Chronic Care Focus: Hepatitis C: Silent, Deadly, Preventable

Elias B. Chahine, PharmD, and Dana A. Brown, PharmD, BCPS
Published Online: Tuesday, April 1, 2008

Drs. Chahine and Brown are both assistant professors of pharmacy practice at Palm Beach Atlantic University, Lloyd L. Gregory School of Pharmacy, West Palm Beach, Florida.


Hepatitis C affects more than 3 million US individuals and approximately 170 million worldwide. The disease is caused by the hepatitis C virus (HCV); of all individuals exposed to HCV, 55% to 85% develop chronic hepatitis, which rarely resolves without treatment.1 Hepatitis C infections are often asymptomatic, and no FDA-approved vaccination exists.

Intravenous drug users, recipients of blood products before the advent of virus screening (1990s), and patients with multiple sexual partners are at the highest risk of acquiring HCV. Acute infections may manifest with jaundice, but chronic infections are usually silent until progression to cirrhosis. Liver injury that results from chronic hepatitis appears to be a consequence of immunologic reactions rather than a direct cytopathic effect of HCV.1

HCV is a single-stranded RNA virus belonging to the Flaviviridae family and the Hepacivirus genus. Six genotypes (1-6) and >90 subtypes are unique to hepatitis C. Genotype 1, the most common genotype in North America, is the most resistant to treatment. Desired treatment outcomes include achieving undetectable HCV RNA levels and attaining a sustained virologic response (SVR)—defined as the absence of HCV RNA in serum for at least 6 months after therapy—relieving signs and symptoms, controlling the spread of the disease, and preventing progression to cirrhosis, end-stage liver disease, and hepatocellular carcinoma.

Pharmacologic Therapy

Patients with confirmed chronic hepatitis C—defined as antibodies against HCV in the blood, infection persisting >6 months, and viral replication confirmed by HCV RNA levels—should be evaluated for treatment with interferon alfa and ribavirin. Therapy is indicated in patients with chronic hepatitis C who have detectable HCV RNA in serum, elevation of liver function tests (LFTs), histologic evidence of progressive liver disease, and no other serious comorbidities or contraindications to interferons.2,3

Pharmacotherapy regimens for patients with chronic hepatitis C are recommended based on the patient's genotype. Table 1 lists those effective regimens against genotypes 1, 4, 5, and 6, and Table 2 lists recommendations for genotypes 2 and 3.4

Interferons are cytokines that bind to specific receptors on the cell surface, leading to rapid activation of gene transcription. Interferon-stimulated genes inhibit viral replication and cell proliferation, and interferons have immunomodulatory activity. Interferon alfa is available as alfacon-1 (Infergen), alfa-2a recombinant (Roferon-A), and alfa-2b recombinant (Intron A). Interferon alfa also is available in a pegylated formulation known as peginterferon alfa-2a (Pegasys) and peginterferon alfa-2b (PEG-Intron).5 Pegylated interferon is produced by the attachment of polyethylene glycol to the interferon molecule, increasing its half-life and allowing for once-weekly administration.6 All formulations must be administered subcutaneously.

Ribavirin (Rebetol, Copegus) is a nucleoside analog that blocks viral RNA and protein synthesis by inhibiting cellular enzymes and is thought to have immunomodulatory effects. The mechanism of inhibition of HCV RNA by combination therapy with interferon has not been established.5

Peginterferons combined with ribavirin are more effective than standard interferons combined with ribavirin.7-10 If the patient cannot take ribavirin, monotherapy with interferons may be considered. Ribavirin monotherapy should not be used for the treatment of chronic hepatitis C.

Alfa interferons are associated with serious, but mostly reversible, neuropsychiatric, autoimmune, ischemic, and infectious complications. Interferon therapy should be monitored with a complete blood count (CBC) with differential, blood pressure, electrocardiogram (ECG), thyroid function tests, and blood glucose, uric acid level, renal function, serum amylase, serum triglycerides, and ophthalmologic examinations. Monitoring parameters for ribavirin include CBC, pregnancy test (monthly and for 6 months after therapy), LFTs, electrolyte panel, thyroidfunction tests, ECG, and CD4 count.5 Patients should be monitored closely with periodic clinical and laboratory evaluations. Treatment is generally withheld in cases of hepatic decompensation.

