NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Chou R, Carson S, Chan BKS, et al. Drug Class Review: Pegylated Interferons for Chronic Hepatitis C Infection: Final Report [Internet]. Portland (OR): Oregon Health & Science University; 2007 May.

Cover of Drug Class Review: Pegylated Interferons for Chronic Hepatitis C Infection

Drug Class Review: Pegylated Interferons for Chronic Hepatitis C Infection: Final Report [Internet].

Show details

Results

Overview

Figure 1 shows the flow of studies. Literature searches identified 829 citations, and 166 of these were potentially relevant. After review of the full text of these 166, we included 86 studies: 41 reports of randomized controlled trials (in 46 publications),33–78 five systematic reviews (in 6 publications),9, 13–15, 79, 80 and 40 uncontrolled studies that provided information on adverse events.81–120 Excluded studies are listed in Appendix C.

Figure 1. Results of literature search.

Figure 1

Results of literature search.

Among the 41 included randomized controlled trials, two were short-term head-to-head trials of dual therapy with pegylated interferon alfa-2a versus dual therapy with pegylated interferon alfa-2b,71, 72 15 trials compared pegylated interferon plus ribavirin to non-pegylated interferon plus ribavirin,34, 35, 40, 43–46, 58, 59, 61, 63, 68, 70, 73, 74 and five compared dual therapy with pegylated interferon plus ribavirin to pegylated interferon monotherapy (Evidence Table 1).42, 48, 53, 56, 57 Nineteen trials compared different doses or treatment durations of the same peginterferon (Evidence Table 2).33, 37, 39, 41, 47, 49, 50, 54, 55, 60, 62–64, 67, 69, 75–78 Two trials directly compared different doses of ribavirin as part of dual therapy with pegylated interferon.50, 52 Two trials were included in more than one category.50, 63

One head-to-head trial available as an abstract was excluded because it only reported interim (8-week) results of a short-term (12 weeks) trial.121 We identified six other unpublished trials from pharmaceutical company dossiers that otherwise met inclusion criteria (Appendix D). These trials were not included in our primary analyses, but results were considered in sensitivity analyses in order to determine how they affected conclusions. A large (N=4913) trial compared weight-based to fixed, lower-dose ribavirin in patients on dual therapy with pegylated interferon alfa-2b.122 The other five trials evaluated effects of different doses or duration of therapy123–126 or compared effects of therapy in different racial groups.127

Overview of methodological quality of included trials

Details of our quality assessment of included randomized controlled trials are shown in Evidence Table 3. Two of 41 included trials were rated good quality, 9 were rated poor, and the rest were fair (Table 4). Fourteen of 41 trials (34.1%) described adequate randomization methods, 39% described adequate allocation concealment, 12.2% masked patients and providers, 12.2% masked outcome assessors, and 85.4% reported ITT results.

Table 4. Summary of quality assessment of included published trials.

Table 4

Summary of quality assessment of included published trials.

Key Question 1. What is the comparative effectiveness of regimens of peginterferon alfa-2a plus ribavirin versus peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C virus infection?

Summary of evidence

We found insufficient evidence to determine if dual therapy with pegylated interferon alfa-2a is superior to dual therapy with pegylated interferon alfa-2b for achieving SVR or SBR. Head-to-head trials data were sparse (two trials), short-term (8 to 12 weeks), clinically diverse, and had methodological flaws. Indirect analysis of trials comparing dual therapy with pegylated interferon alfa-2a or alfa-2b to a common comparator (dual therapy with non-pegylated interferon) indicate no significant differences in rates of SVR, though interpretation of findings is limited by clinical diversity across trials and imprecise estimates of effects. There are also no clear differences in SBR. Data on histologic outcomes and quality of life are sparse and there are no comparative data on other outcomes such as cirrhosis, hepatocellular cancer, liver transplant, or functional status.

Effectiveness versus efficacy

We considered all of the trials included in this report efficacy studies, as they generally applied numerous inclusion criteria, were conducted in specialty settings, used rigid dosing regimens, and evaluated relatively short-term, intermediate outcomes (SVR and SBR rates).128

Systematic reviews

We identified five systematic reviews (reported in six publications) on efficacy of dual therapy with pegylated interferon.9, 13–15, 79, 80 All of the systematic reviews included the same two published trials (one evaluating dual therapy with pegylated interferon alfa-2a48 and the other pegylated interferon alfa-2b63). In both trials, dual therapy with pegylated interferon was compared to dual therapy with non-pegylated interferon or monotherapy with pegylated interferon. We excluded four of the systematic reviews because they did not assess comparative efficacy of dual pegylated interferon regimens and are missing new, relevant trials.9, 13–15, 79 The fifth systematic review focused on efficacy of dual therapy with pegylated interferon in patients with HCV genotype 4 infection and is reviewed for key question 3.79

Head-to-head trials

Two head-to-head trials compared dual therapy with pegylated interferon alfa-2a versus pegylated interferon alfa-2b.71, 72 Both were short-term (eight to twelve weeks) efficacy trials that only assessed end-of-treatment virologic responses. Results of the two trials cannot be directly compared or combined because of differences in study quality, patient populations, and interventions (Table 5). One trial (rated fair-quality), sponsored by the manufacturer of pegylated interferon alfa-2b, only included treatment-naïve patients infected with HCV genotype 1 and initially placed patients on four weeks of pegylated interferon monotherapy before ribavirin was added for the last four weeks.71 The other trial, sponsored by the manufacturer of pegylated interferon alfa-2a, was rated poor quality (flaws include allocating consecutive patients to alternating therapy), did not restrict to genotype 1, initiated patients on dual therapy, and included treatment-experienced patients (30% of enrolled population).72 In both trials, end-of- treatment virologic response was defined as >=2.0 log10 decrease in HCV load.

Table 5. Head-to-head trials of dual therapy with pegylated interferon alfa-2a vs. dual therapy with pegylated interferon alfa-2b.

