May 7, 2012

Clinical Liver Disease

Volume 1, Issue 2, pages 32–35, April 2012

Review

Syed-Mohammed R. Jafri M.D.*, Stuart C. Gordon M.D.

Article first published online: 26 APR 2012

DOI: 10.1002/cld.30

Copyright © 2012 the American Association for the Study of Liver Diseases

Abstract

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A2M, alpha-2-macroglobulin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BOC44, boceprevir for 44 weeks; BOC RGT, boceprevir and response-guided therapy; CDS, cirrhosis discriminant score; DAA, direct-acting antiviral; GGT, gamma-glutamyl transpeptidase; HA, hyaluronic acid; INR, international normalized ratio; ITT, intention to treat; Pbo, placebo; PIIINP, amino-terminal propeptide of type III collagen; PR48, peginterferon/ribavirin for 48 weeks; SVR, sustained virological response; T12PR, telaprevir for 12 weeks and peginterferon/ribavirin; T12/PR48, telaprevir for 12 weeks and peginterferon/ribavirin for 48 weeks; TIMP1, tissue inhibitor of metalloproteinase 1.

Current guidelines emphasize the importance of liver biopsy in the management of patients with hepatitis C because liver histology provides patients and their physicians with important prognostic information and helps to guide therapy decisions and treatment regimens.1,2 Recent improvements in antiviral therapy along with the development of alternate modes of evaluating fibrosis have led to a global reassessment of the risks and benefits and the overall wisdom of performing liver biopsy in these patients.

The presence of advanced or worsening fibrosis has traditionally served as an unequivocal indication for therapy,3 and clinicians still use the degree of fibrosis as a means for justifying therapy sooner rather than later. The availability of direct-acting antiviral (DAA) agents, which bring the promise of rapid viral negativity with therapy, intuitively appears to lessen the need for biopsy in therapeutic decision making; this is analogous to previously held perceptions about genotype 2/3 patients, who had higher sustained virological response (SVR) rates. Because of the increased efficacy of the newer regimens and even better regimens around the corner, clinicians and patients may choose to forgo biopsy with the compelling argument that the benefits of such effective therapy justify its use, even in those with minimal disease.

On the basis of the results of pivotal registration trials, the US Food and Drug Administration has suggested that therapy with DAA agents mandates an assessment of the degree of fibrosis because of the vastly different therapeutic regimens for patients with more advanced fibrosis. The recommended treatment with peginterferon/ribavirin and either telaprevir or boceprevir must be longer (48 weeks) because of the consistently lower efficacy of the therapy in patients with cirrhosis2 (Figs. 1–3). Accordingly, an assessment of the degree of fibrosis is crucial before the initiation of therapy. Treatment with interferon and ribavirin has led to higher rates of adverse events, including anemia, in the face of cirrhosis,8,9 and this information must be discussed with patients with cirrhosis before the initiation of current DAA-based therapies that include peginterferon and ribavirin.

nfig001

Figure 1. SVR rates by the degree of fibrosis in the ADVANCE and ILLUMINATE studies. Abbreviations: ITT, intention to treat; PR48, peginterferon/ribavirin for 48 weeks; T12PR, telaprevir for 12 weeks and peginterferon/ribavirin. Adapted with permission from New England Journal of Medicine.4, 5

nfig002

Figure 2. SVR rates for patients with bridging fibrosis or cirrhosis in the Serine Protease Inhibitor Therapy 2 trial. Abbreviations: BOC44, boceprevir for 44 weeks; BOC RGT, boceprevir and response-guided therapy; PR48, peginterferon/ribavirin for 48 weeks. Adapted with permission from Journal of Hepatology.6

nfig003

Figure 3. SVR rates by the degree of fibrosis in the REALIZE trial. Abbreviations: Pbo, placebo; PR48, peginterferon/ribavirin for 48 weeks; T12/PR48, telaprevir for 12 weeks and peginterferon/ribavirin for 48 weeks. Adapted with permission from the European Association for the Study of the Liver.7

In comparison with peginterferon/ribavirin dual therapy, the telaprevir- and boceprevir-based regimens have superior efficacy,4,10-14 but the field is moving forward quite rapidly, and we are currently learning about (1) far more potent DAA agents with better pharmacokinetic profiles, (2) interferon-sparing regiments, and (3) SVR rates approaching 100%. Thus, there is the likelihood that superior regimens will become available over the next few years. As physicians and patients with hepatitis C virus ponder their options, information obtained from liver biopsy samples may greatly assist in the decision to wait yet longer for future regimens with improved efficacy, shorter durations, and lower side-effect profiles.

The establishment of the fibrosis stage remains a key parameter that guides the management of patients with chronic hepatitis C. The presence of advanced fibrosis requires future lifelong screening for the development of varices and hepatocellular carcinoma, regardless of future responses to antiviral therapy. Unfortunately, an all-too-common scenario in clinical practice is the patient with known or unknown hepatitis C who learns of his cirrhosis only after the discovery of liver cancer or a large variceal bleed. Advanced fibrosis may exist in patients with normal liver enzyme levels and synthetic parameters.15 The identification of fibrosis at biopsy can be used as a realistic justification for encouraging reduced alcohol intake and weight reduction, which are factors that would otherwise accelerate the progression to cirrhosis.16-21

For the post–liver transplant patient with chronic hepatitis C, liver biopsy information is essential not only for assessing patients for fibrosis but also for differentiating between recurrent hepatitis C–induced inflammation and acute cellular rejection. Accelerated fibrosis progression in the posttransplant patient with chronic hepatitis C leads to graft loss in up to 30% of infected patients.22-24 Preemptive antiviral therapy without the guidance of biopsy information is often precluded by cytopenias, renal insufficiency, increased side effects, and the possibility of rejection.25,26 Current guidelines suggest the initiation of therapy only after the demonstration of significant cholestasis or fibrosis on liver biopsy.1,27 Accordingly, the information gained from liver biopsy, including the demonstration of either fibrosis progression or a lack of rejection, before the institution of antiviral therapy is vital to the posttransplant care of the hepatitis C patient.

The risks of liver biopsy include severe pain, organ perforation, and bleeding.28,29 This potential for complications has generated an increasing acceptance of alternative assessments of hepatic fibrosis, especially in patients with hepatitis C (Table 1). Unfortunately, for many such panels, availability, third-party payment, or widespread clinical consensus is lacking. Fibrosis related to chronic hepatitis C progresses slowly (on average 0.15 stages per year30), and a feasible alternative to liver biopsy must be able to measure this progression over time. Evaluations using standard laboratory tests, including the aspartate aminotransferase/alanine aminotransferase ratio, the cirrhosis discriminant score, the age-platelet index, the Pohl score, the aspartate aminotransferase to platelet ratio index, and platelet counts, lack either the sensitivity or the specificity needed to be useful in clinical practice.31,34,35 In addition, these noninvasive fibrosis markers may have reduced performance in hepatitis C patients with normal alanine aminotransferase levels.36 Larger test panels, including Hepascore, Liverscore, and FibroTest, have high potential for false-positive results and are not readily available in clinical practice.32,37-39 These laboratory tests and panels have not reliably detected intermediate stages of fibrosis or the progression of fibrosis, and this is valuable information for clinical decision making.30,40 Transient elastography produces suboptimal results in obese patients and in tracking changes in fibrosis.41-43 The reproducibility of transient elastography is significantly reduced (P < 0.05) in patients with steatosis, an increased body mass index, or lower degrees of hepatic fibrosis.

