HCV Weekend Reading-What you need to know about Direct-Acting Antiviral (DAA) Therapy for hepatitis C



Weekend Reading

Most weekends this blog offers up a few substantial links to relevant HCV information, click here for previous "Weekend Reading" articles.


First up from CAP is the April "Pubmed Review" of the most relevant research on hepatitis C.



Next offered at -"Projects In Knowledge" are six chapters on what you need to know about "Direct-Acting Antiviral (DAA) Therapy" for hepatitis C. The site is a great source for easy to understand information, although like any site offering continuing medical education - CME, it requires a free quick registration.

The six chapters listed below can be a useful learning tool for anyone considering hepatitis C therapy. The last chapter "Neuropsychiatric Adverse Effects" has been made available on the blog below. Once you register at "Projects In Knowledge"  view all eHandbook Chapters -- here.

Release date: October 31, 2011

Chapter 1
Getting Ready for Direct-Acting Antiviral (DAA) Therapy
Chapter 2
What You Need to Know About the New Direct-Acting Antiviral (DAA) Regimens
Chapter 3
Hematologic Adverse Effects
Chapter 4
Dermatologic Adverse Effects
Chapter 5
Gastrointestinal Adverse Effects

Chapter 6
Neuropsychiatric Adverse Effects
Release date: October 31, 2011
Introduction
Depression
Irritability and Anxiety

Related:View List-FDA Alert-Statins and HIV or Hepatitis C Drugs
Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk of myopathy, kidney damage, and kidney failure, which can be fatal.
View the list of HIV or HCV Drugs which interact with statins Here or Here.
..
Hepatitis C — Neuropsychiatric Adverse Effects –  eHandbook Chapter
  • Depression, irritability, and anxiety are common in HCV patients receiving peginterferon/ribavirin treatment. The addition of direct-acting antiviral (DAA) therapy to peginterferon/ribavirin does not appear to further increase the incidence of these neuropsychiatric events, but drug-drug interactions limit the treatment options for depression and anxiety. In the sixth chapter of this eHandbook, HCV Care and Guidance: Practical Education and Resources for Nurse Practitioners and Physician Assistants, Jill Y. Chang, PA-C outlines management strategies for these adverse effects that may help improve patient outcomes


  • Introduction

  • Interferon/ribavirin therapy for chronic hepatitis C virus (HCV) infection is associated with neuropsychiatric effects, including depression, irritability, and anxiety; other effects, such as mania or suicidal ideation and behavior, may also occur.1-3 While the direct-acting antivirals (DAAs) boceprevir and telaprevir do not appear to add to the incidence of these adverse effects, they complicate management because they are associated with drug-drug interactions with several commonly prescribed psychotropic medications, including antidepressants and sedatives/hypnotics.


  • Important Take-Away Points

    • Clinicians need to be aware of drug-drug interactions between the DAAs and drugs used to treat neuropsychiatric adverse effects.
    • Patients should be screened for depression and assessed for history of other psychiatric disorders prior to initiating anti-HCV therapy and should be monitored for symptoms during and after therapy.
    • If interferon therapy is discontinued due to neuropsychiatric or other adverse effects, it is also necessary to discontinue ribavirin and the protease inhibitor.
    .
    Neuropsychiatric Adverse Effects

    Depression
    Major depression is estimated to affect at least 25% of patients with chronic HCV infection compared with approximately 7% of the general population.4,5 Interferon treatment is associated with depression, and a prevalence of 23% to 44% has been shown in chronic HCV patients receiving interferon monotherapy.2 Moreover, patients initiating therapy for chronic HCV commonly have pre-existing psychiatric disorders, including depression, and this may predispose them to new or worsened interferon-associated depression.1,2 The postulated physiologic mechanisms responsible for the increase in depression with interferon include monoamine dysfunction (in particular, decreased serotonin levels), hypothalamic-pituitary-adrenocortical axis activation, proinflammatory cytokine activation, decreased peptidase levels, increased levels of intracellular adhesion molecule-1 in tissues and in its soluble form in serum, and increased nitric oxide levels.2

