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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Background  The benefits of prolonging peginterferon and ribavirin after 48 weeks of treatment to maximize sustained virological responses (SVR) in hepatitis C virus (HCV) genotype 1-infected patients remain to be understood.

Aim  To investigate whether extended treatment longer than 72 weeks may be superior to 72-week treatment.

Methods  A total of 120 treatment-naïve or retreated patients with HCV genotype 1 were treated with peginterferon-alpha-2b (1.5 μg/kg/week) plus weight-based ribavirin. We had 34 late responders, in whom HCV RNA first became undetectable at week 12–48, and randomized them into three groups receiving standard-dose peginterferon-alpha-2b plus low-dose ribavirin (200 mg/day) for extended 24 weeks (group A), receiving low-dose peginterferon-alpha-2b (0.75 μg/kg/week) plus low-dose ribavirin for extended 48 weeks (group B) or no extended treatment (group C), and evaluated the outcome according to their virological response.

Results  Multivariate analysis showed that the treatment for 96 weeks was identified as a significant, independent factor associated with SVR in HCV genotype 1-infected late responders in comparison with group A [odds ratio (OR), 10.002; = 0.080] and group C (OR, 17.748; = 0.025).

Conclusion  Extending the treatment duration from 48 weeks to 96 weeks improves SVR rates in genotype 1-infected patients with late virological response to peginterferon-alpha-2b and ribavirin.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

The hepatitis C virus (HCV) is a common cause of cirrhosis and hepatocellular carcinoma. For the management of HCV genotype 1 infection, 48 weeks of therapy with pegylated interferon plus ribavirin is recommended.1 Although the introduction of pegylated interferon in combination with ribavirin in recent years greatly improved the treatment outcome of HCV infection, the treatment outcome of HCV type 1-infected patients remains unsatisfactory and sustained virological responses (SVR) can be obtained in only approximately 45%.2–4

Hepatitis C virus kinetics during the early phase of treatment is recognized as a predictor of the final therapeutic outcome. Assessment of early virological response (EVR) correlates closely with the likelihood of the ultimate eradication of HCV in patients treated with ribavirin in combination with interferon5 or pegylated interferon.6–8 After 48 weeks of treatment, the likelihood of SVR was approximately 90% in patients who achieved undetectable serum HCV RNA at week 4 of treatment in subjects infected with HCV genotype 1, whereas patients with less than 2-log decrease in HCV RNA levels by week 12 of treatment had virtually no chance of developing SVR.6, 7 On the basis of these findings, discontinuation of treatment in nonresponders at this time was recommended to avoid unnecessary therapy.1, 9 However, high relapse rates in slow responders may indicate that treatment was not administered for a sufficient duration in patients with slow virological response.

An analysis based on a mathematic model from a phase III randomized trial of peginterferon-alpha-2a and ribavirin, Drusano and Preston suggested that the rate of SVR in patients infected with HCV genotype 1 directly correlates with the duration of treatment once HCV RNA has been cleared from serum.10 As the average time to clear serum HCV RNA was over 30 weeks, the authors concluded that 48-week duration of therapy was inadequate for most patients with genotype 1. Indiscriminate extension of treatment in patients with HCV genotype 1 is not beneficial. It has been currently reported that there is a subgroup of genotype 1-infected patients, the so-called ‘slow responders’, who benefit from extending the treatment duration from 48 weeks to 72 weeks that significantly improves SVR rates.11–14 Therefore, prolonged treatment has the potential to improve cure rates, although it will increase the cost of treatment and may increase the probability that a patient will experience adverse events. However, prolonged duration and optimal doses of pegylated interferon or ribavirin after 48 weeks of treatment to maximize SVR still remain to be understood. We aimed to investigate whether extended treatment longer than 72 weeks using the dose reduction of pegylated interferon after 48 weeks of treatment may be superior to the 72-week treatment using the standard dose of pegylated interferon. To tolerate such a long treatment, we tapered doses of pegylated interferon and/or ribavirin substantially after 48 weeks of treatment.

