Clinical Guidelines for the Medical Management of Hepatitis C
Appendix A - Side Effects of Treatment
Flu-like symptoms commonly develop on combination therapy. These symptoms include, but are not limited to, fever, chills, muscle aches, joint pains, headache, and fatigue. Thesesymptoms usually occur within 2-24 hours ofinjection of pegylated interferon and tend tolessen in severity during the course of treatment.Injection of pegylated interferon at bedtime maylessen the severity of these side effects. Well-balanced meals and exercise may help the fatigueassociated with therapy. As combination therapycan lead to mild dehydration, the importanceof maintaining adequate hydration cannot beoveremphasized. One twelve ounce glass of waterevery 3-4 hours can be very effective in treatingthe flu-like symptoms which may occur. Avoidingloud noises, bright lights, alcohol, caffeine andfoods with tyramine and phenylalanine may alsohelp to treat headaches. The headache, joint pains and muscle aches associated with therapy can be improved with the use of acetaminophen or non-steroidal anti-inflammatory medications such as ibuprofen. Regular-strengthacetaminophen (325 mg tablets) use should not exceed six tablets a day and extra-strength (500 mg tablets) use should not exceed four a day. Ifheadaches persist, despite these interventions,a physician should be consulted to look for other potential causes or treatment.
Gastrointestinal Side Effects
Nausea, anorexia and diarrhea may also complicate therapy. Ribavirin can cause nausea if taken on an empty stomach so it is important to take ribavirin with food. Smaller, morefrequent meals will help to maintain adequatenutritional intake. Fatty foods should be avoidedas these foods may worsen nausea. If nauseapersists, anti-nausea medications such asondansetron or prochlorperazine can be used.
Diarrhea should be initially evaluated by a physician to determine whether or not the medications are felt to be responsible. If diarrhea is due to interferon therapy, increased hydration,the use of anti-diarrheals and the institution ofthe BRAT (bananas, rice, apple sauce and toast)diet may improve symptoms. Significant weightloss secondary to nausea, anorexia and diarrheamay also occur. If treated patients begin to losemore than two pounds weekly for several weeks,aggressive treatment of the above listed adverseeffects is indicated.
Vitamin supplementation with a multi-vitamin that does not contain iron is recommended during therapy to ensure appropriate intake as adequate vitamin ingestion may decrease duringthis time.
Injection Site Reactions
Injection site reactions occur with pegylated interferon and appear to be more common with the use of pegylated interferon alfa 2b. Injection site reactions may appear unsightly, but rarelylimit therapy. These reactions can be minimizedby applying ice to the injection site prior toinjection, allowing the alcohol to dry aftercleaning the injection site and ensuring that theinterferon is at room temperature immediatelyprior to the injection. The injection should begiven at a 45-90 degree angle. Following theinjection, manipulate of the site should beavoided. As pegylated interferon is given oncea week, it is helpful to use six to eight differentinjection sites around the body to minimizethe reactions in each given area and allow foradequate healing over time.60
Hair loss may occur on therapy but it is generally mild. Women tend to be more cognizant of mild hair loss than men. Male pattern baldness does not occur as a result of therapy nor does thedramatic hair loss seen in cancer chemotherapy.Rather, hair loss with interferon and ribavirinis usually noticed in the shower or uponmanipulation. It is important to understandthat hair loss in this situation is temporary andthat hair loss will stop and normal hair growthwill return upon cessation of therapy. Rarely,hair loss can be the result of the development of thyroid disease so all patients who complain of hair loss should have thyroid testing performed.Hair loss on therapy can be minimized by cuttinghair short, towel drying instead of blow drying,and avoiding the use of harsh chemicals.
One of the most common complaints reported early in therapy is the inability to get a good night sleep and the development of insomnia. This must be addressed early on as persistentlack of sleep can lead to irritability andsubstantial decreases in overall quality of life.Poor sleep habits may be one of the initialsigns of depression and people with insomniamust be evaluated for depression. If there areno signs of depression, the insomnia can beaddressed. Good sleep hygiene is essential togetting a good night sleep. Caffeine and alcoholuse should be limited as these interfere with theability to fall asleep or sleep through the nightwithout frequent wake ups. Patients should becounseled to go to sleep only when drowsy andto maintain a regular sleep schedule. Daytimenapping should be limited and patients shouldwind down and relax for about one hour before going to bed. Relaxation techniques such as yoga or biofeedback can be helpful. If these therapies are unsuccessful, pharmacologic therapy may be necessary. Common medications used to aid insleep include zolpidem, zaleplon and low doses ofalprazolam.
