Hepatol Int (2014) 8:517–526 DOI 10.1007/s12072-014-9555-3
ORIGINAL ARTICLE
Extended treatment with pegylated interferon alfa/ribavirin in patients with genotype 2/3 chronic hepatitis C who do not achieve a rapid virological response: final analysis of the randomised N-CORE trial Mitchell L. Shiffman • Hugo Cheinquer • Christoph P. Berg • Thomas Berg • Cla´udio de Figueiredo-Mendes • Gregory J. Dore • Maria Lu´cia Ferraz • Maria Ca´ssia Mendes-Correˆa • Maria Patelli Lima • Edison R. Parise • Alma Minerva Perez Rios • Tania Reuter • Arun J. Sanyal • Stephen D. Shafran Marc Hohmann • Fernando Tatsch • George Bakalos • Stefan Zeuzem
•
Received: 19 June 2014 / Accepted: 21 June 2014 / Published online: 24 July 2014 Ó Asian Pacific Association for the Study of the Liver 2014
Abstract Background and aims The combination of pegylated interferon alfa/ribavirin will likely remain the treatment of choice for HCV genotype 2/3 patients in financially constrained countries for the foreseeable future. Patients with poor on-treatment response may benefit from treatment extension. This study examined the effect of 48 versus 24 weeks of peginterferon alfa-2a/ribavirin on the sustained virological response (SVR) in patients with HCV genotype 2/3 who did not achieve rapid virological response (RVR). Methods N-CORE was a multicentre, randomised, phase III study. HCV genotype 2/3 patients receiving peginterferon alfa-2a/ribavirin without a rapid but with an early virological response were randomised at week 24 to stop
treatment (Arm A) or continue to 48 weeks (Arm B). The primary efficacy endpoint was SVR. Results Two hundred thirty-five patients were enrolled. End of treatment response was similar in both treatment arms. SVR24 rates were not significantly greater in the extended treatment arm compared with the standard 24-week treatment in either the intention-to-treat or the per-protocol populations (61 vs. 52 %, p = 0.1934 and 63 vs. 52 %, p = 0.1461, respectively). Serious adverse events occurred more frequently in patients receiving extended treatment duration (12 %) versus 24-week therapy (4 %). Conclusions It is unclear whether the extension of peginterferon alfa-2a/ribavirin treatment may benefit HCV genotype 2/3 patients who do not achieve RVR. The study was stopped early because recruitment was slower than
M. L. Shiffman (&) Liver Institute of Virginia, Bon Secours Health System, Richmond and Newport News, 5855 Bremo Road, Suite 509, Richmond, VA 23226, USA e-mail:
[email protected]
C. de Figueiredo-Mendes Hospital Geral, Santa Casa da Miserico´rdia do Rio de Janeiro, Rio de Janeiro, Brazil e-mail:
[email protected]
H. Cheinquer Department of Gastroenterology, Hospital de Clı´nicas de Porto Alegre, Porto Alegre, Brazil e-mail:
[email protected] C. P. Berg Department of Internal Medicine, Medizinische Universita¨tsklinik Tu¨bingen, Tu¨bingen, Germany e-mail:
[email protected] T. Berg Hepatology Section, Department of Gastroenterology and Rheumatology, Universita¨tsklinikum Leipzig, Leipzig, Germany e-mail:
[email protected]
G. J. Dore Kirby Institute, The University of New South Wales and St. Vincent’s Hospital, Sydney, NSW, Australia e-mail:
[email protected] M. L. Ferraz E. R. Parise Department of Gastroenterology, Escola Paulista de Medicina, UNIFESP, Sa˜o Paulo, Brazil e-mail:
[email protected] E. R. Parise e-mail:
[email protected]
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anticipated, and this may have limited the statistical impact of these findings. Keywords Hepatitis C virus Chronic hepatitis C Genotype 2/3 Peginterferon/ribavirin N-CORE Slow virological responders
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recommended 24 weeks in those patients who were still viraemic at week 4 [8]. The N-CORE study (NCT00623428; [9]) was a randomised, open-label, international multicentre study to determine whether extending PegIFN alfa-2a/RBV treatment to 48 weeks in patients with HCV genotype 2/3 who do not achieve RVR would enhance SVR24.
