Journal of Gastroenterology

, Volume 47, Issue 9, pp 1014–1021

Randomized trial of peginterferon α-2a plus ribavirin versus peginterferon α-2b plus ribavirin for chronic hepatitis C in Japanese patients

Authors

    • Department of Gastroenterology and HepatologyNTT West Kyushu Hospital
  • Katsuki Haraoka
    • Department of Gastroenterology and HepatologyNTT West Kyushu Hospital
  • Yoshihiro Ouchida
    • Department of Gastroenterology and HepatologyNTT West Kyushu Hospital
  • Yuko Morishita
    • Department of Gastroenterology and HepatologyNTT West Kyushu Hospital
  • Shigetoshi Fujiyama
    • Department of Gastroenterology and HepatologyNTT West Kyushu Hospital
Original Article—Liver, Pancreas, and Biliary Tract

DOI: 10.1007/s00535-012-0560-9

Cite this article as:
Miyase, S., Haraoka, K., Ouchida, Y. et al. J Gastroenterol (2012) 47: 1014. doi:10.1007/s00535-012-0560-9

Abstract

Background

Pegylated interferon (PegIFN) plus ribavirin is the standard therapy for patients with chronic hepatitis C genotype 1. Although several randomized clinical trials have compared PegIFNα-2a with PegIFNα-2b, these 2 regimens have not been directly compared in Asian patients. We, therefore, compared the safety and antiviral efficacy of these agents in Japanese patients.

Methods

A total of 201 PegIFN-naïve, chronic hepatitis C patients were randomly assigned to once-weekly PegIFNα-2a (180 μg) or PegIFNα-2b (60–150 μg) plus ribavirin. We compared the sustained virological response (SVR) rates between the 2 regimens and analyzed their effects in relation to baseline characteristics, including single nucleotide polymorphisms (SNPs) near the interleukin-28B (IL28B) gene (rs8099917).

Results

PegIFNα-2a was associated with a higher SVR rate than PegIFNα-2b (65.3 vs. 51.0%, P = 0.039). PegIFNα-2a and SNPs near IL28B independently predicted SVR (odds ratio 2.36; 95% confidence interval [CI] 1.19–15.50, and odds ratio 7.31; 95% CI 3.45–4.68, respectively) in logistic regression analysis. PegIFNα-2a was more effective than PegIFNα-2b (81.8 vs. 62.7%, P = 0.014) in IL28B TT genotype patients, despite similarly low SVR rates in patients with TG or GG genotypes (36.4 vs. 35.9%). Patients weighing <60 kg, women, and patients aged >60 years had significantly higher SVR rates with PegIFNα-2a than with PegIFNα-2b (63.9, 61.3, and 67.3% vs. 43.8, 43.3,and 39.2%, respectively).

Conclusions

PegIFNα-2a plus ribavirin resulted in higher SVR rates than PegIFNα-2b plus ribavirin in Japanese patients. PegIFNα-2a-based treatment should therefore be the preferred choice for women, older or low-weight patients, and those with the IL28B TT genotype.

Keywords

Chronic hepatitis CPeginterferon α-2aPeginterferon α-2bInterleukin-28B

Introduction

According to the World Health Organization, 170 million people are chronically infected with hepatitis C virus (HCV), and 3–4 million persons are infected each year [1]. In Japan, 2 million people are infected with HCV and >30 000 patients die of hepatocellular carcinoma and/or liver cirrhosis every year [2]. The combined use of pegylated interferon (PegIFN) and ribavirin (RBV) is the standard treatment for chronic hepatitis C [3, 4]. A sustained virological response (SVR) to PegIFN plus RBV is associated with the eradication of HCV infection and the prevention of cirrhosis, liver failure, and hepatocellular carcinoma [5]. The 2 forms of PegIFN, PegIFNα-2a and PegIFNα-2b, have different dosing regimens: a fixed dosage of 180 μg/week for PegIFNα-2a and a body weight-based dosage of 1.5 μg/(kg week) for PegIFNα-2b. Therefore, it is possible that their efficacies differ as well. Several randomized clinical trials (RCTs) have compared these 2 treatment options [68]. One large-scale multicenter RCT performed in the United States reported no significant differences in SVR rates or adverse events between the 2 regimens [6]. Other prospective studies, however, performed at a single center in Italy showed that PegIFNα-2a-based treatment was associated with a greater SVR rate than that based on PegIFNα-2b [7, 8]. The reason for these contrasting results may have been the fact that the RCTs were conducted using subjects of different ethnic groups, ages, and physiques. The relative efficacies of PegIFNα-2a plus RBV and PegIFNα-2b plus RBV in Asian patients with chronic hepatitis C remain unclear. Therefore, we conducted a prospective randomized head-to-head clinical trial to compare the efficacies of these 2 regimens in Japanese patients with chronic hepatitis C genotype 1.

