Antiviral Therapy 2015; 20:185–192 (doi: 10.3851/IMP2805)
Original article Non-invasive fibrosis assessment predicts sustained virological response to telaprevir with pegylated interferon and ribavirin for chronic hepatitis C Eiichi Ogawa1*, Norihiro Furusyo1, Motohiro Shimizu1, Takeshi Ihara1, Takeo Hayashi1, Yuji Harada1, Kazuhiro Toyoda1, Masayuki Murata1, Jun Hayashi2 Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan
1 2
*Corresponding author e-mail: [email protected]
Background: Liver fibrosis remains one of the most important predictors of sustained virological response (SVR) in this era of direct-acting antiviral treatment of chronic hepatitis C. We compare non-invasive fibrosis assessment with liver biopsy (METAVIR) in terms of their ability to predict SVR by telaprevir (TVR)-based triple therapy. Methods: This prospective study consisted of 108 patients with chronic HCV genotype 1 infection who received TVR in combination with pegylated interferon (PEG-IFN)-a2b and ribavirin (RBV). Non-invasive fibrosis data included transient elastography (FibroScan), FIB-4 index and aspartate aminotransferase to platelet ratio index (APRI). Results: SVR was achieved by 84.3% of the patients by intention-to-treat analysis. In contrast to the high SVR rates for treatment-naive patients (87.1%, 27 of 31) and
patients who previously relapsed (97.9%, 46 of 47), the SVR rate of prior partial/null responders was significantly lower (60.0%, 18 of 30). The impact of fibrosis on SVR was greater for prior partial/null responders, and fibrosis data, including both METAVIR score and non-invasive fibrosis assessments, were useful for predicting SVR. The METAVIR score (area under the receiver operating characteristic curve [AUROC] 0.91, cutoff ≤F2), FibroScan values (AUROC 0.99, cutoff ≤10.0 kPa), FIB-4 index (AUROC 0.91, cutoff ≤3.5) and APRI (AUROC 0.91, cutoff ≤0.80) were shown to have equal, excellent predictive power. Conclusions: An alternative to METAVIR score by liver biopsy, non-invasive fibrosis assessments are useful options for predicting SVR by prior partial or null responders in TVR-based triple therapy.
Introduction Chronic HCV infection is a major cause of liver cirrhosis and hepatocellular carcinoma, affecting about 150 million people worldwide [1]. Eradication of HCV infection by antiviral treatment, as indicated by sustained virological response (SVR), has contributed to a reduction of the number of patients who develop hepatocellular carcinoma and hepatic decompensation and to prolonged survival [2–4]. Since the approval of directacting antivirals (DAAs) in 2011, the administration of two first-generation non-structural (NS) 3/4A protease inhibitors, telaprevir (TVR) and boceprevir, has resulted in significantly improved SVR rates for patients infected with HCV genotype 1 [5–8]. Many background factors associated with SVR to pegylated interferon-a (PEG-IFN-a) and ribavirin (RBV) do not appear to be significant predictors of response to TVR-based triple therapy based on the ©2015 International Medical Press 1359-6535 (print) 2040-2058 (online)
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drastic improvement of treatment outcome. Nevertheless, the stage of fibrosis continues to be one of the most useful pretreatment predictors of success [6–9]. Pretreatment predictors of response are useful in selecting the most appropriate treatment, reducing the cost of therapy while optimizing treatment outcome. Japanese HCV patients, most of whom are elderly and have advanced fibrosis [10], need evaluation of the stage of fibrosis so that the treatment strategy can be individually tailored. In recent years, several routine laboratory tests such as aspartate aminotransferase (AST) to platelet ratio index (APRI) [11], FIB-4 index [12], and devices such as transient elastography (FibroScan) [13–15] have been developed and validated for the non-invasive assessment of advanced fibrosis or cirrhosis and serve as alternatives to liver biopsy. However, these 185
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non-invasive assessments have not been evaluated as predictors of antiviral treatment outcome. The aim of this study is to further compare the non-invasive assessment of fibrosis with METAVIR score by liver biopsy on their ability to assess predictors of the success of TVR-based triple therapy.
