Factors associated with sustained virological response in 24-week telaprevir-based triple therapy...

1

This article is protected by copyright. All rights reserved.

Article Type: Original Article 1

Received Date: 28-Nov-2013 2

Revised Date: 11-Mar-2014 3

Accepted Date: 15-May-2014 4

Factors associated with sustained virological response in 24-week 5

telaprevir-based triple therapy for chronic hepatitis C genotype 1b 6

patients with the IL28B minor genotype 1 7

8

Hiroshi Abea*

, Akihito Tsubotab, Noritomo Shimada

c, Masanori Atsukawa

d, Keizo Kato

c, 9

Koichi Takaguchie, Toru Asano

f, Yoshimichi Chuganji

f, Choitsu Sakamoto

g, Hidenori 10

Toyodah, Takashi Kumada

h, Tatsuya Ide

i, Michio Sata

i and Yoshio Aizawa

a 11

12

aDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei 13

University School of Medicine Katsushika Medical Center, Tokyo, Japan 14

bInstitute of Clinical Medicine and Research, The Jikei University School of Medicine, 15

Kashiwa City Chiba, Japan 16

cDepartment of Gastroenterology and Hepatology, Shinmatsudo Central General 17

Hospital, Matsudo City, Chiba, Japan 18

dDivision of Gastroenterology, Department of Internal Medicine, Nippon Medical 19

School Chiba Hokusoh Hospital, Inzai City, Chiba, Japan 20

eDepartment of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu City, 21

Kagawa, Japan 22

This article has been accepted for publication and undergone full peer review but has not been through the

copyediting, typesetting, pagination and proofreading process, which may lead to differences between this

version and the Version of Record. Please cite this article as doi: 10.1111/hepr.12360 Acc

epte

d A

rticl

e

2


fDepartment of Gastroenterology, Tokyo Metropolitan Bokutoh Hospital, Sumida-ku, 23

Tokyo, Japan

24

gDepartment of Gastroenterology, Nippon Medical School, Graduate School of 25

Medicine, Tokyo, Japan 26

hDepartment of Gastroenterology, Ogaki Municipal Hospital, Ogaki City, Gifu, Japan

27

iDivision of Gastroenterology, Department of Medicine, Kurume University School of 28

Medicine, Kurume City, Fukuoka, Japan 29

30

Running title 31

Telaprevir-based therapy for IL28B minor genotype 32

33

34

*Corresponding author: 35

Hiroshi Abe, MD 36

6-41-2 Aoto, Katsushika-ku, Tokyo 125-8506, Japan 37

Tel.: +81 3 3603 2111 38

Fax: +81 3 3838 9944 39

E-mail: [email protected] 40

41

42

Key words 43

Hepatitis C virus, peginterferon, ribavirin, telaprevir, IL28B, minor genotype, fasting 44

low density lipoprotein-cholesterol 45

46 Acc

epte

d A

rticl

e

3


Number of text pages: 27 47

Number of tables: 3 48

Number of illustrations: 1 49

50

Manuscript category: Original Article 51

52

53

ABSTRACT 54

Aim: Single nucleotide polymorphisms (SNPs) near the interleukin-28B (IL28B) gene 55

affect the outcome of 24-week telaprevir-based triple therapy with telaprevir, pegylated 56

interferon-α, and ribavirin for chronic hepatitis C (HCV) genotype 1b patients. We 57

aimed to identify factors associated with treatment outcomes in patients with the 58

unfavorable minor IL28B SNP genotype, who have poor response to combination 59

therapy. 60

Methods: Pre-treatment and on-treatment factors associated with sustained virological 61

response (SVR) for 24-week telaprevir-based triple therapy were analyzed using 62

multiple logistic regression analysis in 106 HCV genotype 1b patients with the minor 63

IL28B SNP rs8099917 genotype (non-TT). 64

Results: Of the 106 non-TT patients, 62 (58.5%) achieved SVR. Of the 44 remaining 65

patients, 22 experienced relapse, 13 experienced viral breakthrough, and 9 were 66

non-responders. Pre-treatment factors such as treatment naïve/prior treatment response 67

(P = 0.0041), high fasting serum low-density lipoprotein-cholesterol (LDL-C) 68

concentration (P = 0.0068), and low serum HCV RNA levels (P = 0.0088) were 69

significantly and independently associated with SVR. On-treatment factors such as 70 Acc

epte

d A

rticl

e

4


achievement of rapid virological response (RVR) were significantly and independently 71

associated with SVR (P = 0.0001). For both pre- and on-treatment factors, 72

treatment-naïve/prior treatment response (P = 0.0018), low pre-treatment serum fasting 73

LDL-C (P = 0.0062), and achieving RVR (P = 0.0021) were significantly and 74

independently associated with SVR. 75

Conclusion: In HCV genotype 1b patients with the minor IL28B SNP rs8099917 76

genotype, evaluating prior treatment response and achieving RVR and pre-treatment 77

serum fasting LDL-C concentrations were useful for predicting SVR achievement after 78

24-week telaprevir-based triple therapy. 79

80

Acc

epte

d A

rticl

e

5


81

INTRODUCTION 82

Approximately 150 million people are chronically infected with the hepatitis C virus 83

(HCV) worldwide 1, and chronic HCV infection is one of the most common causes of 84

liver cirrhosis, portal hypertension, hepatic failure, and hepatocellular carcinoma.2,3

