Optimizing Outcomes by Helping Patients Through ... · Optimizing Outcomes by Helping Patients Through Peginterferon/Ribavirin ... anemia/ John G. McHutchison, MD Faculty Ira

Optimizing Outcomes by Helping Patients Through Peginterferon/Ribavirin Therapy

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hepatitis C, go to

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Release Date: March 26, 2004.Termination Date: March 26, 2005.Estimated time for completion of this newsletter: 1 hour.

Chair

John G. McHutchison, MD Director, GI/Hepatology Research Duke Clinical Research Institute Division of Gastroenterology Duke University Medical Center Durham, North Carolina

Education Initiative in Gastroenterology



SM

SM

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Target AudienceThis activity is designed for gastroenterologists and hepatology healthcare professionals who treat patients with hepatitis C.

Activity GoalThe goal of this activity is to discuss strategies to prevent and manage side effects of antiviral ther-apy for hepatitis C in order to promote treatment adherence and maximize treatment outcomes.

Learning ObjectivesAfter completing this activity, the physician should be able to:• Describe the impact of treatment adherence on

the likelihood of early and sustained virologic response.

• Develop and implement strategies to alleviate common side effects of PEG IFN/RBV and to allow maintenance of recommended doses.

• Consider use of hematopoietic growth factors and other strategies to manage hematologic side effects.

• Evaluate, prevent, and manage common neuropsychiatric side effects of treatment with PEG IFN/RBV.

• Implement appropriate adjuvant therapies to treat other common side effects of PEG IFN/RBV therapy.

Copyright © 2004, Projects In Knowledge, Inc. Little Falls, NJ 07424. All rights reserved.

Download additional copies of this CME Tx Reporter at www.projectsinknowledge.com/anemia/

John G. McHutchison, MD

Faculty

Ira M. Jacobson, MD Chief, Division of Gastroenterology and Hepatology Vincent Astor Professor of Clinical Medicine Weill Medical College of Cornell University New York Presbyterian Hospital New York, New York

Mark S. Sulkowski, MD Assistant Professor of Medicine Division of Infectious Diseases Medical Director, Viral Hepatitis Center Johns Hopkins University School of Medicine Baltimore, Maryland

Ira M. Jacobson, MD

Mark S. Sulkowski, MD

Dear Colleague:

Peginterferon/ribavirin (PEG IFN/RBV) is a highly successful treatment for hepatitis C, producing sustained virologic response (SVR) in more than half of all treated patients. However, virtually all patients experience side effects, most commonly in the early weeks of therapy. These side effects may result in dose reduction or treatment discontinuation, which decreases the likelihood of successful treatment outcome.

In this Tx Reporter, Mark S. Sulkowski, MD, describes evolving strategies for management of PEG IFN/RBV side effects. These strategies minimize the need for dose reduction or treatment discontinuation, and can improve patient motivation. Physicians can thereby make therapy more tolerable, improve treatment adherence, and give each patient the best chance of achieving treatment goals.

I hope you find this newsletter informative, and that the strategies presented herein enhance patient acceptance of treatment and overall care.

Sincerely,

Continued on page 2

1666-TxReporterKK3-23v4.indd 1 3/23/04 5:33:08 PM

IntroductionOver the past 5 years, significant advances have been achieved in the treatment of chronic hepatitis C virus (HCV) infection. The current standard of care is combination therapy with PEG IFN and RBV. The results of recent clinical trials indicate that SVR may be achieved in approximately 54% to 56% of patients treated with PEG IFN/RBV for 48 weeks.1-3 More importantly, long-term studies suggest that these SVRs are durable, consistent with HCV

eradication, and may lead to regression of HCV-related liver disease among successfully treated patients.4,5 Thus, antiviral therapy is now quite effective. The primary factor that now limits treatment outcomes is medication-related toxicity.

To achieve successful outcomes, adherence to HCV treatment is critically important. Not surprisingly, adherence to the recommended doses and duration of therapy, particularly RBV, has been shown

2

Figure 1. Peginterferon alfa-2b/ribavirin: effect of adherence on response7

54

63

0

50

75

SVR

(%)

All PatientsPEG IFN 1.5 µg/kg +

RBV 800 mg

ITT

80+80+80

52

61

25

All PatientsPEG IFN

1.5 µg/kg + RBV>10.6 mg/kg

72

5748

63

100

Genotype 1PEG IFN 1.5 µg/kg + RBV >10.6 mg/kg

34

<80/<80/<80

P < .05vs

R E P O R T E RSM : Optimizing Outcomes by Helping Patients Through Peginterferon/Ribavirin Therapy

Inside this

Introduction ........................................................................................... 2

Hematologic Side Effects ....................................................................... 3

Neuropsychiatric Side Effects ................................................................ 7

Other Side Effects .................................................................................. 8

Case Study: An Illustration of Side Effect Management ...................... 9

Conclusion ........................................................................................... 10

References ............................................................................................ 11

Posttest/Evaluation ....................................................................Enclosed

CME InformationStatement of AccreditationProjects In Knowledge is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit DesignationProjects In Knowledge designates this educational activ-ity for a maximum of 1 hour category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

This activity is planned and implemented as an inde-pendent CME activity in accordance with the ACCME Essential Areas and Policies.

Successful completion for 1 hour of CME credit requires a passing score of 70% or higher on the posttest. Full instructions for submission are included on the posttest.

