Vol. 55, No. 6, 2012
Issue release date: October 2012
Intervirology 2012;55:417–425
(DOI:10.1159/000323526)
Original Paper
Add to my selection

Amino Acid Substitution in HCV Core Region and Genetic Variation near the IL28B Gene Affect Viral Dynamics during Telaprevir, Peginterferon and Ribavirin Treatment

Akuta N.a · Suzuki F.a · Hirakawa M.a · Kawamura Y.a · Yatsuji H.a · Sezaki H.a · Suzuki Y.a · Hosaka T.a · Kobayashi M.a · Kobayashi M.b · Saitoh S.a · Arase Y.a · Ikeda K.a · Chayama K.d · Nakamura Y.c · Kumada H.a
aDepartment of Hepatology, and bLiver Research Laboratory, Toranomon Hospital, cLaboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, and dDepartment of Medical and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
email Corresponding Author


 Outline


 goto top of outline Key Words

  • Hepatitis C virus
  • Core region
  • IL28B
  • Telaprevir
  • Peginterferon
  • Ribavirin
  • Viral dynamics

 goto top of outline Abstract

Objectives: Genetic variation near the IL28B gene and substitution of aa 70 and 91 in the core region of HCV-1b are useful as predictors of treatment efficacy to telaprevir/pegylated interferon (PEG-IFN)/ribavirin, but its impact on viral dynamics is not clear. Methods: This study investigated predictive factors of viral dynamics during 12- or 24-week regimen of triple therapy in 80 Japanese adults infected with HCV-1b. Results: After 24 h of commencement of treatment, the proportion of patients with Arg70 and Leu91 substitutions in the core region who showed ≥3.0 log drop in HCV RNA level was significantly higher than that of patients with Gln70 (His70) and/or Met91. At 8 and 12 weeks, HCV RNA loss rate of patients with rs8099917 genotype TT near IL28B gene was significantly higher than that of patients with non-TT. Multivariate analysis identified substitution of aa 70 and 91 as a predictor of ≥3.0 log fall in HCV RNA level at 24 h (Arg70 and Leu91) and SVR (Arg70), and rs8099917 (TT) as a predictor of HCV RNA loss at 12 weeks and SVR. Conclusions: This study identified genetic variation near IL28B gene and aa substitution of the core region as predictors of viral dynamics during triple therapy.

Copyright © 2012 S. Karger AG, Basel


goto top of outline Introduction

Hepatitis C virus (HCV) usually causes chronic infection that can result in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) [1,2]. At present, treatments based on interferon (IFN), in combination with ribavirin, are mainstay for combating HCV infection. In Japan, HCV genotype 1b (HCV-1b) in high viral loads (>100 kIU/ml) accounts for more than 70% of HCV infections, making it difficult to treat patients with chronic hepatitis C [3]. Such a background calls for efficient treatments of Japanese patients with chronic HCV infection.

Even with pegylated IFN (PEG-IFN) combined with ribavirin, a sustained virological response lasting over 24 weeks after the withdrawal of treatment is achieved in at most 50% of the patients infected with HCV-1b and high viral loads [4,5]. Recently, a new strategy was introduced in the treatment of chronic HCV infection by means of inhibiting protease in the NS3/NS4 of the HCV polyprotein. Of these, telaprevir (VX-950) was selected as a candidate agent for treatment of chronic HCV infection [6]. Later, it was found that telaprevir, when combined with PEG-IFN and ribavirin, gains a robust antiviral activity [7,8]. Two previous studies (PROVE1 and PROVE2) showed that the 12- and 24-week regimen of telaprevir/PEG-IFN/ribavirin could achieve sustained virological response rates of 35–60 and 61–69% in patients infected with HCV-1, respectively [9,10]. Furthermore, a recent study (PROVE3) also showed that the 24- and 48-week regimen of triple therapy could achieve sustained virological response rates of 51 and 53% in HCV-1 infected patients in whom initial PEG-IFN/ribavirin treatment failed, respectively [11].

