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Hyporesponsiveness to PegIFNα2B plus ribavirin in patients with hepatitis C-related advanced fibrosis
Research Article
Hyporesponsiveness to PegIFNa2B plus ribavirin in patients with hepatitis C-related advanced fibrosis Gian Maria Prati1, Alessio Aghemo1,⇑, Maria Grazia Rumi2, Roberta D’Ambrosio1, Stella De Nicola1, Maria Francesca Donato1, Elisabetta Degasperi1, Massimo Colombo1 1
A.M. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy; 2Liver Unit, San Giuseppe Hospital, Università degli Studi di Milano, Milan, Italy
Background & Aims: The success of pegylated-interferon (PegIFN)/ribavirin (Rbv) therapy of chronic hepatitis C is compromised by liver fibrosis. Whether fibrosis equally affects the two PegIFNa-based therapies is unknown. To assess the response to the two PegIFN regimens in patients with different degree of liver fibrosis. Methods: A sub-analysis of the MIST study: 431 consecutive naïve patients randomly assigned, based on HCV genotype, to receive either (A) PegIFNa2a 180 lg/wk plus daily Rbv 800–1200 mg or (B) PegIFNa2b 1.5 lg/kg/week plus daily Rbv 800–1200 mg, were stratified according to Ishak staging (S) into mild (S0–S2) or moderate (S3, S4) fibrosis and cirrhosis (S5, S6). Results: In A the sustained virological response (SVR) rates were not significantly influenced by fibrosis stage (71% in S0–S2, 66% in S3, S4, 53% in S5, S6, p = 0.12), compared to B where the SVR rates differed according to fibrosis stage (65%, 46%, and 38%, p = 0.004, respectively). This was even more so in HCV-1/4 patients treated with PegIFNa2b where the SVR rates were twice as many in S0–S2 vs. S P3 (44% vs. 22%, p = 0.02), while in A the SVR rates were similar between the two fibrosis subgroups (S0–S2: 47% vs. S P3: 48%, p = 0.8). By logistic regression analysis genotype 1/4 and lack of rapid virological response were independent predictors of treatment failure in both treatment groups, while S P3 fibrosis was associated to PegIFNa2b treatment failure, only (OR 2.83, 95% CI 1.4–5.68, p = 0.004). Conclusions: Liver fibrosis was an independent moderator of treatment outcome in patients receiving PegIFNa2b, not in those receiving PegIFNa2a. Ó 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Keywords: Hepatitis C virus; Liver fibrosis; Pegylated interferon; Ribavirin; Sustained virological response. Received 18 March 2011; received in revised form 3 May 2011; accepted 7 May 2011; available online 12 July 2011 ⇑ Corresponding author. Address: 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Via F. Sforza 35, 20122 Milan, Italy. Tel.: +39 0255035432; fax: +39 0250320410. E-mail address: [email protected] (A. Aghemo). Abbreviations: HCV, hepatitis C virus; PegIFN, pegylated-interferon; Rbv, ribavirin; Peg, polyethylene glycol; SVR, sustained virological response; RVR, rapid virological response; cEVR, complete early virological response; ETR, end of treatment response; S, Ishak fibrosis score; ITT, intention-to-treat.
Introduction Infection with the hepatitis C virus (HCV) is a major cause of morbidity and anticipated liver-related mortality worldwide [1] and pegylated-interferon (PegIFN)/ribavirin (Rbv) is the only therapeutic approach to prevent these complications [2–4]. While liver fibrosis is of paramount importance in determining the risk of anticipated liver related death, unfortunately it represents one of the strongest independent moderators of treatment outcome to IFN based therapies [5–7]. As a consequence of this paradox, the success of treatment has long been dichotomized according to the presence or absence of advanced liver fibrosis in patients with chronic hepatitis C, even though the exact mechanism by which fibrosis conflicts with the antiviral effects of PegIFN and Rbv remains elusive. Indeed, the negative role of liver fibrosis could reflect the anatomical subversion of the liver architecture, which theoretically prevents optimal interaction between IFN and target liver cells as well as a long lasting duration of HCV infection in these patients. Moreover, the defective adherence to the optimal schedule of treatment due to cytopenia remains a challenge of IFN based therapy of HCV patients with advanced fibrosis, since it increases the chances of hypo-responsiveness [8]. In the light of these interactions between therapy of HCV and advanced liver fibrosis, we asked ourselves whether hepatic fibrosis affects the clinical activity of the two available PegIFN regimens used to treat HCV. Indeed, PegIFNalfa2a and PegIFNalfa2b, while sharing the same mechanisms of action, are markedly different in terms of pharmacokinetic and pharmacodynamic properties [9–14], which might relate to their clinical activity. The two drugs, in fact are characterized by significant differences in the pegylation process of the native IFN molecule that ultimately affect the volume of distribution, the serum half life and the in vitro antiviral activity of the two compounds. As a direct consequence of the different volume of distribution, the two drugs concentrate differently into the liver, a feature that, in theory, could translate into a different therapeutic activity of the two PegIFNs in the presence of advanced fibrosis. A sub-analysis of the MIST study [15] allowed us to compare the effectiveness of the two PegIFNa regimens according to the extent of liver fibrosis, histologically evaluated at the time of enrolment into the study.
Journal of Hepatology 2012 vol. 56 j 341–347
Research Article Materials and methods
Patients
Aim
Patients enroled into the MIST study were randomized by a computer-generated allocation list stratified by HCV genotype, to receive a combination of PegIFNa2a (Pegasys, Roche, Basel Switzerland) 180 lg/week plus daily Rbv (Rebetol, Schering Plough corp, Kenilworth New Jersey USA) 800–1200 mg (A) or PegIFNa2b (PegIntron, Schering Plough corp) 1.5 lg/kg/week plus daily Rbv 800–1200 mg (B), for a standard duration based on HCV genotype. Patients with HCV-1 and HCV-4 were treated for 48 weeks: PegIFNa2a was associated with Rbv 1000– 1200 mg day (<75 kg, P75 kg); PegIFNa2b with Rbv 800 mg for patients of less than 65 kg body weight, 1000 mg for 65–85 kg and 1200 mg for P85 kg. HCV-2 and HCV-3 patients were treated for 24 weeks: PegIFNa2a was associated with Rbv 800 mg day; PegIFNa2b with Rbv 800 mg for patients of less than 65 kg body weight, 1000 mg for 65–85 kg and 1200 mg for P85 kg.
This is a sub-analysis of the MIST study [15] that was originally designed to compare safety and effectiveness of PegIFNa2a and PegIFNa2b therapy associated with Rbv. In the present study, we assessed the outcome of PegIFN therapy according to the stage of liver fibrosis classified by the Ishak score system in liver biopsies, performed 2–20 months (median ± standard deviation: 12 ± 6) before the start of therapy.
Assessed for eligibility (n = 473)
Measurements
Excluded (n = 26) • Not meeting inclusion criteria (n = 7) • Refused to participate (n = 18) • Other reasons (n = 1)
Underwent randomization (n = 447)
Allocated to PegIFNα2a group (n = 223)
Allocated to PegIFNα2b group (n = 224)
• Received allocated intervention (n = 212)
• Received allocated intervention (n = 219)
• Did not receive allocated intervention (n = 11)
• Did not receive allocated intervention (n = 5)
Given reasons: • Refuse to participate (n = 8)
Given reasons: • Refuse to participate (n = 4)
• Laboratory abnormalities (n = 3)
• Lost to follow-up (n = 1)
Discontinued intervention (n = 46)
Discontinued intervention (n = 73)
Given reasons: • Adverse event (n = 16) • Lost to follow-up (n = 1) • Other reason (n = 1) • Met stopping rule* (n = 28)
Given reasons: • Adverse event (n = 17) • Lost to follow-up (n = 2) • Withdrew consent (n = 2) • Other reason (n = 2) § • Met stopping rule (n = 50)
ITT analysis in 212 patients
ITT analysis in 219 patients
Fig. 1. Flow chart of the MIST study. Patients allocated to PegIFNa2a group: ⁄19 patients met the week 12 stopping rule, 7 patients met the week 24 stopping rule and 2 patients had a virological breaktrough. Patients allocated to PegIFNa2b group: §32 patients met the week 12 stopping rule; 15 patients met the week 24 stopping rule and 3 patients had a virological breaktrough. ITT (intention-totreat) analysis.
