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doi:10.1111/jgh.12467

H E PAT O L O G Y

Treatment efficacy of pegylated interferon plus ribavirin therapy in chronic hepatitis C patients with mixed genotype 1/2 infection Ching-I Huang,*,†,‡,1 Chung-Feng Huang,*,†,§,1 Jee-Fu Huang,†,¶,** Chia-Yen Dai,†,††,¶ Ming-Lun Yeh,† Ming-Yen Hsieh,‡ Zu-Yau Lin,†,¶ Shinn-Cherng Chen,†,¶ Liang-Yen Wang,†,¶ Ming-Lung Yu†,¶ and Wan-Long Chuang†,¶ *Institute of Clinical Medicine, College of Medicine, Departments of ‡Internal Medicine and §Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, ¶Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, †Hepatobiliary Division, Department of Internal Medicine, **Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, and ††Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

Key words HCV, IL-28B, mixed infection, RGT, treatment. Accepted for publication 25 November 2013. Correspondence Professor Wan-Long Chuang, Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, 100 Tzyou 1st Road, Kaohsiung City, Taiwan. Email: [email protected]; [email protected] 1

Ching-I Huang and Chung-Feng Huang contributed equally to this work.

Abstract Background and Aim: The treatment efficacy of patients with mixed hepatitis C virus (HCV) genotype 1/genotype 2 (HCV-1/2) remains unknown. We aimed to elucidate the sustained virological response (SVR) rate in patients with HCV-1/2 infection. Methods: One hundred and ten HCV-1/2 patients treated with response-guided peginterferon/ribavirin therapy (24 weeks for patients with a rapid virological response [RVR] and low viral loads; 48 weeks for patients without a RVR or high viral loads) were allocated. Two hundred HCV-1 patients were selected as a historical control. Interleukin28B (IL-28B) rs8099917 genotype was tested for the association with an SVR. Results: The rates of RVR, sustained virologic response (SVR), and relapse rate were 71.8%, 87.3%, and 11.1%, respectively. The SVR rate was significantly higher in patients with an abbreviated regimen as compared with those with 48-week regimen (95.5% vs 75.0%, P = 0.002), and both were similar to the HCV-1 historical control. Stepwise logistic regression analysis revealed that lower baseline viral loads were the single factor predictive of an RVR (odds ratio/95% confidence intervals [OR/CI] of 41.62/9.72–178.19, P < 0.001). The achievement of an RVR was the single best factor predictive of an SVR (OR/CI: 7.5/1.33–42.27, P = 0.02). Nevertheless, an abbreviated regimen became the single factor associated with an SVR if treatment regimen was taken into consideration (OR/CI: 11.0/1.25–96.79, P = 0.03). The SVR rate did not differ between patients with rs8099917 TT and TG/GG genotype (91.7% vs 87.5%, P = 0.63). Conclusions: The treatment efficacy of patients with HCV-1/2 was satisfactory. The role of IL-28B genetic variants in the population with response-guided therapy was limited.

Introduction Hepatitis C virus (HCV) infection is the leading cause of liver diseases worldwide. It has become the main indication for liver transplantation and the leading cause of death among cirrhotic patients globally. In estimation, over 170 million people are chronically infected with HCV.1,2 Eradication of HCV is crucial in a clinical setting because it is associated with reduction of cirrhosis and liver cancer development and prolongation of survival.3,4 In the past two decades, combination therapy with pegylated interferon (pegIFN)-α plus ribavirin has greatly improved the treatment efficacy of chronic HCV infection (CHC). So far, it remains to be the standard of care (SOC) for CHC patients with favorable treatment efficacy in Asia despite the great innovation of 1012

direct antiviral agents.5 Several clinical predictors of the sustained virologic response (SVR), a reliable indicator of successful viral eradication, to combination therapy have been elucidated. The viral factors include genotypes, pretreatment viral load and on-treatment viral kinetics, whereas the host factors constitute interleukin-28B (IL-28B) polymorphisms, insulin resistance, age, body mass index, races etc.6–9 Viral genotypes have been initially regarded as a critical predictor of SVR achievement. There are currently six major HCV genotypes and more than 50 subtypes according to the phylogenetic difference of viral genome. HCV-1b, the most common genotype worldwide, is also the dominant genotype in Asia– Pacific, particularly in Japan, South Korea, China, and Taiwan. HCV-2a and 2b are also commonly distributed particularly in

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Japan, South Korea, and southern Taiwan.5 Genotype-guided therapeutic consideration has prevailed for one decade based on the previous observation that the treatment efficacy of HCV-2 is superior to that of HCV-1 infection.10–12 Such a consideration further shed the light on the evolution of individualized therapy in CHC. Previous studies addressing the issue of treatment efficacy of different genotypes were derived from an assessment of single genotype HCV infection. However, study elucidating the clinical manifestations and the treatment efficacy of patients with different genotypes mixed infection has rarely been made. Consequently, the current study aimed to evaluate the characteristics and treatment efficacy of patients with mixed HCV genotype 1 and 2 (HCV-1/2) infection. We also aimed to explore the impacts of IL-28B polymorphisms and the viral kinetics during treatment on the treatment response in the special population.

