McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, et al.; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580–593. (Reprinted with permission.)
Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared. Methods: At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 μg per kilogram of body weight per week or a low dose of 1.0 μg per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 μg per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa- 2b regimen and the peginterferon alfa-2a regimen. Results: Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P = 0.20 for standard dose vs. low-dose peginterferon alfa-2b; P = 0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], −2.3 to 6.0) between standard-dose and low-dose peginterferon alfa-2b and −1.1% (95% CI, −5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for low dose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa-2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively. Conclusions: In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferon-ribavirin regimens or between the two doses of peginterferon alfa-2b. (ClinicalTrials. gov number, NCT00081770.)
The current standard of care of therapy for treatment-naïve patients with chronic hepatitis C virus (HCV) infection is a combination of pegylated interferon with ribavirin.1 To date, there are two licensed pegylated interferons in the United States: peginterferon alfa-2b (Peg-Intron; Schering Plough Corp., Kenilworth, NJ), with a 12-kDa linear polyethylene glycol (PEG) covalently linked to the standard interferon alfa-2b molecule, and peginterferon alfa-2a (Pegasys; Hoffmann-La Roche, Nutley, NJ) with a 40-kDa branched PEG covalently linked to the standard interferon alfa-2a molecule. The doses and pharmacology of these two forms of pegylated interferon differ considerably: peginterferon alfa-2b is given in a weight-adapted manner whereas peginterferon alfa-2a can be used as a flat dose.1, 2 In the respective large registration trials, similar sustained virological response (SVR) rates (i.e., 42%-46%) for patients with genotype 1 infection were obtained,2, 3 although until now peginterferon alfa-2b and alfa-2a combination therapy regimes have never been compared head to head in a large, prospective, randomized study.
In the August 6 issue of the New England Journal of Medicine, the final results of the long-awaited4, 5 and controversial6 IDEAL trial were published. The IDEAL study (Individual Dosing Efficacy versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy), which is a phase 3d, randomized, parallel group, U.S.-based, multicenter trial in treatment of naïve genotype 1 patients with chronic hepatitis C monoinfection, was originally only intended as post-approval commitment to the U.S. Food and Drug Administration (FDA) to assess the safety and efficacy of weight-based ribavirin dosing with two different doses of peginterferon alfa-2b.5 Previous smaller studies had shown similar SVR rates for 1.5 and 1.0 μg/kg/week doses of peginterferon alfa-2b when used with 800 mg ribavirin,7 but subsequent trials only used 1.5 μg/kg/week. In an attempt to also compare head to head the different peginterferons approved by the FDA, a third study arm was added that looked at the standard treatment with peginterferon alfa-2a at a dose of 180 μg/week, plus ribavirin at a dose of 1000–1200 mg/day (Table 1). However, we have to keep in mind the intention of this study was to compare two different peginterferon/ribavirin therapy regimes and not the two different peginterferons alfa-2b and alfa-2a.
|1.0 μg/kg Peg-IFN Alfa-2b + Ribavirin (800–1400 mg) (N = 1016)||1.5 μg/kg Peg-IFN Alfa-2b + Ribavirin (800–1400 mg) (N = 1019)||180 μg Peg-IFN Alfa-2a + Ribavirin (1000–1200 mg) (N = 1035)||P Value|
|Low vs. Standard Alfa-2b||Standard Alfa-2b vs. Standard Alfa-2a|
|SVR number (%)||386 (38.0)||406 (39.8)||423 (40.9)||0.20||0.57|
|ETR number (%)||500 (49.2)||542 (53.2)||667 (64.4)||0.04||<0.001|
|Relapse rate number/total number (%)||95/475 (20.0)||123/523 (23.5)||193/612 (31.5)||Not provided||Not provided|
|Patients with ribavirin dose reduction:|
|SVR number/total number (%)||132/268 (49.3)||175/338 (51.8)||168/322 (52.2)|
|ETR number/total number (%)||160/268 (59.7)||224/338 (66.3)||238/322 (73.9)|
|Relapse rate number/total number (%)||23/155 (14.8)||43/216 (19.9)||63/227 (27.8)|
The primary endpoint of the IDEAL study was to compare overall SVR rates in patients with genotype 1 infection. Overall, similar rates of SVR (standard-dose alfa-2b [39.8%] versus low-dose alfa-2b [38.0%] versus alfa-2a [40.9%]) were found for the three regimens with similar rates of side effects (around 10%). Surprisingly, the lower dose interferon alfa-2b arm performed similarly as the higher dosing arm of peginterferon (Table 1).
However, there are several controversial points regarding the design of the IDEAL trial. First, because of the different formulation of peginterferon alfa-2b and alfa-2a, doctors were only blinded for the two different doses of peginterferon alfa-2b but not for the type of interferon used. Secondly, and more importantly, the starting doses of ribavirin (800, 1000, 1200, and 1400 mg for interferon alfa-2b versus 1000 and 1200 mg for interferon alfa-2a) and dose reductions protocols for side effects were different for the study arms. In view of the increasing evidence of ribavirin dose being an important factor for therapeutic success in chronic hepatitis C infection, this difference might be critical.