In 85

Japan, approximately 70% of HCV patients carry HCV genotype 1.4 Pegylated 86

interferon-α (PEG-IFNα) plus ribavirin (RBV) combination therapy is frequently used 87

to treat chronic HCV-infected patients and yields a sustained virological response (SVR) 88

rate of 40% to 50% among patients with HCV genotype 1.5-8

Addition of telaprevir, a 89

first generation non-structural 3/4A HCV protease inhibitor, to the combination of 90

PEG-IFNα plus RBV (PEG-IFNα/RBV) has been shown to significantly improve the 91

SVR rate in both naïve and previously treated patients.9-12

In previous studies, single 92

nucleotide polymorphisms (SNPs) near the interleukin-28B (IL28B) gene was one of the 93

most important predictors of SVR in PEG-IFNα/RBV dual combination therapy.8,13,14

94

Although it was reported that the value of the IL28B SNPs is attenuated with 48-week 95

PEG-IFNα/RBV/telaprevir triple therapy in a predominantly Caucasian cohort,15

the 96

SNPs remained informative as a predictor of SVR to 24-week 97 Acc

epte

d A

rticl

e

6


PEG-IFNα/RBV/telaprevir triple therapy for East Asian genotype 1b patients.16,17

In a 98

previous East Asian cohort treated with the 24-week telaprevir-based triple therapy, the 99

SVR rate was very high (94 - 97%) in patients with the rs8099917 genotype TT (IL28B 100

major genotype), whereas it was relatively low (50 - 56%) in those with the genotype 101

TG/GG (IL28B minor genotype).16,17

Therefore, patients with the IL28B minor 102

genotype remain difficult-to-treat and further information is required to determine what 103

patients should be treated or wait for the next-generation treatment. 104

In this study, we clarified which factors could contribute to SVR in the case of 105

24-week telaprevir-based triple therapy in patients with the unfavorable IL28B minor 106

genotype and evaluated what patients could be predicted to be optimal candidates for 107

the treatment. 108

109

110

Acc

epte

d A

rticl

e

7


111

METHODS 112

Study population 113

Between January 2012 and August 2013, 436 consecutive patients who were 114

chronically infected with HCV genotype 1b (G1b) received triple combination therapy 115

with telaprevir (Telavic; Tanabe Mitsubishi Pharma, Osaka, Japan), PEG-IFNα-2b 116

(PegIntron; MSD, Tokyo, Japan), and ribavirin (Rebetol, MSD) at multiple participating 117

institutions. Of the 436 patients, 146 (33.5%) had the IL28B minor genotype. Of the 146 118

patients, 137 completed or discontinued treatment, and 9 were undergoing treatment. Of 119

the 137 patients, 116 were followed up for at least 24 weeks after treatment, and 21 120

were followed up for less than 24 weeks. One hundred and six of the 116 patients were 121

treated with 24-week telaprevir with telaprevir-based triple therapy and were included 122

in this analysis, and 10 patients were excluded because they had undergone 48-week 123

telaprevir-based triple therapy. This study complied with the standards of the 2008 124

Declaration of Helsinki and current ethical guidelines, as reflected by the approval of 125

the human ethics review committee of each institution. Written informed consent was 126 Acc

epte

d A

rticl

e

8


obtained from each patient before entry into the study. 127

All of the patients satisfied the following criteria: The patients were persistently 128

seropositive for HCV RNA for >6 months, and the amount of serum HCV RNA, as 129

determined by a quantitative real-time polymerase chain reaction (RT-PCR) method 130

(COBAS® TaqMan® HCV test; Roche Diagnostics, Tokyo, Japan). Each patient had a 131

white blood cell count ≥ 2000/μL, neutrophil count ≥ 1500 /μL, hemoglobin level ≥ 11 132

g/dL, and platelet count ≥ 70,000 /μL; the age range for the patients was 18–79 years 133

and they weighed >35 kg at the time of study entry. The presence or absence of cirrhosis 134

was determined by liver biopsy, using METAVIR scores 18

within 12 months of 135

enrollment, or by an aspartate aminotransferase (AST) to platelet ratio index (APRI) of 136

> 2, as proposed by Wai et al. 19

at the time of enrollment. The serum fasting 137

low-density lipoprotein-cholesterol (LDL-C) concentrations were calculated using the 138

Friedewald formula20

because there were no patients whose serum fasting triglyceride 139

levels were ≥ 400 mg/dL. The exclusion criteria were as follows: positive results for the 140

hepatitis B surface antigen; positive results for the anti-human immunodeficiency virus 141

antibody; hepatocellular carcinoma; other liver diseases; psychiatric conditions; 142 Acc

epte

d A

rticl

e

9


consumption of >20 g alcohol /day. 143

All patients were scheduled to receive telaprevir (1500 – 2250 mg /day) combined 144

with weekly subcutaneous injections of PEG-IFNα-2b (1.5 µg/kg) and ribavirin (600 145

–1000 mg/day, according to body weight: < 60 kg, 600 mg/day; 60 – 80 kg, 800 146

mg/day; > 80 kg, 1000 mg/day. If the patient’s hemoglobin level was <13 g/dL at the 147

start of therapy, the ribavirin dose was reduced by 200 mg for 12 weeks. This was 148

followed by 12 weeks of PEG-IFNα-2b/RBV combination therapy. When the baseline 149

hemoglobin concentration was <13 g/dL, the dose of RBV was reduced by 200 mg. 150