Table 5

Head-to-head trials of dual therapy with pegylated interferon alfa-2a vs. dual therapy with pegylated interferon alfa-2b.

In the fair-quality trial, there was no significant difference (p=0.09) in 8-week virologic response rates between dual therapy with pegylated interferon alfa-2a (44% or 8/18) and dual therapy with pegylated interferon alfa-2b (72% or 13/18) (Table 5).71 In the poor-quality trial, there was also no difference in 12-week virologic response rates, though the trend was in the opposite direction (83% or 48/58 for pegylated interferon alfa-2a versus 67% or 39/58 for pegylated interferon alfa-2b, p=0.08).72 In a subgroup analysis of treatment-naïve patients in this trial, the same trend was observed (90% vs. 75%, p=0.61). Biochemical, histological, and clinical outcomes were not reported in either trial.

A third short-term (12 weeks) head-to-head trial was excluded because only interim results have been reported in a conference abstract.121 It found no significant difference in rates of virologic response through eight weeks of dual therapy with pegylated interferon alfa-2a versus pegylated interferon alfa-2b (66% or 29/44 versus 50% or 22/44). Results of a large (expected enrollment 2,880), head-to-head trial of 48-week dual pegylated interferon regimens in patients with HCV genotype 1 infection (the IDEAL study) are not yet available, but expected later in 2007.129 This trial is sponsored by the manufacturer of pegylated interferon alfa-2b.

Active-controlled trials

Dual therapy with pegylated interferon versus dual therapy with non-pegylated interferon

Active-controlled trials of dual therapy with pegylated interferon alfa-2a and pegylated interferon alfa-2b against a common comparator could provide indirect evidence on comparative effectiveness. We identified five trials comparing dual therapy with pegylated interferon alfa-2a plus ribavirin versus dual therapy with non-pegylated interferon alfa-2a plus ribavirin35, 44, 61, 73 or dual therapy with non-pegylated interferon alfa-2b plus ribavirin48 and 11 trials comparing dual therapy with pegylated interferon alfa-2b plus ribavirin versus dual therapy with non-pegylated interferon alfa-2b plus ribavirin.34, 40, 43, 45, 46, 58, 59, 63, 68, 70, 74 One trial was rated good-quality,73 three trials poor-quality,35, 46, 68 and the remainder fair-quality. Sample sizes ranged from 2135 to 153063 enrollees. Common methodological shortcomings observed in the trials were inadequate description of randomization and allocation concealment methods and open-label design. All trials of pegylated interferon alfa-2a evaluated a dose of 180 μg /kg once weekly. Seven trials of pegylated interferon alfa-2b evaluated a dose of 1.5 μg/kg once weekly,43, 45, 46, 59, 63, 70, 74 and the other four34, 40, 58, 68 evaluated a range of different doses (Table 6). Ribavirin doses varied in both sets of trials, ranging from 600 to 1600 mg daily. In one trial, patients randomized to dual therapy with pegylated interferon and non-pegylated interferon also received amantadine.61

Table 6. Characteristics of trials comparing dual therapy with pegylated interferon to dual therapy with non-pegylated interferon.

Table 6

Characteristics of trials comparing dual therapy with pegylated interferon to dual therapy with non-pegylated interferon.

Three of the pegylated interferon alfa-2a35, 44, 73 and four of the pegylated interferon alfa-2b trials43, 45, 58, 68 evaluated HIV co-infected patients. Two trials did not specify whether patients had previously been exposed to interferon therapy.35, 68 The other trials evaluated only treatment-naïve patients. Three trials focused exclusively46, 47 or primarily34 on patients with HCV genotype 4 infection and three trials40, 70, 74 evaluated only patients with HCV genotype 1 infection. The proportion of patients with HCV genotype 1 ranged from 44% to 78% in the other trials. All trials required patients to have liver biopsy findings consistent with HCV infection and at least mild inflammation or fibrosis for enrollment. Only one trial specifically included patients with normal transaminases.77 Three trials (all evaluating HIV co-infected patients)43, 44, 68 did not use transaminase elevations as an eligibility criterion. In all other trials, transaminase elevation was required for enrollment. No trial included patients with decompensated cirrhosis. Rates of SVR ranged from 27% to 65% on dual therapy with pegylated interferon alfa-2a, and from 27% to 67% on dual therapy with pegylated interferon alfa-2b, with the exception of one poor-quality, non-randomized trial68 of HIV co-infected patients that reported an SVR of 5% (1/20).

No trial was designed to evaluate rates of cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, or liver transplant. Only one trial48 reported effects on quality of life.51

All trials reported rates of SVR. In pooled analysis, dual therapy with pegylated interferon alfa-2a plus ribavirin was superior to non-pegylated interferon alfa-2a or alfa-2b plus ribavirin (five trials, RR 2.14, 95% CI 1.32 to 3.47) (Figure 2). There was a significant difference between estimates based on the subgroup of four trials (N=969)35, 44, 61, 73 comparing dual therapy with pegylated interferon alfa-2a to dual therapy with non-pegylated interferon alfa-2a (RR 2.55, 95% CI 1.75 to 3.74) and the single, large (N=897) trial48 comparing dual therapy with pegylated interferon alfa-2a to dual therapy with non-pegylated interferon alfa-2b (RR 1.28, 95% CI 1.12 to 1.46; p=0.038 for difference).

Figure 2. Forest plot on sustained virologic response, dual therapy with pegylated interferon alfa-2a versus dual therapy with non-pegylated interferon alfa-2a or alfa-2b.

Figure 2

Forest plot on sustained virologic response, dual therapy with pegylated interferon alfa-2a versus dual therapy with non-pegylated interferon alfa-2a or alfa-2b.

Pegylated interferon alfa-2b plus ribavirin was also superior to non-pegylated interferon alfa-2b plus ribavirin for achieving an SVR (11 trials, RR 1.28, 95% CI 1.10 to 1.49) (Figure 3).

