Globally, an estimated 170 million people are chronically infected with hepatitis C virus, and 3 to 4 million persons are infected each year.1 Analysts estimate the United States prescription market for hepatitis C to be approximately $3 billion annually. A combination of weekly subcutaneous injections of long-acting pegylated interferon (peginterferon) and oral ribavirin represents the current standard of care according to the American Association for the Study of Liver Diseases practice guideline.2 Currently, there are two licensed products: peginterferon alpha-2a (Pegasys, Hoffmann-La Roche) and peginterferon alfa-2b (PegIntron, Schering-Plough Corporation). Lately, there has been considerable controversy over which treatment options are the most effective. A recent randomized clinical trial (RCT) published in the New England Journal of Medicine concluded that the two treatments are comparable in both benefits and harms.3 However, findings from a single RCT, even a very large one, are rarely definitive, and caution should be taken to ensure reproducibility of its findings.4–9 Systematic reviews and meta-analysis including all available trials are considered the highest level of evidence, and provide valuable information on the quality and strength of the available evidence.10 We therefore conducted a Cochrane systematic review to identify, assess, and collectively analyze all RCTs that would add to the body of evidence and strengthen inferences about which form of peginterferon may work best.
A combination of weekly pegylated interferon (peginterferon) alpha and daily ribavirin represents the standard of care for the treatment of chronic hepatitis C according to current guidelines. It is not established which of the two licensed products (peginterferon alpha-2a or peginterferon alfa-2b) is most effective. We performed a systematic review of head-to-head randomized trials to assess the benefits and harms of the two treatments. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and LILACS through July 2009. Using standardized forms, two reviewers independently extracted data from each eligible trial report. We statistically combined data using a random effects meta-analysis according to the intention-to-treat principle. We identified 12 randomized clinical trials, including 5,008 patients, that compared peginterferon alpha-2a plus ribavirin versus peginterferon alfa-2b plus ribavirin. Overall, peginterferon alpha-2a significantly increased the number of patients who achieved a sustained virological response (SVR) versus peginterferon alfa-2b (47% versus 41%; risk ratio 1.11, 95% confidence interval 1.04–1.19; P = 0.004 [eight trials]). Subgroup analyses of risk of bias, viral genotype, and treatment history yielded similar results. The meta-analysis of adverse events leading to treatment discontinuation included 11 trials and revealed no significant differences between the two peginterferons. Conclusion: Current evidence suggests that peginterferon alpha-2a is associated with higher SVR than peginterferon alfa-2b. However, the paucity of evidence on adverse events curbs the decision to definitively recommend one peginterferon over the other, because any potential benefit must outweigh the risk of harm. (HEPATOLOGY 2010.)
Materials and Methods
The present systematic review is based on our peer-reviewed published Cochrane Hepato-Biliary Group protocol.11
This review includes RCTs, irrespective of language or publication status, comparing peginterferon alpha-2a with peginterferon alfa-2b given with or without cointerventions (such as ribavirin) in patients with chronic hepatitis C. We excluded RCTs if they included patients that had undergone liver transplantation.
The prespecified primary outcomes were sustained virological response (SVR), liver-related morbidity plus all-cause mortality, and adverse events leading to treatment discontinuation. SVR was defined as the number of patients with undetectable hepatitis C virus RNA in serum by sensitive test 6 months after the end of treatment.
Data Sources and Searches.
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and LILACS through July 2009. We identified further trials by searching conference abstracts, journals, and gray literature. We used the key words hepatitis C, peginterferon, pegylated interferon, viraferonpeg, pegintron, and pegasys either as MeSH terms or as free-text words.
Study Selection and Data Collection.
Two authors independently screened titles and abstracts for potential eligibility and the full texts for final eligibility. We extracted the data using a standardized data collection form to record study design and methodological characteristics, patient characteristics, interventions, outcomes, and missing outcome data. Authors of included trials were contacted for additional information not described in the published reports.
Methodological Quality Assessment.
Methodological quality and hence risk of bias was defined as the confidence that the design and the report of the RCT would restrict bias in the comparison of the intervention.12 The assessment was based on published reports and information provided by the authors of included trials. Following the implications of empirical evidence,12–14 the methodological quality of the trials was assessed based on sequence generation allocation concealment, blinding of outcome assessors, incomplete outcome data (lost to follow-up and adherence to intention-to-treat analysis), and early stopping for benefit.
Data Synthesis and Analysis.
The analyses were performed using Review Manager 5.0 and Trial Sequential Analysis version 0.8. Dichotomous data were expressed as the risk ratio (RR) with 95% confidence interval (CI). Furthermore, the number needed to treat was derived from the RR in meta-analyses where the 95% CI (or the RR) did not include zero. Heterogeneity was explored using a chi-square test, and the quantity of heterogeneity was measured using the I2 statistic.15 Sources of heterogeneity were assessed with subgroup analysis and meta-regression whenever possible. Subgroup analyses were performed only when data from at least two trials were available for each subgroup. Meta-regression was performed only for meta-analyses including more than 10 trials. Suitable sensitivity analysis was identified during the review process. When patients were lost to follow-up, data were analyzed according to the intention-to-treat principle. Intention-to-treat analysis was performed assuming poor outcome in both groups, where dropouts were considered failures and the total number of patients was used as the denominator. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach16 to present the summary of findings for the patient important outcomes.
Assessment of Reliability and Meta-analysis Sample Size Requirements.
To assess the reliability of pooled inferences from our meta-analysis on SVR, we calculated the optimum information size (OIS)—that is, the required meta-analysis sample size—to detect a 10% relative risk reduction in SVR, assuming an average event rate of 50% in the two treatment arms, assuming that 30% of the variation in the meta-analysis would be explained by variation across trials, and using statistical error levels of alpha = 5% and beta = 10% (90% power). Meta-analyses conducted before surpassing their OIS are analogous to interim analyses in single RCTs, and thus necessitate adjustment of the threshold for statistical significance to maintain the predetermined maximum risk of obtaining a false positive results (set to alpha 5% in our analysis). We therefore substituted the conventional 5% threshold for statistical significance with those of Lan-DeMets alpha-spending monitoring boundaries.8, 17–19
Figure 1 shows the results of the study screening. Twelve trials, including a total number of 5,008 participants,3, 20–30 that met our inclusion criteria31 were retrieved. All trials compared peginterferon alpha-2a (180 μg/week) versus peginterferon alfa-2b (1-1.5 μg/kg/week). All trials administered ribavirin as a cointervention to both peginterferon arms. The dose of ribavirin was weight-based, ranging from 800 to 1,400 mg. The hepatitis C genotype of the included patients varied among trials. One trial included patients with history of previous hepatitis C treatment.26 One trial included patients with human immunodeficiency virus patients.24 Table 1 presents the patient and intervention characteristics. Table 2 presents the methodological quality of eligible randomized trial.
|Study||Peginterferon||Ribavirin||Ribavirin Dose Modification||Baseline Treatment History||HCV Genotype||Outcome Reported|
|Ascione (2008)||alpha-2a, 180 μg/week alfa-2b, 1.5 μg/kg/week for 24–48 weeks*||1,000–1,200 mg/day†||200 mg‡||Treatment-naïve||1, 2, 3, 4||SVR, adverse events|
|Berak (2005)||alpha-2a, 180 μg/week alfa-2b, 1.0 μg/kg/week for 12 weeks||Weight-based||NR||NR||Non 2/3||Adverse events|
|Bruno (2004)||alpha-2a, 180 μg/week alfa-2b, 1.0 μg/kg/week for 12 weeks||1,000–1,200 mg/day†||NR||Treatment-naïve||1, 2, 3||Adverse events|
|DiBisceglie (2007)||alpha-2a, 180 μg/week alfa-2b, 1.5 μg/kg/week for 12 weeks||1,000–1,200 mg/day†||NR§||Treatment-naïve||1||Adverse events|
|Kolakowska (2008)||alpha-2a, 180 μg/week alfa-2b, 1.5 μg/kg/week for 24 weeks||Weight-based||NR||Treatment-naïve||3||SVR, adverse events|
|Laguno (2009)||alpha-2a, 180 μg/week alfa-2b, 1.5 μg/kg/week for 48 weeks||800–1,200 mg/day¶||NR||Treatment-naïve||1, 2, 3, 4||SVR, adverse events|
|McHutchison (2009)||alpha-2a, 180 μg/week alfa-2b, 1–1.5 μg/kg/week for 24–48 weeks*||800–1,400 mg/day$||200–600 mg**||Treatment-naïve||1||SVR, adverse events|
|Rumi (2008)||alpha-2a, 180 μg/week alfa-2b, 1.5 μg/kg/week for 24–48 weeks*||800–1,200 mg/day††||200 mg#||Treatment-naïve||1, 2, 3, 4||SVR, adverse events|
|Scotto (2008)||alpha-2a, 180 μg/week alfa-2b 1.5 μg/kg/week for 24–48 weeks*||15 mg/kg/day||4.6 mg/kg/day||Nonresponders||1, 2, 3, 4||SVR, adverse events|
|Silva (2006)||alpha-2a, 180 μg/week alfa-2b, 1.5 μg/kg/week for 8 weeks||13 mg/kg/day||None allowed||Treatment-naïve||1||Adverse events|
|Sinha (2004)||alpha-2a, 180 μg/week alfa-2b, 1.5 μg/kg/week for 24–48 weeks*||1,000–1,200 mg/day||NR||Treatment-naïve||1, 2, 3, 4||SVR, adverse events|
|Yenice (2006)||alpha-2a, 180 μg/week alfa-2b, 1.5 μg/kg/week for 24–48 weeks*||800–1,200 mg/day§§||200–600 mg¶¶||Treatment-naïve||1||SVR, adverse events|
|Trial||Concealment of Allocation||Outcome Assessors Blinded||Loss to Follow-up||Adherence to Intention-to-Treat Principle||Stopping Early for Benefits|
Effects of Interventions.
The meta-analysis using intention-to-treat analysis for SVR included eight trials (4,335 participants).3, 23–26, 28–30 Overall, peginterferon alpha-2a significantly increased the number of patients who achieved an SVR (47%) versus peginterferon alfa-2b (41%) (RR 1.11, 95% CI 1.04–1.19; P = 0.004). The number needed to treat was 25 patients (95% CI 14–100). Using RR as the measure of effect, the Cochran homogeneity test statistic yielded a P value of 0.58, and the heterogeneity was I2 = 0% (Fig. 2).
Most subgroup analyses revealed no significant interactions. Data from six trials3, 24–26, 29, 30 for genotype 1 and 4 yielded an RR in favor of peginterferon alpha-2a (RR 1.21, 95% CI 1.03–1.42). Using relative risk as the measure of effect, the Cochran homogeneity test statistic yielded a P value of 0.21, and the heterogeneity was I2 = 30%. Data from five trials23–26, 30 for genotype 2 and 3 yielded an RR in favor of peginterferon alpha-2a (RR 1.11, 95% CI 1.02–1.22). Using RR as the measure of effect, the Cochran homogeneity test statistic yielded a P value of 0.89, and the heterogeneity was I2 = 0%.
Sensitivity analyses revealed no change in the significance of effects, and there was no significant change of magnitude of treatment effects. A sensitivity analysis including only trials with adequate randomization and allocation concealment did not change the pooled estimate. Additionally, excluding the trial that included patients with human immunodeficiency virus and the trial with nonresponder patients did not change the pooled estimate.
To assess the reliability of pooled inferences from our meta-analysis on SVR, we calculated the OIS required to detect a 10% relative risk reduction in SVR to be 5,990 patients. Statistical significance assessed with Lan-DeMets alpha-spending monitoring boundaries are presented in Fig. 3. Based on the adjusted threshold for statistical significance the meta-analysis on SVR was still significant in favor to peginterferon alpha-2a.
Adverse events leading to treatment discontinuation were reported in 11 trials.3, 20–22, 24–30 Data from these trials yielded an RR of 0.79 (95% CI 0.51–1.23). Using RR as the measure of effect, the Cochran homogeneity test statistic yielded a P value of 0.42, and the heterogeneity was I2 = 2% (Fig. 4). Furthermore, the included trials reported on numerous adverse events that did not lead to treatment discontinuation. Adverse events included hematological changes (neutropenia, thrombocytopenia, and anemia), psychological changes (depression), and other systemic events (fatigue, headache, insomnia, fever, nausea, and dyspnea). None of the included trials reported on any patients with liver-related morbidity.
Only one trial reported on all-cause mortality.3 Seven patients died during the treatment period, and five died during or after the follow-up period. Two of these deaths were due to a suicide 6 months after the end of treatment with peginterferon alfa-2b and a myocardial infarction during treatment with peginterferon alfa-2a.
Table 3 presents the GRADE evidence profile regarding SVR and adverse events leading to treatment discontinuation.
|Outcomes||Illustrative Comparative Risks* (95% CI)||Relative Effect (95% CI)||No. of Participants (Studies)||Quality of the Evidence (GRADE)†||Comments|
|Assumed Risk: Peginterferon alfa-2b||Corresponding Risk: Peginterferon alpha-2a|
|SVR||Medium risk population||RR 1.1 (1.03–1.18)||4,335 (8)||⊕⊕⊕⊕|
|481 per 1,000||529 per 1,000 (495–568)||High‡|
|Adverse events leading to treatment discontinuation||Medium risk population||RR 0.8 (0.51–1.26)||4,621 (10)||⊕⊕⊖⊖|
|75 per 1,000||60 per 1,000 (38–94)||Low§¶#|
In this systematic review, we have summarized the available evidence from RCTs comparing peginterferon alpha-2a with peginterferon alfa-2b, both given in combination with weight-based ribavirin. Our results suggest that the combination of peginterferon alpha-2a and weight-based ribavirin may achieve significantly higher SVR than the combination of peginterferon alfa-2b and weight-based ribavirin. Only one trial reported mortality.3 None of the included trials reported on liver-related morbidity. Our results also suggest that the two peginterferons may be comparable with regard to adverse events leading to treatment discontinuation. However, evidence on liver-related morbidity or mortality and adverse events is sparse, and the meta-analysis on adverse events is likely to be underpowered to detect any difference.
The GRADE findings in Table 3 show that in general, we can have high confidence in the current evidence on treatment benefits (measured as SVR), whereas we can only have low confidence in the current evidence on harms (measured as adverse events leading to discontinuation). For both outcomes, there were no serious limitations in the study design of the included trials. Information on the methodological quality was incomplete in a few small-sized trials. However, our sensitivity analyses did not reveal any important change of intervention effects. In our study, the trials that adequately reported methodological quality items are large trials, and dominate the pooled estimates of effect. Therefore, it is unlikely that pooled estimates are biased. In the meta-analyses for SVR, there were no serious inconsistencies across trials and the meta-analyses had adequate precision adjudicated by crossing of the adjusted threshold for statistical significance (the Lan-DeMets monitoring boundaries). Only a comparison of the largest trial3 with the second and third largest trials25, 30 yielded moderate discrepancy. The latter two were both sufficiently statistically powered to detect a difference between the two peginterferons, and unlike the largest trial, which was funded by the manufacturer of peginterferon alfa-2b, these two trials were not funded by either of the two manufacturers. Because the meta-analysis for SVR only included eight trials, we did not perform a funnel plot to explore publication bias; however, because this meta-analysis included a seemingly reasonable mix of small and large trials yielding fairly consistent results, publication bias presented little concern. Nonetheless, we have some concerns with regard to indirectness. In the identified trials, virological response was the predominant measure of benefit. Many of the trials measured SVR, which is currently the commonly used surrogate outcome measure of benefit. Recent large cohort studies show correlation between the presence of viremia and mortality.31, 32 However, it is important to remember that SVR (and early virological response and end-of-treatment virological response) is still only a putative (that is, nonvalidated) surrogate outcome.33 Because RCTs need to inform clinical practice, clinical outcomes such as the risk of liver failure, hepatocellular carcinoma, and mortality would be of greater interest to patients and clinicians. Such measures nevertheless require a follow-up of at least 5 years. Currently, no RCTs comparing the two peginterferons are of such longevity. In the meta-analysis on adverse events, there were serious discrepancies across trials. The proportions of observed adverse events differed greatly across the trials, and the direction of effect was also heterogeneous. It is noteworthy that the IDEAL trial3 included three intervention arms: one for peginterferon alpha-2a and two for peginterferon alfa-2b. The two peginterferon alfa-2b arms consisted of a regular 1.5 μg/kg/week dosage and a low 1.0 μg/kg/week dosage. The regular dosage arm yielded a similar proportion of adverse events as the peginterferon alpha-2a arm, whereas the low-dose peginterferon alfa-2b group yielded a lower proportion of adverse events. Including or excluding the low-dose peginterferon alfa-2b arm from the meta-analysis had no visible impact on the estimated effect. Furthermore, the meta-analysis on adverse events had low precision. A post hoc OIS calculation that was geared to detect a minimally important difference of 10% relative risk reduction, based on the assumption of average population risk rate of 10%, and employed a 5% maximum type I error and 80% power, suggested that a minimum of 27,000 patients would need to be randomized for a conclusive adverse events meta-analysis. The current number of patients in the adverse events meta-analysis is approximately 5,000 (less than 20% of what is required).
There are some concerns regarding the nonstandardization of the ribavirin dose given across trials. The weight-based dose of ribavirin ranged from 800 to 1,400 mg. However, the weight cutoff varied among trials as well as within the same trial. In the largest included trial,3 patients weiging 40-65 kg received a lower dose of ribavirin (800 mg) in the peginterferon alfa-2b arm compared with a higher dose of ribavirin (1,000 mg) in the peginterferon alpha-2a arm. However, patients in the peginterferon alfa-2b arm achieved higher SVR compared with patients in the peginterferon alpha-2a arm (46% versus 43%). Also, patients weighing more than 105 kg received a higher dose of ribavirin in the peginterferon alfa-2b arm (1,400 mg) compared with a lower dose of ribavirin (1,200 mg) in the peginterferon alpha 2a arm. Regardless, patients in the peginterferon alfa-2b arm achieved higher SVR compared with patients in the peginterferon alpha-2a arm (42% versus 39%). It is also interesting that in the same trial, patients who developed anemia and thus required ribavirin dose reduction achieved a higher SVR than patients who did not require the ribavirin dose to be reduced. Accordingly, we do not think that the varying doses of ribavirin have major confounding influence on our observations regarding type of peginterferon. More research needs to be performed to explore the optimal ribavirin dose. Ribavirin dose reduction due to adverse events was only reported in five trials.3, 25, 26, 29, 30 Four of these trials applied the same dose reduction in both arms.25, 26, 29, 30 Only one trial applied different ribavirin dose reduction for two arms.3 Excluding this trial from our meta-analysis for SVR did not change our estimate.
The strengths of this Cochrane Hepato-Biliary Group systematic review are that it is built on a peer-reviewed published protocol, used extensive searches until recently, considers risks of systematic errors (bias), and considers risks of random errors (chance) by adjusting the threshold for statistical significance according to the information and strength of evidence in the cumulative meta-analysis. A possible limitation is the unavailability of full reports of all included trials. Two of the eight included trials in the meta-analysis for SVR are only available as abstracts. However, we were able to successfully retrieve the necessary data for one of the two abstracts via e-mail correspondence with the authors,28 and thus, the bias risk assessment of the included trial was performed to a satisfactory extent. Our sensitivity analysis did not show any important changes. In our study, the trials that were published as a full paper are large, and dominated the pooled estimates of effects. Moreover, empirical evidence suggests that trials that fail to refute the null hypothesis have lower odds of being published, especially those not funded by the industry.34–40 Thus, many of the included abstracts may have a low probability of being published. In fact, including these abstracts in our systematic review may likely be a strength rather than a limitation. By including abstracts, we are looking at the complete available body of evidence. By excluding abstracts, we would only be looking at a subset defined through the biased publication mechanisms of the present day, which would increase the likelihood of publication bias considerably. Selective outcome reporting was difficult to assess in this review. Most of the included trials were not adequately registered or had their protocols publicly available prior to trial completion. Hopefully, the initiation of the World Health Organization International Clinical Trials Registry Platform will facilitate such assessments for future trials.41, 42 Another limitation in this review was insufficient reporting. Investigators of future trials are therefore well advised to adhere to the Consolidated Standards for Reporting of Trials in order to improve the quality of trial reports.43
These potential limitations and concerns may lower our confidence in the estimates of intervention effect. However, in our meta-analysis for SVR there is no apparent heterogeneity (I2 = 0%), and the direction of the treatment effect is the same across all included trials. Further research is unlikely to change our confidence in the estimate of the effect. It is a common misconception that large RCTs are generally more reliable than meta-analyses. The reason this misconception has prevailed is due to a number of highly cited papers that compared high-quality large trials with collections of low-quality small trials (an unfair comparison). In empirical studies where high-quality large trials are compared with a collection of high-quality small trials, the results from the two are typically nondiscrepant. In the case of the IDEAL trial,3 the results still show an effect—albeit small—in favor of peginterferon alpha-2a. There are many examples of large trials that underestimate the treatment effect simply by chance.
Current evidence suggests that peginterferon alpha-2a is significantly superior to peginterferon alfa-2b regarding benefits (SVR, which is clearance of the virus from the blood). However, there is insufficient evidence to detect any differences regarding harms (mortality and adverse events). Future trials must further the correlation between achieving SVR and clinically relevant outcomes such as risk of cirrhosis, hepatocellular carcinoma, and mortality.
We thank the patients and investigators who participated in the included trials, with special thanks to the investigators who responded to our inquiries. We also thank our colleagues Dimitrinka Nikolova and Sarah Louise Klingenberg.