342
Serum HCV-RNA was quantified by Versant HCV-RNA 3.0 assay (bDNA 3.0, Bayer Corporation, Emeryville, CA), with a sensitivity limit of 615 IU/ml and a dynamic range from 615 to 7700,000 IU/ml. Serum HCV-RNA was assessed by qualitative RT-PCR assay (COBAS Amplicor HCV test version 2.0, Roche Diagnostics) with a detection limit of 50 IU/ml, during treatment at weeks 4, 12, 24, and 48, and after therapy at weeks 4, 12, 24. HCV was genotyped by Line Probe Assay (INNO-LIPA HCV 2, Innogenetics, Zwijndrecht, Belgium). Assessment of efficacy was SVR, defined as undetectable HCV-RNA by RT-PCR at week 24 of post-treatment follow up. Clearance of serum HCV-RNA by RT-PCR was assessed at week 4 (rapid virological response, RVR), at week 12 (complete early virological response, cEVR), at week 24, and at week 48 of treatment (end of treatment response, ETR). Patients with an ETR who tested HCV-RNA positive during follow-up were classified as relapsers. Patients who had a virological breakthrough were considered as non-responders. Therapy was discontinued in HCV-1 and HCV-4 patients if quantitative HCV-RNA testing at week 12 dropped by less than 2 log compared to baseline values (week 12 stopping rule), and at week 24 if HCV-RNA was still detectable in those patients in whom HCV-RNA dropped >2 log at week 12 (week 24 stopping rule). All liver biopsies were performed with a 16 gauge Tru-Cut needle (Uro-Cut 16G, TSK, Tokyo, Japan) and read by a single pathologist (MFD), who was unaware of patient’s identity and treatment regimen. The severity of hepatic inflammation was evaluated by the Ishak score [16] in separate reports for grading and staging. Patients were stratified according to the Ishak fibrosis score (S) on the baseline liver biopsy into mild (S0–S2) or moderate (S3, S4) fibrosis, and cirrhosis (S5, S6). Statistical analysis Comparisons between groups were made by using the Mann–Whitney U test or the Student t test for continuous variables and the v2 or Fisher exact probability test for categorical data. Intention-to-treat (ITT) analysis included all the 431 patients enroled: 212 of whom were treated with PegIFNa2a and 219 with PegIFNa2b (Fig 1). A probability value of p <0.05 was considered statistically significant. Logistic regression analysis was performed to identify variables associated with PegIFN/Rbv treatment failure. All variables with statistical significance at the univariate analysis were included in the final model and odds ratios (OR) and corresponding 95% confidence interval (95% CI) were computed. Calculations were done with Stata 10.0 statistical package (Stata 1944–2007, College Station, TX, USA).
Results The clinical and demographic features of the two treatment groups stratified by fibrosis stage are shown in Table 1A and B. In both groups patients with S P3 were more often male, older and had higher body mass index and serum ALT values than patients with S <3. The same was true for HCV-1, 4 patients (Supplementary Table 1A and B), while in HCV-2,3 patients, a similar prevalence of male gender was seen in S P3 compared to S <3 patients (Supplementary Table 1C and D). Overall 10% (41/431) patients had to discontinue therapy for non virological reasons. Treatment discontinuation was not influenced by fibrosis stage being 9% (20/213) for S0–S2, 8% (11/136) for S3, S4
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JOURNAL OF HEPATOLOGY Table 1. Baseline characteristics of patients treated with PegIFNa2a (A) or PegIFNa2b (B) stratified according to liver fibrosis stage (S).
A Features Patients, n
p value
Fibrosis stage S0-S2
S3, S4
S5, S6
104
65
43
Gender, male; n (%)
58 (56)
40 (62)
30 (70)
0.3
Age, years (mean ± SD)
47 ± 12.5
55.9 ± 9.8
56.4 ± 9.8
0.0001 0.04
Weight, kg (mean ± SD)
69.5 ± 14.5
74 ± 13.2
75.7 ± 15.8
BMI, kg/m 2 (mean ± SD)
24.4 ± 4.2
26.3 ± 4.1
26.7 ± 4.6
0.001
Alanine aminotransferase, IU/L mean ± SD
116.5 ± 124.1
138.5 ± 86.6
148.7 ± 69.6
0.0001
48 (46)
44 (68)
34 (79)
0.0001
59 (57)
34 (52)
19 (44)
0.4
≥2 fold increase at baseline; n (%) HCV RNA ≥0.6x106 IU/L; n (%)
B Features
p value
Fibrosis stage S0-S2
S3, S4
S5, S6
Patients, n
109
71
39
Gender, male; n (%)
57 (52)
40 (56)
23 (59)
0.7
Age, years (mean ± SD)
49.4 ± 12.6
55.6 ± 11.1
57.5 ± 8.7
0.0002
Weight, kg (mean ± SD)
67.4 ± 12.8
69.4 ± 11.4
72.2 ± 10.3
0.06
BMI, kg/m 2 (mean ± SD)
24.2 ± 3.9
25.2 ± 3.3
25.9 ± 3.7
0.03
Alanine aminotransferase, IU/L mean ± SD
132.6 ± 109.3
125.3 ± 114.1
125.8 ± 65.7
0.4
62 (57)
40 (56)
28 (72)
0.2
62 (57)
42 (59)
17 (44)
0.3
≥2 fold increase at baseline; n (%) HCV RNA ≥0.6x106 IU/L; n (%)
The values listed in this table are percentages or means ± standard deviation (SD). BMI, body mass index.
and 12% (10/82) for S5, S6 (p = 0.62). PegIFNa dose reduction and Rbv dose reduction rates were not influenced by fibrosis stage being 8% (16/213) for S0–S2, 8% (11/136) for S3, S4 and 11% (9/ 82) for S5, S6 (p = 0.61) and 55% (117/213), 57% (78/136) and 57% (47/82) (p = 0.89), respectively. In the overall population, ETR rates were 78% (167/213) in S0–S2 patients, 68% (93/136) in S3, S4 and 63% (52/82) in S5, S6 (p = 0.01), whereas the corresponding figures for SVR rates were 68% (145/213), 56% (76/136), and 46% (38/82) (p = 0.01). Relapse rates were 13% (22/167), 18% (17/93), and 27% (14/52) (p = 0.07). PegIFNa2a group Treatment discontinuation for non virological reasons was not influenced by fibrosis stage being 9% (9/104) for S0–S2, 8% (5/ 65) for S3, S4 and 9% (4/43) for S5, S6 (p = 1.0). PegIFNa2a dose reduction and Rbv dose reduction rates were not influenced by fibrosis stage being 10% (10/104) for S0–S2, 9% (6/65) for S3, S4, 14% (6/43) for S5, S6 (p = 0.7) and 51% (53/104), 65% (42/ 65), 56% (24/43) (p = 0.2), respectively. The ETR rates were 81% (84/104) in S0–S2 patients, 77% (50/ 65) in S3, S4 and 74% (32/43) in S5, S6 (p = 0.64) with the SVR rates being: 71% (74/104), 66% (43/65), and 53% (23/43) (p = 0.12). Relapse rates were 12% (10/84) in S0–S2 patients,
14% (7/50) in S3, S4 and 28% (9/32) in S5, S6 (p = 0.1). In S5, S6 patients, the relapse rate was significantly higher than in S 64 patients (28% vs. 13%, p = 0.05) (Fig. 2A). In HCV-1, 4 patients, the ETR rates were independent from fibrosis stage, being 63% (27/43) for S0–S2, 62% (24/39) for S3, S4 and 63% (17/27) for S5, S6 (p = 1.0). The corresponding figures for SVR were 47% (20/43) for S0–S2, 51% (20/39) for S3, S4, and 44% (12/27) for S5, S6 (p = 0.88). The relapse rates were also not influenced by the stage of fibrosis: 26% (7/27) for S0–S2, 17% (4/24) for S3, S4, and 29% (5/17) for S5, S6 (p = 0.6) (Fig. 2B). In HCV-2, 3 patients, the ETR and SVR rates were not influenced by liver fibrosis, as shown in Fig. 2C. Conversely, the relapse rate was influenced by liver fibrosis being 5% (3/57) in S0–S2 patients, 12% (3/26) in S3, S4 and 27% (4/15) in S5, S6 (p = 0.05). The relapse rate was significantly higher in S5, S6 compared to S 64 patients (27% vs. 7%, p = 0.04) (Fig. 2C). The RVR rates were 74% (77/104) for S0–S2, 52% (34/65) for S3, S4 and 51% (22/43) for S5, S6 (p = 0.004), being higher in S0–S2 than S P3 patients (74% vs. 52%, p = 0.001). The SVR rates in patients with a RVR were 87% (67/77) for S0–S2, 79% (27/34) for S3, S4 and 73% (16/22) for S5, S6 patients (p = 0.23) (Table 2). In HCV-1, 4 patients the RVR rates were 49% (21/43) for S0–S2, 28% (11/39) for S3, S4 and 33% (9/27) for S5, S6 (p = 0.14). In HCV-2, 3 patients the RVR rates were 92% (56/61)
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343
Research Article
80
81 77 74
60
71
66 53
40
28
20
12 14
0
B
S0-S2 S3, S4 S5, S6
100 80
63
62
C
63
60
47 51
44
40
29
26
20
17
100 Response (%)
S0-S2 S3, S4 S5, S6
100
Response (%)
Response (%)
A
0
100 93
94
S0-S2 S3, S4 S5, S6
89 88
80
69
60 40 27
20
5
12
0
84/ 50/ 32/ 104 65 43
74/ 43/ 23/ 104 65 43
10/ 7/ 9/ 84 50 32
27/ 24/ 17/ 43 39 27
20/ 20/ 12/ 43 39 27
7/ 4/ 5/ 27 24 17
57/ 26/ 15/ 61 26 16
54/ 23/ 11/ 61 26 16
3/ 3/ 4/ 57 26 15
ETR
SVR
Relapse
ETR
SVR
Relapse
ETR
SVR
Relapse
Fig. 2. Virological response rates in (A) overall population, (B) HCV-1,4 and (C) HCV-2,3 patients treated with PegIFNa2a, stratified according to liver fibrosis stage.
Table 2. RVR rates and SVR rates according to RVR in patients treated with PegIFNa2a or PegIFNa2b regimen.