Telaprevir was administered every 8 hours after meals at a dose of 500 mg or 750 mg, 151

or every 12 hours after meals at a dose of 750 mg or 1125 mg. Ribavirin was orally 152

administered every 12 hours after meals. Telaprevir adherence was calculated based on 153

a dose of 2250 mg/day. On-treatment dose reduction, modification, and discontinuation 154

of PEG-IFN, RBV, or telaprevir followed the criteria and procedures according to the 155

proper usage guidelines for telaprevir21

or patient condition to reduce or avoid adverse 156

effects and treatment discontinuation. In patients who had HCV RNA levels of >3 log10 157

IU/mL at week 4, detectable HCV RNA levels at week 12, or a 2 log10 IU/mL increase 158 Acc

epte

d A

rticl

e

10


in HCV RNA from the lowest level during therapy, the therapy was discontinued due to 159

the extremely low likelihood of achieving SVR and the high risk of developing antiviral 160

resistance. In patients who had HCV RNA levels of ≤ 3 log10 IU/mL at week 4, the 161

therapy was continued as the 24-week telaprevir-based triple therapy, though the 162

therapy was discontinued on viral breakthrough. 163

Virological response was analyzed on an intent-to-treat basis. The primary end-point 164

was SVR, defined as an undetectable serum HCV RNA level at 24 weeks 165

post-treatment. Relapse was defined as undetectable HCV RNA levels by the end of 166

treatment and detectable levels during the follow-up period. Viral breakthrough was 167

defined as undetectable HCV RNA levels during treatment but detectable levels prior 168

to the end of treatment. Non-response (NR) was diagnosed when HCV RNA levels did 169

not drop below the detection level during therapy. NR was further divided into partial 170

response and null response. Partial response was defined as viral load decline from the 171

baseline level of ≥ 2.0 log10 IU/mL at 12 weeks of treatment but with persistently 172

detectable viremia during treatment. Null response was defined as a viral load decline 173

of <2.0log10 IU/mL at 12 weeks of treatment and persistent viremia during treatment. 174 Acc

epte

d A

rticl

e

11


We also defined rapid virological response (RVR) as the absence of detectable HCV 175

RNA levels at 4 weeks after starting treatment. 176

177

HCV-related markers 178

The HCV G1b genotype was determined by direct sequencing followed by 179

phylogenetic analysis of the NS5B resion.22

The serum HCV RNA concentration was 180

measured at the initiation of therapy and every 4 weeks thereafter until 24 weeks after 181

the end of therapy. This was performed using the previously described RT-PCR method. 182

The linear dynamic range of the assay was 1.2 – 7.8 Log10 IU/mL. Samples below the 183

level of detection were considered HCV-negative. Amino acid (aa) substitutions at aa 70 184

of the viral core and in the interferon sensitivity-determining region (ISDR) between 185

sites 2209–2248 of NS5A were determined using a direct sequencing method.23,24

The 186

“wild-type” aa 70 in the core region is arginine and a “mutant-type” causes a change to 187

glutamine or histidine. 188

189

Acc

epte

d A

rticl

e

12


190

Genetic variation near the IL28B gene 191

Genomic DNA was extracted from whole blood using the MagNA Pure LC and the 192

DNA Isolation Kit (Roche Diagnostics). The rs8099917 SNP near the IL28B gene 14

193

was genotyped by RT-PCR using the TaqMan SNP Genotyping Assay and the 7500 Fast 194

RT-PCR System (Applied Biosystems, Foster City, CA, USA). The rs8099917 genotype 195

was classified into 2 categories: TT (major genotype) and non-TT genotype (minor 196

genotype, TG or GG). 197

198

Statistical analyses 199

The Mann-Whitney U-test was used to analyze differences between continuous 200

variables. Fisher’s exact tests were used to analyze differences in categorical data. To 201

determine the baseline factors associated with SVR, univariate and multivariate logistic 202

regression analyses were performed. Statistical significance was determined by applying 203

a two-tailed test and resulted in a P-value < 0.05. P-values < 0.1 were considered 204

marginal. To identify independent predictive factors of SVR, variables that were 205 Acc

epte

d A

rticl

e

13


significant or marginal in the univariate analysis were used as candidates for 206

multivariate logistic regression analysis by the forward and backward stepwise selection 207

method. All statistical analyses were carried out using STATISTICA for Windows 208

version 6 (StatSoft, Tulsa, OK, USA). 209

210

211

Acc

epte

d A

rticl

e

14


RESULTS 212

Treatment outcome 213

The baseline characteristics of the 106 non-TT patients are summarized in Table 1. 214

Of the 106 patients, 62 (58.5%) achieved SVR. The remaining 44 (41.5%) patients were 215

classified as non-SVR. Of the 44 non-SVR patients, 22 experienced relapse, 13 had 216

viral breakthrough, and 9 were NR. Of the 106 patients, 11 patients (10.4%) did not 217

complete the triple therapy; this was because of the stopping rule (serum HCV RNA 218

detectable at 12 weeks of therapy) for seven patients (6.6%) and adverse events (severe 219

skin lesion in one patient, severe digestive syndrome in 2 patients, and severe anemia 220

with renal dysfunction in one patient) for four patients (3.8%). 221

222

Pre-treatment factors contributing to SVR 223

Low serum HCV RNA level (per 1.0 log10IU/mL, P = 0.0193), high white blood cell 224

count (per 1,000 /μL, P = 0.0431), high platelet count (per 10,000 /μL, P = 0.0285), low 225

serum AST level (per 10 IU/L, P = 0.0327), high fasting serum LDL-C concentration 226

