Interferon can decrease your white blood cell count (these are the cells that fight infections). Your doctor will check your blood cell count often while you are taking interferon, and If your white cell count falls too low, your doctor may lower the dosage of interferon for awhile to give your body a chance to rebuild its defenses. When your white count is lower than normal, it is very important to try to
prevent infections by taking the following steps:

Wash your hands often during the day. Be sure to wash them extra well before you eat and before and after you use the bathroom.
Clean your rectal area gently but thoroughly after each bowel movement. Ask your doctor or nurse for advice if the area becomes irritated or if you have hemorrhoids.
Stay away from people who have diseases you can catch, such as a cold, the flu, measles, or chickenpox. Also try to avoid crowds.
Don’t cut or tear the cuticles of your nails. Use cuticle cream and remover instead.
Be careful not to cut or nick yourself when using scissors, needles, or knives.
Use an electric shaver instead of a razor to prevent breaks or cuts in your skin.
Use a soft toothbrush that won’t hurt your gums.
Don’t squeeze or scratch pimples.
Take a warm (not hot) bath, shower, or sponge bath every day.
Pat your skin dry using a light touch. Don’t rub.
Use lotion or oil to soften and heal your skin if it becomes dry and cracked.
Clean cuts and scrapes right away with warm water, soap, and an antiseptic.
Wear protective gloves when gardening or cleaning up after animals.
Do not get any immunization shots without checking first with your doctor to see if it’s all right.

Even if you take extra care, you may still get an infection. Be alert to the signs that you might have an infection and check your body regularly for its signs, paying special attention to your eyes, nose, mouth, and genital and rectal areas. The symptoms of infection include:
Fever over 100 degrees F.
Chills.
Sweating.
Loose bowels
A burning feeling when you urinate.
A severe cough or sore throat.
Unusual vaginal discharge or itching.
Redness or swelling, especially around a wound, sore, pimple, or boil.
Report any signs of infection to your doctor right away.
---

Flulike Syndrome

FEVER, CHILLS, AND RIGORS

PATHOPHYSIOLOGY

Fever is a commonplace response to most biologic agents and is strongly dependent on

dosage. As part of the FLS associated with interferon, initial fevers of 104°F are not

uncommon.1 The patient’s overall condition, including general health, age, CV status,

and potential for infection should be assessed before administering antipyretics.1 Severity

of fever, chills, and rigors abates somewhat as treatment continues and as tachyphylactic

response occurs.2 Flulike symptoms that appeared upon initial administration, first with

chills and rigors, followed by fever about an hour later, may recur if dosage is increased.3

Fever has come to be viewed as an adaptive mechanism that facilitates body defenses.

Many of the cytokines, including the interferons, interleukins, and TNF-a, are

endogenous mediators of fever (endogenous pyrogens), although TNF may also be an

endogenous antipyretic.4 These and other mediators of immunity initiate a pathway that

raises the thermoregulatory set point of about 98.6°F (37°C) to raise body temperature—a

neuro-immunomodulatory reaction.5,6 The cytokines within the hypothalamus may

initiate fever, but the signals may originate from peripheral nerves within the brain.4 High

fevers (over 104°F) may be induced by the initial dose of interferon, other biologic

response modifiers, biologic agents, disease, malignancy, and many other causes. The

fever process may be induced via a multipathway mechanism that may have therapeutic

value. Thus, controversy still exists as to the wisdom of administering antipyretics to

reduce a mild fever.1

Interferon alfa modulates fever by changing the body’s release of hypothalamic

prostaglandin E2, which may stimulate a neurotransmitterlike substance to raise the

temperature set point.7 Fever is a multiphasic process that is a series of physiologic

responses (eg, peripheral vasoconstriction and shivering) and compensatory behavioral

responses (eg, adding clothing or changing body position).4 The stages of fever include:

· Stage I: Chill or Cold5

As the body is working to raise the temperature set point, vasoconstriction and

shivering (during which the patient feels cold) may occur, which may lead to

increased oxygen consumption and tissue catabolism. Other responses include thirst

and chills.

· Stage II: Hot or Plateau5

The body temperature achieves or exceeds the new set point. Skin is flushed and

warm, basal metabolic rate and oxygen demand are elevated, and tachycardia and

tachypnea will be experienced. Thirst is common, as are headaches and myalgias.

The cause for the fever may be determined and treated, or antipyretics may be

administered at this point.

Side Effects Management Handbook • VII. Flulike Syndrome • p. 9

· Stage III: Wet (Defervescence)5

Responses include vasodilation, flushing, and diaphoresis (especially above 38°C),

and dehydration.