In hepatitis C genotype 1 patients, a slow virological responder was commonly defined as a patient with at least a 2-log decrement in baseline serum HCV RNA, albeit detectable viraemia at 12 weeks and undetectable serum HCV RNA at 24 weeks.13 However, Mangia et al. reported that SVR rates of HCV genotype 1 patients who first achieved undetectable HCV RNA at week 12 were 38.1% and 63.4% in 48 weeks and 72 weeks treatment respectively.14 In a multicentre study in Japan, SVR rate of HCV genotype 1b patients in whom HCV RNA became negative for the first time at week 12 was 41.2% in 48 weeks treatment, although SVR rate of patients in whom HCV RNA became negative within 8 weeks was over 80% (personal communication to Dr Kuboki).15 These studies indicate that extended treatment duration is recommended in patients with undetectable HCV RNA at week 12 to improve cure rates.

Following these concepts, we randomized HCV genotype 1-infected late responders, in whom HCV RNA was positive at 8 weeks of treatment and negative for the first time during 12–48 weeks of treatment, into groups receiving standard-dose peginterferon-alpha-2b (1.5 μg/kg/week) plus low-dose ribavirin (200 mg/day) for additional 24 weeks (total 72 weeks) or receiving low-dose peginterferon-alpha-2b (0.75 μg/kg/week) plus low-dose ribavirin (200 mg/day) for additional 48 weeks (total 96 weeks) and evaluated the outcome according to their virological response.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Patients

The purpose of this study was to assess prospectively the efficacy of extended treatment duration of peginterferon-alpha-2b plus ribavirin in HCV genotype 1-infected late responders. Adult patients of both genders aged more than 18 years testing positive for anti-HCV, with consistent detection of HCV RNA above 100 000 IU/mL by reverse-transcription polymerase chain reaction [RT-PCR; Amplicor HCV (version 2), Roche Diagnostics, Branchburg, NJ, USA] and elevated serum alanine aminotransferase (ALT) levels were eligible for enrollment. Patients were excluded if they had decompensated liver diseases, other causes of liver disease, hepatitis B infection, haemoglobin values <13 g/dL, white blood cell count <4000/μL, thrombocytopenia <100 000 /μL, neoplastic, severe cardiac, neurological, autoimmune or thyroid disease. Also excluded were patients with alcohol or drug abuse, women who were pregnant or considering pregnancy in the next 18 months or men whose partners were considering pregnancy in the next 18 months. A late responder was defined as a patient with HCV RNA positive at 8 weeks of treatment and negative for the first time during 12–48 weeks of treatment. Written informed consent was obtained from all patients, and an institutional review board at each participating centre approved the study protocol.

Study design

This study was conducted between December 2004 and December 2005 at eight centres (two university hospitals and six general hospitals) in Japan. In this partially randomized, open-label, parallel-group, multicentre study, one hundred twenty treatment-naïve or retreated patients who met the criteria for entry were enrolled and received treatment with subcutaneous peginterferon-alpha-2b (1.5 μg/kg/week) (Peg-Intron; Schering Corp., Kenilworth, NJ, USA) and oral ribavirin (600–1000 mg/day based on weight: ≤60 kg, 600 mg; 61–80 kg, 800 mg; and >80 kg, 1000 mg) (Schering Corp.) for 48 weeks. Thirty-seven of 120 patients had been treated previously with conventional interferon or conventional interferon plus ribavirin for 24 weeks (‘relapsers’ and ‘nonresponders’ were included), but had not been treated previously with pegylated interferon and ribavirin. Pegylated interferon and ribavirin dose modifications followed standard criteria and procedures. The late responders whose serum HCV RNA became undetectable during 12–48 weeks after treatment were randomized to 1 of the 3 treatment groups: extended therapy for an additional 24 weeks with standard-dose peginterferon-alpha2b (1.5 μg/kg/week) plus low-dose ribavirin (200 mg/day) (total treatment duration of 72 weeks; group A); extended therapy for an additional 48 weeks with low-dose peginterferon-alpha-2b (0.75 μg/kg/week) plus low-dose ribavirin (200 mg/day) (total treatment duration of 96 weeks; group B); and not-extended therapy (total treatment duration of 48 weeks; group C).