Disclosure InformationThe Disclosure Policy of Projects In Knowledge requires that faculty participating in a CME activity disclose to the audience: any significant relationship they may have with a pharmaceutical or medical equipment company, product, or service that may be mentioned as part of their presenta-tion; any relationship with the commercial supporter of this activity; if discussion includes 1) therapies that are unapproved for use or are investigational; 2) ongoing research; or 3) preliminary data. Faculty will disclose such discussion.For complete prescribing information on the products discussed during this CME activity, please see your cur-rent Physicians’ Desk Reference (PDR).Ira M. Jacobson, MD, has received grant/research sup-port from InterMune Inc, Isis Pharmaceuticals, Inc, Prometheus Laboratories, Inc, Ribozyme Pharmaceuticals, Inc, and Schering-Plough Corporation; is a consultant for Akros Pharma Inc, Amgen Inc, Centocor, Inc, InterMune Inc, Ortho Biotech Products, LP, Prometheus Laboratories, Inc, and Schering-Plough Corporation; and is on the speakers bureau of Gilead Sciences, Inc, and Schering-Plough Corporation. John G. McHutchison, MD, has received grant/research support from Akros Pharma Inc, Amgen Inc, Bayer, Biomedicines, Bristol-Myers Squibb Company, Cytel Corporation, Fujisawa Healthcare, Inc, Genprobe, Gilead Sciences, Inc, IDUN, Isis Pharmaceuticals, Inc, Ortho Diagnostics, Prometheus Laboratories, Inc, Ribozyme Pharmaceuticals, Inc, Roche Pharmaceuticals, Schering-Plough Corporation, SciClone Pharmaceuticals, Triangle Pharmaceuticals Inc, and Vertex Pharmaceuticals; is a consultant for Amgen Inc, Anadys Pharmaceuticals, Inc, Centocor, Inc, GlaxoSmithKline, InterMune Inc, Isis Pharmaceuticals, Inc, National Genetics Institute, Novartis Pharmaceuticals Corporation, Pfizer Inc, Prometheus Laboratories, Inc, Ribozyme Pharmaceuticals, Inc, and Schering-Plough Corporation; and is on the speakers bureau of InterMune Inc, Roche Pharmaceuticals, and Schering-Plough Corporation. Mark S. Sulkowski, MD, has received grant/research support from Amgen Inc, Ortho Biotech Products, LP, Roche Pharmaceuticals, and Schering-Plough Corporation; is a consultant for Bristol-Myers Squibb Company; and is on the speakers bureau of Ortho Biotech Products, LP, Roche Pharmaceuticals, and Schering-Plough Corporation.There will be no discussion of labeled/unapproved uses of drugs or devices in this activity.The opinions expressed in this activity are those of the faculty and do not necessarily reflect those of Projects In Knowledge. This CME activity is provided by Projects In Knowledge solely as an educational service. Specific patient care decisions are the responsibility of the physician caring for the patient.

This independent CME activity is supported by an educational grant from Amgen Inc.


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TREATMENT REPORTER: G A S T R O E N T E R O L O G Y

to correlate with the likelihood of SVR (Fig. 1).6,7 Unfortunately, adherence to PEG IFN/RBV may be undermined by treatment-related side effects that prompt physicians to reduce treatment doses or discontinue therapy, and by poor treatment tolerability leading to patient dropout. Common treatment-limiting side effects include hematologic effects (ie, anemia, neutropenia, thrombocytopenia), fatigue, neuropsychiatric effects (eg, depression, insomnia, irritability), and other side effects (eg, rash, cough, dyspnea, weight loss). While psychiatric side effects were the most common reason for treatment discontinuation, hematologic side effects were most frequently the reason for dose modifications of PEG IFN/RBV in large clinical trials.8,9

To optimize outcomes with current therapies for HCV infection, prompt recognition and aggressive management of adverse effects are essential to increase treatment adherence and tolerability. Fortunately, many side effects can be managed, which improves quality of life for the patient. It has not yet been confirmed that the decreased need for treatment discontinuation and dose reduction will improve SVR, but this makes intuitive sense.

Hematologic Side EffectsAnemiaRBV causes a rapid decrease in hemoglobin in the first 4 weeks, with an average decline of 2.5 g.10 Hemoglobin level remains suppressed throughout treatment and then returns to normal posttreatment. In large clinical trials, hemoglobin

level declined in approximately 95% of patients treated with PEG IFN/RBV, and anemia (defined as a hemoglobin level <10 g/dL) occurred in 10% to 13% of patients treated with PEG IFN/RBV regimens, usually within the first few weeks of treatment.8,9 Furthermore, a recent retrospective multicenter survey of “real world” patients scheduled to receive IFN/RBV for chronic hepatitis C found that about one quarter fail to complete therapy and identified anemia as the cause of 36% of treatment discontinuations.11 Moreover, in a recent retrospective review of 770 charts from HCV-infected patients in 209 centers, about half (58% of men and 46% of women) had a ≥3 g/dL reduction in hemoglobin. RBV dose reduction was four times more likely if hemoglobin dropped to ≤12 g/dL and nearly 2.5 times more likely if a ≥3 g/dL reduction in hemoglobin occurred compared with those who had hemoglobin >12 g/dL or experienced a <3 g/dL reduction, respectively. (McHutchison JG, unpublished data, 2003.)

Erythropoietin has been used to treat cancer- and chemotherapy-related anemia for more than a decade. The efficacy, safety, and quality-of-life benefits have been demonstrated in three large, open-label, nonrandom-ized, community-based studies of more than 7000 patients.12-14 In these studies, erythropoietin increased hemoglobin (mean, 1.8–2.0 g/dL) and decreased the percentage of patients requiring transfusions and the mean number of units transfused. Quality-of-life and functional status positively correlated with hemoglobin levels, and were substantially

improved with treatment, particularly when hemoglobin increased by ≥2 g/dL. Hypertension thought to be related to erythropoietin therapy occurred in 0.3% to 1% of patients. Furthermore, in a prospective, open-label study,15 erythropoietin also corrected anemia in cancer patients who were not receiving chemotherapy. Mean hemoglobin level at baseline was 9.0 g/dL, but one fourth of patients reached levels ≥14 g/dL with erythropoietin. The mean hemoglobin increase in evaluable patients who completed the study was 2.5 g/dL. There was a significant decline in transfusion requirements, and significant improvements in quality-of-life and performance status measures. Erythropoietin was well tolerated, although headache, fever, and nausea were noted in 1.6% to 3.8%, and serious adverse events occurred in 3.3%.

