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Impact of Reducing Peginterferon Alfa-2a and Ribavirin Dose During Retreatment in Patients With Chronic Hepatitis C (HALT-C Study)
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Gastroenterology Dec 2007
Mitchell L. Shiffman, Marc G. Ghany, Timothy R. Morgan, Elizabeth C. Wright, Gregory T. Everson, Karen L. Lindsay#, Anna S.F. Lok, Herbert L. Bonkovsky, Adrian M. Di Bisceglie, William M. Lee, Jules L. Dienstag, David R. Gretch##
ABSTRACT
Background & Aims: Reducing the dose of peginterferon and/or ribavirin to <80% when treating chronic hepatitis C virus has been associated with a reduction in sustained virologic response (SVR). However, prior studies did not assess the impact of reducing the dose of peginterferon independent of ribavirin or differentiate between dose reduction or interrupting or prematurely discontinuing treatment.
Methods: Nine hundred thirty-six patients with chronic hepatitis C genotype 1, advanced fibrosis, or cirrhosis (Ishak 3-6) and prior nonresponse to standard interferon ± ribavirin were retreated with peginterferon alfa-2a (180 μg/wk) and ribavirin (1000-1200 mg/day) during the lead-in phase of the HALT-C trial. The percentage of each medication actually taken during treatment was calculated.
Results: Reducing the total cumulative dose of peginterferon received during the first 20 weeks of treatment from full dose (≥98%) to ≦60% reduced week 20 virologic response (W20 VR) from 35% to 12% and SVR from 17% to 5%. Reducing the dose of ribavirin from full dose (≥98%) to ≦60% did not affect either W20 VR or SVR as long as ribavirin dosing was not interrupted for more than 7 consecutive days. Prematurely discontinuing ribavirin, even at full-dose peginterferon, reduced W20 VR to ≦19% and SVR to ≦4%.
Conclusions: Reducing the peginterferon dose during the first 20 weeks of treatment reduced viral clearance and SVR. In contrast, reducing ribavirin did not affect either W20 VR or SVR as long as patients remained on full-dose peginterferon. Discontinuing ribavirin prematurely was associated with a marked decline in both VR and SVR.
Background
Peginterferon and ribavirin represent the most effective therapy and the treatment of choice for patients with chronic hepatitis C virus (HCV) infection.1, 2, 3 Therapy with this combination yields a sustained virologic response (SVR) in approximately 40%-45% of patients with HCV genotype 1 and 80% of patients with genotypes 2 or 3. SVR occurs more frequently in patients with genotype 1 who are able to remain on near full doses of these medications and is reduced substantially in those patients who require reduction in the doses of these medications.4, 5, 6 In contrast, dose reduction does not appear to influence adversely the SVR in patients with genotypes 2 or 3. In the first study addressing this issue, patients who received at least 80% of their total expected cumulative dose of peginterferon and/or ribavirin for at least 80% of the planned duration of therapy (38 weeks) had an SVR of 51% compared with only 34% for patients who received lesser amounts of one or both medications.4 The impact of dose reduction in patients with genotype 1 appeared to be greatest in patients who required dose reduction within the first 12 weeks of treatment. Patients who received ≥80% of both medications for the full 48 weeks of treatment had an SVR of 61%; dose reduction after week 12 yielded an SVR of 51%, but patients with dose reduction before week 12 had an SVR of only 34%. In a subsequent analysis, reducing the dose of peginterferon and ribavirin to <80% of the full planned dose within the first 12 weeks reduced early virologic response (EVR) from 80% to only 33%.5 The impact of dose reduction during the first several weeks of treatment on SVR has also been assessed in patients with prior nonresponse to interferon-based therapy during retreatment with peginterferon alfa-2a and ribavirin.6 In that study, a stepwise reduction in the dose of either peginterferon and/or ribavirin during the first 20 weeks of treatment from ≥80% to ≦60% of the planned total dose was associated with a stepwise decline in SVR from 20%-21% to 11%-13%, respectively. In contrast, reducing the dose of these medications after week 20 in patients in whom HCV RNA had already become undetectable did not appear to adversely influence SVR.6 However, neither of these prior studies included a sufficient sample size to assess adequately the impact of reducing the dose of peginterferon independent of ribavirin in patients with genotype 1, and patients with dose reductions were analyzed together with those who discontinued either 1 or both drugs prematurely. Therefore, the real impact of dose reduction on SVR in patients with HCV genotype 1 infection remains inadequately defined.