Table 1. Noninvasive Markers for Liver Histological Assessments (Including Tests for Fibrosis, Necroinflammation, and Steatosis)
Test Components Sensitivity/Specificity for Advanced Fibrosis (%/%)
  1. The data for this table were taken from Rockey and Bissell,30 Lackner et al.,31 Adams et al.,32 Sanai and Keeffe,33 and Sebastiani et al.36

  2. Abbreviations: A2M, alpha-2-macroglobulin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; HA, hyaluronic acid; INR, international normalized ratio; PIIINP, amino-terminal propeptide of type III collagen; TIMP1, tissue inhibitor of metalloproteinase 1.

FibroTest-ActiTest Age, sex, A2M, GGT, haptoglobin, total bilirubin, apolipoprotein A1, ALT 87/59
FIBROSpect II HA, TIMP1, A2M 83/66
European Liver Fibrosis Group algorithm Age, PIIINP, HA, TIMP1 90/41
FibroMeter Age, sex, A2M, HA, platelet count, AST, prothrombin 82/−
Hepascore Age, sex, HA, A2M, GGT 67/92
AST-to-platelet ratio index AST, platelet count 41/95
AST/ALT ratio AST, ALT 53/100
Forns index Age, platelet count, GGT, cholesterol 94/51
Pohl score AST, ALT, platelets 18/98
Age-platelet index Age, platelet count 68/55
Cirrhosis discriminant score AST, ALT, platelet count, INR 10/100
Fibrosis prediction index Age, AST, cholesterol, past alcohol use, insulin resistance 85/48
FibroScan Hepatic transient elastography 64/87
FIB-4 Age, AST, ALT, platelet count 71/65

Percutaneous liver biopsy is considered the gold standard for histology assessment, yet it has a widely recognized sampling error rate as high as 20% for the detection of encircling fibrotic nodules with the evaluation of just 1/50,000 of the total organ.44 Such samples can be useful only if there are an adequate number of complete portal tracts, and with a length of 2 cm and a width of 1.4 mm, this goal is often not achieved in clinical practice. Moreover, the discordance between biopsy samples taken from right and left lobes further demonstrates the inherent limitations of this time-honored diagnostic test.44,47 Despite these challenges, a liver biopsy sample from a patient with hepatitis C in the new antiviral era remains a source of invaluable information. This information can be combined with available clinical and laboratory evidence (often surrogate markers with their own inherent limitations) to best serve the patient. A physician's or patient's reluctance to undertake the risks of biopsy should not represent a contraindication to antiviral therapy but rather should serve as the basis for a discussion of our limitations in assessing liver function and disease severity.

References

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Clinical Liver Disease

Volume 1, Issue 2, pages 54–57, April 2012

Douglas L. Nguyen M.D.1, Timothy R. Morgan M.D.2,*

Article first published online: 26 APR 2012

DOI: 10.1002/cld.33

Copyright © 2012 the American Association for the Study of Liver Diseases

Abstract

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DRESS, drug reaction with eosinophilia and systemic symptoms; ESA, erythropoietin-stimulating agent; FDA, Food and Drug Administration; PEG-IFN, peginterferon; RBV, ribavirin; SJS, Stevens-Johnson syndrome; SSRI, selective serotonin reuptake inhibitor.

Adverse events (side effects) are commonly observed in patients undergoing treatment for chronic hepatitis C (Table 1). Treatment with telaprevir and boceprevir can worsen side effects frequently associated with peginterferon (PEG-IFN) and ribavirin (RBV) treatment and can cause different adverse events. This overview focuses on the management of common adverse events that are associated with protease inhibitor treatment (Table 2).

Table 1. Commonly Encountered Side Effects During the Treatment of Chronic Hepatitis C

  • Hematological
  • Anemia
  • Neutropenia
  • Thrombocytopenia
  • Neuropsychiatric
  • Difficulty with concentration
  • Depression
  • Insomnia
  • Irritability
  • Dermatological
  • Alopecia
  • Localized skin irritation at the PEG-IFN injection site
  • Erythematous maculopapular eruptions
  • DRESS
  • SJS
  • Other
  • Flu-like symptoms
  • Fatigue
  • Generalized achiness
  • Thyroid disorders
  • Dysgeusia
  • Anorectal discomfort
  • Diarrhea
  • Hyperuricemia

 

Table 2. Management Strategies for Common Side Effects
  1. *Trazodone and zolpidem have drug interactions with boceprevir and telaprevir and initially should be used at low doses.

Flu-like symptoms Rest, fluid intake, and antipyretics (i.e., acetaminophen and nonsteroidal anti-inflammatory drugs)
Fatigue Rest and psychostimulants, ondansetron, or dopamine agonists
Dyspnea RBV dose reduction
Generalized aches Serotonin-norepinephrine reuptake inhibitor (i.e., duloxetine)
Depression 1. SSRIs (e.g., citalopram)
2. Psychiatric referral for refractory depression or suicidal ideation
Insomnia Trazodone or non-benzodiazepine hypnotics*
Alopecia 1. Hats and head coverings
2. Reassurance that hair will regrow after the discontinuation of therapy
Anemia 1. RBV dose reduction
2. ESAs (not FDA-approved for this indication)
3. Discontinuation of protease inhibitors if anemia is refractory to RBV dose reduction and ESAs
Hyperuricemia Allopurinol if the serum uric acid level is >9.5-10 mg/dL
Before Starting Treatment

It is important for providers to anticipate, recognize, and respond to side effects in order to achieve compliance with therapy. Patient education before treatment should include a full discussion of potential side effects. Patients should be instructed to call the physician's office if they experience significant side effects.

Symptomatic Adverse Events
Flu-Like Symptoms

The most common side effects associated with PEG-IFN therapy are flu-like symptoms, which include fever, headache, myalgias, general aches and pains, sweating, chills, and nausea. These symptoms occur shortly after the first injection and often decrease during the course of treatment. Management is symptomatic, with reassurance, rest, oral fluid intake, and nonsteroidal analgesics used as needed. For generalized aches and pains, a serotonin-norepinephrine reuptake inhibitor (i.e., duloxetine) can be considered.1 More than half of the patients undergoing treatment with triple therapy report fatigue.2-4 Psychostimulants (methylphenidate and dextroamphetamine), odansetron,5 and dopamine agonists6 may alleviate fatigue but are not commonly prescribed.

