Peginterferon Alfa-2a/Ribavirin for 48 or 72 Weeks in Hepatitis C Genotypes 1 and 4 Patients With Slow Virologic Response

Transcription

1 GASTROENTEROLOGY 2010;138: Peginterferon Alfa-2a/Ribavirin for 48 or 72 Weeks in Hepatitis C Genotypes 1 and 4 Patients With Slow Virologic Response PETER FERENCI,*,## HERMANN LAFERL, THOMAS MATTHIAS SCHERZER,* ANDREAS MAIERON, HARALD HOFER,* RUDOLF STAUBER, MICHAEL GSCHWANTLER, HARALD BRUNNER, # CHRISTOPH WENISCH, MARTIN BISCHOF,** MICHAEL STRASSER, CHRISTIAN DATZ, WOLFGANG VOGEL, KARIN LÖSCHENBERGER, and PETRA STEINDL MUNDA* for the Austrian Hepatitis Study Group *Department of Internal Medicine III, Medical University, Vienna, Austria; Department of Internal Medicine, Kaiser-Franz-Josef-Spital, Vienna, Austria; Department of Internal Medicine, Elisabethinen Hospital, Linz, Austria; Department of Internal Medicine, Medical University, Graz, Austria; Department of Internal Medicine IV, Wilhelminenspital, Vienna, Austria; # Department of Internal Medicine I, Hospital Hietzing, Wien, Austria; **Department of Internal Medicine IV, Rudolfshospital, Vienna, Austria, Department of Internal Medicine I, Paracelsus Private University, Salzburg, Austria; Krankenhaus, Oberndorf, Austria; Department of Gastroenterology and Hepatology, Medical University, Innsbruck, Austria; Roche Austria, Vienna, Austria; and ## Universitätsklinik für Innere Medizin III, AKH Wien, Vienna, Austria BACKGROUND & AIMS: This randomized multicenter trial evaluated individualization of treatment duration with peginterferon alfa-2a 180 g/wk plus ribavirin 1000/1200 mg/day in patients with chronic hepatitis C genotype 1/4 based on the rapidity of virologic response (VR). METHODS: Patients with a rapid VR (RVR; undetectable hepatitis C virus [HCV]-RNA level ( 50 IU/mL at week 4) were treated for 24 weeks, those with an early VR (EVR; no RVR but undetectable HCV-RNA level or 2-log 10 decrease at week 12) were randomized to 48 (group A) or 72 weeks of treatment (group B; peginterferon alfa-2a was reduced to 135 g/wk after week 48). Patients without an EVR continued treatment until week 72 if they had undetectable HCV-RNA levels at week 24. The primary end point was relapse; sustained VR (SVR; undetectable HCV-RNA level after 24 weeks of follow-up evaluation) was a secondary end point. RESULTS: Of 551 genotype 1/4 patients starting treatment, 289 were randomized to group A (N 139) or group B (N 150). The relapse rate was 33.6% in group A (95% confidence interval [CI], 24.8% 43.4%) and 18.5% in group B (95% CI, 11.9% 27.6%; P.0115 vs group A) and the SVR rate was 51.1% (95% CI, 42.5% 59.6%) and 58.6% (95% CI, 50.3% 66.6%; P.1), respectively. The overall SVR rate was 50.4% (278 of 551; 95% CI, 46.2% 54.7%), including 115 of 150 patients with an RVR treated for 24 weeks and 4 of 78 patients without an EVR. CONCLUSIONS: Extending therapy with peginterferon alfa-2a/ribavirin to 72 weeks decreases the probability of relapse in patients with an EVR. If they can be maintained on extended-duration therapy, SVR rates also may improve. The treatment of choice for chronic infection with hepatitis C virus (HCV) is the combination of pegylated interferon plus ribavirin, 1 which produces an overall cure rate (sustained virologic response [SVR]) of approximately 50% 60%. 2 4 The probability of eradicating HCV varies according to genotype; thus, it is recommended that the duration of therapy be chosen according to HCV genotype 48 weeks for difficult-to-cure patients infected with genotypes 1 or 4, and 24 weeks for the less difficult-to-cure patients infected with genotypes 2or3. 1 Pretreatment characteristics such as age, HCV-RNA level, and histologic diagnosis can be used to identify patients with a higher or lower probability of successful treatment outcome, although it is not possible to predict with certainty which individuals will achieve an SVR before treatment begins. Once treatment has begun, it is possible to identify patients most likely to respond and it has long been recognized that those with the most rapid decline in HCV-RNA level have the best chance of a cure. However, it is less clear what strategies may improve the chance of achieving an SVR in a given individual. Response-guided therapy is a dynamic approach to management of chronic hepatitis C that involves individualization of therapy on the basis of the virologic response at weeks 4 and 12 of treatment. Abbreviated therapy is appropriate for selected genotype 1 patients with a rapid virologic response (RVR) (HCV-RNA level, 50 IU/mL at week 4). 5,6 The shortened duration of therapy reduces the burden of treatment-related adverse events while maintaining the high rate of SVR. At the other extreme, an extended duration of therapy increases the chance of achieving an SVR, 7,8 and may be appropriate for slow responders patients who do not clear HCV RNA by week 12, but have a lower quantitative response to therapy (defined as a 2-log 10 decrease in HCV-RNA level over baseline) and are negative at 24 weeks. To better define the benefits of response-guided therapy, we designed a prospective, partly randomized study Abbreviations used in this paper: CI, confidence interval; EVR, early virologic response; PCR, polymerase chain reaction; RVR, rapid virologic response; SVR, sustained virologic response by the AGA Institute /10/$36.00 doi: /j.gastro