Methods Patients. Patients were consecutively included in a medical center and in two core regional hospitals from 2003 to 2007 in Taiwan. Eligible patients were treatment-naive Taiwanese patients with CHC, aged 18–65 years, who (1) were seropositive for HCV antibodies and HCV-RNA positive; (2) displayed an abnormal serum alanine aminotransferase (ALT) level preceding the study entry; and (3) maintained at 80% of assigned treatment duration. Other eligibility criteria included neutrophil count > 1500/mm3, platelet count > 9 × 104/mm3, hemoglobin concentration > 12 g/dL for men and 11 g/dL for women, serum creatinine concentration < 1.5 mg/dL, no pregnancy or lactation, and the use of a reliable method of contraception for women. Patients with hepatitis B surface antigen seropositive, human immunodeficiency virus infection, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, Wilson’s disease, α1-antitrypsin deficiency, decompensated cirrhosis (Child–Pugh class B or C), overt hepatic failure, current alcohol misuse or history of alcohol misuse (> 20 g/day), psychiatric condition, previous liver transplantation, or evidence of hepatocellular carcinoma (HCC) were excluded from the study. Study design. The ethical committee of the Kaohsiung Medical University Hospital approved the study before it began. The study was carried out according to the guidelines of the International Conference on Harmonization for Good Clinical Practice. Written informed consent for interview, anthropomorphic measurements, blood sampling including IL-28B genetic tests, and medical record review were obtained from patients prior to enrolment. All the enrolled patients received either pegIFN α-2a (Pegasys, Hoffmann-La Roche, Basal, Switzerland) at a dose of 180 μg/ week subcutaneously or pegIFN α-2b (PEG-Intron, ScheringPlough Inc., Kenilworth, NJ, USA) at a dose of 1.5 mcg/kg/week subcutaneously plus weight-based ribavirin (1000 mg/d for weight < 75 kg and 1200 mg/d for weight > 75 kg). All the patients were treated according to response-guided therapeutic strategies (RGT).10,13 HCV-1/2 patients with lower baseline viral loads (< 400 000 IU/mL) and a rapid virological response (RVR, defined as seronegative of HCV-RNA at week 4 of treatment) received an abbreviated 24-week regimen. A SOC regimen, namely 48 weeks

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of treatment duration, was prescribed for patients without achieving an RVR or high baseline viral loads. Patients had biweekly outpatient visits during the first month and monthly visits during the rest of the treatment period and during the 24-week follow-up period. To compare the treatment efficacy of the patients with those with HCV-1 infection, 200 HCV-1 patients of our previous randomized control trial were selected as historical control for comparison.14 Assessment of efficacy. The primary outcome was to measure the achievement of an SVR, defined as seronegativity of HCV-RNA throughout 24 weeks of post-treatment follow-up period. RVR was defined as seronegativity of HCV-RNA at treatment week 4. Early virological response (EVR) was defined as seronegative or at least a 2-log10 decrease from baseline of serum HCV-RNA at 12 weeks of treatment. End-of-treatment virological response (EOTVR) was defined as seronegativity of HCV-RNA at the end of treatment. Relapse was defined as HCV-RNA reappearance during the follow-up period in patients who achieved an EOTVR. Laboratory analyses. Hepatitis B surface antigen and antiHCV antibody were detected using a third-generation, commercially available enzyme-linked immunosorbent assay kit (AxSYM 3.0, Abbott Laboratories, Chicago, IL, USA). Detection of serum HCV-RNA was performed using a standardized automated qualitative reverse transcription–polymerase chain reaction assay (COBAS AMPLICOR Hepatitis C Virus Test, ver. 2.0; Roche, Branchburg, NJ, USA). The detection limit was 50 IU/mL. HCV genotypes were determined by the Okamoto method.15 Biochemical items were measured on a multichannel autoanalyzer (Hitachi Inc. Tokyo, Japan). IL-28B rs8099917 was selected as candidate single nucleotide polymorphism (SNP) in the current study based on previous studies.6–8 IL-28B genotypes of the patients were determined by the ABI TaqMan® SNP genotyping assays (Applied Biosystems, Foster City, CA, USA) by using the predesigned commercial genotyping assays (ABI Assay ID: C__11710096_10). Briefly, polymerase chain reaction (PCR) primers and two allelic-specific probes were designed to detect specific SNP target. The PCR reactions were performed in the 96-well microplates with ABI 7500 real-time PCR (Applied Biosystems). Allele discrimination was achieved by detecting fluorescence using its System SDS software version 1.2.3 (Applied Biosystems). Statistical analyses. Frequency was compared between groups using the χ2 test, with the Yates correction, or Fisher’s exact test. Group means, presented as mean values standard deviation, were compared using analysis of variance and the Student’s t-test or the Mann–Whitney U-test. Serum HCV-RNA levels were expressed after logarithmic transformation of original values. The aspartate aminotransferase (AST)-to-platelet ratio index (APRI) was calculated by the following equation: (AST level/upper limit of normal range)/platelet counts (109/L) × 100, to represent the severity of liver fibrosis.16,17 The frequencies of the rare allele (G) of rs8099917 genotype were too low, and the rare homozygote (GG) and heterozygote (GT) were combined together while analyzing the SNP. To assess the relative contribution of predictors of