In defense of the study design, it needs to be stressed that the full impact of weight-based ribavirin dosing and high initial ribavirin doses has only been fully recognized in the last couple of years8, 9 and could therefore not be taken into consideration when designing this trial. In this study, only 51% of patients across the three treatment arms were exposed to the same initial ribavirin dose, and these had comparable outcomes in all three arms. The ribavirin-dose reduction was performed in two steps for patients receiving peginterferon alfa-2b, as established by the WIN-R (Weight-Based Dosing of Pegintron and Rebetol) trial9: At first, a reduction of either 200 mg (in patients receiving 800–1200 mg of ribavirin per day) or 400 mg (in patients receiving 1400 mg/day) was scheduled; next, a reduction by another 200 mg was scheduled, if required for resolution of the adverse event.8, 9 For patients receiving peginterferon alfa-2a, ribavirin dose reduction was less conservative and consisted of a reduction to 600 mg/day, on the basis of FDA-approved prescribing information, possibly leading to subtherapeutic drug levels in a large subset of patients. Altogether, the ribavirin dose was reduced in around 30% of patients. Interestingly, the patients with dose reduction showed higher SVR rates in all three treatment arms (standard-dose alfa-2b [51.8%] versus low-dose alfa-2b [49.3%] versus alfa-2a [52.2%]) (Table 1). Some experts have suggested that ribavirin concentrations should be monitored and adjusted to achieve optimum serum concentrations.10 As discussed by the authors, these results suggest that ribavirin-induced anemia might be a good clinical biomarker of effective exposure levels to ribavirin.11
Although the SVR rates—the primary endpoints of the trial—were not significantly different in the three treatment arms, the IDEAL study did find a minor difference of two of its secondary endpoints: patients who were treated with the interferon alfa-2a regimen showed a significantly higher end-of-treatment response rate (ETR) (alfa-2a [64.4%] versus standard-dose alfa-2b [53.2%] versus low-dose alfa-2b [49.2%]), but also a higher relapse-rate (alfa-2a [31.5%] versus standard-dose alfa-2b [23.5%] versus low-dose alfa-2b [20.0%]) than patients of either of the interferon alfa-2b arms (Table 1). The reasons for this discrepancy are unclear. The clinical significance of this result might lie in the fact that predictability of an SVR in patients with a rapid virological response (RVR) (undetectable virus at week 4) was lower in patients of the peginterferon alfa-2a study arm (alfa-2a [79.7%] versus standard-dose alfa-2b [92.2%] versus low-dose alfa-2b [87.3%]). However, it needs to be stressed that because ETR as well as relapse rate were only secondary endpoints, these results can be used to generate further hypotheses at most.12 Our only criticism of this otherwise well-designed and well-written study concerns this point: Mentioning only some of these observations (relapse rate) in the abstract of the article while omitting others (primary response rates) is misleading and cannot be considered best practice medical trial reporting.12
Indeed, patients on peginterferon alfa-2a showed consistently higher virologic suppression rates at weeks 12, 24, and 48 of treatment in this trial, but because this was not the primary endpoint, both findings (response during treatment and relapse after treatment) should be viewed with caution. It remains to be seen whether tailoring of the duration of therapy or the (initial?) ribavirin (peginterferon) dose will reduce relapse rates of patients on peginterferon alfa-2a drastically. The final results of ongoing studies like two smaller randomized studies that look at different peginterferon alfa-2a and ribavirin doses (ClinicalTrials.gov number NCT00077649 and NCT00394277) will help us to make our final verdict.
However, future therapy of hepatitis C will soon consist of novel “specifically targeted antiviral therapy for HCV” (STAT-C) peginterferon combination therapy regimens with additional drugs (proteinase and/or polymerase inhibitors), and thus optimizing current regimens for genotype 1 patients will soon be less important.13–16 The intriguing question for the future will be if these higher rates of viral suppression observed with peginterferon alfa-2a will make a difference for STAT-C–based regimens, and if lower doses of peginterferon will still be equally effective when used in these regimens in which primary viral suppression might be even more critical.
Finally, the results of the IDEAL study are only directly applicable to North America and patients infected with genotype 1 and should not be extended to other genotypes or ethnic backgrounds.17 For example, a recent Japanese dose comparison study for peginterferon alfa-2b combination therapy for 24 weeks showed significant differences between the standard 1.5 μg/kg dose or a low dose of 1.0 μg/kg (SVR = 74.1% versus 38.5%; P < 0.013), although the ribavirin dosing was rather low in this study.18
Despite the almost inevitable limitations of the study, we should acknowledge the authors and the sponsors for their great effort to conduct this enormous study. Anyone treating patients for their chronic hepatitis should be familiar with the results and limitations12 of this landmark study. The IDEAL trial with its large patient cohort provided us with much-needed data, but is also a fantastic basis for further studies of the pathophysiology and therapy of HCV infection. The IDEAL cohort has already led to intriguing and innovative scientific findings that will open up new potential therapeutic avenues.19 Most importantly, we now have reassurance that both interferon preparations appear to have comparable efficacies used in standard combination regimens, so whatever peginterferon combination regimen we used in recent years, we were right!
What then are the practical implications of the results of this study for the clinical hepatologist? Should the standard dose of peginterferon alfa-2b be lowered? The results clearly suggest such an approach, which could substantially decrease the costs of therapy. The authors of the study are cautious with this interpretation: although the SVR rates as well as the rates of discontinuation and serious side effects were overall similar for standard-dose peginterferon alfa-2b and low-dose peginterferon alfa-2b, subgroup analysis showed lower SVR rates in women (P < 0.01) and a trend toward lower SVR rates in African Americans in the low-dose group. However, once again, the trial was not primarily designed to test these subgroups, and we should be careful not to draw definite conclusions from these analyses. On the basis of the evidence presented, lower doses of interferon may be justified in the majority of patients. At the same time, higher doses of ribavirin might be at least as important as the choice of peginterferon preparation and dose.
Although the debate about the two forms of peginterferon might subside a little for now, we can expect a new controversy: Are regimes based on peginterferon alfa-2a or alfa-2b comparable when used in combination with the new STAT-C drugs? One can only hope that this time around, head-to-head trials will be initiated at the beginning rather than the end of an era.