Discussion

As of early 2013, the state-of-the-art treatment of chronic hepatitis C (HCV) consists of a combination of peginterferon alfa and ribavirin for 24 to 48 weeks and depending on the patient's genotype, the possible addition of telaprevir (Incivek) or boceprevir (Victrelis), one of the two currently available HCV NS3/4A protease inhibitors [1,2]. Triple therapy with peginterferon and ribavirin plus telaprevir or boceprevir is recommended for genotype 1 infection (Figure 1)[1], whereas dual therapy with peginterferon plus ribavirin is recommended for genotype 2 and 3 infection (Figure 2)[2]. The following discussion will summarize the medications used for treatment of hepatitis C, with an emphasis on mechanism of action, preparations and dosing, adverse effects, and appropriate use as part of combination therapy.

Interferon Alfa and Peginterferon Alfa

  • Mechanism of Action: Interferon alfa has potent antiviral and antiproliferative properties, but does not act directly against HCV. Instead, interferon alfa creates a non-specific antiviral environment within the hepatocyte by inducing interferon-stimulated genes (Figure 3)[3,4]. As an immunomodulator, interferon impacts both adaptive and innate immune responses against HCV. Peginterferon alfa is a modified form of interferon alfa that consists of a polyethylene glycol moiety covalently attached to interferon. This modification confers a 10-fold longer serum half-life than the parent interferon drug.
  • Preparations and Dosing: For the treatment of hepatitis C, peginterferon alfa has replaced standard interferon alfa. Indeed, several studies have shown that once weekly peginterferon alfa, when combined with ribavirin, has superior virologic efficacy compared with combination therapy with standard interferon alfa[5,6]. Two forms of peginterferon are licensed for use in the United States: peginterferon alfa-2a (Pegasys) and peginterferon alfa-2b (PegIntron)[7]. Peginterferon alfa-2a is administered as a fixed dose of 180 mcg injected subcutaneously once a week and is nearly always combined with ribavirin when treating chronic HCV. Peginterferon alfa-2b is also administered once weekly, but is dosed by weight at 1.5 mcg per kilogram.  Similar to peginterferon alfa-2a, peginterferon alfa-2b is typically given with ribavirin. Studies have shown peginterferon alfa-2a and peginterferon alfa-2b have comparable efficacy against HCV[7].
  • Adverse Effects: Side effects of interferon or peginterferon include predictable constitutional or “flu-like” symptoms of fever, chills, headache, and myalgias[8]. These symptoms typically become more pronounced during the few days immediately following the injection, although usually resolve completely after 4 to 6 weeks of treatment. Gastrointestinal side effects include nausea, anorexia, and less commonly, diarrhea. Skin dryness, pruritus, rash, hair thinning, and weight loss also occur to varying frequency. Local injection site reactions—typically characterized as mild patches of erythema—are common and generally fade with time. As a result of peginterferon’s immunodulatory properties, treatment may cause an emergence or exacerbation of immune-mediated disorders, such as thyroiditis, inflammatory bowel disease, atopic dermatitis, or psoriasis. Autoimmune hepatitis and other serious autoimmune conditions, such as uncontrolled systemic lupus erythematosus, are contraindications to treatment with peginterferon.
  • Neuropsychiatric Complications: The use of peginterferon or standard interferon frequently causes neuropsychiatric complications. This adverse effect is a major cause of treatment nonadherence and discontinuation[8]. The mechanism of this effect is not well understood, but presumably results from interferon’s influence on the serotonin and corticotropin neurohumoral pathways[9]. Persons with a history of psychiatric illness may have enhanced susceptibility for developing depressive symptoms while on interferon treatment[10]. Approximately 20 to 30% of patients may experience some form of depression. Patients also frequently complain of emotional lability, irritability, anxiety, nervousness, and impairment in concentration. Neurovegetative symptoms that may include fatigue, sleep disturbance, and psychomotor slowing can also occur during treatment. These neuropsychiatric symptoms tend to become more pronounced as treatment duration extends[9]. Since most individuals do not develop clinically significant depression, clinicians typically use antidepressant therapy for symptomatic rather than preemptive therapy.
  • Hematologic Adverse Effects: Hematologic effects are an important toxicity of both peginterferon and standard interferon and are caused by myelosuppression. Close monitoring of complete blood counts is essential during therapy (every 2 to 6 weeks depending on degree and rapidity of drop). With therapy that includes peginterferon and ribavirin, anemia is the most common cytopenia, followed by neutropenia, and thrombocytopenia.  Since ribavirin is often the primary cause of anemia, most experts typically manage the anemia first by reducing the dose of ribavirin. For further discussion on anemia, see the discussion below related to ribavirin and HCV protease inhibitors. Management of neutropenia and thrombocytopenia generally starts with dose reduction of peginterferon. Manufacturers recommend a threshold absolute neutrophil count of less than 750 cells/mm3 or platelets less than 50,000 cells/mm3 as prompts for peginterferon dose reduction[11,12]. Use of colony-stimulating factors for neutrophils or platelets is not routinely recommended. If, despite dose adjustments, the absolute neutrophil count remains less than 500 cells/mm3 or the platelet count less than 25,000 cells/mm3, manufacturers of both forms of peginterferon recommend discontinuing treatment[11,12].