Liver biopsies, which were not mandatory for the patients to be enrolled, were performed in 100 patients within 6 months before study entry, and histological changes were recorded according to the criteria of Desmet et al.,16 with the grading of activity and the staging of fibrosis being defined as A0 (no histological activity), A1 (mild activity), A2 (moderate activity), A3 (severe activity), and as F0 (no fibrosis), F1 (mild fibrosis), F2 (moderate fibrosis), F3 (severe fibrosis) and F4 (cirrhosis) respectively.

On the basis of SVR rate of 35% in the 48 weeks treatment (Group C in our study)14, 15 and predicted improvement of the rate of 50% or higher in Group A or B (SVR rate of 85%), we calculated the required sample size of 14 for each group with α-error of 0.05 and ß-error of 0.80.

Measurement of HCV RNA

Serum samples were collected in each institution and centrally stored at −80 °C. Anti-HCV was tested by third-generation enzyme-linked immunoassay (Abbott Laboratories, North Chicago, IL, USA). Quantification of serum HCV RNA was performed by a single central laboratory (SRL Laboratory Co., Tokyo, Japan) to avoid variability between available assays using RT-PCR (Amplicor HCV Monitor test [version 2], Roche Diagnostics, Branchburg, NJ, USA) with a lower limit of detection of 600 IU/mL. Serum HCV qualitative test (detection limit 50 IU/mL; Amplicor HCV kit [version 2], Roche Diagnostics) was assessed at every 4 weeks after treatment. HCV genotyping was performed by RT-PCR using genotype-specific primers17 in a single central laboratory (SRL Laboratory Co.) using a modification of a method described by Ohno et al.18

Determination of nucleotide and deduced amino-acid sequences of the IFN-sensitivity-determining-region (ISDR) and core region

RNA coding for ISDR in the NS5A region was amplified by nested RT-PCR. For direct sequencing of the NS5A (2209–2248) region, after the first-round PCR, the second round of nested RT-PCR was performed using an external sense primer and internal antisense primer.19 The second-round PCR products were purified and directly sequenced using the BigDye Terminator Cycle Sequencing kit (Perkin Elmer Applied Biosystem, Warrington, UK) in a 310 DNA sequencer (ABI 3100 Genetic Analyzer, Perkin Elmer Applied Biosystems). Electropherograms were analysed using Sequence Navigator software (Perkin Elmer Applied Biosystems). The deduced amino acid sequences of ISDR were compared with the sequence of the prototype isolate of HCV-J. Detection of amino acid substitutions of aa 70 and aa 91 in core region of HCV genotype 1b was performed using mutation-specific primer as an alternative to the direct sequencing method.20 The major protein type was determined based on the relative intensity of the bands for wild (aa 70, arginine; aa 91, leucine) and mutant (aa 70, glutamine/histidine; aa 91, methionine) in agarose gel electrophoresis. All of the above procedures were performed centrally by SRL Laboratory.

Efficacy end points

The primary aim of the study was to assess the effect of extended treatment duration of peginterferon-alpha-2b plus ribavirin on sustained virological response (SVR) for patients with late virological response defined as HCV-RNA positive at week 8, but negative at weeks 12–48. SVR was defined as the sustained disappearance of serum HCV RNA for 24 weeks after the end of treatment. Treatment failure was categorized as relapse (reappearance of HCV RNA during the follow-up period after an end of treatment response), nonresponse (HCV RNA positive at week 48) or discontinuation (treatment withdrawn for any reason).

The secondary endpoint was the evaluation of discontinuation. It was thought important to decrease the numbers of patients with discontinuation to achieve higher SVR.

Statistical analysis

The efficacy analysis was conducted on an intention-to-treat basis. All patients who received at least one dose of study medication were included in the intention-to-treat population. The baseline characteristics of patients randomized to groups A, B and C were compared using Fisher’s exact test for categorical data and Kruskal–Wallis test for continuous variables. Univariate and stepwise multivariate logistic regression analyses were used to determine independent predictive factors that were associated with SVR. Correlations were tested using Pearson’s rank correlation coefficient.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Patient profiles

The median age of the enrolled population of 120 patients from eight centres was 60 years, 61% were men, and 98% were infected with genotype 1b. The trial participant flow is shown in Figure 1. Of 120 patients with genotype 1 infection treated with peginterferon-alpha-2b and ribavirin during that study period, 39 patients (33%) were late responders to therapy and met inclusion criteria. However, only 35 patients participated and were randomized, because four late responders declined to participate in the study. Of 120 enrolled patients, 25 patients (21%) stopped treatment within 48 weeks.

image

Figure 1.  Flow of participants throughout the study.