2 504 FERENCI ET AL GASTROENTEROLOGY Vol. 138, No. 2 to evaluate a treatment algorithm with peginterferon alfa-2a plus ribavirin in genotype 1 and 4 patients. Here we report the final results of treatment for patients without an RVR (HCV-RNA level, 50 IU/mL at week 4) but with an early virologic response (EVR) (HCV- RNA level, 600 IU/mL or 2 log 10 decrease from baseline at week 12) who were randomized to 48 or 72 weeks of treatment at week 12. We also report the final results of 72 weeks of treatment for patients who did not achieve an RVR or EVR. Each of these 3 treatment strategies then are compared with patients with an RVR who were allocated to 24 weeks of treatment, which has been reported elsewhere. 6 Materials and Methods The complete inclusion and exclusion criteria and study design have been published elsewhere. 6 Patients Patients eligible for the trial were aged 18 to 65 years, had detectable HCV RNA in serum by a commercial quantitative polymerase chain reaction (PCR) assay (COBAS Amplicor HCV Monitor Test, v2.0; Roche Diagnostics, Branchburg, NJ; limit of quantitation 600 IU/mL), increased serum alanine aminotransferase (ALT) levels, genotype 1 or 4 infection, and had not received previous interferon-based treatment for chronic hepatitis C. Patients also were required to have had a liver biopsy within the previous 6 months, the results of which were consistent with the diagnosis of chronic hepatitis C. Patients with bridging fibrosis or cirrhosis (Metavir stages 3 or 4) were eligible provided that they had compensated liver disease (Child Pugh class A). The maximum number of patients allowed to have cirrhosis was set at 20%. Fertile male and female patients enrolled in the trial were required to use 2 forms of effective contraception during treatment and for 6 months after completing or stopping treatment. Exclusion criteria included a neutrophil count of /L or less, a platelet count of /L or less, and a hemoglobin level of 130 g/l or less in men and 120 g/l or less in women. Patients also were ineligible if they had compromised renal function, as indicated by a serum creatinine level greater than 1.5 times the upper limit of normal, or an abnormal thyroid-stimulating hormone level. Patients with a history or evidence of a serious chronic or poorly controlled medical or psychiatric condition, those infected with human immunodeficiency virus or hepatitis B virus, and individuals who had received systemic immunomodulatory or antineoplastic therapy within the previous 6 months also were excluded. Pregnant or breastfeeding women and men with pregnant partners were ineligible. Study Design All patients initiated treatment with subcutaneous peginterferon alfa-2a (PEGASYS; Roche, Basel, Switzerland) 180 g/wk and oral ribavirin (COPEGUS 200-mg tablets; Roche) at a dosage of 1000 mg/day (for patients with a body weight 75 kg) or 1200 mg/day (for patients with a body weight 75 kg). The duration of treatment was determined on the basis of the virologic response to treatment at weeks 4 and 12 (ie, the results of a qualitative HCV-RNA test after 4 weeks of treatment and a quantitative HCV-RNA test after 12 weeks of treatment). Patients with an RVR at week 4 of treatment (HCV- RNA level, 50 IU/mL by qualitative PCR assay, COBAS Amplicor HCV Test, v2.0; Roche Diagnostics) were assigned to complete a total of 24 weeks of combination therapy (group D). Those with detectable HCV RNA at week 4 continued treatment and their serum HCV-RNA levels were reassessed at week 12. Patients with an EVR were randomized shortly after week 12 to complete a total of either 48 (group A) or 72 weeks (group B) of therapy. An EVR was defined as undetectable serum HCV RNA ( 600 IU/mL) by quantitative PCR or a 2-log 10 decrease or greater from baseline in serum HCV RNA by quantitative PCR. In some analyses patients were categorized as having a complete EVR (detectable HCV RNA at week 4, and undetectable HCV RNA by qualitative assay [ 50 IU/mL] at week 12) or a partial EVR (detectable HCV RNA at weeks 4 and 12, with a 2-log 10 decrease from baseline in serum HCV RNA at week 12). Patients without an EVR at week 12 (ie, 2-log 10 decrease in HCV RNA as compared with baseline) were treated until week 24; if HCV RNA became undetectable at week 24 then treatment was continued for a total of 72 weeks (group C). Patients with detectable HCV RNA ( 50 IU/mL) at week 24 were required to discontinue treatment. Those patients who entered a 72-week treatment group (group B or C) received a lower dose of peginterferon alfa-2a after week 48 (135 g/wk) than that administered during the first 48 weeks of treatment (180 g/wk). Stepwise dose reductions were allowed in the event of adverse events or laboratory abnormalities as described elsewhere. 6 Assessment and End Points Serum HCV-RNA levels were determined by the qualitative PCR assay at weeks 4, 12, 24, 48 (groups A, B, and C), and 72 (groups B and C) during treatment, and after 12 weeks (week 60 in group A, week 84 in groups B and C) and 24 weeks (week 72 in group A, week 96 in groups B and C) of untreated follow-up evaluation. HCV- RNA testing was performed in a central laboratory (Medical University of Graz, Harald H. Kessler).