    Although interferon treatment has been associated with depression in other disease settings, such as cancer, it appears that patients with chronic HCV may be more susceptible, possibly because of lower baseline levels of serotonin.2 Studies with ribavirin either alone or in combination with interferon or peginterferon have indicated that it too may play a role in the increase in depression seen with interferon.2 However, studies of triple therapy with DAA therapy in combination with peginterferon/ribavirin for the treatment of chronic HCV infection have provided no evidence that the addition of a DAA increases the risk of depression.6-9

    Boceprevir Triple-Therapy Data

    In two phase III clinical trials, the rate of depression was not significantly different between patients receiving boceprevir triple therapy and patients receiving peginterferon/ribavirin combination therapy. In the treatment-naive trial, depression occurred in 22% of patients in the peginterferon/ribavirin group compared with 23% and 19% in the two triple-therapy groups (P = .86 and .36, respectively).6 In the treatment-experienced trial, depression occurred in 15.0% of patients in the peginterferon/ribavirin group compared with 12.3% and 16.8% in the two triple-therapy groups (P = not significant for both).7

    Telaprevir Triple-Therapy Data

    The incidence of depression was similar between patients receiving telaprevir triple therapy and patients receiving peginterferon/ribavirin therapy in two phase III clinical trials. Depression occurred in 22% of patients in the peginterferon/ribavirin group compared with 18% and 17% in the two telaprevir triple-therapy groups in the treatment-naive trial.8 Depression occurred in 14% of patients in the peginterferon/ribavirin group compared with 9% and 13% in the two telaprevir triple-therapy groups in the treatment-experienced trial.9

    Management Strategies

    Given the risk of worsening depression, interferon-based therapy should be used with extreme caution in patients with a history of depression, and clinicians should monitor all patients for evidence of depression. In addition, mood and anxiety symptoms prior to treatment are important risk factors for developing interferon-induced depression.10 Clinicians treating patients with chronic HCV infection should be familiar with the various depression screening tools, and all patients should receive a pretreatment assessment for pre-existing depression or risk factors and follow-up assessments throughout therapy.2,11,12 The key is not which tool to use, but rather to be consistent in your practice and use the same tool for both baseline screening and follow-ups. In addition, it is important that clinicians are extremely vigilant for the symptoms associated with major depressive syndrome, as sometimes the symptoms are subtle and may be missed. The clinician should educate all patients and their families about the individual risk for depression, the symptoms of depression, and a plan to address the development of depression.1 There are many preventive strategies that a clinician can implement to avoid significant depression, as noted in Table 1.
    .
    Table 1. Management of Depression
    Note: Strategies included within this table are based on expert opinion and experience.
    .
    Symptoms2
    • Depressed mood
    • Diminished interest or pleasure in activities
    • Significant weight loss/gain or decrease/increase in appetite
    • Insomnia or hypersomnia
    • Psychomotor agitation or retardation
    • Fatigue or loss of energy
    • Feelings of worthlessness or excessive guilt
    • Diminished ability to think or concentrate; indecisiveness
    • Recurrent thoughts of death or suicidal ideation
    Screening tools2,12
    • Center for Epidemiologic Studies-Depressed Mood Scale (CES-D) - preferred screening tool
    • Beck Depression Inventory (BDI) - good for patients with physical complaints
    • Zung Self-Rating Depression Scale (ZSDS)
    • Hospital Anxiety and Depression Scale (HADS)
    • Montgomery-Asberg Depression Rating Scale (MADRS)
    Preventive strategies
    Most important strategies:
    • Treat/stabilize pre-existing depression before starting anti-HCV therapy*
    • Consider prophylactic antidepressant therapy for those deemed high risk for depression*
    • Educate patient/family regarding risk of depression; encourage early reporting of depressive symptoms
    • Refer patient to a local hepatitis C support group, or online support programs, if available
    • Provide positive feedback/reinforcement for proactive side-effect management efforts
    • Patients infected with HCV with history of injection drug addiction: subcutaneous injection may trigger feelings of drug hunger, anxiety, depression, or provoke posttraumatic stress disorder.13 Reassure the patient and arrange for outpatient injection or family member administration
    Additional strategies that may be helpful:
    • The patient may benefit from the practice of stress reduction, including relaxation periods (yoga, meditation, etc)
    • Encourage regular exercise
    • Encourage patient to recognize and "reroute" negative thinking patterns; eg, use a journal to record thoughts and daily activities
    • Maintain adequate hydration. Limit caffeine, alcohol, and processed-food intake

    *See product labeling for drug-drug interactions between DAAs and drugs that may be used to treat neuropsychiatric adverse effects.

