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Mark S Sulkowski,
Fred Poordad,
Michael P Manns,
Jean-Pierre Bronowicki,
K Rajender Reddy,
Stephen A Harrison,
Nezam H Afdhal, Heather L Sings,
Lisa D Pedicone,
Kenneth J Koury,
Vilma Sniukiene,
Margaret H Burroughs,
Janice K Albrecht,
Clifford A Brass,
Ira M Jacobson
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ABSTRACT: Boceprevir (BOC) added to peginterferon alfa-2b (PegIFN) and ribavirin (RBV) significantly increases sustained virologic response (SVR) rates over PegIFN/RBV alone in previously-untreated adults with chronic hepatitis C genotype-1. We evaluate the relationship of incident anemia with triple therapy. 1097 patients received a 4-week lead-in of PegIFN/RBV followed by: 1) placebo plus PegIFN/RBV for 44 weeks (PR48); 2) BOC plus PegIFN/RBV using response-guided-therapy (BOC/RGT); and 3) BOC plus PegIFN/RBV for 44 weeks (BOC/PR48). The management of anemia (hemoglobin [Hb]<10g/dL) included RBV dose reduction and/or erythropoietin (EPO) use. 1080 patients had ò1 Hb measurement during treatment. The incidence of anemia was 50% in the BOC arms combined (363/726) and 31% in the PR48 arm (108/354, p< 0.001). Among BOC recipients, lower baseline Hb and creatinine clearance were associated with incident anemia. In the BOC-containing arms, anemia was managed by the site investigators as follows: EPO without RBV dose reduction, 38%; RBV dose reduction without EPO, 8%; EPO with RBV dose reduction, 40%; and neither RBV dose reduction nor EPO, 14%. SVR rates were not significantly impacted by management strategy (70-74%) and overall patients with anemia had higher rates of SVR than those who did not develop anemia (58%). Serious and life-threatening adverse events (AE) and discontinuations due to AEs among BOC-treated patients did not differ by EPO use. Conclusions: With BOC/PR therapy, SVR rates in patients with incident anemia were higher than non-anemic patients and did not vary significantly according to the investigator-selected approach for anemia management. Prospective studies are needed to confirm this observation (HEPATOLOGY 2012.).
Hepatology 10/2012; · 11.66 Impact Factor
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Steven L Flamm,
Eric Lawitz,
Ira Jacobson,
Marc Bourlière,
Christophe Hezode,
John M Vierling,
Bruce R Bacon,
Claus Niederau,
Morris Sherman,
Venkata Goteti, Heather L Sings,
Richard O Barnard,
John A Howe,
Lisa D Pedicone,
Margaret H Burroughs,
Clifford A Brass,
Janice K Albrecht,
Fred Poordad
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ABSTRACT: BACKGROUND & AIMS: The addition of boceprevir to therapy with peginterferon alfa-2b and ribavirin (PEG2b/R) results in significantly higher rates of sustained virologic response (SVR) in previously treated patients with chronic hepatitis C virus (HCV) genotype-1 infection, compared to PEG2b/R alone. We assessed SVR with boceprevir plus peginterferon alfa-2a-ribavirin (PEG2a/R) in patients with identical study entry criteria. METHODS: In a double-blind, placebo-controlled trial, 201 patients with HCV genotype-1 who had relapsed or not responded to previous therapy were assigned to groups (1:2) given a 4-week lead-in phase of PEG2a/R, followed by placebo plus PEG2a/R for 44 weeks (PEG2a/R) or boceprevir plus PEG2a/R for 44 weeks (BOC/PEG2a/R). The primary endpoint was SVR 24 weeks after therapy ended. RESULTS: The addition of boceprevir after 4 weeks lead-in therapy with PEG2a/R significantly increased the rate of SVR, from 21% in the PEG2a/R group to 64% in the BOC/PEG2a/R group (P <.0001). Among patients with poor response to interferon therapy (<1-log(10) decline in HCV-RNA at week 4), 39% in the BOC/PEG2a/R group had SVRs, compared with none of the patients in the PEG2a/R group. Among patients with good response to interferon (≥1-log(10) decline), 71% in the BOC/PEG2a/R group had SVRs, compared with 25% in the PEG2a/R group. A ≥1-log(10) decline in HCV-RNA at treatment week 4 was the strongest independent predictor of a SVR, exceeding that of IL-28B