3 February 2010 TREATMENT EXTENSION FOR SLOW RESPONDERS 505 If HCV RNA was detected with the qualitative PCR assay the sample was retested with the quantitative assay. Treatment success in the trial was defined as SVR (undetectable serum HCV RNA: 50/mL by qualitative PCR) at the end of the 24-week untreated follow-up phase (study week 72 in patients randomized to 48 weeks of treatment in group A and study week 96 in those randomized to 72 weeks of treatment in groups B and C). Relapse was defined as detection of HCV RNA during the 24-week untreated follow-up period in a patient who had undetectable HCV RNA at the end of the assigned treatment period. Safety Assessments As described previously, 6 safety and tolerability was assessed by physical examinations, laboratory tests, and reports of clinical adverse events. Statistical Analysis The primary efficacy end point was the difference in the virologic relapse rates among patients randomized to 48 or 72 weeks of treatment. Relapse was defined as detection of HCV RNA during the 24-week untreated follow-up period in a patient who had undetectable HCV RNA at the end of treatment. The planned sample size was based on the assumption that the relapse rate would be 30% in patients with an EVR randomized to 48 weeks of treatment and 15% in patients with an EVR randomized to 72 weeks of treatment, resulting in a necessary sample size of 242 patients with a 2-sided significance level of 5% and a statistical power of 80%. We originally assumed that 15% of patients would have an RVR at week 4 and that 80% of all patients enrolled would have an EVR (undetectable HCV RNA or a 2-log 10 decrease in HCV RNA) by week 12. A total enrollment of 440 patients was considered sufficient to meet the aims of the study. However, a protocol-planned interim analysis revealed a much higher than expected RVR rate (29%). 6 At that point the protocol was revised to accommodate the higher RVR rate (30%) and the overall planned enrollment was increased to 558 patients. All patients who received at least one dose of study drug were included in the intention-to-treat population. Patients without an HCV-RNA test result at the end of follow-up period were considered not to have achieved an SVR. All patients who received at least one dose of study medication and had at least one postbaseline safety assessment were included in the safety population. Study Conduct The institutional review board of each study center approved the protocol, and all patients provided written informed consent before any study procedures were conducted. The study was conducted according to the criteria of the Declaration of Helsinki. Results Patients were recruited at 13 study centers in Austria between March 2003 and July 2006 with the last patient completing follow-up evaluation in August A total of 551 genotype 1 or 4 patients received at least one dose of study medication, of whom 22 individuals dropped out before week 4, and a further 12 individuals dropped out before week 12 (including 1 who was HCV RNA negative at week 4). One patient who violated exclusion criteria (having HCV genotype 3a infection) was not included in this analysis. (One patient was screened before the deadline but initiated treatment after the deadline. This individual did not have an EVR at week 12 and was assigned to group C.) Thus, 517 patients eventually were assigned to 1 of the 4 treatment groups. Seven patients randomized at week 12 to group A (n 4) or B (n 3) did not continue treatment after randomization. One additional patient who had detectable HCV RNA at week 12 was assigned to group B, but was only treated for 24 weeks under the assumption by the investigator that the patient was in group D (he relapsed during follow-up evaluation). The flow of patients through all arms of the trial is illustrated in Supplementary Figure 1. Baseline characteristics overall and in the 3 treatment groups determined after 12 weeks of therapy are shown in Table 1. Patients randomized to groups A and B were well matched with respect to baseline characteristics (Table 1). More patients who did not achieve an EVR and were assigned to group C had a Metavir fibrosis stage of 3 or 4 on the pretreatment liver biopsy (Table 1). A total of 150 patients (27%) had undetectable HCV RNA ( 50 IU/mL) after 4 weeks of treatment and were assigned to complete a total of 24 weeks of combination therapy (group D). The outcome of group D has been reported elsewhere. 6 Of the patients with detectable HCV RNA at week 4 and who had at least a 2-log decrease in HCV RNA after 12 weeks of treatment, 289 were randomized to 48 weeks (group A) or 72 weeks (group B) of treatment. A further 78 patients did not achieve an EVR at week 12 and were assigned to 72 weeks of therapy (group C). The rates of discontinuation from treatment during the first 48 weeks of treatment were similar in groups A and B (Supplementary Figure 1). Between treatment weeks 48 and 72 a further 19 patients withdrew from treatment in group B. Only 6 of 78 patients (8%) in group C completed treatment most of the patients who withdrew from group C did so because of an insufficient therapeutic response. Outcomes in Patients Randomized to Groups A and B At the end of treatment a similar proportion of patients in group A (107 of 139; 77.0%) and in group B

4 506 FERENCI ET AL GASTROENTEROLOGY Vol. 138, No. 2 Table 1. Baseline Characteristics of Patients Enrolled in the Trial According to Treatment Group Assignment at Week 12 Group A Patients with an EVR Group B Patients without an EVR: group C All patients recruited a Total patients, n b 551 Male, n (%) 90 (64) 98 (65) 55 (71) 360 (65.3) Mean age, y SD Mean weight, kg SD Mean ALT level, IU SD Fibrosis stage 0 2, N (%) 111 (79.8) 121 (80.7) 52 (65.3) 435 (78.9) Fibrosis stage 3 4, N (%) 28 (20.2) 29 (19.3) 25 (33.7) 106 (21.1) Genotype 1, n (%) 127 (91.4) 134 (89.3) 70 (89.6) 483 (87.6) Genotype 4, n (%) 12 (8.6) 16 (10.7) 8 (10.5) 68 (12.4) HCV-RNA level, IU/mL 10 6 median, (range) 0.65 ( ) 0.7 ( ) 0.7 ( ) ( ) HCV-RNA level 400,000 IU, n (%) 34 (24.4) 35 (23.3) 14 (18.0) 168 (30.5) HCV-RNA level 400, ,000 IU, n (%) 52 (37.4) 49 (32.7) 35 (44.8) 195 (35.4) HCV-RNA level 800,000 IU, n (%) 53 (38.2) 66 (44.0) 29 (37.2) 188 (34.1) EVR, early virologic response defined as detectable serum HCV RNA at week 4 ( 50 IU/mL) and either undetectable HCV RNA ( 600 IU/mL) or 2-log 10 decrease in serum HCV RNA at week 12; No EVR, nonresponse defined as detectable serum HCV RNA at week 4 ( 50 IU/mL) and 2 log 10 decrease in serum HCV RNA at week 12; RVR, rapid virologic response defined as HCV RNA 50 IU/mL at week 4. a Includes data from 150 patients who had undetectable HCV RNA at week 4 of treatment. The outcomes of treatment in these individuals are published elsewhere. 