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

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Pharmacy Times, Volume 0, 0

Pharmacists are well-positioned to recommend screening and ensure that protocols are followed when presented with patients suspected to have hepatitis C.

Drs. Chahine and Brown are bothassistant professors of pharmacypractice at Palm Beach AtlanticUniversity, Lloyd L. Gregory School ofPharmacy, West Palm Beach, Florida.

Hepatitis C affects more than 3million US individuals andapproximately 170 millionworldwide. The disease is caused bythe hepatitis C virus (HCV); of all individualsexposed to HCV, 55% to 85%develop chronic hepatitis, which rarelyresolves without treatment.1 HepatitisC infections are often asymptomatic,and no FDA-approved vaccination exists.

Intravenous drug users, recipients ofblood products before the advent ofvirus screening (1990s), and patientswith multiple sexual partners are at thehighest risk of acquiring HCV. Acuteinfections may manifest with jaundice,but chronic infections are usually silentuntil progression to cirrhosis. Liverinjury that results from chronic hepatitisappears to be a consequence ofimmunologic reactions rather than adirect cytopathic effect of HCV.1

HCV is a single-stranded RNA virusbelonging to the Flaviviridae family andthe Hepacivirus genus. Six genotypes(1-6) and >90 subtypes are unique tohepatitis C. Genotype 1, the most commongenotype in North America, is themost resistant to treatment. Desiredtreatment outcomes include achievingundetectable HCV RNA levels andattaining a sustained virologic response(SVR)—defined as the absenceof HCV RNA in serum for at least 6months after therapy—relieving signsand symptoms, controlling the spreadof the disease, and preventing progressionto cirrhosis, end-stage liver disease,and hepatocellular carcinoma.

Pharmacologic Therapy

Patients with confirmed chronic hepatitisC—defined as antibodies againstHCV in the blood, infection persisting>6 months, and viral replication confirmedby HCV RNA levels—should beevaluated for treatment with interferonalfa and ribavirin. Therapy is indicatedin patients with chronic hepatitis Cwho have detectable HCV RNA inserum, elevation of liver function tests(LFTs), histologic evidence of progressiveliver disease, and no other seriouscomorbidities or contraindications tointerferons.2,3

Pharmacotherapy regimens forpatients with chronic hepatitis C arerecommended based on the patient'sgenotype. Table 1 lists those effectiveregimens against genotypes 1, 4, 5, and6, and Table 2 lists recommendationsfor genotypes 2 and 3.4

Interferons are cytokines that bind tospecific receptors on the cell surface,leading to rapid activation of gene transcription.Interferon-stimulated genesinhibit viral replication and cell proliferation,and interferons have immunomodulatoryactivity. Interferon alfa isavailable as alfacon-1 (Infergen), alfa-2a recombinant (Roferon-A), and alfa-2b recombinant (Intron A). Interferonalfa also is available in a pegylated formulationknown as peginterferon alfa-2a (Pegasys) and peginterferon alfa-2b(PEG-Intron).5 Pegylated interferon isproduced by the attachment of polyethyleneglycol to the interferon molecule,increasing its half-life and allowingfor once-weekly administration.6 Allformulations must be administeredsubcutaneously.

Ribavirin (Rebetol, Copegus) is anucleoside analog that blocks viral RNAand protein synthesis by inhibiting cellularenzymes and is thought to haveimmunomodulatory effects. The mechanismof inhibition of HCV RNA by combinationtherapy with interferon hasnot been established.5

Peginterferons combined with ribavirinare more effective than standardinterferons combined with ribavirin.7-10If the patient cannot take ribavirin,monotherapy with interferons may beconsidered. Ribavirin monotherapyshould not be used for the treatment ofchronic hepatitis C.

Alfa interferons are associated withserious, but mostly reversible, neuropsychiatric,autoimmune, ischemic, andinfectious complications. Interferontherapy should be monitored with acomplete blood count (CBC) with differential,blood pressure, electrocardiogram(ECG), thyroid function tests, andblood glucose, uric acid level, renalfunction, serum amylase, serum triglycerides,and ophthalmologic examinations.Monitoring parameters for ribavirininclude CBC, pregnancy test(monthly and for 6 months after therapy),LFTs, electrolyte panel, thyroidfunctiontests, ECG, and CD4 count.5Patients should be monitored closelywith periodic clinical and laboratoryevaluations. Treatment is generallywithheld 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 ishemolytic anemia, which may worsencardiac disease and lead to myocardialinfarction. The ribavirin dose must beadjusted in patients with renal impairmentbecause those patients are atincreased risk of developing this seriousadverse drug reaction. Ribavirin iscontraindicated if creatinineclearance is <50 mL/min.Teratogenic effects havebeen demonstrated in animalsexposed to ribavirin;therefore, ribavirin is contraindicatedin pregnancyand lactation. At least 2 reliableforms of contraceptionmust be used during and 6months after treatment. Thisholds true for both men andwomen receiving ribavirin.5

Efficacy of treatment isgenerally defined by a decrease of atleast 2 log10 international units/mL andnormalization of hepatic enzymes.When assessing patients' improvement,3 different scenarios areencountered. Most of the patients, particularlythose infected with genotypes2 and 3, will experience an SVR. Otherswill experience a transient virologicresponse&#8212;defined as a complete virologicresponse with the completion oftherapy followed by a reemergence ofthe virus or increased LFTs during follow-up. Few patients will have noresponse to therapy; therefore, it isimportant to monitor HCV RNA levels,LFTs, and liver histology.11 Early virologicresponse (EVR) is defined as a &#8805;2 log10 reduction in HCV RNA levels duringthe first 12 weeks of therapy. In theabsence of an EVR, the likelihood ofachieving SVR is 0% to 3%.Therapy may be discontinuedafter 12 weeks if thepatient is not experiencingan EVR.

Patients should be counseledand monitored for thedevelopment of side effects.Interferon-induced depressionand irritability aretreated with antidepressantsand anxiolytics withvariable success. Ribavirininducedhemolytic anemiamay be managed with a dosage reduction,particularly in the case of cardiacdiseases. The use of growth factors iscontroversial.

Because no FDA-approved vaccinationfor hepatitis C exists, prevention iskey, which includes avoiding high-riskbehaviors (eg, sharing needles, sexualintercourse with multiple partners).Pharmacists are in a pivotal position torecommend screening high-risk patientsand to ensure that protocols arefollowed when presented with patientssuspected to have hepatitis C.

Regimens for the Treatment of Chronic Hepatitis C&#8212;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