genotype. Among 8 patients who began the study with HCV amino acid variants associated with boceprevir resistance, 3 (38%) achieved SVRs. Fifty percent of patients in the in the BOC/PEG2a/R group developed anemia (Hb<10.0 g/dL), compared with 27% in the PEG2a/R group; 43% vs 21%, respectively, developed neutropenia (neutrophil count <750/mm(3)). CONCLUSIONS: The addition of boceprevir after 4-weeks of lead-in therapy with PEG2a/R caused significantly higher rates of SVR in previously treated patients with chronic HCV genotype-1 infection, compared with patients given only PEG2a/R. ClinicalTrials.gov Identifier: NCT00845065.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 10/2012; · 5.64 Impact Factor
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Fred Poordad,
Jean-Pierre Bronowicki,
Stuart C Gordon,
Stefan Zeuzem,
Ira M Jacobson,
Mark S Sulkowski,
Thierry Poynard,
Timothy R Morgan,
Cliona Molony,
Lisa D Pedicone, Heather L Sings,
Margaret H Burroughs,
Vilma Sniukiene,
Navdeep Boparai,
Venkata S Goteti,
Clifford A Brass,
Janice K Albrecht,
Bruce R Bacon
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ABSTRACT: Little is known about factors associated with a sustained virologic response (SVR) among patients with hepatitis C virus (HCV) infection to treatment with protease inhibitors.
Previously untreated patients (from the Serine Protease Inhibitor Therapy 2 [SPRINT-2] trial) and those who did not respond to prior therapy (from the Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 [RESPOND-2] trial) received either a combination of peginterferon and ribavirin for 48 weeks or boceprevir, peginterferon, and ribavirin (triple therapy) after 4 weeks of peginterferon and ribavirin (total treatment duration, 28-48 wk). A good response to interferon was defined as a ≥ 1 log(10) decrease in HCV RNA at week 4; a poor response was defined as a <1 log(10) decrease. We used multivariate regression analyses to identify baseline factors of the host (including the polymorphism interleukin [IL]-28B rs12979860) associated with response. The polymorphism IL-28B rs8099917 also was assessed.
In the SPRINT-2 trial, factors that predicted a SVR to triple therapy included low viral load (odds ratio [OR], 11.6), IL-28B genotype (rs 12979860 CC vs TT and CT; ORs, 2.6 and 2.1, respectively), absence of cirrhosis (OR, 4.3), HCV subtype 1b (OR, 2.0), and non-black race (OR, 2.0). In the RESPOND-2 trial, the only factor significantly associated with a SVR was previous relapse, compared with previous nonresponse (OR, 2.6). Most patients with rs12979860 CC who received triple therapy had undetectable levels of HCV RNA by week 8 (76%-89%), and were eligible for shortened therapy. In both studies, IL-28B rs12979860 CC was associated more strongly with a good response to interferon than other baseline factors; however, a ≥ 1 log(10) decrease in HCV-RNA level at week 4 was associated more strongly with SVR than IL-28B rs12979860. Combining the rs8099917 and rs12979860 genotypes does not increase the association with SVR.
The CC polymorphism at IL-28B rs12979860 is associated with response to triple therapy and can identify candidates for shorter treatment durations. A ≥ 1 log(10) decrease in HCV RNA at week 4 of therapy is the strongest predictor of a SVR, regardless of polymorphisms in IL-28B.
Gastroenterology 05/2012; 143(3):608-18.e1-5. · 11.68 Impact Factor
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Bruce R Bacon,
Stuart C Gordon,
Eric Lawitz,
Patrick Marcellin,
John M Vierling,
Stefan Zeuzem,
Fred Poordad,
Zachary D Goodman, Heather L Sings,
Navdeep Boparai,
Margaret Burroughs,
Clifford A Brass,
Janice K Albrecht,
Rafael Esteban
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ABSTRACT: In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.
To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks.
A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls.
The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.).
New England Journal of Medicine 03/2011; 364(13):1207-17. · 53.30 Impact Factor