Introduction Despite the recent approval of interferon-free regimens for the chronic hepatitis C virus (CHC) genotypes (G)2 and 3 [1, 2], the combination of pegylated interferon alfa with ribavirin (PegIFN alfa/RBV) will likely remain the treatment of choice in financially constrained countries for the foreseeable future [3–5]. The standard PegIFN alfa/RBV treatment duration is 24 weeks. The ACCELERATE study demonstrated that patients with HCV genotype 2/3 who did not achieve a rapid virological response (RVR; undetectable HCV RNA at week 4 of treatment) had an overall sustained virological response (SVR24) rate of only 45 % after 24 weeks of treatment with PegIFN alfa-2a 180 lg/week plus ribavirin 800 mg/day compared with 85 % SVR24 rate in patients achieving RVR [6]. In a retrospective analysis it was demonstrated that extending the duration of treatment from 24 to 48 weeks in patients with genotype 2/3 who did not achieve RVR reduced relapse rates and increased SVR24 [7]. Furthermore, a study conducted in HCV G3-infected patients treated with PegIFN alfa-2b plus RBV 1,000–1,200 mg/day showed that SVR rates were numerically higher after 36 weeks of treatment than after the
Materials and methods Patients Patients C18 years old with CHC genotype 2 or 3, having started therapy with PegIFN alfa-2a/RBV and with detectable HCV RNA (Roche COBASÒ AmpliPrep/COBASÒ TaqManÒ HCV Test C15 IU/ml) at week 4 (nonRVR) were eligible for enrolment. Patients co-infected with hepatitis A, hepatitis B or HIV, or with a history or other evidence of decompensated liver disease or prior treatment with pegylated or standard interferon with or without ribavirin therapy were not eligible. In addition, patients who did not achieve an early virological response (EVR; undetectable HCV RNA or a drop of C2-log10 from baseline at week 12 after start of treatment) were not eligible for randomisation 24 weeks after start of treatment. Study design The N-CORE study was a phase III, international, multicentre trial with a randomised, open-label, parallel-group
M. C. Mendes-Correˆa Infectious Diseases Research Unit, ABC Foundation Medical School, Santo Andre´, Brazil e-mail:
[email protected]
S. D. Shafran Division of Infectious Diseases, University of Alberta, Edmonton, AB, Canada e-mail:
[email protected]
M. P. Lima Medical Sciences, Pontifı´cia Universidade Cato´lica de Campinas, Sa˜o Paulo, Brazil e-mail:
[email protected]
M. Hohmann IST GmbH, Mannheim, Germany e-mail:
[email protected]
A. M. P. Rios Centro de Investigacio´n Farmace´utica Especializada, Guadalajara, JAL, Mexico e-mail:
[email protected] T. Reuter Centre for Infectious Diseases, Universidade Federal do Espı´rito Santo, Vito´ria, Brazil e-mail:
[email protected] A. J. Sanyal Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA e-mail:
[email protected]
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F. Tatsch G. Bakalos F. Hoffmann-La Roche Ltd, Basel, Switzerland e-mail:
[email protected] G. Bakalos e-mail:
[email protected] Present Address: F. Tatsch AbbVie, Chicago, IL, USA S. Zeuzem Department of Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany e-mail:
[email protected]
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design (NCT00623428; ClinicalTrials.gov). Centres were located in Australia (5), Austria (2), Belgium (6), Brazil (13), Canada (1), Germany (15), Mexico (3), Switzerland (3) and the USA (16). Patients were enrolled into the study between weeks 4 and 8 of treatment once RVR status had been confirmed and eligibility criteria fulfilled. Patients continued with the regimen of PegIFN alfa-2a (40KD) (PEGASYSÒ, Roche, Basel, Switzerland) plus ribavirin (COPEGUSÒ, Roche) that had been initiated prior to enrolment (according to local standard of care) for up to 24 weeks of treatment. At week 24, patients who did not achieve RVR but did achieve an EVR were randomised to one of two study groups: immediately stop treatment with PegIFN alfa-2a/RBV, with an untreated follow-up period of 48 weeks (Arm A), or continue with PegIFN alfa-2a 180 lg/week plus RBV 800–1,200 mg/day to complete a total of 48 weeks, followed by an untreated follow-up period of 24 weeks (Arm B) (Fig. 1). Non-EVR patients stopped all treatment at week 24. Randomisation was centrally controlled and used a permuted block method. Assignment to treatment arm was performed by the investigator at week 24 of treatment using an Interactive Web Response System integrated in the electronic case report form. The study was conducted in accordance with the principles of the Declaration of Helsinki; the protocol was approved by the institutional review board of each centre and each patient provided informed consent. Endpoints and assessments Endpoints were assessed by measurement of virological response, defined as HCV RNA\15 IU/ml as measured by the Roche COBAS AmpliPrep/COBAS TaqMan HCV Test. The primary efficacy endpoint, sustained virological response at 24 weeks (SVR24), was defined as HCV RNA \15 IU/ml, as measured by the Roche COBAS AmpliPrep/