C.R.Bard, Covington, GA, USA) under ultrasound guidance. The minimum length of the liver sample was 15 mm and at least 10 complete portal tracts were necessary for inclusion. For each specimen, the stage of fibrosis was established according to the METAVIR score [17].
Methods
Non-invasive fibrosis assessment
Patients This prospective study consisted of 108 Japanese patients with chronic HCV infection aged 20 years or older who received TVR in combination with PEGIFN-a2b and RBV. All initiated treatment between December 2011 and December 2012 and it was completed by the end of June 2013. This study included both treatment-naive (n=31, 28.7%) and -experienced patients (n=77, 71.3%). Of the 77 patients previously treated with PEG-IFN-a and RBV, 47 (43.5%) had a relapse, 16 (14.8%) had partial response and 14 (13.0%) had null response. Exclusion criteria were: positivity for antibody to HIV or positivity for hepatitis B surface antigen; clinical or biochemical evidence of hepatic decompensation (Child–Pugh B or C, ascites, bleeding varices or encephalopathy); other causes of liver disease (haemochromatosis, autoimmune hepatitis or primary biliary cirrhosis); excessive active alcohol consumption (a daily intake of more than 40g of ethanol), drug abuse or severe mental disorder; the presence of active cancer at entry; or treatment with antiviral or immunosuppressive agents prior to enrolment. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was approved by the Ethics Committee of each participating hospital. Informed consent was obtained from all patients before enrolment. The study was registered on the University Hospital Medical Information Network (ID 000012850).
Clinical and laboratory assessment Clinical parameters were measured by standard laboratory techniques at a commercial laboratory (SRL Laboratory, Tokyo, Japan). Body mass index was calculated as weight in kilograms/height in square meters. The estimated glomerular filtration rate was calculated based on the Modification of Diet in Renal Disease formula. Human genomic DNA was extracted from peripheral blood. Genotyping of the interleukin-28B (IL28B; rs8099917) gene [16] was performed using the ABI TaqMan allelic discrimination kit (7500 Real Time PCR System; Applied Biosystems, Carlsbad, CA, USA). Liver biopsy was done by experienced hepatologists with a 16G disposable needle (Bard® Monopty®; 186
AVT-14-OA-3207_Ogawa.indd 186
Transient elastography was performed at entry using FibroScan (Echosens, Paris, France) within two weeks of liver biopsy following the previously reported methods [14,15,18]. The FibroScan values are shown as kilopascal (kPa). All examinations were performed by accomplished operators each of whom had experienced over 200 examinations. Only liver stiffness measurements obtained with at least six successful acquisitions and a success rate of at least 60% were considered reliable. The validity of FibroScan values depends on an IQR of all successful measurements of less than 30% of median values [19]. The serum fibrosis markers used for assessment in this study were the APRI [11] and FIB-4 index [12]. APRI was calculated as AST (/upper limit of normal [U/L]) ×100/platelet count (×109/l). The FIB-4 index was calculated from the published formula: [age (years) ×AST (U/L)] / [platelet count (×109/l) × {alanine aminotransferase (U/L)}1/2].