Methods

Patients

The study was conducted at NTT West Kyushu Hospital (Kumamoto, Japan) from May 2007 to January 2010. Consecutive PegIFN-naïve adults (≥18 years of age) who were infected with HCV genotype 1 were eligible for enrollment. The inclusion criteria were a serum HCV RNA level >5.0 log IU/mL, a liver biopsy performed within 6 months of starting treatment, and use of contraceptive methods during therapy and for 6 months after the end of treatment. The patients were excluded if they had any of the following: hemoglobin level <10 g/dL; white blood cell count <1.8 × 103/mm3 or platelet count <7.0 × 104/mm3; abnormal serum creatinine level; hepatitis B surface antigen positivity; human immune deficiency virus positivity; other cause of liver disease; history of liver decompensation; clinically relevant depression or any other psychiatric disease; cancer; severe cardiac, pulmonary, or renal disease; uncontrolled diabetes; or severe hypertension with vascular complications, including retinopathy.

Study design

This prospective, randomized, open-label, single-center trial was designed to assess the efficacy of the combined use of RBV with either PegIFNα-2a or PegIFNα-2b as treatment for chronic hepatitis C. The study design was approved by the independent ethics committee of the institution, and all the patients provided written informed consent for the treatment. The patients who accepted the treatment were randomly assigned to 1 of 2 treatment arms, to which the treating physician was blinded. The patients assigned to the PegIFNα-2a regimen received RBV combined with subcutaneous PegIFNα-2a at a dosage of 180 μg once weekly. The patients assigned to the PegIFNα-2b regimen received RBV combined with subcutaneous PegIFNα-2b once weekly at a dosage of 60–150 μg/kg of body weight (35–45 kg, 60 μg; 46–60 kg, 80 μg; 61–75 kg, 100 μg; 76–90 kg, 120 μg; 91–120 kg, 150 μg). The RBV dosage was determined by body weight in both regimens (600 mg/day in patients ≤60 kg; 800 mg/day in patients 60–80 kg; 1000 mg/day in patients >80 kg). The patients showing an early virological response (EVR) (undetectable serum HCV RNA levels after 12 weeks of treatment) were treated for 48 weeks, whereas patients showing a slow virological response (undetectable serum HCV RNA levels 12–36 weeks after the start of treatment) were treated for 72 weeks according to a standard treatment protocol for Japanese patients. Therapy was discontinued if the HCV RNA level at treatment week 12 had decreased by <2 log or if HCV RNA was still detectable at treatment week 36. Histological specimen interpretation was performed by experienced liver pathologists who were blinded to the patients’ clinical information. The histological appearances of the liver sample sections were evaluated according to the METAVIR scoring system [9]. Fibrosis stage was evaluated on a scale of 0–4.