Darbepoetin—a recently approved erythropoietic molecule that may allow an earlier and more sustained effect with less frequent dosing than erythropoietin16—has also shown efficacy and safety in studies of cancer patients on chemotherapy. Compared with placebo, darbepoetin improved hemoglobin levels, and reduced fatigue and the need for transfusions.17,18

In addition to its oncologic indications, epoetin also has a long history of efficacy and safety in HIV-infected patients taking zidovudine. In a combined analysis of four multicenter, randomized, clinical trials of HIV-infected persons with zidovudine-induced anemia, erythropoietin increased hematocrit



6.9% in transfusion-independent patients and 3.4% in transfusion-dependent patients compared with hematocrit increases of 0.6% and 0.5% in these populations, respectively, with placebo. Forty-three percent of transfusion-dependent patients who received erythropoietin became transfusion independent. No differences in incidence or severity of side effects were found between erythropoietin and placebo.19 Other studies demonstrated quality-of-life improvements when anemic HIV-infected patients were treated with erythropoietin.20-22

More recently, data indicate that treatment of IFN/RBV-related anemia with erythropoietin substantially

increases hemoglobin level, allows for maintenance of RBV dose, and improves quality of life in patients with hepatitis C. In an open-label, proof-of-principle pilot study, Dieterich et al23 treated 62 HCV-infected patients on IFN/RBV with either epoetin (40,000 IU QW) or the standard of care (observation and dose reduction). Mean hemoglobin level at week 16 was 14.2 ± 1.7 g/dL with epoetin versus 11.2 ± 1.3 g/dL with standard of care (P < .05), and the mean hemoglobin change in these two groups was +2.9 versus +0.3 g/dL, respectively (P < .05). At week 16, the epoetin group had received a mean daily RBV dose of 900 ± 238 mg, whereas the standard-

of-care group received a mean daily dose of 707 ± 217 mg, which is less than the minimum recommended RBV dose (P < .05). Adverse events were not significantly different between treatment groups.

These investigators have since initiated a larger, follow-up, open-label multicenter study. In this study, patients who developed anemia (hemoglobin ≤12 g/dL) while taking IFN/RBV for hepatitis C were randomized to 40,000 IU epoetin SQ QW with subsequent dose adjustments according to response or to standard of care (RBV dose reduction/discontinuation, transfusions as needed). (See Figure 224 for study protocol.) The epoetin

Patients receivingRBV/IFN alfa-2b

therapy:Determine Hb level

during therapy

Hb ≤12 g/dL:Randomize

Hb >12 g/dL:Exclude from study

If Hb increase ≥1 g/dLfrom study entry after

8 weeks of epoetin alfa:Continue epoetin alfa therapy

at 40,000 U SC QW

If Hb increase <1 g/dLfrom study entry after

8 weeks of epoetin alfa:Discontinue epoetin alfa

If Hb <13 g/dL (women) or <15 g/dL (men):– Resume epoetin alfa by reducing dosage to 30,000 U SC QW– Titrate epoetin alfa dosage up or down by increments of 5,000 to 10,000 U (maximum dosage of 40,000 U SC QW)

If Hb >14 g/dL (women)or >16 g/dL (men):

Temporarily withhold epoetin alfa

Responding Patients

Treatment for up to 36 Weeks

Nonresponding Patients

Randomization

SOC

SC = subcutaneously; QW = once weekly. Reprinted from Dieterich DT et al.24

Epoetin alfa40,000 USC QW

Figure 2. Epoetin alfa vs standard of care for IFN/RBV-induced anemia: study protocol

4


5


group also received dose reductions/discontinuations and transfusions as considered necessary. Epoetin alfa produced a greater increase in hemoglobin level than did standard of care: the mean change in hemo-globin from baseline to week 16 was 2.8 versus 0.4 g/dL, respectively (P < .0001) (Fig. 3). At week 16, mean hemoglobin level was 13.8 g/dL in the epoetin group compared with 11.4 g/dL in the standard-of-care group (P < .0001). In addition, epoetin reduced the need for RBV dose reduction (Fig. 4), such that significantly (P < .011) fewer epoetin-treated patients had ribavirin dose reductions during the first 4 weeks. At week 16, mean change in RBV dose was –34 mg/d for epoetin versus –146 mg/d for standard of care (P = .060). At the end of the study, a ribavirin dose of at least 800 mg/d was maintained by 83% of the epoetin patients and only 54% of the patients treated with standard of care (P = .022). At week 16, epoetin was also associated with quality-

of-life improvements on the SF-12 physical component score and mental component summary score relative to those who received standard of care. Quality-of-life improvements associated with epoetin were also evident on LASA energy and activity

scores. Epoetin was considered well tolerated in this study, with a similar incidence of adverse events and no statistically significant differences between treatment groups.24

Before considering erythropoietin therapy, all other correctable causes of anemia (eg, gastrointestinal blood loss) should be excluded or corrected. Appropriate candidates are those with adequate iron stores and hemoglobin <12 g/dL for men or <11 g/dL for women, or a hemoglobin decrease ≥3 g/dL. Erythropoietin is usually initiated at a dose of 40,000 IU QW. Response should be assessed every 2 to 4 weeks. Continue at the original dose if hemoglobin increases at least 1 g/dL. The dose can be increased in increments of 5000 to 10,000 IU to a maximum of 60,000 IU. Erythropoietin should be discontinued if no response occurs or when hemoglobin reaches >12 g/dL. Because erythropoietin can exacerbate

895 ± 273 mg/dayEpoetin alfa

Observations

Epoetin alfa

SOC

Mea

n R

BV

Dos

age

(mg/

day)