Figure 3. Forest plot on sustained virologic response, dual therapy with pegylated interferon alfa-2b versus dual therapy with non-pegylated interferon.

Figure 3

Forest plot on sustained virologic response, dual therapy with pegylated interferon alfa-2b versus dual therapy with non-pegylated interferon.

Excluding trials of HIV-infected patients attenuated the difference in pooled estimates between dual therapy with pegylated interferon alfa-2a (2 trials, RR 1.55, 95% CI 1.02 to 2.36, see Figure 2) and dual therapy with pegylated interferon alfa-2b (7 trials, RR 1.12, 95% CI 1.03 to 1.23, see Figure 3), and decreased heterogeneity in the pegylated interferon alfa-2a trials. Some of the remaining heterogeneity in the two trials of pegylated interferon alfa-2a in patients without HIV co-infection may be related to the addition of amantadine to both treatment arms in one of the trials.61 Estimates were stable after excluding poor-quality trials or trials evaluating only patients with genotype 1 or genotype 4 infection. Estimates were also stable after excluding results of patients randomized to lower-dose pegylated interferon alfa-2b from a trial that evaluated lower (0.5 μg /kg/wk) and higher (1.5 μg/kg/wk) dose dual therapy.63

We performed an adjusted indirect analysis to evaluate relative efficacy of dual therapy with pegylated interferon alfa-2a versus dual therapy with pegylated interferon alfa-2b on rates of SVR, based on trials in which each was compared to dual therapy with non-pegylated interferon. However, results of the indirect analysis should be interpreted with caution. Although indirect meta-analyses usually agree with direct meta-analyses of head-to-head trials, results can be discordant or contradictory if the critical assumption that treatment effects are consistent across all the trials is violated.25, 27, 28 This can occur when there are methodological flaws in the studies or differences in patient populations, interventions, or other factors. In this set of trials, substantial clinical diversity was observed in patient populations, dosing of interventions (both for pegylated interferon and for ribavirin), and comparator treatments (interferon alfa-2a versus interferon alfa-2b). In addition, confidence intervals for our estimates are wide, due to a relatively small data set and decreased precision of indirect compared to direct analyses.

Including all trials, adjusted indirect analysis (Table 7) found no significant differences (and wide confidence intervals) in efficacy for SVR between dual therapy with pegylated interferon alfa-2a versus dual therapy with pegylated interferon alfa-2b, using dual therapy with non-pegylated interferon alfa-2a or alfa-2b as the common comparator (RR 1.67, 95% CI 0.56 to 5.04). Because comparing dual therapy with pegylated interferon to dual therapy with different non-pegylated interferons (alfa-2a or alfa-2b) could violate assumptions about relative treatment effects across both sets of trials, we also performed the indirect analysis using only trials that compared dual therapy with pegylated interferon to dual therapy with non-pegylated interferon alfa-2b. This analysis found no difference in the point estimate of relative efficacy (RR 1.00, 95% CI 0.47 to 2.11). We did not perform an adjusted indirect analysis for the subgroup of trials in non-HIV infected persons, as confidence intervals for estimates of relative risk for SVR from the direct analyses overlapped substantially and the number of available trials was small.

Table 7. Adjusted indirect analysis for sustained virologic response rates.

Table 7

Adjusted indirect analysis for sustained virologic response rates.

Seven trials reported rates of SBR. One trial found dual therapy with pegylated interferon alfa-2a superior to dual therapy with non-pegylated interferon alfa-2a, each in combination with amantadine (RR 1.98, 95% CI 1.49 to 2.63).61 The six other trials evaluated dual therapy with pegylated interferon alfa-2b versus dual therapy with non-pegylated alfa-2b.34, 40, 58, 59, 70, 74 There was no difference in pooled risk of SBR (RR 1.17, 95% CI 0.98 to 1.40) (Figure 4). There were too few trials reporting SBR to perform indirect meta-analysis.

Figure 4. Forest plot on sustained biochemical response, dual therapy with pegylated interferon alfa-2b versus dual therapy with non-pegylated interferon alfa-2b.

Figure 4

Forest plot on sustained biochemical response, dual therapy with pegylated interferon alfa-2b versus dual therapy with non-pegylated interferon alfa-2b.

The three trials that evaluated histologic outcomes found no differences between dual therapy with pegylated interferon alfa-2b and dual therapy with non-pegylated interferon alfa-2b in liver biopsy scores for fibrosis or inflammation.43, 59, 63 The one trial reporting health-related quality of life and fatigue severity scores in patients randomized to different treatments (as opposed to responders versus non-responders) found dual therapy with pegylated interferon alfa-2a to be associated with improved scores in a variety of domains during therapy compared to dual therapy with non-pegylated interferon alfa-2b. Yet differences were small (generally less than 5 points on 100 point scales) and scores had returned to baseline values or better in both groups 24 weeks after the end of treatment.48, 51 In addition, patients in this trial were aware of their virologic response to therapy, which could have affected assessments of health-related quality of life.

The funnel plot for the eleven trials of dual therapy with pegylated interferon alfa-2b versus dual therapy with non-pegylated interferon alfa-2b for SVR is difficult to interpret because of a small outlier trial.68 However, after excluding this trial, no funnel plot asymmetry was apparent.