Antiviral treatment All patients received a combination treatment of TVR (Telavic; Mitsubishi Tanabe Pharma, Osaka, Japan), PEG-IFN-a2b (PEG-Intron; MSD, Tokyo, Japan) and RBV (Rebetol; MSD) for 12 weeks, followed by an additional 12 weeks of PEG-IFN-a2b and RBV alone. TVR 750 mg was administrated three times a day at an 8-h interval, after each meal. If the patient was female, aged over 65 or weighed less than 50 kg, the TVR dose of 1,500 mg/day (750 mg twice a day at a 12-h interval after each meal) could be initiated. PEGIFN-a2b was injected subcutaneously once weekly at a dose of 1.5 mg/kg. RBV was given orally at a daily dose of 600–1,000 mg based on body weight. If marked anorexia, an elevation of serum creatinine, or severe anaemia developed, the TVR dose could be reduced from 2,250 to 1,500 mg/day, as previously reported [20]. For patients with grade 1 (localized to one or several sites) or 2 (diffuse skin eruption involving up to 50% of the body surface) dermatological disorders, medical management was performed at the discretion of the physicians at each hospital. If a progressive grade 3 dermatological disorder developed (involving more than 50% of the body surface or rash with the appearance of substantial systemic signs or symptoms), TVR was discontinued, but the patients ©2015 International Medical Press
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Non-invasive fibrosis assessment in TVR-based triple therapy
continued to receive PEG-IFN-a2b and RBV. All treatment was discontinued if HCV RNA was more than 1,000 IU/ml at week 12 or later in case of viral breakthrough (defined as an increase of more than 1 log10 IU/ml compared with the lowest recorded on-treatment value or a confirmed more than HCV RNA 100 IU/ml if previously below the level of quantification).
HCV RNA level and HCV genotype Clinical follow-up of HCV viraemia was done by real-time reverse transcriptase PCR assay (COBAS® TaqMan® HCV assay; Roche Diagnostics, Tokyo, Japan) with a lower limit of quantitation of 15 IU/ml and an outer limit of quantitation of 6.9×107 IU/ml (1.2 to 7.8 log IU/ml referred to log10 IU/ml) [21]. The HCV RNA level was measured at baseline, at 4-week intervals during treatment, at early discontinuation and at follow-up visits after the end of treatment. HCV genotype determination was by sequence determination in the 5′-non-structual region of the HCV genome followed by phylogenetic analysis [22]. Previous virological response to PEG-IFN-a and RBV treatment was categorized as follows: prior relapse, undetectable HCV RNA at the end of treatment but detectable HCV RNA within 24 weeks after the end of treatment and the re-appearance of HCV RNA at any time during treatment after virological response (breakthrough); prior partial response, a more than 2 log10 IU/ml decrease in the HCV RNA level from baseline at week 12 but detectable HCV RNA at weeks 12 and 24; prior null response, a decrease in the HCV RNA level of less than 2 log10 IU/ml at week 12. The primary measure of efficacy was the rate of SVR, defined as undetectable HCV RNA at week 24 after the end of treatment.
Statistical analyses Statistical analyses were conducted using SPSS Statistics 22.0 (IBM SPSS Inc., Chicago, IL, USA). Baseline continuous data are expressed as median (first-third quartiles) and categorical variables are reported as frequencies and percentages. Univariate analyses were done using the c2, Fisher’s Exact, or Mann–Whitney U test as appropriate. The results are expressed as odds ratios (OR) and their 95% CIs. Receiver operating characteristic (ROC) curve analysis was done to evaluate the relationship between the fibrosis values and SVR. The cutoff values were calculated from the ROC curve to maximize the total sensitivity and specificity and we showed the values of the area under the ROC curve (AUROC). We compared the AUROCs pairwise among all ROC curves using the method described by Delong et al. [23]. A P-value less than 0.05 was regarded as statistically significant in all analyses. Antiviral Therapy 20.2
