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1365 ACUTE KIDNEY INJURY NETWORK (AKIN) CRITERIA FOR ACUTE RENAL FAILURE PREDICTS OUTCOME IN HOSPITALIZED CIRRHOTIC PATIENTS. A PROSPECTIVE STUDY
LATE-BREAKING ABSTRACTS changes in ribavirin-preferred G–A and C–T nucleotide transitions throughout the full HCV genome during ribavirin monotherapy in comparison to placebo (p = 0.001, Figure 1). These changes were mainly observed in the core to NS4B regions (Figure 1) and varied within the different intervals during ribavirin monotherapy (baseline to day 7, day 21 and week 6). Conclusions: Ribavirin has a strong mutagenic effect on the HCV genome during monotherapy in comparison with placebo. 1365 ACUTE KIDNEY INJURY NETWORK (AKIN) CRITERIA FOR ACUTE RENAL FAILURE PREDICTS OUTCOME IN HOSPITALIZED CIRRHOTIC PATIENTS. A PROSPECTIVE STUDY 1,2,3 C. Fagundes1,2,3 , M. Guevara1,2,3 , E. Garc´ıa-Lopez ´ , G.H. Pereira1,2,3 , E. Sola` 1,2,3 , E. Rodr´ıguez1,2,3 , M. Pavesi1,2,3 , V. Arroyo1,2,3 , P. Gines ` 1,2,3 . 1 2 3 Liver Unit, University of Barcelona, IDIBAPS, CIBER de Enfermedades Hep´ aticas y Digestivas (CIBERehd), Barcelona, Spain E-mail: [email protected] Renal Failure in cirrhosis is currently defined as serum creatinine greater than 1.5 mg/dL. This definition has two shortcomings: (1) it represents a very low glomerular filtration rate (GFR), and (2) it may not detect significant changes in GFR because it does not take into account variations in creatinine values. Recently, the AKIN criteria, which consider renal failure as an increase in serum creatinine ≥0.3 mg/dL or a ≥50% increase compared to baseline within 48 hours, have been described. The usefulness of these criteria in cirrhosis has not been investigated. Three-hundred consecutive patients admitted for complications of cirrhosis were included in a prospective study aimed at assessing the value of the AKIN criteria in predicting outcome. During hospitalization, 88 patients (29%) developed renal failure according to AKIN criteria. Three-month survival of these patients was 38%, compared with 87% of patients who did not develop renal failure (p < 0.01). When the AKIN criteria were combined with the current definition of renal failure, patients meeting the AKIN criteria in whom serum creatinine reached a peak value of >1.5 mg/dL (n = 60) had a survival significantly lower compared to that of patients with a peak value ≤1.5 mg/dL (n = 28) (29% vs 58%, respectively; p = 0.026). Out of the 300 patients, 30 patients had serum creatinine >1.5 mg/dL but did not meet the AKIN criteria. Three-month survival of these patients was 80%. On multivariate analyses, both AKIN and current criteria were independent predictors of survival, but models using AKIN criteria had higher odds ratio and predictive capacity than those using current criteria (odds ratios: 9.44 vs. 4.87, and area under ROC curve 0.81 (95% CI 0.75–0.88) vs. 0.76 (0.7–0.83), respectively). In conclusion, the development of renal failure using the AKIN criteria is frequent and associated with poor outcome in hospitalized patients with cirrhosis, even when small increases in serum creatinine are considered. The AKIN criteria have high sensitivity in identifying patients at increased risk of death. If these results are confirmed in larger studies, the AKIN criteria for definition of acute renal failure in hospitalized cirrhotic patients should be used instead of the current criteria.