Neuropsychiatric Effects

In phase 3 trials, approximately 15% to 25% of patients receiving PEG-IFN, RBV, and a protease inhibitor suffered from depression.3,4 Symptoms that should be treated as depression equivalents include irritability, anger, insomnia, and easy crying. The use of a standardized questionnaire (e.g., the Beck Depression Inventory, the Center for Epidemiologic Studies Depression Scale or the Major Depression Inventory) may detect more patients with depression than routine clinical examinations.7, 8

Mild to moderate depression can be managed by the hepatitis C specialist with the use of selective serotonin reuptake inhibitors (SSRIs).9 Among patients with preexisting depression or anxiety, pretreatment with an antidepressant can significantly reduce aggravating depression and anxiety during the treatment course.10,11 Insomnia can be treated with SSRIs, non-benzodiazepine hypnotics, or trazodone.

A comprehensive and multidisciplinary mental health program improves adherence to hepatitis C virus therapy.12 Patients with significant depression despite SSRI treatment should be referred for psychiatric consultation. Patients with suicidal ideation should stop treatment and/or be followed closely by a psychiatrist.

Dermatological Effects

Approximately 50% of patients treated with telaprevir develop cutaneous reactions, with most rashes occurring during the first 4 weeks of treatment.13-15 Although most skin reactions are mild to moderate, approximately 5% to 6% may be severe enough to require the discontinuation of telaprevir (and possibly PEG-IFN and RBV) (Table 3).13-15 It is not possible to predict which patients will develop progressive skin reactions; occasionally, skin reactions progress quickly.

The rashes are erythematous, maculopapular eruptions (morbiliform drug eruptions) that typically occur on the torso, arms, and head, but they can also occur on the legs. Patients should be assessed every 1 to 2 weeks to determine whether there is an increased percentage of skin involved or an increase in erythema or induration.

 

Table 3. Management of Telaprevir-Associated Rashes
Mild to moderate rash This type of rash is erythematous and macular. It is usually found on the torso, arms, and head and involves less than 50% of the body surface area. Eosinophilia is often present. 1. Monitor every 1-2 weeks for the progression of the rash (a greater extent or greater erythema or induration) or the development of systemic symptoms.
2. Use oral antihistamines (nonsedating or sedating) as needed:
Cetirizine (5-10 mg daily)
Fexofenadine (60-180 mg daily)
Loratadine (5-10 mg daily)
Diphenhydramine (12.5-25 mg 4 times daily)
Hydroxyzine (10-25 mg 4 times daily)
3. Apply topical corticosteroids to pruritic areas (but not the face):
Triamcinolone (0.1% twice daily)
Fluocinonide (0.05% twice daily)
Hydrocortisone [2.5% with 1% pramoxine in a hydrophilic lotion (Pramosone)]
Severe rash This type of rash involves more than 50% of the body surface area. Eosinophilia is usually present. 1. Discontinue telaprevir.
2. Continue PEG-IFN and RBV.
3. If there is no improvement in the rash after 7 days, discontinue PEG-IFN and RBV.
4. Monitor weekly until the rash is resolved
5. Consider a dermatological consultation.
Serious skin reactions (DRESS or SJS) There are systemic symptoms such as fatigue. Eosinophilia (DRESS) is present. Alanine aminotransferase levels are often increased. There are mucous membrane ulcerations (SJS) and bullae. 1. Discontinue telaprevir, RBV, and PEG-IFN.
2. A dermatological consultation is strongly recommended.
3. Do not use oral steroids to treat the rash.
4. Monitor weekly until the rash is resolved.
Skin care tips 1. Apply moisturizers at least twice daily.
2. Use mild, unscented soaps and take warm (not hot) showers.
3. Limit sun exposure.

General skin care includes the use of non–alcohol-containing skin moisturizers at least twice daily, the limitation of sun exposure, the use of mild, unscented soaps, and the avoidance of hot showers. Mild to moderate rashes can be managed with topical steroids and oral antihistamines; oral steroids are not recommended as a treatment for rashes. Rashes involving more than 50% of the body surface area, especially when there are worsening generalized symptoms (e.g., more fatigue) or increases in alanine aminotransferase or aspartate aminotransferase levels, suggest a serious drug reaction requiring the discontinuation of telaprevir. Patients should be evaluated 1 week after the discontinuation of telaprevir to ensure that the rashes have stabilized or improved. If the rashes progress despite the discontinuation of telaprevir, then PEG-IFN and RBV should be stopped. Significant skin reactions may take 4 to 6 weeks to completely resolve.

Severe rashes [e.g., Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS)] have been reported in less than 1% of patients receiving telaprevir. The US Food and Drug Administration (FDA) recommends the immediate discontinuation of all three drugs if serious skin reactions occur (i.e., SJS or DRESS).13 Consultation with a dermatologist is strongly recommended.

Other Symptoms

The addition of boceprevir and telaprevir to PEG-IFN/RBV results in a higher incidence of dysgeusia, nausea, vomiting, and diarrhea in comparison with PEG-IFN/RBV alone.4,14,15 These symptoms are usually mild and rarely require the discontinuation of the protease inhibitor. Bowel movements can be controlled with loperamide or diphenoxylate and atropine.

 

Table 4. Management of Anorectal Discomfort
Topical steroids (low potency) 1% hydrocortisone cream or ointment (may cause skin atrophy if it is used for more than 2 weeks and can be alternated with petrolatum jelly)
Hydrocortisone acetate suppositories (e.g., Anucort-HC)
Topical local anesthetics 1% hydrocortisone/1% pramoxine foam (Proctofoam-HC)
Lidocaine jelly
Nocturnal itching Diphenhydramine
Loratadine
Diarrhea Fiber supplementation
Loperamide
Diphenoxylate and atropine

Up to 25% of patients receiving telaprevir complain of anal/perirectal symptoms, which have been described as discomfort, burning, itching, and/or hemorrhoids.13-15 Treatment is symptomatic and includes careful cleaning (with wet toilet paper or commercial products such as hemorrhoidal wipes) followed by a topical hydrocortisone cream (1%-2.5%) (Table 4). Hydrocortisone acetate suppositories (e.g., Anusol-HC), Proctofoam-HC, and lidocaine jelly have also been used.16-18

Laboratory Adverse Events
Hematological Events

In patients receiving PEG-IFN/RBV, the hemoglobin level decreases approximately 3 g/dL during the first 12 weeks of therapy19,20; 9% to 16% of patients have a hemoglobin nadir less than 10 g/dL.21-23 The addition of boceprevir or telaprevir to PEG-IFN/RBV leads to an additional decrease in the hemoglobin level of approximately 1 g/dL beyond that observed with PEG-IFN/RBV alone.4,13-15,23 A hemoglobin nadir less than 10 g/dL occurred in 52% of patients receiving boceprevir and PEG-IFN/RBV4 and in 37% of patients receiving telaprevir and PEG-IFN/RBV.13 It is important to note that the use of erythropoietin-stimulating agents (ESAs) was permitted for the treatment of anemia in phase 3 trials of boceprevir but not in phase 3 trials of telaprevir.

Neutropenia and thrombocytopenia are also common side effects of PEG-IFN.24-26 Despite the reduction in the absolute neutrophil count, the rate of bacterial sepsis is low and does not appear to correlate with the duration or nadir of neutropenia in PEG-IFN/RBV–treated patients.24,25 Telaprevir and boceprevir have been associated with neutropenia and thrombocytopenia beyond that seen with PEG-IFN/RBV alone,4,27 presumably because of bone marrow suppression.