    Often, depression will require medical intervention; this is especially true in patients with previous history or active depression. Patients with symptoms of moderate depression should be considered for antidepressant therapy and may benefit from a temporary interferon dose reduction as outlined in the peginterferon product labeling.14,15 Patients experiencing severe depression or suicidal ideation should discontinue therapy and be followed closely with appropriate medical management and psychiatric intervention.11 It is important to note that if interferon is discontinued, the protease inhibitor and ribavirin also must be discontinued.16-18 In general, psychiatric adverse events resolve on cessation of therapy; however, in some cases resolution may take several months or longer and psychiatric medications may be required. Commonly used medications for depression are listed in Table 2, with selective serotonin reuptake inhibitors often being used as first-line therapy. Clinicians need to be aware of drug-drug interactions with DAAs when treating patients with antidepressants or sedatives/hypnotics, as outlined in the boceprevir and telaprevir product labeling.

    Table 2. Treatment Options for the Pharmacologic Management of Interferon-Induced Depression1

    Class
    Agents
    SSRIs
    • Citalopram
    • Escitalopram (has drug-drug interactions with DAAs: boceprevir - interaction not studied, an interaction is predicted based on drug metabolic profiles; telaprevir - escitalopram concentrations may decrease, may need to adjust escitalopram dose)
    • Sertraline
    • Fluoxetine
    • Paroxetine
    • Fluvoxamine
    SNRIs
    • Venlafaxine
    • Desvenlafaxine
    • Duloxetine
    DNRIs
    • Bupropion
    Mixed-receptor
    • Mirtazapine
    • Nefazodone
    TCAs
    • Nortriptyline
    • Imipramine
    D2/5HT2 agents*
    • Risperidone
    • Paliperidone
    • Olanzapine
    • Quetiapine
    • Ziprasidone
    • Aripiprazole

    *No evidence regarding use of these agents in patients receiving interferon-alfa; none of these agents are approved for the treatment of unipolar major depressive disorder.

    Abbreviations: DNRIs, dopamine/norepinephrine reuptake inhibitors; SNRIs, serotonin/norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.

    Disclaimer: Drug-drug interaction information in this table is correct as of the time of writing, but testing for potential interactions between the approved protease inhibitors and other drugs and supplements is ongoing. Clinicians should always check the most recent product labeling for all known drug-drug interactions before prescribing any drug in combination with either boceprevir triple therapy or telaprevir triple therapy.

    One of the most important decisions during the treatment of depression is when to refer a patient for a psychiatric consultation, as this will not be required for all patients.1 If further psychiatric evaluation is warranted based on initial screening, it should include an assessment of any current psychiatric disorders, whether they have been stable for the preceding 3 to 6 months, any barriers to adherence (either for psychiatric or antiviral treatments), and whether the current level of depressive symptoms warrants antidepressants.1 A signed informed consent form allowing communication between the psychiatrist and the hepatologist or other clinicians helps to ensure coordination of the patient's care.1 Regular follow-up should be available, especially for patients at an increased risk of developing depression.1 Based on the outcome of this initial assessment, some patients may require additional psychiatric treatment, monitoring, or education prior to initiating anti-HCV therapy.1 It may also be necessary to address any barriers to adherence or to defer anti-HCV therapy if necessary.1 Any clinical decisions should involve both the hepatologist and psychiatrist, and should take into consideration the patient's liver disease, comorbidities, and any other patient-specific requirements.1
    Often, patients may not display depressive symptoms until after anti-HCV therapy is discontinued; these are most likely not related to interferon and are instead due to an underlying or pre-existing condition. Clinicians should also consider the patient's psychologic/emotional issues, history (including alcohol or drug abuse), and social situation when these symptoms occur. It is important to continue to follow these patients clinically posttherapy as well.
    .
    Neuropsychiatric Adverse Effects