1366 HIGH SUSTAINED VIROLOGIC RESPONSE (SVR) AMONG GENOTYPE 1 PREVIOUS NON-RESPONDERS AND RELAPSERS TO PEGINTERFERON/RIBAVIRIN WHEN RE-TREATED WITH BOCEPREVIR (BOC) PLUS PEGINTERFERON ALFA-2A/RIBAVIRIN S. Flamm1 , E. Lawitz2 , I. Jacobson3 , R. Rubin4 , M. Bourliere5 , C. Hezode6 , J. Vierling7 , C. Niederau8 , M. Sherman9 , V. Goteti10 , R. Vilchez10 , C. Brass10 , J. Albrecht10 , F. Poordad11 . 1 Northwestern Feinberg School of Medicine, Chicago, IL, 2 Alamo Medical Research, SanAntonio, TX, 3 Weill Cornell Medical College, New York, NY, 4 Liver Center of Atlanta, Atlanta, GA, USA; 5 Fondation Hˆ opital Saint Joseph, Marseille, 6 A.P.H. Paris, Hopital Henri Mondor, Cr´eteil Cedex, France; 7 Baylor College of Medicine, Houston, TX, USA; 8 St. Josef-Hospital Oberhausen, Oberhausen, Germany; 9 Toronto General Hospital, Toronto, ON, Canada; 10 Merck Sharp & Dohme Corp., Whitehouse Station, NJ, 11 Cedars-Sinai Medical Center, Los Angeles, CA, USA E-mail: s-fl[email protected] Background: The RESPOND-2 trial demonstrated significantly increased SVR for prior non-responders and relapsers when BOC was added to peginterferon alfa-2b/ribavirin (66% vs. 21% control). We assessed SVR with BOC combined with peginterferon alfa-2a (PEG2a) and ribavirin (R) in patients who met identical entry criteria. Methods: This double-blind, placebo-controlled trial randomized 201 genotype-1 relapsers and non-responders to two arms (1:2 ratio, Table). Arm 1 (control) received a 4-week lead-in of PEG2a/R followed by placebo + PEG2a/R for 44 weeks. Arm 2 received a 4-week lead-in of PEG2a/R followed by BOC + PEG2a/R for 44 weeks. Therapy was discontinued if HCV-RNA was detectable (undetectable HCV RNA <9.3 IU/mL [Roche TaqMan, LLD]) at week 12. Primary endpoint: SVR 24-weeks post-therapy. Results: Baseline demographics: 70% male; 10% black; 16% cirrhotic. The addition of BOC after a 4-week lead-in with PEG2a/R significantly increased SVR: 21% in Arm 1 vs. 64% in Arm 2 (p < 0.0001). SVR for patients with poor interferon responsiveness (<1-log10 decrease in HCV-RNA after 4-week lead-in) was 0% in Arm 1 and 39% in Arm 2. For patients responsive to interferon (≥1-log10 decrease in HCV-RNA after 4-week lead-in), SVR was 25% in Arm 1 and 71% in Arm 2. Discontinuation due to adverse events (AEs) occurred in 4% and 17% of patients in Arms 1 and 2. Rates of serious AEs were 10% in Arm 1 and 13% in Arm 2. The frequencies of anemia (<10.0 g/dL) in Arms 1 and 2 were 27% vs. 49%; neutropenia (WHO grade 3–4 [<750/mm3 ]) 21% vs. 43%; erythropoietin use 30% vs. 47%. There were no serious AEs due to anemia and one discontinuation due to anemia (Arm 2). Table 1
End of treatment response Relapse rates SVR
Previous non-responders‡ Previous relapsers‡
Poor interferon responders§ Interferon responders§
Arm 1 (Control) PEG2a [180 mg weekly) + R [1000–1200 mg/day, weight based) 48 weeks N = 67
Arm 2 PEG2a [180 mg weekly) + R [1000–1200 mg/day, weight based] for 4 weeks (lead-in) then PEG2a/R + 800 mg BOC TID for 44 weeks N = 134
42% (28/67) 33% (7/21) 21% (14/67)
74% (99/134) 12% (11/95) 64% (86/134)*
5% (1/20)
47% (17/36)
28% (13/47)
70% (69/98)
0% (0/9)
39% (7/18)
25% (14/57)
71% (79/112)
*P < 0.0001 vs control. ‡ Eligible patents demonstrated previous partial interferon responsiveness. Previous non-responders were defined as ≥2-log10 HCV RNA decrease by week 12 of prior therapy but with detectable HCV-RNA throughout the course of therapy. Previous relapsers had undetectable HCV-RNA at end of prior therapy without subsequent attainment of a sustained virologic response. § One patient in Arm 1 and 4 patients in Arm 2 had missing week 4 data.