ASSESSMENT STRATEGIES

1. Educate patients regarding appropriate way to take temperature (eg, avoid taking

temperature immediately after drinking coffee or smoking; keep thermometer in place

for adequate time).

2. Investigate infectious causes for development of high fever or fever persisting for

more than 48 hours after administration of peginterferon.

PATIENT EDUCATION

Patients should be informed that:

1. Flulike symptoms often accompany biologic therapy and severity may vary.

2. Adaptation or tachyphylaxis usually develops to fever and chills in about 2 to

3 weeks.

3. To ensure adequate hydration, they should drink the equivalent, in fluid ounces per

day, of one half their body weight (in lb). For example, a 160-lb person should

consume 80 fl oz water/d.

4. Relaxation and guided imagery techniques can minimize discomfort and anxiety.

5. A diary can be used to record fever patterns and other symptoms.

6. They should report to medical personnel any fevers uncontrolled by antipyretics or

unrelated to treatment.

7. They should notify medical personnel of “red flags” such as fever >104°F, prolonged

rigors, altered mental state, or cyanosis.

TREATMENT STRATEGIES

1. Evening administration (but earlier than at bedtime) of interferon may be helpful in

reducing the patient’s awareness of fever and other flulike symptoms, although the

patient may experience loss of sleep.2 Depending on the timing of symptoms, patients

may need to try even earlier administration.

2. Comfort measures (warm blankets, extremity wraps, ice packs) can be helpful.

3. Promote adequate hydration and give IV hydration if needed.

4. Antipyretics may be administered to reduce temperature >101°F and as analgesia,

but controversy exists as to their overall effect.1 Some providers recommend

premedicating with these agents and others inform patients to take them as soon as

flulike symptoms begin to develop.

a. Acetaminophen (Tylenol®) 325 to 650 mg Q6H PRN, not to exceed 2 to 3 g/d.

b. Ibuprofen (Motrin®, Advil®) 200 to 800 mg TID, not to exceed 2400 mg/d, with

food.

5. Prednisone is known to limit therapeutic effect and should not be used.8

6. Diphenhydramine (Benadryl®) 35 to 50 mg PO is infrequently used in resistant cases

as premedication and Q6H PRN.

7. Anti-HCV treatment can be dose reduced or discontinued should fever and other side

effects become unmanageable, but patients should be advised that the biologic effects

Side Effects Management Handbook • VII. Flulike Syndrome • p. 10

may be compromised by dose reduction and that the fever may contribute to the

therapeutic response.2

REFERENCES

1. Sandstrom SK. Nursing management of patients receiving biological therapy. Semin Oncol

Nurs. 1996;12:152-162.

2. Borden EC, Parkinson D. A perspective on the clinical effectiveness and tolerance of

interferon-a. Semin Oncol. 1998;25(suppl 1):3-8.

3. Kiley KE, Gale DM. Nursing management of patients with malignant melanoma receiving

adjuvant alpha interferon-2b. Clin J Oncol Nurs. 1998;2:11-16.

4. Kluger MJ, Kozak W, Leon LR, Soszynski D, Conn CA. Cytokines and fever.

Neuroimmunomodulation. 1995;2:216-223.

5. Haeuber D. The flu-like syndrome. In: Rieger PT, ed. Biotherapy: A Comprehensive

Overview. Boston, Mass: Jones and Barlett; 1995:243-258.

6. Mackowiak PA. Concepts of fever. Arch Intern Med. 1998;158:1870-1881.

7. Dinarello CA. Cytokines as endogenous pyrogens. J Infect Dis. 1999;(suppl 2):

S294-S304.

8. Vial T, Descotes J. Clinical toxicity of the interferons. Drug Saf. 1994:10:115-150.

Side Effects Management Handbook • VII. Flulike Syndrome • p. 11

Increased Cholesterol and Triglycerides

HYPERTRIGLYCERIDEMIA

Increased triglyceride levels are a rare side effect of interferon-based therapy. Secondary

hypertriglyceridemia can be seen with other conditions commonly associated with anti-

HCV therapy, including thyroid dysfunction, poorly controlled DM, and nephrotic

syndrome.

PATHOPHYSIOLOGY

Serum levels of total triglycerides and cholesterol have been studied in chronic hepatitis

patients before, during, and after treatment with interferon. Ruiz-Moreno et al1 found no

elevations in serum cholesterol during treatment. However, although an uncommon

occurrence, a significant increase in total serum triglycerides was observed at the first

month of therapy in the treatment groups and remained until the end of therapy.