Regimens for the Treatment of Chronic Hepatitis C—Genotype 1, 4, 5, or 6

Drug Combination

Adult Dosage

Route of Administration

Frequency of Administration

Duration of Treatment

Peginterferon alfa-2a
+
Ribavirin

180 mcg

1000 mg*-1200 mg#

SC

PO

Weekly

Daily

48 weeks+

48 weeks+

Peginterferon alfa-2b
+
Ribavirin

1.5 mcg/kg

1000 mg*-1200 mg#

SC

PO

Weekly

Daily

48 weeks+

48 weeks+

*Ribavirin 1000 mg, divided 400 mg in the morning and 600 mg in the evening for patients .75 kg.
#Ribavirin 1200 mg, divided 600 mg in the morning and 600 mg in the evening for patients .75 kg.
+Check HCV RNA after 12 weeks; if it does not decrease by ≥2 log10, stop treatment.
HCV = hepatitis C virus; SC = subcutaneously; PO = by mouth.
Adapted from reference 4.


The primary toxicity of ribavirin is hemolytic anemia, which may worsen cardiac disease and lead to myocardial infarction. The ribavirin dose must be adjusted in patients with renal impairment because those patients are at increased risk of developing this serious adverse drug reaction. Ribavirin is contraindicated if creatinine clearance is <50 mL/min. Teratogenic effects have been demonstrated in animals exposed to ribavirin; therefore, ribavirin is contraindicated in pregnancy and lactation. At least 2 reliable forms of contraception must be used during and 6 months after treatment. This holds true for both men and women receiving ribavirin.5

Efficacy of treatment is generally defined by a decrease of at least 2 log10 international units/mL and normalization of hepatic enzymes. When assessing patients' improvement, 3 different scenarios are encountered. Most of the patients, particularly those infected with genotypes 2 and 3, will experience an SVR. Others will experience a transient virologic response—defined as a complete virologic response with the completion of therapy followed by a reemergence of the virus or increased LFTs during follow-up. Few patients will have no response to therapy; therefore, it is important to monitor HCV RNA levels, LFTs, and liver histology.11 Early virologic response (EVR) is defined as a ≥2 log10 reduction in HCV RNA levels during the first 12 weeks of therapy. In the absence of an EVR, the likelihood of achieving SVR is 0% to 3%. Therapy may be discontinued after 12 weeks if the patient is not experiencing an EVR.

Patients should be counseled and monitored for the development of side effects. Interferon-induced depression and irritability are treated with antidepressants and anxiolytics with variable success. Ribavirininduced hemolytic anemia may be managed with a dosage reduction, particularly in the case of cardiac diseases. The use of growth factors is controversial.

Because no FDA-approved vaccination for hepatitis C exists, prevention is key, which includes avoiding high-risk behaviors (eg, sharing needles, sexual intercourse with multiple partners). Pharmacists are in a pivotal position to recommend screening high-risk patients and to ensure that protocols are followed when presented with patients suspected to have hepatitis C.

Regimens for the Treatment of Chronic Hepatitis C—Genotype 2 or 3

Drug Combination

Adult Dosage

Route of Administration

Frequency of Administration

Duration of Treatment

Peginterferon alfa-2a
+
Ribavirin

180 mcg

800 mg*

SC

PO

Weekly

Daily

24 weeks

24 weeks

Peginterferon alfa-2b
+
Ribavirin

1.5 mcg/kg

800 mg*

SC

PO

Weekly

Daily

24 weeks

24 weeks

*Ribavirin 800 mg, divided 400 mg in the morning and 400 mg in the evening.
SC = subcutaneously; PO = by mouth.
Adapted from reference 4.


Common Side Effects

Interferons

Ribavirin

Alopecia

Anorexia

Anxiety

Conjunctivitis

Fatigue

Fatigue

Fever

Headache

Flu-like syndrome

Indigestion

Headache

Nausea

Injection-site reaction

Pruritis

Insomnia Rash

 

Irritability

 

Myalgia

 

Pruritis

 

Rigor

 

Adapted from reference 5.


Factors Associated with Low Response Rate

Genotype 1

Standard interferons

Short duration of therapy

High initial levels of HCV RNA

Male sex

Obesity

Advanced liver fibrosis

African-American race

HCV = hepatitis C virus.
Adapted from reference 11.


References



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