6 b Includes 1 patient who initiated treatment after the deadline for initiating treatment. (110 of 150; 73.3%) had undetectable HCV RNA in serum (Table 2). The rate of virologic relapse between the end of treatment and end of follow-up evaluation (the primary efficacy end point) was significantly lower in patients randomized to 72 weeks (group B: 20 of 108; 18.5%; 95% confidence interval [CI], 11.9% 27.6%) of treatment as compared with 48 weeks of treatment (group A: 36 of 107; 33.6%; 95% CI, 24.8% 43.4%, ; P.0115; Figure 1). The lower relapse rate in patients treated for 72 weeks was offset by a higher overall drop-out rate in group B (48 of 150; 32.0%) as compared with group A (26 of 139; 18.7%). As a result, the overall rate of SVR in the intentionto-treat population was 51.1% (95% CI, 42.5% 59.6%) in patients randomized to group A and 58.6% (95% CI, 50.3% 66.6%) in patients randomized to group B (P.1). Based on a strict per-protocol that included only patients who completed the planned treatment duration, the SVR rates were 58.3% (71 of 127) in group A and 62.6% (77 of 123) in group B. When HCV-RNA negative patients in group B who stopped treatment at week 48 but completed follow-up evaluation were included in the calculation, the SVR rate was 64.7% (88 of 136) (P.1 vs group A). For genotype 1 patients, SVR rates were 56% (65 of 116) in group A, 65% (71 of 109) in group B, and 68% (81 of 120) in the modified group B (P.07). The baseline characteristics of patients in groups A and B are presented according to virologic response (SVR, relapse, or nonresponse) in Table 3. Patients with an SVR tended to be younger than those who experienced virologic relapse or nonresponse. Outcome by HCV Genotype, Baseline HCV-RNA Level, and Fibrosis Stage Relapse rates were consistently higher in patients randomized to 48 weeks of treatment in group A when only patients with HCV genotype 1 infection were considered and when grouped according to baseline HCV- RNA level ( 400,000 IU/mL or 400,000 IU/mL) or according to baseline Metavir fibrosis stage (F0 2 or F3 4) (Table 2). Consistent with the overall results of the trial, the relapse rate was significantly lower in genotype 1 infected patients randomized to group B (16.5%; 95% CI, 9.7% 25.4%) than to group A (33.0%; 95% CI 23.8% 43.8%; P.05) (Table 2). As a result, the rate of SVR was lower among genotype 1 patients in group A compared with patients in group B (51.2%; 95% CI, 42.2% 60.1% vs 60.4%; 95% CI, 51.6% 68.8%). Outcome by Virologic Response at Week 12 Among patients randomized to 48 (group A) or 72 weeks (group B) of treatment and who completed follow-up evaluation, a total of 87 and 93 individuals, respectively, had undetectable HCV RNA at week 12 (complete EVR). A further 52 and 57 patients, respectively, had detectable HCV RNA, but had a 2-log 10 or greater decrease in viral load (partial EVR) (Table 2). Although the end-of-treatment virologic response rates were similar in patients with a complete EVR in groups A and B (82.8% and 87.1%; Table 2), the rate of relapse was higher in group A (22.2% vs 13.6%). Thus, the rate of SVR was lower in patients with a complete EVR treated for 48 weeks compared with those treated for 72 weeks (64.4% vs 73.1%).

5 February 2010 TREATMENT EXTENSION FOR SLOW RESPONDERS 507 Table 2. Efficacy in Patients Who Were Assigned to Treatment at Week 12 Patients with an EVR Group A (N 139) n/n (%; 95% CI) Group B (N 150) n/n (%; 95% CI) Patients without an EVR: group C (N 78) a n/n (%; 95% CI) All patients EOT response 107/139 (77.0; ) 110/150 a (73.3; ) 6/78 (7.7; ) SVR rate (ITT) 71/139 (51.1; ) 88/150 b (58.7; ) 4/78 (5.1; ) Relapse 36/107 (33.6; ) c 20/108 d (18.5; ) 2/6 (33.3; ) Genotype 1 EOT response 97/127 (76.4; ) 96/134 e (71.6; ) 6/70 (8.6; ) SVR rate (ITT) 65/127 (51.2; ) 81/134 (60.4; ) 4/70 (5.7; ) Relapse 32/97 (33.0; ) f 16/97 (16.5; ) 2/6 (33.3; ) Genotype 4 EOT response 10/12 (83.3; ) 12/16 (75.0; ) 0/8 (0) SVR rate (ITT) 6/12 (50.0; ) 7/16 (43.8; ) 0/8 (0) Relapse 4/10 (40.0; ) 4/11 (36.4; ) Baseline HCV-RNA level 400,000 IU/mL EOT response 28/34 (82.3; ) 26/37 d (70.3; ) 3/16 (18.8; ) SVR rate (ITT) 20/34 (58.8; ) 24/37 a (64.9; ) 3/16 (18.8; ) Relapse 8/28 (28.6; ) g 2/26 (7.7; ) 0/3 Baseline HCV-RNA level 400,000 IU/mL EOT response 79/105 (75.2; ) 84/113 b (74.3; ) 3/62 (4.8; ) SVR rate (ITT) 51/105 (48.6; ) 64/113 (56.6; ) 1/62 (1.6; 0 8.7) Relapse 28/79 (35.4; ) 18/82 (21.9; ) 2/3 (66.7%) Baseline fibrosis stage F0-2 EOT response 80/107 (74.8; ) 88/116 e (75.9; ) 2/52 (3.8; ) SVR rate (ITT) 53/107 (49.5; ) 69/116 (59.5; ) 1/52 (1.9; ) Relapse 27/80 (33.7; ) 16/85 (18.8; ) 1/2 (50%) Baseline fibrosis stage F3-4 EOT response 27/32 (84.4; ) 22/34 h (64.7; ) 4/26 (15.4; ) SVR rate (ITT) 18/32 (56.3; ) 19/34 (55.9; ) 3/26 (11.5; ) Relapse 9/27 (33.3; ) 4/22 (18.2; ) 2/4 (50) Undetectable HCV RNA at week 12 (complete EVR) EOT response 72/87 (82.8; ) 81/93 b (87.1; ) SVR rate (ITT) 56/87 (64.4; ) 68/93 (73.1; ) Relapse 16/72 (22.2; ) 11/81 (13.6; ) 2-log 10 drop in HCV RNA at week 12, but detectable HCV RNA (partial EVR) EOT response 35/52 (67.3; ) 29/57 c (50.9; ) SVR rate (ITT) 15/52 (28.8; ) 20/57 (35.1; ) Relapse 20/35 (57.1; ) g 9/29 (31.0; ) EOT, end of treatment; ITT, intention to treat. a Includes 13 patients who stopped treatment after week 48. b Includes 11 patients who stopped treatment after week 48. c P.0115, group A vs group B. d Includes 2 patients who stopped treatment after week 48. e Includes 12 patients who stopped treatment after week 48. f P.01, group A vs group B. g P.05, group A vs group B. h Includes 1 patient who stopped treatment after week 48. The end-of-treatment response rate was higher in patients with a partial EVR who were randomized to 48 weeks as compared with 72 weeks of treatment (67.3% vs 50.9%) from group B who had undetectable HCV RNA at week 48; however, consistent with the pattern observed in patients with a complete EVR, the relapse rate was higher in those treated for 48 weeks (57.1% vs 31.0% in those treated for 72 weeks) and the SVR rate was somewhat lower in patients treated for 48 weeks (28.8% vs 35.1% in those treated for 72 weeks). Outcomes in Patients Assigned to Group C Nine of 78 patients (11.5%) without an EVR who were assigned to 72 weeks of treatment in group C became HCV-RNA negative by week 24 and continued therapy. Six of these individuals completed ther-

