Interferon-α-2b Plus Ribavirin

Relatively few patients (≤20%) with chronic hepatitis C achieve a sustained virological response after interferon-α monotherapy. Hence, alternative treatment strategies such as the addition of the broad spectrum antiviral agent ribavirin to interferon-a-2b have been investigated.

Combination therapy with subcutaneous interferon-α-2b [3 million units (MU) three times per week] plus oral ribavirin (1000 to 1200 mg/day) has proven effective in several well designed trials of 24 to 48 weeks’ duration in adult patients with compensated chronic hepatitis C. Compared with interferon-α-2b (3 or 6MU three times per week) with or without placebo, combination treatment with interferon-α-2b plus ribavirin significantly enhanced end-of-treatment and sustained virological and biochemical response rates in treatment-naive and treatment-experienced patients [sustained virological response rates in treatmentnaive recipients (6 to 19% vs 31 to 43% of patients); sustained overall (virological plus biochemical) response rates in nonresponders to (1 vs 14%) or relapsers (4 to 5% vs 30 to 44%) after previous interferon-a monotherapy]. Forty-eight weeks of combination therapy was superior to 24 weeks in treatment-naive patients infected with hepatitis virus C (HCV) genotype 1, whereas response rates were similar at 24 and 48 weeks in those infected with other HCV genotypes. Furthermore, there were marked improvements in histological inflammatory scores in patients who responded to treatment with either interferon-α-2b plus ribavirin or interferon-α-2b alone.

Although adverse events associated with either drug during combination therapy occurred frequently, these were generally mild to moderate in intensity and were consistent with those reported for each individual agent. Twenty-six percent of patients required dosage modifications of one or both drugs during combination therapy.

The precise mechanisms of action of interferon-α-2b and ribavirin, either alone or in combination, are not yet fully defined but appear to be multifactorial and complex. Although inhibition of viral activity and modulation of immune responses are postulated to play a key role in the mechanism of action of these two drugs, several other effects have also been reported that may contribute to their actions in patients with chronic hepatitis C, including effects on proliferation and extracellular matrix formation.

Although ribavirin has been shown to inhibit several viruses in vitro and in vivo, in patients with chronic hepatitis C ribavirin monotherapy lowered serum ALT concentrations, but had a negligible effect on serum hepatitis virus C (HCV) RNA concentrations. Results from in vitro studies suggest that several mechanisms may account for the antiviral effects of this agent, including the depletion of intracellular guanosine pools, inhibition of viral RNA polymerase and/or interference with transcription of viral messenger RNA. Ribavirin is actively transported into cells via membrane transporters, such as the sodium-dependent nucleoside transporters and nitrobenzylthioinosine-sensitive (es)-transporter on erythrocytes. Once internalised, the drug is metabolised by intracellular enzymes into active mono-, di- and triphosphates that act to inhibit viral replication.

No direct synergistic or additive antiviral effects were observed with interferon-α [3 to 6 million units (MU) three times per week] plus oral ribavirin (900 to 1200 mg/day) combination therapy in patients with chronic hepatitis C.

Oral ribavirin (1000 to 1200 mg/day) monotherapy had no effect on serum IL-2, IL-4 or interferon-y concentrations in patients with chronic hepatitis C in a double-blind, placebo-controlled study. However, in liver transplant patients with recurrent HCV infection, the effects of ribavirin monotherapy on immune responses were equivocal. Nevertheless, in vitro and in vivo studies indicated that ribavirin may alter the balance between immune T-cell responses in favour of TH-1 type responses.

Notably, recent investigations indicated that interferon-a plus ribavirin combination therapy alters immune responses in favour of TH-1 type responses in patients with chronic hepatitis C. In 20 patients with chronic hepatitis C receiving subcutaneous interferon-a (type not stated) 5MU three times per week alone or in combination with oral ribavirin 1200 mg/day, there was a markedly greater upregulation of TH-1 cytokines (interferon-y and IL-2), natural killer cell subsets and accessory molecules (CD54+ CD14+, CD86+ CD14+, CD14/B7) in patients receiving combination therapy compared with interferon-a monotherapy (p < 0.001).