PegIFNα2a n/N (%) Overall population RVR (+) SVR in RVR (+) RVR (−) SVR in RVR (−) HCV-1,4 RVR (+) SVR in RVR (+) RVR (−) SVR in RVR (−) HCV-2,3 RVR (+) SVR in RVR (+) RVR (−) SVR in RVR (−) ⁄
PegIFNα2b n/N (%)
S0-S2 77/104 (74) 67/77 (87) 27/104 (26) 7/27 (26)
S3, S4 34/65 (52) 27/34 (79) 31/65 (48) 16/31 (52)
S5, S6 22/43 (51) 16/22 (73) 21/43 (49) 7/21 (33)
S0-S2 67/109 (61) 55/67 (82) 42/109 (39) 16/42 (38)
S3, S4 36/71 (51) 28/36 (78) 35/71 (49) 5/35 (14)
S5, S6 22/39 (56) 15/22 (68) 17/39 (44) 0/17 (0)*
21/43 (49) 15/21 (71) 22/43 (51) 5/22 (23)
11/39 (28) 7/11 (64) 28/39 (72) 13/28 (46)
9/27 (33) 6/9 (67) 18/27 (67) 6/18 (33)
18/50 (36) 12/18 (67) 32/50 (64) 10/32 (31)
7/38 (18) 5/7 (71) 31/38 (82) 3/31 (10)
10/25 (40) 6/10 (60) 15/25 (60) 0/15 (0)§
56/61 (92) 52/56 (93) 5/61 (8) 2/5 (40)
23/26 (88) 20/23 (87) 3/26 (12) 3/3 (100)
13/16 (81) 10/13 (77) 3/16 (19) 1/3 (33)
49/59 (83) 43/49 (88) 10/59 (17) 6/10 (60)
29/33 (88) 23/29 (79) 4/33 (12) 2/4 (50)
12/14 (86) 9/12 (75) 2/14 (14) 0/2 (0)
p = 0.001; §p = 0.01. v2 or Fisher exact probability test.
⁄,§
for S0–S2, 88% (23/26) for S3, S4 and 81% (13/16) for S5, S6 (p = 0.4). The SVR rates in HCV-1, 4 and HCV-2, 3 patients with a RVR are shown in Table 2. By stepwise logistic regression analysis, lack of RVR (OR 4.58, 95% CI 2.24–9.36; p <0.001) and HCV genotype 1 and 4 (OR 3.16, 95% CI 1.49–6.73; p = 0.003) were the only significant predictors of treatment failure (Table 3). PegIFNa2b group The rates of treatment discontinuation for non virological reasons were not influenced by fibrosis stage being 10% (11/109) for S0–S2, 8% (6/71) for S3, S4 and 15% (6/39) for S5, S6 (p = 0.5). PegIFNa2b dose reduction and Rbv dose reduction rates were not influenced by fibrosis stage being 6% (6/109) for S0–S2, 7% (5/71) for S3, S4, 8% (3/39) for S5, S6 (p = 0.8) and 59% (64/ 109), 51% (36/71), 59% (23/39) (p = 0.5), respectively. The ETR rates decreased in parallel to the increase in fibrosis staging being 76% (83/109) in S0–S2 patients, 61% (43/71) in S3, S4 and 51% (20/39) in S5, S6 (p = 0.008), with the SVR rates being: 65% (71/109), 46% (33/71) and 38% (15/39) (p = 0.004). 344
Table 3. Odds ratio (OR) and corresponding 95% confidence intervals (95% CI) from the multivariate logistic regression analysis including independent predictors of treatment failure in each treatment group.
PegIFNα2a RVR (−) HCV genotype 1, 4 PegIFNα2b RVR (−) HCV genotype 1, 4 S ≥3 liver fibrosis
OR
95% CI
p value
4.58 3.16
2.24-9.36 1.49-6.73
<0.001 0.003
7.98 2.9 2.83
3.77-16.9 1.44-6.22 1.4-5.68
0.001 0.003 0.004
RVR, rapid virological response; S, liver fibrosis stage.
The SVR rates were significantly higher in S0–S2 patients (65%; 95% CI 55.4–74.0) compared to S P3 patients (44%; 95% CI 34.2–53.4) (p = 0.002). Relapse rates were not influenced by the stage of fibrosis as shown in Fig. 3A. In HCV-1, 4 patients, the ETR and SVR rates were significantly affected by fibrosis staging being 58% (29/50) in S0–S2 patients,
Journal of Hepatology 2012 vol. 56 j 341–347
JOURNAL OF HEPATOLOGY
80 60
76 65
61 51
40
46
38 23 25
20
14
0
B
S0-S2 S3, S4 S5, S6
100
C
80 60
58 44
40
29 32
20
21 24
24
27 25
0
100
92
S0-S2 S3, S4 S5, S6
97 86
Response (%)
S0-S2 S3, S4 S5, S6
100
Response (%)
Response (%)
A
80
83
76 64
60 40 22 25
20
9
0
83/ 43/ 20/ 109 71 39
71/ 33/ 15/ 109 71 39
12/ 10/ 5/ 83 43 20
29/ 11/ 8/ 50 38 25
22/ 8/ 6/ 50 38 25
7/ 3/ 2/ 29 11 8
54/ 32/ 12/ 59 33 14
49/ 25/ 9/ 59 33 14
5/ 7/ 3/ 54 32 12
ETR
SVR
Relapse
ETR
SVR
Relapse
ETR
SVR
Relapse
Fig. 3. Virological response rates in (A) overall population, (B) HCV-1, 4 and (C) HCV-2, 3 patients treated with PegIFNa2b, stratified according to liver fibrosis stage.
29% (11/38) in S3, S4, 32% (8/25) in S5, S6 (p = 0.01) and 44% (22/ 50), 21% (8/38), 24% (6/25) (p = 0.046), respectively. The SVR rates were twice as many in S0–S2 patients (44%; 95% CI 29.9–58.7) compared to S P3 patients (22%; 95% CI 12.7–34.4) (p = 0.02). The relapse rates were not influenced by the stage of fibrosis as shown in Fig. 3B. In HCV-2, 3 patients, the ETR, SVR and relapse rates were not influenced by liver fibrosis staging as shown in Fig. 3C. In patients receiving PegIFNa2b, RVR rates were not influenced by fibrosis stage being 61% (67/109) for S0–S2, 51% (36/ 71) for S3, S4 and 56% (22/39) for S5, S6 patients (p = 0.3). The SVR rates in patients with a RVR were not influenced by fibrosis stage being: 82% (55/67), 78% (28/36) and 68% (15/22) (p = 0.4) (Table 2). In HCV-1, 4 patients the RVR rates were 36% (18/50) for S0–S2, 18% (7/38) for S3, S4 and 40% (10/25) for S5, S6 (p = 0.1). In HCV-2, 3 patients the RVR rates were 83% (49/59) for S0–S2, 88% (29/33) for S3, S4 and 86% (12/14) for S5, S6 (p = 0.9). The SVR rates in HCV-1, 4 and HCV-2, 3 patients with a RVR are shown in Table 2. By stepwise logistic regression analysis, lack of RVR (OR 7.98, 95% CI 3.77–16.9; p = 0.001), HCV genotype 1 and 4 (OR 2.9, 95% CI 1.44–6.22; p = 0.003) and S P3 liver fibrosis (OR 2.83, 95% CI 1.4–5.68; p = 0.004) were significant independent predictors of treatment failure (Table 3).
vs. 38% (16/42) for PegIFNa2b, p = 0.43. On the contrary, in S P3 patients without a RVR, the SVR rates were higher in PegIFNa2a regimen than in PegIFNa2b regimen [44% (23/52) (95% CI 30.4– 58.6) vs. 10% (5/52) (95% CI 3.1–21.0) (p = 0.0001)].
Comparison of virological responses in the two treatment regimens
HCV-2, 3 patients The SVR rates between the two therapeutic regimens did not differ significantly in S0–S2 patients [89% (54/61) PegIFNa2a vs. 83% (49/59) PegIFNa2b, p = 0.44] nor in S P3 patients [81% (34/42) vs. 72% (34/47), p = 0.45, respectively]. In S0–S2 patients with a RVR, the SVR rates were similar between the two treatment regimens: 93% (52/56) for PegIFNa2a vs. 88% (43/49) for PegIFNa2b, p = 0.5. The same was true for the corresponding SVR rates in S P3 patients with a RVR: 83% (30/ 36) vs. 78% (32/41), p = 0.78. In S0–S2 patients without a RVR, the SVR rates were similar between the two treatment regimens: 40% (2/5) for PegIFNa2a vs. 60% (6/10) for PegIFNa2b, p = 0.61. The same was true for the corresponding SVR rates in S P3 patients without a RVR: 67% (4/6) vs. 33% (2/6), p = 0.57.