    Irritability and Anxiety
    A syndrome of irritability/labile anger that is distinct from major depressive disorder has been reported in up to 25% of patients receiving interferon therapy and has also been linked to ribavirin.1,2 In patients taking interferon, the underlying physiologic mechanisms responsible for this syndrome may include decreased tryptophan levels as well as a polymorphism in tumor necrosis factor-alpha.19,20
    Interferon and ribavirin are also associated with anxiety, which has been reported in 10% to 20% of patients taking interferon.2,3,21 It is not clear, however, that the anxiety associated with interferon/ribavirin is distinct from depression.21 Interferon-associated anxiety is related to increased levels of proinflammatory cytokines and reductions in tryptophan levels.21 Studies with triple therapy have reported that adding a DAA to peginterferon/ribavirin has little effect on the incidence of irritability or anxiety except for an increase in irritability with boceprevir triple therapy in previously treated patients.8,9,17

    Boceprevir Triple-Therapy Data
    In combined safety data from a phase II and a phase III trial in treatment-naive patients, the incidence of irritability was 23% in the peginterferon/ribavirin group and 22% in the boceprevir triple-therapy group in treatment-naive patients.17 In the phase III trial in previously treated patients, irritability occurred in 13% of patients in the peginterferon/ribavirin group and 21% in the boceprevir triple-therapy group.17
    The incidence of anxiety did not meet the threshold for reporting in the boceprevir prescribing information (incidence 10% or greater with boceprevir triple therapy and at least 5% greater with triple therapy compared with peginterferon/ribavirin therapy).17 Anxiety frequency also did not meet the threshold for reporting in the two phase III trials (incidence 15% or greater in any treatment group).6,7

    Telaprevir Triple-Therapy Data
    The incidence of irritability in the treatment-naive phase III trial was 18% in the peginterferon/ribavirin group and 22% and 19% in the two telaprevir triple-therapy groups.8 In the treatment-experienced trial, irritability occurred in 16% of patients in the peginterferon/ribavirin group compared with 14% and 14% in the two telaprevir triple-therapy groups.9
    Anxiety did not meet the threshold for reporting in the telaprevir prescribing information (incidence in the telaprevir triple-therapy group at least 5% greater than in the peginterferon/ribavirin group).18 Anxiety was reported in 12% of patients in the peginterferon/ribavirin group compared with 10% and 9% in the two telaprevir triple-therapy groups in the treatment-naive trial, but did not meet the threshold for reporting in the treatment-experienced trial (incidence 10% or greater of patients in any study group).8,9

    Management Strategies
    Note: Strategies included within this section are based on expert opinion and experience as well as published studies.

    The recommendations for screening and psychiatric consultation outlined in the section on depression also apply to other psychiatric disorders, including irritability and anxiety. In particular, clinicians should be aware that some patients may minimize or deny neuropsychiatric symptoms because of embarrassment22 or fear of dose reduction or treatment cessation. Various preventive, nonpharmacologic, and pharmacologic strategies for managing patients with irritability or anxiety are listed in Tables 3 and 4. As with the pharmacologic treatment of depression, it is important to recognize the potential for drug-drug interactions between the DAAs and any antidepressants or anxiolytics used to treat irritability or anxiety. For patients resistant to single-drug interventions for the treatment of irritability, combining two antidepressants or reducing the interferon dose may be effective. If these strategies are not successful, interferon treatment should be discontinued, keeping in mind that when interferon is discontinued it is also necessary to discontinue the protease inhibitor and ribavirin.16-18


    Table 3. Management of Irritability/Labile Anger
    Note: Strategies included within this table are based on expert opinion and experience.

