Peginterferon-α-2a (40kD) Plus Ribavirin

Pegylation of interferon-α-2a is associated with improved sustained virological response rates in patients with chronic hepatitis C. Subsequently, combination therapy with peginterferon-α-2a (40kD) [Pegasys®¹] and ribavirin (Copegus™, Rebetol®) was investigated to establish if the efficacy of peginterferon-α-2a (40kD) monotherapy could be further enhanced. Subcutaneous peginterferon-α-2a (40kD) was administered at a dosage of 180μg once weekly and oral ribavirin was usually administered at a dosage of 1000 or 1200 mg/day.

In treatment-naive patients with chronic hepatitis C, the sustained virological response rate (assessed 24 weeks after the end of a 48-week treatment period) was significantly higher in peginterferon-α-2a (40kD) plus ribavirin recipients than in peginterferon-α-2a (40kD) plus placebo recipients or interferon-α-2b plus ribavirin recipients (56% vs 29% and 44%). Retrospective analysis revealed that peginterferon-α-2a (40kD) plus ribavirin recipients who did not achieve an early virological response were unlikely to achieve a sustained response.

Treatment with peginterferon-α-2a (40kD) plus another antiviral agent (ribavirin, mycophenolate mofetil, amantadine, or ribavirin and amantadine) was beneficial in patients with chronic hepatitis C who had relapsed during or after, or had not responded to, treatment with interferon-α-2b plus ribavirin. In the relapse study, sustained virological response rates in recipients of peginterferon-α-2a (40kD) plus ribavirin were 45% with and 38% without amantadine.

Peginterferon-α-2a (40kD) plus ribavirin appears beneficial in patients with chronic hepatitis C considered difficult to treat (e.g. patients infected with hepatitis C virus genotype 4, African-American patients, patients with advanced fibrosis or cirrhosis and patients co-infected with HIV).

Flu-like symptoms and depression occurred significantly less frequently with peginterferon-α-2a (40kD) plus ribavirin than with interferon-α-2b plus ribavirin. Similar proportions of patients receiving peginterferon-α-2a (40kD) plus ribavirin, peginterferon-α-2a (40kD) plus placebo and interferon-α-2b plus ribavirin withdrew from treatment because of laboratory abnormalities or other adverse events.

In conclusion, combination therapy comprising subcutaneous peginterferon-α-2a (40kD) and oral ribavirin is an important new treatment option for chronic hepatitis C. Peginterferon-α-2a (40kD) plus oral ribavirin is significantly more effective than peginterferon-α-2a (40kD) monotherapy or interferon-α-2b plus ribavirin at inducing a sustained virological response in treatment-naive patients with chronic hepatitis C. Preliminary data suggest that peginterferon-α-2a (40kD) plus ribavirin is also beneficial in treatment-experienced patients and in patients who have traditionally been considered difficult to treat. Combination therapy with peginterferon-α-2a (40kD) and oral ribavirin is poised to become a valuable first-line treatment option in chronic hepatitis C.

The antiviral activity of interferon-α-2a (determined according to serum 2′, 5′-oligoadenylate synthetase activity) is augmented by pegylation. The first phase of the decline in hepatitis C virus (HCV) RNA levels in patients with chronic hepatitis C treated with once-weekly peginterferon-α-2a (40kD) 180μg occurs within the first 48 hours and is probably due to inhibition of HCV replication and degradation of the free virus; the second phase is characterised by a stable exponential decay possibly related to the rate of degradation of the infected cells. The first and second phases of viral decline were significantly larger in patients infected with HCV non-1 genotypes than in those infected with HCV genotype 1 (patients received peginterferon-α-2a [40kD] or interferon-α-2a).

Viral decline was also HCV genotype-dependent in recipients of peginterferon-α-2a (40kD) plus ribavirin: a biphasic viral decline was observed in 92% of 60 patients infected with HCV genotypes 2 or 3, but in only 44% of 104 patients infected with HCV genotype 1. In addition, early viral kinetics in patients infected with HCV genotype 4 who received peginterferon-α-2a (40kD) in combination with ribavirin were similar to those of patients infected with HCV genotype 1. In patients with chronic hepatitis C infected with HCV genotype 1, viral decay after 28 days’ treatment was significantly more rapid in patients treated with peginterferon-α-2a (40kD) in combination with ribavirin than that in patients treated with peginterferon-α-2a (40kD) alone. In addition, mean viral load after 12 weeks’ therapy was significantly lower in patients with chronic hepatitis C who received peginterferon-α-2a (40kD) 180μg once weekly plus ribavirin 1000 or 1200 mg/day than in patients who received peginterferon-α-2b (12kD) 1 μg/kg once weekly plus ribavirin 1000 or 1200 mg/day (2.8 vs 3.9 log₁₀ IU/mL).

Ribavirin inhibits several viruses in vitro and in vivo. In vitro studies suggest that several mechanisms may account for the antiviral action of ribavirin (e.g. the depletion of intracellular guanosine pools and inhibition of viral RNA polymerase). However, in clinical trials in patients with chronic hepatitis C, oral ribavirin monotherapy had a negligible effect on serum HCV RNA levels. Ribavirin may alter the helper T-cell response in favour of a type 1 response. The addition of ribavirin to phytohaemagglutinin-stimulated peripheral blood mononuclear cells isolated from patients with chronic hepatitis C resulted in a decrease in the synthesis of interferon-γ, inhibition of total DNA, RNA and protein synthesis, and apoptosis of CD45+ and CD14+ cells.

Treatment with peginterferon-α-2a (40kD) alone or with ribavirin for 48 weeks induced a vigorous, multispecific, sustained, HCV-specific, CD4+ T-helper 1 response in therapy-naive patients with chronic hepatitis C (patients had weak or no HCV-specific CD4+ T-cell responses before treatment); a multispecific response is characterised by a response to multiple (core and nonstructural) HCV antigens. In comparison, the HCV-specific, CD4+ T-cell response in interferon-α-2a recipients was of lower magnitude, more narrowly focused and, in the majority of patients, short lived. In patients who achieved a sustained virological response, the frequency, vigour and breadth of the HCV-specific, CD4+ T-cell response was significantly greater than in patients who relapsed or had a partial or no response to treatment. Patients who achieved a sustained response had high interferon-γ and low interleukin (IL)-4 and IL-10 production.

Data regarding the pharmacokinetics of peginterferon-α-2a (40kD) and ribavirin when administered as combination therapy are lacking (although no pharmacokinetic interaction between these two drugs was observed in a substudy of a large clinical trial).

Pegylation slows the absorption rate of interferon-α; in healthy volunteers, the mean time (t_max) taken to reach the maximum serum concentration (C_max) was 78 hours for peginterferon-α-2a (40kD) and 10 hours for interferon-α. In patients with chronic hepatitis C, C_max values of 15.4 and 25.6 μg/L were reached after single and multiple (once weekly) doses of peginterferon-α-2a (40kD) 180μg; t_max values were 80 and 45 hours. Steady-state serum concentrations were reached 5–8 weeks after the initiation of a once-weekly regimen.

In healthy volunteers, the clearance of peginterferon-α-2a (40kD) after a single 180μg dose was >100-fold lower than that of interferon-α (dose not stated) [0.08 vs 11.8 L/h] and the terminal elimination half-life (t½) of peginterferon-α-2a (40kD) was almost 9-fold longer than that of interferon-α (77 vs 9 hours). Total body clearance values for patients with chronic hepatitis C after single and multiple (once weekly for 48 weeks) doses of peginterferon-α-2a (40kD) 180μg were 0.08 and 0.06 L/h.

The absorption of a single dose of subcutaneous peginterferon-α-2a (40kD) 180μg was slower in healthy elderly men than in healthy younger men (t_max 116 vs 81 hours). Although the elderly men had a greater systemic exposure to the drug than the younger men (area under the serum concentration-time curve [AUC] of 1.66 vs 1.30 mg · h/L), this was not considered clinically significant. The t½ of peginterferon-α-2a (40kD) was longer in the elderly than in the younger men (110 vs 61 hours).

The pharmacokinetics of peginterferon-α-2a (40kD) in patients with various degrees of renal impairment were not appreciably different from those in patients with normal renal function, although clearance of the drug was reduced by 25–45% in patients with end-stage renal disease undergoing haemodialysis. The pharmacokinetics of peginterferon-α-2a (40kD) were similar in patients with chronic hepatitis C who did and did not have cirrhosis.

The clearance of theophylline was reduced in healthy volunteers receiving multiple doses of peginterferon-α-2a (40kD).

Ribavirin

Ribavirin is rapidly and extensively absorbed following oral administration. However, because of first-pass metabolism, the mean absolute bioavailability was 64% in patients with chronic hepatitis C. There was a linear relationship between ribavirin dose (200–1200mg) and AUC from time zero to the final timepoint (AUC_tf) and a curvilinear relationship between ribavirin dose and C_max. In patients with chronic hepatitis C, mean C_max values after single or multiple (twice daily) doses of ribavirin 600mg were 782 and 3680 μg/L (reached after 1.7 and 3 hours) and AUC_tf values were 13.4 and 228.0 mg · h/L. Steady-state plasma concentrations were attained in about 4 weeks (oral ribavirin 600mg twice daily). Oral ribavirin has a large volume of distribution (2825L) and shows no detectable binding to plasma proteins.

Metabolism of ribavirin occurs via a reversible phosphorylation pathway in nucleated cells and a degradative pathway which yields a triazole carboxylic acid metabolite. The principal route of elimination for both ribavirin and its triazole metabolites is renal. The t½ of ribavirin after a single oral dose of 600mg was 43.6 hours. The mean t½ value of 298 hours obtained after discontinuation of multiple doses of ribavirin 600mg most likely reflects the high tissue affinity of the drug and its slow elimination from nonplasma compartments.

In individuals without chronic hepatitis C administered a single oral dose of ribavirin 400mg, the ribavirin AUCtf was 3-fold higher in patients with a creatinine clearance of 0.6–1.8 L/h (10–30 mL/min) than in healthy volunteers. Ribavirin was not effectively removed by haemodialysis.

In patients with varying degrees of hepatic dysfunction, the pharmacokinetics of oral ribavirin 600mg administered as a single dose were not significantly different from those in healthy volunteers, apart from mean C_max values which were significantly lower in healthy volunteers than in patients with mild, moderate or severe hepatic impairment.

A number of studies have examined the efficacy of combination therapy with peginterferon-α-2a (40kD) and ribavirin in patients with chronic hepatitis C. Most of these studies are currently only available as abstracts or posters. In most studies, patients received subcutaneous peginterferon-α-2a (40kD) 180μg once weekly in combination with oral ribavirin 1000 or 1200 mg/day (depending on bodyweight) for 48 weeks. The primary endpoint in most studies was the sustained virological response rate (assessed 24 weeks after the cessation of therapy and defined as an undetectable HCV RNA level).

Forty-eight weeks’ treatment with peginterferon-α-2a (40kD) plus ribavirin induced a significantly (p < 0.001) higher sustained virological response rate (56%) than peginterferon-α-2a (40kD) plus placebo (29%) or interferon-α-2b plus ribavirin (44%) in treatment-naive patients with chronic hepatitis C (n = 1121) in a randomised, multicentre, fully published study. Retrospective analysis of this study suggested that peginterferon-α-2a (40kD) plus ribavirin recipients who do not achieve an early virological response at 12 weeks are unlikely to achieve a sustained virological response. Another analysis of this study found that peginterferon-α-2a (40kD) plus ribavirin recipients had better health-related quality of life than interferon-α-2b plus ribavirin recipients, as assessed by the Short Form-36 Health Survey and the Fatigue Severity Scale.

Preliminary results from a randomised, multicentre study indicate that in patients infected with HCV non-1 genotypes, 24 weeks’ therapy with peginterferon-α-2a (40kD) in combination with ribavirin is as effective as 48 weeks’ therapy, and a lower dosage of ribavirin (800 mg/day) is as effective as the standard dosage (1000 or 1200 mg/day) with regards to sustained virological response. However, in patients infected with HCV genotype 1, the sustained virological response rate was highest in patients who received treatment with peginterferon-α-2a (40kD) and the higher dosage of ribavirin for 48 weeks.

The addition of amantadine to peginterferon-α-2a (40kD) plus ribavirin was examined in treatment-naive patients with chronic hepatitis C in two studies. After 24 weeks’ treatment, patients had biochemical response rates of 63% and 76% and virological response rates of 76% and 65%.

Combination therapy with peginterferon-α-2a (40kD) and another antiviral agent (ribavirin 800–1000 mg/day, mycophenolate mofetil 1g twice daily, amantadine 100mg twice daily, or ribavirin plus amantadine) was beneficial in patients with chronic hepatitis C who had relapsed during or after, or had not responded to, treatment with interferon-α-2b in combination with ribavirin. In the relapse study, sustained virological response rates of 45% and 38% were seen in recipients of peginterferon-α-2a (40kD) plus ribavirin with or without amantadine, respectively; a sustained biochemical response rate was observed in 16–55% of patients across all treatment groups. In the nonresponse study, the end-of-treatment virological response rate at 48 weeks was 11–40%.

The use of combination therapy with peginterferon-α-2a (40kD) and ribavirin has been examined in a number of patient groups that have traditionally been considered difficult to treat. In patients infected with HCV genotype 4, peginterferon-α-2a (40kD) in combination with ribavirin was associated with numerically higher end-of-treatment (week 48) virological response rates than interferon-α-2a plus ribavirin, interferon-α-2b plus ribavirin or peginterferon-α-2a (40kD) plus placebo, in two analyses. In one of these analyses, the sustained virological response rate was 77% in peginterferon-α-2a (40kD) plus ribavirin recipients, 44% in peginterferon-α-2a (40kD) plus placebo recipients and 42% in interferon-α-2b plus ribavirin recipients.

An end-of-treatment (week 48) virological response was reported in 33% of non-Hispanic African-American patients and 54% of Caucasian patients (intent-to-treat analysis) who received peginterferon-α-2a (40kD) in combination with ribavirin (patients were infected with difficult-to-treat HCV genotype 1). A biochemical response occurred in 51% and 50% of patients, respectively.

In treatment-naive patients with chronic hepatitis C and advanced fibrosis or cirrhosis, combination therapy with peginterferon-α-2a (40kD) and ribavirin 600–1200 mg/day was associated with a virological response rate of 89% after 24 weeks’ treatment. A sustained virological response occurred in 43% of peginterferon-α-2a (40kD) plus ribavirin recipients, 21% of peginterferon-α-2a (40kD) plus placebo recipients and in 33% of interferon-α-2b plus ribavirin recipients in a subgroup analysis of the fully published trial that included treatment-naive patients with cirrhosis. In treatment-experienced patients with chronic hepatitis C and advanced cirrhosis/fibrosis, 18% of patients who had not responded to previous treatment with interferon or interferon plus ribavirin achieved a sustained virological response after 48 weeks’ combination therapy with peginterferon-α-2a (40kD) and ribavirin.

Combination therapy with peginterferon-α-2a (40kD) and ribavirin was associated with a significantly (p = 0.0003) higher virological response rate after 24 weeks’ treatment than interferon-α-2a plus ribavirin (44% vs 15%) in patients with chronic hepatitis C who were co-infected with HIV. In another trial in patients who were co-infected with HCV and HIV and who had not responded to prior treatment with interferon-α, 5 of 13 (38%) peginterferon-α-2a (40kD) monotherapy recipients and 4 of 17 (24%) peginterferon-α-2a (40kD) plus ribavirin 800 mg/day recipients achieved a virological response after a mean 24 weeks’ therapy.

Flu-like symptoms (e.g. pyrexia, myalgia and rigor) and depression occurred significantly (p ≤ 0.02) less frequently in peginterferon-α-2a (40kD) plus ribavirin recipients than in interferon-α-2b plus ribavirin recipients in a fully published study (incidence of 22–43% vs 30–56%). Clinical adverse events such as fatigue, headache, insomnia, nausea, dermatitis, alopecia and irritability occurred with similar frequency in the two treatment groups (21–54% vs 18–55%).

Similar proportions of patients receiving peginterferon-α-2a (40kD) plus ribavirin, peginterferon-α-2a (40kD) plus placebo and interferon-α-2b plus ribavirin withdrew from treatment because of laboratory abnormalities (1–3%) or other adverse events (6–10%). Occurrence of a laboratory abnormality such as anaemia, neutropenia or thrombocytopenia resulted in modification of the dosage of peginterferon-α-2a (40kD) in 25% of patients and ribavirin in 24% of patients who received this combination, of peginterferon-α-2a (40kD) in 24% of patients and placebo in 4% of patients who received this combination and of interferon-α-2b in 8% of patients and ribavirin in 19% of patients who received this combination.

In clinical studies, <1% of peginterferon-α-2a (40kD) plus ribavirin recipients required dosage modification or discontinued therapy because of an increase in alanine aminotransferase (ALT) levels. Abnormalities in thyroid function tests that required clinical intervention occurred in 4.9% of combination therapy recipients.

Combination therapy with peginterferon-α-2a (40kD) and ribavirin is approved in the EU for use in the treatment of adults with histologically proven chronic hepatitis C who have elevated serum transaminase levels and who are serum HCV RNA-positive, including patients with compensated cirrhosis; treatment is indicated both in treatment-naive patients and in patients relapsing after an initial response with interferon-α. In the US, combination therapy with peginterferon-α-2a (40kD) and ribavirin is approved for use in adults with chronic hepatitis C who have compensated liver disease and who have not previously received interferon-α.

The recommended dosage of peginterferon-α-2a (40kD) is 180μg administered once weekly by subcutaneous injection. It is recommended that ribavirin be administered orally (with food) at a dosage of 1000 or 1200 mg/day according to bodyweight (US prescribing information recommends that patients infected with HCV genotypes 2 or 3 receive ribavirin 800 mg/day). The recommended duration of the combination treatment is 48 weeks in patients infected with HCV genotypes 1 or 4, although patients infected with HCV genotypes 2 or 3 may be treated for only 24 weeks. Treatment discontinuation may be considered at 12 weeks in patients who fail to achieve an early virological response, particularly if they do not have cirrhotic disease.

A reduction in the dosage of peginterferon-α-2a (40kD) or ribavirin, or treatment discontinuation, may be needed in certain patient populations (e.g. patients with end-stage renal disease) or in patients who experience certain adverse events (e.g. neutropenia, thrombocytopenia, anaemia or increased ALT levels). Dosage reduction is not necessary when starting treatment with peginterferon-α-2a (40kD) in elderly patients. The use of peginterferon-α-2a (40kD) in patients with decompensated cirrhosis (i.e. patients with Child-Pugh class B or C disease or bleeding oesophageal varices) has not been evaluated.

In the EU and the US, contraindications to the use of peginterferon-α-2a (40kD) plus ribavirin include autoimmune hepatitis and hepatic decompensation; combination therapy is also contraindicated in neonates and infants and in women who are pregnant and men whose partners are pregnant (because ribavirin has been shown to have teratogenic and/or embryocidal effects). At least two forms of effective contraception should be used during combination therapy and for 6 months after discontinuing ribavirin treatment. Additional contraindications in the EU include a history of severe pre-existing cardiac disease, severe hepatic dysfunction, some psychiatric conditions and lactation. Combination therapy is also contraindicated in the US in patients with haemoglobinopathies. US prescribing information recommends that peginterferon-α-2a (40kD) be used with caution in patients with pre-existing cardiac disease, autoimmune disorders or a history of depression and that ribavirin should not be administered to patients with severe renal impairment (creatinine clearance <3 L/h [<50 mL/min]).

Standard haematological, biochemical and thyroid function tests should be performed before starting combination therapy and should be repeated periodically during treatment (women of childbearing potential should also be screened for pregnancy). Patients with pre-existing cardiac disorders should have an ECG performed before starting treatment.

Patients with chronic hepatitis C who are co-infected with HIV should be closely monitored and treatment should be discontinued in patients who progress to a Child-Pugh score of ≥7. Combination therapy should not be commenced in patients with a Child-Pugh score of ≥6 at baseline.

Serum theophylline levels should be monitored, and the dosage of theophylline adjusted as required, in patients receiving theophylline in addition to combination therapy with peginterferon-α-2a (40kD) and ribavirin. Combination therapy with ribavirin and didanosine is not recommended, and the use of ribavirin in combination with stavudine or zidovudine should be avoided.