Thereafter, the triglyceride levels returned again to basal values. This was observed with

varying schedules and doses of interferon. Moreover, these changes in triglyceride levels

were not related to (1) type of interferon, (2) response to therapy, (3) liver disease

activity, or (4) the etiologic agent (hepatitis B, C, or D). Fortunately, no

hypertriglyceridemia-related disease was observed.

PREVENTION STRATEGIES

1. Assess pretreatment risk, and if hyperlipidemia is present, treat underlying cause prior

to therapy initiation.

2. Follow serum triglycerides and cholesterol at baseline and monthly in patients with

lipid metabolism alteration.

3. Monitor Hgb A1c in diabetic patients monthly and TSH at baseline and quarterly.

(See also “Endocrine” section.)

TREATMENT STRATEGIES

1. Consider gemfibrozil (Lopid®) 600 mg BID.

2. Consider interferon dose reduction.

REFERENCE

1. Ruiz-Moreno M, Carreño V, Rúa MJ, et al. Increase in triglycerides during a-interferon

treatment of chronic viral hepatitis. J Hepatol. 1992;16:384.

TRIGLYCERIDE LEVELS (ECOG Scale)

Male Female

Grade 1 401–800 338–675

Grade 2 801–1600 676–1350

Grade 3 >1601 >1350

Depression

http://www.medadvocates.org/conferences/NIHHCVConsensusConference/NIHHCVSideEffects.htm

Prevention of Interferon Alfa-related Depression in Psychiatric Risk Patients with Chronic Hepatitis C

Interferon alfa (IFN-α)-induced depression is a major limitation for the treatment of chronic hepatitis C, especially for patients with psychiatric disorders. Researchers prospectively studied the efficacy of a pre-emptive treatment with the antidepressant citalopram to prevent depression during hepatitis C treatment with pegylated IFN-α-2b (PegIntron) plus ribavirin.

14 HCV-infected patients with psychiatric disorders received a prophylactic medication with citalopram (20mg/day) before and during therapy with IFN-α. The incidence of major depression was compared with 22 HCV-infected patients with psychiatric disorders (group B; n=11) and without psychiatric risk factors (group C; n=11), who underwent IFN-α treatment without a pre-emptive antidepressant therapy. Depression was diagnosed by DSM-IV criteria.

Results

Pre-treatment of psychiatric patients with citalopram significantly reduced the incidence of major depression during the first 6 months of antiviral treatment as compared to the two control groups (group A 14% vs. 64% and 55% in group B and C; P=0.032). Patients who developed symptoms of major depression during IFN-therapy could be also improved by anti-depressive treatment.

Conclusions

In conclusion, the authors write, “Our open label pilot study, even small, clearly indicates that IFN alfa-induced depression in psychiatric risk patients can be ameliorated by both the use of antidepressants as well as by intensive psychiatric care. However, larger, double blind placebo controlled trials in other patient populations are required to confirm these preliminary findings.”

05/13/05

Reference
M Schaefer and others. Journal of Hepatology 42(6): 799-805. June 2005.

http://www.hivandhepatitis.com/hep_c/news/2005/aa/051305_a.html

Psychiatric Side Effects of Pegylated Interferon Alfa-2b as Compared to Conventional Interferon Alfa-2b in Patients with Chronic Hepatitis C

(DDW 2004)

Arne Schaefer, Michael Scheurlen, Herbert Csef, Michael R. Kraus 

Background Aims

Psychiatric side effects of interferon alfa are frequently observed during therapy of patients with chronic hepatitis C infection. When introduced in 2000, peginterferon was suggested to be better tolerable than unmodified interferon.  

Aim

The goal of the present study was to assess systematically the spectrum and extent of psychiatric symptoms (especially depression and anger/hostility), comparing patient groups receiving peginterferon or conventional interferon, respectively. 

Methods

Ninety-eight patients with chronic hepatitis C and interferon-based therapy (+ribavirin) were consecutively enrolled in a longitudinal study. According to the respective therapy standards, patients were treated with conventional interferon alfa-2b (48/98 patients; 5 MIU interferon alfa-2b thrice weekly) or peginterferon alfa-2b (50/98 patients; 80-150 ìg peginterferon alfa-2b). Repeated psychometric testing was performed before, three times during and once after antiviral therapy: Depression was evaluated by the Hospital Anxiety and Depression Scale (HADS), anger/hostility by the Symptom Checklist-90 Items Revised (SCL-90-R).  