SOC891 ± 300 mg/day

779 ± 263 mg/day707 ± 217 mg/day

36 32 34 33

Week

29 21 3528 23 21 21 15

1000

800

600

400

1200

14 24

Study Entry 2 4 8 12 16 LVCF#

Mean RBV dosages: epoetin alfa versus SOC, *P = .0134, †P < .0380; SOC versus study entry, P < .0056 with ANOVA and Bonferroni adjustment. ‡One patient in theepoetin alfa group and four patients in the SOC group did not have postbaseline measurements. LVCF = last value carried forward.Reprinted from Dieterich DT et al.24

†

‡‡

*

Figure 4. Epoetin alfa vs standard of care for IFN/RBV-induced anemia: effects on RBV dosage

14.2 ± 1.7 g/dLEpoetin alfa

Observations

Epoetin alfa

SOC

Mea

n H

b (g

/dL)

SOC†

†‡†‡†‡

†‡

*‡

13.8 ± 1.8 g/dL

11.4 ± 1.3 g/dL11.2 ± 1.3 g/dL

36 32 34 33 29 21 3528 23 21 21 15

1514131211109

16

14 24

WeekStudy Entry

*P = .0022 with Bonferroni adjustments, †P < .0001 with Bonferroni adjustment; epoetin alfa versus study entry, ‡P < .0001 with ANOVA and Bonferroni adjustment. LVCF = last value carried forward.Reprinted from Dieterich DT et al.24

2 4 8 12 16 LVCF#

Figure 3. Epoetin alfa vs standard of care for IFN/RBV-induced anemia: effects on hemoglobin level



pre-existing hypertension or induce de novo hypertension, it is contraindicated in patients with uncontrolled hypertension or any condition conferring an increased risk of thrombosis, especially in the presence of chronic renal disease.

NeutropeniaPEG IFN produces a rapid decrease in neutrophil count during the first few weeks of therapy, which then remains stable throughout treatment and then returns to pretreatment levels after the end of therapy. PEG IFN-related neutropenia occurs in approximately 20% of patients, requiring dose reduction of PEG IFN.8,9 Antiviral activity of IFN is dose-dependent, so reductions in IFN dose early in the course of therapy may decrease the

likelihood of SVR. Some physicians use granulocyte colony-stimulating factor (G-CSF) to improve neutrophil counts and allow maintenance of higher doses of antiviral therapy. This practice is based largely on anecdotal reports, but one randomized study of high-dose (5 mIU) daily IFN showed that the addition of G-CSF increased mean and peak white blood cell counts, although nadir values were the same with and without G-CSF.25 G-CSF is typically given at a dose of 300 µg SC once to thrice weekly to patients with absolute neutrophil counts <0.5 or 0.75 x 109/L when there is concern about the need for dose reduction in the first 12 weeks. It is unknown whether use of G-CSF will affect either early or sustained virus response rates or decrease the

risk of infection, but it is likely to improve neutrophil counts and prevent the need for dose reduction.

However, the clinical significance of neutropenia in HCV-infected patients on treatment is unknown. For example, in an interval analysis of the WIN-R study, 64 patients who developed serious infectious adverse events (SAEs) were compared with more than 4700 patients who did not develop such SAEs. The infected patients did not have significantly lower mean nadir neutrophil counts, and there was no temporal relationship between reduced neutrophil count and infection. Moreover, patients who developed neutrophil counts <0.75 or even 0.5 x 109/L did not have higher rates

Review IFN doseand administration

Exclude contributingfactor

Assess severity ofneuropsychiatric

symptoms

Moderate• Reassure and counsel• Consider dose reduction• Adjuvant medications• Increase clinical monitoring• Psychiatric referral

Severe• Discontinue IFN• Psychiatric referral

Mild• Reassure and counsel• Increase clinical

monitoring• Adjuvant medications

Adapted from Fontana RJ. Digestive Diseases. 2000;18:107. With permission.

Proper dosing

Nocturnal administration

Analgesic/antipyretic, antihistamine premedsAdequate hydration

AnemiaThyroid (hyper or hypo)New medical conditionsOther psychosocial stressors

Figure 5. Management of neuropsychiatric effects of anti-HCV therapy

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of infection than the remainder of the cohort.26 These findings reinforce the conclusions of an earlier study from the National Institutes of Health group,27 which evaluated a group of about 120 patients treated with IFN/RBV and found no discernible relationship between bacterial infections and neutropenia.

ThrombocytopeniaPEG IFN reduces platelet counts to a greater extent than does standard IFN. However, serious reductions in platelet count are largely limited to patients with cirrhosis. Moreover, reductions to <25,000/mm3 are rare, and no bleeding complications related to thrombocytopenia were reported in registration trials of PEG IFN alfa-2a or alfa-2b.1,2 Thus, intervention for thrombocytopenia is rarely necessary, except in a few patients with cirrhosis.

Neuropsychiatric Side EffectsFatigue, which may be exacerbated by anemia, and other neuropsychiatric effects of treatment (irritability, insomnia, depression, anxiety, mania) occur in nearly 80% of patients and commonly result in patient-driven treatment discontinuation. Figure 5 provides an overview of management of neuropsychiatric side effects.28 Discussion of these side effects and assessment of the patient’s neuropsychiatric status should be initiated prior to initiation of antiviral therapy. Assessment should then be ongoing throughout treatment. Patients should be advised to take antiviral therapies at night and to remain adequately hydrated, which can help reduce the risk of neuropsychiatric side effects. Factors that may

contribute to neuropyschiatric side effects, including anemia, thyroid dysfunction, co-morbid medical conditions, substance use, and psychosocial stressors, should also be addressed.