Overall population In S0–S2 patients, the SVR rates were similar between the two treatment regimens: 71% (74/104) for PegIFNa2a vs. 65% (71/ 109) for PegIFNa2b, p = 0.38. On the contrary, in S P3 patients, the SVR rates were higher in those receiving PegIFNa2a compared to those treated with PegIFNa2b being 61% (66/108) (95% CI 51.2–70.3) vs. 44% (48/110) (95% CI 34.2–53.4), (p = 0.01). In S0–S2 patients, logistic regression analysis identified lack of RVR (OR 6.6, 95% CI 3.2–13.8; p = 0.001) and HCV genotype 1 and 4 (OR 3.6, 95% CI 1.7–7.5; p = 0.001) as independent predictors of treatment failure. In S P3 patients, lack of RVR (OR 5.7, 95% CI 2.8–11.8, p = 0.001), HCV genotype 1 and 4 (OR 2.8, 95% CI 1.3–5.9 p = 0.007), and PegIFNa2b (OR 2.8, 95% CI 1.4–5.5, p = 0.002) were significant independent predictors of treatment failure. In patients with a RVR, the SVR rates were similar between the two treatment regimens independently from fibrosis stage. In S0–S2 patients without a RVR, the SVR rates were similar between the two treatment regimens: 26% (7/27) for PegIFNa2a
HCV-1, 4 patients In S0–S2 patients, the SVR rates were similar between the two treatment regimens: 47% (20/43) for PegIFNa2a vs. 44% (22/50) for PegIFNa2b, p = 0.84. On the contrary, in S P3 patients the SVR rates were higher in patients receiving PegIFNa2a compared to those treated with PegIFNa2b being 48% (32/66) (95% CI 35.9–61.1) vs. 22% (14/63) (95% CI 12.7–34.4), (p = 0.003). In S0–S2 patients with a RVR, the SVR rates were similar between the two treatment regimens: 71% (15/21) for PegIFNa2a vs. 67% (12/18) for PegIFNa2b, p = 1.0. The SVR rates in S P3 patients with a RVR were similar between PegIFNa2a regimen and PegIFNa2b regimen: 65% (13/20) vs. 65% (11/17) (p = 1.0). In S0–S2 patients without a RVR, the SVR rates were similar between the two treatment regimens: 23% (5/22) for PegIFNa2a vs. 31% (10/32) for PegIFNa2b, p = 0.56. On the contrary, the SVR rates in S P3 patients without a RVR were higher in PegIFNa2a regimen than in PegIFNa2b regimen: 41% (19/46) (95% CI 26.9–56.7) vs. 7% (3/46) (95% CI 1.3–17.8) (p = 0.0001).
Discussion This sub-analysis of the MIST study indicates that liver fibrosis, assessed by Ishak score, differently affects the clinical activity
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Research Article of the two available PegIFN-based regimens for treating chronic hepatitis C. Patients receiving PegIFNa2a/Rbv showed ETR and SVR rates that were independent from liver fibrosis extent, whereas PegIFNa2b/Rbv led to substantially reduced rates of both ETR and SVR in the subset of patients with S P3. In this stage category, the higher rates of treatment failure compared to patients with lower fibrosis stage were the consequence of a lower rate of ETR. The finding of reduced ETR and, consequently SVR rates, paralleling the extent of hepatic fibrosis in chronic hepatitis C patients, is not unprecedented. In fact, in a previous study by Marotta et al. [17] including 718 treatment-naïve HCV-1 patients treated with PegIFNa2b/Rbv, histologically evaluated by the METAVIR score, the ETR rates and the corresponding SVR rates were influenced by liver fibrosis stage, being significantly higher in patients with F1–F2 fibrosis than in those with F3–F4 fibrosis (59% vs. 34%, p <0.0001 and 48% vs. 22%, p <0.0001, respectively). Although the semi-quantitative staging scores METAVIR and Ishak are difficult to compare directly, S P3 and F3–F4 fibrosis encompass similar histological findings such as portal to portal or portal to central bridging, as well incomplete or complete cirrhosis. Our findings also replicate a previous uncontrolled study in our center [18], where cirrhosis was an independent predictor of treatment failure to PegIFNa2b/Rbv in HCV-1, 4 patients, again as a consequence of reduced rates of on-treatment virological responses compared to patients without cirrhosis. In the present analysis of a randomized study, hypo-responsiveness in patients with advanced fibrosis did not appear to be determined by a reduced exposure to PegIFNa2b/Rbv therapy, since no correlation was found between the rates of discontinuation for non virological reasons or dose reduction and fibrosis stage assessed by the Ishak scoring system. While we are still in the search for an explanation of hyporesponsiveness in patients with advanced fibrosis being treated with PegIFNa2b, we can speculate that its large volume of distribution may lead to impaired drug concentration in the liver when blood circulation is subverted by extensive fibrosis and sinusoidal capillarization. The small distribution volume of PegIFNa2a could, in theory, allow for the drug to better concentrate in the fibrotic liver, explaining the observed differences. We think that in the interplay between liver fibrosis and PegIFN, Rbv is not a mere bystander but it may play a role as a culprit when administered at suboptimal dosing. Indeed, in HCV-1, 4 cirrhotics receiving PegIFNa2a where Rbv was dosed on body weight, SVR rates were not influenced by liver fibrosis. On the contrary, in HCV-2, 3 patients receiving the standard of care flat dosing of Rbv, treatment with PegIFNa2a resulted in higher rates of post-treatment relapse in cirrhotics compared to patients without cirrhosis. This finding confirms the results of a recent analysis of 3 prospective studies [19] in which a flat Rbv dosing could not maintain the ontreatment virological response in patients with cirrhosis, and adds to the debate on which is the optimal Rbv dose to associate to PegIFNalfa2a in easy to cure genotypes of HCV [20–22]. Overall, our findings strengthen the positive value of a RVR [6,23] in predicting treatment outcome independently of the stage of liver fibrosis. Indeed, SVR rates were extremely high once an RVR was achieved in both PegIFN based treatment regimens irrespective of fibrosis stage. Conversely, the novel finding is the negative predictive power of the lack of a RVR in patients with cirrhosis that was influenced by the type of PegIFN regimen, since it was associated with extremely low rates of SVR in the PegIFNa2b arm, only. Indeed, none of the patients without a
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RVR ultimately achieved a SVR with PegIFNa2b vs. 33% of those treated with PegIFNa2a. If confirmed in a larger set of cirrhotic patients, the lack of a RVR could be eventually used as an additional stopping rule for HCV-1, 4 cirrhotic patients receiving dual therapy with PegIFNa2b. We do acknowledge that the stratification of patients according to HCV genotype and liver fibrosis stage may have significantly reduced the sample size of the cells and the power of our statistical analysis. Moreover, being these data generated by a sub-analysis of a prospective study not directly designed to assess the impact of liver fibrosis on PegIFN responsiveness, we can not completely exclude other potential uncontrollable biases such as skewed distribution of the IL28B single nucleotide polymorphisms. However, this seems high unlikely as recent data showed no correlation between IL28B genotype and liver fibrosis in the IDEAL trial [24]. Finally, since these data were generated in Caucasian patients, they should be extrapolated with caution to patients from other geographical regions. Still, we think that the clinical implications of the present study are applicable to the last years of the era preceding the development of directly acting antiviral (DAA) based therapy, particularly as far as the potential benefit of the PegIFNa2a regimen over the PegIFNa2b regimen in S P3 patients infected with HCV-1, 4, and the similarity between the two regimens in the S <3 patients, is concerned. Although we do wonder whether differences in the clinical activity between the PegIFNs will still matter once DAA agents become available to treat hepatitis C infection [25–27], nevertheless the finding that S P3 patients with HCV-1, 4 are likely to benefit more from the PegIFNalfa2a regimen, supports this regimen as the ideal backbone of DAA triple therapy in this category of patients, in order to minimize the risk of resistant mutants to DAA [28].
Conflict of interest Massimo Colombo. Grant and Research support: ScheringPlough, Roche, Bristol-Myers Squibb, Gilead, Bayer. Advisory committees: Schering-Plough, Roche, Novartis, Vertex, BristolMyers Squibb, Gilead, Bayer, Tibotec. Speaking and Teaching: Schering-Plough, Roche, Novartis, Vertex, Bristol-Myers Squibb, Gilead, Bayer. Maria Grazia Rumi. Speaking and Teaching: Roche. Advisory committees: Roche. Alessio Aghemo. Advisory committees: Roche. Maria Francesca Donato. Speaking and Teaching: ScheringPlough, Roche, Gilead, Kedrion. Other authors have no financial disclosure to declare.
Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jhep.2011.05.022. References [1] Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005;5:558–567. [2] Shiratori Y, Ito Y, Yokosuka O, Imazeki F, Nakata R, Tanaka N, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival 1. Ann Intern Med 2005;142:105–114.
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JOURNAL OF HEPATOLOGY [3] Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnu L, Mazzella G, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study 3. Hepatology 2007;45:579–587. [4] Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, Zeuzem S, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007;147:677–684. [5] Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. PegInterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–965. [6] Kau A, Vermehren J, Sarrazin C. Treatment predictors of a sustained virologic response in hepatitis B and C. J Hepatol 2008;49:634–651. [7] Jacobson IM, Brown RS, Freilich B, Afdhal N, Kwo PY, Santoro J, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology 2007;46:971–981. [8] McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123:1061–1069. [9] Bailon P, Palleroni A, Schaffer CA, Spence CL, Fung WJ, Porter JE, et al. Rational design of a potent, long-lasting form of interferon: a 40 KDa branched polyethylene glycol-conjugated interferon-a-2a for the treatment of hepatitis C. Bioconjug Chem 2001;12:195–202. [10] Perry CM, Jarvis B. Peginterferon-a-2a (40 kd): a review of its use in the management of chronic hepatitis C. Drugs 2001;61:2263–2288. [11] Glue P, Fang JW, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK, et al. Pegylated interferon-a-2b: pharmacokinetics, pharmacodynamics, safety and preliminary efficacy data. Clin Pharmacol Ther 2000;68:556–567. [12] Grace M, Youngster S, Gitlin G, Sydor W, Xie L, Westreich L, et al. Structural and biologic characterization of pegylated recombinant IFN-a-2b. J Interferon Cytokine Res 2001;21:1103–1115. [13] Foster GR. Pegylated interferons for the treatment of chronic hepatitis C: pharmacological and clinical differences between peginterferon-alpha-2a and peginterferon-alpha-2b. Drugs 2010;70:147–165. [14] Aghemo A, Rumi MG, Colombo M. Pegylated interferons alpha2a and alpha2b in the treatment of chronic hepatitis C. Nat Rev Gastroenterol Hepatol 2010;7:485–494. [15] Rumi MG, Aghemo A, Prati GM, D’Ambrosio R, Donato MF, Soffredini R, et al. Randomized study of peginterferon-alpha2a plus ribavirin vs peginterferonalpha2b plus ribavirin in chronic hepatitis C. Gastroenterology 2010;138:108–115. [16] Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696–699.
