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Re-treatment of Patients With Chronic Hepatitis C Who Do Not Respond to Peginterferon-{alpha}2b
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A Randomized Trial
Donald M. Jensen, MD; Patrick Marcellin, MD; Bradley Freilich, MD; Pietro Andreone, MD; Adrian Di Bisceglie, MD; Carlos E. Brandao-Mello, MD, PhD; K.. Rajender Reddy, MD; Antonio Craxi, MD; Antonio Olveira Martin, MD; Gerlinde Teuber, MD; Diethelm Messinger, MS; James A. Thommes, MD; and Andreas Tietz, MD
Annals of Internal Medicine, 21 April 2009 | Volume 150 Issue 8 | Pages 528-540
Editors' Notes
Context
* Some patients with chronic hepatitis C virus infection do not respond to initial treatment with pegylated interferon plus ribavirin..
Contribution
* This randomized trial compared peginterferon-{alpha}2a plus ribavirin for either 48 or 72 weeks in adults with hepatitis C who had not responded to peginterferon-{alpha}2b plus ribavirin. Re-treating the nonresponders for 72 weeks increased sustained virologic response rates more than did re-treatment for 48 weeks (16% vs. 8%).
Implication
* Re-treating nonresponders for a longer duration improved response rates, although the rates remained disappointingly low in these patients.
ÑThe Editors
ABSTRACT
Background: Many patients with chronic hepatitis C have not responded to therapy with pegylated interferon plus ribavirin.
Objective: To evaluate use of peginterferon-{alpha}2a plus ribavirin to re-treat nonresponders to peginterferon-{alpha}2b plus ribavirin.
Design: Randomized, parallel-group trial conducted between September 2003 and February 2007. Patients and researchers were not blinded to intervention assignment. Random assignment was centralized, computer-generated, and stratified by geographic region, hepatitis C virus (HCV) genotype, and histologic diagnosis.
Setting: 106 international centers.
Patients: 950 nonresponders to 12 or more weeks of therapy with peginterferon-{alpha}2b plus ribavirin.
Intervention: Peginterferon-{alpha}2a, 360 µg/wk, for 12 weeks, then 180 µg/wk to complete 72 weeks (group A) or 48 weeks (group B), or peginterferon-{alpha}2a, 180 µg/wk for 72 weeks (group C) or 48 weeks (group D). All patients received ribavirin, 1000 or 1200 mg/d.
Measurements: Sustained virologic response (SVR), defined as undetectable (<50 IU/mL) HCV RNA levels 24 weeks after the end of treatment.
Results: The SVR rates in groups A (n = 317), B (n = 156), C (n = 156), and D (n = 313) were 16%, 7%, 14%, and 9%, respectively (relative risk [RR] for group A vs. group D [the primary comparison], 1.80 [95% CI, 1.17 to 2.77]; P = 0.006). Extended treatment duration increased SVR rates (16% for 72 weeks [groups A and C] vs. 8% for 48 weeks [groups B and D]; RR, 2.00 [CI, 1.32 to 3.02]; P < 0.001). Complete viral suppression (HCV RNA level <50 IU/mL)at week 12 was achieved in 21% of patients in groups A and B and 13% of those in groups C and D. Rates of SVR were 49% (77 of 157 patients) and 4% (32 of 719 patients) among those with and without complete viral suppression at week 12, respectively.
Limitation: Nonresponders to peginterferon-{alpha}2a plus ribavirin were not evaluated.
Conclusion: Re-treating nonresponders to therapy with peginterferon-{alpha}2b plus ribavirin for 72 weeks significantly increases SVR rates compared with re-treating them for 48 weeks. The overall SVR rate was low, but patients who are most likely to respond to re-treatment can be identified at week 12.
Primary Funding Source: Roche
The standard of care for patients with chronic hepatitis C is treatment with pegylated interferon plus ribavirin (1, 2). Despite the increasing efficacy of therapy, approximately 50% of patients with hepatitis C virus (HCV) genotype 1 infection and 20% to 30% of patients with HCV genotype 2 or 3 infection do not achieve a sustained virologic response (SVR) after a first course of therapy (3), which adds to the large and growing pool of patients who have not responded to treatment with the standard of care and are therefore difficult to treat. These persons are at risk for cirrhosis, liver failure, and hepatocellular carcinoma (4).