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Results Patient characteristics The baseline characteristics of the patients are shown in Table 1. Of the 108 patients enrolled, 105 (97.2%) were infected with HCV genotype 1b and the others (only 3) were genotype 1a. The median age was 63 and 48.1% of the patients were men. Almost all (95.4%) received liver biopsy within the two weeks before the initiation of triple therapy, five did not due to being under anticoagulation therapy or as they had prolonged bleeding time: 32.0% had advanced fibrosis
Table 1. Patient baseline characteristics Baseline characteristics
Values
Patients, n 108 Age, years 63 (52–68) Male 52 (48.1) Body mass index, kg/m2 23.2 (20.9–25.3) Serum albumin, g/l 41 (38–43) Total bilirubin, mmol/l 15 (12–21) Aspartate aminotransferase, U/l 45 (31–78) Alanine aminotransferase, U/l 48 (28–79) g-glutamyl transpeptidase, U/l 39 (25–76) Estimated glomerular filtration rate, 81 (70–94) ml/min/1.73 m2 a-fetoprotein, ng/ml 4.8 (2.9–9.1) White blood cell count, ×109/l 5.1 (4.1–6.0) Haemoglobin, g/l 138 (130–149) Platelet count, ×109/l 159 (124–195) HCV genotype 1a 3 (2.8) 1b 105 (97.2) HCV RNA level, log10 IU/ml 6.5 (6.1–7.0) Fibrosis stage (METAVIR score) F0–1 61 (59.2) F2 9 (8.7) F3 13 (12.6) F4 20 (19.4) Not determined, n 5 FibroScan, kPa 8.6 (5.7–14.5) FIB-4 index 2.6 (1.7–4.0) APRI 0.7 (0.5–1.7) IL28B SNPs (rs8099917) TT 63 (58.3) TG 43 (39.8) GG 2 (1.9) Treatment-naive 31 (28.7) Treatment-experienceda Prior relapse 47 (43.5) Prior partial response 16 (14.8) Prior null response 14 (13.0) Data are expressed as n (%) or median (first–third quartiles) unless otherwise indicated. aTreatment-experienced patients had received pegylated interferon-a and ribavirin dual therapy. APRI, aspartate aminotransferase to platelet ratio index; IL28B, interleukin 28B; SNP, single nucleotide polymorphism. 187
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(F3–4). The data of FibroScan, FIB-4 index, APRI and IL28B single nucleoside polymorphism (SNP; rs8099917) were available for all studied patients.
Correlation between fibrosis stage determined by liver biopsy (METAVIR score) and the non-invasive assessment tools The METAVIR score was significantly correlated with each non-invasive assessment tool (Additional file 1). Of them, the FibroScan value had the highest coefficient correlation value (r=0.642; P
Original article Non-invasive fibrosis assessment predicts sustained virological response to telaprevir with pegylated interferon and ribavirin for chronic hepatitis C Eiichi Ogawa1*, Norihiro Furusyo1, Motohiro Shimizu1, Takeshi Ihara1, Takeo Hayashi1, Yuji Harada1, Kazuhiro Toyoda1, Masayuki Murata1, Jun Hayashi2 Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan
1 2
*Corresponding author e-mail: [email protected]
Background: Liver fibrosis remains one of the most important predictors of sustained virological response (SVR) in this era of direct-acting antiviral treatment of chronic hepatitis C. We compare non-invasive fibrosis assessment with liver biopsy (METAVIR) in terms of their ability to predict SVR by telaprevir (TVR)-based triple therapy. Methods: This prospective study consisted of 108 patients with chronic HCV genotype 1 infection who received TVR in combination with pegylated interferon (PEG-IFN)-a2b and ribavirin (RBV). Non-invasive fibrosis data included transient elastography (FibroScan), FIB-4 index and aspartate aminotransferase to platelet ratio index (APRI). Results: SVR was achieved by 84.3% of the patients by intention-to-treat analysis. In contrast to the high SVR rates for treatment-naive patients (87.1%, 27 of 31) and
patients who previously relapsed (97.9%, 46 of 47), the SVR rate of prior partial/null responders was significantly lower (60.0%, 18 of 30). The impact of fibrosis on SVR was greater for prior partial/null responders, and fibrosis data, including both METAVIR score and non-invasive fibrosis assessments, were useful for predicting SVR. The METAVIR score (area under the receiver operating characteristic curve [AUROC] 0.91, cutoff ≤F2), FibroScan values (AUROC 0.99, cutoff ≤10.0 kPa), FIB-4 index (AUROC 0.91, cutoff ≤3.5) and APRI (AUROC 0.91, cutoff ≤0.80) were shown to have equal, excellent predictive power. Conclusions: An alternative to METAVIR score by liver biopsy, non-invasive fibrosis assessments are useful options for predicting SVR by prior partial or null responders in TVR-based triple therapy.