Amino acid (aa) substitutions at positions 70 and/or 91 in the HCV core region of patients infected with HCV-1b and high viral loads are pretreatment predictors of poor virological response to PEG-IFN plus ribavirin combination therapy [12,13,14], and also affect clinical outcome, including hepatocarcinogenesis [15,16]. Furthermore, genetic variations near the IL28B gene (rs8099917, rs12979860) on chromosome 19 as host-related factor, which encodes IFN-λ-3, are pretreatment predictors of virological response to 48-week PEG-IFN plus ribavirin combination therapy in individuals infected with HCV-1 [17,18,19,20], and also affect clinical outcome, including spontaneous clearance of HCV [21]. A recent report identified genetic variation near IL28B gene and aa substitution of the core region as predictors of sustained virological response to triple therapy of telaprevir/PEG-IFN/ribavirin in Japanese patients infected with HCV-1b [22]. However, it is not clear at this stage whether genetic variation near the IL28B gene and aa substitution of the core region can be used before therapy to predict viral dynamics during triple therapy.

The present study included 80 patients with HCV-1b and high viral loads, who received the triple therapy of telaprevir with PEG-IFN plus ribavirin. The aims of the study were to identify the pretreatment factors that could predict viral dynamics during treatment, including viral- (aa substitutions in the HCV core and NS5A regions) and host-related factors (genetic variation near IL28B gene).

 

goto top of outline Patients and Methods

goto top of outline Study Population

Between May 2008 and September 2009, 81 patients infected with HCV were recruited to this study at the Department of Hepatology in Toranomon Hospital in metropolitan Tokyo. The study protocol was in compliance with the Good Clinical Practice Guidelines and the 1975 Declaration of Helsinki, and was approved by the institutional review board. Each patient gave an informed consent before participating in this trial. Patients were divided into two groups: 20 (25%) patients were allocated to a 12-week regimen of triple therapy [telaprevir (MP-424), PEG-IFN and ribavirin] (the T12PR12 group), and 61 patients (75%) were assigned to a 24-week regimen of the same triple therapy for 12 weeks followed by dual therapy of PEG-IFN and ribavirin for 12 weeks (the T12PR24 group).

Eighty of the 81 patients met the following inclusion and exclusion criteria: (1) Diagnosis of chronic hepatitis C. (2) HCV-1b confirmed by sequence analysis. (3) HCV RNA levels of ≥5.0 log IU/ml determined by the COBAS TaqMan HCV test (Roche Diagnostics, Tokyo, Japan). (4) Japanese (Mongoloid) ethnicity. (5) Age at study entry of 20–65 years. (6) Body weight ≥35 kg and ≤120 kg at the time of registration. (7) Lack of decompensated liver cirrhosis. (8) Negativity for hepatitis B surface antigen (HBsAg) in serum. (9) Negative history of HCC. (10) No previous treatment for malignancy. (11) Negative history of autoimmune hepatitis, alcohol liver disease, hemochromatosis, and chronic liver disease other than chronic hepatitis C. (12) Negative history of depression, schizophrenia or suicide attempts, hemoglobinopathies, angina pectoris, cardiac insufficiency, myocardial infarction or severe arrhythmia, uncontrollable hypertension, chronic renal dysfunction or creatinine clearance of ≤50 ml/min at baseline, diabetes requiring treatment or fasting glucose level of ≥110 mg/dl, autoimmune disease, cerebrovascular disorders, thyroidal dysfunction uncontrollable by medical treatment, chronic pulmonary disease, allergy to medication or anaphylaxis at baseline. (13) Hemoglobin level of ≥12 g/dl, neutrophil count ≥1,500/mm3, and platelet count of ≥100,000/mm3 at baseline. Pregnant or breast-feeding women or those willing to become pregnant during the study and men with a pregnant partner were excluded from the study. In this study, all of the 80 patients were evaluated for the pretreatment predictors for viral dynamics during triple therapy, and 77 of the 80 patients were followed up for at least 24 weeks after the completion of treatment. The treatment efficacy was evaluated by 24 weeks after the completion of therapy (sustained virological response), based on the COBAS TaqMan HCV test (Roche Diagnostics).