    Nonpharmacologic treatment strategies
    Encourage patients to:
    • Engage in mild to moderate aerobic and/or anaerobic exercise, as a mechanism to channel anger and irritability
    • Try meditation/relaxation techniques (yoga, biofeedback, imagery, massage)
    • Maintain good sleep habits (consistent times for sleeping; avoid caffeine; consume tryptophan-containing foods, such as warm milk, turkey, and salmon)
    • Avoid overstimulating environments (crowds, heavy traffic, loud noise)
    • Ensure adequate hydration
    • Enjoy small pleasures (movies, music, friends, pets, laughter, positive reminiscence)
    • Recognize and report warning signs (early detection and intervention are crucial)
    Providers should:
    • Educate and support families to help them cope with unpredictable, difficult personality changes and mood swings
    Pharmacologic treatment strategies
    SSRIs
    • Citalopram*
    • Escitalopram* (has drug-drug interactions with DAAs: boceprevir - interaction not studied, an interaction is predicted based on drug metabolic profiles; telaprevir - escitalopram concentrations may decrease, may need to adjust escitalopram dose)
    • Sertraline*
    SNRIs
    • Venlafaxine* (has a sedating effect, reducing irritability and combative behavior)
    Mixed-receptor
    • Mirtazapine*
    • Nefazodone* (has a sedating effect, reducing irritability and combative behavior)
    • Trazodone* (useful adjunct for sleep disturbance and is well tolerated; has drug-drug interactions with DAAs: use with caution with telaprevir and boceprevir, adverse events such as nausea, dizziness, hypotension, and syncope may occur, trazodone concentrations may increase, consider lower dose of trazodone)
    DNRIs
    • Bupropion* (has a sedating effect, reducing irritability and combative behavior)
    Anticonvulsant
    • Gabapentin* (may prove useful for mild to moderate irritability or impulsivity in the absence of depressive symptoms)

    *Not approved for the treatment of irritability/labile anger.

    Abbreviations: DNRIs, dopamine/norepinephrine reuptake inhibitors; SNRIs, serotonin/norephinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors.
    Disclaimer: Drug-drug interaction information in this table is correct as of the time of writing, but testing for potential interactions between the approved protease inhibitors and other drugs and supplements is ongoing. Clinicians should always check the most recent product labeling for all known drug-drug interactions before prescribing any drug in combination with either boceprevir triple therapy or telaprevir triple therapy.

    Table 4. Management of Anxiety
    Note: Strategies included within this table are based on expert opinion and experience.

    Preventive strategies
    Encourage patients to:
    • Reduce or eliminate alcohol, caffeine, nicotine, and other stimulants, and to eat smaller, more frequent meals
    • Keep a food diary to detect correlation between attacks and foods consumed
    • Consider stress management/biofeedback interventions, including relaxation exercises and tapes, guided imagery, and meditation. Talking with family or friends can diffuse anxiety
    • Exercise: walking, swimming, yoga, aerobics, etc. Conversely, assess for and ensure adequate sleep and rest
    Providers should:
    • Educate the patient regarding disease, treatment, subcutaneous injection, side effects, and symptom management to allay concerns and anxiety level
    • Provide contact numbers of office nurse, local hepatitis C support group, and "buddy," if available
    • Perform pretreatment assessment for current/past history of anxiety or panic disorder, and/or depression. Consider prescription antidepressants prior to or concomitantly with therapy to prevent progression of the disorder. See "Depression" section for further information
    • Discuss expectations of therapy, including side effects and management, and make specific plans for behavior modification in individuals with prior psychiatric history. This may prevent onset of symptoms or prompt reporting of the development of new symptoms
    • Involve family members in education and treatment planning to minimize "sick role"
    Nonpharmacologic treatment strategies
    Encourage patients to:
    • Create relaxation times throughout the day and evening, exercise, and limit daily tasks and pressure situations
    Providers should:
    • Instruct the patient how to manage panic attacks: Inhale to a count of four, exhale slowly to a count of four, do nothing to a count of four; repeat until the attack subsides. Patient should remind self that attacks are time-limited and will pass
    • Be aware that graded exposure (desensitization) may be required to treat panic attacks
    Anxiolytics
    • Buspirone
    • Meprobamate
    • Hydroxyzine
    Benzodiazepines
    • Alprazolam (has drug-drug interactions with DAAs: alprazolam concentrations may increase with boceprevir and telaprevir, clinical monitoring is warranted, alprazolam dose reduction should be considered)
    • Chlordiazepoxide
    • Clorazepate
    • Diazepam
    • Lorazepam
    • Oxazepam
    • Clonazepam*
    TCAs
    • Doxepin
    Antidepressants may also be used
    • SSRIs
    • TCAs
    • Mixed-receptor
    • Some antidepressants have drug-drug interactions with DAAs, see product labeling

    Abbreviations: SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.