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Thirty-five late responders, all of whom were genotype 1b, were assigned to group A (n = 12), group B (n = 10) or group C (n = 13). However, one patient of group B who was found to be HCV RNA negative at week 8 and did not meet inclusion criteria was excluded for this analysis. Baseline demographic, biochemical and virological characteristics of patients did not differ among three groups (Table 1). Time when patients first achieved undetectable HCV RNA did not differ among three groups.

Table 1.   Characteristics of patients at baseline
  1. HCV, hepatitis C virus; ISDR, interferon-sensitivity-determining-region.

  2. *Normal range of ALT: 7–40 IU/L.

  3. Fisher’s exact test was used for categorical data to compare differences, and continuous variables were compared by Kruskal-Wallis test.

  4. Hepatic histology was not evaluated in three patients in group A, because liver biopsy was not performed.

  5. Lack of completeness was due to incomplete sampling.

Treatment durationGroup A (N = 12) 72 weeksGroup B (N = 9) 96 weeksGroup C (N = 13) 48 weeks P-value
Gender
 Male8 (67%)5 (56%)8 (62%)0.908
 Female4 (33%)4 (44%)5 (38%)
Age (year)54 (35–73)60 (48–70)62 (35–71)0.657
Serum ALT (IU/L)*52 (26–255)61 (40–108)64 (17–171)0.437
HCV RNA (KIU/mL)
 <15004 (33%)5 (56%)3 (23%)0.317
 ≥15008 (67%)4 (44%)10 (77%)
Number of mutations in ISDR
 05 (45%)6 (67%)9 (75%)0.282
 1–35 (45%)3 (33%)3 (25%)
 4-1 (9%)0 (0%)0 (0%)
Core 70 mutation
 W9 (75%)8 (89%)9 (75%)0.708
 M3 (25%)1 (11%)3 (25%)
Core 91 mutation
 W9 (75%)6 (67%)10 (83%)0.595
 M3 (25%)3 (33%)2 (17%)
Fibrotic stage
 0–12 (22%)3 (33%)5 (38%)0.559
 2–47 (77%)6 (67%)8 (62%)
Activity grade
 0–13 (33%)4 (44%)4 (31%)0.893
 2–36 (67%)5 (56%)9 (69%)
Loss of HCV RNA (week)
 126680.653
 16204
 20000
 24311
 28110
 32010

Outcomes of patients

At week 48 of treatment, HCV RNA was undetectable in all of 34 patients in groups A, B and C. At the end of therapy, HCV RNA was undetectable in 92%, 100% or 100% of patients from each group A, B or C respectively (Figure 2). At the end of the follow-up period, virological response was sustained in 58% (7/12) of patients in group A, 89% (8/9) of patients in group B and 38% (5/13) of patients in group C (Figure 2). Surprisingly, one patient in group B who first became HCV negative at week 28 of treatment achieved SVR. As shown in Figure 2, relapse rate was lesser in patients treated for 96 weeks (11%) than in those treated for 72 weeks (42%, = 0.178) or 48 weeks (62%, = 0.031). Moreover, we have assessed the treatment outcome of patients who had detectable HCV RNA at week 12, but undetectable HCV RNA at week 48. Although patient numbers among the treatment subgroup were limited, virological response was sustained in 33% (2/6) of patients in group A, 67% (2/3) of patients in group B and 0% (0/5) of patients in group C.

image

Figure 2.  Frequency of virological response rates at the end of therapy and virological relapse rates in groups A, B and C. These rates are shown as a percentage and the number of patients with virological response or virological relapse in relation to the total number of patients examined is shown at the bottom of each column. *P < 0.05 compared with group C.