Dual therapy with pegylated interferon versus pegylated interferon monotherapy

We identified six trials of dual therapy with pegylated interferon (5 trials evaluating pegylated interferon alfa-2a48, 53, 56, 57, 73 and one trial evaluating pegylated interferon alfa-2b42) versus pegylated interferon monotherapy. One trial was rated good-quality,73 one poor-quality,56 and the remainder fair-quality. The number of patients randomized to pegylated interferon monotherapy or dual therapy ranged from 2053 to 89748 enrollees. Two trials42, 57 evaluated HIV co-infected patients and one53 evaluated thalassemic patients. The proportion of patients with HCV genotype 1 infection ranged from 44% to 86%. All trials only evaluated treatment-naïve patients. Rates of SVR for dual therapy ranged from 33% to 57% with pegylated interferon alfa-2a, with the exception of one trial57 that reported an SVR of 5%. This trial only randomized HIV co-infected patients who failed to respond to 14 weeks of initial pegylated interferon monotherapy. The single trial of dual therapy with pegylated interferon alfa-2b evaluated HIV co-infected patients and reported an SVR of 22%.42

The pooled relative risk for an SVR in patients randomized to dual therapy with pegylated interferon alfa-2a versus pegylated interferon alfa-2a monotherapy was 1.92 (5 trials, 95% CI 1.63 to 2.26) (Figure 5). Excluding either the small (N=20) trial53 of thalassemic patients or the trial of HIV-infected non-responders57 yielded similar estimates (RR 1.92, 95% CI 1.63 to 2.27 and RR 1.91, 95% CI 1.62 to 2.28, respectively). The small (N=56) trial of dual therapy with pegylated interferon alfa-2b versus pegylated interferon alfa-2b monotherapy reported an RR for SVR of 2.39 (95% CI 0.99 to 5.79).42 We did not attempt an indirect analysis because estimates of SVR for dual versus monotherapy overlapped and there was only one trial of dual therapy with pegylated interferon alfa-2b. One trial found that patients randomized to dual therapy with pegylated interferon alfa-2a plus ribavirin experienced greater declines in health-related quality of life and fatigue severity scores during treatment compared to those randomized to pegylated interferon alfa-2a monotherapy.48, 51 No trial reported SBR, histologic outcomes, or other clinical outcomes.

Figure 5. Forest plot on sustained virologic response, dual therapy with pegylated interferon alfa-2a versus pegylated interferon alfa-2a monotherapy.

Figure 5

Forest plot on sustained virologic response, dual therapy with pegylated interferon alfa-2a versus pegylated interferon alfa-2a monotherapy.

Observational studies of long-term clinical outcomes

We identified no observational studies evaluating long-term clinical outcomes such as cirrhosis, hepatocellular cancer, need for liver transplant, or mortality.

Key Question 1a. How does duration of treatment or dosing protocols (including weight-based or maintenance dosing or dosing of ribovirin) affect estimates of comparative effectiveness?

Summary

Published trials directly comparing different doses of pegylated interferon as part of dual therapy are only available for pegylated interferon alfa-2b. No dose has been shown to be more effective than 1.5 μg/kg/week for achieving an SVR. The optimal dose of pegylated interferon alfa-2b as part of dual therapy in non-responders or relapsers is unclear.

Trials directly comparing different durations of therapy are characterized by substantial clinical diversity. In general, in patients with HCV genotype 1 infection, 48 weeks of dual therapy with pegylated interferon appears to be more effective than shorter courses. On the other hand, in patients with HCV genotype 2 or 3 infection, shorter courses appear equally effective compared to a 48 week course, particularly in early responders to therapy, in whom a 12 week-course of therapy appears as effective as 24 weeks.

Studies evaluating effects of dose and duration are of limited value for evaluating comparative effectiveness of dual therapy with pegylated interferon alfa-2a versus pegylated interferon alfa-2b because none directly compared effects of duration or dose between the two regimens. Pooling trials or performing meta-regression was not possible because of substantial clinical diversity across trials in patient populations, dosing of drugs, and/or duration of therapy.

Overview of trials on dose or duration

Understanding effects of dose and duration on efficacy of dual therapy with pegylated interferon would be very helpful for selecting optimal treatment regimens and interpreting results of clinical trials. We included 19 trials on efficacy of dual therapy with pegylated interferon at different doses, varying duration, or with standardized versus tailored (to early response) treatment.33, 37, 39, 41, 47, 49, 50, 52, 54, 55, 60, 62, 64, 67, 69, 75–78 None of the 19 trials directly compared dual therapy regimens of pegylated interferon alfa-2a versus pegylated interferon alfa-2b. Two trials directly compared different doses of ribavirin as part of dual therapy with pegylated interferon.50, 52 We did not pool trial results or perform meta-regression because of differences in study populations, doses of pegylated interferon, doses of ribavirin, and/or duration of therapy. Because of this clinical diversity, the indirect evidence from this set of trials is of limited value for evaluating comparative effectiveness of dual therapy with pegylated interferon alfa-2a versus pegylated interferon alfa-2b.

Dose of pegylated interferon

All eight dose-ranging trials evaluated pegylated interferon alfa-2b (Table 8).33, 41, 49, 54, 60, 63, 64, 67 No trial evaluated standardized versus weight-based dosing.

Table 8. Trials evaluating efficacy of different doses in regimens of dual therapy with pegylated interferon alfa-2b.

Table 8

Trials evaluating efficacy of different doses in regimens of dual therapy with pegylated interferon alfa-2b.

In treatment-naïve patients, one large (N=1,025), fair-quality trial found a dose of 0.5 μg/kg/week inferior to 1.5 μg/kg/week for achieving an SVR (47% vs. 54%, p=0.01).63 Benefits of the higher dose were only observed in the subgroup of patients with genotype 1 infection (42% vs. 34%). Three smaller, fair-quality trials found no differences in SVR between 0.5 μg/kg/week verses 1.0 μg/kg/week,41 1.0 μg/kg/week versus 1.5 μg/kg/week,67 or 0.75 μg/kg/week versus 1.5 μg/kg/week of pegylated interferon alfa-2b,33 each in combination with ribavirin 800 mg/day. The latter trial33 evaluated patients with severe fibrosis (METAVIR fibrosis stage F3 or F4) and the other two trials evaluated patients with less severe biopsy findings. A poor quality trial found both 0.7 μg/kg/week and 1.4 μg/kg/week doses superior to 0.35 μg/kg/week, at varying ribavirin doses.49 Three trials of relapsers or non-responders to prior interferon-based therapy (two fair-quality, one poor-quality) found no significant differences in SVR rates between higher and lower-dose regimens of peginterferon alfa-2b, though trends favored the higher-dose regimen in each trial.54, 60, 64 However, each trial evaluated a different dose comparison.

Two unpublished trials compared efficacy of different doses of pegylated interferon alfa-2a as part of combination therapy. One small (N=40) trial found no clear difference in rates of SVR between patients randomized to a dose of 180 μg/week versus those randomized to 270 μg/week (70% vs. 79%, p not reported).123 The second trial compared dual therapy using higher induction doses of pegylated interferon alfa-2a compared to standard dosing in patients without an early virologic response.124 In addition, this trial evaluated effects of different durations of therapy, however final results are not yet available.

Duration

We identified nine trials evaluating effects of duration of dual therapy with pegylated interferon plus ribavirin on SVR rates (Table 9).37, 39, 47, 50, 55, 69, 75–77 The only good-quality trial found 48 weeks of dual therapy with pegylated interferon alfa-2a plus ribavirin more effective than 24 weeks of therapy for achieving SVR (OR 1.53, 95% CI 1.17 to 2.01).50 In subgroup analyses, 48 weeks of therapy was superior to 24 weeks only in patients with genotype 1 infection (OR 2.19, 95% CI 1.52 to 3.16, compared to OR 0.89, 95% CI 0.56 to 1.42 with genotypes 2 or 3). A fair-quality trial also found 48 weeks superior to 24 weeks in patients with normal transaminases, with benefits limited to the subgroup of genotype 1-infected patients.77

Table 9. Trials evaluating efficacy of different durations of dual therapy with pegylated interferon.

Table 9

Trials evaluating efficacy of different durations of dual therapy with pegylated interferon.

Five other trials (all rated fair-quality) also evaluated effect of treatment duration, but limited enrollment to patients with specific HCV genotypes.37, 47, 55, 75, 76 In patients with HCV genotype 1 infection, two trials found 48 weeks of dual therapy with pegylated interferon alfa-2a39 or alfa-2b76 superior to 24 weeks for achieving an SVR (80% vs. 49%, p<0.0576 and 48% vs. 28%, p=0.017539). A third trial found no difference between 72 and 48 weeks of dual therapy with pegylated interferon alfa-2a.37 In this trial, however, the subgroup of patients who were "slow responders" (defined as HCV-positive at week 12 but negative at week 24) had a better sustained viral response with 72 weeks versus 48 weeks of treatment (29% vs. 17%, P=0.04). In patients with HCV genotypes 2 or 3, one trial found 16 weeks of dual therapy with pegylated interferon alfa-2a as effective for achieving an SVR as 24 weeks in patients with an early (six week) response to treatment.75 In patients with HCV genotype 4, results from two trials were inconsistent, with one trial finding 36 or 48 weeks of dual therapy with pegylated interferon superior to 24 weeks,55 but no differences between 24 and 48 weeks in the second trial.47

Longer courses of dual therapy with pegylated interferon therapy could be more effective in patients who do not respond to treatment within the first four to six weeks. One fair-quality trial found 72 weeks of dual therapy with pegylated interferon alfa-2a superior to 48 weeks for achieving SVR in early non-responders.69 An alternative to using a fixed interferon regimen is to individualize the dose or duration of therapy based on an individual's early virologic response to treatment. One trial found that in patients with HCV genotype 2 or 3 infection, shortening the duration of therapy from 24 to 12 weeks in patients who cleared their virus by week 4 was as effective as treating all patients for 24 weeks.62 A second trial found no differences between a standardized 48 week regimen and individualized therapy based on a more complicated protocol for classifying early response and modifying treatment.78

Two trials currently available only as abstracts evaluated effects of duration on efficacy of dual therapy with pegylated interferon alfa-2a. One trial found 16 weeks inferior to 24 weeks for achieving SVR in patients with HCV genotype 2 or 3 infection (66% vs. 74%, p<0.005).126 Unlike other trials evaluating less than 24 weeks of therapy, it was not limited or tailored to patients with an early virologic response. Another trial (N=377) found no difference between 24 and 48 weeks of dual therapy with pegylated interferon plus ribavirin 800 mg (28% vs. 26%) in patients with genotype 1 infection and compensated cirrhosis, though the longer course appeared superior in patients randomized to ribavirin 1000 to 1200 mg (37% vs. 26%, p not reported).125 There was no difference in patients with non-genotype 1 infection.

Dose of ribavirin

Different ribavirin dosing schemes could influence efficacy of dual therapy regimens, but have only been directly evaluated in two trials.50,52 One trial found dual therapy with pegylated interferon alfa-2a in combination with higher dose ribavirin (1000 to 1200 mg, depending on weight) more effective than dual therapy with lower dose ribavirin (800 mg) for achieving SVR in the subgroup of patients with genotype 1 infection (OR 1.55, 95% CI 1.14 to 2.10), but not in those with genotype 2 or 3 infection (OR 1.00, 95% CI 0.63 to 1.61).50 A second trial also found dual therapy with pegylated interferon alfa-2a in combination with higher dose ribavirin more effective than lower dose ribavirin in patients with advanced fibrosis or cirrhosis.52 However, in contrast to the other trial, higher dose ribavirin (1000 to 1200 mg) was superior to lower dose ribavirin (600 to 800 mg) for SVR (72% vs. 45%, p=0.03) in patients with genotype 2 or 3 infection, but not in patients with genotype 1 or 4 infection (SVR 32% vs. 32%). In two other published trials, patients were randomized to different doses of ribavirin, but pegylated interferon doses also varied, making it difficult to determine dose effects of the individual drugs.49, 54

A large (N=4,913, 62% HCV genotype 1) trial available only as an abstract found pegylated interferon alfa-2b modestly more effective combined with higher, weight-based dosing of ribavirin (800 to 1400 mg) than when combined with fixed-dose, 800 mg ribavirin (SVR 44% vs. 41%, p=0.02).130 A second trial published only as an abstract found 48 weeks of pegylated interferon alfa-2a more effective in combination with weight-based dosing of ribavirin (1000 to 1200 mg) than with fixed-dosing (800 mg) in patients with genotype 1 infection and compensated cirrhosis.125 In this same trial, the ribavirin dosing regimen was associated with no differences in rates of SVR in patients with non-genotype 1 infection or in those randomized to 24 weeks of therapy.