The primary management of hematological side effects during treatment for hepatitis C, as recommended in the package inserts, is the reduction of the dose of PEG-IFN or RBV.13,27 Reducing the dose of RBV, even below 60% of the cumulative dose, does not appear to reduce the sustained viral response as long as RBV is not interrupted for more than 7 consecutive days.28,29 Post hoc analyses suggest that an RBV dose reduction for anemia does not reduce the sustained viral response among patients receiving boceprevir or telaprevir.4,13,27

Although ESAs are not approved by the FDA for the treatment of anemia among patients undergoing hepatitis C treatment, this strategy is employed in clinical practice.4,28-30 The FDA has given ESAs black-box warnings for increased risks of thrombosis, stroke, cancer (among patients with prior cancer), and pure red cell aplasia.30 Our clinical practice is to use ESAs only if an RBV dose reduction is ineffective. ESAs should be reduced when the hemoglobin level is greater than 10 g/dL and stopped before the hemoglobin level reaches 12 g/dL. If dose reductions of RBV and the administration of erythropoietin are inadequate, consider the discontinuation of the protease inhibitor.13,27

The dose of PEG-IFN should be reduced when the absolute neutrophil count is less than 750/μL and stopped when it is less than 500/μL; a minority of hepatologists continue to use low doses of PEG-IFN despite a neutrophil count less than 500/μL. A small clinical trial has demonstrated that filgrastim can be used to stimulate neutrophil production in patients receiving interferon.31 Eltrombopag, a thrombopoietin agonist, can increase the platelet count in patients with cirrhosis and thrombocytopenia.32 However, eltrombopag is associated with an increased risk of portal vein thrombosis in patients with chronic liver disease33 and should be used only with close monitoring and full disclosure to patients.

Other Laboratory Abnormalities

Telaprevir is associated with an elevation of serum uric acid, which begins during the first few weeks and continues as long as telaprevir is being used.13 Allopurinol should be considered when the serum uric acid level exceeds 9.5 to 10 mg/dL. A typical regimen is 100 mg of allopurinol daily for the first week and 100 mg twice a day thereafter.

References

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Clinical Liver Disease

Volume 1, Issue 2, pages 41–45, April 2012

Review

Corinne Wentworth-Kotara*, P.A-C.

Article first published online: 26 APR 2012

DOI: 10.1002/cld.9

Copyright © 2012 the American Association for the Study of Liver Diseases

Abstract

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HCV, hepatitis C virus; INO, independent nonprofit organization; PAP, patient assistance program; PCR, polymerase chain reaction.

The recent introduction of direct-acting antiviral agents to the armamentarium for treating patients chronically infected with hepatitis C virus (HCV) genotype 1 has improved the efficacy of antiviral treatment,1-3 but it also presents new challenges. As advanced and complex therapies evolve, ancillary staff will have to overcome a steep learning curve to ensure that patients are appropriately managed and successfully complete their treatment.

The selection of candidates for treatment is critical. The documentation of a patient's previous experience with interferon-based therapy, including dose reductions, side effects, and responses (null response, partial response, or relapse), is important in planning the treatment and estimating the chance of a response. Potential drug-drug interactions must be addressed; this may require changing or discontinuing some medications. These issues are described in other articles of this issue of Clinical Liver Disease.

This article presents practical guidelines for implementing antiviral treatment and monitoring patients throughout the course of the treatment. Triple-drug therapy is expensive and labor-intensive for both the provider and the patient. Considerable time and effort can be saved by the development of standardized protocols and flow sheets, familiarity with the drug approval process, patient education, and patient support services. Although these issues may seem mundane and require a considerable investment of time, they ultimately provide the most efficient way of administering therapy and optimizing outcomes.

Prescribing Information
Selection of a Pharmacy

Most prescriptions for HCV therapy now require the use of specialty pharmacies. Although the patient's insurance may require a specific pharmacy, knowing what services are provided by the specialty pharmacies in your area can save you considerable work. For example, some handle the prior authorization process, whereas others defer this time-consuming process to the provider. Others offer patient education services and 24-7 phone support. All should notify you about drug shipments, potential disruptions in shipment schedules, and patient calls. The initial drug shipment should not occur before the patient has been instructed in dose timing, side-effect management, and so forth (discussed later). Finally, ensure that the pharmacy is able to refill the prescription for the entire treatment course; beware of the one-time fill situation in which the insurance company requires a different pharmacy to provide the refills. This can disrupt the continuity of care if there is a delay in transferring the prescription or reauthorization is required.

Prior Authorization

Patients must have adequate funding to afford the medications and the required monitoring during treatment. Commercial and government health insurance generally covers at least part of this cost, although coverage and copays vary widely. The process of prior authorization differs among carriers and can be straightforward or painfully complex. At a minimum, it requires demographic information, recent laboratory results (including the viral load and genotype), clinical notes, and documentation that the patient does not have an absolute contraindication to therapy.

Co-Pays, Patient Assistance Programs (PAPs), and Independent Nonprofit Organizations (INOs)

Specialty pharmacies that assist with prior authorization generally communicate information about copays to patients before they dispense medications; otherwise, this falls to the provider. Copays may differ for each of the drugs and may vary from nothing to more than half of the cost. For patients unable to afford the copays, assistance is available, but it may not be sufficient to cover the difference. Unfortunately, those with Medicare, Medicaid, and other forms of government insurance (e.g., residents of Massachusetts) are excluded from these programs. These programs are listed in Table 1. Patients with commercial insurance who have large out-of-pocket expenses may be referred to a third-party copay assistance program. These INOs sometimes offer grants to patients, and these grants vary in amount and duration. Manufacturers and PAPs can refer patients to INOs but cannot influence or control INOs or guarantee copay assistance. It is important to understand the difference between the programs and the assistance that they offer. INOs are reviewed in Table 2.


Table 1: Industry-Sponsored PAPs

Genentech

Pegasys
Pegasys Access Solutions4
888-941-3331 888-941-3331 http://www.genentechaccesssolutions.com
The company refers patients to INOs for copay assistance programs and assists with the application process.

Copegus
Genentech Access to Care Foundation
1 DNA Way, Mail Stop 858a, South San Francisco, CA 94080-4990 888-941-3331 888-941-3334 (fax)
The company provides free medicine for up to 1 year to uninsured patients, patients denied by health care plans, and patients not covered by Medicare or Medicaid. The adjusted gross income must be <$100,000. Patients must meet medical criteria. The company does not cover the costs of monitoring or office visits.

Kadmon

Ribasphere Ribapak
Aspire5
1640 Century Center Parkway, Department 053, Memphis, TN 38134 888-668-3393 800-724-8036 (fax)
Patients have no insurance and meet undisclosed program guidelines.

Merck

  1. Peg-Intron
  2. Rebetol
  3. Victrelis

ACT Program6
833-363-6379  http://www.merck.com/merckhelps/act-program/home.html
The company provides free reimbursement support services related to insurance issues and refers patients to the PAP for free medication if they are eligible.