Sustained virologic response to interferon-based treatment is associated with eradication of HCV infection and histologic improvement in liver disease (5). Data suggest that re-treatment of patients with pegylated interferon plus ribavirin can eradicate HCV infection in patients who have not responded to a first course of conventional interferon-based therapy (6, 7), but few data exist on the efficacy of re-treatment in patients who have not responded to pegylated interferon plus ribavirin (8).
Intensification of therapy by increasing the dose of interferon or ribavirin or extending the duration of treatment has been shown to enhance efficacy, not only in treatment-naive persons (9, 10) but also in nonresponders to conventional interferon plus ribavirin (11, 12). Current guidelines (13) advise against re-treatment with pegylated interferon and ribavirin.
We recruited patients who had not responded to previous treatment with peginterferon-{alpha}2b plus ribavirin to evaluate the efficacy of a 12-week, fixed-dose induction regimen of peginterferon-{alpha}2a plus standard-dose ribavirin and extended treatment with standard doses of both drugs.
Results
Patients were predominantly white (89%) and were infected with HCV genotype 1 (91%), and they had received a mean of 225 days of previous treatment with peginterferon-{alpha}2b (mean initial dosage, 1.5 µg/kg per week) plus ribavirin (mean initial dosage, 1020 mg/d) (Table 1). Approximately one quarter (27%) of the patients had bridging fibrosis or cirrhosis.
All patients received their assigned treatment regimen, with no crossover. More patients assigned to groups A (135 of 317 [43%]) and C (65 of 156 [42%]) than groups B (42 of 156 [26.9%]) and D (84 of 313 [26.8%]) withdrew from treatment prematurely (Figure 2). The Appendix Figure shows the timing of withdrawal during treatment and follow-up. Most patients in the 4 treatment groups (92% to 96%) received concomitant medication during treatment and follow-up. The most commonly used medication was acetaminophen, which was taken by 43% to 54% of patients in the 4 treatment groups. Selective serotonin inhibitors were taken by 19% to 26% of patients, erythropoietin-stimulating agents by 5% to 10%, and granulocyte colony-stimulating factor by 4% to 7%. A medical procedure was performed on 21% to 26% of patients during the study, the most common of which was electrocardiography.
Efficacy
Table 2 shows the rate of SVR in the 4 groups, and Table 3 shows the relative risks and risk differences for the treatment effects. A small proportion of patients were HCV RNAÐnegative at their last HCV RNA measurement, but final 24-week posttreatment follow-up HCV RNA results are missing (Table 2). These patients were counted as nonresponders in the efficacy analysis.
The rate of SVR in patients assigned to fixed-dose induction and 72 weeks of treatment was 1.8 times higher than that in patients assigned to the standard 48-week regimen (16% [52 of 317] in group A vs. 9% [27 of 313] in group D; RR, 1.80 [95% CI, 1.17 to 2.77]; P = 0.006, CochranÐMantelÐHaenszel test; P = 0.21, BreslowÐDay test for treatment-by-stratum interaction). The pooled analyses show that the likelihood of achieving SVR was 2 times higher with 72 weeks of treatment than with 48 weeks of treatment (16% for groups A and C combined vs. 8% for groups B and D combined; RR, 2.00 [CI, 1.32 to 3.02]; P < 0.001, CochranÐMantelÐHaenszel test; P = 0.22, BreslowÐDay test).
In the analysis of SVR between patients assigned to the fixed-dose induction regimens and those assigned to the standard-dose regimens, the BreslowÐDay test indicated a heterogeneous treatment effect across the various strata (P = 0.025), and logistic regression analysis identified an interaction between geographic region and induction dose (P = 0.029). Table 3 shows RRs and risk differences by geographic region. The results suggested discrepant effects of induction dosing on SVR for the 2 geographic regions: Rates of SVR were equivocal for fixed-dose induction compared with the standard-dose regimen in Europe and Brazil (RR, 1.49 [CI, 0.87 to 2.54]; P = 0.133) but were lower in patients randomly assigned to the fixed-dose induction regimen than the standard-dose regimen in the United States and Canada (RR, 0.58 [CI, 0.33 to 1.01]; P = 0.053).