Effects of duration or dose on adverse events

We found no consistent pattern showing an association between longer duration or higher doses of dual therapy with pegylated interferon and increased rates of withdrawal due to adverse events (Tables 8 and 9). Other adverse events were reported inconsistently.

Key Question 2. What is the comparative tolerability and safety of peginterferon alfa-2a plus ribavirin versus peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C virus infection?

Summary

We found insufficient evidence to determine if dual therapy with one pegylated interferon is safer than dual therapy with the other pegylated interferon. Data from head-to-head trials are extremely sparse (one short-term trial) and inadequate for judging comparative safety. Indirect analysis of trials comparing dual therapy with pegylated interferon alfa-2a or alfa-2b to dual therapy with non-pegylated interferon show no significant differences in rates of withdrawal due to adverse events or other adverse events, but interpretation of findings is limited by clinical diversity across trials, imprecise estimates of effects, and inconsistent reporting of adverse events. Observational studies were almost all uncontrolled and provided no additional useful information on comparative safety, as rates of withdrawal due to adverse events on dual therapy ranged widely across trials for the same pegylated interferon and overlapped for therapy based on each of the two pegylated interferons.

Systematic reviews

One systematic review included two large, pivotal trials that reported similar rates of withdrawal due to adverse events in patients randomized to dual therapy with pegylated interferon plus ribavirin versus dual therapy with non-pegylated interferon plus ribavirin (10% vs. 11% in one trial of dual therapy with pegylated interferon alfa-2a48 and 14% vs. 13% in one trial of pegylated interferon alfa-2b63).13 It did not evaluate other adverse events.

Head-to-head trials

One small, short-term, fair-quality randomized trial found no differences between dual therapy with pegylated interferon alfa-2a and pegylated interferon alfa-2b in withdrawals due to adverse events (11% or 2/18 vs. 22% or 4/18), flu-like symptoms (17% or 3/18 vs. 28% or 5/18), or the proportion of patients with anemia or leukopenia.71 The only other head-to-head trial did not report adverse events or withdrawals due to adverse events.72

Active-controlled trials

Dual therapy with pegylated interferon versus dual therapy with non-pegylated interferon

Adverse events reported in randomized controlled trials are shown in Evidence Table 4 (randomized controlled trials of efficacy) and Evidence Table 5 (dose- or duration-ranging trials). Eleven trials reported rates of withdrawal due to adverse events in patients randomized to dual therapy with pegylated interferon versus dual therapy with non-pegylated interferon.34, 35, 40, 43–46, 48, 58, 63, 73 Six deaths were reported during therapy in patients randomized to dual therapy with pegylated interferon,43, 59 five of which occurred in HIV co-infected patients.43 Rates of withdrawal due to adverse events on dual therapy with pegylated interferon ranged from 6% to 16%.

In pooled analyses, there was no significant difference in rates of withdrawal due to adverse events for dual therapy with pegylated interferon alfa-2a versus dual therapy with non-pegylated interferon (4 trials, RR 0.80, 95% CI 0.60 to 1.07, Figure 6) or dual therapy with pegylated interferon alfa-2b versus dual therapy with non-pegylated interferon (7 trials, RR 0.94, 95% CI 0.68 to 1.31, Figure 7). Other adverse events were less consistently reported. Compared to dual therapy with non-pegylated interferon, dual therapy with pegylated interferon alfa-2a (one trial, RR 2.33, 95% CI 1.64 to 3.33) and dual therapy with pegylated interferon alfa-2b (four trials, RR 2.58, 955 CI 1.52 to 4.37) were associated with similarly increased risks for neutropenia. A similar trend was observed for risk of anemia. There were no significant differences between dual therapy with pegylated interferon alfa-2a or alfa-2b and dual therapy with non-pegylated interferon in rates of depression or flu-like symptoms.

Figure 6. Forest plot on withdrawal due to adverse events, dual therapy with pegylated interferon alfa-2a versus dual therapy with non-pegylated interferon alfa-2a or -2b.

Figure 6

Forest plot on withdrawal due to adverse events, dual therapy with pegylated interferon alfa-2a versus dual therapy with non-pegylated interferon alfa-2a or -2b.

Figure 7. Forest plot on withdrawal due to adverse events, dual therapy with pegylated interferon alfa-2b versus dual therapy with non-pegylated interferon alfa-2b.

Figure 7

Forest plot on withdrawal due to adverse events, dual therapy with pegylated interferon alfa-2b versus dual therapy with non-pegylated interferon alfa-2b.

Dual therapy with pegylated interferon versus pegylated interferon monotherapy

Three of six trials reported rates of withdrawal due to adverse events in patients randomized to dual therapy with pegylated interferon versus patients randomized to pegylated interferon monotherapy. Two trials evaluated pegylated interferon alfa-2a48, 73 and the third evaluated pegylated interferon alfa-2b.42 No deaths were reported in patients randomized to dual therapy. Rates of withdrawal due to adverse events on dual therapy ranged from 6% to 12% and were very similar between dual therapy and monotherapy in all three trials (RR 1.07, 95% CI 0.74 to 1.53). There were also no clear differences in rates of depression or in hematologic side effects (each reported by three trials).

In the pegylated interferon alfa-2b trial, rates of flu-like symptoms were higher in patients randomized to dual therapy versus those randomized to pegylated interferon monotherapy (22% vs. 3%).42 However, the 3% rate of flu-like symptoms associated with pegylated interferon monotherapy appears unusually low.