6 508 FERENCI ET AL GASTROENTEROLOGY Vol. 138, No. 2 Figure 1. Relapse rates in patients randomized to 48 or 72 weeks of treatment. apy, 4 of whom achieved an SVR (5.1%; 95% CI, 1.4% 12.6%). Overall Efficacy of the Treatment Strategy Overall, 278 of 551 patients (50.4%; 95% CI, ) who started treatment achieved an SVR including (71 [51.1%] in group A; 88 [58.7%] in group B; 4 [5.1%] in group C; and 115 [76.7%] in group D). Safety Among the 367 patients who were assigned to 48 or 72 weeks of treatment in groups A, B, or C, 75 serious adverse events were reported in 67 individuals (24 of 139, [17.3%] in group A; 34 of 150 [22.7%] in group B; and 9 of 78 [11.5%] in group C) (Table 4). Treatment with both peginterferon alfa-2a and ribavirin was discontinued for adverse events, at least temporarily, in 17 patients (12.2%) in group A, and in 9 patients in group B (6%). Study treatment was terminated because of serious adverse events in 6 patients in group A (4.3%), 8 patients in group B (5.3%), and 3 patients in groups C (3.9%). The mean hemoglobin concentration at the end of treatment was similar in groups A ( g/l), B ( g/l), and C ( g/l), as was the mean decrease over baseline in groups A ( g/l), B ( g/l), and C ( g/l). A decrease in hemoglobin concentration to less than 85 g/l at some time during treatment and follow-up evaluation was recorded in 1 individual in group A, 5 individuals in group B, and 1 individual in group C. Grade 4 neutropenia (neutrophils /L) occurred in 1 patient in group A during treatment. The dose of ribavirin was decreased because of laboratory abnormalities in 16 patients (11.5%) in group A (1 discontinued ribavirin, 8 received erythropoiesis stimulating agents), 19 patients (12.7%) in group B (5 received erythropoiesis-stimulating agents), and 9 patients in group C (1 discontinued ribavirin, 2 received erythropoiesis-stimulating agents). The dose of peginterferon alfa-2a was reduced because of laboratory abnormalities in 19 patients (13.7%) in group A (2 discontinued treatment, 7 received filgrastim) and 25 patients (16.7%) in group B (2 discontinued treatment, 11 received filgrastim). Discussion The present study was designed to evaluate a response-guided therapy algorithm that individualized treatment on the basis of virologic response at weeks 4 and 12 of therapy. We previously reported an SVR rate of 77% in patients with an RVR at week 4 who were assigned (not randomized) to complete 24 weeks of treatment. 6 Overall, 50.4% of genotype 1 or 4 patients achieved an SVR with individualized therapy in the present study. The main finding of this study is that an extended 72- week regimen with peginterferon alfa-2a plus ribavirin significantly reduces the rate of virologic relapse, compared with the standard 48-week regimen, in genotype 1 or 4 patients who have detectable HCV RNA at week 4 of treatment and who subsequently achieve an EVR at week 12. The rate of relapse was 18.5% in those assigned to the extended regimen and 33% in those assigned to the standard regimen. Table 3. Baseline Characteristics of Patients Randomized to 48 (Group A) or 72 (Group B) Weeks of Treatment According to Treatment Outcome Group A (N 139) Group B (N 150) SVR (n 71) Relapse (n 36) Nonresponse (n 20) SVR (n 88) Relapse (n 20) Nonresponse (n 28) Mean age, y SD Mean weight, kg SD Fibrosis grade 0 2, N (%) 42 (59.2) 27 (75) 10 (50) 53 (60.2) 12 (60.0) 20 (71.4) Fibrosis grade 3 4, N (%) 29 (40.9) 9 (25) 10 (50) 35 (39.8) 8 (40.0) 8 (28.6) Genotype 1, n (%) 65 (91.6) 32 (88.9) 19 (95) 81 (92.1) 16 (80.0) 24 (85.7) Genotype 4, n (%) 6 (8.5) 4 (11.1) 1 (5) 7 (7.9) 4 (20) 4 (14.3) HCV-RNA level 400,000 IU, n (%) 21 (29.6) 8 (22.2) 3 (15) 24 (27.3) 3 (15) 7 (25) HCV-RNA level 400, ,000 IU, n (%) 24 (33.8) 13 (36.1) 9 (45) 31 (35.2) 6 (30) 8 (28.5) HCV-RNA level 800,000 IU, n (%) 26 (36.6) 15 (41.7) 8 (40) 33 (35.7) 11 (55) 13 (46.4)

7 February 2010 TREATMENT EXTENSION FOR SLOW RESPONDERS 509 Table 4. Serious Adverse Events Group A (N 139) Group B a (N 150) Group C (N 78) SAEs occurring between baseline and end of study, n SAEs occurring after week (time of group assignment), n Patients with at least 1 SAE after 24 (17.3) 34 (22.7) 9 (11.5) week 12, n (%) Individual SAEs by body system occurring after week 12, n Hematologic 1 (pancytopenia) 2 (anemia) 0 Gastrointestinal 5 (pancreatitis [1], cholecystitis [1], 2 (antral gastritis) 2 (gastroenteritis) appendicitis [1], epigastric pain [2]) Infection 2 (urinary tract, gastrointestinal tract), 1 acute hepatitis B 8 (sepsis, respiratory tract, urinary tract [2], other site [3], HIV infection [1]) 2 (respiratory tract, urinary tract) Pulmonary 3 pneumonia 5 (alveolitis, pneumonia, sarcoidosis, tuberculosis, COPD) Neuropsychiatric 5 (alcohol abuse, seizures, suicide 4 (drug abuse, suicide attempt, vertigo [2]) 2 (depression [2]) attempt, depression [2]) Cardiovascular 3 (syncope, deep vein thrombosis [2]) 3 (subclavian arterial stenosis, coronary heart disease [2]) 1 (complex tachycardia) Skin 1 1 (maculopapular exanthema) 0 Other 2 (hearing loss, thyroiditis) 16 (accident [1], ulcus cruris [1], dyspnea [1], mononeuritis [1], pregnant partner b [3], surgery [9]) 2 (arthralgia, disc prolapse) COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; SAE, serious adverse event. a Two patients in group B stopped treatment because of an SAE after week 48 (1 because of HIV infection and 1 because of an abscess that required surgery) b Patients refused to stop treatment. All 3 babies were healthy. The rate of SVR also was higher (by 7.5%) in patients randomized to extended therapy, although the difference was not statistically significant. The results of this trial are generally in agreement with those of other randomized trials that have evaluated an extended 72-week regimen of peginterferon alfa-2a plus ribavirin in treatment-naive patients with chronic HCV infection. 