Dose modification

Dose reduction was performed on the basis of the intensity of the hematological adverse effects according to the manufacturer’s drug information. The PegIFNα-2a dose was reduced to 90 μg if the neutrophil count decreased to <750/mm3 or the platelet count decreased to <5 × 104/mm3, and the agent was discontinued if the neutrophil count decreased to <500/mm3 or the platelet count decreased to <2.5 × 104/mm3. The dose of PegIFNα-2b was reduced by half if the neutrophil count decreased to <750/mm3 or the platelet count decreased to <7.5 × 104/mm3, and this agent was discontinued if the neutrophil count decreased to <500/mm3 or the platelet count decreased to <5 × 104/mm3. The RBV dose was also reduced in 200-mg decrements, as required, if the hemoglobin level decreased to <10 g/dL and the agent was discontinued if the hemoglobin level decreased to <8.5 g/dL. No hematopoietic growth factors, such as erythropoietin α or granulocyte–macrophage colony-stimulating factor, were administered during this therapy.

Measurements and endpoints

HCV RNA levels were measured using the Cobas TaqMan assay (Roche Diagnostics, Tokyo, Japan) before treatment (week 0); at study weeks 2, 4, 8, 12, 24, and 36; at the end of treatment; and at week 24 after the end of the treatment. SVR was defined as the absence of detectable serum HCV RNA at week 24 after the end of the treatment. The homeostatic model of insulin resistance (HOMA-IR) was calculated from the fasting plasma glucose and insulin values, which were measured as described previously [10]. Insulin values were unobtainable for 4 patients in the PegIFNα-2a group and 2 patients in the PegIFNα-2b group because they were receiving insulin treatment. Adherence to treatment was measured according to the mean doses of PegIFN and RBV administered during the planned treatment (percentage of the planned dose). Single nucleotide polymorphisms (SNPs) near the interleukin-28B (IL28B) gene (rs8099917) were determined using the Invader assay as described previously [11, 12]. We were unable to determine the genotypes for 2 patients in the PegIFNα-2a group and 1 patient in the PegIFNα-2b group. Patients homozygous (GG) or heterozygous (TG) for the minor sequence were defined as having the IL28B minor allele, whereas those homozygous for the major sequence (TT) were defined as having the IL28B major allele. The patients with a <2-log decrease in HCV RNA level at treatment week 12 compared with the baseline level and those with a detectable HCV RNA level at treatment week 36 stopped treatment and were classified as nonresponders. Adverse events were recorded during each outpatient visit.

Statistical analysis

The study was designed to have 80% power to detect a difference of 15% or more in SVR rates between the 2 treatment groups. On the basis of this assumption, a total of 100 patients was planned for each group. All the patients who took at least 1 dose of the study medication were included in the efficacy analysis according to the intention-to-treat principle. The patients who withdrew from the study for any reason were categorized as nonresponders in the efficacy assessment. Continuous variables are expressed as means and standard deviations. The frequencies were calculated for categorical variables, and the differences between randomization groups were evaluated using the χ2 or Fisher’s exact test. The Mann–Whitney U-test was used to compare the continuous variables. When relevant, 95% confidence intervals (CIs) were calculated to evaluate the differences between the treatments. Stepwise multivariate logistic regression analysis was used to explore the independent effects of the treatment and the baseline factors, including age, body mass index (BMI), sex, HOMA-IR, HCV RNA level, alanine aminotransferase (ALT) level, γ-glutamyl transpeptidase (GTP) level, albumin level, platelet count, α-fetoprotein (AFP) level, SNPs near IL28B (rs8099917), histological appearance, and treatment history, on the likelihood of achieving SVR. All the P values were 2-sided, with a 0.05 threshold for statistical significance. All the statistical procedures were performed using the PASW Statistics version 18 for Windows (SPSS, Chicago, IL, USA).

Results

Patient characteristics

A total of 206 patients were randomized between March 2008 and January 2010, 201 of whom received at least 1 dose of 1 of the study medications. The 2 treatment groups had similar demographic, clinical, and virological features (Table 1). Most of the patients were women, the mean patient age was 59.1 years, and the mean patient body weight was 57.5 kg.
Table 1

Baseline characteristics of the study patients

 

Peg IFNα-2a plus RBV (n = 101)

Peg IFNα-2b plus RBV (n = 100)

P value

Age (years)

59.2 ± 9.1

58.9 ± 10.8

0.702a

Sex, male/female (% male)

39/62 (38.6%)