[17] Marotta P, Cooper C, Wong DK, Farley J, Elkashab M, Peltekian KM, et al. Impact of advanced fibrosis and cirrhosis on sustained virologic response of HCV G1-infected patients: results of the Canadian POWeR program. Hepatology 2008;48:849A–850A. [18] Aghemo A, Rumi MG, Monico S, Prati GM, D’Ambrosio R, Donato MF, et al. The pattern of pegylated interferon-alpha2b and ribavirin treatment failure in cirrhotic patients depends on hepatitis C virus genotype. Antivir Ther 2009;14:577–584. [19] Bruno S, Shiffman ML, Roberts SK, Gane EJ, Messinger D, Hadziyannis SJ, et al. Efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in hepatitis C patients with advanced fibrosis and cirrhosis. Hepatology 2010;51:388–397. [20] Ferenci P, Brunner H, Laferl H, Scherzer TM, Maieron A, Strasser M, et al. A randomized, prospective trial of ribavirin 400 mg/day versus 800 mg/day in combination with peginterferon alfa-2a in hepatitis C virus genotypes 2 and 3. Hepatology 2008;47:1816–1823. [21] Aghemo A, Rumi Mg, Prati GM, Colombo M. The optimal ribavirin dose for patients infected with hepatitis C virus genotype 3: should we utilize more? Hepatology 2009;49:702–703. [22] Mangia A, Dalgard O, Minerva N, Verbaan H, Bacca D, Ring-Larsen H, et al. Ribavirin dosage in patients with HCV genotypes 2 and 3 who completed short therapy with peg-interferon alpha-2b and ribavirin. Aliment Pharmacol Ther 2010;31:1346–1353. [23] Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006;44:97–103. [24] Thompson AJ, Clark PJ, Fellay J, Muir AJ, Tillmann H, Patel K, et al. IL28B genotype is not associated with advanced hepatic fibrosis in chronic hepatitis C patients enrolled in the IDEAL study. Hepatology 2010;52:229A. [25] Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM, Pound D, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010;376:705–716. [26] McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, et al. PROVE1 Study Team. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009;360:1827–1838. [27] Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al. PROVE2 Study Team. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009;360:1839–1850. [28] Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 2010;138:447–462.
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Hyporesponsiveness to PegIFNa2B plus ribavirin in patients with hepatitis C-related advanced fibrosis Gian Maria Prati1, Alessio Aghemo1,⇑, Maria Grazia Rumi2, Roberta D’Ambrosio1, Stella De Nicola1, Maria Francesca Donato1, Elisabetta Degasperi1, Massimo Colombo1 1
A.M. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy; 2Liver Unit, San Giuseppe Hospital, Università degli Studi di Milano, Milan, Italy
Background & Aims: The success of pegylated-interferon (PegIFN)/ribavirin (Rbv) therapy of chronic hepatitis C is compromised by liver fibrosis. Whether fibrosis equally affects the two PegIFNa-based therapies is unknown. To assess the response to the two PegIFN regimens in patients with different degree of liver fibrosis. Methods: A sub-analysis of the MIST study: 431 consecutive naïve patients randomly assigned, based on HCV genotype, to receive either (A) PegIFNa2a 180 lg/wk plus daily Rbv 800–1200 mg or (B) PegIFNa2b 1.5 lg/kg/week plus daily Rbv 800–1200 mg, were stratified according to Ishak staging (S) into mild (S0–S2) or moderate (S3, S4) fibrosis and cirrhosis (S5, S6). Results: In A the sustained virological response (SVR) rates were not significantly influenced by fibrosis stage (71% in S0–S2, 66% in S3, S4, 53% in S5, S6, p = 0.12), compared to B where the SVR rates differed according to fibrosis stage (65%, 46%, and 38%, p = 0.004, respectively). This was even more so in HCV-1/4 patients treated with PegIFNa2b where the SVR rates were twice as many in S0–S2 vs. S P3 (44% vs. 22%, p = 0.02), while in A the SVR rates were similar between the two fibrosis subgroups (S0–S2: 47% vs. S P3: 48%, p = 0.8). By logistic regression analysis genotype 1/4 and lack of rapid virological response were independent predictors of treatment failure in both treatment groups, while S P3 fibrosis was associated to PegIFNa2b treatment failure, only (OR 2.83, 95% CI 1.4–5.68, p = 0.004). Conclusions: Liver fibrosis was an independent moderator of treatment outcome in patients receiving PegIFNa2b, not in those receiving PegIFNa2a. Ó 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Keywords: Hepatitis C virus; Liver fibrosis; Pegylated interferon; Ribavirin; Sustained virological response. Received 18 March 2011; received in revised form 3 May 2011; accepted 7 May 2011; available online 12 July 2011 ⇑ Corresponding author. Address: 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Via F. Sforza 35, 20122 Milan, Italy. Tel.: +39 0255035432; fax: +39 0250320410. E-mail address: [email protected] (A. Aghemo). Abbreviations: HCV, hepatitis C virus; PegIFN, pegylated-interferon; Rbv, ribavirin; Peg, polyethylene glycol; SVR, sustained virological response; RVR, rapid virological response; cEVR, complete early virological response; ETR, end of treatment response; S, Ishak fibrosis score; ITT, intention-to-treat.
Introduction Infection with the hepatitis C virus (HCV) is a major cause of morbidity and anticipated liver-related mortality worldwide [1] and pegylated-interferon (PegIFN)/ribavirin (Rbv) is the only therapeutic approach to prevent these complications [2–4]. While liver fibrosis is of paramount importance in determining the risk of anticipated liver related death, unfortunately it represents one of the strongest independent moderators of treatment outcome to IFN based therapies [5–7]. As a consequence of this paradox, the success of treatment has long been dichotomized according to the presence or absence of advanced liver fibrosis in patients with chronic hepatitis C, even though the exact mechanism by which fibrosis conflicts with the antiviral effects of PegIFN and Rbv remains elusive. Indeed, the negative role of liver fibrosis could reflect the anatomical subversion of the liver architecture, which theoretically prevents optimal interaction between IFN and target liver cells as well as a long lasting duration of HCV infection in these patients. Moreover, the defective adherence to the optimal schedule of treatment due to cytopenia remains a challenge of IFN based therapy of HCV patients with advanced fibrosis, since it increases the chances of hypo-responsiveness [8]. In the light of these interactions between therapy of HCV and advanced liver fibrosis, we asked ourselves whether hepatic fibrosis affects the clinical activity of the two available PegIFN regimens used to treat HCV. Indeed, PegIFNalfa2a and PegIFNalfa2b, while sharing the same mechanisms of action, are markedly different in terms of pharmacokinetic and pharmacodynamic properties [9–14], which might relate to their clinical activity. The two drugs, in fact are characterized by significant differences in the pegylation process of the native IFN molecule that ultimately affect the volume of distribution, the serum half life and the in vitro antiviral activity of the two compounds. As a direct consequence of the different volume of distribution, the two drugs concentrate differently into the liver, a feature that, in theory, could translate into a different therapeutic activity of the two PegIFNs in the presence of advanced fibrosis. A sub-analysis of the MIST study [15] allowed us to compare the effectiveness of the two PegIFNa regimens according to the extent of liver fibrosis, histologically evaluated at the time of enrolment into the study.
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Research Article Materials and methods
Patients
Aim
Patients enroled into the MIST study were randomized by a computer-generated allocation list stratified by HCV genotype, to receive a combination of PegIFNa2a (Pegasys, Roche, Basel Switzerland) 180 lg/week plus daily Rbv (Rebetol, Schering Plough corp, Kenilworth New Jersey USA) 800–1200 mg (A) or PegIFNa2b (PegIntron, Schering Plough corp) 1.5 lg/kg/week plus daily Rbv 800–1200 mg (B), for a standard duration based on HCV genotype. Patients with HCV-1 and HCV-4 were treated for 48 weeks: PegIFNa2a was associated with Rbv 1000– 1200 mg day (<75 kg, P75 kg); PegIFNa2b with Rbv 800 mg for patients of less than 65 kg body weight, 1000 mg for 65–85 kg and 1200 mg for P85 kg. HCV-2 and HCV-3 patients were treated for 24 weeks: PegIFNa2a was associated with Rbv 800 mg day; PegIFNa2b with Rbv 800 mg for patients of less than 65 kg body weight, 1000 mg for 65–85 kg and 1200 mg for P85 kg.
This is a sub-analysis of the MIST study [15] that was originally designed to compare safety and effectiveness of PegIFNa2a and PegIFNa2b therapy associated with Rbv. In the present study, we assessed the outcome of PegIFN therapy according to the stage of liver fibrosis classified by the Ishak score system in liver biopsies, performed 2–20 months (median ± standard deviation: 12 ± 6) before the start of therapy.