    Disclaimer: Drug-drug interaction information in this table is correct as of the time of writing, but testing for potential interactions between the approved protease inhibitors and other drugs and supplements is ongoing. Clinicians should always check the most recent product labeling for all known drug-drug interactions before prescribing any drug in combination with either boceprevir triple therapy or telaprevir triple therapy.

    Conclusion
    Recognizing and addressing neuropsychiatric problems in chronic HCV patients increases the likelihood of positive outcomes.1 It is essential to assess all patients prior to treatment for any psychiatric concerns and to follow with ongoing close psychiatric monitoring during treatment. With the addition of DAAs, clinicians need to be well versed in drug-drug interactions with antidepressants in order to ensure patient safety. Prompt initiation and adjustment of antidepressants and continuing bidirectional communication between the psychiatrist and other clinicians are essential for overall treatment success.
    .
    References
    1.Lotrich F. Management of psychiatric disease in hepatitis C treatment candidates. Curr Hepat Rep. 2010;9:113-118.
    2.Asnis GM, De La Garza R II. Interferon-induced depression in chronic hepatitis C: a review of its prevalence, risk factors, biology, and treatment approaches. J Clin Gastroenterol. 2006;40:322-335.
    3.Sockalingam S, Links PS, Abbey SE. Suicide risk in hepatitis C and during interferon-alpha therapy: a review and clinical update. J Viral Hepat. 2011;18:153-160.
    4.Evon DM, Simpson KM, Esserman D, Verma A, Smith S, Fried MW. Barriers to accessing care in patients with chronic hepatitis C: the impact of depression. Aliment Pharmacol Ther. 2010;32:1163-1173.
    5.Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617-627.
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    7.Bacon BR, Gordon SC, Lawitz E, et al. Supplementary materials for: Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-1217.
    8.Jacobson IM, McHutchison JG, Dusheiko G, et al. Supplementary materials for: Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.
    9.Zeuzem S, Andreone P, Pol S, et al. Supplementary materials for: Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428.
    10.Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs. 2005;19:105-123.
    11.Valentine AD, Meyers CA, Kling MA, Richelson E, Hauser P. Mood and cognitive side effects of interferon-alpha therapy. Semin Oncol. 1998;25(suppl 1):39-47.
    12.Zdilar D, Franco-Bronson K, Buchler N, Locala JA, Younossi ZM. Hepatitis C, interferon alfa, and depression. Hepatology. 2000;31:1207-1211.
    13.Maunder RG, Hunter JJ, Feinman SV. Interferon treatment of hepatitis C associated with symptoms of PTSD.
    Psychosomatics. 1998;39:461-464.
    14.Pegasys [package insert]. Nutley, NJ: Hoffman-La Roche, Inc; 2011.
    15.PegIntron [package insert]. Whitehouse Station, NJ: Schering Corp; 2011.
    16.Copegus [package insert]. South San Francisco, CA: Genentech, Inc; 2010.
    17.Victrelis [package insert]. Whitehouse Station, NJ: Schering Corp; 2011.
    18.Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Inc; 2011.
    19.Russo S, Kema IP, Haagsma EB, et al. Irritability rather than depression during interferon treatment is linked to increased tryptophan catabolism. Psychosom Med. 2005;67:773-777.
    20.Lotrich FE, Ferrell RE, Rabinovitz M, Pollock BG. Labile anger during interferon alfa treatment is associated with a polymorphism in tumor necrosis factor alpha. Clin Neuropharmacol. 2010;33:191-197.
    21.Crone CC, Gabriel GM, Wise TN. Managing the neuropsychiatric side effects of interferon-based therapy for hepatitis C. Cleve Clin J Med. 2004;71(suppl 3):S27-S32.
    22.Renault PF, Hoofnagle JH, Park Y, et al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med. 1987;147:1577-1580.

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