Ribavirin

  • Mechanism of Action: Ribavirin is a guanosine nucleoside analogue with broad antiviral activity in vitro against a range of RNA and DNA viruses. The exact mechanism of action against HCV remains incompletely understood, but presumably involves one or more of the following mechanisms: (1) enhanced host T-cell immune clearance of HCV, (2) inhibition of the host enzyme inosine monophosphate dehydrogenase (IMPDH), with depletion of pools of guanosine triphosphate, an essential substrate for viral RNA synthesis (3) direct inhibition of HCV replication, and (4) RNA virus mutagenesis that drives HCV to error catastrophe (Figure 4 )[3,13]. When used alone in patients with chronic hepatitis C, ribavirin results in only a small transient drop in HCV RNA levels, but interestingly can lead to normalization of serum alanine aminotransferase levels[14].  Despite this apparent minimal impact on HCV viremia, ribavirin, when combined with interferon alfa or peginterferon alfa, provides a synergistic effect and an improvement of sustained virologic response (SVR) rate that greatly exceeds the SVR rates observed with interferon alfa or peginterferon alfa monotherapy. The addition of ribavirin greatly reduces the risk of viral relapse and this benefit directly correlates with drug exposure[15] and adherence[16]. This well-established synergism of ribavirin and peginterferon alfa is why ribavirin remains a crucial component of hepatitis C treatment, even in the era of HCV direct-acting antiviral agents.
  • Preparations and Dosing: Ribavirin (Copegus, Rebetol, Riba Tab, Ribasphere) is always used in combination with interferon or peginterferon and it is available in several preparations. When used to treat genotype 2 or 3 HCV, it is typically given as a fixed dose of 800 mg daily (divided into two doses), regardless of the patient’s weight. When ribavirin is combined with peginterferon alfa to treat genotype 1 HCV, the dose depends on the patient’s weight and whether the patient is treated with peginterferon alfa-2a or peginterferon alfa-2b.  For patients with genotype 1 who receive peginterferon alfa-2a, the recommended dose of ribavirin is 1000 mg per day (divided twice a day or BID) if the patient weighs less than or equal to 75 kilograms (kg) or 1200 mg per day (divided BID) if the weight is greater than 75 kg. When combined with peginterferon alfa-2b for treatment of genotype 1 infection, ribavirin is dosed using a multilevel weight-based scale of 800 mg/day for patients weighing less than 65 kg; 1000 mg/day for patients 65 to 85 kg; 1200 mg/day for patients 86 to 105 kg; and 1400 mg/day for those greater than 150 kg[1,11,12].
  • Adverse Effects: Because of its significant teratogenic and embryocidal effects in animal studies, ribavirin is contraindicated in women who are pregnant, women who may become pregnant, or men whose female partners are pregnant. Patients with chronic hepatitis C who are of reproductive age should be advised to use two forms of contraception during treatment and at least 6 months following the end of therapy[11,12]. Hemolytic anemia is one of the main toxicities of ribavirin and occurs within 1 to 2 weeks of treatment and may be accompanied by a rise in indirect bilirubin. Hemoglobin or hematocrit should be checked before starting treatment as well as at weeks 2 and 4 and every 4 to 8 weeks thereafter as indicated. Ribavirin dose reduction in 200 to 600 mg increments is often the first step in managing anemia and the amount of reduction depends in part on how steeply the hemoglobin drops and whether protease inhibitors are being used[11,12]. Ribavirin is contraindicated in patients with hemoglobinopathies. Caution is advised in patients who are particularly vulnerable to anemia, such as those with underlying renal or cardiac disease.