Rates of SVR were generally higher in patients assigned to 72 weeks of treatment than in those assigned to 48 weeks of treatment when grouped by genotype 1, histologic diagnosis, age, body weight, and baseline HCV RNA level (Figure 3).
The exploratory multivariable logistic regression analyses identified the following factors as significant predictors of a higher SVR rate: genotype other than 1 (P = 0.009), no cirrhosis (P = 0.002), low viral load (P < 0.001), lower body weight (P < 0.001), and younger age (P = 0.022). The analysis also confirmed that treatment for 72 weeks increased the probability of SVR compared with 48 weeks of treatment. The treatment effect was very similar (OR, 2.41 [CI, 1.50 to 3.87]; P < 0.001, adjusted for the stratification factors genotype; histologic diagnosis; geographic region; and the predictive factors HCV RNA level, weight, and age) to that observed in the primary analysis using the MantelÐHaenszel estimates (OR, 2.22 [CI, 1.40 to 3.52]). We found no interaction between treatment duration and induction dose. Analysis of interaction between treatment factors (duration and induction) and the possible confounding factors confirmed the interaction effect between region and induction dose (P = 0.029) and the lack of interaction between region and treatment duration. Logistic regression analysis by region, with adjustment for genotype, cirrhosis state, induction dose, HCV RNA level, body weight, and age, confirmed the significant effect of longer treatment duration (OR, 2.04 [P = 0.030] for Europe and Brazil and 2.88 [P = 0.004] for the United States and Canada) but identified no significant effect for induction dose (OR, 1.54 [P = 0.19] for Europe and Brazil and 0.57 [P = 0.107] for the United States and Canada).
The frequency of early virologic response (undetectable HCV RNA or ³2-log10 decrease in HCV RNA) at week 12 of treatment was 61% in groups A plus B combined and 44% in groups C plus D combined (Figure 4, A). Although complete viral suppression (HCV RNA <50 IU/mL) at week 12 was less frequent (21% in groups A and B combined and 13% in groups C and D combined) (Figure 4, B), this variable was a stronger on-treatment predictor of SVR than early virologic response (Figure 4, C and D). Among patients with complete viral suppression at week 12, the overall rate of SVR was 49% across all treatment groups (77 of 157 patients). In contrast, the rate of SVR was 4% (32 of 719 patients) among those with detectable HCV RNA at week 12.
Among patients with complete viral suppression at week 12, the rate of SVR was 57% (57 of 100 patients) in the pooled 72-week treatment group and 35% (20 of 57 patients) in the pooled 48-week treatment group. In contrast, the rate of SVR among patients with detectable HCV RNA at week 12 was 4% in both pooled 72- and 48-week treatment groups (15 of 339 patients and 17 of 380 patients, respectively).
Adverse Events
The adverse event profile of study participants (Table 4) was similar to that reported in patients treated with peginterferon-{alpha}2a plus ribavirin. Premature withdrawal because of an adverse event or intercurrent illness occurred in 37 (12%), 6 (4%), 18 (12%), and 20 (6%) patients in groups A, B, C, and D, respectively. One death attributed to a ruptured cerebral aneurysm occurred during treatment and was considered to be unrelated to study treatment (Table 4). Four other deaths, attributed to metastatic esophageal adenocarcinoma, malignant hepatic neoplasm, esophageal variceal hemorrhage, and a thermal burn, were considered to be unrelated to treatment and occurred more than 12 weeks after the end of treatment (range, 23 to 35 weeks). The rate of premature withdrawal was significantly higher among patients assigned to 72 weeks of treatment (groups A plus C) than among those assigned to 48 weeks of treatment (groups B plus D), after stratification for induction dose (P = 0.002). In contrast, rates of withdrawal did not significantly differ between patients assigned to induction regimens (groups A plus B) and those assigned to noninduction regimens (groups C plus D), after stratification for treatment duration (P = 0.65). The overall rate of serious adverse events was somewhat higher in patients assigned to 72 weeks than 48 weeks of treatment (Table 4). Among patients assigned to 72 weeks of treatment, a higher proportion in group C (18% [28 of 156]) than group A (10% [33 of 317]) experienced 1 or more serious adverse events. The reason for this difference is not readily apparent, given that patients in group A received both induction therapy and extended treatment. Thus, it may be attributable to chance rather than to the induction regimen or duration of therapy.