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RVR and SVR, a multivariable model was applied with age, sex, baseline HCV-RNA levels, body weight, APRI, treatment regimen, and rs8099917 genotype as covariates. The statistical analyses were performed using the SPSS 12.0 statistical package (SPSS, Chicago, IL, USA). All statistical analyses were based on twosided hypothesis tests with a significance level of P < 0.05.

Results Patient characteristics. One-hundred and seventy-eight of the 1229 patients (14.5%) in the treatment population were mixed infected with HCV-1/2 in the treatment cohort. After excluding 68 non-RVR or high viral loads patients treated for only 24 weeks supported by National Health Insurance in Taiwan, 110 patients who received RGT were allocated for final evaluation (Appendix Figure S1). The basic demographical, virological, and clinical features of the patients were shown in Table 1. Sixty-six (60.0%) of the 110 patients were treated with an abbreviated 24-week regimen, whereas 44 (40.0%) patients were treated with a standard 48-week regimen. The mean baseline HCV-RNA levels were 5.1 logs IU/mL. Among the patients with available IL-28B genotype, rs8099917 TT genotype accounted for 78.9% (60/76) of the population, and 16 (21.1%) patients were with rs8099917 non-TT genotype. Treatment responses. The rates of RVR, EVR, EOTVR, SVR, and relapse rates were 71.8% (79/110), 98.2% (108/110), 98.2% (108/110), 87.3% (96/110), and 11.1% (12/108), respectively. For patients with a 24-week abbreviated regimen, the SVR was 95.5% (confidence intervals [CI]: 90.5–100.5%) of the patients with mixed HCV-1/2 infection as compared with 96.4% (CI: 89.5–103.3%) of the HCV-1 historical control, and the relapse rate was 4.5% (CI: −0.5 to 9.5%) of the patients with mixed HCV-1/2 infection as compared with 3.6% (CI: −3.3 to 10.5%) of the HCV-1 control. For patients with a 48-week SOC regimen, the SVR was 75.0% (CI: 62.2–87.8%) of the patients with mixed HCV-1/2 infection as compared with 71.4% (CI: 61.2–81.2%) of Table 1

Impact of IL-28B rs8099917 on treatment responses. The basic characteristics and treatment responses did not differ significantly between patients with or without available IL-28B genotype data regarding both (Table 4). Among patients with available IL-28B genotype, treatment responses including the rates of RVR (68.3% vs 81.3%, P = 0.37), EVR (98.3% vs 93.8%, P = 0.38), EOTVR (98.3% vs 100%, P = 1.0), SVR (91.7% vs 87.5%, P = 0.63), and relapse rate (6.8% vs 12.5%, P = 0.60) were not different significantly between patients with rs8099917 TT and non-TT genotype (Fig. 2).

Discussion 55 (50.0) 55 (50.0) 51.1 ± 11.4 65.4 ± 12.4 60 (78.9) 70 (63.6) 5.1 ± 1.2 91.6 ± 74.8 146.0 ± 203.6 5.7 ± 1.7 14.1 ± 1.5 171.4 ± 61.5 2.5 ± 2.1 66 (60.0)

Data available in 76 patients. ALT, alanine aminotransferase; APRI, alanine aminotransferase to platelet ratio index; AST, aspartate aminotransferase; HCV, hepatitis C virus.