(per 10 mg/dL, P = 0.0136), and treatment naïve/prior relapsers/prior partial responders 227 Acc

epte

d A

rticl

e

15


(versus prior null responders, P = 0.0021) were significantly associated with SVR as 228

determined by univariate analysis. Hemoglobin level (P = 0.0586) and HCV core aa 229

substitution 70 (P = 0.0929) were found to be marginally. Multiple logistic regression 230

analysis identified significantly independent pre-treatment factors associated with SVR: 231

low serum HCV RNA level [odds ratio (OR): 0.263, 95% confidence interval (CI): 232

0.097–0.708, P = 0.0088], high fasting serum LDL-C concentration (OR: 1.394, 95% 233

CI: 1.098–1.768, P = 0.0068), and response to prior PEG-IFNα-2b/RBV treatment (OR: 234

0.023, 95% CI: 0.001–0.292, P = 0.0041) (Table 2). There was no significant correlation 235

between fasting serum LDL-C concentration and the presence of cirrhosis (P = 0.1691, 236

data not shown). 237

238

On-treatment factors contributing to SVR 239

High adherence to PEG-IFNα-2b (per 10%, P = 0.0092), high adherence to RBV (per 240

10%, P = 0.0361), and achievement of RVR (versus non-RVR, P = 7.35 × 10-5

) were 241

significantly associated with SVR, as determined by univariate analysis. Multiple 242

logistic regression analysis identified achievement of RVR (OR: 7.543, 95% CI: 243 Acc

epte

d A

rticl

e

16


2.783–20.440, P = 0.0001) as a significantly independent on-treatment factor associated 244

with SVR (Table 2). 245

246

SVR rates according to each significantly independent factor 247

Pre-treatment HCV RNA levels were 5.9 log10IU/mL or less in 31 patients, 6.0–6.9 248

log10IU/mL in 52 patients, and 7.0 log10IU/mL or more in 23 patients. SVR rates of 249

patients with pre-treatment HCV RNA levels of 5.9 log10IU/mL or less, 6.0–6.9 250

log10IU/mL, and 7.0 log10IU/mL or more were 64.5%, 59.6%, and 47.8%, respectively. 251

Fasting serum LDL-C concentrations were 69 mg/dL or less in 19 patients, 70 - 79 252

mg/dL in 14 patients, 80 - 89 mg/dL in 21 patients, 90 - 99 mg/dL in 19 patients, 100 - 253

109 mg/dL in 19 patients, and 110 mg/dL or more in 14 patients. SVR rates of patients 254

with fasting serum LDL-C concentrations of 69 mg/dL or less, 70 - 79 mg/dL, 80 - 89 255

mg/dL, 90 - 99 mg/dL, 100 - 109 mg/dL, and 110 mg/dL or more were 31.6%, 50.0%, 256

47.6%, 68.4%, 78.9%, and 78.6%, respectively. The SVR rates of treatment-naïve, 257

relapsers, partial responders, and null responders to prior PEG-IFNα-2b/RBV treatment 258

were 57.1%, 82.4%, 59.1%, and 6.7%, respectively. The SVR rates of patients with 259 Acc

epte

d A

rticl

e

17


RVR achievement was 72.0%, while the rate of patients with RVR failure was 25.8% 260

(Fig. 1). 261

262

Pre- and on-treatment factors contributing to SVR 263

Multiple logistic regression analysis identified three independent pre- and 264

on-treatment factors that were significantly associated with SVR (Table 3): prior 265

treatment response (Naïve/Relapse/Partial versus Null, P = 0.0018), serum fasting 266

LDL-C (per 10 mg/dL, P = 0.0062), and early virological response (non-RVR versus 267

RVR, P = 0.0021). Pre-treatment serum HCV RNA level was not identified as an 268

significant independent factor. 269

270

271

DISCUSSION 272

IL28B SNPs are one of the strongest factors that contribute to SVR in 273

PEG-IFNα/RBV dual combination therapy.8,13,14

Addition of telaprevir to the 274

PEG-IFNα/RBV combination remarkably improves the SVR rate in both 275 Acc

epte

d A

rticl

e

18


treatment-naïve and previously treated patients,9-12

which may decrease the value of 276

IL28B SNPs as a predictor of SVR.15

However, in the 24-week telaprevir-based triple 277

therapy for HCV genotype 1b Japanese patients, IL28B SNPs still remained informative 278

as a strong predictor of SVR: the rate of 94 - 97% for those with the rs8099917 major 279

genotype TT and 50 - 56% for those with the minor genotype TG/GG.16,17

Therefore, 280

this study focused on patients with the unfavorable IL28B minor genotype and analyzed 281

factors associated with SVR in such a refractory patient sub-group. 282

In this study, high pre-treatment serum fasting LDL-C and serum HCV RNA levels 283