The proportion of patients with neutrophil counts less than 1 x 109 cells/L, platelet counts less than 50 x 109 cells/L, and hemoglobin concentrations less than 85 g/L was generally similar across the 4 treatment groups, as was the rate of dose reductions of either peginterferon-{alpha}2a or ribavirin in response to adverse events or laboratory abnormalities (Table 4).
Discussion
Our large, randomized, international study shows that some patients who do not achieve an SVR despite at least 12 weeks of combination therapy with peginterferon-{alpha}2b plus ribavirin can be successfully re-treated with peginterferon-{alpha}2a plus ribavirin. In addition, re-treatment with a 72-week regimen produces a statistically significant increase in SVR rates compared with the standard 48-week regimen. In contrast, fixed-dose induction therapy with 360 µg/wk of peginterferon-{alpha}2a for the first 12 weeks did not significantly improve outcomes compared with the standard-dose regimen.
We have no explanation for the interaction detected between induction dose and geographic region. The induction dose protocol used in Europe and Brazil was identical to that used in the United States and Canada, and we could identify no differences in the baseline characteristics of patients or on-treatment factors that might account for the differences between the 2 regions. This finding could be due to chance because of repeated significance testing, and it should be interpreted with caution.
Some aspects of our study design and patient population limit broad application of the results to all non-responders. First, we limited eligibility to patients whose previous course of treatment with peginterferon-{alpha}2b plus ribavirin did not fail because of significant hematologic adverse events; in addition, few black patients and patients infected with genotypes other than 1 were enrolled. Consequently, the results cannot be used to provide specific recommendations for the management of these groups beyond those based on the overall analysis. Most important, we did not test whether nonresponders to peginterferon-{alpha}2a plus ribavirin can be successfully re-treated with peginterferon-{alpha}2b plus ribavirin, and our results do not suggest in any way that this might not be the case.
Although our trial was designed in 2002, the definition of nonresponse that we used is similar to a subsequent consensus definition developed by an expert advisory panel convened in 2006 by the U.S. Food and Drug Administration (15). The strict definition of nonresponse that we used as an inclusion criterion resulted in a well-defined patient population and ensured that we enrolled only the patients who were most difficult to treat.. This is an important strength of the study, because the response to re-treatment varies considerably depending on the nature of the response to previous treatment (nonresponse vs. relapse) and the type of previous treatment (such as conventional vs. pegylated interferon or monotherapy vs. combination therapy with ribavirin) (6, 16, 17). For example, when re-treated with peginterferon-{alpha}2b plus ribavirin, nonresponders to a previous course of pegylated interferon plus ribavirin had much lower rates of SVR than those who had relapse (4% and 36%, respectively) (17, 18).
One of our most practical findings is that complete viral suppression at week 12 can be used as an on-treatment milestone to limit continued treatment exposure to patients who are most likely to achieve SVR. Undetectable HCV RNA (<50 IU/mL) at week 12 of re-treatment was a strong predictor of SVR; 57% of patients with complete viral suppression at week 12 achieved SVR after 72 weeks of treatment, compared with 35% of patients after 48 weeks of treatment. In contrast, patients with detectable HCV RNA at week 12 were unlikely to achieve SVR (<5%), regardless of treatment duration. For this reason, the stopping rule used for treatment-naive patientsÑlack of early virologic response at week 12 (19)Ñmust be revised to emphasize the importance of achieving complete viral suppression during the first 12 weeks of re-treatment.
Overall, treatment with peginterferon-{alpha}2a and ribavirin was generally well tolerated. Individual adverse event rates were similar to or lower than those previously reported in treatment-naive patients (20); this is probably due to selection bias, because we excluded patients who had previously discontinued treatment because of hematologic adverse events. However, the 72-week treatment duration was associated with a greater treatment burden, as indicated by the lower number of patients who completed treatment because of a higher incidence of adverse events and the higher percentage of patients who were prematurely withdrawn from treatment with peginterferon-{alpha}2a because of adverse events or laboratory abnormalities. We observed a similar tendency in the percentage of patients who were prematurely withdrawn from ribavirin treatment for adverse events or laboratory abnormalities in the 72-week treatment groups (13%) and in the 48-week treatment groups (6% and 7%).