Conclusions: Lead-in with PEG2a and ribavirin followed by addition of boceprevir resulted in high SVR rates similar to that observed using an identical treatment regimen with peginterferon alfa-2b. Therapy was generally well-tolerated. These are the first large trials Journal of Hepatology 2011 vol. 54 | S535–S546
S541
1366 HIGH SUSTAINED VIROLOGIC RESPONSE (SVR) AMONG GENOTYPE 1 PREVIOUS NON-RESPONDERS AND RELAPSERS TO PEGINTERFERON/RIBAVIRIN WHEN RE-TREATED WITH BOCEPREVIR (BOC) PLUS PEGINTERFERON ALFA-2A/RIBAVIRIN S. Flamm1 , E. Lawitz2 , I. Jacobson3 , R. Rubin4 , M. Bourliere5 , C. Hezode6 , J. Vierling7 , C. Niederau8 , M. Sherman9 , V. Goteti10 , R. Vilchez10 , C. Brass10 , J. Albrecht10 , F. Poordad11 . 1 Northwestern Feinberg School of Medicine, Chicago, IL, 2 Alamo Medical Research, SanAntonio, TX, 3 Weill Cornell Medical College, New York, NY, 4 Liver Center of Atlanta, Atlanta, GA, USA; 5 Fondation Hˆ opital Saint Joseph, Marseille, 6 A.P.H. Paris, Hopital Henri Mondor, Cr´eteil Cedex, France; 7 Baylor College of Medicine, Houston, TX, USA; 8 St. Josef-Hospital Oberhausen, Oberhausen, Germany; 9 Toronto General Hospital, Toronto, ON, Canada; 10 Merck Sharp & Dohme Corp., Whitehouse Station, NJ, 11 Cedars-Sinai Medical Center, Los Angeles, CA, USA E-mail: s-fl[email protected] Background: The RESPOND-2 trial demonstrated significantly increased SVR for prior non-responders and relapsers when BOC was added to peginterferon alfa-2b/ribavirin (66% vs. 21% control). We assessed SVR with BOC combined with peginterferon alfa-2a (PEG2a) and ribavirin (R) in patients who met identical entry criteria. Methods: This double-blind, placebo-controlled trial randomized 201 genotype-1 relapsers and non-responders to two arms (1:2 ratio, Table). Arm 1 (control) received a 4-week lead-in of PEG2a/R followed by placebo + PEG2a/R for 44 weeks. Arm 2 received a 4-week lead-in of PEG2a/R followed by BOC + PEG2a/R for 44 weeks. Therapy was discontinued if HCV-RNA was detectable (undetectable HCV RNA <9.3 IU/mL [Roche TaqMan, LLD]) at week 12. Primary endpoint: SVR 24-weeks post-therapy. Results: Baseline demographics: 70% male; 10% black; 16% cirrhotic. The addition of BOC after a 4-week lead-in with PEG2a/R significantly increased SVR: 21% in Arm 1 vs. 64% in Arm 2 (p < 0.0001). SVR for patients with poor interferon responsiveness (<1-log10 decrease in HCV-RNA after 4-week lead-in) was 0% in Arm 1 and 39% in Arm 2. For patients responsive to interferon (≥1-log10 decrease in HCV-RNA after 4-week lead-in), SVR was 25% in Arm 1 and 71% in Arm 2. Discontinuation due to adverse events (AEs) occurred in 4% and 17% of patients in Arms 1 and 2. Rates of serious AEs were 10% in Arm 1 and 13% in Arm 2. The frequencies of anemia (<10.0 g/dL) in Arms 1 and 2 were 27% vs. 49%; neutropenia (WHO grade 3–4 [<750/mm3 ]) 21% vs. 43%; erythropoietin use 30% vs. 47%. There were no serious AEs due to anemia and one discontinuation due to anemia (Arm 2). Table 1
End of treatment response Relapse rates SVR
Previous non-responders‡ Previous relapsers‡
Poor interferon responders§ Interferon responders§
Arm 1 (Control) PEG2a [180 mg weekly) + R [1000–1200 mg/day, weight based) 48 weeks N = 67
Arm 2 PEG2a [180 mg weekly) + R [1000–1200 mg/day, weight based] for 4 weeks (lead-in) then PEG2a/R + 800 mg BOC TID for 44 weeks N = 134
42% (28/67) 33% (7/21) 21% (14/67)
74% (99/134) 12% (11/95) 64% (86/134)*
5% (1/20)
47% (17/36)
28% (13/47)
70% (69/98)
0% (0/9)
39% (7/18)
25% (14/57)
71% (79/112)
*P < 0.0001 vs control. ‡ Eligible patents demonstrated previous partial interferon responsiveness. Previous non-responders were defined as ≥2-log10 HCV RNA decrease by week 12 of prior therapy but with detectable HCV-RNA throughout the course of therapy. Previous relapsers had undetectable HCV-RNA at end of prior therapy without subsequent attainment of a sustained virologic response. § One patient in Arm 1 and 4 patients in Arm 2 had missing week 4 data.
Conclusions: Lead-in with PEG2a and ribavirin followed by addition of boceprevir resulted in high SVR rates similar to that observed using an identical treatment regimen with peginterferon alfa-2b. Therapy was generally well-tolerated. These are the first large trials Journal of Hepatology 2011 vol. 54 | S535–S546
S541