NS3/4A Protease Inhibitors: Boceprevir and Telaprevir

  • Mechanism of Action: In 2011, a new class of HCV medications was introduced with the FDA approval of two HCV protease inhibitors: boceprevir (Victrelis) and telaprevir (Incivek). These agents are the first of the direct-acting antivirals to receive FDA approval. During the HCV lifecycle, the single-stranded HCV RNA gets translated within the host cytoplasm to a large polyprotein that gets processed into structural proteins (for viral particle production) or nonstructural proteins (key components of viral replication) (Figure 5)[17]. These drugs work by inhibiting the NS3/4A serine protease, a major enzyme that cleaves the viral polyprotein after translation (Figure 6)[17]. Tripletherapy with peginterferon and ribavirin plus one of the protease inhibitors results in SVR rates of 63 to 75% in treatment naïve genotype 1 HCV patients (compared with 38 to 44% with dual therapy) [18,19,20,21]. The use of boceprevir or telaprevir in non-genotype 1 HCV infection is not approved nor recommended at this time due to lack of sufficient data supporting efficacy[2,22].
  • Viral Resistance: Despite their potent activity against HCV viral replication, a single point mutation in the viral genome can confer resistance to boceprevir or telaprevir. Drug resistance can emerge rapidly when either drug is used as monotherapy[23]. Therefore, monotherapy with a protease inhibitor is never an option: the protease inhibitor must be used in combination with peginterferon and ribavirin as a triple therapy regimen[2,24,25]. Furthermore, these drugs once started must be taken in an all or nothing manner—at full dose without interruption or discontinued entirely. Unlike with ribavirin, dose reduction is not permitted. Prior to the initiation of triple therapy, patients should receive thorough counseling regarding the importance of strict adherence. To minimize the risk of resistance and to avoid unnecessary treatment in those cases highly unlikely to be successful due to slow viral decline, clinicians must follow the stopping or futility rules that are recommended for each drug.  For a detailed discussion of this topic, see Virologic Responses during Treatment of Hepatitis C.
  • Drug Interactions: Drug interactions are important to consider when using the HCV protease inhibitors. Clinicians should review all medications carefully before starting any patient on either boceprevir or telaprevir. These agents are potent inducers of cytochrome p450 3A4 (CYP3A4). They can alter the serum levels of other medications metabolized by that pathway, possibly impacting the efficacy or risk of toxicity of those medications. They are also substrates of CYP3A4 and can themselves be affected by the co-administration of other medications: for example, certain antifungal medications, such as ketoconazole, can increase the serum levels of boceprevir and telaprevir, with the potential for QTc prolongation. Major drug interactions can occur when using either boceprevir or telaprevir and clinicians should consider using online resources such as the University of Liverpool Hep-Drugs Interaction site or a thorough assessment of potential interactions. Certain medications can be dose-reduced for concurrent use with the protease inhibitor, with careful monitoring. Statins should be discontinued temporarily during triple therapy to reduce risk of myopathy with concurrent use. Women of child-bearing age on systemic hormonal contraceptive therapy should be advised that such therapy may not be as effective when used with a protease inhibitor and two alternative forms of contraception, such as a combination of barrier protection and intrauterine device, may be necessary during treatment to avoid pregnancy.