7 9 Collectively, these trials show that extending therapy is of benefit in a select subgroup of slow or partial early virologic responders, although when comparing the results it is important to consider methodologic differences across the various trials. Berg et al 7 randomized genotype 1 patients at baseline to either 48 or 72 weeks of treatment and the respective SVR rates were 53% and 54%. The trial did not show a significant difference in favor of extended therapy, presumably because the 2 treatment groups comprised a mixture of rapid and slow virologic responders. When the analysis was restricted to patients who remained HCV-RNA positive at week 12 (ie, true partial early responders), the extended regimen was shown to have produced a significantly higher SVR rate (29% vs 17% in those randomized to 48 weeks). Sanchez-Tapias et al 8 randomized patients who failed to achieve an RVR at week 4 of treatment to either 48 or 72 weeks of treatment regardless of genotype ( 90% of randomized patients were infected with genotype 1). Extended therapy did prove beneficial in this trial SVR rates of 32% and 45% were obtained in the 48- and 72-week treatment groups (P.01). It is important to acknowledge that these 2 trials used a low fixed dose of ribavirin (800 mg/day), 7,8 which, in the case of genotype 1 or 4 patients, has been shown to be inferior to the higher standard dose (1000 or 1200 mg/day) used in the present trial. 4 Pearlman et al 9 also showed that an extended 72-week regimen significantly increased SVR rates (38% vs 18% in patients randomized to 48 weeks; P.026) by reducing the rate of relapse during follow-up evaluation. Although that study was smaller than the present study, its ability to show the superiority of extended treatment likely derived from the selection of only true slow responders (those with an EVR and detectable HCV RNA at week 12 and undetectable HCV RNA at week 24 of treatment) to complete 48 or 72 weeks of treatment with peginterferon alfa-2b 1.5 g/wk plus ribavirin 800 to 1400 mg/day. These investigators initiated treatment in 361 genotype 1 patients, among whom 112 patients (31%) were confirmed to have a slow response at week 12. In contrast, we initiated treatment in 551 patients and observed an overall slow response (partial EVR) rate of 14%. The reason for the larger percentage of slow responders in the former study 9 likely is related to the patient population. All patients in the study by Pearlman et al 9 had genotype 1 infection, 26% had advanced fibrosis, and nearly half were

8 510 FERENCI ET AL GASTROENTEROLOGY Vol. 138, No. 2 of African American ethnicity, a group with relatively inferior response rates. Ide et al 10 recently showed that extended therapy might be beneficial in genotype 1b patients with a high baseline viral load. The SVR rate in 56 patients randomized to a standard 48-week course of treatment with peginterferon alfa-2b plus ribavirin was 36%, which was lower than the 53% SVR rate obtained in 57 patients randomized to complete 44 weeks of treatment after their first HCV-RNA negative test result (ie, 48 weeks in those with an RVR, 56 weeks in those with a complete EVR, and 68 weeks in those who did not become negative until week 24); however, the difference was not statistically significant (P.07). The greatest difference in SVR rates in favor of extended therapy was obtained in a small group of 20 slow responders who became HCV-RNA negative between weeks 16 and 24 (78% vs 11%). The small sample size in this trial precludes one from drawing definite conclusions about the value of this strategy. A secondary analysis in patients with partial EVR in our study confirmed that the largest reduction in relapse rates was obtained in this subgroup. However, a reduction in the rate of relapse with extended therapy was not restricted to those with a partial EVR relapse was significantly lower in all patients with an EVR treated for 72 weeks. This finding suggests that week 12 may not be the optimal time point at which to identify patients who may benefit from extended treatment. A preliminary analysis of data from a subgroup of patients enrolled at the largest center in our study (Internal Med 3, University of Vienna, Austria) indicated that patients with detectable HCV at week 8 benefited most from treatment extension, independent of the HCV results at week This observation is consistent with the results of the study of treatment individualization by Mangia et al. 12 In that study, treatment-naive genotype 1 patients were randomized at baseline to a standard 48-week regimen or an individualized regimen of peginterferon plus ribavirin. Those randomized to the individualized regimen were assigned to complete a total of 24, 48, or 72 weeks of combination therapy if they became HCV-RNA negative at weeks 4, 8, or 12, respectively. Among those randomized to the standard or individualized regimens, there was no significant difference in the overall SVR rate (45.1% vs 48.8%) or relapse rate (19.1% vs 19.4%). The rate of RVR was 29% in our trial compared with 27% in the trial by Mangia et al. 12 Similarly, the respective SVR rates in rapid responders were 77% and 80% and the overall rates of SVR were 49% and 50% in the 2 trials. Patients without an RVR who had undetectable HCV RNA at week 8 had the highest likelihood of achieving an SVR with 48 weeks of combination therapy. The potential problem with having SVR as an end point in a trial with different treatment durations is that a difference in SVR rates may be obscured by a differential rate of voluntary withdrawal. Indeed, this has been observed in some but not all studies of extended therapy including the present study rates of voluntary withdrawal are higher in patients randomized to extended therapy than in those randomized to the standard 48- week regimen. The study by Pearlman et al 9 is an exception, the withdrawal rate was similar in patients randomized to extended and standard treatment durations. In our trial, most patients were followed up until week 96, and a week-96 response was available for the intentionto-treat analysis. The choice of nonrelapse rather than SVR as the primary efficacy end point allowed us to focus exclusively on the efficacy of extended therapy in our analysis. In addition to showing that extended therapy significantly reduced relapse in nonrapid responders who achieve an EVR at week 12, we have confirmed that the probability of eradicating HCV is low in patients who do not achieve an EVR, even when treatment is extended from 48 to 72 weeks. The SVR rate in non-evr patients (group C) was 5%, which reinforces established stopping rules and indicates that these individuals have the greatest need for new therapies. When considering extended therapy it is important to consider safety in addition to efficacy. In this regard, it is reassuring that the number of patients withdrawn for adverse events was low overall and similar in the 2 treatment groups (6 patients in the 48-week group and 8 patients in the 72-week group). This finding is also consistent with those of previous studies that have compared 48- and 72-week regimens of peginterferon alfa-2a plus ribavirin. 