• 5
    Jun
  • Pharmacotherapy for Hepatitis C Virus Infection: Dosing and Formulations

Doctor and patient.The current gold standard for treatment of HCV is pegylated IFN alfa-2b combined with for 48 weeks, depending on the genotype. However, more than 50% of patients do not respond completely to combination therapy, suggesting the need for more treatment options, such as ribavirin. The manufacturer recommends that patients weighing 75 kg or less receive 1,000 mg/day of ribavirin and that patients weighing 75 kg or more receive 1,200 mg/day.

There are two formulations of pegylated interferon, with each differing in their pharmacokinetic and chemical properties.

Peginterferon alfa-2b (Peg-Intron®, Schering-Plough) has a smaller molecule of peg (12 kD) attached to the protein than the newly approved peginterferon alfa-2a (Pegasys®, Roche), which has a larger peg molecule (40 kD) attached to IFN. Pegylated IFN alfa-2b, which was approved by the Food and Drug Administration (FDA) in October 2001, is a modified form of IFN alfa-2b.

Pegylated IFN alfa-2b has an added polyethylene glycol molecule, which produces a biologically active molecule with more favorable pharmacokinetics. Peginterferon alfa-2a, which was approved by the FDA in 2002, has sustained absorption and an extended half-life equal to that of peginterferon alfa-2b. canadian pharmacy generic viagra

One of the most valuable properties of pegylated interferons is their decreased systemic clearance rate plus a prolonged plasma half-life, allowing for once-weekly administration. As a result of this reduced clearance rate, these interferons have more exposure and enhanced efficacy than do nonpegylated proteins; they can stay in the body and fight off the virus for a longer time compared with other interferon agents.

Clinical trials have shown that although pegylated IFN alfa-2b monotherapy improves SVR rates (30% vs. 5%-10%) for genotype 1, compared with conventional IFNs, relapse rates after cessation of therapy are still high. Manns et al. found that HCV-infected patients who took pegylated IFN alfa-2b (3 million units SQ) plus oral ribavirin (1,000-1,200 mg/day) for 48 weeks had higher SVR rates than patients taking low-dose pegylated IFN alfa-2b plus ribavirin or IFN alfa-2b (3 million units SQ) plus ribavirin (1,000-1,200 mg/day orally) for 48 weeks (54% vs. 47% vs. 47%).

In addition, patients with genotype 1 had SVR rates of 42% vs. 34% vs. 33%, respectively. Fried et al. compared the use of peginterferon alfa-2a plus ribavirin or placebo with that of IFN alfa-2b plus ribavirin in 1,211 patients. Significantly more patients taking peg-interferon alfa-2a plus ribavirin had higher ETRs than did patients taking IFN alfa-2a plus ribavirin (69°% vs. 52°%, P < .001) or peginterferon alfa-2a plus placebo (69% vs. 59%, P < .01). The SVR rates of patients receiving peginterferon alfa-2a plus ribavirin were significantly greater than those of patients taking IFN alfa-2a plus ribavirin (56% vs. 44%, P < .001) or peginterferon alfa-2a plus placebo (56% vs. 29%, P < .001).

In assessments of responses to various therapies based on genotype, patients with genotype 1 who received peginterferon alfa-2a plus ribavirin had higher SVR rates (46%) than did patients who received IFN alfa-2b plus ribavirin (36%). Patients with HCV genotype 2 or 3 and who received peg-interferon alfa-2a plus ribavirin had higher SVR rates than patients taking IFN alfa-2b plus ribavirin (76% vs. 61%, P = 0.005) (Table 2).
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Table 2   Treatment of Hepatitis C Virus Infection

Generic Name

Brand Name and Manufacturer

Dose

Durationof

Therapy*

HCV Genotype-1 Only (Average Percentageof Sustained Virological Response)

Interferon alfa-2b

Intron® A (Schering)

3 million units SQ three times weekly

48 wk

13%-20%

Interferon alfa-2a

Roferon® (Roche)

3-5 million units SQ three times weekly

48 wk

25%

Interferon alfacon-1 or

Consensus interferon

Infergen® (Amgen) High-dose Infergen®

9 mcg SQ three times weekly

48 wk

13%-20%

Interferon alfa-2b +

Ribavirin

Rebetron® (Schering-Plough)

3 million units SQ three times weekly 800-1,200 mg orally daily (based on weight)

48 wk

28%-31%

Peginterferon alfa-2b +

Ribavirin

PegIntron®

(Schering-Plough) Rebetol®

(Schering-Plough)

1-1.5 mcg/kg SQ weekly

800-1,200 mg/day orally (based on weight)

48 wk

42%

Peginterferon alfa-2a +

Ribavirin

Pegasys®

(Roche) Rebetol®

(Schering-Plough)

180 mcg/wk

1,000-1,200 mg/wk (based on weight)

48 wk

46%

SQ = subcutaneously; wk = week.Data from References 52-54, 57, 60, 64, and 65.

In general, the new pegylated formulations appear to offer enhanced SVR rates in all groups, regardless of genotype or viral load, and the once-weekly dosing makes this form preferable to other interferon therapies.

Adherence to medication regimens is always a major concern in disease treatment. The primary cause of patient non-adherence is the intolerable adverse drug effects (ADEs) of anti-HCV therapy, which are, at times, difficult to tolerate and control.

IFNs can cause flu-like symptoms during the first month of therapy, bone marrow suppression, and psychiatric ill-ness. These symptoms often appear 12 hours after the dose is taken and disappear 24 hours after dosing, despite elevated serum IFN concentrations.

Neutropenia and thrombocytopenia are manageable when the IFN dosage is reduced and when IFN therapy is discontinued, but blood counts usually return to those of the baseline examination after four weeks of therapy.

Psychiatric illnesses (e.g., depression, irritability, suicidal ideations) and insomnia are sometimes associated with IFN therapy and occur at even higher rates when IFNs are administered with ribivarin. From the onset, patients with a history of depressive illness or psychosis should probably not be considered candidates for any IFN formulations. Other ADEs include thyroid dysfunction, rash, headache, and reversible arthralgias.

Adverse Drug Reactions

A predose of acetaminophen (500 mg-1 g) is commonly administered at bedtime to patients who are taking IFNs to reduce the incidence of flu-like symptoms (e.g., myalagia in 56% of patients and arthralgia in 34%). Other ADEs include alopecia (36%), nausea (43%), anorexia (32%), weight loss (29%), and mpruritus (29%). Patients with untreated autoimmune thyroid disease, neutropenia, thrombocytopenia, organ transplantation (other than liver), symptomatic heart disease, decom-pensated cirrhosis, uncontrolled seizures, or active alcohol or IV drug usage should probably not receive any formulations of IFN. Men and women should be advised to use two methods of contraception when taking IFNs and should not plan to conceive during any course of IFN therapy and for up to six months after the discontinuation of treatment.

Ribavirin may cause mild anemia (a hemoglobin count of 8-10 g/dl) or severe anemia (below 8 g/dl); this is a common occurrence in nearly all patients and is a result of dose-dependent hemolysis of red blood cells with ribavirin canadian doses of 1,200 to 1,600 mg/day. The anemia is manageable upon a dose reduction of 800 mg/day or upon discontinuation of ribavirin. Other ADEs include fatigue, depression, rash, cough, shortness of breath, and irritability. Men and women should be advised to use two methods of contraception and should not plan to conceive during any course of ribavirin therapy and for up to six months after the discontinuation of treatment.

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