Although more patients randomly assigned to the 72-week regimens experienced adverse events, a recently reported retrospective analysis of the adverse event profile associated with treatment duration in our study (21) showed that 72 weeks of treatment was associated with a more favorable benefitÐrisk ratio than 48 weeks of treatment. Both the total cumulative exposure to treatment and the number of adverse events associated with the attainment of each SVR were considerably lower in patients assigned to 72 weeks of treatment (6.7 patient-years of exposure and 55 adverse events per SVR) compared with 48 weeks of treatment (10.0 patient-years of exposure and 100 adverse events per SVR). In a clinic that implements a 12-week stopping rule, this estimate of cumulative treatment exposure associated with a successful outcome continues to favor 72 weeks of treatment: 3.6 patient-years, compared with 7.1 patient-years with a 48-week treatment duration (21).
We found few data from randomized trials in which nonresponders were re-treated with peginterferon plus ribavirin. A MEDLINE search that we conducted on 28 October 2008, using the keywords chronic hepatitis C and re-treatment with the limitations humans and randomized controlled trial, produced 49 citations, of which 6 were for randomized trials that had patients re-treated with peginterferon plus ribavirin (16, 22Ð26). We identified 1 additional trial and included it in the literature review (27). Appendix Table 2 provides an overview of these 7 trials. All trials recruited patients who had not responded to or had relapse after receiving treatment with a less effective, conventional interferon-based regimen (none recruited nonresponders to peginterferon-based regimens). Most trials recruited heterogeneous populations that comprised patients who did not respond to or had relapse after receiving conventional interferon with or without ribavirin. As a result, the SVR rates vary greatly across these trials, from 6% in a well-defined group of nonresponders to previous interferon plus ribavirin therapy (16) to 44% in those who had relapse after monotherapy or combination therapy (25). Several small trials evaluated induction dosing and concluded that this strategy provided no significant benefit over a standard-dose regimen of peginterferon plus ribavirin (25Ð27).
We are aware of 1 large noncomparative clinical trial program that included nonresponders to peginterferon alone or in combination with ribavirin and re-treated them with peginterferon-{alpha}2b plus ribavirin for 48 weeks (17). Only limited data are available from this as-yet unpublished trial; however, the final SVR rate in patients with genotype 1 or 4 who did not respond to previous peginterferon plus ribavirin therapy was 4% (18)..
Future trials should follow our example and recruit patients by using a stringent definition of nonresponse and should measure serum HCV RNA levels at both weeks 4 and 12 of treatment. This might allow physicians to identify patients who are most likely to respond at an earlier time. Given that we and others could not demonstrate a benefit of induction therapy in the re-treatment of nonresponders, this strategy should probably be abandoned.
A topic of emerging interest is how novel direct-acting antiviral agents will improve outcomes and influence treatment strategies, given the expectation that new molecules will dramatically shorten the duration of treatment and improve the tolerability of antiviral regimens for chronic hepatitis C. Such expectations are based on preliminary data from phase II trials that show significantly increased SVR rates compared with peginterferon plus ribavirin. However promising these trials are, few data are available on the efficacy of triple therapy in nonresponders to peginterferon plus ribavirin, although it is becoming clear that the triple combination of telaprevir, peginterferon-{alpha}2a, and ribavirin may be less well tolerated than a control regimen of peginterferon plus ribavirin (28, 29). Of note, the most advanced of the new direct-acting antiviral agents in development (telaprevir and boceprevir) have been studied only in patients with noncirrhotic genotype 1 hepatitis C and added against a backbone of therapy with standard-dose peginterferon plus ribavirin.
Although it may be tempting to delay re-treatment of patients until these new molecules are commercially available, many patients who felt a sense of urgency to start a previous course of therapy may find it difficult to wait another 2 or 3 years before beginning a re-treatment course with 1 of these novel agents. Our findings provide important information for caregivers and patients faced with difficult decisions about re-treatment after an unsuccessful first course of therapy.