Adverse events reported in uncontrolled studies

Forty uncontrolled or observational studies provided information about adverse events associated with dual therapy with pegylated interferon (Evidence Table 6).81–120

In one study that enrolled patients taking either pegylated interferon alfa-2a or alfa-2b, the type of pegylated interferon was not associated with discontinuation (rates not reported).88 Nine other studies included patients receiving dual therapy with pegylated interferon alfa-2a90, 91, 95, 96, 98, 99, 113, 114, 116 and 31 included patients receiving dual therapy with pegylated interferon alfa-2b.81–89, 92–94, 97, 100–112, 115, 117–120 Six studies were designed to measure specific adverse events, including depression,87, 109 psychiatric side effects,97 infections,96 weight loss,112 and ocular changes.89

Eleven studies, all of dual therapy with pegylated interferon alfa-2b, included patients with HIV co-infection81, 82, 88, 89, 92, 93, 103, 104, 107, 110, 117 and seven studies included patients who were non-responders or relapsers following standard interferon therapy.81, 84, 91, 107, 113, 115, 118

Table 10 shows the ranges for rates of withdrawals due to adverse events reported in these studies. Rates of withdrawal due to adverse events (and other adverse events) overlapped and ranged widely in trials of dual therapy with pegylated interferon alfa-2b.

Table 10. Rates of withdrawals due to adverse events reported in uncontrolled studies.

Table 10

Rates of withdrawals due to adverse events reported in uncontrolled studies.

This body of evidence does not provide additional evidence about comparative safety or tolerability of dual therapy with pegylated interferon beyond data reported in clinical trials. The type and incidence of adverse events observed were similar to those reported in trials. Most studies followed patients for 24 weeks post-treatment. The longest period of follow-up was 84 weeks. Almost all of the studies were non-comparative, and ranges for rates of adverse events overlapped for dual therapy with the two pegylated interferons.

Key Question 3. Does the comparative effectiveness or tolerability and safety of peginterferon alfa-2a plus ribavirin versus peginterferon alfa-2b plus ribavirin vary in patient subgroups defined by demographics (age, racial groups, gender, genotype, markers of disease severity), use of other medications, or presence of co-morbidities (such as HIV infection)?

Summary

There is insufficient evidence to determine if comparative efficacy or safety of dual therapy with pegylated interferon alfa-2a versus dual therapy with pegylated interferon alfa-2b varies in specific patient subgroups. Data from head-to-head trials are limited to one short-term head-to-head trial in patients with genotype 1 infection. Estimates from indirect analysis of SVR for specific HCV genotypes and in HIV co-infected patients are too imprecise to make reliable judgments about comparative efficacy. There are almost no data to determine whether comparative efficacy or safety varies according to race, gender, age, presence of obesity, severity of baseline disease, or other co-morbid conditions.

Race, gender, or age

Some studies have found older age40, 44, 48, 62 and black race95, 106, 127 to be associated with poorer response to dual therapy with pegylated interferon. However, we found no studies evaluating whether comparative effectiveness and safety of dual therapy with pegylated interferon alfa-2a versus dual therapy with pegylated interferon alfa-2b varies according to race, gender, or age. In all trials except for one,72 the majority of enrollees were male. Average age in the trials ranged from 34 years35 to 54 years,74 with the exception of a trial of thalassemic patients with a mean age of 20 years.53

Race was not reported in the two short-term, head-to-head trials.71, 72 Race was reported in four of 19 other trials comparing dual therapy with pegylated interferon to either dual therapy with non-pegylated interferon or to pegylated interferon monotherapy.44, 48, 57, 73 The proportion of black enrollees ranged from 5% to 33% in these trials. One small subgroup analysis (N=32) of Mexican patients enrolled in a large, international multicenter trial48 reported SVR rates of 50% (7/14) for dual therapy with pegylated interferon alfa-2a versus 33% (4/12) for dual therapy with non-pegylated interferon alfa-2b.38 Other trials have been conducted in Saudi Arabia or Egypt and in Asia.34, 46, 47, 59 Two non-randomized studies reported adverse events rates in black patients compared to white patients.95, 106 However, no study directly compared efficacy or safety of dual therapy with pegylated interferon alfa-2a versus dual therapy with pegylated interferon alfa-2b by ethnic or racial subgroups.

HCV genotype

Several trials of dual therapy with pegylated interferon have found HCV genotype 1 independently associated with a lower likelihood of SVR.43, 48, 58, 59, 61, 73 One small (N=36), short-term, head-to-head trial directly compared dual therapy with pegylated interferon alfa-2a to dual therapy with pegylated interferon alfa-2b in patients with HCV genotype 1 infection.71 Because of it's small size, short duration of follow-up, and non-standard dosing (4 weeks of monotherapy followed by 4 weeks of dual therapy), it is of very limited value for judging comparative efficacy (see Key Questions 1 and 2). The large (N=2,880) IDEAL study is a head-to-head trial in patients with HCV genotype 1 infection, but results are not yet available.129

Twelve trials provide indirect evidence on efficacy of dual therapy with pegylated interferon alfa-2a versus dual therapy with pegylated interferon alfa-2b. Eight trials of dual therapy with pegylated interferon versus dual therapy with non-pegylated interferon restricted enrollment to genotype 1 patients70, 74 or reported subgroup results for patients with genotype 1 infection.44, 45, 48, 59, 63, 73 Four trials reported results for the subgroup of patients with either genotype 1 or 4 infection.43, 45, 58, 61 Six trials reported results for patients infected with HCV genotype 2 or 3.45, 48, 58, 61, 63, 73 Three trials reported SVR in patients with genotype 1 or genotypes 1 or 4 randomized to dual therapy with pegylated interferon versus pegylated interferon monotherapy.42, 48, 56

There is insufficient evidence from pooled analyses to conclude that dual therapy with one pegylated interferon is superior to the other for HCV genotypes 1, 2, or 3 infection. Estimates of relative risk for SVR on dual therapy with pegylated interferon alfa-2a versus dual therapy with non-pegylated interferon and for dual therapy with pegylated interferon alfa-2b versus non-pegylated interferon were imprecise (particularly for trials of dual therapy with pegylated interferon alfa-2a), with overlapping confidence intervals (Table 11).