Telaprevir (MP-424; Mitsubishi Tanabe Pharma, Osaka, Japan) was administered at 750 or 500 mg three times a day at an 8-hour (q8) interval after the meal. PEG-IFNα-2b (PEG-Intron; Schering Plough, Kenklworth, N.J., USA) was injected subcutaneously at a median dose of 1.5 µg/kg (range 1.3–2.0 µg/kg) once a week. Ribavirin (Rebetol; Schering Plough) was administered at 200–600 mg twice a day after breakfast and dinner (daily dose 600–1,000 mg).

PEG-IFN and ribavirin were discontinued or their doses reduced, as required, upon reduction of hemoglobin level, leukocyte count, neutrophil count or platelet count, or the development of adverse events. Thus, the dose of PEG-IFN was reduced by 50% when the leukocyte count decreased below 1,500/mm3, neutrophil count below 750/mm3 or platelet count below 80,000/mm3; PEG-IFN was discontinued when these counts decreased below 1,000/mm3, 500/mm3 or 50,000/mm3, respectively. When hemoglobin decreased to <10 g/dl, the daily dose of ribavirin was reduced from 600 to 400, 800 to 600 and 1,000 to 600 mg, depending on the initial dose. Ribavirin was withdrawn when hemoglobin decreased to <8.5 g/dl. However, the dose of telaprevir (MP-424) remained the same, and its administration was stopped when the discontinuation was appropriate for the development of adverse events. In those patients who discontinued telaprevir, treatment with PEG-IFNα-2b and ribavirin was also terminated.

Table 1 summarizes the profiles and laboratory data of the 80 patients at the commencement of treatment. They included 43 males and 37 females, aged 23–65 years (median 55 years).

TAB01
Table 1. Profile and laboratory data at commencement of telaprevir, peginterferon and ribavirin triple therapy in Japanese patients infected with HCV-1b

goto top of outline Measurement of HCV RNA

The antiviral effects of the triple therapy on HCV were assessed by measuring plasma HCV RNA levels. In this study, HCV RNA levels during treatment were evaluated at least once every month before, during, and after therapy. Furthermore, to investigate the pretreatment predictors for viral dynamics, HCV RNA levels during treatment were evaluated at 7 time points; 24 h, 1, 2, 4, 6, 8 and 12 weeks after the commencement of treatment. HCV RNA levels during treatment were evaluated in 80 (100%), 80 (100%), 80 (100%), 79 (98.8%), 75 (93.8%), 74 (92.5%), and 69 (86.3%) of the 80 patients, at the above time intervals, respectively. HCV RNA concentrations were determined using the COBAS TaqMan HCV test (Roche Diagnostics). The linear dynamic range of the assay was 1.2–7.8 log IU/ml, and the undetectable samples were defined as loss of HCV RNA. Especially, falls in HCV RNA levels at 24 h relative to baseline were investigated as very early dynamics.

goto top of outline Detection of Amino Acid Substitutions in Core and NS5A Regions of HCV-1b

With the use of HCV-J (accession No. D90208) as a reference [23], the sequence of 1–191 aa in the core protein of HCV-1b was determined and then compared with the consensus sequence constructed on 80 clinical samples to detect substitutions at aa 70 of arginine (Arg70) or glutamine/histidine (Gln70/His70) and aa 91 of leucine (Leu91) or methionine (Met91) [12]. The sequence of 2209–2248 aa in the NS5A of HCV-1b (IFN sensitivity-determining region; ISDR) reported by Enomoto et al. [24] was determined, and the numbers of aa substitutions in ISDR were defined as wild-type (0, 1) or non-wild-type (≥2). In the present study, aa substitutions of the core region and NS5A-ISDR of HCV-1b were analyzed by direct sequencing [22].

goto top of outline Genetic Variation near IL28B Gene

Samples for genomewide association survey were genotyped using the Illumina HumanHap610-Quad Genotyping BeadChip. Genotyping data were subjected to quality control before the data analysis. Genotyping for replication and fine mapping was performed by use of the Invader assay, TaqMan assay, or direct sequencing as described previously [25,26].