7 9,12 Extended treatment is thus more effective than, and has a safety profile similar to, the standard regimen in slow virologic responders (and in previous nonresponders 13 ); however, the potentially higher rates of voluntary withdrawal indicate that careful patient selection, and attention to education and motivation, is necessary to help patients complete 72 weeks of treatment. In the present study, in an attempt to decrease drop-out rates beyond week 48, the protocol specified that the dose of peginterferon alfa-2a be reduced from 180 g/wk to 135 g/wk after week 48 in those receiving an extended regimen. This dosage was evaluated during the development of peginterferon alfa-2a and was shown to have a similar safety and efficacy profile to the higher standard dose. 14 The higher dosage regimen now has been evaluated extensively in patients randomized to 72-week extended regimens in a series of clinical trials, 7,8,13 and there appears to be no reason to lower the dose in those assigned to an extended regimen. Another strength of our study was that it included a sizeable number of patients with genotype 4. Kamal et al 15 also examined individualized therapy for patients infected with HCV genotype 4. SVR rates of 86% and 76% were obtained in patients who were HCV-RNA negative at weeks 4 and 12 and who were treated for a total of 24 and 36 weeks, respectively. Those with detectable HCV

9 February 2010 TREATMENT EXTENSION FOR SLOW RESPONDERS 511 RNA at week 12 completed 48 weeks of treatment, among whom the SVR rate was 56%. 15 The results of the present study and the various trials of treatment extension and individualization show that it is feasible to adjust the duration of treatment on the basis of the virologic response during the first 12 weeks of treatment. Although this strategy is effective in reducing the relapse rate, only one study (Pearlman et al 9 ) has shown that this strategy improves the overall SVR rate. One reason is that no study of extended therapy has been powered to detect a difference in SVR rate that is less than 10%. Di Martino et al 16 conducted a meta-analysis of studies that have compared different treatment durations and found that patients infected with genotype 1 and who have a slow virologic response derived significant benefit from therapy extension to 72 weeks (odds ratio, 1.82 vs 48 wk; 95% CI, ). However, the individual studies included in the analysis cannot be compared directly. The ribavirin dosage regimens differed, and the timing and criteria for randomization to different treatment durations varied widely. In our study patients with an EVR (complete and partial EVR) were randomized to different treatment durations. Because patients with a complete EVR have a much higher probability of achieving an SVR than patients with a partial EVR, 17 a larger group of patients with a partial EVR may be required in a study such as this to show a statistically significant improvement in SVR rates with extended treatment. Data handling rules used in clinical trials also may contribute to the difficulty in showing significantly higher SVR rates with extended therapy. Patients randomized to extended regimens have a higher chance of discontinuing therapy and thus being counted as treatment failures in an intention-to-treat analysis, if they are not followed up after treatment withdrawal. If a slow responder can be kept on therapy for an extended duration, not only would the probability of relapse decrease, but the probability of achieving an SVR also might improve. The advantage of optimizing treatment duration in slow virologic responders is that it maximizes an individual patient s probability of achieving an SVR and minimizes the probability of adverse events from overexposure or unnecessary exposure to treatment. In the subset of patients with a slow virologic response, extended therapy increases the probability of viral eradication by minimizing the likelihood of relapse. When considering whether to adopt response-guided therapy, policy makers need to consider economic variables in addition to efficacy. The overall results of our study show that 30% of patients infected with genotype 1 or 4 achieve an RVR and are eligible for abbreviated therapy. In contrast, the proportion of patients with a partial EVR at week 12, those most likely to benefit from extended therapy comprised approximately 20% of the overall population. Thus, individualization of therapy should reduce the cost of treatment because more patients would be eligible for abbreviated therapy than for extended therapy. As noted earlier there was little difference in the incidence of adverse events between patients assigned to extended and standard treatment durations, so the costs associated with adverse effects would be similar regardless of treatment duration. However, the higher drop-out rate in those assigned to extended therapy has the potential to increase costs because patients who do not complete therapy are less likely to be cured. For this reason, it may be worthwhile to devote additional resources to help keep patients on therapy. An economic analysis of the impact of an extended 72-week course of treatment with peginterferon alfa-2a plus ribavirin in a cohort of patients with a slow virologic response showed that this strategy could be cost effective. 