During the lead-in phase of the Hepatitis Antiviral Long-term Treatment Against Cirrhosis (HALT-C) clinical trial, over 900 patients with HCV genotype 1 infection and prior nonresponse to interferon-based therapy were retreated with peginterferon alfa-2a and ribavirin.6, 7 This trial provided a population of sufficient size to examine critically the effects of reducing peginterferon and ribavirin on virologic response (VR) and SVR. Our results demonstrated that the dose of ribavirin could be markedly reduced within the first 20 weeks of treatment without affecting SVR significantly as long as the dose of peginterferon alfa-2a was maintained and/or ribavirin was not prematurely interrupted or discontinued. These observations have important implications for the management of patients with chronic hepatitis C.
Discussion
This report analyzed the effects of reducing either peginterferon and/or ribavirin on SVR rates in patients with chronic hepatitis C undergoing retreatment after previous nonresponse. Reducing the dose of peginterferon alfa-2a and ribavirin during the first 20 weeks of treatment had minimal impact on SVR as long as patients received >60% of the anticipated total dose of both medications. Furthermore, SVR was not adversely affected even in patients who received ≦60% of the total anticipated ribavirin dose during the first 20 weeks of treatment as long as they remained on full-dose peginterferon and as long as ribavirin was not discontinued. In contrast, patients who interrupted ribavirin dosing for more than 1 week or who missed >14 days of ribavirin during the first 12 weeks of treatment had an SVR of only 9%. Discontinuing ribavirin permanently reduced SVR to only 3%. Most patients who initially responded to treatment but frequently missed doses or stopped ribavirin prematurely either developed breakthrough or relapse. This observation is entirely consistent with the results of a recently published randomized controlled trial that evaluated the impact of discontinuing ribavirin in patients who were HCV RNA undetectable at week 24.8 Prematurely discontinuing ribavirin in this study increased breakthrough from 2% to 12% and relapse from 29% to 42%.
Previous studies have suggested that reducing the ribavirin dose within the first 12-20 weeks of treatment in patients with HCV genotype 1 was associated with a decline in SVR.4, 5, 6 However, these studies did not analyze ribavirin dose reductions independent of peginterferon dose reductions, did not differentiate dose reduction from prematurely discontinuing ribavirin, or simply evaluated dose reduction by dividing patients into only 2 groups: those who received more or less than 80% of one or both of these medications.4, 5 Furthermore, in both our previous report6 and the study by McHutchison et al,4 the majority of patients who reduced the dose of ribavirin also dose-reduced peginterferon. As a result, it has been impossible to determine from these previous studies if one of these medications could be reduced and to what degree without adversely affecting SVR. The present study represents the largest cohort in which the effects of dose reduction have been examined to date. This enabled the cohort to be divided into 20 smaller groups so that the impact of dose reducing ribavirin or peginterferon at multiple intervals independent of each other on W20 VR, relapse, and SVR could be assessed. The analysis was limited to patients with genotype 1 because previous studies have suggested that SVR in patients with genotypes 2 or 3 is not adversely affected by dose reduction.4, 5 The impact of dose reduction during weeks 20-48, in patients who had already become HCV RNA undetectable, was also assessed. However, because the sample size for this particular analysis was much smaller (only 269 patients), our conclusions regarding the impact of dose reduction between weeks 20 and 48 on SVR are less certain.