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Factors associated with treatments responses. In univariate analysis, a lower baseline HCV-RNA level and a lower body weight were factors significantly associated with an RVR. Stepwise logistic regression analysis revealed that a lower baseline viral load was the single factor predictive of an RVR with an odds ratio (OR)/CI of 41.62/9.72–178.19, P < 0.001 (Table 2). Patients with low body weight, low pretreatment HCV-RNA levels, the achievement of an RVR, and with an abbreviated regimen were factors predictive of an SVR in univariate analysis (Table 3). Logistic regression revealed that the achievement of RVR was the single best factor predictive of an SVR (OR/CI: 7.5/1.33–42.27, P = 0.02). Nevertheless, an abbreviated regimen became the single factor associated with an SVR (OR/CI: 11.0 /1.25–96.79, P = 0.031) if treatment regimen was taken into consideration (Table 3).

Basic demographic and clinical features of the 110 patients

Sex, n (%) Male Female Age (years, mean ± SD) Body weight (kg, mean ± SD) Rs8099917 genotype (TT), n (%)† Baseline viral loads, < 400 000 IU/mL, n (%) Baseline HCV-RNA (log IU/mL, mean ± SD) AST (IU/L, mean ± SD) ALT (IU/L, mean ± SD) White blood cell count (× 103u/L, mean ± SD) Hemoglobin (g/dL, mean ± SD) Platelet count (×103 u/L, mean ± SD) APRI (mean ± SD) Twenty-four weeks treatment duration, n (%) †

the HCV-1 control, and the relapse rate was 21.4% (CI: 9.0– 33.8%) of the patients with mixed HCV-1/2 infection as compared with 16.7% (CI: 7.7–25.7%) of the HCV-1 control. The SVR rate was significantly higher in patients with an abbreviated regimen than those who received a standard 48-week regimen (P = 0.002). Among patients with a RVR, the SVR rate did not differ between patients with a 24 -week abbreviated regimens and those with high viral loads who received 48-week treatments (95.5% vs 84.6%, P = 0.19). Among non-RVR patients who received 48 weeks regimen, the SVR rate was similar between patients with low or high baseline HCV-RNA levels (66.7% vs 71.4%, P = 1) (Fig. 1).

Although the acquisition route of HCV-1/2 mixed infection remains to be elusive from the viewpoint of public health, there was an urgent need to treat the patients to prevent liver disease progression, HCC development and to improve their survival.18–21 The issue is particularly essential in regions where HCV infection is endemic and both HCV-1 and HCV-2 are the main genotypes.5,22 We demonstrated that the overall SVR rate reached 87% with response-guided therapeutic regimen in mixed-infection patients. Of particular note was that a more favorable SVR rate of 95.5% was observed in the patients eligible for a shorten treatment duration of 24 weeks. The SVR rate of those who had a lower baseline viral load and achieved a RVR was significantly higher than those receiving a standard 48 weeks of treatment duration, and both were similar to HCV-1 controls. Our results further showed that host IL-28B genetic variant did not play a determined role in the prediction of treatment efficacy in patients with mixed HCV-1/2

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Figure 1 Treatment responses according to baseline viral loads, the achievement of a rapid virological response (RVR) and treatment duration. HVL, high viral loads, defined as hepatitis C virus (HCV) RNA levels > 400,000 IU/mL; LVL, low viral loads, defined as HCV-RNA levels < 400,000 IU/mL; SVR, sustained virological response.

Table 2 Univariate and logistic regression analysis for factors associated with rapid virological response in 110 chronic hepatitis C patients with genotype 1/2 mixed infection

Male gender, n (%) Age (years, mean ± SD) IL-28B rs8099917 TT genotype, n (%)† Viral load, < 400 000 IU/mL, n (%) Body weight (kg, mean ± SD) AST (IU/L, mean ± SD) ALT (IU/L, mean ± SD) APRI(mean ± SD)

RVR (+) (n = 79)

RVR (−) (n = 31)

P value

40 (50.6) 51.8 ± 11.9 41 (75.9) 67 (84.8) 63.9 ± 11.8 98.3 ± 84.3 159.5 ± 235.7 2.7 ± 2.2