Table 11. Pooled analyses on sustained virologic response rates for genotypes 1, 2, and 3.

Table 11

Pooled analyses on sustained virologic response rates for genotypes 1, 2, and 3.

We included one systematic review that found dual therapy with pegylated interferon alfa-2a superior to dual therapy with pegylated interferon alfa-2b for achieving SVR in patients with HCV genotype 4.79 HCV genotype 4 is far more common in Egypt, Saudi Arabia, and other North African Countries (up to two-thirds of infected patients) than in North America and Europe (less than 4% of patients in the two largest trials48, 63). The systematic review included subgroup data from the two largest published trials48, 63 and data from four other trials of patients with HCV genotype 4 infection published as conference abstracts (one trial since published as a journal article).34 All of the trials compared dual therapy with pegylated interferon to dual therapy with non-pegylated interferon (three trials of pegylated interferon alfa-2a and three pegylated interferon alfa-2b). Compared to dual therapy with non-pegylated interferon, the systematic review found dual therapy with pegylated interferon alfa-2a significantly superior for achieving an SVR (RR 2.41, 95% CI 1.35 to 4.13), but no significant difference for dual therapy with pegylated interferon alfa-2b (RR 1.17, 95% CI 0.80 to 1.70). However, all of the trials of dual therapy with pegylated interferon alfa-2b used lower, non-weight based doses of ribavirin and two of the three trials did not use FDA-approved body-weight based doses of pegylated interferon. In addition, conclusions about relative efficacy from this data are likely to be misleading, as confidence intervals overlap for the two dual pegylated interferon regimens, and no formal indirect analysis was performed. We re-analyzed the data from the systematic review with additional data from two new trials45, 46 of patients with HCV genotype 4 infection. Our indirect analysis shows no significant differences between pegylated interferon regimens on indirect analysis, with very wide confidence intervals (Table 12).

Table 12. Direct and indirect analyses on sustained virologic response rates for dual therapy with pegylated interferon.

Table 12

Direct and indirect analyses on sustained virologic response rates for dual therapy with pegylated interferon.

Baseline viral load and histologic findings

Several trials of dual therapy with pegylated interferon have found lower viral loads associated with a greater likelihood of achieving an SVR, particularly in patients with genotype 1 infection.44, 48, 50, 63, 73 Analyses of the association between less severe baseline histologic findings and greater response to dual therapy with pegylated interferon are less consistent, with some trials showing no association after controlling for other factors.40, 43, 44, 46

We identified no trials evaluating comparative effectiveness or safety of dual therapy with pegylated interferon alfa-2a versus dual therapy with pegylated interferon alfa-2b in patients with higher viral loads, more severe fibrosis or inflammation, or other markers of more severe baseline HCV disease.

Obese patients

Subgroup analyses of three trials found dual therapy with pegylated interferon alfa-2a48 and alfa-2b42, 63 less effective at achieving an SVR in patients over 75 to 80 kg, compared to those below 75 to 80 kg. A potential advantage of pegylated interferon alfa-2b is that it is normally dosed according to weight (compared to uniform dosing for pegylated interferon alfa-2a), which could theoretically help insure adequate drug levels in more obese patients. However, no trials have evaluated whether dual therapy with pegylated interferon alfa-2b is superior to dual therapy with pegylated interferon alfa-2a in obese patients, or whether weight-based versus standardized dosing is more effective in such patients.

HIV co-infection

HCV infection is present in approximately 30% of HIV-infected persons. We identified no head-to-head trial comparing dual therapy with pegylated interferon alfa-2a to dual therapy with pegylated interferon alfa-2b in HIV co-infected patients. We also found insufficient indirect evidence to determine if dual therapy with interferon alfa-2a differs from dual therapy with interferon alfa-2b for efficacy or safety. Three trials35, 44, 73 compared pegylated interferon alfa-2a versus dual therapy with non-pegylated interferon alfa-2a or alfa-2b, and four trials43, 45, 58, 68 compared pegylated interferon alfa-2b versus dual therapy with non-pegylated interferon alfa-2b in HIV co-infected patients. Pooled rates of sustained virologic response were 3.22 (95% CI, 2.36 to 4.39) and 1.63 (95% CI 1.07 to 2.48), respectively (see Figures 2 and 3). However, the latter analysis included the only trial to report lower rates of SVR on dual therapy with pegylated interferon compared to dual therapy with non-pegylated interferon.68 This was the only non-randomized trial and was rated poor-quality. Excluding this trial, the relative risk for SVR was 1.70 (95% CI 1.25 to 2.32). Rates of SBR were only reported in one trial of HIV co-infected patients.58 Risk of withdrawal due to adverse events were similar in three trials of dual therapy with pegylated interferon alfa-2a versus dual therapy with non-pegylated interferon alfa-2a (RR 0.86, 95% CI 0.59 to 1.25) and three trials of dual therapy with pegylated interferon alfa-2b versus dual therapy with non-pegylated interferon alfa-2b (RR 1.12, 95% CI 0.76 to 1.65). We did not perform indirect analysis because of overlapping confidence intervals and small numbers of trials.

Other co-morbid conditions

There is no evidence to evaluate comparative efficacy or safety of dual therapy with pegylated interferon alfa-2a versus dual therapy with pegylated interferon alfa-2b in patients with severe psychiatric illness or decompensated cirrhosis. Such patients were excluded from the trials and no observational studies were designed to evaluate these patient populations.

Some randomized trials and observational studies included patient populations not represented well in clinical trials, such as patients with thalassemia,53 patients on hemodialysis,131 patients with mixed cryoglobulinemia,83, 102 and patients on methadone maintenance.101 However, there was no evidence of clear difference in estimates of efficacy or safety from these studies compared to efficacy or safety of dual therapy with pegylated interferon in general.

Copyright © 2007, Oregon Health & Science University, Portland, Oregon.
Bookshelf ID: NBK10667

Views

Other titles in this collection

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...