In this study, genetic variations near IL28B gene (rs8099917, rs12979860), reported as the pretreatment predictors of treatment efficacy and clinical outcome [17,18,19,20,21,22], were investigated.

goto top of outline Statistical Analysis

Nonparametric tests (χ2 test and Fisher’s exact probability test) were used to compare the characteristics of the groups. Univariate and multivariate logistic regression analyses were used to determine those factors that significantly contributed to viral dynamics and sustained virological response. The ORs and 95%CI were also calculated. All p values less than 0.05 by the two-tailed test were considered significant. Variables that achieved statistical significance (p < 0.05) on univariate analysis were entered into multiple logistic regression analysis to identify significant independent predictive factors. Each variable was transformed into categorical data consisting of two simple ordinal numbers for univariate and multivariate analyses. The potential pretreatment factors associated with treatment efficacy included the following variables: sex, age, history of blood transfusion, familial history of liver disease, body mass index, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, gamma-glutamyl transpeptidase (γGTP), leukocyte count, hemoglobin, platelet count, HCV RNA level, α-fetoprotein, total cholesterol, fasting blood sugar, PEG-IFN dose/body weight, ribavirin dose/body weight, telaprevir dose/day, treatment regimen of triple therapy, past history of IFN therapy, genetic variation near the IL28B gene, and amino acid substitution in the core region, and NS5A-ISDR. Statistical analyses were performed using the SPSS software (SPSS Inc., Chicago, Ill., USA).

 

goto top of outline Results

goto top of outline Virological Response to Therapy and Loss of HCV RNA during Treatment

Sustained virological response was achieved by 63.6% (49 of 77 patients). The disappearance rate of HCV RNA during treatment was 0% (0 of 80), 1.3% (1 of 80), 33.8% (27 of 80), 81.0% (64 of 79), 90.7% (68 of 75), 94.6% (70 of 74), and 89.9% (62 of 69) at 24 hours, 1, 2, 4, 6, 8, and 12 weeks, respectively.

goto top of outline Very Early Dynamics according to Amino Acid Substitutions in Core Region and Genetic Variation near the IL28B Gene

After 24 h of commencement of the triple therapy, the proportion of patients with Arg70 and Leu91 substitutions who showed ≥3.0 log drop in HCV RNA level (45.2%; 14 of 31 patients) was significantly higher than that of patients with Gln70 (His70) and/or Met91 (14.3%; 7 of 49) (p = 0.004). Thus, patients with Arg70 and Leu91 (median 2.9 log IU/ml; range 1.8–4.0 log IU/ml) significantly showed the steeper decline of HCV RNA level than those with Gln70 (His70) and/or Met91 (median 2.7 log IU/ml; range 1.6–3.5 log IU/ml) (fig. 1a).

FIG01
Fig. 1.a Very early dynamics according to amino acid substitutions in core region. After 24 h of commencement of the triple therapy, patients with Arg70 and Leu91 (median 2.9 log IU/ml; range 1.8–4.0 log IU/ml) significantly showed the steeper decline of HCV RNA level than those with Gln70 (His70) and/or Met91 (median 2.7 log IU/ml; range 1.6–3.5 log IU/ml). b Very early dynamics according to genetic variation near the IL28B gene. After 24 h of commencement of the triple therapy, the decline of HCV RNA level of patients with rs8099917 genotype TT (median 2.8 log IU/ml; range 1.6–4.0 log IU/ml) was not significantly different from that of patients with genotype TG and GG (median 2.7 log IU/ml; range 2.2–3.5 log IU/ml).

After 24 h of commencement of treatment, the proportion of patients with rs8099917 genotype TT who showed ≥3.0 log drop in HCV RNA level (30.4%; 14 of 46 patients) was not significantly different from that of patients with genotype TG and GG (21.9%; 7 of 32). Thus, the decline of HCV RNA level of patients with genotype TT (median 2.8 log IU/ml; range 1.6–4.0 log IU/ml) was not significantly different from that of patients with genotype TG and GG (median 2.7 log IU/ml; range 2.2–3.5 log IU/ml) (fig. 1b).