COBAS TaqMan HCV Test, 6 months post-treatment. Secondary efficacy endpoints included the percentage of patients who experienced virological relapse (HCV RNA \15 IU/ml at end of treatment [EOT] but [15 IU/ml 6 months post-treatment). Endpoints were analysed using the Cochran-Mantel-Haenszel test stratified by genotype (2 vs. 3), ribavirin dose (800 vs. 1,000–1,200 mg) and geographic region (US vs. non-US). Patients without measurements at least 140 days after EOT were considered as nonresponders. Exploratory multiple logistic regression (MLR) analyses were performed to examine the effect of treatment duration and baseline characteristics on the probability of achieving SVR24. A scoring system was devised for the prediction of SVR24 and relapse. MLR analyses (stepwise selection) and receiver-operating characteristic curves were used to identify the variables (baseline and on-treatment factors) and the relevant cutoffs to be used for the score. Predictive factors that were identified to construct the score were: age, gender, cirrhosis status, baseline HCV RNA and HCV RNA at week 4. To derive the total score for a given patient, the individual’s characteristics were assigned either a score of 0 (B50 years; female; no cirrhosis/not assessed; baseline HCV RNA[1,200,000 IU/ml and HCV RNA[15 IU/ml at week 4; HCV RNA B1,000 IU/ml at week 4) or 1 ([50 years; male; cirrhosis/transition to cirrhosis; baseline HCV RNA B1,200,000 IU/ml and HCV RNA [15 IU/ml at week 4; HCV RNA [1,000 IU/ml at week 4), as shown in Table 1, and the sum was calculated. The total score ranged from 0 to 5, and higher scores were associated with a lower chance of treatment success (lower probability of an SVR24, higher probability of relapse). Table 1 Scoring system for prediction of SVR24 and relapse Predictor
Score
Age (years) 48-week follow-up
Non-RVR patients on P/R P/R
0
4
8
12
24
0 1
Gender
STOP CHC G2/3 patients on P/R
B50 years [50
0
Male
1
Cirrhosis status
24-week follow-up
48
Female
72
Fig. 1 Study design. (Downwards arrow) Entry into study at week 8 if no RVR. (Asterisk) Randomisation of patients without RVR, but with undetectable HCV RNA or C2-log drop in HCV RNA from baseline at week 12. CHC chronic hepatitis C virus; P/R peginterferon alfa-2a 180 lg plus ribavirin 800 mg or 1,000/1,200 mg; RVR rapid virological response (undetectable HCV RNA at week 4 of treatment)
No cirrhosis/not assessed
0
Cirrhosis/transition to cirrhosis
1
Baseline HCV RNA (IU/ml) [1,200,000 IU/ml and HCV RNA [15 IU/ml at week 4
0
B1,200,000 IU/ml and HCV RNA [15 IU/ml at week 4
1
HCV RNA at week 4 (IU/ml) B1,000 [1,000
0 1
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Analysis populations
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(a)
Enrolled N = 235 Withdrew prior to randomisation: n = 47
The intention-to-treat (ITT) population comprised all patients who were randomised at week 24. Patients were analysed according to the treatment group to which they were assigned at randomisation regardless of the treatment dose and duration received. The per-protocol (PP) population excluded randomised patients with major protocol violations, including deviation from the assigned treatment group. The safety population included all patients randomised who received C1 dose of study medication with C1 post-baseline safety assessment.
• Violation of selection criteria (n = 31)
• AE (n = 9) • Withdrew consent/refused treatment (n = 3)
• Failure to return (n = 3) • Randomisation not performed in due time (n = 1) Randomised at week 24 of treatment: n = 188 Arm A: n = 95 Arm B: n = 93 Discontinued treatment prematurely (Arm B): n = 27
• Safety reasons (n = 10) • Non-safety reasons (n = 17)
Sample size calculation It was estimated that the overall rate of SVR24 in Arm A would be in the region of 55–60 %. In order to detect an improvement in SVR24 with an odds ratio (OR) of approximately 2 (i.e. an increase in SVR24 by 15–16 % in Arm B vs. Arm A) with 80 % power and a two-sided significance level of 0.05, 160 patients per treatment group (320 patients in total) were required. In order to account for dropouts between enrolment and randomisation (e.g., patients without EVR, withdrawals due to adverse events [AEs]), the number of patients enrolled was increased to 400 to ensure that 320 patients would be available for randomisation.
Completed treatment: Arm A: n = 95 Arm B: n = 66
(b)
Withdrew prior to randomisation: n = 47 • Violation of selection criteria (n = 31) • AE (n = 9) • Withdrew consent/refused treatment (n = 3) • Failure to return (n = 3) • Randomisation not performed in due time (n = 1) Randomised at week 24 of treatment: n = 188
Results
Arm A: n = 95 Arm B: n = 93
Patients A total of 235 patients were enrolled, with the first patient entering the study in June 2008 and the last patient completing follow-up in May 2012. Details of patient disposition and flow through the study are shown in Fig. 2. The study was stopped before the target 400 patients had been enrolled because recruitment was slower than anticipated. There were 47 withdrawals before randomisation at week 24, which were mainly due to either not fulfilling the selection criteria or for safety reasons (Fig. 2). The ITT and safety populations comprised 95 patients who had received PegIFN alfa-2a/RBV for 24 weeks (Arm A; stopped treatment at randomisation) and 93 who were randomised to receive PegIFN alfa-2a/RBV for further 24 weeks (Arm B; randomised to receive a total of 48 weeks of treatment) (Fig. 2). The PP population included 95 patients in Arm A and 81 patients in Arm B (Fig. 2). Baseline characteristics Baseline characteristics of patients were well balanced between treatment arms in the ITT population and
