Management of adverse events during the treatment of chronic hepatitis C infection

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Abbreviations

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

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

Table 1. Commonly Encountered Side Effects During the Treatment of Chronic Hepatitis C
Hematological
 Anemia
 Neutropenia
 Thrombocytopenia
Neuropsychiatric
 Difficulty with concentration
 Depression
 Insomnia
 Irritability
Dermatological
 Alopecia
 Localized skin irritation at the PEG-IFN injection site
 Erythematous maculopapular eruptions
 DRESS
 SJS
Other
 Flu-like symptoms
 Fatigue
 Generalized achiness
 Thyroid disorders
 Dysgeusia
 Anorectal discomfort
 Diarrhea
 Hyperuricemia
Table 2. Management Strategies for Common Side Effects
  1. *Trazodone and zolpidem have drug interactions with boceprevir and telaprevir and initially should be used at low doses.

Flu-like symptomsRest, fluid intake, and antipyretics (i.e., acetaminophen and nonsteroidal anti-inflammatory drugs)
FatigueRest and psychostimulants, ondansetron, or dopamine agonists
DyspneaRBV dose reduction
Generalized achesSerotonin-norepinephrine reuptake inhibitor (i.e., duloxetine)
Depression1. SSRIs (e.g., citalopram)
2. Psychiatric referral for refractory depression or suicidal ideation
InsomniaTrazodone or non-benzodiazepine hypnotics*
Alopecia1. Hats and head coverings
2. Reassurance that hair will regrow after the discontinuation of therapy
Anemia1. RBV dose reduction
2. ESAs (not FDA-approved for this indication)
3. Discontinuation of protease inhibitors if anemia is refractory to RBV dose reduction and ESAs
HyperuricemiaAllopurinol if the serum uric acid level is >9.5-10 mg/dL

Before Starting Treatment

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

Symptomatic Adverse Events

Flu-Like Symptoms

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

Neuropsychiatric Effects

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

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

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

Dermatological Effects

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

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

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

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

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

Other Symptoms

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

Table 4. Management of Anorectal Discomfort
Topical steroids (low potency)1% hydrocortisone cream or ointment (may cause skin atrophy if it is used for more than 2 weeks and can be alternated with petrolatum jelly)
Hydrocortisone acetate suppositories (e.g., Anucort-HC)
Topical local anesthetics1% hydrocortisone/1% pramoxine foam (Proctofoam-HC)
Lidocaine jelly
Nocturnal itchingDiphenhydramine
Loratadine
DiarrheaFiber supplementation
Loperamide
Diphenoxylate and atropine

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

Laboratory Adverse Events

Hematological Events

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

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

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

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

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

Other Laboratory Abnormalities

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

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