Ribavirin frequently leads to anemia which can cause fatigue and place a patient at risk for the development of chest pain, shortness of breath and even heart attack. The degree of hemoglobindrop is directly proportional to the ribavirindose, with many patients having a decrease inhemoglobin by as much as three to four gramswithin four to eight weeks of starting treatment.In the major clinical studies with pegylatedinterferon and ribavirin, significant anemiarequiring a ribavirin dose reduction occurredin 13-22% of treated patients. 2,60 The currentstandard of care and approved recommendationfor the management of anemia secondary toribavirin is dose reduction. Patients withouta history of heart disease should have theirribavirin dose reduced by 200 mg or one pill ifthe hemoglobin falls below 10 grams/dl, andribavirin must be stopped if the hemoglobin falls below 8.5 grams/dL. In patients with a history of heart disease, ribavirin should be dose reduced if there is a greater than two gram drop in hemoglobin during any fourweek period on therapy and discontinued if the hemoglobin remains below 12 grams/dL despite dose reduction.64 Recently, data has suggested that even a small decrease in ribavirin dose may decrease sustained viral response rates in cirrhotic patients with hepatitis C.67 Therefore, it seems reasonable to use other means to counterthe anemia caused by ribavirin and allow for thecontinuation of ribavirin without dose reductionat the initially recommended doses. This concepthas led to the widespread use of erythropoietinas an adjunct therapy, although erythropoietin isnot currently approved for use in this indication.Erythropoietin is an injectable medication thathas been shown at doses of 40,000-60,000 units per week to increase hemoglobin level in people currently being treated with ribavirin, to allow ribavirin to be used without dose reduction, and to most importantly, relieve the fatigueassociated with therapy and dramaticallyimprove patients reported quality of life ontherapy.118
Pegylated interferons have been associated with a greater decrease in absolute neutrophil counts than standard interferons, requiring dose reduction secondary to neutropenia in 18-20% of treated patients.2,60 While neutropeniais common, rarely is the neutropenia severeenough to warrant permanent discontinuationof therapy. If the neutrophil count drops below0.75 x 109 / L, the pegylated interferon doseshould be reduced by 50%. If the neutrophilcount falls below 0.50 x 109 / L, therapy shouldbe discontinued.2,60 Neutrophil counts usuallyreturn to pretreatment levels within four weeksof stopping therapy. Based upon the concern ofneutropenia, many physicians have advocatedthe use of granulocyte-colony stimulating factor(G-CSF) at a dose of up to 300 ug subcutaneouslyper week. Currently, there are no clinical trialsto demonstrate the effectiveness of G-CSF although clinical experience does support its efficacy in certain situations.
Pulmonary conditions such as shortness of breath or cough may develop on combination therapy. If cough develops, patients should be evaluated for such conditions as pneumonia orpulmonary fibrosis. Assuming no other cause ofcough is found, increasing fluid intake, avoidanceof environmental irritants such as cigarettesmoke, use of a humidifier, and the use ofcough drops or non-sedating cough medicationsmay help to alleviate this annoying symptom.Shortness of breath is another symptom whichcan occur on combination therapy. If shortnessof breath occurs, anemia must be evaluatedfor as ribavirin can cause significant and lifethreatening anemia. If shortness of breath occursin the absence of anemia, other lung conditionssuch as pneumonia, interstitial pneumonitis andsarcoidosis must be looked for.56,57
Pegylated interferon therapy may cause or aggravate the thyroid resulting in either the development of hypothyroidism or hyperthyroidism. Thyroid studies should bechecked periodically while on therapy and in thesix months following therapy. The use of thyroidreplacement hormones to treat symptomatic hypothyroidism while on antiviral therapy is not uncommon. Thyroid dysfunction as a result of antiviral therapy may be irreversible following cessation of interferon therapy and may requirethe lifelong use of thyroid replacement hormonein patients with hypothyroidism.56,57
Complaints related to the eye are being more widely reported with the widespread use of pegylated interferons and ribavirin. People with pre-existing eye problems such as retinopathy,especially people with diabetes and hypertension,should receive periodic eye examinations priorto and during therapy. Any complaints ofblurry vision, floaters or loss of vision shouldbe evaluated immediately as retinal artery andcentral vein thrombosis, retinal hemorrhages,optic neuritis and papilledema may by induced oraggravated by interferon therapy.56,57
Neuropsychiatric Side Effects
Neuropsychiatric side effects are commonly seen with the use of pegylated interferon and ribavirin. The most common reason for premature discontinuation of pegylatedinterferon and ribavirin therapy for hepatitis C is the development of neuropsychiatric symptoms such as depression. The incidence of depression described with combination pegylated interferon and ribavirin ranges between 21-31%.2,60 Signs and symptoms of depression are usually noted in the first three months of therapy althoughthese symptoms may occur at any time during therapy. Depression may manifest as a spectrum of findings including insomnia, irritability,impaired concentration, change in eating habitsresulting in either weight gain or loss, loss ofinterest in sex, and the inability to get pleasurefrom things previously enjoyed. Therefore, itis important to conduct routine assessments for depression throughout the entire course of therapy.
Depression is best managed with a combination of therapy with a trained mental health professional and with the use of anti-depressant medications. The most popular class of anti-depressants used by hepatitis C treatingphysicians is the selective serotonin reuptakeinhibitors (SSRIs) such as fluoxetine, sertraline,paroxetine, and citalopram. Once recognized,depression should be treated as early as possible,as SSRIs take several weeks to become effective.
Several other conditions have been reported with the use of pegylated interferons. Ulcerative, hemorrhagic and ischemic colitis have been observed with twelve weeks of initiating therapyand typically present with abdominal pain,bloody diarrhea and fever. Pancreatitis has alsobeen reported. If these conditions occur, therapyshould be stopped immediately and the patientreferred to the appropriate physician.56,57