Assessed for eligibility (n = 473)
Measurements
Excluded (n = 26) • Not meeting inclusion criteria (n = 7) • Refused to participate (n = 18) • Other reasons (n = 1)
Underwent randomization (n = 447)
Allocated to PegIFNα2a group (n = 223)
Allocated to PegIFNα2b group (n = 224)
• Received allocated intervention (n = 212)
• Received allocated intervention (n = 219)
• Did not receive allocated intervention (n = 11)
• Did not receive allocated intervention (n = 5)
Given reasons: • Refuse to participate (n = 8)
Given reasons: • Refuse to participate (n = 4)
• Laboratory abnormalities (n = 3)
• Lost to follow-up (n = 1)
Discontinued intervention (n = 46)
Discontinued intervention (n = 73)
Given reasons: • Adverse event (n = 16) • Lost to follow-up (n = 1) • Other reason (n = 1) • Met stopping rule* (n = 28)
Given reasons: • Adverse event (n = 17) • Lost to follow-up (n = 2) • Withdrew consent (n = 2) • Other reason (n = 2) § • Met stopping rule (n = 50)
ITT analysis in 212 patients
ITT analysis in 219 patients
Fig. 1. Flow chart of the MIST study. Patients allocated to PegIFNa2a group: ⁄19 patients met the week 12 stopping rule, 7 patients met the week 24 stopping rule and 2 patients had a virological breaktrough. Patients allocated to PegIFNa2b group: §32 patients met the week 12 stopping rule; 15 patients met the week 24 stopping rule and 3 patients had a virological breaktrough. ITT (intention-totreat) analysis.
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Serum HCV-RNA was quantified by Versant HCV-RNA 3.0 assay (bDNA 3.0, Bayer Corporation, Emeryville, CA), with a sensitivity limit of 615 IU/ml and a dynamic range from 615 to 7700,000 IU/ml. Serum HCV-RNA was assessed by qualitative RT-PCR assay (COBAS Amplicor HCV test version 2.0, Roche Diagnostics) with a detection limit of 50 IU/ml, during treatment at weeks 4, 12, 24, and 48, and after therapy at weeks 4, 12, 24. HCV was genotyped by Line Probe Assay (INNO-LIPA HCV 2, Innogenetics, Zwijndrecht, Belgium). Assessment of efficacy was SVR, defined as undetectable HCV-RNA by RT-PCR at week 24 of post-treatment follow up. Clearance of serum HCV-RNA by RT-PCR was assessed at week 4 (rapid virological response, RVR), at week 12 (complete early virological response, cEVR), at week 24, and at week 48 of treatment (end of treatment response, ETR). Patients with an ETR who tested HCV-RNA positive during follow-up were classified as relapsers. Patients who had a virological breakthrough were considered as non-responders. Therapy was discontinued in HCV-1 and HCV-4 patients if quantitative HCV-RNA testing at week 12 dropped by less than 2 log compared to baseline values (week 12 stopping rule), and at week 24 if HCV-RNA was still detectable in those patients in whom HCV-RNA dropped >2 log at week 12 (week 24 stopping rule). All liver biopsies were performed with a 16 gauge Tru-Cut needle (Uro-Cut 16G, TSK, Tokyo, Japan) and read by a single pathologist (MFD), who was unaware of patient’s identity and treatment regimen. The severity of hepatic inflammation was evaluated by the Ishak score [16] in separate reports for grading and staging. Patients were stratified according to the Ishak fibrosis score (S) on the baseline liver biopsy into mild (S0–S2) or moderate (S3, S4) fibrosis, and cirrhosis (S5, S6). Statistical analysis Comparisons between groups were made by using the Mann–Whitney U test or the Student t test for continuous variables and the v2 or Fisher exact probability test for categorical data. Intention-to-treat (ITT) analysis included all the 431 patients enroled: 212 of whom were treated with PegIFNa2a and 219 with PegIFNa2b (Fig 1). A probability value of p <0.05 was considered statistically significant. Logistic regression analysis was performed to identify variables associated with PegIFN/Rbv treatment failure. All variables with statistical significance at the univariate analysis were included in the final model and odds ratios (OR) and corresponding 95% confidence interval (95% CI) were computed. Calculations were done with Stata 10.0 statistical package (Stata 1944–2007, College Station, TX, USA).
Results The clinical and demographic features of the two treatment groups stratified by fibrosis stage are shown in Table 1A and B. In both groups patients with S P3 were more often male, older and had higher body mass index and serum ALT values than patients with S <3. The same was true for HCV-1, 4 patients (Supplementary Table 1A and B), while in HCV-2,3 patients, a similar prevalence of male gender was seen in S P3 compared to S <3 patients (Supplementary Table 1C and D). Overall 10% (41/431) patients had to discontinue therapy for non virological reasons. Treatment discontinuation was not influenced by fibrosis stage being 9% (20/213) for S0–S2, 8% (11/136) for S3, S4
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JOURNAL OF HEPATOLOGY Table 1. Baseline characteristics of patients treated with PegIFNa2a (A) or PegIFNa2b (B) stratified according to liver fibrosis stage (S).
A Features Patients, n
p value
Fibrosis stage S0-S2
S3, S4
S5, S6
104
65
43
Gender, male; n (%)
58 (56)
40 (62)
30 (70)
0.3
Age, years (mean ± SD)
47 ± 12.5
55.9 ± 9.8
56.4 ± 9.8
0.0001 0.04
Weight, kg (mean ± SD)
69.5 ± 14.5
74 ± 13.2
75.7 ± 15.8
BMI, kg/m 2 (mean ± SD)
24.4 ± 4.2
26.3 ± 4.1
26.7 ± 4.6
0.001
Alanine aminotransferase, IU/L mean ± SD
116.5 ± 124.1
138.5 ± 86.6
148.7 ± 69.6
0.0001
48 (46)
44 (68)
34 (79)
0.0001
59 (57)
34 (52)
19 (44)
0.4
≥2 fold increase at baseline; n (%) HCV RNA ≥0.6x106 IU/L; n (%)
B Features
p value
Fibrosis stage S0-S2
S3, S4
S5, S6
Patients, n
109
71
39
Gender, male; n (%)
57 (52)
40 (56)
23 (59)
0.7
Age, years (mean ± SD)
49.4 ± 12.6
55.6 ± 11.1
57.5 ± 8.7
0.0002
Weight, kg (mean ± SD)
67.4 ± 12.8
69.4 ± 11.4
72.2 ± 10.3
0.06
BMI, kg/m 2 (mean ± SD)
24.2 ± 3.9
25.2 ± 3.3
25.9 ± 3.7
0.03
Alanine aminotransferase, IU/L mean ± SD
132.6 ± 109.3
125.3 ± 114.1
125.8 ± 65.7
0.4
62 (57)
40 (56)
28 (72)
0.2
62 (57)
42 (59)
17 (44)
0.3
≥2 fold increase at baseline; n (%) HCV RNA ≥0.6x106 IU/L; n (%)
The values listed in this table are percentages or means ± standard deviation (SD). BMI, body mass index.
and 12% (10/82) for S5, S6 (p = 0.62). PegIFNa dose reduction and Rbv dose reduction rates were not influenced by fibrosis stage being 8% (16/213) for S0–S2, 8% (11/136) for S3, S4 and 11% (9/ 82) for S5, S6 (p = 0.61) and 55% (117/213), 57% (78/136) and 57% (47/82) (p = 0.89), respectively. In the overall population, ETR rates were 78% (167/213) in S0–S2 patients, 68% (93/136) in S3, S4 and 63% (52/82) in S5, S6 (p = 0.01), whereas the corresponding figures for SVR rates were 68% (145/213), 56% (76/136), and 46% (38/82) (p = 0.01). Relapse rates were 13% (22/167), 18% (17/93), and 27% (14/52) (p = 0.07). PegIFNa2a group Treatment discontinuation for non virological reasons was not influenced by fibrosis stage being 9% (9/104) for S0–S2, 8% (5/ 65) for S3, S4 and 9% (4/43) for S5, S6 (p = 1.0). PegIFNa2a dose reduction and Rbv dose reduction rates were not influenced by fibrosis stage being 10% (10/104) for S0–S2, 9% (6/65) for S3, S4, 14% (6/43) for S5, S6 (p = 0.7) and 51% (53/104), 65% (42/ 65), 56% (24/43) (p = 0.2), respectively. The ETR rates were 81% (84/104) in S0–S2 patients, 77% (50/ 65) in S3, S4 and 74% (32/43) in S5, S6 (p = 0.64) with the SVR rates being: 71% (74/104), 66% (43/65), and 53% (23/43) (p = 0.12). Relapse rates were 12% (10/84) in S0–S2 patients,
14% (7/50) in S3, S4 and 28% (9/32) in S5, S6 (p = 0.1). In S5, S6 patients, the relapse rate was significantly higher than in S 64 patients (28% vs. 13%, p = 0.05) (Fig. 2A). In HCV-1, 4 patients, the ETR rates were independent from fibrosis stage, being 63% (27/43) for S0–S2, 62% (24/39) for S3, S4 and 63% (17/27) for S5, S6 (p = 1.0). The corresponding figures for SVR were 47% (20/43) for S0–S2, 51% (20/39) for S3, S4, and 44% (12/27) for S5, S6 (p = 0.88). The relapse rates were also not influenced by the stage of fibrosis: 26% (7/27) for S0–S2, 17% (4/24) for S3, S4, and 29% (5/17) for S5, S6 (p = 0.6) (Fig. 2B). In HCV-2, 3 patients, the ETR and SVR rates were not influenced by liver fibrosis, as shown in Fig. 2C. Conversely, the relapse rate was influenced by liver fibrosis being 5% (3/57) in S0–S2 patients, 12% (3/26) in S3, S4 and 27% (4/15) in S5, S6 (p = 0.05). The relapse rate was significantly higher in S5, S6 compared to S 64 patients (27% vs. 7%, p = 0.04) (Fig. 2C). The RVR rates were 74% (77/104) for S0–S2, 52% (34/65) for S3, S4 and 51% (22/43) for S5, S6 (p = 0.004), being higher in S0–S2 than S P3 patients (74% vs. 52%, p = 0.001). The SVR rates in patients with a RVR were 87% (67/77) for S0–S2, 79% (27/34) for S3, S4 and 73% (16/22) for S5, S6 patients (p = 0.23) (Table 2). In HCV-1, 4 patients the RVR rates were 49% (21/43) for S0–S2, 28% (11/39) for S3, S4 and 33% (9/27) for S5, S6 (p = 0.14). In HCV-2, 3 patients the RVR rates were 92% (56/61)
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80
81 77 74
60
71
66 53
40
28
20
12 14
0
B
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100 80
63
62
C
63
60
47 51
44
40
29
26
20
17
100 Response (%)
S0-S2 S3, S4 S5, S6
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Response (%)
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0
100 93
94
S0-S2 S3, S4 S5, S6
89 88
80
69
60 40 27
20
5
12
0
84/ 50/ 32/ 104 65 43
74/ 43/ 23/ 104 65 43
10/ 7/ 9/ 84 50 32
27/ 24/ 17/ 43 39 27
20/ 20/ 12/ 43 39 27
7/ 4/ 5/ 27 24 17
57/ 26/ 15/ 61 26 16
54/ 23/ 11/ 61 26 16
3/ 3/ 4/ 57 26 15
ETR
SVR
Relapse
ETR
SVR
Relapse
ETR
SVR
Relapse
Fig. 2. Virological response rates in (A) overall population, (B) HCV-1,4 and (C) HCV-2,3 patients treated with PegIFNa2a, stratified according to liver fibrosis stage.