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During the extended treatment for patients in groups A and B, only one patient in group A discontinued ribavirin intake, but none except the patient in both groups needed dose reductions of peginterferon-alpha-2b or ribavirin. In addition, haemoglobin levels increased again in groups A and B after 48-week treatment probably because of the dose reduction of ribavirin during the extended treatment (Figure 3). The rate of SVR among HCV genotype 1-infected patients was significantly higher in patients treated for 96 weeks than in those treated for 48 weeks (= 0.034, Table 2 and Figure 2), although the difference between the rates of SVR in group A and group C was not significant (Table 2). The rate of SVR of patients in group B (89%) was comparable to that of patients achieving early virological response whose HCV RNA was negative at week 8 [78% (29/37)].

image

Figure 3.  Time course of haemoglobin levels in groups A, B and C during therapy. The patients in groups A and B were given low-dose ribavirin (200 mg/day) beyond 48 weeks.

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Table 2.   Predictors of sustained virological response to combination therapy
FactorDefinitionOR (95% CI)P-value
  1. OR, odds ratio; 95% CI, 95% confidence interval; HCV, hepatitis C virus; ISDR, interferon-sensitivity-determining-region.

  2. Normal range of ALT: 7–40 IU/L.

Univariate logistic regression analysis
GroupB vs. C12.800 (1.208–135.579)0.034
B vs. A5.714 (0.532–61.409)0.150
A vs. C2.240 (0.451–11.114)0.324
GenderFemale2.045 (0.477–8.773)0.336
Age<60 years3.344 (0.802–13.941)0.098
Previous IFN courseNaïve1.750 (0.420–7.288)0.442
Serum ALT*≥63 (IU/L)2.500 (0.584–10.696)0.217
Total cholesterol≥170 (mg/dL)4.480 (0.986–20.354)0.052
HCV RNA<1500 KIU/mL3.000 (0.636–14.150)0.165
ISDR mutationW1.072 (0.250–4.591)0.926
Core 70 mutationW1.200 (0.221–6.520)0.833
Core 91 mutationW0.900 (0.175–4.630)0.900
Fibrotic stage2–41.625 (0.355–7.434)0.532
Activity grade2–32.229 (0.497–9.997)0.295
Stepwise multivariate logistic regression analysis
GroupB vs. C17.748 (1.427–220.746)0.025
B vs. A10.002 (0.757–132.148)0.080
A vs. C1.774 (0.315–10.010)0.516
Age<60 years4.963 (0.922–26.710)0.062

Several baseline and on-treatment predictors of SVR (group, age, activity grade, total cholesterol), which P values were lower than 0.2 using Fisher’s exact test, were examined by logistic regression analysis. The stepwise multivariate logistic regression analyses for four variables showed that group and age were independent predictive factors of SVR. The treatment for 96 weeks was identified as a significant, independent factor associated with SVR in HCV genotype 1-infected late responders [group B vs. group A; odds ratio (OR), 10.002; confidence interval (CI), 0.757–132.148; = 0.080, group B vs. group C; OR, 17.748; 95% CI, 1.427–220.746; = 0.025].

Sustained virological responses in the total study population

Sustained virological responses was obtained in 52 of 120 (43%) of the total intention-to-treat population and 52 of 117 (44%) of those with 24-week follow-up data. SVR was obtained in 2 of 25 (8%) of patients with treatment discontinuation. For the improvement of SVR in the total population, it must be important to decrease the number of patients with treatment discontinuation. Interestingly, we found that the number of patients enrolled per hospital was significantly associated with the reduced ratio of patients with treatment discontinuation (Figure 4).

image

Figure 4.  Correlation between the number of treated patients and percentage of discontinuation at each hospital. All 25 patients who stopped treatment within 48 weeks of treatment were analysed. Pearson’s correlation coefficient is indicated on the graph.