Results

Therapy with pegylated interferon alfa-2b produced comparable scores (with respect to time course and extent) for depression (ANOVA main effect treatment P > 0.05; main effect time course within treatment P < 0.001) as compared to conventional interferon. Observed maximums of depression scores were even higher (however, statistically not significant) and cases of clinically relevant depression were frequent during therapy with peginterferon and ribavirin. Scores for anger/hostility were comparable for both therapy subgroups (P > 0.05).  

Conclusions

Our findings suggest that the extent and frequency of depressive symptoms (and symptoms of anger/hostility) in total are not reduced by peginterferon as compared to conventional interferon alfa. Therefore, monitoring and management of neuropsychiatric toxicity - especially depression - have to be considered as much as in former antiviral therapy with unmodified interferon

http://www.hcvadvocate.org/news/reports/DDW_2004/HCV%20Posters_1.htm#P2

Contraindications and Cautionary Use

PSYCHIATRIC HISTORY/SUICIDE

Life-threatening or fatal neuropsychiatric events, including suicide, suicidal and

homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive

behavior have occurred in patients with and without a previous psychiatric disorder

during peginterferon treatment and follow-up. Psychoses, hallucinations, bipolar

disorders, and mania have been observed in patients treated with alpha interferons.

Peginterferon should be used with extreme caution in patients with a history of

psychiatric disorders. Patients should be advised to report immediately any symptoms of

depression and/or suicidal ideation to their prescribing physicians. Providers should

monitor all patients for evidence of depression and other psychiatric symptoms. In severe

cases, peginterferon/ribavirin should be stopped immediately and psychiatric intervention

instituted.

NOTE: Refer to the “Psychologic” section for assessment and management of

depression and suicidal ideation.

Side Effects Management Handbook • III. Contraindications/Cautions • p. 13

Contraindications and Cautionary Use

OTHER CONDITIONS

Extra caution should be used when evaluating and considering patients for treatment of

HCV infection.

Patients with the following conditions should be identified, and the conditions should be

well controlled prior to consideration for therapy:

· Uncontrolled diabetes and thyroid disorders

· Acute alcohol abuse and/or other substance abuse

· Decompensated liver disease

· Pre-existing renal and lung disease

· Ophthalmic disorders

· Hemoglobinopathies

If anti-HCV therapy is undertaken, these patients should be monitored carefully. Some

such conditions may be induced or exacerbated by peginterferon/ribavirin.

Peginterferon/ribavirin should also be discontinued in the rare case of severe acute

hypersensitivity reaction, colitis, or pancreatitis.

In addition, since peginterferon/ribavirin therapy suppresses bone marrow function and

can result in severe cytopenias, CBCs should be obtained pretreatment and monitored

routinely during therapy. Peginterferon/ribavirin should be used with caution in patients

with baseline neutrophil counts <1500 cells/mm3 and with baseline platelet counts

<90,000 cells/mm3 or baseline hemoglobin <10 g/dL. Peginterferon/ribavirin should be

discontinued, at least temporarily, in patients who develop severe decreases in neutrophil

and/or platelet counts. (See “Hematologic” section for management strategies.) The

peginterferon alfa-2a package insert includes a warning regarding serious and severe

bacterial infections (including some fatalities), some of which are associated with

neutropenia. Peginterferon alfa-2a/ribavirin should be discontinued in patients who

develop severe infections and appropriate antibiotic therapy should be instituted.

(Some of the conditions listed above are discussed in more details in other sections of this

handbook. Please also refer to the package inserts for more information about

contraindications and warnings.)

Side Effects Management Handbook • IV.

Internet Conference Report
39th EASL - April 14 - 18, 2004, Berlin Germany

Mood Disorders Occur in 41% of Patients Who Use Therapy with Peginterferon Alfa Plus Ribavirin

Psychiatric side effects are common with interferon therapy and responsible for treatment discontinuation in 10% to 20% of cases. The aim of this study was to characterize psychiatric events (incidence, time course, type and management) occuring during CHC treatment and their impact on adherence.

98 naive CHC patients (57 males, mean age 42±12 yrs) treated with peginterferon-alpha (1.5µg/kg/week) plus ribavirin (800-1200 mg/d) for 24 to 48 weeks were systematically assessed by a trained psychologist using the MINI-DSM-IV (a semi-structured interview) at baseline, week 4, W12, W24, W48 and W72.