  1. Peg-Intron
  2. Victrelis

Merck Cares7
http://www.merck-cares.comhttp://www.victrelis.com
A copay assistance card covers up to $200 per fill for 12 fills. The encompassing site includes access to education, resources, and support for patients.

Vertex

Incivek
Guidance and Patient Support8
855-837-8394 http://www.incivek.com/vertex-guidance-patient-support
There is no income requirement. The company covers 20% (up to $10,000) of any type of out-of-pocket expense.

Patients are required to disclose their annual income (typically Internal Revenue Service form 1040) and the number of household members; each program has specific financial coverage and requires certification that patients are treatment-appropriate candidates. Patients also must be US residents without Medicare, Medicaid, or other federal government insurance coverage (e.g., Tricare or Champus). Patients residing in Massachusetts are excluded from participation.

Table 2: INOs That May Provide Grants for Drug Support

Patient Access Network Foundation9
P.O. Box 221858, Charlotte, NC 28222-1858 866-316-7263 http://www.panfoundation.org
There is an online application. Insurance is required. Income must be below the federal poverty level. Patients must reside and receive treatment in the United States.

Patient Advocate Foundation: Co-Pay Relief Program10
421 Butler Farm Road, Hampton, VA 23666 866-512-3861 http://www.patientadvocate.org
There is an online application. Direct financial support is provided to insured patients, including Medicare Part D beneficiaries who qualify. Patients are helped on a first-come, first-serve basis.

Chronic Disease Fund11
6900 North Dallas Parkway, Suite 200, Plano, TX 75024 877-968-7233 http://www.cdfund.org
This program is for privately insured patients and Medicare Part D patients unable to afford medication. There are three programs (public, private foundation, and PAP). An online application is available. Only Pegasys and Peg-Intron are covered.

INOs operate independently. Qualifications and awards are specific to INOs and are not influenced or controlled by manufacturers of specific HCV medications.


Getting Started

Patient Education

Patient education is essential to the success of therapy. Structured one-on-one or group sessions work best and should be conducted immediately before therapy is begun. The key points of this discussion are listed in Table 3. Because this education is extensive, it should be considered a billable event, and a bill for appropriate reimbursement should be submitted to the insurance company (Current Procedural Terminology code 99215). Patients must be instructed not to start oral therapy before pegylated interferon is initiated because of the risk of drug resistance.

Table 3. Pretreatment Patient Education
Talking Point Specifics Key Points
Disease Simple explanation of HCV The virus is like other viruses but lives in and can damage the liver.
The virus level does not influence disease severity.
The virus level is important only for the treatment response.
The virus can be eradicated; this is the goal of treatment.
Liver disease The course is usually slow (over decades), but it is different in everyone.
Inflammation leads to scar tissue.
Scarring may lead to cirrhosis.
Cirrhosis can lead to complications.
The goal is to avoid cirrhosis.
Treatment background Pegylated interferon The drug stimulates the body's defense system against viruses.
Review potential side effects.
Ribavirin Unknown mechanism.
Review potential side effects.
Direct-acting antivirals for genotype 1 They interfere with the virus machinery.
Review potential side effects.
They do not work without the other drugs!
Goal of treatment Definition of endpoints Permanent eradication of the virus (viral cure).
This does not negate the need for subsequent follow-up of liver disease.
Drug-drug interactions Patient's medications Absolutely contraindicated drugs.
Relatively contraindicated drugs
Need for dose adjustments or changes in medications.
Notify the provider of any new medications before starting them.
Contraception Potential teratogenicity Potential for reduced effect of oral contraception.
Alternatives: spermicide/condoms, intrauterine device, and diaphragm.
Adherence to therapy Adherence is critical. Take medications on time (every 8 hours and not just 3 times daily).
Do not change doses or hold doses without instructions.
Do not interrupt any medication (P/R/DDA).
Treatment initiation Order of doses Pegylated interferon is always first.
Start ribavirin and telaprevir after the interferon dose.
Pegylated interferon/ribavirin lead-in with boceprevir.
Therapy monitoring Weekly and monthly labs It is important to identify drug toxicity and treatment responses.
Missing a week 4 viral load prohibits truncation of therapy.
Side-effect management Anemia Ribavirin dose reduction, erythropoiesis stimulating agents, and blood transfusions
Rash Topical antihistamines or topical steroids. Dermatology consult.
Stop for severe rash (vesicle or bullae), drug reaction with eosinophilia and systemic symptoms, or Stevens-Johnson syndrome.
Consider a dermatology consult if the rash is severe.
Anorectal events Over-the-counter hemorrhoidal preparations.
3% topical lidocaine.
There may be improvement with an increased amount of fat in the diet.
Provider's ability to manage these events Who to call on weekends and evenings.
Drug-Drug Interactions

Drug-drug interaction can influence the safety, tolerance, and effectiveness of therapy. This is discussed in detail in another article in this journal. The patient's medication list should be reviewed at each visit, and the patient should be instructed to check with you before any new medications, including over-the-counter and herbal preparations, are started.

On-Treatment Monitoring

Laboratory testing must follow a predefined schedule in order to appropriately modify the treatment duration, address adverse events, and discontinue treatment when it becomes futile. Viral load evaluation time points are critical in determining eligibility for truncating therapy, and the results are sometimes required by the patient's insurer to continue therapy.

Because therapy is guided by viral levels, your laboratory should use a sensitive test (lower limit of detection = 10-15 IU/mL) and should provide results within a week. Thus, you may need to do some investigation to find out which assays are available from each laboratory and what their turn-around times will be. Although most tests (not all) currently available through reference laboratories are sensitive to this level, they are not all able to quantitate viral levels to this lower limit of detection. This is fine as long as one recognizes that “below the limit of quantification” does not mean that the virus is undetectable. The same assay should be used on each occasion, and this typically requires requesting the test by its specific laboratory code rather than simply requesting “HCV RNA, quantitative.” Assays and their accession numbers with the common reference labs are shown in Table 4.

Because the monitoring points, stopping rules, and treatment durations are complicated and differ with the drug being used and the patient's previous response, we find it helpful to use flow sheets that identify these critical time points and remind us about what action is indicated. These have proven to be invaluable for monitoring viral responses, cytopenia, and dose modifications.

Side-Effect Management

Side effects are discussed in detail in another article in this journal. The patient should recognize and report side effects as soon as possible so that early intervention can minimize their severity. Although most side effects develop gradually, anemia can sometimes develop rapidly and can be a challenge to manage. We find it helpful to measure the hemoglobin level more frequently, perhaps even weekly, if the patient is elderly or has renal dysfunction, preexisting anemia, or a history of anemia with a previous course of therapy. Ribavirin dose reduction is the first step and can often circumvent the need for growth factors, transfusions, or dose interruptions. Erythropoietin should be considered if the hemoglobin level falls quickly (erythropoietin is not Food and Drug Administration–approved for this indication).