Introduction Chronic HCV infection is a major cause of liver cirrhosis and hepatocellular carcinoma, affecting about 150 million people worldwide [1]. Eradication of HCV infection by antiviral treatment, as indicated by sustained virological response (SVR), has contributed to a reduction of the number of patients who develop hepatocellular carcinoma and hepatic decompensation and to prolonged survival [2–4]. Since the approval of directacting antivirals (DAAs) in 2011, the administration of two first-generation non-structural (NS) 3/4A protease inhibitors, telaprevir (TVR) and boceprevir, has resulted in significantly improved SVR rates for patients infected with HCV genotype 1 [5–8]. Many background factors associated with SVR to pegylated interferon-a (PEG-IFN-a) and ribavirin (RBV) do not appear to be significant predictors of response to TVR-based triple therapy based on the ©2015 International Medical Press 1359-6535 (print) 2040-2058 (online)
AVT-14-OA-3207_Ogawa.indd 185
drastic improvement of treatment outcome. Nevertheless, the stage of fibrosis continues to be one of the most useful pretreatment predictors of success [6–9]. Pretreatment predictors of response are useful in selecting the most appropriate treatment, reducing the cost of therapy while optimizing treatment outcome. Japanese HCV patients, most of whom are elderly and have advanced fibrosis [10], need evaluation of the stage of fibrosis so that the treatment strategy can be individually tailored. In recent years, several routine laboratory tests such as aspartate aminotransferase (AST) to platelet ratio index (APRI) [11], FIB-4 index [12], and devices such as transient elastography (FibroScan) [13–15] have been developed and validated for the non-invasive assessment of advanced fibrosis or cirrhosis and serve as alternatives to liver biopsy. However, these 185
23/04/2015 10:47:42
E Ogawa et al.
non-invasive assessments have not been evaluated as predictors of antiviral treatment outcome. The aim of this study is to further compare the non-invasive assessment of fibrosis with METAVIR score by liver biopsy on their ability to assess predictors of the success of TVR-based triple therapy.
C.R.Bard, Covington, GA, USA) under ultrasound guidance. The minimum length of the liver sample was 15 mm and at least 10 complete portal tracts were necessary for inclusion. For each specimen, the stage of fibrosis was established according to the METAVIR score [17].
Methods
Non-invasive fibrosis assessment
Patients This prospective study consisted of 108 Japanese patients with chronic HCV infection aged 20 years or older who received TVR in combination with PEGIFN-a2b and RBV. All initiated treatment between December 2011 and December 2012 and it was completed by the end of June 2013. This study included both treatment-naive (n=31, 28.7%) and -experienced patients (n=77, 71.3%). Of the 77 patients previously treated with PEG-IFN-a and RBV, 47 (43.5%) had a relapse, 16 (14.8%) had partial response and 14 (13.0%) had null response. Exclusion criteria were: positivity for antibody to HIV or positivity for hepatitis B surface antigen; clinical or biochemical evidence of hepatic decompensation (Child–Pugh B or C, ascites, bleeding varices or encephalopathy); other causes of liver disease (haemochromatosis, autoimmune hepatitis or primary biliary cirrhosis); excessive active alcohol consumption (a daily intake of more than 40g of ethanol), drug abuse or severe mental disorder; the presence of active cancer at entry; or treatment with antiviral or immunosuppressive agents prior to enrolment. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was approved by the Ethics Committee of each participating hospital. Informed consent was obtained from all patients before enrolment. The study was registered on the University Hospital Medical Information Network (ID 000012850).