were elucidated as independent pre-treatment predictors of SVR. Chronic HCV 284

infection is known to strongly affect host lipid metabolism. In previous studies, low and 285

high pre-treatment serum LDL-C concentrations were found to be associated with poor 286

response and SVR, respectively, to PEG-IFNα/RBV dual combination therapy, 25, 26

287

especially in IL28B minor (but not major) genotype patients.26, 27

Interestingly, the 288

IL28B genotype was reported to be linked to LDL-C levels, and low HCV RNA levels 289

as well as high serum LDL-C concentrations were determined to be important 290

predictors of SVR.27

However, there was no report that supported these findings in 291 Acc

epte

d A

rticl

e

19


telaprevir-based triple combination therapy. The pre-treatment serum HCV RNA level is 292

no longer believed to be a predictor of SVR in direct-acting antiviral therapies for 293

patients including both IL28B minor and major genotypes. This study is the first 294

reportto identify the pre-treatment fasting serum LDL-C concentration and serum HCV 295

RNA level as significantly independent factors associated with SVR in the 24-week 296

telaprevir-based triple therapy for the IL28B minor (but not major) genotype patients. 297

However, the pre-treatment serum HCV RNA level was excluded in this multivariate 298

analysis including pre-treatment and on-treatment factors, because it also significantly 299

influenced RVR in this study (data not shown) but consequently less significant than 300

RVR. At the 24-week telaprevir-based triple therapy for the IL28B minor genotype 301

patients start, pre-treatment serum HCV RNA level may be useful to the estimation of 302

SVR. 303

In this study, accomplishment of RVR was implicated as an important factor for 304

achieving SVR in rs8099917 non-TT patients for the 24-week telaprevir-based triple 305

therapy. In a previous Japanese study, the significance of RVR for achieving SVR was 306

not seen for 24-week telaprevir-based triple therapy,12

although the trial was performed 307 Acc

epte

d A

rticl

e

20


for only naïve patients. On the other hand, in a study of non-responders to prior 308

PEG-IFNα/RBV dual combination therapy, the SVR rate was significantly higher in 309

patients who achieved RVR than in patients who did not achieve RVR.28

Although 310

IL28B was not evaluated, it seemed that rs8099917 non-TT patients occupied many of 311

the non-responders to prior PEG-IFNα/RBV dual combination therapy. Therefore, our 312

results do not contradict the previous study.28

313

The significance of the response to prior PEG-IFNα/RBV dual combination therapy 314

with respect to the SVR rate for telaprevir-based triple therapy has been extensively 315

studied. In the REALIZE trial,29

the telaprevir-based treatment was continued for 48 316

weeks, and the SVR rates of previous relapsers and partial responders were quite similar 317

to those in our 24-week therapy: a previous relapse (83% to 88% in the REALIZE study 318

and 82.4% in our study) and a partial response (54% to 59% and 59.1%, respectively). 319

These findings suggested that prior response to combination therapy is critical for 320

predicting SVR for telaprevir-based triple therapy without respect for genotype of 321

IL28B. In addition, elongation of the phase of combination treatment from 12 weeks to 322

24 weeks may not be effective for these patients.11

However, as the SVR rate of prior 323 Acc

epte

d A

rticl

e

21


null response patients in our study was extremely low (only 6.7%), target of the 324

extension of therapy should be limited in prior null responders. 325

In this study, we found that high adherences of PEG-IFNα and RBV were tended to 326

associated with achieving SVR as shown in the previous studies,12,29

the extension of 327

treatment duration should be considered in the patients who was not gave sufficient 328

dose of drugs in order to maintain the adherence. 30

In this study, however, adherence of 329

telaprevir did not participate in SVR. In Japanese previous report,31

there was no 330

difference in SVR rate between telaprevir-based regimens of 2250 mg and 1500 mg. In 331

our study, most patients were able to take 1500 mg as a minimum dose and the dose was 332

rarely reduced. This may lead that telaprevir dose doses not participate in SVR in this 333

study. 334

In conclusion, pre-treatment serum fasting LDL-C concentration, prior treatment 335

response, and RVR achievement were useful for predicting SVR achievement for 336

24-week telaprevir-based triple therapy in patients with the non-TT genotype in 337

rs8099917 near the IL28B gene. This was especially true for patients with a prior null 338

response, as it was difficult to achieve SVR with the 24-week telaprevir-based triple 339 Acc

epte

d A

rticl

e

22


therapy, it should be considered the extension of treatment or standing by the 340

next-generation therapies. 341

342

ACKNOWLEDGEMENTS 343

We thank the physicians and the staff of the participating institutions for their help. 344

345

346

APPENDIX 347

The patients were treated at Jikei University Katsushika Medical Center, Jikei 348

University Kashiwa Hospital, Shinmatsudo Central General Hospital, Nippon Medical 349

School Chiba Hokusoh Hospital, Nippon Medical School Hospital, Kagawa Prefectural 350

Central Hospital, Kurume University School of Medicine, Tokyo Metropolitan Bokutoh 351

Hospital, or Ogaki Municipal Hospital. 352

353

354

COMPLIANCE WITH ETHICAL REQUIREMENTS 355

Conflict of Interest 356

Yoshio Aizawa received grants from Merck Sharp & Dohme (MSD), Tokyo, Japan, 357

and Tanabe Mitsubishi Pharma, Osaka, Japan. Masanori Atsukawa received grants from 358

Merck Sharp & Dohme (MSD), Tokyo, Japan, and Tanabe Mitsubishi Pharma, Osaka, 359

Japan. 360

361 Acc

epte

d A

rticl

e

23


362

REFERENCES 363

1. Geneva: World Health Organization. Hepatitis C., 2012. 364

(http://www.who.int/entity/mediacentre/factsheets/fs164/en/.) 365

2. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of 366

hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer 367

worldwide. J Hepatol 2006; 45: 529–38. 368

3. Thomas MB, Jaffe D, Choti MM, et al. Hepatocellular carcinoma: consensus 369

recommendations of the National Cancer Institute Clinical Trials Planning Meeting. J 370

Clin Oncol 2010; 28: 3994–4005. 371

4. Okamoto H, Sugiyama Y, Okada S, et al. Typing hepatitis C virus by polymerase 372

chain reaction with type-specific primers: Application to clinical surveys and tracing 373

infectious sources. J Gen Virol 1992; 73: 673–9. 374

5. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin 375

compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis 376

C. Lancet 2001; 358: 958–65. 377 Acc

epte

d A

rticl

e

24


6. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for 378

chronic hepatitis C virus infection. N Engl J Med 2002; 34: 975–82. 379

7. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a 380

with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361: 580–93. 381

8. Tsubota A, Shimada N, Yoshizawa K, et al. Contribution of ribavirin transporter gene 382

polymorphism to treatment response in peginterferon plus ribavirin therapy for HCV 383

genotype 1b patients. Liver Int 2012; 32: 826–36. 384

9. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and 385

ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360: 1827–38. 386

10. Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or 387

without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839–50. 388

11. McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated 389

chronic HCV infection. N Engl J Med 2010; 362: 1292–303. 390

12. Kumada H, Toyota J, Okanoue T, Chayama K, Tsubouchi H, Hayashi N. Telaprevir 391

with peginterferon and ribavirin for treatment-naive patients chronically infected with 392

HCV of genotype 1 in Japan. J Hepatol 2012; 56: 78–84. 393 Acc

epte

d A

rticl

e

25


13. Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C 394

treatment-induced viral clearance. Nature 2009; 461: 399–401. 395

14. Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with 396

response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nat 397

Genet 2009; 41: 1105–9. 398

15. Pol S, Aerssens J, Zeuzem S, et al. Limited impact of IL28B genotype on response 399

rates in telaprevir-treated patients with prior treatment failure. J Hepatol 2013; 58: 400

883–9. 401

16. Chayama K, Hayes CN, Abe H, et al. IL28B but not ITPA polymorphism is 402

predictive of response to pegylated interferon, ribavirin, and telaprevir triple therapy in 403

patients with genotype 1 hepatitis C. J Infect Dis 2011; 204: 84–93. 404

17. Tsubota A, Shimada N, Atsukawa M, et al. Impact of IL28B polymorphisms on 405

24-week telaprevir-based combination therapy for Asian chronic hepatitis C patients 406

with hepatitis C virus genotype 1b. J Gastroenterol Hepatol 2014; 29: 144–50. 407

18. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. 408

The METAVIR Cooperative Study Group. Hepatology 1996; 24: 289–293. 409 Acc

epte

d A

rticl

e

26


19. Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict 410

both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 411

2003; 38: 518–26. 412

20. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of 413

low-density lipoprotein cholesterol in plasma, without use of the preparative 414

ultracentrifuge. Clin Chem 1972; 18: 499–502. 415

21. TELAVIC. Health, Labour and Welfare Ministry. The proper Usage Guideline for 416

Telaprevir and Product Information. Mitsubishi Tanabe Pharma, Osaka, Japan. 417

September 2011. Cited 17 May 2013. Available from URL: 418

http://medical.mt-pharma.co.jp/intro/tlv/use/use00.shtml 419

22. Simmonds P, Mellor J, Sakuldamrongpanich T et al. Evolutionary analysis of 420

variants of hepatitis C virus found in South-East Asia: comparison with classifications 421

based upon sequence similarity. J Gen Virol 1996; 77:3013-24. 422

23. Akuta N, Suzuki F, Sezaki H, et al. Association of amino acid substitution pattern in 423

core protein of hepatitis C virus genotype 1b high viral load and non-virological 424

response to interferon-ribavirin combination therapy. Intervirology 2005; 48: 372–80. 425 Acc

epte

d A

rticl

e

27


24. Enomoto N, Sakuma I, Asahina Y, et al. Mutations in the nonstructural protein 5A 426

gene and response to interferon in patients with chronic hepatitis C virus 1b infection. 427

N Engl J Med 1996; 334: 77–81. 428

25. Ramcharran D, Wahed AS, Conjeevaram HS, et al. Associations between serum 429

lipids and hepatitis C antiviral treatment efficacy. Hepatology 2010; 52: 854–63. 430

26. Harrison SA, Rossaro L, Hu KQ, et al. Serum cholesterol and statin use predict 431

virological response to peginterferon and ribavirin therapy. Hepatology 2010; 52: 432