In conclusion, for patients who have not responded to an appropriate dose and duration of peginterferon-{alpha}2b plus ribavirin, re-treatment for 72 weeks with standard doses of peginterferon-{alpha}2a and ribavirin provides the greatest opportunity for SVR. New drugs in development may further improve re-treatment options, but until that time, an extended 72-week treatment regimen provides the best therapeutic option in these difficult-to-treat patients.
Methods
Design
Figure 1 shows an overview of the study design. Investigators conducted the study at 106 centers in North America, Europe, and Brazil. Patients were recruited between September 2003 and April 2005, and the last patient completed follow-up in February 2007. We randomly assigned 950 participants to treatment, and 942 received at least 1 dose of a study drug.
Eligible patients received treatment with subcutaneous peginterferon-{alpha}2a (Pegasys, Roche, Basel, Switzerland) plus a standard dose of oral ribavirin (1000 mg/d for patients weighing <75 kg and 1200 mg/d for those weighing ³75 kg) (Copegus, Roche). The institutional review boards of each participating center approved the protocol, and all patients provided written informed consent. We conducted this study according to the guidelines of the Declaration of Helsinki and under the provisions of good clinical practice.
Setting and Participants
We conducted this study in specialist outpatient hepatology clinics. We used no specific methods to recruit patients to the study. Investigators recruited patients from existing patient rolls or through routine referrals from colleagues.
Eligible patients were adults age 18 years or older with serologic evidence of chronic hepatitis C; quantifiable serum HCV RNA levels (>600 IU/mL), as measured by using the Cobas Amplicor HCV Monitor Test, version 2.0 (Roche Diagnostics, Basel, Switzerland); and histologic findings on a liver biopsy specimen consistent with the diagnosis of chronic hepatitis C. Patients with hepatic cirrhosis were eligible if they had compensated liver disease (14).
We had well-defined criteria for previous nonresponse: eligible patients who had received at least 12 weeks of combination therapy with peginterferon-{alpha}2b (³1.0 µg/kg per week) plus ribavirin (³800 mg/d) and had detectable serum HCV RNA at every postbaseline assessment, at least 1 of which was performed after week 12. Treatment must have been discontinued at least 12 weeks before enrollment.
Patients were ineligible if they had discontinued treatment with peginterferon-{alpha}2b plus ribavirin because of hematologic adverse events or had received drugs for HCV infection or immunomodulatory agents within 6 months of enrollment. Patients who were co-infected with hepatitis A or B virus or HIV were also excluded, as were those with a history of chronic liver disease not attributed to chronic hepatitis C, a neutrophil count less than 1.5 x 109 cells/L, platelet count less than 90 x 109 cells/L, or a hemoglobin concentration less than 120 g/L in women or less than 130 g/L in men.
Random Assignment and Interventions
We randomly assigned patients to 1 of 4 open-label treatment groups at baseline in a 2:1:1:2 ratio (Figure 2). We selected this ratio to optimize the power of the primary comparison and thus maximize the number of patients assigned to groups included in the primary comparison of treatment outcomes.
The 4 treatment groups were as follows: peginterferon-{alpha}2a (360 µg/wk) plus ribavirin for 12 weeks, then peginterferon-{alpha}2a (180 µg/wk) plus ribavirin to complete 72 weeks of treatment (group A); peginterferon-{alpha}2a (360 µg/wk) plus ribavirin for 12 weeks, then peginterferon-{alpha}2a (180 µg/wk) plus ribavirin to complete 48 weeks of treatment (group B); peginterferon-{alpha}2a (180 µg/wk) plus ribavirin for 72 weeks (group C); or peginterferon-{alpha}2a (180 µg/wk,) plus ribavirin for 48 weeks (group D). Patients were randomly assigned in permuted blocks of 12, stratified by geographic region, HCV genotype (genotype 1 vs. nonÐgenotype 1), and histologic diagnosis (cirrhosis or transition to cirrhosis vs. no cirrhosis or transition to cirrhosis). The computerized randomization list was generated by the sponsor and incorporated into a central interactive voice-response system managed by S-Clinica (Brussels, Belgium). At the baseline visit, the investigator called the interactive voice-response system to obtain information about a patient's assignment to a treatment group, which was confirmed by fax to the study site within 1 hour. We used stratified random assignment to balance the distribution of regions, genotypes, and histologic diagnoses among the treatment groups.