Clinical and laboratory assessment Clinical parameters were measured by standard laboratory techniques at a commercial laboratory (SRL Laboratory, Tokyo, Japan). Body mass index was calculated as weight in kilograms/height in square meters. The estimated glomerular filtration rate was calculated based on the Modification of Diet in Renal Disease formula. Human genomic DNA was extracted from peripheral blood. Genotyping of the interleukin-28B (IL28B; rs8099917) gene [16] was performed using the ABI TaqMan allelic discrimination kit (7500 Real Time PCR System; Applied Biosystems, Carlsbad, CA, USA). Liver biopsy was done by experienced hepatologists with a 16G disposable needle (Bard® Monopty®; 186
AVT-14-OA-3207_Ogawa.indd 186
Transient elastography was performed at entry using FibroScan (Echosens, Paris, France) within two weeks of liver biopsy following the previously reported methods [14,15,18]. The FibroScan values are shown as kilopascal (kPa). All examinations were performed by accomplished operators each of whom had experienced over 200 examinations. Only liver stiffness measurements obtained with at least six successful acquisitions and a success rate of at least 60% were considered reliable. The validity of FibroScan values depends on an IQR of all successful measurements of less than 30% of median values [19]. The serum fibrosis markers used for assessment in this study were the APRI [11] and FIB-4 index [12]. APRI was calculated as AST (/upper limit of normal [U/L]) ×100/platelet count (×109/l). The FIB-4 index was calculated from the published formula: [age (years) ×AST (U/L)] / [platelet count (×109/l) × {alanine aminotransferase (U/L)}1/2].
Antiviral treatment All patients received a combination treatment of TVR (Telavic; Mitsubishi Tanabe Pharma, Osaka, Japan), PEG-IFN-a2b (PEG-Intron; MSD, Tokyo, Japan) and RBV (Rebetol; MSD) for 12 weeks, followed by an additional 12 weeks of PEG-IFN-a2b and RBV alone. TVR 750 mg was administrated three times a day at an 8-h interval, after each meal. If the patient was female, aged over 65 or weighed less than 50 kg, the TVR dose of 1,500 mg/day (750 mg twice a day at a 12-h interval after each meal) could be initiated. PEGIFN-a2b was injected subcutaneously once weekly at a dose of 1.5 mg/kg. RBV was given orally at a daily dose of 600–1,000 mg based on body weight. If marked anorexia, an elevation of serum creatinine, or severe anaemia developed, the TVR dose could be reduced from 2,250 to 1,500 mg/day, as previously reported [20]. For patients with grade 1 (localized to one or several sites) or 2 (diffuse skin eruption involving up to 50% of the body surface) dermatological disorders, medical management was performed at the discretion of the physicians at each hospital. If a progressive grade 3 dermatological disorder developed (involving more than 50% of the body surface or rash with the appearance of substantial systemic signs or symptoms), TVR was discontinued, but the patients ©2015 International Medical Press
23/04/2015 10:47:42
Non-invasive fibrosis assessment in TVR-based triple therapy
continued to receive PEG-IFN-a2b and RBV. All treatment was discontinued if HCV RNA was more than 1,000 IU/ml at week 12 or later in case of viral breakthrough (defined as an increase of more than 1 log10 IU/ml compared with the lowest recorded on-treatment value or a confirmed more than HCV RNA 100 IU/ml if previously below the level of quantification).
HCV RNA level and HCV genotype Clinical follow-up of HCV viraemia was done by real-time reverse transcriptase PCR assay (COBAS® TaqMan® HCV assay; Roche Diagnostics, Tokyo, Japan) with a lower limit of quantitation of 15 IU/ml and an outer limit of quantitation of 6.9×107 IU/ml (1.2 to 7.8 log IU/ml referred to log10 IU/ml) [21]. The HCV RNA level was measured at baseline, at 4-week intervals during treatment, at early discontinuation and at follow-up visits after the end of treatment. HCV genotype determination was by sequence determination in the 5′-non-structual region of the HCV genome followed by phylogenetic analysis [22]. Previous virological response to PEG-IFN-a and RBV treatment was categorized as follows: prior relapse, undetectable HCV RNA at the end of treatment but detectable HCV RNA within 24 weeks after the end of treatment and the re-appearance of HCV RNA at any time during treatment after virological response (breakthrough); prior partial response, a more than 2 log10 IU/ml decrease in the HCV RNA level from baseline at week 12 but detectable HCV RNA at weeks 12 and 24; prior null response, a decrease in the HCV RNA level of less than 2 log10 IU/ml at week 12. The primary measure of efficacy was the rate of SVR, defined as undetectable HCV RNA at week 24 after the end of treatment.
