Patient Education and Treatment Strategies Implemented at a Pharmacist-Managed Hepatitis C Virus Clinic

Bonnie Kolor, Pharm.D.

Disclosures

Pharmacotherapy. 2005;25(9):1230-1241. 

In This Article

Combination Therapy

Peginterferons are chemically modified derivatives of interferon alfa to which one or more long chains of polyethylene glycol (PEG) have been attached; PEG is soluble in water and inert. Interferon alfa is pegylated to reduce its rate of elimination by the kidneys and decrease its proteolytic degradation and antigenicity, thereby prolonging the time that the interferon is effective.[40,41] Benefits of the pegylated versions of interferon include the need for less frequent drug administration and less fluctuation in plasma interferon concentration between doses.[40]

Peginterferon alfa is available in two forms: peginterferon alfa-2a and peginterferon alfa-2b. Peginterferon alfa-2a consists of the covalent attachment of a 40-kD branched PEG chain to interferon alfa-2a; peginterferon alfa-2b consists of the covalent attachment of a 12-kD PEG linear chain to interferon alfa-2b (Figure 2).[17,40,42,43,44] In peginterferon alfa-2a, the branched PEG chain is joined through a stable amide bond to a lysine amino acid residue on interferon alfa-2a. In peginterferon alfa-2b, the linear PEG chain is joined through a more labile PEG-histidine linkage to interferon alfa-2b.[16,44]

Chemical structures of peginterferon alfa-2a (40 kD) (A), peginterferon alfa-2b (B), and ribavirin (C). Reprinted with permission from references 43 and 44.

The two drugs differ pharmacokinetically in that peginterferon alfa-2a has a mean terminal half-life of approximately 80 hours, whereas the half-life of peginterferon alfa-2b is approximately 40 hours.[16,40] The two drugs also have different serum drug concentration peak:trough ratios. Ratios of 1.5-2:1 were measured with peginterferon alfa-2a at 5-8 weeks after the start of treatment. With peginterferon alfa-2b, the ratio was approximately 14:1 at 4 weeks after the start of treatment.[15,40,41,45,46] The ratio of amount of drug in the body to the concentration of drug in the blood or plasma (i.e., volume of distribution) of these two drugs also differs.[47] Although the volume of distribution of peginterferon alfa-2a is not substantially affected by body weight (e.g., 8-12 L), this parameter is about 1 L/kg with peginterferon alfa-2b.[41,45] Elimination of both drugs is believed to be primarily through metabolic processes in the liver. However, the kidneys appear to play a considerably larger role in eliminating peginterferon alfa-2b than alfa-2a.[40,41]

The mechanism of action of interferon, a naturally produced protein, is not completely understood. This cytokine is thought to facilitate viral clearance partly by inducing cells infected with virus to manufacture antiviral proteins that disrupt viral replication processes and to function through more indirect immunomodulatory and antiinflammatory mechanisms.[41,48] Patients infected with HCV genotype 1 receiving peginterferon alfa-2b monotherapy have experienced a rapid, marked decline in viral load, similar to that observed with interferon alfa-2b administration. In one report, viral rebound occurred 3 days after administration of peginterferon alfa-2b, which was eliminated with twice-weekly administration.[49] The initial rates of viral decline in patients with genotype 1 infection who received peginterferon alfa-2a monotherapy were somewhat slower than rates with administration of unmodified interferon alfa-2b.[50] However, viral rebound was observed in only a few patients during the week-long period between doses.