The present analysis was performed in patients enrolled in the HALT-C Trial. Thus, all patients were nonresponders to prior treatment with standard interferon with or without ribavirin and had advanced fibrosis or cirrhosis. These findings may therefore not be directly applicable to genotype 1 patients receiving peginterferon and ribavirin for the first time. Achieving an SVR in any patient with chronic HCV is dependent upon first becoming HCV RNA undetectable during treatment and then not relapsing after therapy is complete. The former is mediated primarily by peginterferon and the latter by ribavirin.2, 9, 10, 11, 12, 13 The results of the present study, conducted in a "difficult-to-treat" population of previous nonresponders, are consistent with these observations. It is therefore unlikely that reducing the dose of ribavirin within the range described by this analysis would adversely affect SVR in patients receiving their first course of therapy. Recent studies have strongly suggested that 15%-25% of treatment nave genotype 1 patients will achieve rapid VR (HCV RNA negative within 4 weeks of initiating treatment). The SVR in this subset of patients with rapid VR exceeds 90%, and this may occur with just 24 weeks of treatment and even if ribavirin is discontinued prematurely.8, 14, 15
Some studies have suggested that an SVR is increased when patients receive a higher dose of ribavirin according to body weight.1, 16 In the original analysis by Manns et al,1 a higher dose of peginterferon was associated with a higher SVR at all weight-based doses of ribavirin. At each peginterferon dose, SVR increased with increasing ribavirin dose up 13 mg/kg, at which point SVR was relatively flat despite further increases in ribavirin dose. In that study, the fixed starting dose of ribavirin (800 mg for all patients) was utilized to calculate the weight-based dose; no adjustments were made for patients who reduced the dose of ribavirin during treatment. As a result, the calculated weight-based ribavirin dose was likely to be considerably higher than the ribavirin dose, in mg/kg, actually received. In the present study, the mean prescribed initial dose (13 mg/kg) was nearly identical to that observed in the study by Manns et al.1 However, we chose to analyze our data based on the mean dose of ribavirin actually taken, and patients who interrupted or prematurely discontinued ribavirin dosing were considered to have received 0 mg/kg during that time interval. As a result, the ribavirin doses received by patients in the current study were approximately 38% lower than that reported by Manns et al. Despite these differences, our data also demonstrate that higher doses of peginterferon are associated with a higher W20 VR and SVR at any given ribavirin dose. At the higher peginterferon dose, increasing the dose of ribavirin was associated with an increase in SVR up to approximately 5.5 mg/kg per day, at which point SVR remained relatively stable despite further increases in the ribavirin dose.
Adverse events, especially hematologic toxicities, account for the vast majority of dose reductions in patients being treated with peginterferon and ribavirin.1, 2, 17 In previous studies of treatment-nave patients, anemia requiring dose reduction was observed in approximately 20%-25% of patients.1, 2, 9, 10, 18 In the present study of retreatment in prior nonresponders, approximately half the ribavirin dose reductions and nearly 75% of peginterferon dose reductions were due to the hematologic toxicities of these drugs. The high frequency of cytopenias in patients treated for chronic hepatitis C led to studies of erythropoietin-alfa and other hematopoietic growth factors to limit the impact of anemia, neutropenia, and thrombocytopenia and the need to reduce doses of peginterferon and ribavirin.19, 20, 21, 22 A randomized, double-blind, placebo-controlled trial in patients treated with peginterferon and ribavirin demonstrated that erythropoietin-alfa was highly effective in correcting ribavirin-associated hemolytic anemia, limiting the need for ribavirin dose reduction, and improving quality of life19, 22; but this study did not evaluate the effect of erythropoietin on SVR. Preliminary data from a prospective controlled trial has suggested that the routine use of erythropoeitin could reduce the need for dose reduction in patients treated with weight-based ribavirin but would not enhance SVR given the same starting dose of ribavirin.23 The results of the present study suggest that the use of erythropoietin to avoid ribavirin dose reductions is also unlikely to enhance SVR, except in those patients whose anemia and poor quality of life is so severe that ribavirin must either be interrupted or prematurely discontinued. In contrast, the use of granulocyte colony stimulating factor has the potential to enhance both VR and SVR in those patients who develop severe neutropenia and would otherwise have to dose reduce peginterferon by more than 80% within the first 20 weeks This possibility should be explored in a randomized controlled trial.