In case of occurrence of a psychiatric event, they were referred to a psychiatrist for diagnosis and management. As the study is still ongoing, researchers at the 39^th EASL in Berlin reported on 86 patients who have completed at least 24 weeks of follow-up.

Results

Psychiatric events occurred in 35 patients (41%) (30 (86%) between D0 and W12, 5 (14%) between W12 and W24 and none after W24). They consisted of mood disorders (according to DSM-IV) in all cases with irritable hypomania in 19 cases (22%) and major depression with manic features in 16 cases (19%).

Their occurence was significantly associated with a past history of depression (p<0.008). A specific treatment (antidepressant or neuroleptic) was necessary in 25 cases (71%) allowing all patients but one to continue antiviral treatment.

Conclusions

Mood disorders are common (41%) during peginterferon and ribavirin therapy for CHC, mainly occurring within the first 12 weeks of treatment. Their early recognition and specific treatment improve adherence to antiviral therapy.

04/26/04

Reference
L Castera and others. PSYCHIATRIC EVENTS DURING PEGINTERFERON AND RIBAVIRIN THERAPY IN CHRONIC HEPATITIS C (CHC): RESULTS OF A PROSPECTIVE STUDY IN 98 PATIENTS. Abstract 460. 39^th EASL. April 14-18, 2004. Berlin Germany.

www.hivandhepatitis.com

Interferon Therapy Can Cause Depression NEW YORK (Reuters) --

 Interferon-alpha -- which is used to treat adult leukemia, certain kidney cancers, the skin cancer melanoma, and hepatitis B and C -- may cause depression and other side effects, researchers report. But, they add that these symptoms can be treated if patients and physicians are aware of potential risk factors and monitor the treatment process. "Common side effects associated with IFN-a (interferon-alpha) therapy include depression, paresthesias (changes in sensation), impaired concentration, amnesia, confusion, and anxiety," write Dr. Alan D. Valentine of the University of Texas M.D. Anderson Cancer Center in Houston and colleagues in the journal Seminars in Oncology. "These symptoms are rarely severe and appear to be dose related and reversible." The primary factor that may lead to such side effects is length of treatment with IFN-a, while dosage, the way IFN-a is administered, prior brain radiation, and a history of psychiatric illness may also increase risk. "Most adverse effects of IFN-a improve with dose reduction or cessation of therapy," the authors note, "but some individuals appear to have persistent deficits even years after treatment is discontinued." The investigators are confident that IFN-a therapy can be safe and effective. "These side effects can be treated successfully with antidepressants, but it is vital that those administering interferon-alpha become aware of potential psychiatric complications and routinely assess their patients' emotional and mental states," one of the researchers, Dr. Peter Hauser, said in a university press release. The investigators are conducting further research assessing the effects of IFN-a therapy accompanied by the use of antidepressants to treat central nervous system side effects. SOURCE: Seminars in Oncology (1998;25:39-47)

Diabetes Type One

Increased Risk for Type I Diabetes in Chronic Hepatitis C Patients Undergoing Interferon Therapy: a Review

A DGReview of :"Type 1 diabetes mellitus in patients with chronic hepatitis C before and after interferon therapy"
Alimentary Pharmacology & Therapeutics

09/25/2003
By Keely S. Solomon, PhD
 

Type 1 diabetes mellitus is caused by an autoimmune reaction characterised by the progressive destruction of insulin-producing pancreatic beta cells. The onset of the disease is preceded and accompanied by the circulation of autoantibodies to the endocrine pancreas.

Patients with other autoimmune diseases and relatives of people with type 1 diabetes have traditionally been considered the highest-risk groups for developing the disease. In a recent review, Paolo Fabris, MD, of San Bortolo Hospital, Vicenza, Italy, and colleagues, suggest that individuals with chronic hepatitis C (CHC) who are positive for beta cell autoantibodies should also be considered a high-risk group.

According to Dr Fabris, several studies have shown that patients with CHC do not have a significantly higher prevalence of pancreatic autoantibodies. However, treatment of the CHC with alpha-interferon therapy appears to increase the risk for development of diabetes in the small percentage of these patients who are seropositive for autoantibodies.

The reviewers focus on the 9 studies that have evaluated the effect of alpha-interferon on pancreatic immunity. In total, 484 patients (CHC, 440; chronic hepatitis B [CHB], 44) have been assessed. Before interferon therapy, 3% (12/440) of CHC patients and 2% (1/44) of CHB patients were positive for at least one marker of pancreatic autoimmunity. After treatment, the prevalence of pancreatic autoantibodies rose to 7% (33/440) for CHC patients and 5% (2/44) for CHB patients, suggesting that alpha-interferon is able to stimulate pancreatic autoimmunity.