Hence, the fall in HCV RNA level at 24 h was influenced by aa substitution patterns in the core region, but was independent of genetic variation near IL28B gene.

goto top of outline Rates of Loss of HCV RNA according to Amino Acid Substitutions in Core Region and Genetic Variation near the IL28B Gene

According to the substitution of core aa 70 and 91, the rate of HCV RNA loss of patients with Arg70 and Leu91 was not significantly different from that of patients with Gln70 (His70) and/or Met91 at each time point (1, 2, 4, 6, 8 and 12 weeks).

According to genetic variation near the IL28B gene, the rate of HCV RNA loss at 1, 2, 4 and 6 weeks was not significantly different between rs8099917 genotype TT and non-TT (TG and GG). However, at 8 and 12 weeks, the rate of HCV RNA loss of patients with genotype TT was significantly higher than that of patients with genotype non-TT (fig. 2).

FIG02
Fig. 2. Rates of loss of HCV RNA according to genetic variation near the IL28B gene. According to genetic variation near the IL28B gene, the rate of HCV RNA loss at 1, 2, 4 and 6 weeks was not significantly different between rs8099917 genotype TT and non-TT (TG and GG). However, at 8 and 12 weeks, the rate of HCV RNA loss of patients with genotype TT was significantly higher than that of patients with genotype non-TT.

goto top of outline Predictive Factors Associated with ≥3.0 log Fall in HCV RNA Level at 24 Hours

Univariate analysis identified two parameters that correlated with ≥3.0 log fall in HCV RNA level at 24 h significantly: substitution of aa 70 and 91 (Arg70 and Leu91; OR 4.94, p = 0.003) and body mass index (≥25.0; OR 3.92, p = 0.022). Two factors were identified by multivariate analysis as independent parameters that either significantly (p < 0.05) or marginally (p < 0.10) influenced ≥3.0 log fall in HCV RNA level at 24 h [Arg70 and Leu91 (OR 3.99, p = 0.015) and body mass index ≥25.0 (OR 3.24, p = 0.061)] (table 2).

TAB02
Table 2. Factors associated with treatment efficacy of telaprevir, peginterferon and ribavirin triple therapy in Japanese patients infected with HCV-1b, identified by univariate and multivariate analysis

goto top of outline Predictive Factors Associated with Loss of HCV RNA at 2, 4 and 12 Weeks

Univariate analysis identified two parameters that correlated with loss of HCV RNA at 2 weeks significantly: platelet count (≥15.0 × 104/mm3; OR 6.99, p = 0.014) and level of viremia (<7.0 log IU/ml; OR 3.13, p = 0.045). One factor was identified by multivariate analysis as independent parameter that either significantly or marginally influenced loss of HCV RNA at 2 weeks (platelet count ≥15.0 × 104/mm3; OR 6.99, p = 0.014) (table 2).

Univariate analysis identified two parameters that correlated with loss of HCV RNA at 4 weeks significantly: history of blood transfusion (absence; OR 5.71, p = 0.006) and body mass index (≥20.0; OR 4.29, p = 0.019). Two factors were identified by multivariate analysis as independent parameters that either significantly or marginally influenced loss of HCV RNA at 4 weeks (history of blood transfusion: absence; OR 4.29, p = 0.026, and body mass index ≥20.0; OR 3.47, p = 0.069) (table 2).

Univariate analysis identified two parameters that correlated with loss of HCV RNA at 12 weeks significantly: sex (male; OR 9.52, p = 0.043) and genetic variation in rs8099917 (genotype TT; OR 9.00, p = 0.048). Two factors were identified by multivariate analysis as independent parameters that either significantly or marginally influenced loss of HCV RNA at 12 weeks (male sex; OR 11.0, p = 0.036, and rs8099917 genotype TT; OR 10.3, p = 0.042) (table 2).

goto top of outline Predictive Factors Associated with Sustained Virological Response

Univariate analysis identified three parameters that correlated with sustained virological response significantly: substitution of aa 70 (Arg70; OR 3.51, p = 0.011), and genetic variation in rs8099917 (genotype TT; OR 11.1, p < 0.001) and rs12979860 (genotype CC; OR 10.2, p < 0.001). Two factors were identified by multivariate analysis as independent parameters that either significantly or marginally influenced sustained virological response (rs8099917 genotype TT; OR 9.94, p<0.001, and Arg70; OR 3.15, p = 0.055) (table 2).