Statistical analyses Statistical analyses were conducted using SPSS Statistics 22.0 (IBM SPSS Inc., Chicago, IL, USA). Baseline continuous data are expressed as median (first-third quartiles) and categorical variables are reported as frequencies and percentages. Univariate analyses were done using the c2, Fisher’s Exact, or Mann–Whitney U test as appropriate. The results are expressed as odds ratios (OR) and their 95% CIs. Receiver operating characteristic (ROC) curve analysis was done to evaluate the relationship between the fibrosis values and SVR. The cutoff values were calculated from the ROC curve to maximize the total sensitivity and specificity and we showed the values of the area under the ROC curve (AUROC). We compared the AUROCs pairwise among all ROC curves using the method described by Delong et al. [23]. A P-value less than 0.05 was regarded as statistically significant in all analyses. Antiviral Therapy 20.2
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Results Patient characteristics The baseline characteristics of the patients are shown in Table 1. Of the 108 patients enrolled, 105 (97.2%) were infected with HCV genotype 1b and the others (only 3) were genotype 1a. The median age was 63 and 48.1% of the patients were men. Almost all (95.4%) received liver biopsy within the two weeks before the initiation of triple therapy, five did not due to being under anticoagulation therapy or as they had prolonged bleeding time: 32.0% had advanced fibrosis
Table 1. Patient baseline characteristics Baseline characteristics
Values
Patients, n 108 Age, years 63 (52–68) Male 52 (48.1) Body mass index, kg/m2 23.2 (20.9–25.3) Serum albumin, g/l 41 (38–43) Total bilirubin, mmol/l 15 (12–21) Aspartate aminotransferase, U/l 45 (31–78) Alanine aminotransferase, U/l 48 (28–79) g-glutamyl transpeptidase, U/l 39 (25–76) Estimated glomerular filtration rate, 81 (70–94) ml/min/1.73 m2 a-fetoprotein, ng/ml 4.8 (2.9–9.1) White blood cell count, ×109/l 5.1 (4.1–6.0) Haemoglobin, g/l 138 (130–149) Platelet count, ×109/l 159 (124–195) HCV genotype 1a 3 (2.8) 1b 105 (97.2) HCV RNA level, log10 IU/ml 6.5 (6.1–7.0) Fibrosis stage (METAVIR score) F0–1 61 (59.2) F2 9 (8.7) F3 13 (12.6) F4 20 (19.4) Not determined, n 5 FibroScan, kPa 8.6 (5.7–14.5) FIB-4 index 2.6 (1.7–4.0) APRI 0.7 (0.5–1.7) IL28B SNPs (rs8099917) TT 63 (58.3) TG 43 (39.8) GG 2 (1.9) Treatment-naive 31 (28.7) Treatment-experienceda Prior relapse 47 (43.5) Prior partial response 16 (14.8) Prior null response 14 (13.0) Data are expressed as n (%) or median (first–third quartiles) unless otherwise indicated. aTreatment-experienced patients had received pegylated interferon-a and ribavirin dual therapy. APRI, aspartate aminotransferase to platelet ratio index; IL28B, interleukin 28B; SNP, single nucleotide polymorphism. 187
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(F3–4). The data of FibroScan, FIB-4 index, APRI and IL28B single nucleoside polymorphism (SNP; rs8099917) were available for all studied patients.
Correlation between fibrosis stage determined by liver biopsy (METAVIR score) and the non-invasive assessment tools The METAVIR score was significantly correlated with each non-invasive assessment tool (Additional file 1). Of them, the FibroScan value had the highest coefficient correlation value (r=0.642; P