Strategies to manage fatigue include:

• Administration of PEG IFN in the afternoon or evening

• Antidepressant therapy to increase energy levels (eg, bupropion 100–400 mg QD in divided doses or mirtazapine 15–30 mg QHS)

• Relaxation strategies

• Multivitamins without iron

• Use of psychostimulants (reserved for profound fatigue), such as methylphenidate 20 mg PO SR every morning or (rarely) BID

There is a high prevalence (35%–57%29) of major depression among patients with chronic viral hepatitis, and depression may be induced or exacerbated by treatment with PEG IFN. A standardized screening tool, such as the Beck Depression Inventory, Hamilton Depression Rating Scale, Hamilton Anxiety Scale, or Neurotoxicity Rating Scale can be used to evaluate patients at baseline, and should be repeated at every visit for patients with a history of mental illness. Any pre-existing depression or other neuropsychiatric condition should be treated/stabilized prior to starting antiviral therapy for hepatitis C. Prophylactic antidepressants should be considered for those at high risk for depression. A well-controlled, double-blind study demonstrated that the selective serotonin reuptake inhibitor (SSRI) paroxetine, given

before initiation of IFN, is superior to placebo in preventing major depression and reducing the need for discontinuation of high-dose IFN in the treatment of malignant melanoma (Fig. 6).30

Most mild to moderate depression or other neuropsychiatric effects of PEG IFN can be managed successfully by physicians who treat hepatitis C. Such patients should receive reassurance and counseling, increased clinical monitoring, and adjuvant treatment with an antidepressant. Dose reduction and psychiatric referral or consultation should be considered as needed if symptoms worsen. Discontinuation of PEG IFN and psychiatric referral are necessary for severe cases of depression, especially in the presence of suicidal ideation, or for any case of mania, which constitutes a psychiatric emergency.

Numerous antidepressants are available, and most are effective. Selection should take into account potential drug interactions. Citalopram, for example, has few drug interactions and therefore may be a good choice for patients taking multiple therapies. Side effect profiles vary and should also be considered, taking into account that some side effects may actually be beneficial. For example, a medication that promotes weight gain (eg, mirtaza-pine, olanzapine) may be a good choice for treating depression or other mood effects in an HCV-infected patient with little appetite, and trazodone may help promote sleep in a patient with insomnia. Bupropion is associated with fewer sexual side effects than other antidepressants. It should be noted that onset of



antidepressant effects takes 2 weeks, and 4 to 8 weeks is needed to reach full benefit. If no improvement is observed after 2 weeks, a different agent should be tried or a psychiatrist consulted.

Other Side EffectsMany other common side effects of PEG IFN/RBV can be managed

with adjuvant therapies to make treatment more tolerable and allow patients to maintain recommended doses. Most flulike symptoms (eg, arthralgia/myalgia, fever, headache) can be treated with acetaminophen or nonsteroidal anti-inflammatory agents, adequate hydration, PM administration of PEG IFN, and comfort measures.

Acetaminophen dose should not exceed 2 grams/d, and ibuprofen dose should not exceed 2400 mg/d. Stronger analgesics (eg, triptan preparations) can be used for migraine headaches if necessary.

Hair thinning and slight-to-mild hair loss are among the most common cutaneous reactions to IFN. Alopecia may be more pronounced after discontinuation of PEG IFN and may continue for 1 to 3 months; however, in general, PEG IFN-associated alopecia is reversible. Patients concerned about hair loss should avoid excessive brushing and shampooing, gels/mousse/hair spray, peroxide-based hair dye, permanent wave solutions, pulsating showerheads, pressure-based hair items (eg, caps, barrettes, ponytail clips, hair bands). Hair loss through friction or shearing can be minimized by pinning a silk scarf to the pillowcase or using a satin pillowcase. To date, minoxidil has not been adequately studied in treating PEG IFN-related hair loss.

Generalized cutaneous reactions and local injection-site reactions are also associated with PEG IFN. Patients should be instructed to monitor injection sites and report any development of erythema. Patients should avoid injecting at or around any erythematous areas. Subcutaneous technique should be assessed for any patient with complaints of injection-site reactions. Drug solution should always be room temperature prior to injection, and slower injection may also be beneficial. Other treatment strategies may include application of warm or cool compresses before and after injection, lidocaine gel, topical povidone-iodine cream

8

Figure 6. Paroxetine pretreatment reduced (A) the incidence of major depression and (B) the rate of treatment discontinuation due to severe depression or neurotoxicity during first 12 weeks of IFN alfa in patients with malignant melanoma

(A)

(B)

Free

of

Maj

or D

epre

ssio

n (%

)

0 2 4 6 8 10 120

20

40

60

80

100

Placebo

Paroxetine

Weeks of IFN alfa

Free

of S

ever

e D

epre

ssio

n R

equi

ring

IFN

alfa

D

isco

ntin

uatio

n (%

)

0 2 4 6 8 10 12

Placebo

Paroxetine

Weeks of IFN alfa

0

20

40

60

80

100

Reprinted with permission from Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344:961-966. Copyright © 2001 Massachusetts Medical Society. All rights reserved.


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or mild corticosteroid cream for rash/pruritus, premedication with diphenhydramine, and hydroxyzine or naltrexone as needed.

Antidiarrheal agents (eg, bismuth subsalicylate [Pepto-Bismol®], kaolin-pectin [Kaopectate®], or loperamide [Imodium®]) and antiemetics (eg, promethazine [Phenergan®], metoclopramide [Reglan®], ondansetron [Zofran®], dimenhydrinate [Dramamine®], granisetron [Kytril®], prochlorperazine [Compazine®]) are often effective in mitigating gastrointestinal side effects. SSRIs and dronabinol (Marinol®) may also help modulate nausea and may decrease anorexia. Obviously, patients should also avoid foods and smells that trigger nausea/vomiting or diarrhea.