goto top of outline Comparison of Factors Associated with Each Treatment Efficacy Identified by Multivariate Analysis

Table 3 shows independent parameters that either significantly or marginally influenced multivariate logistic regression for each evaluation of treatment efficacy. Multivariate analysis identified substitution of aa 70 and 91 as a predictor of ≥3.0 log fall in HCV RNA level at 24 h (Arg70 and Leu91) and sustained virological response (Arg70), and rs8099917 (TT) as a predictor of HCV RNA loss at 12 weeks and sustained virological response. Thus, genetic variation near IL28B gene and aa substitution of the core region affect viral dynamics of different phases during triple therapy.

TAB03
Table 3. Comparison of factors associated with treatment efficacy of telaprevir, peginterferon and ribavirin triple therapy in Japanese patients infected with HCV-1b identified by multivariate analysis

The other significant predictors of HCV RNA loss were platelet count (≥15.0 × 104/mm3) at 2 weeks, history of blood transfusion (absence) at 4 weeks, and sex (male) at 12 weeks.

 

goto top of outline Discussion

Thompson et al. [27] reported that genetic variation near IL28B gene was also associated with increased on-treatment and sustained virological response and effectively predicted treatment outcome in treatment-naive HCV-1 patients treated with PEG-IFN plus ribavirin. However, HCV RNA loss at 4 weeks (rapid virological response) was a strong predictor of sustained virological response regardless of genetic variation near the IL28B gene. This phenomenon probably explains why it might be important to identify the pretreatment factors that could predict viral dynamics during treatment. The present study is the first to identify the pretreatment factors that could predict viral dynamics during triple therapy in patients infected with HCV-1. These results should be interpreted with caution since races other than Japanese and the patients infected with HCV-1a were not included. Any generalization of the results should await confirmation by studies including patients of other races and with HCV-1a to explore whether genetic variation near IL28B gene and aa substitution of core region also affect viral dynamics during triple therapy.

Two studies showed that aa substitution of the core region and genetic variation near IL28B gene affected viral dynamics during treatment, and sustained virological response to 48-week PEG-IFN plus ribavirin therapy in patients infected with HCV-1 [27,28]. Furthermore, a recent report also showed that aa substitutions of core region might be used to predict very early dynamics (within 48 h) after the start of triple therapy of telaprevir with PEG-IFN and ribavirin [29]. In the present study, multivariate analysis identified substitution of aa 70 and 91 as a predictor of ≥3.0 log fall in HCV RNA level at 24 hours (i.e. viral dynamics of very early phase) and sustained virological response, and rs8099917 as a predictor of HCV RNA loss at 12 weeks (i.e. viral dynamics of later phase) and sustained virological response. This study is the first to report that genetic variation near IL28B gene and aa substitution of the core region affect viral dynamics of different phases during triple therapy, and probably explains why the combination of these independent factors is very useful as pretreatment predictors of sustained virological response by triple therapy [22]. The underlying mechanisms of the different viral dynamics to treatment are still unclear, and further studies based on a larger number of patients are necessary to investigate the present results.

Previous data indicated that absence of advanced liver fibrosis and male gender were positive predictors of virological response to 48-week PEG-IFN plus ribavirin therapy [13,28]. The present study also showed that higher levels of platelet count at 2 weeks, as a surrogate marker of milder liver fibrosis, and male gender at 12 weeks were significant positive predictors of HCV RNA loss during triple therapy. The other positive predictors were absence of history of blood transfusion at 4 weeks and higher levels of body mass index at 24 h and 4 weeks, but the underlying mechanisms are still unclear. Thus, this report identified the pretreatment factors that could predict viral dynamics during triple therapy, but this study, based on a small number of patients, might provide misleading results (e.g. possible type error). Further studies of a larger number of patients are required to explore predictors, including viral- and host-related factors.

The limitations of the present study were that aa substitutions in areas other than the core region and NS5A-ISDR of the HCV genome, such as the interferon/ribavirin resistance determining region (IRRDR) [30], were not examined. Furthermore, HCV mutants with aa conversions for resistance to telaprevir during triple therapy, such as the 156S mutation [31], were also not investigated. In this regard, telaprevir-resistant HCV mutants were reported to be susceptible to IFN in both in vivo and in vitro studies [32,33]. Thus, viral factors before and during triple therapy should be investigated in future studies, and identification of these factors should facilitate the development of more effective therapeutic regimens.