864–74. 433

27. Clark PJ, Thompson AJ, Zhu M, et al. Interleukin 28B polymorphisms are the only 434

common genetic variants associated with low-density lipoprotein cholesterol (LDL-C) 435

in genotype-1 chronic hepatitis C and determine the association between LDL-C and 436

treatment response. J Viral Hepat 2012; 19: 332–40. 437

28. Hayashi N, Okanoue T, Tsubouchi H, Toyota J, Chayama K, Kumada H. Efficacy 438

and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with 439

genotype 1 chronic hepatitis C. J Viral Hepat 2012; 19: e134-42. 440

29. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N 441 Acc

epte

d A

rticl

e

28


Engl J Med 2011; 364: 2417–28. 442

30. Muir AJ, Poordad FF, McHutchison JG, et al. Retreatment with telaprevir 443

combination therapy in hepatitis C patients with well-characterized prior treatment 444

response. Hepatology 2011; 54: 1538–46. 445

31. Suzuki F, Suzuki Y, Sezaki H, et al. Exploratory study on telaprevir given every 8 h 446

at 500 mg or 750 mg with peginterferon-alpha-2b and ribavirin in hepatitis C patients. 447

Hepatol Res 2013; 43: 691–701. 448

Acc

epte

d A

rticl

e

0%

20%

40%

60%

80%

100%

≤ 5.9 6.0-6.9 7.0≤

100%

SVR Rate

SVR Rate SVR Rate

(a) (b)

(c)(n=31) (n=52) (n=23) (n=19) (n=14) (n=21) (n=19) (n=19) (n=14)

64.5%59.6%

47.8%

31.6%

50.0% 47.6%

68.4%

78.9% 78.6%

Pre-treatment serum HCV RNA level

(log10IU/mL) (mg/dL)

Fasting serum LDL-C concentration

Response prior to PEG-IFNα-2b/RBV 100%SVR Rate

(d)

0%

20%

40%

60%

80%

100%

≤ 69 70-79 80-89 90-99 100-109 110≤

0%

20%

40%

60%

80%

100%

Naïve Relapse Partial

response

Null

response

(n=35) (n=34) (n=22) (n=15)

57.1%

82.4%

59.1%

6.7%

Figure 1. Sustained virological response (SVR) rates according to each independent, significant factor. (a) Pre-treatment serum HCV RNA

level (P = 0.0088). (b) Fasting serum low density lipoprotein-cholesterol (LDL-C) concentration (P = 0.0068). (c)Treatment-naïve/ prior

relapsers/ prior partial responders versus prior null responders (P = 0.0041). (d) Achievement of rapid virilogical response (RVR) versus non-

RVR (P = 0.0001).

Response prior to PEG-IFNα-2b/RBV

0%

20%

40%

60%

80%

100%

RVR non-RVR

72.0%

25.8%

(n=75) (n=31)

Acc

epte

d A

rticl

e

Table1.Patient profile at start of 24-week telaprevir-based peginterferon plus ribavirin combination therapy in HCV genotype 1b infected patients with the minor genotype at the rs8099917 single nucleotide polymorphism near the interleukin-28B gene.

Demographic dataNumber of patients 106Sex （Male/Female） 55/51Age （years） 61 (18-79)Body weight (kg) 60.3 (40.8-92.8)Body mass index (kg/m2) 23.3 (17.2-31.9)Absence or presence of cirrhosis 80/26(non-cirrhosis/cirrhosis)

Amino acid substitutions in the HCV genotype 1b Core amino acid substitution 70 52/53/1(wild-type/mutant-type/ND)*Number of amino acid substitution in ISDR (0-1/ 2≤/ND) 87/17/2

Laboratory dataHCV-RNA （Log10IU/mL） 6.3 (5.0-7.6)White blood cells (/μL) 4660 (2000-11100)Hemoglobin （g/dL） 14.1 (11.4-17.7)Pletelets （×104/μL） 17.35 (6.4-40.7)Aspartate aminotransferase （IU/L） 42 (16-149)Alanine aminotransferase （IU/L） 41.5 (14-261)gamma-glutamyl-transpeptitase （IU/L） 48 (12-427)Albumin （g/dL） 4.2 (2.8-4.8)Fasting total cholesterol (mg/dL) 163 (111-253)Fasting low density lipoprotein-cholesterol (mg/dL) 88 (39-204)Fasting plasma glucose （mg/dL） 99 (74-210)Homeostasis model assessment-Insulin Resistance 2.17 (0.33-24.92)Alpha-fetoprotein (ng/mL) 6.2 (1.0-192.0)

TreatmentInitial dose of Peg-IFN (μg /kg) 1.51 (1.04-1.94)Initial dose of RBV (mg /kg) 11.3 (3.5-13.5)Initial dose of TVR (1500/2250mg) 55/51

Prior treatment responseNaïve/Relapse/Partial response/Null response 35/34/22/15

PEG-IFN, peginterferon; RBV, ribavirin; TVR, telaprevir; HCV, hepatitis C virus; ISDR, interferon-sensitivity determining region; RVR, rapid virological response; ND, not determined* ‘wild-type’ (arginine) or ‘mutant-type’ (glutamine or histidine);Data expressed as number of patients or median (range)

Acc

epte

d A

rticl

e

Table2. Patients that achieved a sustained virological response (SVR). Background levels at starting of 24-week telaprevir-based peginterferon plus ribavirin combination in patients infected with the HCV genotype 1b and have the non-TT genotype of the rs8099917 SNP