IFN-based therapy can produce irreversible hypo- or hyperthyroidism. Risk factors include female gender, age >40 years, pre-existing thyroid disease, and family history of thyroid disease. All patients should undergo thyroid-stimulating hormone (TSH) testing at baseline prior to

starting PEG IFN/RBV. If TSH is abnormal, a complete thyroid panel including T4 and free T3 should be performed. Levothyroxine is the preferred treatment at a dose of 75 to 100 g with 25 to 50 µg dose adjustments every 2 to 3 weeks for those younger than 50 years, and a starting dose of 25 to 50 µg with 25 µg dose increments for older patients. Hyperthyroidism should typically be managed in conjunction with an endocrinologist. Antithyroid drugs for hyperthyroidism include methimazole and propylthiouracil. Antiviral therapy can usually continue during treatment of thyroid dysfunction unless the patient is symptomatic or unstable.

Case Study: An Illustration of Side Effect ManagementA 45-year-old Caucasian man employed as a butcher was diagnosed with HCV infection in 1991. His past medical/social history included mild asthma, no tobacco use, previous alcohol consumption (1 beer daily), and intravenous drug use in 1978. He was about 6 feet tall and weighed

102 kg. Medications at the time of diagnosis included an albuterol inhaler PRN. He was found to be infected with HCV genotype 1a, and HCV RNA level was >106 copies/mL by polymerase chain reaction (PCR). Alanine aminotransferase (ALT) level was 51 IU/mL. Liver biopsy in 2001 showed grade 2, stage 2 to 3 disease with moderate macro- and microvesicular steatosis and 1+ iron deposition (heterozygous for C282Y hemochromatosis gene).

In February 2002, he began treatment with PEG IFN alfa-2b 1.5 µg/kg and RBV 1200 mg/d. Initial adverse effects include flulike symptoms, arthralgia, nausea, and headaches. Laboratory findings throughout treatment are shown in Table 1. By week 8, HCV RNA was not detectable, and his ALT level was 50% of baseline. However, his hemoglobin and absolute neutrophil count (ANC) declined noticeably. The patient was started on G-CSF 300 µg BIW without PEG IFN dose reduction. G-CSF dose was decreased to 150 µg QW at week 12.

At week 12, virus remained undetect-able, and ANC level improved on G-CSF. However, hemoglobin had declined to 10.6 g/dL, and the patient reported severe fatigue and mild dyspnea. RBV dose was decreased to 600 mg/d and erythropoietin was started at 40,000 U QW. At week 14, hemoglobin level was 12.4 g/dL and RBV dose was increased to 800 mg/d. At week 17, it was increased further to 1000 mg/d. At week 24, with a hemoglobin level of 15.2 g/dL, the patient was able to increase RBV dose to 1000 mg/d and decrease erythropoietin dose

Date Viral Level/PCR (IU/m) ALT (IU/L) Hb (g/d) ANC (cells/mm3)

Baseline >106 51 16.4 2236

Week 8 <600 26 11.6 370

Week 12 <600 25 10.6 2052

Week 14 <600 25 12.4 2431

Week 24 <600 15 15.2 1450

Week 36 <50 11 12.3 6586

Week 48 <50 11 11.8 1617

Table 1. Case Study: Laboratory Findings During Treatment with PEG IFN alfa-2b/RBV


to 20,000 U QW. He remained on treatment at these doses through week 48, with weight stable at 100 kg. At the end of treatment, his viral level was undetectable and ALT level was normal. However, he relapsed within 12 weeks of discontinuing therapy, with an HCV RNA level of 284,00 IU/mL and an ALT level of 94 IU/L.

DiscussionThe patient’s liver biopsy in 1991 showed early bridging fibrosis, which is of concern. He had several factors as baseline that could predict nonresponse to treatment, including steatosis, hepatic iron deposition, genotype 1 infection, high viral load, and heavy body weight. Some physicians might consider phlebotomy and weight loss prior to initiation of antiviral therapy, though there is no clear evidence that these strategies improve the likelihood of response. In this case, his physician encouraged him to lose weight while starting him on weight-based antiviral therapy. Initial flulike side effects were managed without dose reductions, and early virologic clearance was observed.

Decreased neutrophil and hemoglobin counts occurred in the first 8 weeks. It should be noted that an ANC measurement taken within 24 hours of PEG IFN administration is likely to be lower than one taken later in the week, which may influence the extent to which a low ANC count generates

concern. Although the product information stipulates dose reduction or treatment discontinuation for low neutrophil levels, the patient was started on G-CSF immediately because of concern that dose reduction would jeopardize his chance of sustaining the early response he had exhibited. As discussed above, given newer data that now suggest a lack of correlation between low ANC levels and infection, it may be reasonable to simply monitor closely without further intervention while maintaining treatment doses. G-CSF is also still an option, particularly if ANC levels remain persistently low for several months.

Anemia was the most problematic side effect experienced by this patient. At a hemoglobin level of 10.6 g/dL he became symptomatic, with severe fatigue and mild dyspnea. Erythropoietin successfully restored his hemoglobin level to normal, but it is unclear whether concomitant RBV dose reductions contributed to his ultimate posttreatment relapse. Adherence in the early treatment period (ie, the first 12 weeks) appears to have the greatest impact on treat-ment outcome, but even later dose reductions may still contribute to relapse.31

ConclusionPEG IFN/RBV is effective anti-HCV therapy, but effectiveness is limited by adverse effects. Dose

reductions have been associated with decreased antiviral efficacy, and generally produce only small increases in blood cell counts when performed for hematologic toxicity. Accordingly, to maximize treatment outcomes of PEG IFN/RBV therapy, strategies are needed to reduce the medical necessity for dose reduction or treatment discontinuation and to improve patient quality of life to limit early withdrawal from therapy. Research is under way to evaluate the safety and effectiveness of cell-stimulating factors, such as filgrastim, darbepoetin, and epoetin alfa, to correct treatment-associated neutropenia and anemia, respectively. To date, randomized, placebo-controlled clinical trials have demonstrated that adjuvant epoetin alfa can effectively prevent RBV dose reduction, increase hemoglobin, and improve patient quality of life in anemic patients treated with PEG IFN/RBV. Similarly, antidepressants, such as SSRIs and other agents, are increasingly used to improve mood disorders in patients treated with IFN-based therapy. Other adjuvant therapies are used to manage common side effects of treatment with PEG IFN/RBV. These aggressive strategies to manage adverse effects may decrease dose reduction and treatment discontinuation, increase treatment tolerability, and possibly improve the likelihood of SVR. TX

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References

1 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

2. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

3. Hadziyannis SJ, Cheinquer H, Morgan T, et al. Peginterferon alfa-2a (40Kd) (Pegasys) in combination with ribavirin (RBV): efficacy and safety results from a phase III, randomised, double-blind multicentre study examining effect of duration of treatment and RBV dose [abstract 536]. Presented at: 37th Annual Meeting of European Association for the Study of the Liver; April 15-21, 2002; Madrid, Spain.