In conclusion, this study identified genetic variation near IL28B gene and aa substitution of the core region as predictors of viral dynamics during triple therapy of telaprevir/PEG-IFN/ribavirin in Japanese patients infected with HCV-1b. Further large-scale prospective studies are necessary to investigate whether the present results relate to the efficacy of the triple therapy, and further understanding of the complex interaction between virus- and host-related factors should facilitate the development of more effective therapeutic regimens.

 

goto top of outline Acknowledgment

This study was supported in part by a Grant-in-Aid from the Ministry of Health, Labor and Welfare, Japan.


 goto top of outline References
  1. Niederau C, Lange S, Heintges T, Erhardt A, Buschkamp M, Hürter D, Nawrocki M, Kruska L, Hensel F, Petry W, Häussinger D: Progress of chronic hepatitis C: results of a large, prospective cohort study. Hepatology 1998;28:1687–1695.
  2. Kenny-Walsh E: Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin: Irish Hepatology Research Group. N Engl J Med 1999;340:1228–1233.
  3. Tsubota A, Arase Y, Someya T, Suzuki Y, Suzuki F, Saitoh S, Ikeda K, Akuta N, Hosaka T, Kobayashi M, Kumada H: Early viral kinetics and treatment outcome in combination of high-dose interferon induction vs. pegylated interferon plus ribavirin for naive patients infected with hepatitis C virus of genotype 1b and high viral load. J Med Virol 2005;75:27–34.
  4. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling MH, Albrecht JK: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958–965.
  5. Fried MW, Shiffman ML, Reddy R, Smith C, Marinos G, Gonçales FL, Häussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–982.
  6. Lin C, Kwong AD, Perni RB: Discovery and development of VX-950, a novel, covalent, and reversible inhibitor of hepatitis C virus NS3.4A serine protease. Infect Disord Drug Targets 2006;6:3–16.
  7. Modi AA, Hoofnagle JH: New therapies for hepatitis C. Hepatology 2007;46:615–617.
  8. Zeuzem S: Telaprevir, peginterferon alfa-2a, and ribavirin for 28 days in chronic hepatitis C patients. J Hepatol 2008;49:157–159.
  9. McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ, PROVE1 Study Team: Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009;360:1827–1838.
  10. Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, Bronowicki JP, Bourlière M, Gharakhanian S, Bengtsson L, McNair L, George S, Kieffer T, Kwong A, Kauffman RS, Alam J, Pawlotsky JM, Zeuzem S, PROVE2 Study Team: Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009;360:1839–1850.
  11. McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH, Heathcote EJ, Zeuzem S, Reesink HW, Garg J, Bsharat M, George S, Kauffman RS, Adda N, Di Bisceglie AM, PROVE3 Study Team: Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010;362:1292–1303.
  12. Akuta N, Suzuki F, Sezaki H, Suzuki Y, Hosaka T, Someya T, Kobayashi M, Saitoh S, Watahiki S, Sato J, Matsuda M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Association of amino acid substitution pattern in core protein of hepatitis C virus genotype1b high viral load and non-virological response to interferon-ribavirin combination therapy. Intervirology 2005;48:372–380.
  13. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the core region and low-density lipoprotein cholesterol levels. J Hepatol 2007;46:403–410.
  14. Donlin MJ, Cannon NA, Yao E, Li J, Wahed A, Taylor MW, Belle SH, Di Bisceglie AM, Aurora R, Tavis JE: Pretreatment sequence diversity differences in the full-length hepatitis C virus open reading frame correlate with early response to therapy. J Virol 2007;81:8211–8224.
  15. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Amino acid substitutions in the hepatitis C virus core region are the important predictor of hepatocarcinogenesis. Hepatology 2007;46:1357–1364.
  16. Fishman SL, Factor SH, Balestrieri C, Fan X, Dibisceglie AM, Desai SM, Benson G, Branch AD: Mutations in the hepatitis C virus core gene are associated with advanced liver disease and hepatocellular carcinoma. Clin Cancer Res 2009;15:3205–3213.