Table 2. RVR rates and SVR rates according to RVR in patients treated with PegIFNa2a or PegIFNa2b regimen.
PegIFNα2a n/N (%) Overall population RVR (+) SVR in RVR (+) RVR (−) SVR in RVR (−) HCV-1,4 RVR (+) SVR in RVR (+) RVR (−) SVR in RVR (−) HCV-2,3 RVR (+) SVR in RVR (+) RVR (−) SVR in RVR (−) ⁄
PegIFNα2b n/N (%)
S0-S2 77/104 (74) 67/77 (87) 27/104 (26) 7/27 (26)
S3, S4 34/65 (52) 27/34 (79) 31/65 (48) 16/31 (52)
S5, S6 22/43 (51) 16/22 (73) 21/43 (49) 7/21 (33)
S0-S2 67/109 (61) 55/67 (82) 42/109 (39) 16/42 (38)
S3, S4 36/71 (51) 28/36 (78) 35/71 (49) 5/35 (14)
S5, S6 22/39 (56) 15/22 (68) 17/39 (44) 0/17 (0)*
21/43 (49) 15/21 (71) 22/43 (51) 5/22 (23)
11/39 (28) 7/11 (64) 28/39 (72) 13/28 (46)
9/27 (33) 6/9 (67) 18/27 (67) 6/18 (33)
18/50 (36) 12/18 (67) 32/50 (64) 10/32 (31)
7/38 (18) 5/7 (71) 31/38 (82) 3/31 (10)
10/25 (40) 6/10 (60) 15/25 (60) 0/15 (0)§
56/61 (92) 52/56 (93) 5/61 (8) 2/5 (40)
23/26 (88) 20/23 (87) 3/26 (12) 3/3 (100)
13/16 (81) 10/13 (77) 3/16 (19) 1/3 (33)
49/59 (83) 43/49 (88) 10/59 (17) 6/10 (60)
29/33 (88) 23/29 (79) 4/33 (12) 2/4 (50)
12/14 (86) 9/12 (75) 2/14 (14) 0/2 (0)
p = 0.001; §p = 0.01. v2 or Fisher exact probability test.
⁄,§
for S0–S2, 88% (23/26) for S3, S4 and 81% (13/16) for S5, S6 (p = 0.4). The SVR rates in HCV-1, 4 and HCV-2, 3 patients with a RVR are shown in Table 2. By stepwise logistic regression analysis, lack of RVR (OR 4.58, 95% CI 2.24–9.36; p <0.001) and HCV genotype 1 and 4 (OR 3.16, 95% CI 1.49–6.73; p = 0.003) were the only significant predictors of treatment failure (Table 3). PegIFNa2b group The rates of treatment discontinuation for non virological reasons were not influenced by fibrosis stage being 10% (11/109) for S0–S2, 8% (6/71) for S3, S4 and 15% (6/39) for S5, S6 (p = 0.5). PegIFNa2b dose reduction and Rbv dose reduction rates were not influenced by fibrosis stage being 6% (6/109) for S0–S2, 7% (5/71) for S3, S4, 8% (3/39) for S5, S6 (p = 0.8) and 59% (64/ 109), 51% (36/71), 59% (23/39) (p = 0.5), respectively. The ETR rates decreased in parallel to the increase in fibrosis staging being 76% (83/109) in S0–S2 patients, 61% (43/71) in S3, S4 and 51% (20/39) in S5, S6 (p = 0.008), with the SVR rates being: 65% (71/109), 46% (33/71) and 38% (15/39) (p = 0.004). 344
Table 3. Odds ratio (OR) and corresponding 95% confidence intervals (95% CI) from the multivariate logistic regression analysis including independent predictors of treatment failure in each treatment group.
PegIFNα2a RVR (−) HCV genotype 1, 4 PegIFNα2b RVR (−) HCV genotype 1, 4 S ≥3 liver fibrosis
OR
95% CI
p value
4.58 3.16
2.24-9.36 1.49-6.73
<0.001 0.003
7.98 2.9 2.83
3.77-16.9 1.44-6.22 1.4-5.68
0.001 0.003 0.004
RVR, rapid virological response; S, liver fibrosis stage.
The SVR rates were significantly higher in S0–S2 patients (65%; 95% CI 55.4–74.0) compared to S P3 patients (44%; 95% CI 34.2–53.4) (p = 0.002). Relapse rates were not influenced by the stage of fibrosis as shown in Fig. 3A. In HCV-1, 4 patients, the ETR and SVR rates were significantly affected by fibrosis staging being 58% (29/50) in S0–S2 patients,
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80 60
76 65
61 51
40
46
38 23 25
20
14
0
B
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100
C
80 60
58 44
40
29 32
20
21 24
24
27 25
0
100
92
S0-S2 S3, S4 S5, S6
97 86
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100
Response (%)
Response (%)
A
80
83
76 64
60 40 22 25
20
9
0
83/ 43/ 20/ 109 71 39
71/ 33/ 15/ 109 71 39
12/ 10/ 5/ 83 43 20
29/ 11/ 8/ 50 38 25
22/ 8/ 6/ 50 38 25
7/ 3/ 2/ 29 11 8
54/ 32/ 12/ 59 33 14
49/ 25/ 9/ 59 33 14
5/ 7/ 3/ 54 32 12
ETR
SVR
Relapse
ETR
SVR
Relapse
ETR
SVR
Relapse
Fig. 3. Virological response rates in (A) overall population, (B) HCV-1, 4 and (C) HCV-2, 3 patients treated with PegIFNa2b, stratified according to liver fibrosis stage.
29% (11/38) in S3, S4, 32% (8/25) in S5, S6 (p = 0.01) and 44% (22/ 50), 21% (8/38), 24% (6/25) (p = 0.046), respectively. The SVR rates were twice as many in S0–S2 patients (44%; 95% CI 29.9–58.7) compared to S P3 patients (22%; 95% CI 12.7–34.4) (p = 0.02). The relapse rates were not influenced by the stage of fibrosis as shown in Fig. 3B. In HCV-2, 3 patients, the ETR, SVR and relapse rates were not influenced by liver fibrosis staging as shown in Fig. 3C. In patients receiving PegIFNa2b, RVR rates were not influenced by fibrosis stage being 61% (67/109) for S0–S2, 51% (36/ 71) for S3, S4 and 56% (22/39) for S5, S6 patients (p = 0.3). The SVR rates in patients with a RVR were not influenced by fibrosis stage being: 82% (55/67), 78% (28/36) and 68% (15/22) (p = 0.4) (Table 2). In HCV-1, 4 patients the RVR rates were 36% (18/50) for S0–S2, 18% (7/38) for S3, S4 and 40% (10/25) for S5, S6 (p = 0.1). In HCV-2, 3 patients the RVR rates were 83% (49/59) for S0–S2, 88% (29/33) for S3, S4 and 86% (12/14) for S5, S6 (p = 0.9). The SVR rates in HCV-1, 4 and HCV-2, 3 patients with a RVR are shown in Table 2. By stepwise logistic regression analysis, lack of RVR (OR 7.98, 95% CI 3.77–16.9; p = 0.001), HCV genotype 1 and 4 (OR 2.9, 95% CI 1.44–6.22; p = 0.003) and S P3 liver fibrosis (OR 2.83, 95% CI 1.4–5.68; p = 0.004) were significant independent predictors of treatment failure (Table 3).
vs. 38% (16/42) for PegIFNa2b, p = 0.43. On the contrary, in S P3 patients without a RVR, the SVR rates were higher in PegIFNa2a regimen than in PegIFNa2b regimen [44% (23/52) (95% CI 30.4– 58.6) vs. 10% (5/52) (95% CI 3.1–21.0) (p = 0.0001)].