4. Marcellin P, Boyer N, Gervais A, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med. 1997;127:875-881.

5. Shiratori Y, Imazeki F, Moriyama M, et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med. 2000;132:517-524.

6. Shiffman M, HALT-C Trial Investigators. Retreatment of HCV non-responders with peginterferon and ribavirin: results from the lead-in phase of the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial [abstract 527]. Presented at: 53rd Annual Meeting of the American Association for the Study of Liver Diseases; November 1-5, 2002; Boston, Mass.

7. McHutchison JG, Manns M, Patel K, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology. 2002;123:1061-1069.

8. Pegasys (peginterferon alfa-2a) [package insert]. Nutley, NJ: Hoffmann-La Roche Inc; 2002.

9. PEG-Intron (peginterferon alfa-2b) [package insert]. Kenilworth, NJ: Schering Corporation; 2001.

10. Maddrey WC. Safety of combination interferon alfa-2b/ribavirin therapy in chronic hepatitis C-relapsed and treatment-naïve patients. Semin Liver Dis. 1999;19(suppl 1):67-75.

11. Gaeta GB, Precone DF, Felaco FM, et al. Premature discontinuation of interferon plus ribavirin for adverse effects: a multicentre survey in “real world” patients with chronic hepatitis C. Aliment Pharmacol Ther. 2002;16:1633-1639.

12. Glaspy J, Bukowski R, Steinberg D, et al. Impact of therapy with erythropoietin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. J Clin Oncol. 1997;15:1218-1234.

13. Demetri G, Kris M, Wade J, Degos L, Cella D, for the Procrit Study Group. Quality-of-life benefit in chemotherapy patients treated with erythropoietin alfa is independent of disease response or tumor type: results from a prospective community oncology study. J Clin Oncol. 1998;16:3412-3425.

14. Gabrilove J, Cleeland C, Livingston R, Sarokhan B, Winer E, Einhorn L. Clinical evaluation of once-weekly dosing of erythropoietin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol. 2001;19:2875-2882.

15. Quirt I, Robeson C, Lau C, et al. Erythropoietin alfa in patients not on chemotherapy—Canadian data. Semin Oncol. 2002;23 (3, suppl 8):75-80.

16. Aranesp (darbepoetin alfa) [package insert]. Thousand Oaks, Calif: Amgen Inc; 2002.

17. Vansteenkiste J, Pirker R, Mussuti B, et al. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst. 2002;94:1211-1220.

18. Glaspy J, Jadeja J, Justice G, et al. Darbepoetin alfa given every 1 or 2 weeks alleviates anaemia associated with cancer chemotherapy. Br J Cancer. 2002;29:368-376.

19. Henry D, Beall G, Benson C, et al. Recombinant human erythropoietin in the treatment of anemia associated with human immunodeficiency virus (HIV) infection and zidovudine therapy. Overview of four clinical trials. Ann Intern Med. 1992;117:739-748.


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20. Henry D. Experience with erythropoietin alfa and acquired immunodeficiency syndrome anemia. Semin Oncol. 1998;25(3, suppl 7): 64-68.

21. Revicki D, Brown R, Henry D, McNeill M, Rios A, Watson T. Recombinant human erythropoietin and health-related quality of life of AIDS patients with anemia. J Acquir Immune Defic Syndr. 1994;7:474-484.

22. Abrams D, Steinhart C, Frascino R. Erythropoietin alfa therapy for anaemia in HIV-infected patients: impact on quality of life. Int J STD AIDS. 2000;11:659-665.

23. Dieterich DT, Wasserman R, Brau N, Hassanein TI, Bini EJ, Sulkowski M. Once-weekly recombinant human erythropoietin (epoetin alfa) facilitates optimal ribavirin (RBV) dosing in hepatitis C virus (HCV)-infected patients receiving interferon-a-2b (IFN)/RBV combination therapy [abstract 340]. Presented at: Digestive Disease Week; May 20-23, 2001; Atlanta, Ga.

24. Dieterich DT, Wasserman R, Bräu N, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol. 2003;98:2491-2499.

25. Van Thiel DH, Faruki H, Friedlander L, et al. Combination treatment of advanced HCV associated liver disease with interferon and G-CSF. Hepatogastroenterology. 1995;42:907-912.

26. Ahmed F, Jacobson IM, Brown RS JR, et al. Clinical significance of pegylated interferon induced neutropenia: results from the WIN-R trial [abstract ID 105766]. Presented at: Digestive Disease Week; May 17-22, 2003; Orlando, Fla.

27. Soza A, Everhart JE, Ghany MG, et al. Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C. Hepatology. 2002;36:1273-1279.

28. Fontana RJ. Neuropsychiatric toxicity of antiviral treatment in chronic hepatitis C. Dig Dis. 2000;18:107-116.

29. Zdilar D, Franco-Bronson K, Buchler N, Locala JA, Younossi AM. Hepatitis C, interferon alfa, and depression. Hepatology. 2000;31:1207-1211.

30. Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344:961-966.

31. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology. 2003;38:645-652.