In conclusion, the present analyses have enhanced our understanding of how dose reduction can affect a patient's ability to achieve both VR and SVR when being retreated with peginterferon and ribavirin for chronic hepatitis C virus infection. Our findings, therefore, have the potential to alter the way adverse events of peginterferon and ribavirin therapy are managed. We found that reducing the total dose of peginterferon to ≦80% within the first 20 weeks of therapy reduced SVR. In contrast, reducing the dose of ribavirin appeared to have little impact on SVR as long as patients do not miss more than 7 consecutive days of therapy within the first 20 weeks or more than 14 total days within the first 12 weeks or unless they discontinue the use of this agent permanently any time during the 48 week treatment course.
Results
Patient Population
A total of 1145 patients were enrolled in the lead-in phase of the HALT-C Trial between August 2000 and January 2003. One thousand seventeen patients were infected with HCV genotype 1 (89% of the cohort). Eighty-one patients were excluded because HCV RNA data were unavailable at either week 20 or 72. The demographic and clinical characteristics of the remaining 936 patients included in this analysis are listed in Table 1. Their mean age was 50 years; 72% were male and 74% white; 73% had been treated previously with combination interferon and ribavirin. The mean serum alanine aminotransferase (ALT) at baseline was 2.25 times the upper limit of the normal range for each local laboratory, and 15% had a normal serum ALT at entry into the study. The mean HCV RNA level was 6.4-log10 IU/mL. The mean Histologic Activity Index (HAI) score was 7.4, and 38% had cirrhosis (Ishak score, 5 or 6).
BVR and SVR Rates During and Following Treatment With
Peginterferon and Ribavirin
The results for the first 604 patients enrolled in the lead-in phase of HALT-C have been reported previously.6 For the 539 patients with HCV genotype 1 in this prior report, 30% had undetectable serum HCV RNA at W20, 27% achieved an EOT VR, and 14% had an SVR. The results for the complete cohort of 936 genotype 1 patients included in this report were remarkably similar: 29% had undetectable serum HCV RNA at treatment week 20, 26% achieved an EOT VR, and 14% achieved an SVR.
Effect on W20 VR of Reducing Peginterferon and/or Ribavirin Doses During the Initial 20 Weeks of Treatment
The effect on W20 VR of reducing the dose of either peginterferon, ribavirin, or both is tabulated in Table 2. Thirty-six percent of patients (334/936) remained on full doses (98%-100%) of both peginterferon and ribavirin. Of these patients, 35% had undetectable serum HCV RNA at W20. In patients who remained on full-dose ribavirin (98%-100%), no decline in W20 VR was observed as long as the total cumulative peginterferon dose received during the first 20 weeks remained >80%. In contrast, W20 VR declined by nearly 50%, from 35%-41% to 15%-21%, in patients who received ≦80% of the planned peginterferon dose (P = .0009, Fisher exact test). In patients who received full-dose peginterferon (98%-100%) W20 VR was not adversely affected when the cumulative dose of ribavirin was reduced from 98%-100% to ≦60%. In contrast, stopping ribavirin in patients who remained on full-dose peginterferon was associated with a marked decline in W20 VR, to only 19% (5/26; P = .093, Fisher exact test). For all patients, the lowest values for W20 VR were observed in patients who discontinued ribavirin during the initial 20 weeks of treatment. Only 10% of all patients who discontinued ribavirin achieved a W20 VR regardless of the peginterferon dose.