40/60 (40.0%)

0.841b

Treatment history (% naïve)

83/18 (82.2%)

82/18 (82.0%)

0.974b

Weight (kg)

58.3 ± 11.2

56.6 ± 9.4

0.318a

BMI (kg/m2)

23.0 ± 3.3

22.2 ± 3.3

0.062a

HOMA-IR

1.8 ± 1.3

1.8 ± 1.7

0.176a

HCV RNA (log IU/mL)

6.3 ± 0.6

6.2 ± 0.7

0.151a

ALT (IU/L)

61.8 ± 46.1

60.5 ± 45.0

0.298a

Gamma-GTP (IU/L)

51.5 ± 39.9

51.4 ± 53.8

0.124a

Fibrosisc, non-cirrhosis/cirrhosis (% cirrhosis)

81/20 (19.8%)

83/17 (17.0%)

0.134b

Serum albumin (g/dL)

4.2 ± 0.3

4.2 ± 0.3

0.860a

Platelets (×104/μL)

17.5 ± 8.0

16.4 ± 5.2

0.572a

AFP (ng/mL)

10.2 ± 15.3

11.7 ± 28.0

0.951a

rs8099917, TT/TG, GG (% TT)

66/33 (65.3)

61/38 (61.6)

0.645b

Peg IFN pegylated interferon, BMI body mass index, HOMA-IR homeostatic model of insulin resistance HCV hepatitis C virus, ALT alanine aminotransferase, AFP α-fetoprotein, RBV ribavirin, gamma-GTP gamma-glutamyl transpeptidase

aMann–Whitney U-test, bχ2 test, cMETAVIR fibrosis score [9]

Efficacy

Overall, the patients treated with PegIFNα-2a showed a higher SVR rate than those treated with PegIFNα-2b (65.3 vs. 51.0%, respectively; P = 0.039; Table 2). The PegIFNα-2a treatment was associated with a higher SVR rate than that associated with the PegIFNα-2b treatment in the patients with lower BMIs (<25; 68.8 vs. 51.3%, respectively; P = 0.024), in the patients weighing <60 kg (63.9 vs. 43.8%, respectively; P = 0.024), and in those with low insulin resistance (HOMA-IR <2; 72.5 vs. 50.7%, respectively; P = 0.009). Conversely, the 2 regimens showed similar SVR rates in the patients with higher BMIs (>25; 52.4 vs. 50.0%, respectively; P = 0.879), in those weighing >60 kg (67.5 vs. 63.9%, respectively; P = 0.740), and in those with high insulin resistance (HOMA-IR >2; 50.0 vs. 55.2%, respectively; P = 0.696). PegIFNα-2a and PegIFNα-2b were associated with SVR rates of 67.3 and 39.2%, respectively, in the patients >60 years of age (P = 0.005), whereas the corresponding SVRs in the patients aged <60 years were 63.5% for PegIFNα-2a and 63.3% for PegIFNα-2b (P = 0.984). There was no significant difference in the SVR rates between the treatments for the men (P = 0.379), but the SVR rates were higher for the women treated with PegIFNα-2a than for those treated with PegIFNα-2b (P = 0.047). The SVR rates were not significantly different in the patients without cirrhosis (67.9% with PegIFNα-2a vs. 55.4% with PegIFNα-2b; P = 0.100) compared with those with cirrhosis (55.0 and 29.4%, respectively; P = 0.117).
Table 2

Virological response during the treatment and at the end of the follow up

 

Peg IFNα-2a plus RBV (n = 101)

Peg IFNα-2b plus RBV (n = 100)

P valuea

Virological response, no. (%)b

 According to treatment week

  4

24 (23.8)

15 (15.0)

0.116

  12

25 (24.8)

24 (24.0)

0.901

  24

31 (30.7)

28 (28.0)

0.675

  36

4 (4.0)

7 (7.0)

0.344

  Non-response

5 (5.0)

12 (12.0)

0.073

SVR, no. (%)

66 (65.3)

51 (51.0)