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Enrolled N = 235
ITT and safety: n = 188 Arm A: n = 95 Arm B: n = 93 Excluded from PP (Arm B): n = 12 • No treatment after randomisation (n = 12)*
Excluded from PP (Arm A): n=0
PP: n = 176 Arm A: n = 95 Arm B: n = 81
Fig. 2 Patient disposition (a) and patient analysis (b) flow diagrams. (Asterisk) Nine unwilling to extend treatment duration and three because of AEs observed in the first 24 weeks. AE adverse event, HCV hepatitis C virus, ITT intention-to-treat population, PP perprotocol population, SVR24 sustained virological response
remained well balanced in the PP population (Table 2). The majority of randomised patients were male (58 %) and Caucasian (87 %), with predominantly HCV genotype 3 infection (80 %) and HCV RNA [400,000 IU/ml (78 %), and had received a 1,000/1,200 mg starting dose of RBV (72 %). In Arm A, 27 patients (28 %) received RBV at a starting dose of 800 mg and 68 patients (72 %) received 1,000/1,200 mg. In Arm B, 25 patients (27 %) received
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Table 2 Demographics and baseline characteristics Characteristic
ITT population
PP population
Arm A: PegIFN 2a/RBV 24 weeks (n = 95)
Arm B: PegIFN 2a/RBV 48 weeks (n = 93)
Arm A: PegIFN 2a/RBV 24 weeks (n = 95)
Male, n (%)
55 (58)
54 (58)
55 (58)
46 (57)
Median age, range
51.0 (23–69)
49.0 (20–69)
51.0 (23–69)
49.0 (20–69)
47 (49.5) 48 (50.5)
53 (57.0) 40 (43.0)
47 (49.5) 48 (50.5)
48 (59.3) 33 (40.7)
27.1 ± 4.9
27.0 ± 5.1
27.1 ± 4.9
27.1 ± 5.2
Asian
1 (1)
2 (2)
1 (1)
2 (2)
Black
8 (8)
6 (6)
8 (8)
6 (7)
Caucasian/white
82 (86)
81 (87)
82 (86)
70 (86)
Other
4 (4)
4 (4)
4 (4)
3 (4)
B50 years, n (%) [50 years, n (%) Mean BMI, kg/m2
Arm B: PegIFN 2a/RBV 48 weeks (n = 81)
Race, n (%)
Region, n (%) Non-US
85 (89)
82 (88)
85 (89)
71 (88)
US
10 (11)
11 (12)
10 (11)
10 (12)
Assessment of liver fibrosis, n (%) Biopsy
51 (54)
41 (44)
51 (54)
36 (44)
Non-invasive
29 (31)
25 (27)a
29 (31)
19 (23)a
Not assessed
15 (16)
27 (29)
15 (16)
26 (32)
Liver disease stage,b n (%) No cirrhosis 55 (69)
44 (68)
55 (69)
36 (67)
Transition to cirrhosis
8 (10)
11 (17)
8 (10)
9 (17)
Cirrhosis
17 (21)
10 (15)
17 (21)
9 (17)
2
19 (20)
19 (20)
19 (20)
16 (20)
3
76 (80)
74 (80)
76 (80)
65 (80)
6.11 ± 0.624
6.17 ± 0.773
6.11 ± 0.624
6.20 ± 0.796
HCV genotype, n (%)
Mean HCV RNA (± SD), log10 IU/ml B400,000, n (%)
18 (18.9)
23 (24.7)
18 (18.9)
20 (24.7)
[400,000, n (%)
77 (81.1)
70 (75.3)
77 (81.1)
61 (75.3)
B1,200,000, n (%) [1,200,000, n (%) Mean ALT (± SD), IU/l
40 (42.1)
40 (43.0)
40 (42.1)
32 (39.5)
55 (57.9) 144.6 ± 108.3
53 (57.0) 144.8 ± 125.9
55 (57.9) 144.6 ± 108.3
49 (60.5) 137.2 ± 122.2
ALT quotient, n (%) 0–1
13 (14)
14 (16)
13 (14)
13 (17)
[1–3
51 (57)
51 (57)
51 (57)
46 (60)
[3
26 (29)
24 (27)
26 (29)
18 (23)
ALT alanine aminotransferase, BMI body mass index, ITT intention to treat, PegIFN 2a peginterferon alfa-2a 180 lg, PP per protocol, RBV ribavirin 800 or 1,000/1,200 mg a
One patient for whom a non-invasive FibroScan was performed had a missing result
b
Information not available for all patients, % values of those assessed
RBV at a starting dose of 800 mg and 68 patients (73 %) received the 1,000/1,200 mg dose. Patients in Arm A (n = 95) received a mean PegIFN alfa-2a cumulative dose of 4,329 lg (range 3,465– 4,680 lg) and a mean RBV cumulative dose of 172 g (range 103–212 g). Patients in Arm B (n = 93) received a mean PegIFN alfa-2a cumulative dose of 7,546 lg
(range 3,780–8,820 lg) and a mean RBV cumulative dose of 297 g (range 105–413 g). Efficacy Week 12 and EOT response rates were similar in the 24-week and extended treatment arms in both treatment populations
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(a) Virological response at Week 12 P/R 24 weeks
100
(b) EOT
P/R 48 weeks
p = 0.7864
p = 0.9456
93.7 94.6
93.7 93.8
P/R 24 weeks
100
90
90
80
80
70
70 Patients (%)
Patients (%)
Fig. 3 Virological response at week 12 (a), EOT (b), SVR24 (c) and relapse* (d) rates in the ITT and PP populations. CI confidence interval, EOT end of treatment, ITT intention to treat, P/R peginterferon alfa-2a 180 lg plus ribavirin 800 or 1,000/1,200 mg, PP per protocol, SVR24 sustained virological response, last undetectable HCV RNA measured C140 days after EOT. (Asterisk) Proportion experiencing relapse from those who had achieved a virological response at end of treatment. Odds ratios are calculated for 48 versus 24 weeks
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60 50 40
20
10
10 0
n N Odds ratio 95% CI
(n = 188)
(n = 176)
89 88 95 93
89 76 95 81
1.19 0.34–4.13
1.04 0.30–3.63
(c) SVR24
n N Odds ratio 95% CI
63.0
61.2