Effect on SVR of Reducing Peginterferon and/or Ribavirin Doses During the Initial 20 Weeks of Treatment
The effect on SVR of reducing the dose of peginterferon and/or ribavirin during the initial 20 weeks of therapy is summarized in Table 3. An SVR was observed in 17% of the 334 patients who remained on full-dose (98%-100%) peginterferon and ribavirin during the first 20 weeks. In patients who remained on full-dose ribavirin (98%-100%), a stepwise decline in SVR, from 17% to only 7%, was observed when the dose of peginterferon was reduced (P = .033 Cochran-Armitage Trend Test). In patients who received full-dose peginterferon, SVR was not adversely affected when the cumulative dose of ribavirin was reduced from 98%-100% to ≦60%. In contrast, only 4% of patients who stopped ribavirin during the first 20 weeks of therapy achieved an SVR, even though they remained on full-dose peginterferon (P = .065, Fisher exact test for those who stopped vs those who did not). For all patients, stopping ribavirin virtually eliminated the chance for an SVR regardless of the peginterferon dose. Only 2 of 72 (3%; 95% confidence interval: 0%-10%) patients who discontinued ribavirin prior to week 20 achieved an SVR.
Because the impact of discontinuing ribavirin on SVR was so dramatic, we also examined the effect of interrupting ribavirin temporarily during the initial 12 weeks of treatment. Twenty-two patients either stopped ribavirin for 7 or more consecutive days and then restarted this medication and/or missed ≥14 total days of ribavirin during the initial 12 weeks of treatment. Only 2 of these patients (9%) achieved an SVR.
The impact of ribavirin dose during the first 20 weeks on relapse is illustrated in Figure 1. No apparent relationship between relapse rate and the dose of ribavirin was observed in patients who received at least 61% of the maximal target dose. The relapse rate in these patients was 52%. Relapse increased to 59% in patients who received ≦60% of ribavirin and to 71% in patients who discontinued ribavirin during the first 20 weeks of treatment. However, this trend was not statistically significant (P = .27).
Effect of Reducing Peginterferon and/or Ribavirin During Weeks 1-12
The effect of reducing the dose of either peginterferon, ribavirin, or both during weeks 1-12 on W20 VR and SVR were very similar to that already detailed in Table 2, Table 3. In patients who remained on full-dose ribavirin (98%-100%), W20 VR and SVR were observed in 34% and 16% of patients as long as the total cumulative peginterferon dose received during this time remained >80%. W20 VR and SVR declined to 18% and 7%, respectively, in patients who received ≦80% of the planned peginterferon dose during the first 12 weeks of treatment (P = .0032 and 0.044, respectively, Fisher exact test). In patients who received full-dose peginterferon (98%-100%), W20 VR ranged from 32% to 46% when the cumulative dose of ribavirin was reduced from 98%-100% to ≦60%; SVR ranged from 15% to 21%, respectively. Stopping ribavirin prior to week 12 in patients who remained on full-dose peginterferon was associated with a marked decline in W20 VR and SVR to only 17% and 4% (P = .079 and 15, Fisher exact test), respectively.
Effect on SVR of Reducing Peginterferon and/or Ribavirin Doses During Weeks 20-40
All patients who still had detectable serum HCV RNA at week 20 entered the randomized, controlled, maintenance phase of the HALT-C Trial. A total of 269 patients had undetectable HCV RNA at W20 and continued treatment with peginterferon with or without ribavirin through week 48. The effect on SVR of reducing the dose of peginterferon and/or ribavirin in these patients between weeks 20 and 48 is tabulated in Table 4. This analysis excluded 7 patients who had stopped ribavirin during the first 20 weeks of treatment but had nonetheless achieved a W20 VR.
Twenty-seven percent of patients (73/269) in whom HCV RNA was undetectable at week 20 remained on full doses (98%-100%) of both peginterferon and ribavirin throughout the entire 48 weeks of treatment; their SVR was 56%. In patients who remained on full-dose ribavirin (98%-100%), no consistent change in SVR was observed when the dose of peginterferon was reduced, even to <60% of the total planned dose. Similarly, in those patients who remained on full-dose peginterferon, no consistent effect on SVR was observed when the ribavirin dose was reduced to ≦60%, as long as ribavirin was not stopped. Small numbers of patients within each of these groups likely accounted for the large variation in SVR and limited confidence in these observations. As was observed previously, stopping ribavirin at any dose of peginterferon had a negative effect on SVR; this was achieved in only 5 of 16 patients (31%) who discontinued ribavirin between weeks 20 and 48.