0.039

SVR according to treatment duration, no./total no. (%)c (weeks)

 48

41/49 (83.7)

32/39 (82.1)

0.841

 72

22/35 (62.9)

16/35 (45.7)

0.150

SVR according to adherence of treatment, no./total no. (%)d

 PegIFN (%)

  ≥80

49/63 (77.8)

44/64 (68.8)

0.251

  <80

17/23 (73.9)

7/17 (41.2)

0.092

 RBV (%)

   

  ≥80

33/43 (76.7)

29/38 (76.3)

0.964

  <80

33/53 (62.3)

22/50 (44.0)

0.063

SVR according to baseline characteristics, no./total no. (%)

 Age (years)

  <60

33/52 (63.5)

31/49 (63.3)

0.984

  ≥60

33/49 (67.3)

20/51 (39.2)

0.005

 Sex

  Female

38/62 (61.3)

26/60 (43.3)

0.047

  Male

28/39 (71.8)

25/40 (62.5)

0.379

 Weight (kg)

  <60

39/61 (63.9)

28/64 (43.8)

0.024

  ≥60

27/40 (67.5)

23/36 (63.9)

0.740

 BMI (kg/m2)

  <25

55/80 (68.8)

41/80 (51.3)

0.024

  ≥25

11/21 (52.4)

10/20 (50.0)

0.879

 HOMA-IR

  <2

50/69 (72.5)

35/69 (50.7)

0.009

  ≥2

14/28 (50.0)

16/29 (55.2)

0.696

 HCV RNA

  ≤6 log IU/mL

22/28 (78.6)

28/39 (71.8)

0.530

  >6 log IU/mL

44/73 (60.3)

23/61 (37.7)

0.009

 Treatment history

  Naïve

57/83 (68.7)

46/82 (56.1)

0.095

  Retreatment

9/18 (50.0)

5/18 (27.8)

0.171

 Platelets

  <13 × 104/mL

18/27 (66.3)

14/29 (48.3)

0.165

  ≥13 × 104/mL

48/74 (64.9)

37/71 (52.1)

0.119

 Fibrosis

  Non-cirrhosis

55/81 (67.9)

46/83 (55.4)

0.100

  Cirrhosis

11/20 (55.0)

5/17 (29.4)

0.117

 IL28B SNPs (rs8099917)

  TT

54/66 (81.8)

38/61 (62.3)

0.014

  TG, GG

12/33 (36.4)

13/38 (34.2)

0.850

SVR sustained virological response, SNP single-nucleotide polymorphism, IL28B interleukin-28B gene

aχ2 test, b26 patients had discontinued treatment because of adverse events or for any reasons, 43 patients had discontinued treatment, 17 patients had discontinued treatment because of virological non-response

SNPs near IL28B, however, were associated with marked differences in efficacy between the 2 treatment groups. PegIFNα-2a was more effective than PegIFNα-2b in the patients carrying the major allele (TT) at IL28B (81.8 vs. 62.3%, respectively; P = 0.026), whereas the SVR rates were lower and similar between the regimens (36.4% with PegIFNα-2a and 35.9% with PegIFNα-2b; P = 1.000) in the patients with the TG or GG IL28B genotypes.

Factors related to SVR

The stepwise multivariate logistic regression analysis included the following preselected variables: age, sex, treatment history, BMI, HOMA-IR, viral load, serum albumin level, platelet count, ALT level, γ-GTP level, AFP level, histology, SNPs near IL28B, and treatment schedule (Table 3). The PegIFNα-2a treatment showed a significant twofold increased likelihood of SVR [odds ratio (OR) 2.358; 95% CI 1.188–4.681]. The presence of the major allele (TT) at IL28B (OR 7.314; 95% CI 3.450–15.502; P < 0.001), HCV RNA level (OR 0.374; 95% CI 0.197–0.712; P = 0.003), treatment with PegIFNα-2a (OR 2.358; 95% CI 1.188–4.681; P = 0.014), male sex (OR 2.535; 95% CI 1.200–5.353; P = 0.015), and treatment-naïve status (OR 2.910; 95% CI 1.166–7.262; P = 0.022) were all independently associated with SVR.
Table 3