0.74 0.25–2.19
P/R 48 weeks
51.6
51.6
40
70 Patients (%)
Patients (%)
0.73 0.26–2.09
80
60 50
30
20
20
10
10 ITT
PP
(n = 188)
(n = 176)
49 95
49 95
57 93
1.48 0.82–2.64
p = 0.0932
41.0
p = 0.0744
41.0
40
30
(Fig. 3a, b). SVR24 rates were not significantly different in the extended treatment arm compared with the standard 24-week treatment in the ITT and PP populations [61 vs. 52 % (p = 0.1934) and 63 vs. 52 % (p = 0.1461), respectively; Fig. 3c). However, it is interesting to note that amongst the randomised patients who completed the scheduled treatment duration and had the necessary HCV RNA values to derive the primary endpoint [90 in the extended duration treatment group (Arm B) and 63 in the standard duration treatment group (Arm A)], more patients in the 48-week than in the 24-week treatment arm achieved
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88 73 95 81
p = 0.1461
50
Odds ratio 95% CI
88 84 95 93
90 p = 0.1934
70
n N
PP (n = 176)
100
80
0
ITT (n = 188)
P/R 24 weeks
P/R 48 weeks
100
60
90.1
(d) Relapse
P/R 24 weeks
90
92.6
90.3
40
20
PP
p = 0.5940
92.6
50
30
ITT
p = 0.5654
60
30
0
P/R 48 weeks
0
51 81
n N
1.58 0.86–2.89
Odds ratio 95% CI
28.8
27.1
ITT
PP
(n = 163)
(n = 153)
34 83
23 80
0.56 0.29–1.09
34 83
19 70
0.53 0.26–1.06
SVR24 [73 vs. 54 %; OR 2.25, 95 % confidence interval (CI) 1.12–4.51; p = 0.0231]. The SVR24 rates for each genotype were also calculated, but as these were based on a relatively low number of patients, the analysis was not statistically powered to detect clinically relevant differences between treatment arms. The SVR24 rates for genotype 2 patients were 68 % (13/19) with extended treatment versus 53 % (10/19) with 24 weeks of therapy in the ITT population and 69 % (11/16) versus 53 % (10/19) in the PP. In the HCV genotype 3 patients, the SVR24 rates for extended versus 24-week treatment were 59 % (44/74)
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523 0.1
SVR24 less likely
1
SVR24 more likely
10
ITT population
Odds ratio (95% CI)
p value
Age (per 10-year decrease)
1.738 (1.172 –2.580)
0.0060
Weight (per 10 kg decrease)
1.287 (1.031 –1.606)
0.0256
Cirrhosis (no vs. yes*)
3.978 (1.636 –9.668)
0.0023
Cirrhosis (no information vs. yes*)
4.159 (1.489 –11.616) 0.0065
HCV RNA (log10 IU/mL)
1.447 (0.863 –2.425)
0.1613
ALT quotient (decrease)
1.266 (1.062 –1.509)
0.0086
Initial RBV dose (1,000/1,200 mg vs. 800 mg)
2.081 (0.942 –4.596)
0.0699
Treatment group (48 weeks vs. 24 weeks)
1.646 (0.827 –3.275)
0.1560
1
Fig. 4 Stepwise multiple logistic regression analysis identifying baseline factors associated with SVR24. Significance level for entering an effect: 0.25; significance level to stay: 0.2; number of observations = 177 (11 observations deleted due to missing values);
versus 51 % (39/76) in the ITT population and 62 % (40/65) versus 51 % (39/76) in the PP population. Relapse rates in patients who had achieved response at EOT were not significantly different between the two treatment arms (Fig. 3d). However, the relapse rates were significantly lower among the randomised patients who completed the scheduled treatment duration and received extended rather than 24-week treatment duration (22 vs. 41 %; OR 0.41, 95 % CI 0.19–0.88; p = 0.0216). Baseline predictors of SVR24 Baseline factors significantly associated with SVR24 in MLR analysis included well-established predictors of SVR24 with absence of cirrhosis (no cirrhosis vs. cirrhosis), the factor with the strongest association with SVR24 (Fig. 4).
10
dependent variable: SVR 24 weeks after actual end of treatment. (Asterisk) Including transition to cirrhosis. ALT alanine aminotransferase, CI confidence interval, ITT intention-to-treat, RBV ribavirin
P/R 24 weeks P/R 48 weeks
SVR24
Relapse
100 90
84.8
82.8
78.6
80 70 60.5
Patients (%)
0.1
60
51.7
50.0
50 38.5
40
34.8
32.4
30 18.2
20
12.5 7.7
10 0
Virological response according to predictive score Patients with a low score (0–1) had SVR24 and relapse rates that were generally similar between the two treatment arms (24 vs. 48 weeks) in the ITT population, with SVR24 rates [80 % regardless of treatment duration (Fig. 5). In patients with a score C3, SVR24 rates were substantially higher (38 vs. 18 %) and relapse rates substantially lower (50 vs. 79 %) in the 48-week treatment arm compared with the 24-week arm (Fig. 5). Safety Treatment discontinuation and dose modification PegIFN alfa-2a/RBV treatment was discontinued for safety reasons in ten patients (11 %) in Arm B. There
n N
0–1
2
≥3
0–1
2
≥3
28 24 33 29
15 23 29 38
6 10 33 26
4 2 32 26
8 11 23 34
22 10 28 20
Fig. 5 SVR24 and relapse rates in patients with a predictive score of 0–2 and C3 in the ITT population. ITT intention to treat; P/R PegIFN alfa-2a 180 lg plus ribavirin 800 mg or 1,000/1,200 mg
were more safety-related dose modifications of both PegIFN alfa-2a and RBV in Arm B than in Arm A [19 vs. 9 % (p = 0.054) and 28 vs. 16 % (p = 0.044), respectively]. PegIFN alfa-2a was modified because of AEs in one patient (1 %) in Arm A and seven patients (8 %) in Arm B. RBV was modified because of AEs in 6 patients (6 %) in Arm A and 11 patients (12 %) in Arm B.