To date, 31 cases of type 1 diabetes occurring soon after or during interferon therapy have been reported, including some of the seropositive cases described above. Among the reported cases, 9 (50%) of 18 patients tested before treatment were positive for at least one marker of pancreatic autoimmunity, and 23 (77%) of 30 cases evaluated had at least one marker at the onset of diabetes. HLA haplotypes conferring susceptibility to the disease were detected in 16 (89%) of 18 subjects studied.

The reviewers note that the autoimmune attack was at least partially reversible in some cases with the interruption of interferon therapy. In addition, five patients initially negative for pancreatic autoimmunity seroconverted during therapy.

Based on the available studies, Dr Fabris recommends that patients with CHC should be screened for pancreatic autoantibodies before and during interferon therapy. For seropositive patients, "initiation or suspension of the treatment should be evaluated, considering the risk of diabetes and the benefit of the treatment."

Aliment Pharmacol Ther 2003;18:6:549-558. "Type 1 diabetes mellitus in patients with chronic hepatitis C before and after interferon therapy"

DIABETES BACKGROUND

Type I, or insulin-dependent, DM is present in patients with little or no endogenous

insulin secretory capacity. These patients are dependent on injected exogenous insulin

therapy for their survival. Type I can occur at any age, but onset occurs predominantly in

youth.1

Type II, or non–insulin-dependent, diabetes mellitus (NIDDM) occurs in patients who

retain significant endogenous insulin secreting capacity. Although treatment with insulin

may be necessary for the control of hyperglycemia, these patients do not develop ketosis

in the absence of insulin therapy and are not dependent on insulin therapy for immediate

survival. Onset predominantly occurs after age 40 years.1

Autoimmunity plays a major role in the etiology of type I diabetes; 90% of patients have

demonstrable serum titers of islet cell antibodies or insulin auto-antibodies. Patients with

type II diabetes have a 60% incidence of obesity. They have normal or elevated fasting

insulin levels, secrete decreased amounts of insulin following meals, and are insulin

resistant.1

INCIDENCE OF DIABETES IN LIVER DISEASE

Chronic liver disease may be associated with diabetes. The liver is involved in

carbohydrate metabolism, and as many as 70% of patients with cirrhosis may have

impaired glucose tolerance. Hyperinsulinemia, insulin resistance, and hyperglucagonemia

(type II) may be a direct consequence of liver disease, especially cirrhosis. In patients

with chronic liver disease caused by HCV infection rather than by hepatitis B virus

(HBV) infection, the prevalence of diabetes is much higher.2

Type I Diabetes and Hepatitis C

Type I diabetes only rarely develops in patients with HCV infection, whereas type II

diabetes is much more prevalent. In a study assessing evidence of AI disease and

presence of autoantibodies in 70 HCV-infected patients, all patients with type I diabetes

and hepatitis C were positive for one or more markers of pancreatic autoimmunity before

treatment with interferon alfa. Furthermore, all had HLA-DR3 and/or HLA-DR4 genetic

markers of autoimmune type I diabetes. Treatment with interferon alfa might amplify an

already existing AI response against the b cells of the pancreas.3

Type II Diabetes and Hepatitis C

In 45 HCV-infected patients without cirrhosis, 33% were found to have type II

diabetes, compared with 5.6% of controls without liver disease and 12% of HBV-infected

patients.4 HCV-induced liver injury was found to be related to the deterioration of

insulin sensitivity and first-phase insulin response. HCV infection was associated with

diabetes in many patients, and liver cirrhosis was not the cause of their diabetes.4

Side Effects Management Handbook • VI. Endocrine • p. 2

In an evaluation of glycemic control in 49 HCV-infected patients, 15 had known type II

diabetes (NIDDM) and 34 were nondiabetics. In the diabetes group, glycemic control

worsened during interferon therapy in five (33.3%). Three of 11 (27.3%) cases formerly

managed by diet alone required oral hypoglycemic agents (OHA), one of three formerly

managed by OHA required insulin, and a lone insulin patient required intensive insulin

therapy/monitoring. In the nondiabetic group, 17 maintained normal glucose levels and