SVR non-SVR SVR vs. non-SVR (1: non-SVR / 2: SVR)Univaritate analysis

p value OR 95%CI p value

e-treatment factors

Demographic dataNumber of patients 62 44Gender （1:Male/2:Female） 37/25 18/26 0.0611Age （years） 61.5 (18-75) 61 (40-79) 0.6697Body weight (kg) 60.3 (40.8-92.6) 60.3 (44.7-92.8) 0.5854Body mass index (kg/m2) 23.0 (17.3-28.7) 23.4 (17.2-31.9) 0.3756Absence or presence of cirrhosis 49/13 31/13 0.3161(1:non-cirrhosis / 2:cirrhosis)

Prior treatment responseNaïve/Relapse/Partial response/Null response 20/28/13/1 15/6/9/14 0.0021 0.023 0.001-0.292 0.0041(1:Naïve+Relapse+Partial response / 2:Null response) (61 / 1) (30 / 14)

Amino acid substitutions in the HCV genotype 1b Core amino acid substitution 70 35/27/0 17/26/1 0.0929(wild-type / mutant-type / ND)*Number of amino acid substitutions in ISDR (0-1/ 2≤/ ND) 50/12/0 37/5/2 0.3201

Laboratory dataHCV-RNA （Log10IU/mL） 6.2 (5.0-7.2) 6.5 (5.5-7.6) 0.0193 0.263 0.097-0.708 0.0088

(per 1.0Log10IU/mL)White blood cells ( /μL) 5200 (2000-11100) 4450 (2200-7900) 0.0431Hemoglobin （g/dL） 14.45 (11.7-16.8) 13.6 (11.4-17.5) 0.0586Pletelets （×104/μL） 18.45 (7.4-40.7) 14.8 (6.4-25.9) 0.0285Aspartate aminotransferase （IU/L） 37.5 (16-149) 48.5 (22-139) 0.0327Alanine aminotransferase （IU/L） 36 (14-261) 45.5 (20-201) 0.1847gamma-glutamyl-transpeptitase （IU/L） 40 (12-328) 57 (14-427) 0.1603Albumin （g/dL） 4.25 (3.1-4.8) 4.1 (2.8-4.7) 0.2177Fasting total cholesterol (mg/dL) 164 (113-253) 155 (111-250) 0.3923Fasting low density lipoprotein-cholesterol (mg/dL) 96 (50-173) 82 (39-163) 0.0136 1.394 1.098-1.768 0.0068

(per 10mg/mL)Fasting plasma glucose （mg/dL） 100 (74-210) 97 (80-121) 0.1401Homeostasis model assessment-Insulin Resistance 2.22 (0.33-20.7) 1.77 (0.49-24.9) 0.8409Alpha-fetoprotein (ng/mL) 5.0 (1.0-192) 9.0 (2.7-160) 0.2468

TreatmentInitial dose of Peg-IFN (μg /kg) 1.51 (1.04-1.88) 1.56 (1.27-1.94) 0.1954Initial dose of RBV (mg /kg) 11.1 (3.0-13.3) 12.0 (7.6-13.6) 0.5974Initial dose of TVR (1500 / 2250 mg) 31/31 25/23 0.6455Initial dose of TVR (mg/kg ) 30.0 (20.2-47.1) 30.9 (19.0-45.8) 0.9439

-treatment factors

TreatmentAdherence of PEG-IFN (%) 100.0 (24.6-100.0) 100.0 (16.7-100.0) 0.0092Adherence of RBV (%) 76.9 (17.4-100.0) 67.2 (13.9-100.0) 0.0361Adherence of TVR (%)** 66.7 (34.9-100.0) 66.7 (22.2-100.0) 0.1993

Early virological responseAchieving of RVR / non-RVR (1:non-RVR / 2:RVR) 54/8 (87.1%) 21/23 (47.7%) 7.35 × 10-5 7.543 2.783-20.440 0.0001

G-IFN, peginterferon; RBV, ribavirin; TVR, telaprevir; HCV, hepatitis C virus; ISDR, interferon-sensitivity determining region; RVR, rapid virological response;P, single nucleotide polymorphism

wild-type’ (arginine) or ‘mutant-type’ (glutamine or histidine); **calculated on the basis of 2250 mg/day.ta expressed as number of patients or median (range)

Multivaritate analysis

Acc

epte

d A

rticl

e

Table 3. Significantly independent pre-treatment and on-treatment factorss associated with sustained virological response (SVR) to 24-week telaprevir-based peginterferon plus ribavirin combination therapy in patients infected with the HCV genotype 1b and have the non-TT genotype of the rs8099917 SNP (1:non-SVR/ 2: SVR)

Factor Odds ratio 95% Confidence Interval P-value

Prior treatment response 1:Naïve/Relapse/Partial 1 2:Null 0.0186 0.0015-0.2274 0.0018

Serum fasting LDL-C 1.3658 1.0928-1.7071 0.0062 (per 10mg/dL)

Early virological response 1:non-RVR 1 2:RVR 7.0542 2.0310-24.5015 0.0021

LDL-C, low density lipoprotein-cholesterol; RVR, Rapid virological respnonse

Acc

epte

d A

rticl

e

Factors associated with sustained virological response in 24-week telaprevir-based triple therapy...

Documents

Transcript of Factors associated with sustained virological response in 24-week telaprevir-based triple therapy...