Empowering the Patient to Ensure Successful Therapy

Finally, we find that enlisting the patient in the care team helps the patient to take a more active role in maintaining adherence to dosing and the monitoring schedule. This should start during pretreatment education and should be reinforced by including the patient in reviews of laboratory results (particularly viral levels) and by emphasizing the key points of the educational outline during clinic visits during treatment.

References

Source

From Journal of Viral Hepatitis

D. A. Kelly; B. Haber; R. P. González-Peralta; K. F. Murray; M. M. Jonas; J. P. Molleston; M. R. Narkewicz; F. R. Sinatra; T. Lang; A. Lachaux; S. Wirth; M. Shelton; H. S. Te; H. Pollack; W. Deng; S. Noviello; J. K. Albrecht

Posted: 05/07/2012; J Viral Hepat. 2012;19(4):263-270. © 2012 Blackwell Publishing

Abstract and Introduction
Abstract

Summary. Long-term studies in adults indicate that sustained virologic response (SVR) after combination treatment for chronic hepatitis C (CHC) predicts long-term clearance. Although peginterferon plus ribavirin is now standard care for children with CHC, long-term follow-up studies are not yet available. This study evaluated durability of virologic response over 5 years in children previously treated with interferon alfa-2b plus ribavirin (IFN/R). Ninety-seven of 147 children with CHC, who were treated with IFN/R and completed the 6-month follow-up in two previous clinical trials, participated in this long-term follow-up study. All were assessed annually for up to 5 years; patients with SVR were assessed for durability of virologic response. Children with SVR (n = 56) and those with detectable hepatitis C virus (HCV) RNA 24-week post-treatment (n = 41) were followed for a median of 284 weeks. Overall, 70% (68/97) of patients completed the 5-year follow-up. One patient with genotype 1a CHC had SVR and relapsed at year 1 of follow-up with the same genotype. Kaplan–Meier estimate for sustained response at 5 years was 98% (95% CI: 95%, 100%). Six patients with low-positive HCV RNA levels (n = 4) or missing HCV RNA at the 24-week follow-up visit (n = 2) in the initial treatment studies had virologic response during this long-term follow-up study. Linear growth rate was impaired during treatment with rapid increases in the immediate 6 months post-treatment. Mean height percentile at the end of the 5-year follow-up was slightly less than the mean pretreatment height percentile. Five patients experienced serious adverse events; none related to study drug exposure. SVR after IFN/R predicts long-term clearance of HCV in paediatric patients; growth normalized in the majority of children during the long-term follow-up. Similar long-term results could be expected after peginterferon alfa-2b plus ribavirin treatment.

Introduction

The World Health Organization estimates the prevalence of hepatitis C virus (HCV) infection between 1.3% and 1.7% in Europe and the Americas.[1] Seroprevalence of HCV among children is lower than in adults, with estimated rates of 0.1–0.4% in developed countries.[2,3] Although chronic hepatitis C (CHC) is often benign in young children, the occurrence of fibrosis increases with age and duration of the disease.[4] Thus, effective treatment of children with CHC may reduce the progression of liver disease in young adulthood.[5] Studies using interferon (both nonpegylated and pegylated) plus ribavirin for 48 or 52 weeks in children and adolescents with CHC have yielded sustained virologic response (SVR) rates of 46–65%.[6–11] However, the long-term safety of interferon (both nonpegylated and pegylated) plus ribavirin and durability of the virologic response in children are unknown and are essential outcome measures.

In a long-term follow-up study of adults with CHC who attained SVR after treatment with interferon alfa-2b with or without ribavirin, 99% remained virus free during the subsequent 5-year period.[12] Similar findings were seen in adults previously treated with peginterferon alfa-2b plus ribavirin.[13] These findings indicate that sustained loss of serum HCV RNA for 6 months after the end of treatment is an excellent predictor of long-term viral clearance in adult patients with CHC.

The durability of response has not been formally studied in the paediatric population. Although peginterferon plus ribavirin is currently the standard of care for the treatment of paediatric patients with CHC, there are no long-term data on safety or durability of virologic response. Thus, long-term data on children treated with interferon alfa-2b plus ribavirin are uniquely relevant. This study was designed to confirm long-term safety and durability of virologic response in paediatric patients with CHC who were previously treated with interferon alfa-2b plus ribavirin for 48 weeks.[8]

Materials and Methods
Study Design

A phase 3b, multicentre, long-term, follow-up study of paediatric patients with CHC who were previously treated with interferon alfa-2b (Intron A®; Schering-Plough Corporation, now Merck & Co., Whitehouse Station, NJ, USA) 3 MIU/m2 three times per week plus ribavirin (Rebetol®; Schering-Plough Corporation, now Merck & Co.) 8, 12, or 15 mg/kg/day for 48 weeks in two international clinical trials was conducted.[8] The initial treatment studies allowed patients who had detectable HCV RNA levels at treatment week 24 to discontinue as treatment failures at the discretion of individual investigators. Patients who completed 24 weeks of follow-up after the end of treatment in the two clinical trials were eligible for enrolment. No study medications were administered to patients during the 5-year follow-up study.

Baseline data, including gastrointestinal/liver examinations, weight and height measurements, haematology, blood chemistry, and HCV RNA, were obtained from the 24-week follow-up visit in the initial treatment studies. Annual assessments for clinical evidence of liver disease progression and safety in all patients as well as virologic relapse in those who attained SVR in the initial treatment studies were performed for up to 5 years. A patient was considered to have an enduring SVR at a given time point if serum HCV RNA [by quantitative polymerase chain reaction (PCR)] was undetectable at that time point. A patient was considered to have relapsed if a single serum sample had detectable HCV RNA.

Polymerase chain reaction testing for HCV RNA was performed by Schering-Plough Research Institute using a proprietary TaqMan reverse transcriptase–PCR assay (lower limit of detection, <125 IU/mL) and by Quest Diagnostics, Nichols Institute, using the Roche COBAS TaqMan assay (lower limit of quantitation, <50 IU/mL).

The study was conducted in accordance with Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies.

Study Population

Paediatric patients (3–16 years of age) from 24 study sites (17 in the United States and seven international) who participated in one of two clinical trials were invited to enrol in the long-term, follow-up study.[8] Patients who completed 24 weeks of follow-up in the initial treatment studies and whose parents or legal guardians provided informed consent prior to any study-related procedures were included. Patients were excluded if they were currently participating in any other clinical trial for treatment of CHC, if they had received antiviral retreatment for CHC after completing 24 weeks of follow-up in the initial treatment studies or if the investigator determined that the patient had any condition which would make him or her unsuitable for participation in the study. Patients were discontinued from the study if antiviral retreatment for CHC was administered, if the investigator determined that it was in the best interest of the patient or if the patient wished to withdraw.

Efficacy End Point

The primary efficacy end point was the assessment of the durability of SVR in paediatric patients with CHC who were previously treated with interferon alfa-2b plus ribavirin. Durability of SVR was assessed at 1 year after the week-24 follow-up visit of the initial treatment studies and then annually for the next 4 years.