15 (48.4) 49.3 ± 10.2 19 (86.4) 3 (9.7) 69.1 ± 13.3 74.6 ± 37.4 111.4 ± 66.8 2.1 ± 1.6

0.83 0.31 0.37 < 0.001 0.048 0.14 0.27 0.15

Logistic regression analysis OR

95% CI

P value

41.62

9.72–178.19

< 0.001

†

Data available in 76 patients. ALT, alanine aminotransferase; APRI, aspartate aminotransferase to platelet ratio index; AST, aspartate aminotransferase; CI, confidence intervals; HCV, hepatitis C virus; IL-28B, interleukin-28B gene; OR, odds ratio; RVR, rapid virological response.

infection. HCV genotype has been suggested to be the most important viral factor in the management of HCV infection. A 48 weeks of pegINF plus standard doses of ribavirin for HCV-1/4 and a 24-week regimen with lower dose of ribavirin, 800 mg/day for HCV-2/3 patients, is recommended according to genotype-guided therapy.10,13 Response-guided therapy based on on-treatment responses further facilitates the treatment strategy of HCV-1 and HCV-2 infection on an individual basis.14,21,23 The elucidation of HCV viral kinetics on treatment has facilitated response-guided therapy with tailored regimen for CHC. Generally, the achievement of a RVR has replaced HCV genotype as the most viral factor to be concerned during antiviral therapy.14,21,24 Therefore, HCV-1 or -4 patients with lower baseline viral loads and an RVR could have an abbreviated 24-week regimen, which

leads to a comparable and satisfactory treatment outcome with a standard 48-week regimen did.10,14,15 As earlier reports in the West,25,26 an SVR rate of 94–96% could be achieved by Taiwanese patients with an RVR and low baseline viral loads by using an abbreviated 24-weeks regimen.14,23 The Bureau of National Health Insurance in Taiwan reimbursed HCV treatment for a 24-week combination therapy regardless viral genotypes since 2003 until 2009. Patients with high baseline HCV-RNA levels or without an RVR were encouraged to extend to a 48-week standard therapy. However, the treatment strategy toward HCV-1/2 mixed infection has never been set up before. A hypothesis might be that the clinical characteristics of patients with mixed HCV-1/2 infection might act between those with HCV-1 and HCV-2 infection. In the current prove-of-concept study, we tried to explore the efficacy of

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Table 3 Univariate and logistic regression analysis for factors associated with sustained virological response in 110 chronic hepatitis C patients with genotype type 1/2 mixed infection

Male sex, n (%) IL-28B rs8099917(TT), n (%)† Viral load < 400 000 IU/mL, n (%) Baseline HCV-RNA (log IU/mL, mean ± SD) Age (years, mean ± SD) Body weight (kg, mean ± SD) AST (IU/L, mean ± SD) ALT (IU/L, mean ± SD) APRI (mean ± SD) RVR, n (%) 24 weeks treatment duration, n (%)

SVR (+) (n = 96)

SVR (−) (n = 14)

P value

47 (49.0) 55 (79.7) 66 (68.8) 5.0 ± 1.2 51.1 ± 11.2 64.5 ± 12.1 94.2 ± 78.8 152.9 ± 216.8 2.5 ± 2.1 74 (77.1) 63 (65.6)

8 (57.1) 5 (71.4) 4 (28.6) 6.0 ± 0.7 51.1 ± 13.4 71.9 ± 12.7 74.0 ± 32.6 98.1 ± 37.3 2.6 ± 2.0 5 (35.7) 3 (21.4)

0.57 0.63 0.004 0.003 0.98 0.04 0.35 0.35 0.91 0.003 0.002

Logistic regression analysis for SVR without consideration of treatment duration OR 95% CI P value

7.5

1.33–42.27

Logistic regression analysis for SVR if treatment duration is considered OR 95% CI P value

0.02 11.0

1.25–96.79

0.03

†

Data available in 76 patients. ALT, alanine aminotransferase; APRI, aspartate aminotransferase to platelet ratio index; AST, aspartate aminotransferase; CI, confidence intervals; HCV, hepatitis C virus; IL-28B, interleukin-28B gene; OR, odds ratio; RVR, rapid virological response; SD, standard deviation; SVR, sustained virological response.