Multivariate logistic regression analysis for SVR

 

Odds ratio

95% CI

P value

Sex (male)

2.535

1.200–5.353

0.015

Treatment history (naïve)

2.910

1.166–7.262

0.022

HCV RNA (log IU/mL)

0.374

0.197–0.712

0.003

Treatment (PegIFNα-2a)

2.358

1.188–4.681

0.014

IL28B SNPs (TT)

7.314

3.450–15.502

<0.001

95% CI 95% confidence interval

Safety and dose modification

The safety profiles and dose reductions of the 2 regimens are shown in Table 4. Adverse events occurred in most patients, and only 3 (1.5%) of the 201 patients reported no events. Seventeen PegIFNα-2a and 26 PegIFNα-2b patients discontinued the treatment (16.8 vs. 26.0%, respectively; P = 0.124). The reasons for stopping the therapy included adverse events in 9 PegIFNα-2a and 9 PegIFNα-2b patients (8.9 vs. 9.0%, respectively; P = 1.000); treatment cessation and being classified as a nonresponder in 5 PegIFNα-2a and 12 PegIFNα-2b patients (5.0 vs. 12.0%; P = 0.081); and withdrawal of consent in 1 PegIFNα-2b patient (1.0%). The rates of neutropenia (neutrophil count <750/mm3; 42.6 vs. 29.0%; P = 0.056), anemia (hemoglobin <10 g/dL; 61.4 vs. 63.0%; P = 0.885), and thrombocytopenia (platelet count <7.5 × 104/mm3; 29.7 vs. 27.0%; P = 0.755) were similar in the PegIFNα-2a and PegIFNα-2b groups. Consequently, the dose reduction rates for PegIFN (20.8 vs. 12.0%; P = 0.127) and RBV (23.8 vs. 30.0%; P = 0.343) were similar for the PegIFNα-2a and PegIFNα-2b regimens, and only 1 patient in the PegIFNα-2a group discontinued the treatment because of neutropenia and anemia. The proportion of patients with fever was significantly lower in the PegIFNα-2a group than in the PegIFNα-2b group (40.6 vs. 76.0%; P < 0.001). Conversely, the proportion of patients with dermatitis and itching was higher in the PegIFNα-2a group than in the PegIFNα-2b group (70.3 vs. 56.0%; P = 0.041).
Table 4

Adverse events, discontinuation of treatment, and dose reductions in the patients treated with PegIFNα-2a or PegIFNα-2b plus RBV

 

Peg IFNα-2a plus RBV (n = 101)

Peg IFNα-2b plus RBV (n = 100)

P valuea

Discontinuation, no. (%)

17 (16.8)

26 (26.0)

0.124

 For any reasons

3 (3.0)

5 (5.0)

0.498

 Because of adverse events

9 (8.9)

9 (9.0)

1.000

 Because of virological non-response

5 (5.0)

12 (12.0)

0.081

Hematological abnormalities, no (%)

 Neutropenia (<750/mm2)

43 (42.6)

29 (29.0)

0.056

Anemia (<10.0 g/dL)

62 (61.4)

63 (63.0)

0.885

 Thrombocytopenia (<7.5 × 104/mL)

30 (29.7)

27 (27.0)

0.755

Dose modification, no (%)

 Any

13 (12.9)

19 (19.0)

0.253

 Of PegIFN only

21 (20.8)

12 (12.0)

0.127

 Of RBV only

24 (23.8)

30 (30.0)

0.343

 Of both

43 (42.6)

39 (39.0)

0.667

No adverse events, no. (%)

2 (1.9)

1 (1.0)

1.000

Adverse events (≥5% incidence), no. (%)

 Fever

41 (40.6)

76 (76.0)

<0.001

 Dermatitis, itching

71 (70.3)

56 (56.0)

0.041

 Fatigue

47 (46.5)

42 (42.0)

0.571

 Decreased appetite

43 (42.6)

56 (56.0)