We permitted but did not encourage the use of erythropoietin-stimulating agents and granulocyte colony-stimulating factor. In the event of an adverse reaction or laboratory abnormality, we decreased the dose of peginterferon-{alpha}2a in steps from 360 µg/wk to 180, 135, and 90 µg/wk for patients in groups A and B and from 180 µg/wk to 135, 90, and 45 µg/wk for patients in groups C and D. We decreased the dose of ribavirin to 600 mg/d in patients whose hemoglobin level decreased to less than 100 g/L but remained at least 85 g/L or, in patients with clinically significant cardiovascular disease, in the event of a 20-g/L or greater decrease in hemoglobin during any 4-week interval. Ribavirin therapy was to be discontinued if the hemoglobin concentration decreased to less than 85 g/L, or if it remained less than 120 g/L despite 4 weeks of treatment at a reduced dose in patients with clinically significant cardiovascular disease. On resolution of the precipitating event, the investigator could adjust the dosage of either study drug upward at his or her discretion.
Outcomes and Follow-up
We determined serum HCV RNA level by quantitative (Cobas Amplicor HCV Monitor Test, version 2.0) and qualitative (Cobas Amplicor HCV Test, version 2.0; limit of detection, 50 IU/mL) assays at baseline and at weeks 12, 24, and 48 during treatment in all patients; at week 72 of treatment in patients randomly assigned to 72 weeks of treatment (groups A and C); and after 12 and 24 weeks of untreated follow-up. Discontinuation of treatment was allowed in patients with detectable HCV RNA at or after week 24.
Virologic end points were early virologic response at week 12, defined as nondetectable HCV RNA (<50 IU/mL, qualitative assay) in serum or a 2-log10 decrease or greater in serum HCV RNA by quantitative assay, and SVR, defined as nondetectable HCV RNA (<50 IU/mL) in serum at the end of the 24-week untreated follow-up period (week 96 for patients in groups A and C and week 72 for patients in groups B and D). The primary efficacy end point in the trial was SVR at the end of follow-up. The primary comparison was between patients treated with fixed-dose induction plus extended-duration combination therapy (group A) and those treated with the standard regimen (group D).
Study monitors verified and cross-checked study case report forms against investigators' records. In addition, study sites, a central laboratory, and a contract research organization were audited as part of the clinical quality assurance program.
Assessment of Adverse Events
At each scheduled visit (Figure 1), we assessed adverse events by physical examination, laboratory tests, and adverse event reports. Investigators elicited information from patients regarding adverse events that occurred since the last visit by asking open-ended questions. Information collected for each adverse event included a description of the event, date of onset, duration, intensity, relationship to study drugs, required treatment, dosage adjustments to study treatment, and outcome.
Statistical Analysis
We estimated that a total of 592 patients would be required to detect a 10% difference in the rate of SVR between group A (estimated to be 22%) and group D (estimated to be 12%) with a 2-sided significance level of 5% and 90% power. On the basis of these assumptions, we planned a total enrollment of 888 patients. We included all patients who received 1 dose of study medication in the efficacy analysis (Figure 2).
We considered patients without follow-up data to have not achieved an SVR, in accordance with other large clinical trials in the field. Spontaneous viral clearance during untreated follow-up in patients who have detectable HCV RNA at the end of treatment is rare. For this reason, we did not require an HCV RNA test at the end of the 24-week untreated follow-up period in patients who had detectable HCV RNA at end of treatment. We also counted patients as nonresponders if they were HCV RNAÐnegative at their last HCV RNA measurement but their final 24-week posttreatment follow-up HCV RNA results were missing. This is a conservative but reasonable assumption, because many of these patients would probably have had relapse during follow-up.
Predefined secondary end points were a comparison of the rate of SVR in fixed-dose induction regimens (groups A and B combined) with that in the standard-dose regimens (groups C and D combined), a comparison of the rate of SVR in the 72-week regimens (groups A and C combined) with that in the standard 48-week regimens (groups B and D combined), and a comparison of the rate of SVR in patients with and without undetectable HCV RNA at week 12 and with and without a ³2-log10 decreasse in HCV RNA at week 12.