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Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

A 48-week treatment with pegylated interferon plus ribavirin has now become the standard of care for patients with HCV genotype 1. The duration of anti-viral therapy is one of the most important factors influencing treatment outcome, especially in HCV genotype 1-infected patients.11–14 Berg et al. investigated the efficacy of 48 weeks vs. 72 weeks of treatment with peginterferon-alfa-2a plus ribavirin in treatment-naïve patients with HCV type 1 infection. In this study, prolongation of the therapeutic regimen for up to 72 weeks does not lead to higher SVR rates in the intention-to treat population, but patients who still are HCV-RNA positive at week 12 show significantly higher SVR rates when treated for 72 weeks instead of 48 weeks.11 Sánchez-Tapias et al. have recently demonstrated that extension of treatment with peginterferon-alfa-2a plus ribavirin from 48 to 72 weeks significantly increases the rate of SVR in patients with detectable viraemia at week 4 of treatment.12 Pearlman et al. have demonstrated that extending the treatment duration from 48 weeks to 72 weeks in genotype 1-infected patients with slow virological response to peginterferon- alfa2b plus ribavirin, which was defined by achieving at least a 2-log decrement in HCV RNA from baseline, yet having detectable HCV RNA at 12 weeks and undetectable HCV RNA at 24 weeks, significantly improves SVR rates.13

However, all of the aforementioned studies extended the treatment duration to 72 weeks to improve SVR rates in slow responders with HCV genotype 1. Furthermore, it is unclear if the standard doses of peginterferons and ribavirin continued to be used after week 48, although these patients achieved undetectable HCV RNA before 24 weeks. It was reported that treatment discontinuation was more frequent in patients treated for 72 weeks than those for 48 weeks.13 In the prediction model developed by Drusano and Preston, it was concluded that type 1-infected patients required the continuous absence of detectable HCV RNA in serum for 36 weeks to attain 90% probabilities of SVR,10 suggesting the importance of treatment duration when serum HCV RNA is continuously negative. In the present study, we used the minimum dose of ribavirin (200 mg/day) beyond 48 weeks in late responders who first became HCV RNA undetectable after 12 weeks and compared the efficacy and safety of additional 24 weeks of treatment (total 72 weeks) with the standard dose of peginterferon- alfa2b with those of additional 48 weeks of treatment (total 96 weeks) with the half dose of peginterferon- alfa2b.

Our data showed that SVR rates were higher in the 96-week group as compared with the 72-week group as well as the 48-week group (89% vs. 58% or 38%, respectively). The SVR rates seem to be higher than those previously reported.11–13 The differences in the SVR rates could be because of our criteria of late responders that include patients with a first virological response at week 12. Only one of 21 patients in group A and B became HCV RNA positive during the extended treatment after 48 weeks of treatment, suggesting that the intentional dose reductions of peginterferon-alpha-2b and ribavirin between weeks 48 and 96 did not cause adverse effects on viral load. Only one of 21 patients discontinued ribavirin intake, but the others did not need dose reductions of peginterferon-alpha-2b or ribavirin and therapy discontinuation during the extended treatment, indicating that the intentional dose reductions of peginterferon-alpha-2b and ribavirin between weeks 48 and 96 were safe for patients with chronic hepatitis C genotype 1. Moreover, the intentional dose reductions during the last part of the treatment improved haemoglobin levels (Figure 3), which might result in tolerating a long treatment.

Among patients who discontinued treatment up to week 48, the rate of SVR was 8% (intention-to-treat analysis), which is much lower than that with patients treated for at least 48-weeks [53% (50/95)]. These data highlight the relevance of encouraging adherence to therapy.21 Interestingly, the number of patients enrolled per hospital was negatively associated with the numbers of patients with treatment discontinuation. These findings imply that the differences in improved adherence could be the result of physician-driven care and continuity based on the experience of each physician, because almost all of our patients were seen by the same treating physician on a monthly basis throughout the trial. Moreover, low attrition rates in hospitals where a greater numbers of patients were cared could be explained by the patients’ knowledge concerning the adverse and beneficial effects of this combination therapy informed by physicians before and during treatment.

Limitation of this study is the small number of patients as compared to the predicted sample size. Thus, the statistical power is weaker than that of the initial design, and the possibility of ß-error remains.

In conclusion, extension of the treatment duration with peginterferon-alfa-2b plus ribavirin up to 96 weeks significantly increased the likelihood of achieving SVR in HCV genotype 1-infected late responders whose serum HCV RNA became undetectable for the first time during 12–48 weeks after treatment. Treatment extension did not increase the rate of dose reduction or treatment discontinuation.

Acknowledgement

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Declaration of personal and funding interests: None.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References
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