0.067

 Insomnia

34 (33.7)

39 (39.0)

0.465

 Headache

28 (27.7)

24 (24.0)

0.630

 Stomatitis

15 (14.9)

22 (22.0)

0.207

 Nausea

13 (12.9)

19 (19.0)

0.253

 Arthralgia

15 (14.9)

9 (9.0)

0.277

 Irritability

12 (11.9)

8 (8.0)

0.481

 Depression

9 (8.9)

8 (8.0)

1.000

 Cough

6 (5.9)

3 (3.0)

0.498

aFisher’s exact test

Discussion

The results of this randomized head-to-head study demonstrated that PegIFNα-2a treatment was associated with a higher SVR rate than PegIFNα-2b treatment in Japanese patients with HCV genotype 1. Several randomized trials have reported on the antiviral activities of the 2 regimens in patients from the United States and Europe [57]. The IDEAL study was a United States multicenter trial of a large sample of patients (n = 3070) with HCV genotype 1. The patients were randomly assigned to undergo 48 weeks of treatment with 1 of 3 regimens: weekly 1.5 μg/kg (standard dosage) or weekly 1.0 μg/kg (low dose) PegIFNα-2b with daily 800–1400 mg RBV or weekly 180 μg PegIFNα-2a with daily 1000–1200 mg RBV [6]. No differences in SVR rates were detected among the 3 regimens. However, another study conducted as a single-center prospective randomized head-to-head trial of patients with hepatitis C genotypes 1, 2, 3, and 4 in Italy found a higher SVR rate with the use of PegIFNα-2a plus RBV than with the use of PegIFNα-2b (1.5 μg/kg) plus RBV (68.8 vs. 54.4%; P = 0.008) [7]. Also, the SVR rate was higher only among the patients with HCV genotype 1 or 4 (54.8 vs. 39.8%; P = 0.04). Another prospective study found higher antiviral activity with PegIFNα-2a compared with PegIFNα-2b (66 vs. 54%; P = 0.02) in patients with HCV genotypes 1–4 [8]; in that study, the SVR rate in the patients with HCV genotype 1 treated with PegIFNα-2a was higher than that in the patients with HCV genotype 1 treated with PegIFNα-2b (48 vs. 32%, respectively; P = 0.04). A recent meta-analysis of 12 randomized controlled studies (n = 4335) found that the use of a PegIFNα-2a regimen significantly increased the number of patients who achieved SVR compared with the use of PegIFNα-2b (47 vs. 41%, respectively; P = 0.004) [13]. One possible explanation for the discrepancies between these results is that the studies were conducted in patients with different characteristics (Table 5). The IDEAL trial [6] included United States patients with the following characteristics: almost 60% were men, patients of African American ethnicity were included, the mean age was in the 40s, and the mean weight was >80 kg. The present study, in contrast, enrolled only Japanese patients, with the following characteristics: <40% were men, the mean age was in the 60s, the mean weight was <60 kg, and the mean BMI was approximately 23. Subjects in two studies of Italian HCV patients [7, 8] were generally intermediate between those in the IDEAL trial and those in the present study in age, sex ratio, and physique. In the present study, the male patients, those <60 years of age, and those with body weights of >60 kg, who therefore resembled the United States HCV patients, achieved similar SVR rates in the PegIFNα-2a plus RBV and PegIFNα-2b plus RBV groups. However, women, patients >60 years of age, and those with body weights <60 kg responded better to the PegIFNα-2a treatment than to the PegIFNα-2b treatment. It is possible that these differences in efficacy resulted from differences in dosing regimens and dose reduction rules between the PegIFNα-2a and PegIFNα-2b groups. In brief, because the dose of PegIFNα-2a was fixed (180 μg per person), whereas the dose of PegIFNα-2b varied by weight (1.5 μg/kg), the dose of Peg IFNα-2a might have been excessive, whereas that of Peg IFNα-2b might have been too low in patients with lower metabolic rates or those with lower body weights, such as older patients or women. Studies have found that EVR was associated with a high dose of PegIFN during the first 12 weeks, and patients with HCV genotype 1 who achieved EVR also had higher SVR rates [14, 15]. The dose-dependence rule for PegIFN may help explain the higher SVR rates seen when PegIFNα-2a is administered at a fixed dose irrespective of body weight. Some studies also reported that nonstandardization of the RBV dose was related to different outcomes [7, 8, 13, 16]. Differences in starting doses and/or dose reduction rules between the 2 PegIFN regimens in the IDEAL study [6] and an RCT in Italy [7] mean that the pharmacological performances of these regimens may not be directly comparable. The present study used the same dosing regimens and reduction rules for the PegIFNα-2a and PegIFNα-2b regimens and thus provided a more accurate comparison of the antiviral efficacies of the two regimens.
Table 5