Safety Assessments

Signs of clinical disease progression and safety were assessed for patients at 1 year after the week-24 follow-up visit of the initial treatment studies and then annually for the next 4 years. To assess for clinical disease progression, investigators examined patients for ascites, hepatomegaly, splenomegaly and liver tenderness. In addition to the physical exams and laboratory evaluations, height and weight measurements were collected. Growth measurements were converted electronically to an age- and gender-specific percentile according to the method developed by the Centers for Disease Control and Prevention.[14] Growth velocities during the different study periods were compared with age- and gender-standardized norms for the US population. Growth velocity was calculated by regressing assessed height during the period over the day of assessed height from randomization. At least two height assessments at least 90 days apart were required in any period to calculate growth velocity. Growth velocity percentiles relative to those norms were determined to assess the impact of treatment on growth.[14,15]

Results
Patient Disposition

Of the 166 patients who received interferon alfa-2b plus ribavirin in the two initial treatment studies, 147 (78 sustained responders and 69 treatment failures) completed 24 weeks of follow-up and were eligible for enrolment in the long-term follow-up study (Fig. 1). Enrolled patients (N = 97) had been treated with interferon alfa-2b (3 MIU/m2) three times per week plus ribavirin 8 mg/kg/day (n = 11), 12 mg/kg/day (n = 10) or 15 mg/kg/day (n = 76) at 16 study centres. Owing to the timing of the initial treatment studies and long-term study enrolment, the majority of the enrolled patients (54%, 52/97) were initially treated in the second study, the phase 3 trial.[8] Of those enrolled in this long-term follow-up study, 58% (56/97) had attained SVR and 42% (41/97) of them had not attained SVR (Table 1). Therefore, 72% of sustained responders and 59% of treatment failures from the initial treatment studies entered this long-term follow-up study. In genotype 1, infected patients were 77% (75/97) of the study population, of whom 47% (35/75) had achieved SVR.

762506-fig1

Figure 1. Patient disposition. Study 1, a phase 1 trial, includes patients who were treated with IFN alfa-2b plus RBV 8, 12 or 15 mg/kg/day and Study 2, a phase 3 trial, includes patients treated with IFN alfa-2b plus RBV 15 mg/kg/day.8

Duration of Long-term Follow-up

Overall, 70% (68/97) of patients completed the 5 years of long-term follow-up (Table 2). More patients who attained SVR (75%, 42/56) than those who did not attain SVR (63%, 26/41) in the initial treatment studies completed the long-term follow-up. One patient with detectable HCV RNA at the end of the initial treatment study was subsequently retreated with peginterferon alfa-2b and ribavirin and was therefore withdrawn from the long-term follow-up study.

Efficacy Evaluation

Durability of Response Of 56 patients who attained SVR, only one had virologic relapse during long-term follow-up, with detectable serum HCV RNA level of 3.6 million copies/mL at the year-1 annual evaluation. HCV genotype was 1a at initial infection and at relapse. This patient had received interferon alfa-2b plus ribavirin (15 mg/kg/day) and completed 48 weeks of treatment without any known dose reductions. The Kaplan–Meier point estimate (95% confidence intervals) for the likelihood of maintaining SVR at 5 years after the initial treatment studies was 98% (95%, 100%).

Alanine Aminotransferase Levels The majority (98%, 51/52) of patients who attained SVR and had normal alanine aminotransferase (ALT) levels at the 24-week follow-up of the initial treatment studies maintained normal ALT levels throughout their long-term follow-up visits. The remaining patient with SVR had an elevated ALT level during long-term follow-up (67 U/L at the year-5 visit) with hepatomegaly, possibly caused by obesity (body mass index of 37.1 kg/m2). The investigator did not consider this finding to be clinically significant. In addition, three patients who attained SVR but had abnormal ALT levels at week-24 follow-up visit had normalized ALT levels at their last long-term follow-up evaluation. ALT values in the long-term follow-up period were missing for one patient.

Treatment Failures Of the 41 patients who did not respond to therapy and who had detectable HCV RNA levels at the 24-week follow-up in the initial treatment studies, 26 (63%) completed the 5-year follow-up study. Among these 41 patients with treatment failure, 33 (80%) had ALT levels <2 times their baseline ALT level throughout the study; 7 (17%) had elevated ALT levels of at least two times their baseline level within the last 3 years of long-term follow-up, despite having ALT levels <2 times their baseline level at the 24-week follow-up visit in the initial treatment studies; and one had missing ALT levels.

Six patients who enrolled in the long-term follow-up study had been treated with interferon alfa-2b (3 MIU/m2) three times/week plus ribavirin 15 mg/kg/day in the initial treatment studies and were classified as treatment failures. Four of these patients had low detectable serum HCV RNA (125–250 copies/mL) at week-24 follow-up in the initial treatment studies although they had undetectable HCV RNA levels at week 24 during treatment and three of the four patients had undetectable HCV RNA levels at week 12 as well. These patients had undetectable serum HCV RNA and normal ALT values throughout the long-term follow-up study (4–5 years after completing treatment). The two remaining patients were defined as not having responded to therapy when they entered the long-term follow-up study because, although they had undetectable serum HCV RNA at their last visit in the initial treatment protocol, they did not have HCV RNA results available for the 24-week follow-up visit. However, their serum HCV RNA remained undetectable throughout the 5 years of long-term follow-up.

Safety Evaluation

In this long-term follow-up study, 5% (5/97) of patients reported a serious adverse event, all of which were considered unlikely to be related to previous treatment with interferon alfa-2b and ribavirin. The serious adverse events included a cardiac catheterization in a patient with a history of congenital heart disease, injury with loss of consciousness after tipping an all-terrain vehicle, contrast media reaction during magnetic resonance imaging, tooth abscess and depression with self-injurious ideation and drug abuse after an alleged sexual assault. No patients died during the study. During the initial treatment studies, 23 of the 118 patients reported severe adverse events, which included mainly neutropenia as well as more significant events of suicidal ideation (n = 3), attempted suicide (n = 1) and hypothyroidism requiring treatment (n = 3); one patient with hypothyroidism also developed diabetes mellitus.[8] Of these seven patients with more significant events, five patients were followed for up to 5 years in this long-term follow-up study without further serious adverse events reported. Mean changes in haematologic parameters (haemoglobin, platelet and white blood cell counts) during treatment returned to normal levels at the end of the 24-week follow-up period and remained stable during the long-term follow-up study. No patient showed signs of clinical progression of hepatic disease.

Body Weight and Height During the initial treatment studies, weight loss occurred during treatment with compensatory weight gain during the 24-week follow-up and long-term follow-up (Table 3). The mean weight percentile, 60th percentile, for all patients at the end of the long-term follow-up was above their mean baseline weight percentile, 54th percentile, as well as the median for the US population.[14]

The mean height percentile, 44th percentile, for all patients at the end of the long-term follow-up was slightly below the patients' mean pretreatment baseline height percentile, 48th percentile, and below the median for the US population (Table 3). Twenty (21%) patients had >15 height percentiles decrease from baseline to their last visit in the long-term follow-up period. Of these 20 patients, 10 patients had >30 percentiles decreases. Decreases in height of >15 percentiles were most common in patients treated with interferon alfa-2b plus ribavirin during their estimated period of peak growth velocity based on age [girls 9–12 years old (6/15, 40%) vs girls 3–8 and 13–16 years old (1/31, 3%); P = 0.001 and boys 11–14 years old (9/19, 47%) vs boys 3–10 and 15–16 years old (4/32, 13%); P = 0.006]. In contrast, 15 (15%) patients (girls 4–12 years old and boys 5–16 years old) had increases in height of >15 percentiles from baseline to their last visit in the long-term follow-up study.