Impact of Body Weight on Ribavirin Dose and SVR
The impact of body weight on ribavirin dose and SVR is illustrated in Figure 2. The mean weight for all patients was 89 kg (range, 48-167). The mean ribavirin dose prescribed was 13 mg/kg/day (range, 17-21). However, the mean dose actually taken by each patient was only 8 mg/kg per day (range, 0-15). This value was calculated by averaging the actual amount of ribavirin taken by each patient during the first 20 weeks of treatment and utilized the patient's initial body weight. Values were rounded to the nearest 0.5 mg/kg per day. Patients who were intolerant to ribavirin during previous therapy may have received either none or less than 1000 mg/day in accordance with the HALT-C study design.6 Patients who interrupted or prematurely discontinued ribavirin were considered to have received 0 mg/kg during this time. Because Table 2, Table 3 demonstrated that both week 20 VR and SVR declined significantly when the cumulative peginterferon dose fell below 80%, the impact of ribavirin dosing according to body weight was examined at 2 doses of peginterferon (>80% and <80% of the total cumulative dose).
Figure 2. Relationship between ribavirin dose expressed in mg/kg and W20 VR (A) and SVR (B) at 2 doses of peginterferon. Patients were grouped according to the cumulative dose of peginterferon received, either >80% of the total maximum cumulative peginterferon dose or ≦80% of this dose. The dose of ribavirin was calculated by averaging the mean ribavirin dose (mg) taken by each patient every day during their treatment, dividing the average by the patient's baseline body weight (kg), and rounding to the nearest 0.5 mg/kg. Missed doses were counted as 0 mg of ribavirin. The W20 VR and SVR rates for all patients taking this particular dose of ribavirin were then calculated.
Week 20 VR and SVR were dependent on the doses of both peginterferon and ribavirin. Week 20 VR (Figure 2A) and SVR (Figure 2B) rates were always greater in patients who received at least 80% of the total planned cumulative peginterferon dose throughout the entire range of ribavirin dosing. In patients who received >80% of the maximal cumulative peginterferon dose, both week 20 VR and SVR remained relatively stable as long as mean ribavirin doses were greater than approximately 2 mg/kg per day and 5.5 mg/kg per day, respectively. Increasing the ribavirin dose above these values did not appear to have much of an effect on either week 20 VR or SVR. In contrast, for patients who received <80% of the total cumulative peginterferon dose, increasing the dose of ribavirin appeared to enhance both week 20 VR and SVR.
Reasons for Dose Reduction
The reasons for dose reduction are presented in Table 5. Four hundred twenty-six patients reduced peginterferon, and 441 patients reduced or stopped ribavirin. Two hundred sixty-five patients reduced or stopped both drugs. A decline in hematologic counts was the most common indication for reducing peginterferon doses (71%) and reducing the dose of or discontinuing ribavirin (54%). Depression, anxiety, confusion, insomnia, and fatigue were the next most common causes for dose reduction, observed cumulatively in 20% of patients.
Materials and Methods
The HALT-C trial is a prospective, randomized, controlled study of long-term pegylated interferon alfa-2a vs no therapy for patients with chronic hepatitis C and advanced fibrosis or cirrhosis who failed to achieve an SVR following treatment with pegylated interferon and ribavirin. The HALT-C Trial is being conducted in 10 clinical centers in the United States. Details of the trial design and entry criteria have been reported previously.7 The study protocol was approved by the institutional review board of each participating institution, and written consent was obtained from all patients.
Patient Population
Eligibility criteria for entry into the study included a positive test for anti-HCV and HCV RNA in serum, a liver biopsy performed within 12 months of enrollment demonstrating either bridging fibrosis or cirrhosis (Ishak score, 3-6), and evidence of nonresponse to standard interferon therapy with or without ribavirin. Nonresponse was defined as documented failure to clear detectable serum HCV RNA after a minimal treatment duration of 12 weeks and within 4 weeks of completing this therapy. Patients were excluded if they had any other coexistent liver disorder identified by appropriate serologic, genetic, or histologic criteria; if they had a Child-Turcotte-Pugh score >6; or if they had a history of variceal hemorrhage, ascites, or hepatic encephalopathy. Additional exclusion criteria have been reported previously.7 This analysis of the HALT-C Trial cohort was restricted to 936 patients with genotype 1 who entered the lead-in phase, received at least 1 dose of peginterferon, and who had week 20 (W20) and week 72 (W72) HCV RNA results available.