For additional information on gastroenterology, go to www.projectsinknowledge.com





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CME Instructions

To receive CME credit for your participation in this CME activity, please complete the following steps:

1. Read this newsletter carefully.

2. Complete the CME Posttest below, selecting the most appropriate response to each question.

3. Complete the CME Evaluation.

4. Send photocopies of the Posttest and Evaluation to Projects In Knowledge, Overlook at Great Notch, 150 Clove Road, Little Falls, NJ 07424, or fax to: 1-973-890-8866 by March 26, 2005. Please note that we cannot issue certificates of CME credit without both documents.

If you complete these steps and score 70% or higher, Projects In Knowledge will mail you an acknowledgment of participation within 6 weeks of receipt of your materials. If your score is lower than 70%, Projects In Knowledge will notify you by mail and you will be given another chance to take the Posttest.

Name __________________________________________________________________ Degrees/Credentials __________________

Mailing Address ______________________________________________________________________________________________

City _____________________________________________________________________ State ________ ZIP ________________

Phone _________________________________________________ Fax _________________________________________________

E-mail ______________________________________________________________________________________________________

Please indicate your answers below.

1. Which of the following produces SVR in over half of all patients treated for HCV infection?

a. IFN monotherapy b. IFN/RBV c. PEG IFN/RBV d. All of the above

2. Which of the following side effects of PEG IFN/RBV therapy accounted for the most dose modifications in large clinical trials?

a. Neuropsychiatric effects (eg, depression, irritability, insomnia) b. Hematologic effects (ie, anemia, thrombocytopenia, neutropenia) c. Pulmonary symptoms (eg, cough, dyspnea) d. Flulike symptoms (eg, fever, fatigue, headache)

3. In a recent retrospective multicenter survey of “real world” patients, which of the following was identified as the cause of 36% of treatment discontinuations?

a. Depression b. Anemia c. Flulike symptoms d. Injection-site reactions

4. Erythropoietin has been safely and effectively used to treat anemia in patients with:

a. Cancer who are receiving chemotherapy b. Cancer who are not receiving chemotherapy c. HIV-infected patients taking zidovudine d. All of the above


CME Posttest

1666PT-WEB—Page 1 of 2

1666PT-WEB—Page 2 of 2

5. In recent studies of hepatitis C patients with anemia, erythropoietin:

a. Significantly increased hemoglobin levels b. Allowed for closer to recommended RBV doses c. Improved quality of life d. All of the above

6. Erythropoietin is usually initiated at a dose of:

a. 20,000 IU QW b. 30,000 IU QW c. 40,000 IU QW d. 50,000 IU QW

7. Both the National Institutes of Health and WIN-R studies found no discernible relationship between bacterial infections and PEG IFN-induced neutropenia.

a. True b. False

8. A well-controlled, double-blind study demonstrated that the incidence of major depression was reduced in malignant melanoma patients pretreated with the SSRI:

a. Mirtazapine b. Paroxetine c. Olanzapine d. Bupropion e. Citalopram

9. Usually, alopecia, which may be more pronounced after discontinuation of IFN, is:

a. Reversible b. Irreversible

10. Which of the following may be helpful in managing generalized cutaneous reactions and local injection-site reactions?

a. Application of warm or cool compresses b. Topical povidone-iodine or mild corticosteroid cream c. Premedication with diphenhydramine d. Hydroxyzine or naltrexone as needed e. All of the above f. None of the above

11. IFN-based therapy can produce irreversible:

a. Thrombocytopenia b. Skin discoloration c. Hypo- or hyperthyroidism d. Hypertension

12. ANC is likely to be lowest when measured:

a. Within 24 hours of PEG IFN dosing b. 3 days after PEG IFN dosing c. 6 days after PEG IFN dosing d. None of the above—ANC usually remains stable throughout the week

Thank you for your participation.

CME Posttest (cont'd)

Name ______________________________________________________________________________________________________

1666.ES-WEB—Page 1 of 2

Name _____________________________________________________ Degrees/Credentials _______________________________

Address ___________________________________________________________________________________________________

City ______________________________________________________ State _______________ ZIP _______________________

Instructions: Please print out and complete this survey, along with the CME Posttest, and mail or fax to Projects In Knowledge, 150 Clove Road,

Little Falls, NJ 07424; fax: 973-890-8866. We cannot issue CME certificates of credit without both documents.

1. Please rate the extent to which you achieved the learning objectives: Excellent Very Good Good Satisfactory Poor

● Describe the impact of treatment adherence on the likelihood of

early and sustained virologic response. ❑ ❑ ❑ ❑ ❑

● Develop and implement strategies to alleviate common side effects

of PEG IFN/RBV and to allow maintenance of recommended doses. ❑ ❑ ❑ ❑ ❑

● Consider use of hematopoietic growth factors and other strategies

to manage hematologic side effects. ❑ ❑ ❑ ❑ ❑

● Evaluate, prevent, and manage common neuropsychiatric side effects

of treatment with PEG IFN/RBV. ❑ ❑ ❑ ❑ ❑

● Implement appropriate adjuvant therapies to treat other common

side effects of PEG IFN/RBV therapy. ❑ ❑ ❑ ❑ ❑

2. Please rate the relevance of the objectives to the overall purpose/goals

of the educational activity.

The goal of this activity is to discuss strategies to prevent and manage Excellent Very Good Good Satisfactory Poor

side effects of antiviral therapy for hepatitis C in order to promote ❑ ❑ ❑ ❑ ❑

treatment adherence and maximize treatment outcomes.

Strongly Strongly

Agree Agree Disagree Disagree

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1666.ES-WEB—Page 2 of 2

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CME Evaluation Survey (cont’d)

Documents

Optimizing Outcomes by Helping Patients Through ... · Optimizing Outcomes by Helping Patients Through Peginterferon/Ribavirin ... anemia/ John G. McHutchison, MD Faculty Ira