Mean growth velocity (2.46 ± 2.48 cm/year) and mean growth velocity percentile (11 ± 22) were at their lowest during treatment (Table 3). During the 24-week follow-up period of the initial studies, both growth velocity and growth velocity percentile increased to levels above the median for the US population. Mean growth velocity during this period was 5.40 ± 4.13 cm/year, and mean growth velocity percentile increased to 62 ± 40. During the long-term follow-up period, mean growth velocity was 3.29 ± 2.74 cm/year, and mean growth velocity percentile was 36.7 ± 37.6.

Discussion

Chronic hepatitis C is a significant cause of liver disease and a frequent indication for liver transplantation in adults.[16] Long-term follow-up studies in adult patients with CHC have shown that attainment of SVR (defined as undetectable HCV RNA at 24 weeks after the end of therapy) following treatment with interferon (nonpegylated and pegylated) with or without ribavirin therapy is durable and predictive of long-term clinical benefit.[12,17–26] Results of this 5-year follow-up study confirm that the long-term outcome for children who achieved SVR with interferon alfa-2b and ribavirin treatment for CHC is consistent with that observed in adults. Overall, 98% (55/56) of paediatric patients who attained SVR maintained undetectable HCV RNA levels during the long-term follow-up period. In addition to maintaining undetectable HCV RNA levels, 98% of paediatric patients who attained SVR and had normal ALT levels following treatment maintained normal ALT levels at their last long-term follow-up visit. The high percentage of patients who maintained long-term undetectable HCV RNA levels and normalization of ALT confirm the durability of virologic response in this population of paediatric patients, highlighting the success of this therapy in children.

Although nonpegylated interferon plus ribavirin is no longer the standard of care treatment for CHC in children, long-term data on safety and durability of response of any interferon in this population are not yet available. This study of long-term response in children treated with interferon alfa-2b plus ribavirin demonstrates similar durability to that reported in adults and suggests that similar outcomes are likely in children treated with peginterferon plus ribavirin. In addition, this study provides data on decreases in growth during combination therapy and recovery post-treatment, which is of value in selecting children for CHC therapy.

The initial treatment studies indicated that 8% and 20% of patients had haemoglobin level <10 g/dL and/or neutropenia (<1000 cells/L), respectively, while on treatment they recovered to pretreatment levels after therapy.[8] No evidence of latent effects of treatment with interferon alfa-2b and ribavirin on haematologic parameters was apparent. Additionally, no delayed serious adverse events related to previous interferon alfa-2b and ribavirin treatment during the 5-year follow-up period were reported.

Treatment with interferon alfa-2b has been shown to cause a temporary slowing of growth in paediatric patients.[27] Growth analyses of the initial and long-term follow-up studies showed that treatment with interferon alfa-2b and ribavirin slowed patients' growth during treatment and that some patients did not return to their baseline height percentile when treatment was completed. The mean height percentile observed during the 5 years of follow-up was slightly below the mean pretreatment height percentile and the median for the US population, but the mean last weight percentile was above the median for the US population and mean pretreatment weight percentile. Although the largest decreases in height percentiles were mainly seen in patients treated during their estimated peak height velocity based on age, there is much variability in the timing and rate of growth during puberty between individuals, and growth charts only capture a certain standard. In addition, a major limitation of our observations regarding growth is the absence of parental height data that would provide perspective on the patients' estimated final target heights.

Observations regarding a temporary reduction in growth velocity have also been made in paediatric patients receiving peginterferon alfa-2b plus ribavirin. Jara et al. reported a reduction in growth of 1.6 cm compared with the growth velocity 50th percentile for age and sex in 22 of 26 paediatric patients receiving peginterferon alfa-2b plus ribavirin. Despite a return to normal growth velocity after the end of treatment, the authors reported that the modest decrease in height percentile that occurred during treatment was not regained during the 6-month follow-up period.[9] In addition, Wirth et al.[10] reported that the mean height percentile after the 24-week post-treatment follow-up period for 107 paediatric patients treated with peginterferon alfa-2b plus ribavirin was slightly lower than the median of the US population and below the mean pretreatment height percentile. The 5-year long-term follow-up of this study is ongoing. However, Sokal et al.[28] reported no influence of peginterferon alfa-2a plus ribavirin therapy on height in 65 paediatric patients. The trends seen in growth after interferon and ribavirin therapy are not consistent.

The risk/benefit ratio between the possible slowing of growth in paediatric patients receiving interferon products and the clinical consequences if treatment is withheld or delayed must be considered when treating a child with CHC with these agents. Much variability in growth was seen in this population, but supporting data including parental heights, nutritional status, concurrent disease status and medications were not available to firmly assess the impact of treatment on growth in this population. The long-term effect on growth is being further studied in patients who underwent treatment with peginterferon alfa-2b and ribavirin, and will be available in coming years.

Spontaneous resolution of chronic HCV infection is rare in untreated children, whereas persistent viremia after infection is almost universal.[5] The disease course varies, but most children show at least mild or moderate hepatic inflammation and a small proportion have steatosis.[29] Rare cases of children with hepatitis C-related bridging fibrosis, decompensated cirrhosis and hepatocellular carcinoma have been reported.[4,30–33] Delaying therapy until early adulthood may have less impact on growth but increases the risk of liver disease progression or the need for liver transplantation in the interim, which may impede attainment of SVR in later years. In contrast, early treatment with interferon alfa-2b plus ribavirin results in an enduring clinical cure in almost half of all treated paediatric patients. The possibility of successful viral clearance needs to be weighed against the reported adverse events in children, which are largely consistent with the well-described tolerability profile among adult patients with hepatitis C receiving interferon alfa-2b (nonpegylated or pegylated) plus ribavirin.[8] Thus, the arguments for withholding therapy from paediatric patients may be outweighed by the benefits of early viral eradication and the potential difficulties that may be incurred if treatment is delayed until the course of disease is further advanced. In addition, peginterferon alfa plus ribavirin treatment has shown improvement in therapeutic outcome among paediatric patients with CHC and is likely to demonstrate similar durability.[10,11]

In conclusion, results of this 5-year follow-up study confirm that sustained loss of serum HCV RNA 24 weeks after the end of treatment with interferon alfa-2b plus ribavirin is predictive of long-term virologic response in paediatric patients. Most children had normalized (within 15 percentiles of pretreatment height) or improved growth during this 5-year long-term follow-up, although their mean height percentile at their last long-term follow-up visit was slightly below their mean pretreatment height. The findings of this study support the future treatment of paediatric patients with hepatitis C to prevent progression of liver disease.

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