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Tolerability and adverse events The safety profile in both treatment arms was typical of that expected for PegIFN alfa-2a/RBV (Table 3). More patients experienced at least one AE with the extended treatment duration compared with 24 weeks of therapy (95 vs. 85 %). The majority of AEs experienced were mild or moderate in severity (97 and 94 % of total AEs in Arms A and B, respectively). Serious adverse events (SAEs) occurred more frequently in patients in Arm B (12 %) than in Arm A (4 %) (Table 3). No one SAE occurred in more than one patient. One death, which was considered possibly related to PegIFN alfa-2a, occurred in Arm B following a cerebrovascular accident. Table 3 Safety data Variable, n (%)
Randomised safety population Arm A: PegIFN 2a/RBV 24 weeks (n = 95)
Arm B: PegIFN 2a/RBV 48 weeks (n = 93)
Total patients with C1 AE
81 (85)
88 (95)
Total patients with C1 severe AE
13 (14)
24 (26)
Total patients with C1 SAE
4 (4)
11 (12)
Deaths
a
0
1 (1)
AEs occurring at a rate [10 % Fatigueb
33 (35)
47 (51)
Headacheb
17 (18)
30 (32)
Nauseab
13 (14)
24 (26)
Insomnia Pruritus
21 (22) 17 (18)
21 (23) 20 (22)
Alopecia
15 (16)
17 (18)
Asthenia
18 (19)
14 (15)
Dry skin
13 (14)
14 (15)
Myalgiab
8 (8)
18 (19)
Depression
13 (14)
12 (13)
Arthralgia
10 (11)
13 (14)
Decreased appetite
8 (8)
15 (16)
Pyrexia
11 (12)
11 (12)
Diarrhoea
7 (7)
14 (15)
Influenza-like illness
14 (15)
Cough
7 (7)
12 (13)
7 (8)
Anaemia
9 (9)
10 (11)
Irritability
12 (13)
Dyspepsia
2 (2)
4 (4) 10 (11)
AE adverse event, PegIFN 2a peginterferon alfa-2a 180 lg, RBV ribavirin 800 or 1,000/1,200 mg, SAE serious adverse event a
One death, possibly related to peginterferon alfa-2a, in Arm B following cerebrovascular accident
b
A [10 % difference between arms in the frequency of occurrence
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In Arm A, 78 patients (82 %) experienced at least one AE related (remotely, possibly or probably) to PegIFN alfa-2a treatment, and 72 patients (76 %) experienced ribavirin-related (remotely, possibly or probably) AEs. In Arm B, 86 patients (92 %) experienced PegIFN alfa-2arelated AEs and 83 (89 %) experienced RBV-related AEs.
Discussion The treatment of CHC is currently being revolutionised with the introduction of new direct-acting antivirals (in combination with or without PegIFN/RBV), which increase the proportion of patients who can achieve SVR while reducing the total duration of the treatment. These regimens offer both an excellent safety profile and convenience for patients and their treating physicians [1, 2, 10– 12]. Unfortunately, the high cost of these new treatments together with financial constraints in many countries may limit the availability of these oral anti-viral agents [3–5, 13]. Consequently, physicians in several geographical areas worldwide are likely to keep treating patients with HCV genotype 2/3 infections with PegIFN/RBV alone. As such, there is a need to keep optimising this traditional approach to the treatment of HCV infection, with the aim of increasing the efficacy of treatment and identifying the patients who are most likely to respond to this regimen. The benefits of what is termed ‘‘response-guided therapy’’ have been demonstrated in several studies of slowresponding patients with HCV genotype 1. In these studies, extended treatment was associated with a reduction in relapse rates, leading to an enhanced SVR24 [14–19]. The N-CORE trial aimed to explore further the treatment of patients with HCV genotype 2/3 infection but, unfortunately, did not manage to demonstrate a similar effect. Insufficient numbers of patients were recruited into the N-CORE trial. There were several reasons for the lack of recruitment. The most important among these was unwillingness of some patients to be randomised to 48 weeks of treatment, which reflects patient anticipation for novel shortduration antiviral therapies; this is further highlighted by the high rate of dropouts in the 48-week arm immediately after randomisation to continue treatment. As a result, the power of the study was reduced and this trial was not able to demonstrate whether or not the extension of PegIFN alfa-2a/RBV treatment may benefit HCV genotype 2/3 patients who do not achieve RVR. Based on the primary endpoint of SVR24 in the ITT population there was a numerical trend (not statistically significant) showing a benefit with extended duration versus 24-week treatment with PegIFN alfa-2a/RBV. The lower sample size rather than planned may have reduced the ability of the trial to show a significant benefit with 48versus 24-week treatment duration. Analysis of the PP