Backgrounds of the patients in randomized controlled trials (RCTs)

 

No. of cases

Age (years) (α-2a/α-2b)

Sex (% male) (α-2a/α-2b)

Weight (kg) (α-2a/α-2b)

BMI (kg/m2) (α-2a/α-2b)

McHutchison et al. (USA) [6]

3070

47.6/47.5

59.2/60.2

82.8/84.0

Ascione et al. (Italy) [8]

181

51.3a/48.9a

50.6a/58.8a

70.4a/69.9a

25.5a/25.3a

Rumi et al. (Italy) [7]

178

54.8/53.9

54.9/49.4

71.5/68.2

25.3/24.8

Present study (Japan)

201

59.2/58.9

38.6/40.0

58.3/56.6

23.0/22.2

α-2a PegIFNα-2a plus ribavirin, α-2b PegIFNα-2b plus ribavirin

aIncluding patients with HCV genotype 2, 3, 4

Despite the differences in dose according to physique, the rates of adverse events and dose reductions were similar in the 2 regimens in our study. The determined safeties of PegIFNα-2a and PegIFNα-2b in the present study were in line with the results of an adjusted meta-analysis of 12 randomized controlled studies that reported similar rates of withdrawal because of adverse events in patients receiving combination therapy using either PegIFN type [13]. Although the rates of adverse events were similar, event detail and severity varied between the PegIFNα-2a and PegIFNα-2b regimens in our study, and it is therefore necessary to ensure that specific patient populations are treated with the appropriate PegIFN type.

Several host and viral factors have been reported to be associated with the outcome of PegIFN plus RBV therapy in patients with HCV genotype 1 [1720]. Consistent with previous observations, SNPs near IL28B strongly enhanced the natural clearance of HCV infection and virological response to PegIFN combined with RBV [2124]. In the present study, SNP near IL28B (rs8099917) was a strong predictor of eradication of HCV genotype 1 according to the multivariate analysis; in fact, the patients with the major type (TT) IL28B SNP achieved higher SVR rates with PegIFNα-2a than with PegIFNα-2b, although the SVR rates in the patients with the minor type (TG, GG) were lower and similar with both treatments. African Americans have been shown to have higher rates of minor-type IL28B SNPs and lower SVR rates than other ethnic groups [25, 26]. In contrast, East Asian populations, including Japanese, show relatively low rates of minor-type SNPs. The similar rates of SVR between the PegIFNα-2a and PegIFNα-2b treatments in the IDEAL trial in the United States patients may thus have been caused by the inclusion of African American patients. Studies have identified no amino acid (aa) substitutions in the HCV core region (arginine at aa 70 and leucine at aa 91) and ≥2 aa mutations of the interferon sensitivity determining region (ISDR) as a predictor of response to PegIFN and RBV combination therapy in Japanese patients infected with HCV genotype 1b [17, 27]. Examinations including these viral factors need to be conducted in further studies.

In conclusion, PegIFNα-2a combined with RBV was superior to PegIFNα-2b combined with RBV in Japanese patients with HCV genotype 1, especially in older patients, women, patients with low insulin resistance, those with low body weight, and those with the major IL28B SNP genotype.

Conflict of interest

The authors declare that they have no conflict of interest.

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© Springer 2012