Rates of SVR were compared by using the CochranÐMantelÐHaenszel test stratified by HCV genotype, geographic region, and histologic diagnosis in the primary analysis. For the pooled analyses comparing differences in SVR rates by treatment duration or induction dosing, an additional stratification factor was included: treatment duration in the comparison of induction versus noninduction dosing (groups A plus B vs. groups C plus D), and induction dose in the comparison of treatment durations (groups A plus C vs. groups B plus D). We calculated the MantelÐHaenszel relative risk (RR), risk difference, odds ratio (OR), and corresponding 95% CIs for each primary and secondary end point. Homogeneity of the treatment effect across the various strata was assessed by using the BreslowÐDay test.
We constructed several multivariable logistic regression models to explore the interaction between the stratification factors (genotype, geographic region, and histologic diagnosis) and the 2 treatment variables (induction dose and treatment duration), the interaction between the 2 treatment factors, and the effect of various baseline factors on SVR. In addition to the 3 stratification factors, the following baseline covariates were considered: sex, age, body weight, race, HCV RNA level, and alanine aminotransferase ratio.
Statistical analyses were performed by using SAS, version 8.2 (SAS Institute, Cary, North Carolina).
Role of the Funding Source
The study was funded by Roche (Basel, Switzerland) and designed by the sponsor in consultation with an advisory board of expert hepatologists. The sponsor and research organizations working under contract for the sponsor collected the data and conducted the statistical analysis. The lead investigators had unlimited access to the data and were responsible for interpreting the results and writing the first draft of the paper. All other named authors interpreted the results, reviewed and commented on the manuscript, and approved the final version before submission. Dr. Jensen made all final decisions about all aspects of publication. No limitations on publication were imposed by the sponsor.
Author and Article Information
From the Center for Liver Diseases, University of Chicago Hospitals, Chicago, Illinois; Centre de Recherche Biologique Bichat-Beaujon CRB3, H™pital Beaujon, Clichy, France; Liver and Pancreas Institute of Kansas City, Kansas City, Missouri; University of Bologna, Bologna, Italy; Saint Louis University Liver Center, Saint Louis University School of Medicine, Saint Louis, Missouri; University of Rio de Janeiro, Rio de Janeiro, Brazil; University of Pennsylvania, Philadelphia, Pennsylvania; University of Palermo, Palermo, Italy; Hospital La Paz, Madrid, Spain; J.W. Goethe University Hospital, Frankfurt, Germany; IST, Mannheim, Germany; Roche, Nutley, New Jersey; and Roche, Basel, Switzerland.
Note: Drs. Jensen and Marcellin contributed equally to this work.
Acknowledgment: The authors thank all of the patients who volunteered to participate in this study and all of the investigators and other health care professionals who ensured the successful completion of the study. They also thank Blair Jarvis for providing editorial assistance.
Grant Support: By Roche, Basel, Switzerland.
Potential Financial Conflicts of Interest: Employment: D. Messinger (IST [provides various services for sponsor]), J.A. Thommes (Roche), A. Tietz (Roche). Consultancies: D.M. Jensen (Roche, Abbott, Boehringer Ingelheim, Vertex, Novartis, AstraZeneca, HGS), P. Marcellin (Roche, Schering-Plough, Gilead, Bristol-Myers Squibb, GlaxoSmithKline, Vertex, Idenix-Novartis, Valeant, HGS, Pharmasset, Cytheris, Intermune, Wyeth, Tibotec), A. Di Bisceglie (Roche, Schering), K.R. Reddy (Roche, Gilead, Idenix, Vertex), D. Messinger (Roche). Honoraria: P. Marcellin (Roche, Schering-Plough, Gilead, Bristol-Myers Squibb, GlaxoSmithKline, Idenix-Novartis), K.R. Reddy (Roche, Gilead, Idenix, Vertex), G. Teuber (Roche). Grants received: D.M. Jensen (Roche, Vertex, Boehringer Ingelheim), P. Marcellin (Roche, Schering-Plough, Gilead, Bristol-Myers Squibb, GlaxoSmithKline, Vertex, Idenix-Novartis, Valeant, HGS, Pharmasset, Cytheris, Intermune, Wyeth, Tibotec), A. Di Bisceglie (Roche), K.R. Reddy (Roche, Schering, Human Genomics, Novartis). Grants pending: K.R. Reddy (Boehringer Ingelheim, Pharmasset).
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