Pegylated interferon α2b versus pegylated interferon α2a for chronic hepatitis C: The unreached goal of superiority☆
Article Outline
Peginterferon Alfa-2b or Alfa-2a with Ribavirin for Treatment of Hepatitis C Infection. McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, Lee WM, Ghalib RH, Schiff ER, Galati JS, Bacon BR, Davis MN, Mukhopadhyay P, Koury K, Noviello S, Pedicone LD, Brass CA, Albrecht JK, Sulkowski MS, for the IDEAL Study Team.
Background
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 1.5μg per kilogram of body weight per week or a low dose of 1.0μg per kilogram per week, plus ribavirin at a dose of 800 to 1400mg per day, or peginterferon alfa-2a at a dose of 180μg per week plus ribavirin at a dose of 1000 to 1200mg 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.)
[Abstract reproduced by permission of N Engl J Med 2009;361:580–593]
Abbreviations: SVR, sustained virologic response, Peg-IFN, pegylated interferon, RBV, ribavirin, HCV, hepatitis C virus
Sustained virologic response (SVR) rates have improved with the development of combined pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy for patients with chronic hepatitis C (HCV). Up to now, large clinical trials have indicated that in genotype 1 HCV-infected patients treated with either of the two commercially approved formulations of Peg-IFN, Peg-IFN α2b or α2a, plus RBV at variable dosing, SVR rates ranged between 42% and 46% [1], [2]. However, differences in study design, treatment regimens and patient populations precluded comparison of the data between these trials. Indeed, differences in pegylation chemistry and structure are associated with significant pharmacokinetic differences, although the drug exposure in vivo did not appear to correlate with early antiviral activity or clinical efficacy until week 12 [3]. Therefore, data deriving from a prospective head-to-head comparison of the two Peg-IFNs have been eagerly awaited to direct the clinician’s choice towards the better therapeutic option. The results of the IDEAL trial, supported by grants from Schering-Plough, attempted to provide answers in this ongoing debate.
This trial was designed as a very large, multicenter, randomized, comparative study conducted in 118 centers in the US and had as its focus the direct comparison for what concerns efficacy and safety of weight-based RBV dosing in combination with Peg-IFN α2b or Peg-IFN α2a [4]. In fact, the study consisted of two primary comparisons of the efficacy of standard-dose (1.5mcg/kg) Peg-IFN α2b versus the low-dose (1.0mcg/kg) of the same compound and the standard-dose Peg-IFN α2b versus Peg-IFNα2a at a fixed-dose of 180mcg, all in combination with RBV, in 3070 previously untreated patients with genotype 1. Two-thirds of these patients were infected by HCV type 1a, a relatively high rate considering the epidemiological distribution of viral strains in the US. However, as pointed out by the authors, since the dose of RBV administered to each patient and its reduction for the management of adverse events was dependent on the type of Peg-IFN α used, a direct comparison of the two interferons was compromised. Hence, the IDEAL trial provides results of a comparison of two specific regimens for HCV therapy, and not a comparison of the 2 interferon molecules.
The first major result of the study is a response to a post-approval requirement by the FDA, following the finding that the proportion of patients with HCV type 1 reaching an SVR to mono-therapy with 1.0 and 1.5mcg/kg Peg-IFN α2b was similar (14% versus 14%) [5], despite a higher virologic response at the end-of-treatment reached with the standard-dose that diminished following higher relapse rates. Because of the higher end-of-treatment response rates and assuming that the combination with RBV could prevent post-treatment relapse, ultimately the dosage of 1.5mcg/kg was selected as the standard-dose regimen. Surprisingly enough, the IDEAL trial demonstrates that the low-dose Peg-IFN α2b coupled with RBV was as effective as the standard-dose in HCV 1 patients, although a better safety profile was not demonstrated, thus, suggesting that this regimen could be considered as a new standard-of-care. However, since the two primary treatment comparisons for SVR did not yield results of any significance, any other comparison was precluded as outlined by the authors. Nevertheless an interaction between treatment groups after stratification for sex and race seems to favour standard-dose compared to low-dose, in females and blacks, leaving open the possibility to further individualize the treatment choice. By the same token, an additional suggestion for tailoring HCV therapy on the basis of patient characteristics, emerges from the comparison of standard-dose Peg-IFN α2b and Peg-IFN α2a arms. In fact, even if the overall safety profile and therapeutic efficacy are comparable (SVR rate 39.8% for standard-dose Peg-IFN α2b and 40.9% for Peg-IFN α2a), patients weighing between 65 and 75kg and between 75 and 85kg, which represent over 40% of the included population, seem to benefit more from Peg-IFN α2a with the SVR rates being 41.1% versus 36.7% and 45.6% versus 36.4%, respectively. Since the assigned RBV dosage in the 75–85kg group was higher for patients randomized to Peg-IFN α2a, the authors further speculate that RBV was crucial in determining an SVR in this subgroup of patients. Of note, in the patient subset weighing over 85kg, therapy with Peg-IFN α2b was more effective than Peg-IFN α2a, suggesting that a weight-based dosing might be required for the latter formulation of pegylated interferon as well, especially in the particularly difficult-to-cure patients. Whether these results could be interpreted as a further indication for individualizing therapy remains to be seen.
Overall, the reader might find it difficult to understand how the different schedules and the different reduction strategies of RBV impacted on the SVR rates. Indeed, in the results section the SVR rates were stratified on the basis of the assigned RBV dose, which might not reflect the cumulative intake of the drug over the entire therapeutic course. Furthermore, the dramatic one-step reduction of RBV to 600mg in Peg-IFN α2a-treated patients with anemia might have favoured post-treatment relapse, especially in patients whose dose was reduced during the first 12weeks of therapy. Since the relapse rates are also higher in patients who adhered to the planned RBV dose in the first 12 weeks of therapy but who were forced to reduce RBV exposure subsequently, adherence to optimal dosing of RBV over the entire duration of therapy, appears to be crucial [6]. On the other hand, since RBV primarily contributes to therapy success, a more detailed analysis of the relationship between RBV exposure and SVR rates could be of clinical relevance. Curiously, the relapse rates in patient subgroups with RBV dose reduction were lower than those reported in the entire corresponding arm, even if they were calculated on a different number of patients (see table 2: 268, 338 and 322 patients had an end-of-treatment response in the three arms, respectively, while the relapse rates were evaluated on 155, 216 and 227 patients, respectively). This leads to another important issue regarding the full comprehension of the overall outcome of the study, due to some discrepancies between the figure, the tables and the text and between the tables themselves, which might impact on the conclusions. The calculation of patients who relapsed after achieving an SVR is difficult to ascertain due to the many patients who were lost during follow-up at different rates in the three arms. This is not a trivial point, since a considerable number of patients (Table 2: 125, 112 and 172, respectively) had a delayed virologic response, i.e. HCV RNA detectable at week 12 and undetectable at week 24, which implies a high probability of a post-treatment relapse, which can be eventually reduced by an extended treatment duration [7]. Moreover, 61 patients (9, 23, 29, in the 3 arms) who reached a virologic response after 24weeks of therapy only, were maintained on therapy upon the investigators’ request despite this representing a violation of protocol, as can happen when pooling data from studies comprising low-treatment volume and high-treatment volume centers, like in the IDEAL study [8].
Finally, due to the aforementioned caveats, the results of the IDEAL trial should be taken cautiously as providing definitive answers in guiding the clinician’s choice, considering also that a number of previous or ongoing studies in the US and Europe, even if retrospective or smaller in size, indicated a higher anti-HCV effectiveness of Peg-IFN α2a in achieving an SVR. If these differences depend on uncontrolled confounders or selection bias typical for the large retrospective studies [9], [10] or on differences in patient characteristics such as mean age, body weight or genetic background in the two investigator initiated, prospective, single center studies in Italy [11], [12], needs further evaluation. As a matter of fact, while the IDEAL study and two prospective studies in Italy showed similar higher end-of-treatment response rates following Peg-IFN α2a compared to Peg-IFN α2b standard-dose in HCV 1 patients, the studies from Italy also reported less post-treatment relapse rates in the Peg-IFN α2a-treated patients than the IDEAL study, possibly as a consequence of different strategies of RBV dose reduction employed to treat anemia.
In conclusion, with these uncertainties, can we say that the match between the two therapeutic regimens for HCV ended in deuce or a tie-break?
References
- Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958–965
- Peginterferon alfa-2a plus ribavirn for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–982
- . Early virologic response after peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin treatment in patients with chronic hepatitis C. J Viral Hep. 2007;14:721729
- Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580–593
- A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology. 2001;34:395–403
- Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing peginterferon alfa-2a/ribavirin treatment. Clin Gastroenterol Hepatol. 2007;5:124–129
- . Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis C genotype 1-infected slow responders. Hepatology. 2007;46:1688–1694
- Predictors of treatment in patients with chronic hepatitis C infection: role of patients versus nonpatient factors. Hepatology. 2007;46:1741–1749
- Predictors of response of US veterans to treatment for hepatitis C virus. Hepatology. 2007;46:37–47
- Efficacy and safety of peginterferon alfa-2a or -2b plus ribavirin in the routine daily treatment of chronic hepatitis C patients in Germany: the PRACTICE Study. J Hepatol. 2008;48:S315
- Peginterferon alpha-2a plus ribavirin versus peginterferon alpha-2b plus ribavirin in naive patients with chronic hepatitis C virus infection: results of a prospective randomised trial. J Hepatol. 2008;48:S370
- Rumi MG, Aghemo A, Prati GM, D’Ambrosio R, Donato MF, Soffredini R, et al. Randomized study of PEG-interferon-α2a plus ribavirin versus PEG-interferon-α2b plus ribavirin in chronic hepatitis C. Gastroenterology, in press. doi:10.1053/j.gastro.2009.08.071.
☆ The author declared that she does not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript.
PII: S0168-8278(09)00635-7
doi:10.1016/j.jhep.2009.09.013
© 2009 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