Boceprevir

  • Preparations and Dosing:  Boceprevir is dosed as four 200 mg capsules totaling 800 mg every 8 hours (every 7 to 9 hours is acceptable) and should be taken with food (meal or light snack)[19,21]. Triple therapy with boceprevir is distinct from telaprevir in that it requires a 4-week lead-in phase with peginterferon and ribavirin before boceprevir is added at the beginning of week 5. Unlike telaprevir’s fixed 12-week triple therapy duration, the duration of boceprevir-based triple therapy varies from 24 to 44 weeks. The ultimate duration of triple therapy for either drug depends on a variety of patient factors, including the initial HCV response to treatment, presence of cirrhosis, and past treatment history.
  • Adverse Effects:  The most significant adverse effects associated with boceprevir that were observed in the main registration trials (Figure 7) in excess of that seen with peginterferon and ribavirin alone were anemia (45 to 50%), dysgeusia or taste alteration (35 to 44%), and neutropenia (14 to 25%)[24]. Anemia occurred nearly twice as often in the triple therapy protease inhibitor plus peginterferon and ribavirin arms as in the dual therapy peginterferon and ribavirin arms (Figure 8)[26]. Hemoglobin tends to drop an additional 1 g/dl during triple therapy, developing as rapidly as within a few weeks of starting therapy, and will generally recover to levels typically seen with dual therapy after cessation of the protease inhibitor. In both the telaprevir and boceprevir trials, severe anemia with hemoglobin less than 8.5 g/dl occurred in 9% of patients. Hematopoetic growth factor use was given to 43% of triple therapy patients compared with 24% of dual therapy patients[18,19]. Ribavirin dose reduction is the first step in managing this anemia with erythroid stimulating agents reserved for moderately severe anemia (hemoglobin less than 10 g/dl) that persists or worsens despite ribavirin decrease. Neither anemia nor ribavirin dose reduction appears to impact the likelihood of SVR with boceprevir-based triple therapy: patients who develop anemia tend to have higher SVR rates since perhaps the anemia reflects higher circulating plasma levels of ribavirin[26]. If anemia is severe enough to necessitate stopping ribavirin, the protease inhibitor and peginterferon must be stopped as well.

Telaprevir

  • Preparations and Dosing:  Telaprevir is dosed as two 375 mg tablets totaling 750 mg every 8 hours (every 7 to 9 hours is considered acceptable) and should be taken with food (meal or light snack). Because the absorption of telaprevir is enhanced more than 2-fold with a fatty meal, at least 20 grams of fat should be ingested within 30 minutes of taking telaprevir[25,27]. Triple therapy with telaprevir involves initiating the drug with peginterferon and ribavirin for the first 12 weeks and then switching to peginterferon and ribavirin dual therapy for the remainder of the course.
  • Adverse Effects:  The most significant adverse effects reported in the main registration trials with telaprevir (Figure 9) and found to occur in excess of that seen with peginterferon and ribavirin alone were rash (56%), anemia (36%) and anorectal complaints ranging from perianal pruritus to painful hemorrhoids (29%)[25,27]. For discussion regarding anemia, please see the boceprevir section on adverse effects. Rash is the most common side effect attributable to telaprevir with triple therapy. In most cases, the rash is eczematous or maculopapular in character and mild to moderate in severity, resolving with cessation of telaprevir. Pruritus not necessarily accompanied by rash can also be a common complaint. Topical corticosteroids or oral antihistamines may be helpful in managing the rash along with generous hydration of the skin with emollients. Severe rash involving greater than 50% of the total body surface area occurred in 4% of patients[25,27]. Rash prompted the discontinuation of telaprevir in 6% cases. Serious cutaneous reactions such as Stevens-Johnsons’ syndrome or drug rash with eosinophilia and systemic symptoms (DRESS) were rare but did occur (less than 1%) and should be recognized early. In December 2012, a report of a fatal case of toxic epidermal necrolysis in a patient on telaprevir prompted the FDA to add a black box warning highlighting the necessity of stopping therapy immediately in patients with a progressive severe rash or rash with systemic symptoms. Patients on telaprevir should be instructed to alert clinicians immediately of any rash or skin lesions, especially if they are accompanied by blisters, red or inflamed eyes, fever or facial swelling.