17 had impaired glucose tolerance via fasting blood sugars (FBS).5

A threefold increase in incidence of type II diabetes has been found in those with chronic

hepatitis C–related disease and cirrhosis, supporting a link between diabetes and HCV

infection.6

RISK FACTORS FOR DEVELOPING TYPE II DIABETES6,7

· Positive family history

· Increasing age

· Weight/body mass index

· Male sex

· Severity of liver histology*

· Corticosteroid therapy

*Insulin sensitivity and first-phase insulin secretion are negatively related to liver fibrosis score.8

PATHOPHYSIOLOGY: INTERFERON ALFA AND DIABETES

Acute treatment with interferon alfa results in an increase in counter-regulatory hormones

as well as a hypermetabolic response, leading to insulin resistance. These effects are dose

dependent and decrease over time. Accelerated hepatic insulin clearance and a decrease

in free fatty acids following interferon treatment can improve glucose tolerance.8 In a

study using 6 x 10-6 U of interferon alfa subcutaneously, three times a week for 4 months,

no impairment of glucose homeostasis was observed.8

DIABETES FOLLOWING LIVER TRANSPLANTATION

Independent predictors of the presence of diabetes 1-year posttransplant*:

· HCV-related liver failure

· Pretransplantation diabetes

· Male sex

*The prevalence of diabetes 1-year-posttransplant in HCV-infected patients was 37%.9

MANAGEMENT STRATEGIES

1. Pretreatment assessment for occult diabetes or determination of stable blood glucose

levels (fasting glucose). If glucose is elevated, measure Hgb A1c and follow-up as in

step 2 below.

2. If known diabetic, determine stable glycemic control. Maintain close follow-up with

primary care physician and/or endocrinologist. Check Hgb A1c: If ³8.5%, defer

treatment until £8.5%.

3. Before interferon therapy, caution known diabetics regarding compliance with diet,

glucose monitoring, and any diabetes medications.

4. Educate patient about signs of hyperglycemia and hypoglycemia (including seizures

and coma).

Side Effects Management Handbook • VI. Endocrine • p. 3

5. Patients may need to increase frequency of Accu-Chek® while on therapy if glucose

levels are erratic. Patients should be closely followed by their primary physician or

endocrinologist.

6. Providers may need to re-educate patients regarding nutrition and hypoglycemic diet;

consider nutritional consult.

7. Endocrinology consult, as needed. Patient may require OHAs or insulin.

8. If patient becomes OHA or insulin dependent, refer to local Certified Diabetes

Educator.

9. Measure FBS levels for symptomatic patients.

10. During therapy, document patient’s glycemic control or referral, if necessary.

11. Use peginterferon/ribavirin with caution in patients with predisposition for

ketoacidosis.

REFERENCES

1. Diabetes mellitus. In: Kelley WN, ed. Essentials of Internal Medicine. Philadelphia, Pa:

Lippincott; 1994:633-636.

2. Hadziyannis S, Karamanos B. Diabetes mellitus and chronic hepatitis C virus infection.

Hepatology. 1999;29:604-605.

3. Betterle C, Fabris P, Zanchetta R, et al. Autoimmunity against pancreatic islets and other

tissues before and after interferon-a therapy in patients with hepatitis C virus chronic

infection. Diabetes Care. 2000;23:1177-1181.

4. Knobler H, Schihmanter R, Zifroni A, Fenakel G, Schattner A. Increased risk of type 2

diabetes in noncirrhotic patients with chronic hepatitis C virus infection. Mayo Clin Proc.

2000;75:355-359.

5. Iijima T, Kaneko K, Nambu M. Influence on glycemic control for interferon therapy in

patients with chronic hepatitis type C. J Gastroenterol Hepatol. 1995;10(suppl 3):68.

6. Caronia S, Taylor K, Pagliaro L, et al. Further evidence for an association between noninsulin-

dependent diabetes mellitus and chronic hepatitis C virus infection. Hepatology.

1999;30:1059-1063.

7. Mason AL, Lau JY, Hoang N, et al. Association of diabetes mellitus and chronic hepatitis C

virus infection. Hepatology. 1999;29:328-333.

8. Konrad T, Zeuzem S, Vicini P, et al. Evaluation of factors controlling glucose tolerance in

patients with HCV infection before and after 4 months therapy with interferon-a. Eur J Clin

Invest. 2000;30:111-121.

9. Bigam DL, Pennington JJ, Carpentier A, et al. Hepatitis C-related cirrhosis: a predictor of

diabetes after liver transplantation. Hepatology. 2000;32:87-90.

Side Effects Management Handbook • VI. Endocrine • p. 4

Taking Ribavirin with food will help digestive problems. Nausea, vomiting, dyspepsia, diarrhea, and abdominal pain are relatively frequent. Eat small meals, and drink plenty of water to keep you hydrated. Please see our Nutrition page for more help.