  17. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB: Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009;461:399–401.
  18. Tanaka Y, Nishida N, Sugiyama M, et al: Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009;41:1105–1109.
  19. Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, Bassendine M, Spengler U, Dore GJ, Powell E, Riordan S, Sheridan D, Smedile A, Fragomeli V, Müller T, Bahlo M, Stewart GJ, Booth DR, George J: IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009;41:1100–1104.
  20. Rauch A, Kutalik Z, Descombes P, et al: Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010;138:1338–1345.
  21. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O’Huigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchison JG, Goldstein DB, Carrington M: Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009;461:798–801.
  22. Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Chayama K, Nakamura Y, Kumada H: Amino acid substitution in HCV core region and genetic variation near IL28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology 2010;52:421–429.
  23. Kato N, Hijikata M, Ootsuyama Y, Nakagawa M, Ohkoshi S, Sugimura T, Shimotohno K: Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc Natl Acad Sci USA 1990;87:9524–9528.
  24. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Ogura Y, Izumi N, Marumo F, Sato C: Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 1996;334:77–81.
  25. Ohnishi Y, Tanaka T, Ozaki K, Yamada R, Suzuki H, Nakamura Y: A high-throughput SNP typing system for genome-wide association studies. J Hum Genet 2001;46:471–477.
  26. Suzuki A, Yamada R, Chang X, et al: Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginie deminase 4, are associated with rheumatoid arthritis. Nat Genet 2003;34:395–402.
  27. Thompson AJ, Muir AJ, Sulkowski MS, et al: Interleukin-28B Polymorphism Improves Viral Kinetics and Is the Strongest Pretreatment Predictor of Sustained Virologic Response in Hepatitis C Virus-1 Patients. Gastroenterology 2010;139:120–129.
  28. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Predictors of viral kinetics to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b. J Med Virol 2007;79:1686–1695.
  29. Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H: Amino acid substitutions in the hepatitis C virus core region of genotype 1b affect very early viral dynamics during treatment with telaprevir, peginterferon, and ribavirin. J Med Virol 2010;82:575–582.
  30. El-Shamy A, Nagano-Fujii M, Sasase N, Imoto S, Kim SR, Hotta H: Sequence variation in hepatitis C virus nonstructural protein 5A predicts clinical outcome of pegylated interferon/ribavirin combination therapy. Hepatology 2008;48:38–47.
  31. Lin C, Gates CA, Rao BG, Brennan DL, Fulghum JR, Luong YP, Frantz JD, Lin K, Ma S, Wei YY, Perni RB, Kwong AD: In vitro studies of cross-resistance mutations against two hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061. J Biol Chem 2005;280:36784–36791.
  32. Forestier N, Reesink HW, Weegink CJ, McNair L, Kieffer TL, Chu HM, Purdy S, Jansen PL, Zeuzem S: Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C. Hepatology 2007;46:640–648.
  33. Zhou Y, Müh U, Hanzelka BL, Bartels DJ, Wei Y, Rao BG, Brennan DL, Tigges AM, Swenson L, Kwong AD, Lin C: Phenotypic and structural analyses of hepatitis C virus NS3 protease Arg155 variants: sensitivity to telaprevir (VX-950) and interferon alpha. J Biol Chem 2007;282:22619–22628.

 goto top of outline Author Contacts

Norio Akuta, MD
Department of Hepatology, Toranomon Hospital
2-2-2 Toranomon, Minato-ku
Tokyo 105-0001 (Japan)
Tel. +81 44 877 5111, E-Mail akuta-gi@umin.ac.jp


 goto top of outline Article Information

Received: August 11, 2010
Accepted after revision: November 18, 2010
Published online: June 8, 2012
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 3, Number of References : 33


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 55, No. 6, Year 2012 (Cover Date: October 2012)

Journal Editor: Liebert U.G. (Leipzig), Manuguerra J.-C. (Paris)
ISSN: 0300-5526 (Print), eISSN: 1423-0100 (Online)

For additional information: http://www.karger.com/INT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.