Other effects: Fibrosis, a common manifestation of advanced inflammatory diseases of the liver, is characterised by an increase in hepatic extracellular matrix which, in part, is regulated by transforming growth factor (TGF)-βl. Compared with 23 healthy volunteers, plasma TGF-βl concentrations were significantly elevated (1.9 vs 8.1 μg/L; p < 0.01), and correlated with the degree of fibrosis (p < 0.01), in 43 patients with chronic hepatitis C. Interferons-a reduced serum/plasma concentrations of TGF-μ1 in patients with chronic hepatitis C.

The incidence of neutralising antibodies to interferon-α appears to differ among the recombinant and natural forms of interferon-α. Neutralising antibodies developed in significantly fewer patients with chronic hepatitis C treated with interferon-α-2b (6.9% of 144 recipients; p < 0.01) or interferon-a-nl (1.3% of 78 recipients; p < 0.001) than in those who received interferon-a-2a (20% of 74 recipients). There are currently no reports on the incidence of neutralising antibodies in patients receiving interferon-a-2b plus ribavirin combination therapy.

Limited data in adult patients with chronic hepatitis C indicated that no significant drug-to-drug interactions occurred between interferon-a-2b and ribavirin following coadministration of single and multiple doses of these agents. Pharmacokinetic parameters of interferon-α-2b or ribavirin have not been evaluated in patients >65 years of age, and there is a paucity of data in those aged <18 years.

Interferon-α-2b: Following subcutaneous administration of single or multiple doses of interferon-α-2b 3MU, maximum peak plasma concentrations (C_max) were 13.9 and 29.7 IU/ml, respectively, and were attained in 7 and 5 hours in 12 patients with chronic hepatitis C. Total plasma clearance of interferon-α-2b after delivery of a single subcutaneous dose of 3MU was 14.3 L/h. The terminal elimination half-lives (t1/2) of the drug after single or multiple 3MU doses were 6.8 and 6.5 hours, respectively.

Metabolism of ribavirin is mediated via a reversible phosphorylation pathway and a degradative pathway. Currently, there is no evidence of involvement of cytochrome P450 enzymes in the metabolic pathways of ribavirin, with the majority of ribavirin and its triazole metabolites excreted renally. Following multiple 600mg doses, the mean t1/2 of the drug was 298 hours which may reflect the high tissue affinity of the drug and its slow elimination from nonplasma compartments. In six patients with chronic hepatitis C, the mean total clearance of ribavirin following a single oral 600mg dose was 38.2 L/h. Respective mean renal and metabolic clearance rates were 6.9 and 18.1 L/h in six healthy volunteers after administration of a single intravenous 150mg radiolabelled dose of ribavirin followed by an oral 400mg dose of unlabelled drug.

The efficacy of interferon-α-2b plus ribavirin combination therapy in treatmentnaive and -experienced adult patients (>18 years of age) with chronic hepatitis C has been extensively evaluated in several well designed trials (≥300 enrolled patients). In clinical trials, interferon-α-2b (typically 3MU three times per week) was administered subcutaneously, whereas ribavirin (1000 to 1200 mg/day based on bodyweight, as a twice-daily divided dose) was taken orally.

Treatmentnaive adult patients: Markedly more recipients of first-line interferon-α-2b (3MU thrice weekly) plus ribavirin (1000 to 1200 mg/day) combination therapy achieved end-of-treatment virological (49 to 57% vs 24 to 33%) and biochemical (55 to 71 % vs 24 to 44%) responses than recipients of interferon-α-2b with or without placebo after 24 to 48 weeks’ therapy. Furthermore, sustained virological (31 to 43% vs 6 to 19%) and biochemical (32 to 50 vs 11 to 24%) responses were achieved by a significantly (p ≤ 0.003, all comparisons) greater percentage of patients receiving combination therapy than recipients of interferon-α-2b with or without placebo. Although a comparable number of recipients experienced end-of-treatment virological and biochemical responses after 24 and 48 weeks of combination therapy, an increased percentage of patients achieved a sustained virological response in the 48-week treatment group.

In 670 treatment-naive patients, histological responses paralleled therapeutic responses, with recipients of combination therapy (24 or 48 weeks) experiencing significantly (p ≤ 0.005, both comparisons) greater improvements in histological inflammatory scores than those receiving interferon-a-2b plus placebo for 48 weeks. Overall, irrespective of the treatment group, there was no effect on fibrosis scores, although 11 to 17% of patients in any individual group experienced an improvement in fibrosis score.

Treatment-experienced adult patients (nonresponders): In a large non-blind multicentre 24-week study in nonresponders, significantly (p ≤ 0.001) more recipients of combination therapy (interferon-α-2b 3MU three times weekly plus ribavirin 1000 to 1200 mg/day) achieved sustained overall (virological plus biochemical) responses than recipients of interferon-α-2b 6MU three times per week (14 vs 1% of patients). Induction therapy (interferon-α-2b 3MU once daily) during the first month of interferon-a-2b plus ribavirin treatment provided a similar beneficial effect on virological responses to the standard combination therapy regimen (interferon-α-2b three times per week plus ribavirin).

Treatment-experienced patients (relapsers): In relapsers (patients who had relapsed after previous interferon-a monotherapy), appreciably more recipients of interferon-α-2b plus ribavirin combination therapy experienced end-of-treatment and sustained virological and biochemical responses than those receiving interferon-α-2b 3MU three times per week in 24-week studies. In these two treatment groups, sustained overall (virological plus biochemical) responses were experienced by 30 to 44% and 4 to 5% of patients, respectively.

Furthermore, combination therapy was also significantly more effective than interferon-α-2b monotherapy in Black patients with chronic hepatitis C and in patients with cirrhosis of the liver at baseline. These two groups of patients have historically proven to be difficult to treat with interferon-a monotherapy.

In treatment-naive patients, factors shown to be correlated with improved response rates were baseline viral load ≤2 x 10⁶ copies/ml (p < 0.001), the absence of cirrhosis at baseline (p < 0.05), female gender (p = 0.05) and young age (p = 0.005). Of note, regardless of the risk factors present, combination therapy recipients achieved significantly better sustained responses than interferon-α-2b monotherapy patients (p < 0.001, all comparisons).

Chronic HCV infection has a significant impact on a patient’s quality of life. In treatment-naive patients and those who had relapsed after previous interferon-α monotherapy, sustained responders to either interferon-α-2b plus ribavirin or interferon-α-2b treatment experienced appreciable improvements in generic and hepatitis-specific quality-of-life scores.

In treatment-naive patients with chronic hepatitis C, interferon-α-2b plus ribavirin for 24 or 48 weeks prolonged quality-adjusted life expectancy and was cost-effective (1999 values; direct and indirect costs) from the societal perspective compared with interferon-α-2b monotherapy in 1744 participants in a US and a multinational trial. Although treatment with combination therapy for 24 or 48 weeks ($US18 300 and $US20 900, respectively) was more costly than that of interferon-α-2b monotherapy (US$15 000) for 48 weeks, combination treatment yielded greater unadjusted and quality-adjusted life expectancy.

Furthermore, sensitivity analysis indicated that 24 and 48 weeks’ combination therapy remained cost effective at<$US7300 per discounted quality-adjusted life year (QALY) gained versus 48 weeks’ monotherapy, irrespective of gender, location, initial liver histology, viral load, viral genotype or the number of predictors of a positive response to therapy. Additionally, 48 weeks of treatment with combination therapy was more cost effective than 24 weeks for all subgroups except viral genotype 2 and 3.

A cost-utility analysis of 345 relapsers indicated that, at a 3% discounted rate, compared with interferon-α-2b alone, lifetime costs with combination therapy were marginally more expensive, but prognosis was improved by 2 QALYs, providing a marginal cost-effectiveness ratio of $US140 per QALY gained (1995 values). Notably, despite the fact that HCV genotype 1 and high viral loads (>2 million copies/ml) are associated with a poor response rate, the marginal cost-effectiveness ratio in relapse patients with both of these characteristics would be $US7700 per QALY gained.

The outcomes and costs (1998 values) of interferon-α-2b plus ribavirin combination therapy have been compared with other treatment strategies using data from several clinical trials. Compared with interferon-α-2b alone for 48 weeks followed by combination therapy in relapsers, combination therapy based on HCV genotype demonstrated the best incremental cost-effectiveness ratio ($US7500 per QALY) and a cost per additional sustained virological response of $US54 000. All other strategies evaluated were dominated.

Adverse effects are commonly observed in patients with chronic hepatitis C during therapy with interferon-a, including interferon-α-2b, and are related to the dose, frequency and duration of treatment and disease stage. In general, collated tolerability data from 2089 participants in clinical trials indicated that the adverse event profile with combination therapy was consistent with profiles observed with the individual drugs. In these patients, anorexia, dyspnoea, pruritus and rash were shown to occur with at least a 5% greater frequency with interferon-α-2b plus ribavirin combination therapy than interferon-α-2b monotherapy.

Adverse events occurring in recipients of interferon-α-2b plus ribavirin or interferon-α-2b involved all organ systems of the body, with the majority of patients experiencing at least one adverse event. These events included haemolytic anaemia (experienced by ≈7% of patients), influenza-like symptoms (>90%), laboratory abnormalities (8 to 35%), and gastrointestinal (10 to 46%), psychiatric (15 to 40%), respiratory tract (10 to 20%) and dermatological (10 to 30%) adverse events.

Although adverse events occurred frequently with interferon-α-2b plus ribavirin combination therapy, dosage modifications of one or both agents as recommended resulted in relatively few patients discontinuing combination treatment in clinical trials. In large randomised trials, 6 to 11 % of recipients of combination therapy discontinued treatment versus 3 to 9% in the interferon-α-2b groups with 24 weeks’ therapy. Pooled data indicated that haemolytic anaemia (haemoglobin concentrations <100 g/L), associated with ribavirin therapy, led to dosage reductions or discontinuation of treatment in 1 to 14% of patients. Following cessation of therapy, haemoglobin concentrations and reticulocyte counts returned to pretreatment concentrations after 3 to 10 weeks. No clinically relevant changes were observed in leucocyte or platelet counts in either treatment group in large clinical trials.

In comparative trials evaluating interferon-α-2b plus ribavirin combination therapy or interferon-α-2b alone, serious (grade 3) or life-threatening (grade 4) adverse events occurred in 17 and 10% of treatment-naive and treatment-experienced patients, respectively. Notably, there was no difference between combination and interferon-α-2b monotherapy groups in the incidence of these grade 3 and 4 adverse events in pooled data. Clinically significant serious (grades 3 or 4) cardiovascular, psychiatric, gastrointestinal, respiratory and dermatological adverse events occurred in 0.9, 1.1, 0.6, 0.4 and 0.1 % of patients, respectively, in clinical trials.

Combination therapy with subcutaneous interferon-α-2b plus oral ribavirin is recommended for the treatment of chronic hepatitis C in adult patients with compensated liver disease who have not been previously treated with interferon-α, or who have failed to respond to or relapsed after a previous interferon-α therapy. There are currently no recommendations for the use of combination therapy in patients <18 years of age. In treatment-naive patients, the recommended duration of treatment is 24 or 48 weeks, based on baseline disease characteristics, response to therapy and tolerability, whereas 24 weeks’ treatment is recommended for treatment-experienced patients.

The recommended dosage of subcutaneous interferon-α-2b is 3MU three times per week, whereas that of ribavirin is 1000 mg/day in patients with a body-weight ≤75kg and 1200 mg/day in those over 75kg (as a twice-daily divided dose). Ribavirin may be administered without regard for food, but should be administered in a consistent manner. Dosage modification of one or both drugs is required in ≈26% of patients.

Combination therapy with interferon-α-2b plus ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. If pregnancy does occur during or within 6 months of completing therapy, patients must be advised of the significant teratogenic risk of ribavirin therapy to the fetus. In lactating mothers, a decision should be made whether to discontinue treatment with combination therapy or to discontinue nursing.

Combination therapy with interferon-α-2b plus ribavirin is also contraindicated in patients with autoimmune hepatitis or in those with a history of hypersensitivity to either agent or any component of the capsule and/or injection. It should be used with caution in patients with a creatinine clearance <3 L/h (<50 ml/min), since the clearance of ribavirin is reduced in patients with severe renal impairment. Combination therapy is not recommended in patients with haemoglobinopathies, decompensated cirrhosis, previous or current serious psychiatric disorders, diabetes mellitus, pre-existing autoimmune disorders or uncontrolled thyroid disorders.