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    Figure 1. Recommended Triple Therapy Regimens for HCV Genotype 1 Infection

    Abbreviations: SQ = subcutaneous; BID = twice daily; h = hour

    Figure 1
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    Figure 2. Recommended Regimens for Treatment of HCV Genotype 2 or 3 Infection

    Abbreviations: SQ = subcutaneous; BID = twice daily; h = hour

    Figure 2
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    Figure 3. Proposed Mechanism of Action of Interferon Alfa Against HCV.

    Interferon alfa engages receptors on the surface of the hepatocyte, initiating intracellular signal transduction that prompts the transcription of multiple interferon-stimulated genes (ISGs) that encode proteins that can interfere at various stages of the hepatitis C viral life cycle.
    Source: This figure is reproduced from: Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic hepatitis C. N Engl J Med. 2006;355:2444-51. Reproduced with permission from the Massachusetts Medical Society. Copyright© 2006 Massachusetts Medical Society. All rights reserved.


    Figure 3
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    Figure 4. Potential Anti-HCV Mechanism of Action of Ribavirin

    Abbreviations: RBV = ribavirin; CTL = cytotoxic T-lymphocyte; P = phosphate; IMPDH = inosine monophosphate dehydrogenase; GMP = guanosine monophosphate; GTP = guanosine triphosphate; RdRp = RNA-dependent RNA Polymerase

    The exact mechanism of action for ribavirin is not entirely clear, but investigators have proposed multiple possible sites of intervention (1) immune clearance: ribavirin induces a TH1-favored host response. (2) Inhibition of IMPDH: ribavirin-monophosphate inhibits the host enzyme IMPDH that can deplete guanosine triphosphate (GTP), a critical building block for HCV RNA replication. (3) Ribavirin can directly inhibit HCV polymerase activity via its triphosphate form. (4) Ribavirin may also cause a series of lethal mutations in the HCV viral genome


    Figure 4
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    Figure 5.Hepatitis C Translation and Protein Processing

    Following infection in the host, the single stranded HCV RNA is translated into a single polyprotein that is subsequently cleaved into 10 proteins by the enzymes signal peptidase, NS2/3 protease, and NS3/4A serine protease.


    Figure 5
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    Figure 6. Inhibition of NS34A Serine Protease

    The NS34A serine protease inhibitors exert their activity by inhibiting the NS3/4A serine protease, an enzyme that cleaves several key sites in the polyprotein precursor. The end result NS34A serine protease inhibitors is to prevent the formation of several of the critical nonstructural proteins.


    Figure 6
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    Figure 7. Boceprevir Adverse Effects

    Abbreviations: PegIFN = peginterferon; RBV = ribavirin These data are derived from the SPRINT-1 and SPRINT 2 studies.
    Source: Merck. (2012). Boceprevir: Highlights of prescribing information.


    Figure 7
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    Figure 8. Boceprevir-Related Hematologic Adverse Effects

    In the SPRINT-2 trial, previously untreated patients with genotype 1 HCV infection received treatment with peginterferon and ribavirin, with or without boceprevir. As shown in the graph, moderate anemia (hemoglobin less than 10 g/dl) occurred frequently in the study and the rates were highest in those who received triple therapy with peginterferon, ribavirin, and boceprevir.
    Source: Sulkowski MS, Poordad F, Manns MP, et al. Anemia during treatment with peginterferon alfa-2b/ribavirin and boceprevir: Analysis from the sprint-2 trial. Hepatology. 2012 Oct 18. [Epub ahead of print]


    Figure 8
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    Figure 9. Telaprevir Adverse Effects

    Abbreviations: PegIFN = peginterferon; RBV = ribavirin
    Source: Vertex. (2012). Telaprevir: Highlights of prescribing information.


    Figure 9