18 If a long time horizon is incorporated into economic analyses, then individualized therapy also should reduce costs by preventing the devastating effects of progressive liver disease (decompensated cirrhosis). In conclusion, our results show that response-guided therapy is an effective strategy for optimizing the treatment of patients infected with HCV genotype 1 or 4. Among patients without an RVR, but who have an EVR, extending therapy with peginterferon alfa-2a plus ribavirin to 72 weeks decreases the probability of relapse and increases the chance of achieving an SVR. The rate of voluntary withdrawal was higher in patients assigned to the 72-week regimen; thus, careful patient selection, education, and support is needed to minimize the probability of premature drop-out and maximize the probability of achieving an SVR. Further studies are needed to identify those patients who benefit most from extended therapy, including prospectively assessing the viral response at week 8. Appendix Members of the Austrian Hepatitis study group included the following: Graz: Bernhard Bauer, Nicole Hueter, Günther J. Krejs, Csilla Putz-Bankuti, Rudolf Stauber, Barbara Sutter, and Gernot Zollner; Innsbruck: Wolfgang Jessner, Karin Nachbaur, Bernhard Nilica, and Wolfgang Vogel; Krems: Hartwig Bognar; Linz: Franz Hackl, Rainer Hubmann, Andreas Maieron, Andreas Raml, and Sabine Metz; Ried: Björn Jagdt and Fritz Renner; Oberpullendorf: Felix Stockenhuber; Oberndorf: Christian Datz and Hildegard Doppelmayr; Salzburg: Michael Strasser; Vienna: Susanne Bach, Martin Bischof, Harald Brunner, Barbara Bognar, Ulrike Bergholz, Emina Dulic-Lakovic, Daniela Ferenci-Foerster, Peter Ferenci, Elisabeth Formann, Alfred Gangl, Michael Gschwantler, Calin Gurguta, Gerold Hartmann, Brigitte Hellmich, Harald Hofer, Hermann Laferl, Karin Mittischek, Christian Müller, Parnaz Ordubadi, Ali Reza Pourbyiabani, Markus Peck-Radosavljevic, Martha Rosenbeiger, Kurt Schütze, Thomas-Matthias Scherzer, Katharina Staufer,

10 512 FERENCI ET AL GASTROENTEROLOGY Vol. 138, No. 2 Petra Steindl-Munda, Anika Stückler, Christoph Wenisch, and Kerstin Zinober; Villach: Rudolf Foditsch; Wels: Peter Knoflach and Bernhard Stadler. Supplementary Materials Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at and at doi: /j.gastro References 1. Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49: Manns MP, McHutchison JG, Gordon SC, 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: Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347: Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferonalpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140: Jensen DM, Morgan TR, Marcellin P, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006;43: Ferenci P, Laferl H, Scherzer TM, et al. Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 2008;135: Berg T, von Wagner M, Nasser S, et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 2006;130: Sanchez-Tapias JM, Diago M, Escartin P, et al. Peginterferonalfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology 2006;131: Pearlman BL, Ehleben C, Saifee S. Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis C genotype 1-infected slow responders. Hepatology 2007;46: Ide T, Hino T, Ogata K, et al. A randomized study of extended treatment with peginterferon alpha-2b plus ribavirin based on time to HCV RNA negative-status in patients with genotype 1b chronic hepatitis C. Am J Gastroenterol 2009;104: Scherzer TM, Kerschner H, Beinhardt S, et al. Week 8 HCV RNA is the optimal predictor of relapse in HCV genotype 1/4 patients without a rapid virological response randomised to 48 or 72 weeks of peginterferon alfa-2a plus ribavirin (abstr). J Hepatol 2009;50(Suppl 1):S Mangia A, Minerva N, Bacca D, et al. Individualized treatment duration for hepatitis C genotype 1 patients: a randomized controlled trial. Hepatology 2008;47: Jensen DM, Marcellin P, Freilich B, et al. Re-treatment of patients with chronic hepatitis C who do not respond to peginterferonalpha2b: a randomized trial. Ann Intern Med 2009;150: Pockros PJ, Carithers R, Desmond P, et al. Efficacy and safety of two-dose regimens of peginterferon alpha-2a compared with interferon alpha-2a in chronic hepatitis C: a multicenter, randomized controlled trial. Am J Gastroenterol 2004;99: Kamal SM, El Kamary SS, Shardell MD, et al. Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response. Hepatology 2007;46: Di Martino V, Richou C, Thevenot T, et al. Modulations of peginterferon plus ribavirin duration according to HCV-genotype and virologic response at W4 and W12: meta-analyses of RCTs with individual data (abstr). Hepatology 2008;48:404A 405A. 17. Lee SS, Ferenci P. Optimizing outcomes in patients with hepatitis C virus genotype 1 or 4. Antivir Ther 2008;13(Suppl 1): Nakamura J, Toyabe SI, Aoyagi Y, et al. Economic impact of extended treatment with peginterferon alpha-2a and ribavirin for slow hepatitis C virologic responders. J Viral Hepat 2008;15: Received August 9, Accepted October 21, Reprint requests Address requests for reprints to: Professor Dr Peter Ferenci, Universitätsklinik für Innere Medizin III, AKH Wien, Waehringer Guertel 18-20, A 1090 Wien, Austria. peter.ferenci@meduniwien.ac.at; fax: (43) Acknowledgments The authors would like to thank Blair Jarvis (Health Interactions, Ltd, UK) who provided editorial support on behalf of Roche. The statistical analysis of the entire data sets pertaining to efficacy (specifically primary and major secondary efficacy end points) and safety (specifically serious adverse events as defined in federal guidelines) have been confirmed independently by a biostatistician (Dr A. Klingler, Assign Data Management and Biostatistics GmbH, Innsbruck, Austria) who is not employed by the corporate entity. Professor Dr Peter Ferenci had full access to all data and takes full responsibility for the veracity of the data and analysis. The virologic analysis was performed by Dr Harald Kessler. This study is registered as follows: patient/trials/trial html. Conflicts of interest These authors disclose the following: Peter Ferenci serves on advisory boards, is a speaker and investigator for, and also has received research grants from F. Hoffmann-La Roche; Michael Gschwantler, Wolfgang Vogel, Petra Steindl-Munda, and Rudolf Stauber serve as a speaker for F. Hoffmann-La Roche; and Karin Löschenberger is an employee of F. Hoffmann-La Roche. The remaining authors disclose no conflicts. Funding This study was made possible by an unrestricted grant by Roche Austria. Roche Austria had no role in the study design; in the collection, analysis, and interpretation of data; and in the decision to submit the report for publication. The Main Association (Hauptverband) of the Austrian Health Insurers paid for the study medication.