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population showed a stronger trend towards benefit with extended treatment duration compared with 24-week treatment, but again this was still not statistically significant, and the results do not provide a robust basis for this to be applied in clinical practice. Among the patients who completed all study visits and had available HCV RNA measurements in the required time window for SVR24, a significant improvement in the SVR24 rate was observed with extended versus 24-week PegIFN alfa2a/RBV treatment duration. Similarly, the relapse rates among this subpopulation were significantly lower with extended treatment duration than with 24-week treatment. This subanalysis demonstrates a potential benefit for extended PegIFN alfa-2a/RBV treatment in patients who are willing and able to tolerate a prolonged course of treatment. However, these observations should be interpreted with caution because this benefit was only observed in this sub-set analysis. Although individual genotype numbers were small and results are not powered to show statistical significance, the SVR24 results for HCV genotype 3 patients suggested that, particularly in the PP population, extended treatment duration may be beneficial (SVR24 was 62 % with 48 weeks vs. 51 % with 24 weeks of PegIFN alfa-2a/RBV). This is particularly relevant as it becomes the most difficult-to-cure HCV genotype with the current anti-HCV options [13]. Interestingly, the predictive scoring system that was developed for SVR24 and relapse provided a simple method, using readily available baseline characteristics and ontreatment factors (week 4 HCV RNA), to help distinguish between non-RVR patients who did and did not benefit from prolonging treatment to 48 weeks. Patients with a score of 0 or 1 achieved SVR24 [80 % regardless of treatment duration, while in patients with a score C3 SVR24 increased from 18 to 39 % in the ITT population with 48 weeks’ treatment versus 24 weeks. In calculating this predictive score, low baseline HCV RNA was considered a risk factor for low SVR24 and high relapse rates. While this may seem counterintuitive, N-CORE only included patients who did not achieve RVR at week 4. Therefore, taken together, a poor virological response in the first 4 weeks despite a low baseline HCV RNA was considered a risk factor for low SVR24 and high relapse rates. The safety profile was characteristic of PegIFN alfa-2a/ RBV, with a higher rate of AEs during extended treatment duration compared with 24 weeks (95 vs. 85 %). The majority of AEs were mild/moderate in severity. One death occurred in Arm B after a cerebrovascular accident. This death was considered possibly related to PegIFN alfa-2a and unrelated to RBV. SVR24 rates with 24 weeks of treatment in this study (ITT population, 52 %) were slightly higher than SVR24 rates previously reported in non-RVR patients with HCV genotype 2/3 who received 24 weeks of treatment in the
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ACCELERATE trial (ITT population, 45 %) [6]. When ACCELERATE patients who did not achieve RVR but achieved an EVR and completed treatment were considered, however, the SVR24 rate was comparable (53 %). Interpretation of these trials is confounded by including patients who withdrew from treatment immediately after randomisation. As enrolment did not meet the intended number of patients, and because more patients were infected with HCV genotype 3 than genotype 2 (80 %), it was not possible to determine whether extension of treatment duration is of differential benefit in patients with HCV genotype 2 versus genotype 3. In conclusion, from the N-CORE study data it is unclear whether or not extension of PegIFN/RBV treatment may benefit HCV genotype 2/3 patients who do not achieve RVR. Acknowledgements The authors thank the N-CORE Study Group investigators: Australia: Gerry Macquillan, Sam Galhenage, Alice Lee, Greg Dore, Stephen Pianko; Austria: Peter Ferenci, Rudolf Stauber, Michael Gschwantler, Gabriele Fischer, Andreas Maieron, Wolfgang Vogel, Christian Datz; Belgium: Jean-Pierre Mulkay, Marc Van Gossum, Peter Michielsen, Hans Van Vlierberghe, Christophe George, Jean Delwaide, Luc Lasser, Chantal De Galocsy; Brazil: Hugo Cheinquer, Fernando Wolff, Nelson Cheinquer, Edison Roberto Parise, Marcela Pezzoto Laurito, Maria Lucia Ferraz, Ivonete Souza e Silva, Arnaldo Dominici Jesus, Adalgisa Souza Paiva Ferreira, Maria Patelli Lima, Fernando Jose´ Go´es Ruiz, Ligia Ruiz, Angelo Mattos, Cristiane Tovo, Fernanda De Arau´jo, Paulo Roberto Lerias Almeida, Gabriela Coral, Idilio Zamin Junior, Jorge Pinheiro, Sirlei Dittrich, Tania Reuter, Janaı´na Casotti Schneider, Waltesia Perini, Marcelo Costa, Fernando Gonc¸ales Jr., Adilson Cavalcante, Ana Carla Silva, Catia Carpinelli, Maria Ca´ssia Mendes-Correˆa, Virgilio Tiezzi Neto, Andresa Teixeira, Ana De Lourdes Candolo Martinelli, Marcia Villanova, Fernanda Souza, Cla´udio de