Ribavirin is a synthetic nucleoside analog with antiviral properties. Although its mechanism of action is not completely understood, ribavirin may contribute to HCV viral clearance by inhibiting HCV RNA-dependent RNA polymerases or through more indirect immunomodulatory processes.[51,52,53]

Ribavirin monotherapy is not believed to be effective in patients with HCV infection, whereas approximately 30% of those treated with peginterferon monotherapy have achieved a sustained viral response.[16,17] Results from a head-to-head comparison of the relative effectiveness of the two peginterferon alfa preparations in combination therapy are not available. However, clinical studies have shown that peginterferon alfa with ribavirin is the most effective therapeutic regimen for treatment of HCV infection.[7] For example, after treatment with peginterferon alfa-2a (40 kD) 180 µg/week and ribavirin 1000-1200 mg/day, 46-52% of patients infected with HCV genotype 1, and 76-80% of those infected with genotype 2 or 3, achieved sustained viral response.[54,55,56] In addition, treatment with peginterferon alfa-2b (12 kD) 1.5 µg/kg/week and ribavirin 800 mg/day induced sustained viral response in 42% of patients infected with genotype 1, and 82% of patients infected with genotype 2 or 3.

Results from a recent clinical study involving combination therapy with peginterferon alfa-2b and ribavirin showed sustained viral response rates of 93% and 79% for patients infected with HCV genotype 2 and 3, respectively.[57] However, considerably lower sustained viral response rates were observed in two other clinical trials that evaluated the effectiveness of combination therapy in African-American patients infected with genotype 1.[58,59] Treatment with peginterferon alfa-2a 180 µg/week and ribavirin 1000-1200 mg/day was associated with a sustained viral response rate of 26%;[58] with peginterferon alfa-2b 1.5 µg/kg/week and ribavirin 2000 mg/day for the first 12 weeks and then ribavirin 800 mg/day, the rate was 19%.[59]

Reasons for the decreased responsiveness in African-American versus Caucasian patients to treatment with combination therapy are still unclear. However, factors in addition to race, such as high body weight, may be associated with a decreased likelihood of achieving a sustained viral response.[60] Finally, achievement of a sustained viral response is believed to be associated with remaining free of HCV viral infection for most patients treated with combination therapy.[61,62]

Both forms of peginterferon are administered through weekly subcutaneous injections. The dose of peginterferon alfa-2a (40 kD PEG) is fixed at 180 µg, whereas the dose of peginterferon alfa-2b (12 kD PEG) is based on body weight at 1.5 µg/kg.[15,16] Both drugs are available prepackaged in injection devices.[63,64] Peginterferon alfa-2a is available in solution in doses of 180 µg/syringe. In contrast, peginterferon alfa-2b in powder form is stored in one compartment of a Redipen (a pen delivery system; Schering Corp., Kenilworth, NJ); sterile water is stored in a second compartment. Contents from the two compartments are mixed shortly before peginterferon alfa-2b is injected.

Patients and their caregivers need to become familiar and comfortable with the injection procedure, proper injection sites (e.g., top of thigh and abdomen) and the importance of injection-site rotation. In addition, patient education must include injection information specific to the particular form of peginterferon involved. For example, the entire contents of the syringe containing 180 µg of peginterferon alfa-2a typically are injected, whereas only a portion of the solution of peginterferon alfa-2b is injected, depending on the patient's body weight. Patients also must be given information regarding proper methods for disposal of used needles and injection devices. Methods may involve community drop-off programs, household hazardous waste facilities, sharps mail-back programs, or at-home needle destruction devices.

Ribavirin is taken orally twice/day with food.[17] The AASLD recommends that dosage be based on weight for patients infected with HCV genotype 1.[7] Daily doses of ribavirin 800 mg are recommended for patients infected with genotype 2 or 3.[17] For patients with genotype 1 infection, ribavirin 1000 mg/day is recommended for those weighing less than 75 kg, and 1200 mg/day for those weighing 75 kg or more. Recommended subcutaneous starting dosages for the peginterferons are as follows: peginterferon alfa-2a 180 µg once/week, and peginterferon alfa-2b 1.5 µg/kg once/week.[7]

Treatment duration depends on HCV genotype. Typically, patients infected with genotype 1 are treated for 48 weeks, with genotype 2 or 3 for 24 weeks.[7] Current AASLD recommendations advise early termination of treatment in patients with genotype 1 who do not show an early virologic response.[39]

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