producing average serum HCV RNA levels of one to two million genome equivalents per milliliter.1Current research shows that there are six variants of the virus. The most common genotypes in the United States are genotype 1 (approximately 75% of cases), genotype 2 (approximately 15% of cases) and genotype 3 (approximately 5% of cases).1

Although the details behind the hepatitis C virus mechanism of action are not fully understood, research studies provide an overview of the viral composition, replication, and assembly. The positive single-stranded RNA of HCV encodes a poly-protein which is then cleaved into 10 discrete polypeptide units.3 Structural proteins consist of two glycoproteins and a core protein which mediates and directs the assembly of new virions.3 The nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) assemble to form a membrane-bound replication complex with the viral RNA.3 Following replication, the newly formed virion is packaged into lipid droplets and released from cells as lipoviral particles.3

While some HCV patients have an immune response competent to eradicate the virus, chronic infection develops in 55-85% of patients.3 Patients with chronic HCV require drug therapy in order to reduce serum viral levels and attain improved health outcomes. Current therapy for Hepatitis C consists of a combination of subcutaneous Interferon alpha and oral Ribavirin.

One of the two components of current therapy, interferon alpha, blocks viral replication by activating the transcription of interferon-stimulated gene (ISG) mRNA. ISG mRNA encodes proteins that interfere with viral replication, protein synthesis, and assembly. ISGs such as 2’5’ oligoadenylate synthetase, RNA-specific adenosine deaminase, and protein kinase R are thought to be active in the inhibition of viral replication. Oligoadenylate synthetase activates RNases to cleave viral RNA, adenosine deaminase plays a role in editing viral RNA, and protein kinase R inhibits the translation of mRNA to protein.1In addition to activating ISGs, interferon alpha also triggers the antiviral immune response. It contributes to the activation of natural killer cells, the maturation of dendritic cells, the proliferation of memory T-cells, and the prevention of T cell apoptosis.1 Contrary to belief, the long-term damage to liver tissue is not caused the by virus. Instead, it is caused by the immune system which activates the inflammatory response.1

The second component of the current regimen is ribavirin. The general mechanism of the compound remains unclear; however, it is believed that ribavirin causes mutation in virions and exhausts the supply of GTP which is crucial for RNA synthesis of HCV.1

A recent milestone in Hepatitis C therapy has been the peglyation of interferon alpha producing a safer, less toxic compound. Pegylation is the process of covalently attaching a polyethylene glycol molecule to a drug compound in order to reduce immunogenicity and antigenicity.2 In a study that compared the standard interferon- ribavirin with the peginterferon- ribavirin combination, the former presented 44-47% viral eradication whereas the latter presented 54-56% clearance. The pegylated interferon alpha also has an increased half-life, which allows the drug to be administered in weekly doses.5 At this time, there are two peginterferon formulations that are FDA cleared: alfa-2a and alfa-2b.

The recommended regimen for hepatitis C using the peg-interferons consists of weekly subcutaneous injections of peg-interferon and twice daily oral doses of ribavirin. The recommended dose of peg-interferon alfa-2a is 180 μg per week, and that of peg-interferon alfa-2b is 1.5 µg per kilogram of body weight per week.1Patients with genotype 1 should receive ribavirin for 48 weeks at a daily dose of 1000 mg, or 1200 mg if weight exceeds 75 kg.1Patients with genotype 2 or 3 should receive 24 weeks of the therapy, but with a daily dose of 800 mg of ribavirin.1

HCV therapy is gauged by the sustained virologic response (SVR), or the absence of HCV RNA in serum at least 6 months after therapy. Monotherapy of interferon alpha yields a SVR that is less than 20%.1However, when peg-interferon is combined with ribavirin, the SVR is greatly improved to 40-45%.1The current mainstay therapy—combination of weekly peginterferon and ribavirin—is beset with numerous adverse effects, complex dosing regimens, and limited efficacy in patients with HCV genotype 1. Common side effects of peginterferon include muscle aches, fatigue, depression, anxiety, irritability, sleep disturbance, and difficulties in concentrating.3 Anemia, a notorious side effect of ribavirin, is the major cause of dose reductions throughout the course of the 48 week therapy.  According to the New England Journal of Medicine, 30-40% of patients require dose reductions, and 20% require early discontinuation of ribavirin due to the side effect.1Even though recent studies have shown that reducing the dose of ribavirin during week 2 to 600 mg per day is an effective way to manage anemia,1 the probability that a sudden anemia can induce a myocardial infarction in patients with pre-existing coronary artery disease or a history of stroke cannot be overlooked.1For this reason, candidates must meet certain health standards to be considered for therapy. Moreover, patients who do qualify for the treatment must undergo routine blood count to monitor for anemia.

