SIDE EFFECTS IN INTERFERON AND RIBAVIRIN THERAPY FOR CHRONIC VIRAL HEPATITIS

Overview

The current state-of-the-art therapy for chronic viral hepatitis is interferon-based and will remain so for the foreseeable future. One of the major advances of the last decade has been the pegylation of interferon; this allows for weekly dosing rather than the standard triweekly dosing and prevents the subtherapeutic drug levels that contribute to resistance and treatment failure seen with the standard dosing.

Although pegylation substantially improves pharmacokinetics and is more virologically effective, the side effects are similar to standard therapy. Interferon is administered for long durations, is a difficult drug to tolerate, and has numerous side effects. These side effects may be mild, but the majority of patients experience side effects that affect quality of life, which may hinder or thwart completion of therapy. Patients are most likely to complete therapy if educated about possible side effects and means of alleviating them; therefore, a frank, thorough discussion of side effects is critical before initiating therapy. Patient education materials and pharmaceutical-sponsored assistance programs may assist both patients and physicians with management and may improve the success rate.

Non–life-threatening side effects related to interferons

• Physical
  
  Flulike symptoms of fever, chills, and body aches are common after each dose of interferon but are likely to be most pronounced after the first dose, and patients should be forewarned. Coping measures include dosing with acetaminophen prior to injection, injecting at bedtime so that the patient may sleep through some of the worst effects, and/or injecting on the patient’s day off from work. Fatigue is common throughout treatment and may be related to chronic hepatitis, interferon, thyroid dysfunction, anemia, or depression. The multifactorial nature of fatigue should be discussed with the patient, since this may not resolve after discontinuation of interferon. Hepatitis-related fatigue may be exacerbated by interferon, or fatigue may improve with control of viremia. Other common reactions include dry skin, alopecia, insomnia, nausea, and redness and swelling at the injection site.
  
  
• Psychiatric
  
  Depression occurs in approximately 20-60% of patients treated with interferons, and research is providing new insights into its causes. Neuropsychiatric effects may reflect central activation by proinflammatory cytokines; this “cytokine hypothesis” may mirror depression associated with such chronic inflammatory states as rheumatoid arthritis. Cytokines such as interferons may impair serotonin synthesis by inducing enzymes that degrade the serotonin precursor tryptophan, thus reducing serotonin levels. Cytokines may also reduce negative feedback inhibition by endogenous glucocorticoids and stimulate the hypothalamic-pituitary axis; this has been observed in clinical depression. Neurovegetative symptoms may include fatigue, poor appetite, psychomotor retardation, and body aches and may better respond to serotonin-noradrenaline antidepressants or bupropion than to selective serotonin reuptake inhibitors (SSRIs). Increased vegetative symptoms during the first week of treatment appear to precede and predict cognitive depressive symptoms within the first 24 weeks. Female sex, history of depression and anxiety, and greater interferon doses and duration of treatment are also associated with depression. Given the frequency of neurocognitive effects, psychiatric evaluation before therapy should be considered for all patients. Early vegetative symptoms and depression respond well to antidepressants. Accordingly, early aggressive management with SSRIs is best. Antidepressants should not be discontinued solely because interferon therapy has ended, however. A careful assessment with psychiatric consultation should be made as to whether and when antidepressants should be discontinued, especially in patients with personal or family histories of depression. One case documented attempted suicide 6 months after simultaneously stopping interferon and antidepressants; the patient had only a family history of depression.
  
  Aside from depression, interferon may cause acute confusional states (at initiation of high doses), neurovegetative syndromes, and manic episodes. Acute confusional states may manifest with classic delirium, as well as psychomotor retardation and parkinsonian symptoms; treatment involves antipsychotics. Mania is an indication for discontinuation of interferon and antidepressants, emergent psychiatric consultation, and initiation of mood stabilizers.

Serious and/or life-threatening adverse events

• Psychiatric
  
  Suicidal ideation and completed suicides are recognized complications of interferon therapy, and current products carry a warning of this potential. Aggressive or hostile behavior may be exacerbated; cases of homicidal ideation and escalated domestic violence have been reported. Prescreening for high-risk patients, avoidance of interferons in high-risk patients, and close monitoring during therapy of all patients regardless of risk is warranted.
  
  
• Cardiovascular
  
  Anemia related to ribavirin therapy is predominantly hemolytic, with some bone marrow component. It occurs within the first 2 weeks of therapy, with a nadir at 8 weeks, and hemoglobin (Hgb) levels may drop 2-3 g/dL fairly abruptly. This acute drop has been associated with ischemic events in patients with preceding (recognized or not) coronary or peripheral arterial disease. Reports range from myocardial ischemia and infarction to retinal ischemia and hemorrhage. During prescreening, physicians should look for a family or personal history of vascular disease and diabetes, risk factors for the same, and symptoms of unstable vascular disease. If unstable arterial disease is suspected, patients should be appropriately evaluated (eg, stress tests, vascular studies) to assure stable arterial flow before ribavirin therapy is initiated. Close monitoring for anemia in a patient with stable arterial disease is important, with transfusions considered if Hgb drops below 10 g/dL and/or if ischemic symptoms occur. Typically, Hgb is assessed at weeks 1, 2, and 4 and then monthly. Prompt evaluation of suspected ischemic symptoms is warranted. Patients with significant preceding coronary artery disease should avoid ribavirin therapy.
  