Definitions of Response
W20 virologic response (W20 VR) was defined as the absence of detectable serum HCV RNA (<100 IU/mL; Amplicor version 2.0; Roche Molecular Systems, Branchburg, NJ) 20 weeks after starting treatment. W20, rather than the traditional week 24 time point, was chosen to define nonresponse so that sufficient time would be available to analyze HCV RNA and randomize patients into the maintenance phase of the HALT-C Trial at week 24. EVR was defined as a ≥2-log10 decline in serum HCV RNA from the pretreatment baseline or the absence of detectable serum HCV RNA at treatment week 12. End-of-treatment (EOT) VR was defined as absence of detectable serum HCV RNA at treatment week 48. An SVR was defined as absence of detectable serum HCV RNA at W72, 24 weeks after discontinuation of treatment.
Dose Reduction
Patients were treated with peginterferon alfa-2a 180 μg/week and ribavirin 1000 mg/day for those weighing ≦75 kg or 1200 mg/day for those weighing >75 kg. The dose of peginterferon alfa-2a was reduced stepwise from 180 to 135, to 90, and then to 45 μg/week if the neutrophil count declined to <750/mm3 or the platelet count to <40,000/mm3. Ribavirin was reduced to 600 mg/day if the hemoglobin declined to ≦10 g/dL or by >4 g/dL from the pretreatment baseline. Further dose reductions or discontinuation of one or both drugs for hematologic, severe flu-like, neuropsychiatric, and cutaneous or other medication-related adverse effects were implemented at the discretion of the investigator at each of the participating clinical centers. The doses of peginterferon and ribavirin could be increased back to starting doses if these adverse events resolved. The use of hematopoetic growth factors, such as erythropoietin alfa or granulocyte-macrophage colony stimulating factor, were not permitted during the first 20 weeks of treatment but were permitted for patients who became HCV RNA undetectable by week 20 and continued combination-drug therapy after week 24; 8 such patients received growth factor support between weeks 21 and 48.
The doses of both peginterferon and ribavirin actually taken by each patient during the course of the study were evaluated by reviewing nursing records and patient diaries. This process captured physician-directed dose reductions for adverse events and doses missed by patients for both medical and nonmedical reasons. The amounts of both medications taken by each patient during the first 20 weeks of treatment were expressed as a percentage of the total prescribed dose. For peginterferon alfa-2a, the total dose prescribed was 180 μg X 20 weeks or 3600 μg. For ribavirin, the total dose prescribed was 1000-1200 mg X 140 days or 140,000-168,000 mg. The percentage of the total dose of each drug received during the first 12 weeks and between weeks 20 to 48 was calculated in a similar fashion.
Statistical Analysis
Baseline data are reported as means with ranges or as actual values with percentages. Response data are reported as the absolute number of patients and the percentage of patients within each dosing category. Differences in percentages between 2 or among a larger number of groups were determined by χ2 test or Fisher exact test, as appropriate. Significance of trends in values was determined with the Cochran-Armitage trend test. All calculations were performed with SAS release 9.1 (SAS Institute, Cary, NC). All analyses were 2-tailed with an ƒ¿ of 0.05. Analyses that calculated SVR rates according to the dose of ribavirin expressed in mg/kg utilized similar methodology as previously employed by Manns et al.1 The mean dose of ribavirin taken during the entire treatment by each patient was rounded to the nearest 0.5 mg/kg. Missed doses and patients who discontinued ribavirin were factored into the calculation as having received 0 mg/kg during that time. The SVR rate for all patients who received each ribavirin dose in mg/kg was then calculated.
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