As mentioned earlier, the duo yields greater response rates in patients with HCV genotypes 2 and 3 than those with HCV genotype 1. Fortunately, the approval of two NS3/4A protease inhibitors, boceprevir and teleprevir, for patients with genotype 1 has led to a triple combination therapy that markedly improves the SVR in patients with HCV genotype 1.3,1This therapy, only approved for genotype 1 patients, consists of one protease inhibitor, one peg-interferon, and ribavirin.3 The protease inhibitors are always administered as a combination due to the rapid emergence of drug resistant variants in monotherapy.1

However, the triple therapy regimen may lead to adverse effects and antiviral resistance. Common side effects with boceprevir include anemia, neutropenia, and dysgeusia. Telaprevir may cause anemia, rash, and anorectal discomfort.1Similar to the case of ribavirin, anemia is difficult to manage. Erythrocyte-stimulating agents can be used, but they too have numerous side effects, are costly, and are not approved for routine use in patients with chronic hepatitis C.1

Adverse effects are not the only limitation to the proposed therapies. When the drugs are used as monotheraphy, antiviral resistance occurs at the onset of therapy, as early as 4 days after initial administration. 1And because boceprevir and telaprevir share characteristics, if the resistant variants appear in reaction to one protease inhibitor, similar resistant variants will appear with the use of the other. When resistance is observed, drug administration should be stopped to diminish the resistant variants, which disappear eventually with the therapy halted. Still, certain mutations may persist for 3 or more years after discontinuation.1

 A Glimpse into the Future: Therapies under Current Investigation or Undergoing Approval

There are two classes of NS5B polymerase inhibitors—nucleoside and nonnucleoside analogue inhibitors—that are being developed. The nucleoside inhibitors bind to a specific region in the pocket of NS5B and behave as chain terminators.3 The nonnucleoside inhibitors bind to other regions of NS5B and act as allosteric inhibitors.3 Currently, there are about eight NS5A inhibitors and more than twelve NS5B inhibitors undergoing clinical trials phase 2 and 3.3 Other targets that are being explored follow: NS4B, a nonstructural protein which plays a role in the assembly of the membrane-bound replication complex, and p7, responsible for the formation of ion channels necessary for HCV assembly. However, studies show that drugs targeting NS4B and p7 are less efficacious than those that target NS3/4A, NS5A, or NS5B.3

With the development of antiviral therapies which act directly on the viral proteins, host targeting therapies are a debut to the HCV drug therapy scene. One appealing target is Cyclophilin A, an integral component of the viral replication complex. It is known that cyclosporin A is a potent cyclophilin A inhibitor, and the derivatives that lack immunosuppressive properties—alisporivir, NIM811, and SCY-63—are currently undergoing clinical trials.3 A combination of alisporivir with peginterferon and ribavirin has shown improved efficacy over peginterferon and ribavirin alone, both in treatment experienced and treatment naïve patients.3 However, due to reports of severe pancreatitis that may be associated with alisporivir, the approval process has come to a halt.3In addition to host-targeting, combining drugs with different targets to produce synergistic effects is another possible tactic utilized in development of therapy. In improving the current chronic hepatitis C treatments, researchers are seeking for the combination of drugs with the greatest efficacy, minimal adverse effects, and the least viral resistance.

Recent studies have shown that viral clearance can be attained without the use of interferon and ribavirin. In one study, patients with chronic hepatitis C (both treatment naïve and experienced) were treated with a 13-day regimen of a combination of polymerase inhibitor RG7128 (a nucleoside inhibitor) and protease inhibitor danoprevir.3 A large portion of patients who received the higher doses had undetectable HCV RNA levels after only 13 days.3

MicroRNAs— MiR122 in particular–are integral components that bind RNA to facilitate the replication of HCV. MiR122 can be inhibited by introducing into cells antisense oligonucleotides (short DNA or RNA sequences) that are engineered to be complementary to a certain gene sequence.4 Much like the binding of mRNA to DNA, antisense oligonucleotides bind to miR 122 to hinder the HCV RNA replication. While the concept behind antisense oligonucletides may appear relatively simple if not lucid, research studies suggest the contrary. The antisense mechanism of action is complex and much remains unknown. Delivering the nucleic acid to the cytosol in sufficient amounts without causing cytotoxicity is a major challenge.5

Luckily, antisense therapy has witnessed success in the HCV ballpark. In the study conducted by Janssen et al., miravirsen, a chemically modified antisense oligonucleotide that targets miR122, was shown to enter liver cells and binds tightly to miR­122, preventing the latter from binding to HCV RNA.5 In a phase 2a trial of miravirsen, once a week subcutaneous administration led to the reduction in HCV levels (<3 log10) after 5 weeks of monotherapy.5

Hepatitis C may present itself as a burden in the upcoming years as earlier undiscovered cases of the viral infection have progressed into the chronic disease phase. Advances in HCV therapy continue to bring about high sustained virological responses and in notable cases, viral clearance. Major success has been witnessed with therapies currently undergoing clinical trial: viral clearance was attained in 13 days with an interferon and ribavirin-free regimen, and the first antisense oligonucleotide effectively reduced viral load. Current developments undergoing clinical trials are promising and comprehensive mapping of the Hepatitis C virus continues to fuel the development of efficacious therapy. The progress of the future awaits to solve HCV enigma.


  1. Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic hepatitis C. The New England Journal of Medicine. 2006; 355(23): 2444-2450. Accessed June 26, 2013.
  2. Lieberman J, Sarnow P. Micromanaging hepatitis C virus. The New England Journal of Medicine. 2013; 368(18): 1741-1743. Accessed June 26, 2013.
  3. Ghany MG, Liang TJ. Current and future drug therapies for hepatitis C virus infection. The New England Journal of Medicine. 2013; 368(20):1907-1917. Accessed June 26, 2013.
  4. Dias N, Stein CA. Antisense oligonucleotides: basic concepts and mechanisms. Molecular Cancer Therapeutics. 2002; 1: 347-355. Accessed June 26, 2013.
  5. Ahad MA, Alim MA, Saifuddin Ekram ARM. Interferon to peg-interferon: a review. The Journal of Teachers Association. 2004; 17(2): 113-116. Accessed June 26, 2013.
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