Table 4

Basic demographical, virological, clinical features and treatment responses of the patients with or without available IL-28B data

Sex, n (%) Male Female Viral load, < 400 K IU/mL, n (%) Age (years, mean ± SD) Body weight (kg, mean ± SD) AST (IU/L, mean ± SD) ALT (IU/L, mean ± SD) White blood cell count (×103u/L, mean ± SD) Hemoglobin (g/dL, mean ± SD) Platelet count (×103 u/L, mean ± SD) APRI mean ± SD) RVR, n (%) EVR, n (%) EOTVR, n (%) SVR, n (%) Relapse, n (%)

IL-28B data available (n = 76)

IL-28B data unavailable (n = 34)

34 (44.7) 42 (55.3) 26 (34.2) 50.0 ± 11.5 65.8 ± 12.73 88.1 ± 49.2 133.6 ± 84.1 6.0 ± 1.6 14.3 ± 1.5 171.9 ± 50.1 2.4 ± 1.8 54 (71.1) 74 (97.4) 75 (98.7) 69 (90.8) 6 (8.0)

21 (61.8) 13 (38.2) 14 (41.2) 53.5 ± 11.2 64.5 ± 11.9 99.5 ± 113.5 173.5 ± 346.0 5.1 ± 1.7 13.8 ± 1.4 170.3 ± 82.2 2.8 ± 2.6 25 (73.5) 34 (100.0) 33 (97.1) 27 (79.4) 33 (18.2)

P value

0.1

0.48 0.14 0.60 0.46 0.35 0.01 0.17 0.90 0.30 0.79 1 0.53 0.12 0.18

ALT, alanine aminotransferase; APRI, alanine aminotransferase to platelet ratio index; AST, aspartate aminotransferase; EOTVR, end of treatment response; EVR, early virological response; HCV, hepatitis C virus; RVR, rapid virological response; SVR, sustained virological response.

patients with HCV-1/2 infection and decided a more strict strategy by treating patients by using response-guided therapy just as treatment toward HCV-1 infection. We demonstrated an excellent SVR rate up to 96% in patients with an abbreviated regimen, which was similar to that of HCV-1 infection with abbreviated regimen.14,23 As with the studies of HCV-1 or HCV-2 infection,4,14,23 baseline viral loads was a major determinant for attaining a RVR, and the achievement of a RVR was the most important factor associated with the SVR in patients with mixed HCV-1/2 infection Meanwhile, the influence of the virological and on-treatment factor

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might be independent of host IL-28B genetic variants.6–8,27 HCV1/2 patients with high baseline viral loads or without a RVR had a significantly lower SVR rate even with a 48-week regimen. Although it was not a head-to-head comparison, the SVR rate remained to be 75%, which was not far from those HCV-1 historical controls bearing unfavorable baseline or on-treatment viral factors with a standard 48-week regimen.14 Recently, the development of direct antiviral agents has become the SOC for HCV-1 infection in the West,28 and the trials of its application for HCV-2/3 infection are on the way.29,30 However, the role of the innovation toward patients with HCV-1/2 mixed infection is unclear so far.

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Figure 2 Treatment responses stratified by interleukin (IL)-28B genotype. The deep brown bar represented patients with IL-28B rs8099917 TT genotype, and the grey bar represented patients with IL-28B rs8099917 TG/GG genotype. EOTVR, end-of-treatment virological response; EVR, early virological response; RVR, rapid virological response.

The satisfactory result in the current study might provide insight for the management of Asian patients with HCV-1/2 infection by pegINF/ribavirin. Beyond the achievement of an RVR, emerging evidence has demonstrated that host IL-28B genetic variants are the most important pretreatment determinant of SVR achievement.7,8,31 The influence of IL28B genetic variants in the treatment of HCV-1 infection has been well documented7,8,31 despite the results of its role in HCV-2 infection remain an argument of debate.30,32–34 In the current study, host-IL-28B genetic variants did not determine either early viral kinetics or final treatment outcome of the patients with HCV-1/2 infection. It should be interpreted cautiously because some of the data regarding IL-28B genetic variants were unavailable and the sample size might be too small for a definite conclusion to be addressed. However, the basic demographic of the patients and the treatment responses did not differ statically between patients with or without available IL-28B genetic polymorphisms; hence the disturbance of the bias would be minimized. The other limitation of the current study was its retrospective nature. To explore the responses of interferon-based therapy upon the particular population, patients being selected were those who were adherent to treatment regimens, and the current findings might shed light for further prospective study to truly clarify the efficacy in the real world. In conclusion, the outcome of patients with HCV-1/2 infection treated by response-guided therapy was satisfactory. The clinical utility of host IL-28B genetic variants in the management of the special population might be limited.

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Supporting information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Figure S1 Patient flow chart.

Journal of Gastroenterology and Hepatology 29 (2014) 1012–1018 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd