Peginterferon Alfa-2b or Alfa-2a with Ribavirin for Treatment of Hepatitis C

Peginterferon Alfa-2b or Alfa-2a with Ribavirin for Treatment of Hepatitis C Infection -

NEJM July 22 2009


John G. McHutchison, M.D., Eric J. Lawitz, M.D., Mitchell L. Shiffman, M.D., Andrew J. Muir, M.D., Greg W. Galler, M.D., Jonathan McCone, M.D., Lisa M. Nyberg, M.D., William M. Lee, M.D., Reem H. Ghalib, M.D., Eugene R. Schiff, M.D., Joseph S. Galati, M.D., Bruce R. Bacon, M.D., Mitchell N. Davis, M.D., Pabak Mukhopadhyay, Ph.D., Kenneth Koury, Ph.D., Stephanie Noviello, M.D., Lisa D. Pedicone, Ph.D., Clifford A. Brass, M.D., Janice K. Albrecht, Ph.D., Mark S. Sulkowski, M.D., for the IDEAL Study Team



ABSTRACT



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 1.5 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.



Hepatitis C virus (HCV) chronically infects approximately 180 million people worldwide1 and is a frequent cause of liver disease, including liver failure and hepatocellular carcinoma.2 HCV treatment is recommended for persons at the greatest risk for progression of liver disease.3 On the basis of noncomparative studies demonstrating similar safety and efficacy between the two treatments,4,5 consensus guidelines recommend the use of either peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for the treatment of chronic hepatitis C. However, differences between the peginterferons with respect to structural modifications and dosing (weight-adjusted vs. fixed) may lead to important differences in clinical outcomes, and there is some evidence of such differences.6,7,8,9 Randomized, comparative effectiveness trials are necessary to provide patients with evidence-based treatment options.



The Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study was initiated to compare standard-dose and low-dose regimens of peginterferon alfa-2b, plus ribavirin, after it was observed that both dose levels yielded similar rates of sustained virologic response in the absence of ribavirin.10 A third treatment group, peginterferon alfa-2a plus ribavirin, was added to the study because (in addition to standard-dose peginterferon alfa-2b plus ribavirin) it is the other approved regimen. The objective was to compare the safety and efficacy of the two standard regimens and the experimental low-dose peginterferon alfa-2b regimen.



Methods



Study Patients



We enrolled patients from 118 centers in the United States. Eligible patients were 18 years of age or older, had compensated liver disease due to chronic HCV genotype 1 infection and a detectable plasma HCV RNA level, and had not been previously treated for hepatitis C infection. The patients had an absolute neutrophil count of 1500 or more per cubic millimeter, a platelet count of 80,000 or more per cubic millimeter, and hemoglobin level of 12 g (for women) or 13 g (for men) or more per deciliter. Patients were excluded if they had coinfection with human immunodeficiency virus or hepatitis B, any other cause of liver disease, poorly controlled diabetes mellitus (glycated hemoglobin value >8.5%), morbid obesity (weight >125 kg), severe depression or a severe psychiatric disorder, or active substance abuse. All patients had undergone liver biopsy within 3 years before screening. A pathologist at the central site, who was unaware of the treatment assignments, reviewed all the biopsy specimens and determined the METAVIR fibrosis stage and inflammatory grade, as well as the percentage of the tissue containing hepatocytes with steatosis.11



Study Oversight



The study sponsor and the academic principal investigators were jointly responsible for the study design, protocol, statistical analysis plan, and data analysis. The principal investigators had unrestricted access to the data, wrote the manuscript, and vouch for the accuracy and integrity of the data and analyses. A publication committee comprising the academic principal investigators and three independent experts prepared the prespecified data-analysis plan and ensured the unbiased interpretation of the data.



Study Design



Patients were randomly assigned, in a 1:1:1 ratio and with the use of an interactive voice system, to one of the three treatment groups and were stratified according to HCV RNA level (600,000 IU per cubic millimeter or >600,000 IU per cubic millimeter) and self-reported race (black or nonblack). The three treatment groups were as follows: peginterferon alfa-2b at the standard dose, 1.5 µg per kilogram of body weight per week, or at a lower dose, 1.0 µg per kilogram per week, both in combination with oral ribavirin at a dose according to body weight (40 to 65 kg, 800 mg per day; >65 to 85 kg, 1000 mg per day; >85 to 105 kg, 1200 mg per day; and >105 to 125 kg, 1400 mg per day); or peginterferon alfa-2a at a dose of 180 µg per week, plus oral ribavirin at a dose of 1000 to 1200 mg per day, according to body weight (<75 kg, 1000 mg per day; 75 kg, 1200 mg per day).



The study was double-blinded with regard to the dose of peginterferon alfa-2b. For patients receiving peginterferon alfa-2a, the dose of ribavirin was determined on the basis of prescribing information from the Food and Drug Administration (FDA). Because weight-based ribavirin dosing was not approved by the FDA for use with peginterferon alfa-2b when the study was initiated, the dose of ribavirin administered in the two groups receiving peginterferon alfa-2b was calculated to deliver a mean (±SD) of 13±2 mg per kilogram per day, on the basis of data derived from previous trials and from the product information from the European Medicines Agency.4,7,12 Patients underwent treatment for up to 48 weeks and follow-up for 24 weeks. The study was approved by each center's institutional review board and was conducted in accordance with provisions of the Declaration of Helsinki and Good Clinical Practice guidelines.



Efficacy Assessments



HCV RNA levels were measured with the use of the Cobas TaqMan assay (Roche), which has a lower limit of quantitation of 27 IU per cubic millimeter. Measurements were obtained at screening visits 1 and 2 (baseline); weeks 2, 4, 12, 24, and 48 during the treatment period; and follow-up weeks 4, 12, and 24. Per established guidelines, patients with an insufficient virologic response at 12 weeks (a detectable HCV RNA level and a decrease of <2 log10 IU from the baseline level) or at 24 weeks (a detectable HCV RNA level) were considered to have treatment failure, and therapy was discontinued.



Safety Assessments



Adverse events were graded by the investigators as mild, moderate, severe, or life-threatening, according to a modified World Health Organization grading system. Non–life-threatening adverse events were managed by reduction of the dose of peginterferon alfa or ribavirin (or both). The peginterferon-dose reduction was a two-step process: the dose was reduced if the neutrophil count was below 750 per cubic millimeter, and treatment with both drugs was permanently discontinued if the neutrophil count was below 500 per cubic millimeter. For patients receiving peginterferon alfa-2b, the ribavirin-dose reduction occurred in two steps, as established by Jacobson et al.7 The first step was a reduction of either 200 mg (in patients receiving 800 to 1200 mg of ribavirin per day) or 400 mg (in patients receiving 1400 mg per day); the second step was reduction by another 200 mg, if required for resolution of the adverse event. For patients receiving peginterferon alfa-2a, ribavirin-dose reduction consisted of a reduction to 600 mg per day, on the basis of FDA-approved prescribing information. For all patients, ribavirin-dose reduction was required if the hemoglobin level was less than 10 g per deciliter; treatment with both drugs was permanently discontinued if the level was below 8.5 g per deciliter. In patients with a hemoglobin level less than 10 g per deciliter, use of erythrocyte-stimulating agents was permitted after ribavirin-dose reduction. Drug doses could be increased once the cytopenia resolved (i.e., the neutrophil count was 750 per cubic millimeter or the hemoglobin level was 10 g per deciliter).



End Points



Analyses included data from all patients who underwent randomization and who received at least one dose of study medication. The primary end point was a sustained virologic response, defined as undetectable HCV RNA levels 24 weeks after the completion of therapy. If the 24-week post-treatment HCV RNA measurement was missing, the 12-week post-treatment level was used. (This was done for 38, 21, and 25 patients receiving standard-dose and low-dose peginterferon alfa-2b and peginterferon alfa-2a, respectively, all of whom had had undetectable HCV RNA at 12 weeks after treatment.)



The study involved two primary comparisons: standard-dose versus low-dose peginterferon alfa-2b regimens and standard-dose peginterferon alfa-2b versus peginterferon alfa-2a. Secondary end points included the rates of virologic response during the treatment phase and relapse, defined as an undetectable HCV RNA level at the end of the treatment phase, with a detectable HCV RNA level during the follow-up period.



Statistical Analysis



For both primary comparisons, the trial was designed as a superiority study to detect clinically meaningful differences in the rates of sustained virologic response among the three regimens. The study had a statistical power of 80% to detect a significant absolute difference in rates of sustained virologic response of 6.5% between the standard-dose and low-dose peginterferon alfa-2b regimens and of 7% between the standard-dose peginterferon alfa-2b regimen and the peginterferon alfa-2a regimen. A one-sided test was used to compare the two peginterferon alfa-2b regimens, with an assumption that the standard-dose regimen would be at least as effective as the low-dose regimen. A two-sided test was used to compare standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Because there were two primary treatment comparisons, the Holm–Bonferroni method was used to maintain the overall type 1 error rate at 0.05. According to this method, the lowest P value must be below 0.025 to be considered to indicate statistical significance. If this criterion is met, then the higher P value must be below 0.05 to be considered to indicate statistical significance. If the lowest P value is greater than 0.025, no other tests are performed.



P values for the two primary treatment comparisons were calculated on the basis of a logistic-regression model controlling for the stratification factors (race and baseline HCV RNA level). Since neither of the two comparisons was significant, all P values are considered to be nominal and are labeled as such. Similarly, nominal two-sided 95% confidence intervals are reported, calculated for the two primary comparisons according to a Mantel–Haenszel approach controlling for the stratification factors. Summary statistics are reported for each of the three treatment regimens for subgroups of patients defined by prespecified baseline characteristics and one characteristic defined post hoc (baseline fasting glucose level). Multivariable logistic-regression analyses involving treatment regimen, prespecified baseline characteristics, and three post hoc factors (baseline fasting glucose level, hemoglobin value, and platelet count) were performed to study sustained virologic response and relapse. A stepwise procedure was used to identify independent predictors of sustained virologic response and relapse (with P=0.05 as the threshold level for variables to be entered into and retained in the final model). This type of approach was prespecified in the analysis plan for sustained virologic response but not for relapse. As was prespecified, we also explored the relationship between the magnitude and rapidity of virologic response during the treatment phase and the probability of achieving a sustained virologic response.



Results



Characteristics of the Study Patients



Between March 2004 and June 2006, a total of 4469 patients were screened, and 3070 underwent randomization and treatment (Figure 1). Baseline demographic characteristics were balanced among the three treatment groups (Table 1). The majority of patients were men in their 40s; 18.6% of the patients were black; and the mean body weight was 83.4 kg. After stratification on the basis of body weight, 1061 of 2035 patients (52.1%) receiving peginterferon alfa-2b were assigned to receive the same dose of ribavirin as the corresponding patients receiving peginterferon alfa-2a, whereas 773 of the 2035 patients (38.0%) were assigned a lower dose of ribavirin, and 201 of the 2035 (9.9%) were assigned a higher dose. During the treatment period, the mean and median daily ribavirin doses received were significantly higher among patients receiving peginterferon alfa-2a than those in either peginterferon alfa-2b group, regardless of ribavirin-dose reduction, use of erythrocyte-stimulating agents, or efficacy outcome (sustained virologic response, relapse, or nonresponse). The proportion of patients who received, on average, more than 13 mg of ribavirin per kilogram per day was greater in the peginterferon alfa-2a group (56.0%) than in either peginterferon alfa-2b group (29.1% in the standard-dose group and 32.6% in the low-dose group) (P<0.001 for each comparison).




Efficacy



The rates of sustained virologic response did not differ significantly among the three treatment groups, with a rate of 39.8% (95% confidence interval [CI], 36.8 to 42.8) for standard-dose peginterferon alfa-2b, 38.0% (95% CI, 35.0 to 41.0) for low-dose peginterferon alfa-2b, and 40.9% (95% CI, 37.9 to 43.9%) for 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) (Table 2). Estimated differences in response rates were 1.8% (95% 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. Therefore, the two primary trial end points of superiority were not met. Response rates at the end of the treatment phase were higher with peginterferon alfa-2a than with either peginterferon alfa-2b regimen, but the virologic relapse rate was also higher. In all three groups, HCV RNA suppression at treatment weeks 4 and 12 was strongly associated with achievement of sustained virologic response (Table 3). Fewer than 5% of patients who had a reduction from the baseline HCV RNA level of less than 1 log10 IU per cubic millimeter at week 4 also had a sustained virologic response. A prolonged time (>12 weeks of therapy) to undetectable HCV RNA level was associated with a higher likelihood of relapse after treatment (Table 3). Stepwise multivariable logistic-regression analyses identified several baseline factors as independent predictors of sustained virologic response: baseline HCV RNA level (<600,000 IU per cubic millimeter), race (nonblack), minimal fibrosis (METAVIR score of F0, F1, or F2), absence of steatosis, normal baseline fasting glucose level, and elevated baseline serum alanine aminotransferase level. Using the same method, we found that these factors were independently associated with relapse, as were age over 40 years and peginterferon alfa-2a treatment (Table 1 of the Supplementary Appendix, available with the full text of this article at NEJM.org).



Ribavirin Dosing



Rates of sustained virologic response were similar among the three treatment groups, within the subgroups of patients receiving the same dose of ribavirin (those weighing >65 to <75 kg and those weighing >85 to 105 kg) (Table 2). The ribavirin dose was reduced, owing to an adverse event, in 30.2% of patients. The rate of sustained virologic response among these patients was 52.2% in the peginterferon alfa-2a, 51.8% in the standard-dose peginterferon-2b group, and 49.3% in the low-dose peginterferon alfa-2b group. In comparison, the rate of sustained virologic response was higher among patients who had a hemoglobin level that was less than 10 g per deciliter during the treatment phase but who required a ribavirin-dose reduction, as compared with those with levels of 10 g per deciliter or above: 48.8% (422 of 865 patients) versus 36.7% (793 of 2158 patients) (P<0.001).



Safety



The types and frequencies of adverse events were similar among the three groups (Table 4). The most common adverse events included influenza-like symptoms, depression, and the hematologic events of anemia and neutropenia. The proportions of patients with neutropenia who met the criterion for peginterferon-dose reduction (a neutrophil count of <750 and >500 per cubic millimeter were 21.1% receiving peginterferon alfa-2a, 19.4% receiving standard-dose peginterferon alfa-2b, and 12.5% receiving low-dose peginterferon alfa-2b. However, only 2.1 to 5.9% of patients met the discontinuation criterion based on neutropenia. The proportion of patients meeting the hemoglobin criterion for ribavirin-dose reduction (a hemoglobin level <10 and >8.5 g per deciliter) was somewhat higher with standard-dose peginterferon alfa-2b (28.2%) and peginterferon alfa-2a (25.8%) than with low-dose peginterferon alfa-2b (23.2%); only 2.1 to 3.8% of patients met the discontinuation criterion (hemoglobin level <8.5 g per deciliter).



Most psychiatric adverse events were mild or moderate and were not treatment-limiting; however, 1.8 to 2.6% of patients did discontinue treatment. Twelve patients (0.4%) died during the study: seven during the treatment period and five during or after the follow-up period. Two of these deaths were considered by the investigator to be possibly related to study medications: a suicide at 6 months after the end of treatment with standard-dose peginterferon alfa-2b and a myocardial infarction during treatment with peginterferon alfa-2a.



Discussion



Treatment with peginterferon alfa-2a or peginterferon alfa-2b, plus ribavirin, for 48 weeks is recommended for patients infected with HCV genotype 1, the most common variant in the United States and Europe.13 Despite this recommendation, few data comparing these treatment regimens are available. Accordingly, several findings of our large, randomized comparative study affect the care of these patients.



The safety and adverse-event profiles and the efficacy data were similar among patients treated with low-dose or standard-dose peginterferon alfa-2b or peginterferon alfa-2a, in combination with differing ribavirin regimens. The finding that low-dose peginterferon alfa-2b resulted in a similar rate of sustained virologic response as the other regimens was unexpected. Since monotherapy with standard-dose peginterferon alfa-2b has been associated with higher rates of virologic response during the treatment period,10 we aimed to test the hypothesis that use of standard-dose peginterferon alfa-2b with ribavirin would result in a higher rate of sustained virologic response than with the low-dose regimen. Although our data do not support this hypothesis, a significant interaction between treatment group and sex (P=0.01) (Table 2 in the Supplementary Appendix) suggests that women may have higher rates of sustained virologic response with standard-dose than with low-dose peginterferon alfa-2b. Although the interaction with race was not significant, blacks tended to have higher rates of sustained virologic response with the standard dose of peginterferon alfa-2b. Host, virologic, and treatment factors associated with eradication of HCV genotype 1 infection were identified. Consistent with previous observations,14,15,16,17,18,19,20 a sustained virologic response was less frequent among blacks, persons with advanced hepatic fibrosis and steatosis, and those with high baseline HCV RNA levels. Although it was not a prespecified covariate, impaired fasting glucose was also associated with a lower likelihood of sustained virologic response. These data suggest a need for additional research to test the hypothesis that dietary and pharmacologic interventions to correct glucose intolerance can improve treatment response. The magnitude of HCV RNA suppression during the treatment phase was also closely linked to the likelihood of having a sustained virologic response. Among the 10% of patients with undetectable HCV RNA levels at treatment week 4, 86% had a sustained virologic response. The 24% of patients with a minimal decline in HCV RNA level (decline of <1 log10 IU from the baseline value) at treatment week 4 had a probability of sustained virologic response of less than 5%. Thus, virologic response at treatment week 4 is an important predictor of sustained virologic response; HCV RNA levels should be routinely assessed at this time point.



The time to the first undetectable HCV RNA level was associated with the probability of virologic relapse after the end of treatment. Approximately 50% of patients who had HCV suppression for the first time by treatment week 24 also had virologic relapse, as compared with less than 10% of patients who had HCV suppression at treatment week 4. After week 4, patients receiving peginterferon alfa-2a had a higher rate of HCV RNA suppression than did those who were receiving peginterferon alfa-2b; however, this difference was not sustained after the end of the treatment period. Thus, although the rates of sustained virologic response were similar among the three groups, patients treated with peginterferon alfa-2a were more likely to have a response while receiving therapy, followed by relapse after the completion of therapy, whereas patients treated with peginterferon alfa-2b were more likely to discontinue therapy at treatment week 12 or 24 because of an insufficient virologic response.



Increased ribavirin exposure during the treatment phase was associated with an increased likelihood of sustained virologic response among all treated patients. Ribavirin exposure was lower in patients who received peginterferon alfa-2b, which was administered according to four dosing categories (based on body weight), as compared with those who received peginterferon alfa-2a, which was administered according to two. Patients weighing between 75 and 85 kg received 1000 mg of ribavirin per day if they were also receiving peginterferon alfa-2b, as compared with 1200 mg per day if they were also receiving peginterferon alfa-2a. In this large weight group (792 patients), the rate of sustained virologic response was higher by approximately 10 percentage points in the peginterferon alfa-2a group, suggesting that the ribavirin dose for persons who weigh between 75 and 85 kg should be 1200 mg per day in the peginterferon alfa-2b groups. Surprisingly, reducing the ribavirin dose because of treatment-related anemia (as was done in 30% of patients) did not appear to reduce the likelihood of sustained virologic response. Despite the reduction of ribavirin dose by as much as 50% in patients receiving peginterferon alfa-2a, patients with anemia had a higher rate of sustained virologic response than did those without anemia, suggesting that the magnitude of anemia may be a pharmacodynamic marker of drug exposure. The data indicate that the initial ribavirin dose should be at least 13 mg per kilogram per day and that the conservative management of anemia, involving a ribavirin-dose reduction in either one or two steps, appears to maintain safety and not to compromise efficacy.



The findings are subject to several limitations. Because the initial ribavirin dose varied among the patients, the study compares HCV treatment regimens and is not a direct comparison of the type of peginterferon. Nonetheless, more than 51% of patients received the same dose of ribavirin in combination with either peginterferon alfa-2a or peginterferon alfa-2b, and their rates of sustained virologic response were similar. Second, the procedure for ribavirin-dose reduction differed between the peginterferon alfa-2a group and the peginterferon alfa-2b groups. Yet, the rate of sustained virologic response was higher among patients who had the ribavirin dose reduced because of anemia than among those who did not. Third, since the study was conducted in the United States, these comparative data may not be generalizable to other regions or HCV genotypes. Fourth, owing to insurmountable differences in drug formulation (lyophilized powder in the case of peginterferon alfa-2b or solution in the case of peginterferon alfa-2a), patients and investigators were aware of the type of peginterferon being given. After careful inspection, however, no irregularity in data collection or reporting was detected.



In conclusion, the rates of sustained virologic response and the safety and adverse-event profiles were similar among patients infected with HCV genotype 1 who received standard-dose or low-dose peginterferon alfa-2b or peginterferon alfa-2a, in combination with ribavirin.



Supported by grants from Schering-Plough.