Stomach or abdominal cramps may occur within the first two weeks or so on interferon therapy. They are usually self-limited and only occasionally accompanied by diarrhea

Diarrhea sometimes occurs within the first week or two. It does not usually persist. Diarrhea may be managed by using over the counter fiber preparations such as Citrucel or Metamucil. These work to absorb extra fluid in the bowels to create formed bowel movements.

THE EFFECT OF PLAUNOTOL ON STOMATITIS INDUCED BY INTERFERON

Plaunotol was administered to patients with chronic hepatitis C for the purpose of preventing the onset of stomatitis during interferon (IFN) therapy. In this open-label trial, a total of 124 patients with chronic hepatitis C treated with IFN therapy were randomly assigned to two groups: plaunotol treated (n = 58) and nontreated (n = 66). Oral administration of plaunotol at 240 mg/d was started 2 weeks before the initiation of IFN therapy and was continued throughout the 24-week IFN therapy period. Plaunotol produced statistically significant decreases in the symptoms of stomatitis during the first 2 weeks of IFN therapy; thereafter, the differences between treated and untreated patients were not significant. Therefore, plaunotol treatment decreased stomatitis-associated symptoms during the first 2 weeks of IFN therapy for chronic hepatitis C.

Author:  NOMURA H, SHIN KOKURA HOSP, DEPT INTERNAL MED, KOKURAKITA KU, 1-3-1 KANADA KITAKYUSHU FUKUOKA 803

Source:  CURRENT THERAPEUTIC RESEARCH-CLINICAL AND EXPERIMENTAL   1997 JUL;58(7):428-433

DIARRHEA

In interferon patients, diarrhea is usually related to dose, but tends to be mild

and self-limiting. Ingestion of certain foods, fluids, medications, radiation, or the

psychoneuroimmunologic effects of stress, anxiety, or fear are other causes of diarrhea.

Also, persistent diarrhea may indicate the presence of systemic bacterial or protozoal

infection.

PATHOPHYSIOLOGY

Mitotic arrest of intestinal epithelial crypt cells, followed by superficial necrosis and

inflammation of bowel wall, result in production of mucosal factors (leukotrienes,

cytokines, free radicals) that stimulate oversecretion of intestinal water and electrolytes.

In the gastrointestinal system, the endocrine and paracrine cells, acetylcholine-serotoninhistamine,

prostaglandin-releasing cells are affected. This alters the synthesis, release,

and metabolism of vasoactive intestinal polypeptides, gastric inhibitory polypeptides,

cholecystokinin, neurotensin, motilin, bombesin, and neurotransmitters, resulting in

diarrhea.1

ASSESSMENT

1. Obtain history of bowel disease (ie, Crohn’s disease, irritable bowel syndrome, etc).

2. Obtain history of onset and duration of diarrhea, as well as number and composition

of stools (watery, bloody, etc).

3. Assess for fever, dizziness, and weakness to rule out sepsis, bowel obstruction, or

dehydration.

4. Assess if the patient is on any other medications that could cause diarrhea

(eg, antibiotics).

5. Assess dietary intake for diarrhea-enhancing foods and assess for dehydration.

6. Perform stool culture for ova and parasites; check for blood, fecal leukocytes,

Clostridium difficile, Salmonella, Escherichia coli, Campylobacter, and infectious

colitis.

7. Do abdominal examination, and measure CBC, and electrolytes.

NCI COMMON TOXICITY CRITERIA FOR GRADING SEVERITY OF DIARRHEA

Grade 1 Grade 2 Grade 3 Grade 4

W/O Ostomy >4 BM 4–6 BM/d or ³6 BM, incontinence, ICU or hemodynamic

over preTx nocturnal stools or dehydration collapse

W/Ostomy Mild ­ in watery, Mod ­; no ADL Severe ­; ICU or hemodynamic

loose BM change interfering w/ADL collapse

Side Effects Management Handbook • VIII. Gastrointestinal • p. 5

TREATMENT STRATEGIES

Patients should be advised to:

1. Eat small, frequent meals.

2. Maintain adequate hydration (fluid consumption in fluid ounces equal to one-half

body weight in pounds; eg, a 160-lb person should drink 80 fl oz/d). For diarrhea,

fluids should consist of bouillon, apple juice, grape juice, Gatorade®, weak tepid tea,

and gelatin, as well as “flat” caffeine-free carbonated beverages since carbonation