Comparison of virological responses in the two treatment regimens
HCV-2, 3 patients The SVR rates between the two therapeutic regimens did not differ significantly in S0–S2 patients [89% (54/61) PegIFNa2a vs. 83% (49/59) PegIFNa2b, p = 0.44] nor in S P3 patients [81% (34/42) vs. 72% (34/47), p = 0.45, respectively]. In S0–S2 patients with a RVR, the SVR rates were similar between the two treatment regimens: 93% (52/56) for PegIFNa2a vs. 88% (43/49) for PegIFNa2b, p = 0.5. The same was true for the corresponding SVR rates in S P3 patients with a RVR: 83% (30/ 36) vs. 78% (32/41), p = 0.78. In S0–S2 patients without a RVR, the SVR rates were similar between the two treatment regimens: 40% (2/5) for PegIFNa2a vs. 60% (6/10) for PegIFNa2b, p = 0.61. The same was true for the corresponding SVR rates in S P3 patients without a RVR: 67% (4/6) vs. 33% (2/6), p = 0.57.
Overall population In S0–S2 patients, the SVR rates were similar between the two treatment regimens: 71% (74/104) for PegIFNa2a vs. 65% (71/ 109) for PegIFNa2b, p = 0.38. On the contrary, in S P3 patients, the SVR rates were higher in those receiving PegIFNa2a compared to those treated with PegIFNa2b being 61% (66/108) (95% CI 51.2–70.3) vs. 44% (48/110) (95% CI 34.2–53.4), (p = 0.01). In S0–S2 patients, logistic regression analysis identified lack of RVR (OR 6.6, 95% CI 3.2–13.8; p = 0.001) and HCV genotype 1 and 4 (OR 3.6, 95% CI 1.7–7.5; p = 0.001) as independent predictors of treatment failure. In S P3 patients, lack of RVR (OR 5.7, 95% CI 2.8–11.8, p = 0.001), HCV genotype 1 and 4 (OR 2.8, 95% CI 1.3–5.9 p = 0.007), and PegIFNa2b (OR 2.8, 95% CI 1.4–5.5, p = 0.002) were significant independent predictors of treatment failure. In patients with a RVR, the SVR rates were similar between the two treatment regimens independently from fibrosis stage. In S0–S2 patients without a RVR, the SVR rates were similar between the two treatment regimens: 26% (7/27) for PegIFNa2a
HCV-1, 4 patients In S0–S2 patients, the SVR rates were similar between the two treatment regimens: 47% (20/43) for PegIFNa2a vs. 44% (22/50) for PegIFNa2b, p = 0.84. On the contrary, in S P3 patients the SVR rates were higher in patients receiving PegIFNa2a compared to those treated with PegIFNa2b being 48% (32/66) (95% CI 35.9–61.1) vs. 22% (14/63) (95% CI 12.7–34.4), (p = 0.003). In S0–S2 patients with a RVR, the SVR rates were similar between the two treatment regimens: 71% (15/21) for PegIFNa2a vs. 67% (12/18) for PegIFNa2b, p = 1.0. The SVR rates in S P3 patients with a RVR were similar between PegIFNa2a regimen and PegIFNa2b regimen: 65% (13/20) vs. 65% (11/17) (p = 1.0). In S0–S2 patients without a RVR, the SVR rates were similar between the two treatment regimens: 23% (5/22) for PegIFNa2a vs. 31% (10/32) for PegIFNa2b, p = 0.56. On the contrary, the SVR rates in S P3 patients without a RVR were higher in PegIFNa2a regimen than in PegIFNa2b regimen: 41% (19/46) (95% CI 26.9–56.7) vs. 7% (3/46) (95% CI 1.3–17.8) (p = 0.0001).
Discussion This sub-analysis of the MIST study indicates that liver fibrosis, assessed by Ishak score, differently affects the clinical activity
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Research Article of the two available PegIFN-based regimens for treating chronic hepatitis C. Patients receiving PegIFNa2a/Rbv showed ETR and SVR rates that were independent from liver fibrosis extent, whereas PegIFNa2b/Rbv led to substantially reduced rates of both ETR and SVR in the subset of patients with S P3. In this stage category, the higher rates of treatment failure compared to patients with lower fibrosis stage were the consequence of a lower rate of ETR. The finding of reduced ETR and, consequently SVR rates, paralleling the extent of hepatic fibrosis in chronic hepatitis C patients, is not unprecedented. In fact, in a previous study by Marotta et al. [17] including 718 treatment-naïve HCV-1 patients treated with PegIFNa2b/Rbv, histologically evaluated by the METAVIR score, the ETR rates and the corresponding SVR rates were influenced by liver fibrosis stage, being significantly higher in patients with F1–F2 fibrosis than in those with F3–F4 fibrosis (59% vs. 34%, p <0.0001 and 48% vs. 22%, p <0.0001, respectively). Although the semi-quantitative staging scores METAVIR and Ishak are difficult to compare directly, S P3 and F3–F4 fibrosis encompass similar histological findings such as portal to portal or portal to central bridging, as well incomplete or complete cirrhosis. Our findings also replicate a previous uncontrolled study in our center [18], where cirrhosis was an independent predictor of treatment failure to PegIFNa2b/Rbv in HCV-1, 4 patients, again as a consequence of reduced rates of on-treatment virological responses compared to patients without cirrhosis. In the present analysis of a randomized study, hypo-responsiveness in patients with advanced fibrosis did not appear to be determined by a reduced exposure to PegIFNa2b/Rbv therapy, since no correlation was found between the rates of discontinuation for non virological reasons or dose reduction and fibrosis stage assessed by the Ishak scoring system. While we are still in the search for an explanation of hyporesponsiveness in patients with advanced fibrosis being treated with PegIFNa2b, we can speculate that its large volume of distribution may lead to impaired drug concentration in the liver when blood circulation is subverted by extensive fibrosis and sinusoidal capillarization. The small distribution volume of PegIFNa2a could, in theory, allow for the drug to better concentrate in the fibrotic liver, explaining the observed differences. We think that in the interplay between liver fibrosis and PegIFN, Rbv is not a mere bystander but it may play a role as a culprit when administered at suboptimal dosing. Indeed, in HCV-1, 4 cirrhotics receiving PegIFNa2a where Rbv was dosed on body weight, SVR rates were not influenced by liver fibrosis. On the contrary, in HCV-2, 3 patients receiving the standard of care flat dosing of Rbv, treatment with PegIFNa2a resulted in higher rates of post-treatment relapse in cirrhotics compared to patients without cirrhosis. This finding confirms the results of a recent analysis of 3 prospective studies [19] in which a flat Rbv dosing could not maintain the ontreatment virological response in patients with cirrhosis, and adds to the debate on which is the optimal Rbv dose to associate to PegIFNalfa2a in easy to cure genotypes of HCV [20–22]. Overall, our findings strengthen the positive value of a RVR [6,23] in predicting treatment outcome independently of the stage of liver fibrosis. Indeed, SVR rates were extremely high once an RVR was achieved in both PegIFN based treatment regimens irrespective of fibrosis stage. Conversely, the novel finding is the negative predictive power of the lack of a RVR in patients with cirrhosis that was influenced by the type of PegIFN regimen, since it was associated with extremely low rates of SVR in the PegIFNa2b arm, only. Indeed, none of the patients without a
346
RVR ultimately achieved a SVR with PegIFNa2b vs. 33% of those treated with PegIFNa2a. If confirmed in a larger set of cirrhotic patients, the lack of a RVR could be eventually used as an additional stopping rule for HCV-1, 4 cirrhotic patients receiving dual therapy with PegIFNa2b. We do acknowledge that the stratification of patients according to HCV genotype and liver fibrosis stage may have significantly reduced the sample size of the cells and the power of our statistical analysis. Moreover, being these data generated by a sub-analysis of a prospective study not directly designed to assess the impact of liver fibrosis on PegIFN responsiveness, we can not completely exclude other potential uncontrollable biases such as skewed distribution of the IL28B single nucleotide polymorphisms. However, this seems high unlikely as recent data showed no correlation between IL28B genotype and liver fibrosis in the IDEAL trial [24]. Finally, since these data were generated in Caucasian patients, they should be extrapolated with caution to patients from other geographical regions. Still, we think that the clinical implications of the present study are applicable to the last years of the era preceding the development of directly acting antiviral (DAA) based therapy, particularly as far as the potential benefit of the PegIFNa2a regimen over the PegIFNa2b regimen in S P3 patients infected with HCV-1, 4, and the similarity between the two regimens in the S <3 patients, is concerned. Although we do wonder whether differences in the clinical activity between the PegIFNs will still matter once DAA agents become available to treat hepatitis C infection [25–27], nevertheless the finding that S P3 patients with HCV-1, 4 are likely to benefit more from the PegIFNalfa2a regimen, supports this regimen as the ideal backbone of DAA triple therapy in this category of patients, in order to minimize the risk of resistant mutants to DAA [28].
Conflict of interest Massimo Colombo. Grant and Research support: ScheringPlough, Roche, Bristol-Myers Squibb, Gilead, Bayer. Advisory committees: Schering-Plough, Roche, Novartis, Vertex, BristolMyers Squibb, Gilead, Bayer, Tibotec. Speaking and Teaching: Schering-Plough, Roche, Novartis, Vertex, Bristol-Myers Squibb, Gilead, Bayer. Maria Grazia Rumi. Speaking and Teaching: Roche. Advisory committees: Roche. Alessio Aghemo. Advisory committees: Roche. Maria Francesca Donato. Speaking and Teaching: ScheringPlough, Roche, Gilead, Kedrion. Other authors have no financial disclosure to declare.
Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jhep.2011.05.022. References [1] Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005;5:558–567. [2] Shiratori Y, Ito Y, Yokosuka O, Imazeki F, Nakata R, Tanaka N, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival 1. Ann Intern Med 2005;142:105–114.
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