Figueiredo-Mendes; Canada: Stephen D. Shafran, Keith Tsoi, Alnoor Ramji, Nav Anand; Germany: Stefan Zeuzem, Eckart Schott, Peter Buggisch, Dietmar M. Klass, Christoph Eisenbach, Tobias Goeser, Christoph Berg, Bernd Mo¨ller, Ulrich Spengler, Roland M. Schmid, Peter R. Galle, Robert Thimme, Andreas Erhardt, Stefan Mauss, Rainer Gu¨nther, Jo¨rg Schlaak, Thomas Discher, Ralph Link, Andreas Stallmach; Mexico: Ignacio Escalante Sandoval, Jose Isidro Minero Alfaro, Toma´s Marcelino Morales Cadena, Alma Minerva Pe´rez Rı´os, Nahum Mendez Sanchez, Rene Male Velazquez; Switzerland: Andreas Geier, Aref Al Deb’i, Beat Muellhaupt, Heiko Fruehauf, Joachim Mertens, Darius Moradpour, Jan Borovicka, Benedetta Terziroli, Andreas Cerny, Lorenzo Magenta, Marina Knoepfli, Rosita Dell’orto Spadacini; United States: Kimberly Beavers, Raymond Chung, Greg Everson, Norman Gitlin, Paul Pockros, Jatinder Pruthi, Alan Tice, Fernando Alemany-Lopez, Sanjeev Arora, Luis Balart, Ana Maria Corregidor, Edwin Dejesus, Adrian Dibisceglie, Christopher Williams, Tarek Hassanein, Timothy Morgan, Maribel Rodriguez-Torres, Lorenzo Rossaro, Vinod R. Rustgi, John Santoro, Arun Sanyal, Atif Zaman, Kevin Korenblat, Curtis Argo, Douglas Homoky, Robert A. Levine, Joseph Bloomer, John Phillips, Gary Poleynard, Aasim Sheikh, Hillel Tobias, Bindu Balani, Harlan Wright, Edward Piken, Sergio Rojter, Michael Fried, Neville Pimstone, Fred Poordad, Terry Box. This study was supported by F. Hoffmann-La Roche Ltd., Basel, Switzerland. Support for thirdparty writing assistance for this manuscript, furnished by Sarah Davies, Ph.D., was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland.
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526 Compliance with ethical requirements and Conflict of interests All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study. Mitchell L Shiffman—Advisor: Achillion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GenProbe, Gilead, Globeimmune, GlaxoSmithKline, Janssen, Merck, Novartis, Roche/Genentech, Vertex; Speaker: Bayer, Gilead, GlaxoSmithKline, Merck, Roche/Genentech, Vertex; Grant support: Abbott, Achillion, Anadys, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Globeimmune, Idenix, Merck, Novartis, Roche/ Genentech. Hugo Cheinquer—Advisor: Roche; Speaker: BristolMyers Squibb, Roche; Research Grant: Bristol-Myers Squibb, Merck, Roche. Christoph P Berg—Advisor: Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Janssen, Merck, Roche; Speaker: BristolMyers Squibb, Gilead, Janssen, Merck, Roche. Thomas Berg— Advisor: Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Janssen, Merck, Novartis, Roche, Vertex; Speaker: Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Janssen, Merck, Novartis, Roche, Vertex; Research Grants: Bristol-Myers Squibb, Gilead, Janssen, Novartis. Roche Cla´udio de Figueiredo-Mendes— Research support: Bristol-Myers Squibb, Merck, Roche. Gregory J. Dore—Advisor: AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck, Roche; Research Grants: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, Roche, Vertex. Maria Lu´cia Ferraz—Advisor: Abbott, Janssen, Merck, Roche; Speaker: Abbott, Janssen, Merck, Roche; Clinical trials: Abbott, Janssen, Merck, Roche. Maria Lu´cia Ferraz—Advisor: Abbott, Janssen, Merck, Roche; Speaker: Abbott, Janssen, Merck, Roche; Clinical trials: Abbott, Janssen, Merck, Roche. Maria Ca´ssia Mendes-Correˆa—Research support: Bristol-Myers Squibb, Janssen, Merck, Roche. Maria Patelli Lima—None to declare. Edison R. Parise— Advisor: Bristol-Myers Squibb, Merck, Roche; Speaker: BristolMyers Squibb, Janssen, Merck, Roche; Research support: BristolMyers Squibb, GlaxoSmithKline, Janssen, Merck, Roche. Alma Minerva Perez Rios—None to declare. Tania Reuter—Research support: GlaxoSmithKline, Janssen, NIH, Roche; Speaker: Janssen, Roche. Arun J Sanyal—Advisor: Abbott, Galectin, Gilead, Ikaria, Immuron, Merck, Norgine, Novartis, Roche/Genentech, Salix, Takeda; Research Grants: Bayer-Onyx, Exhalenz, Genentech, Gilead, Gore, Ikaria, Intercept, Salix, Takeda, Astellas; Royalties: Up to date. Stephen D Shafran—Advisor: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, Pfizer, Roche, Vertex; Research funding: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck, Pfizer, Roche, Vertex. Marc Hohmann— Employee of IST GmbH; IST GmbH has a contract with Roche to provide statistical support. Fernando Tatsch—Employee of AbbVie, Chicago, IL; was an employee of F. Hoffmann-La Roche Ltd, Basel, Switzerland at the time the study was conducted. George Bakalos— Employee of F. Hoffmann-La Roche Ltd, Basel, Switzerland. Stefan Zeuzem—Advisor: Abbott, Achillion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Janssen, Merck, Novartis, Presidio, Roche, Santaris, Vertex.
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