  
• Pulmonary
  
  Dyspnea, particularly in a patient with underlying lung disease, should prompt radiographic imaging. Interferons may induce or worsen pulmonary infiltrates, fibrosis, interstitial pneumonitis, or sarcoidosis and should be used with caution in patients with significant underlying respiratory disease.
  
  
• Hematologic
  
  Aside from ribavirin-related anemia, neutropenia and thrombocytopenia may be dose-limiting effects of interferons. Aplastic anemia is quite rare. Use of granulocyte-stimulating growth factors may allow continued therapy with the full dose. Early use of erythropoietin may also prevent these possible dose-limiting effects and obviate the need for transfusions. The use of recombinant human thrombopoietin remains investigational.
  
  
• Autoimmune/endocrinologic
  
  Glucose intolerance may be induced or worsened by interferons, as may hypothyroidism or hyperthyroidism. Periodic glucose and thyroid function testing is warranted. Patients whose glucose levels are inadequately controlled before or during therapy should discontinue interferons. In addition, recent reports associate reduced testosterone levels and erectile dysfunction with interferon therapy for chronic hepatitis.
  
  Interferons are contraindicated in patients with autoimmune hepatitis. Collagen vascular diseases, psoriasis, nephritis, myositis, idiopathic thrombocytopenic purpura, and thrombotic thrombocytopenic purpura have been reported with interferon treatment. Other autoimmune syndromes have been reported, including uveomeningoencephalitis (Vogt-Koyanagi-Harada disease) and inflammatory bowel disease.
  
  
• Infectious
  
  Serious infections, some fatal, have been reported with interferon therapy; these are most likely related to cytokine-mediated immunomodulating effects, with some related to significant neutropenia. Interferons should be discontinued in the setting of serious infection.
  
  
• Embryotoxic
  
  Ribavirin, a pregnancy category X drug, is teratogenic and embryocidal, and it may persist in nonplasma compartments for up to 6 months. In women of childbearing potential, pregnancy testing is crucial before initiating ribavirin therapy; pregnancy testing should be conducted monthly throughout treatment and up to 6 months after treatment. This testing should also be considered for the female partners of male patients on treatment. Both men and women on interferon therapy should use 2 forms of effective contraception throughout the above period. The US Food and Drug Administration’s Ribavirin Pregnancy Registry monitors outcomes of pregnancies occurring with ribavirin exposure of either partner during treatment or in the subsequent 6 months. Cases may be reported to the registry at (800) 593-2214.
  
  
• Hepatic
  
  Hepatic decompensation and death may occur in patients with cirrhosis and is more likely in the HIV co-infected patient. Interferons should be initiated with cautious monitoring and discontinued if signs of decompensation occur.
  
  
• Malignant
  
  Past or current malignancy may be exacerbated and is a contraindication to interferon.

Special situations for the HIV-HCV co-infected patient

• Drug interactions with antiretroviral therapy
  
  In vitro, ribavirin may inhibit phosphorylation of lamivudine, zidovudine, and stavudine; however, no clinical or pharmacokinetic effect has been observed in studies of HIV co-infected patients. Ribavirin is not contraindicated with these drugs. Monitoring HIV viral loads for possible effects is prudent.
  
  A drop in the absolute CD4 count is common with initiation of hepatitis therapy. This should be anticipated and antiretroviral therapy initiated or monitored to account for this.
  
  Didanosine is contraindicated because of the increase in active metabolites with ribavirin that results in an increased prevalence of pancreatitis, peripheral neuropathy, and lactic acidosis.
  
  
• Hematologic effects
  
  Since zidovudine may induce anemia, coadministration with ribavirin warrants close observation; use of erythropoietin may allow continued use of full ribavirin doses. HIV co-infection studies have used lower doses of ribavirin, at 800 mg daily, because of higher risks of anemia; however, many physicians initiate full doses of 1000-1200 mg daily, concomitantly with erythropoietin.
  
  Neutropenia, anemia, and thrombocytopenia are more common in HIV co-infected patients during interferon-ribavirin therapy and are treated as discussed above.
  
  
• Substance abuse and psychiatric effects
  
  Depression is more common in HIV co-infected patients, and interferons exacerbate this. Interferons may also exacerbate the depression and neuropsychiatric effects of efavirenz; consider possibly switching the latter.
  
  Intravenous drug use is often a treatment barrier for HIV-infected patients because of needle aversion (patients have poor acceptance), as is alcohol or other substance abuse because these patients have poor adherence.
  
  
• Hepatic effects
  
  Hepatitis is more rapidly progressive and severe in HIV-positive patients; consequently, hepatic decompensation is more likely in co-infected cirrhotic patients initiating therapy.

Special situations concerning patients with renal conditions

Patients on hemodialysis are at risk for hepatitis C because of multiple blood transfusions and possible inadequate sterilization of dialysis equipment between patients, although the degree of risk has decreased. Unfortunately, interferon and ribavirin are contraindicated in patients with significant renal insufficiency or a creatinine clearance <50 mL/min. No published dosing schedule exists for pegylated interferons in patients with severe renal insufficiency.

Summary

The treatment of hepatitis C, particularly when dealing with HIV co-infection, may be complicated by the side effects, drug interactions, and toxicities of interferon and ribavirin regimens. Treating clinicians must be aware of the potential for adverse effects and the management of side effects in order to achieve success.

References

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