Several new anti-viral medications are currently in development, and the first of these will likely be approved in the first or second quarter of 2011. We anticipate the rate of new drug development to increase rapidly in the next 12-18 months, likely involving multiple drugs with the goal of obtaining viral clearance and interferon free regimens. This session is designed to rapidly synthesize the new data in such a way that the information will become meaningful and useful on a real-time basis. The session will allow for questions and answers, and a document will be generated that will be published and rapidly disseminated as an enduring material.
Below : Highlights presented at the AASLD Oct 29-Nov2 in Boston, however during the meeting we will be posting all the data. .
Below : Highlights presented at the AASLD Oct 29-Nov2 in Boston, however during the meeting we will be posting all the data. .
To access the full press releases on this blog Click here , the entries will be listed in the order they were received.
Efficacy and safety of TMC435 in combination with peginterferon α-2a and ribavirin in treatment-naïve genotype-1 HCV patients: 24-week interim results from the PILLAR study
k
M. W. Fried1; M. Buti2; G. J. Dore3; P. Ferenci4; I. Jacobson5; P. Marcellin6; S. Zeuzem7; O. Lenz8; M. Peeters8; V. J. Sekar9; G. . De Smedt8 1. Director of Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. 2. Hospital Vall d'Hebron and Ciberehd, Barcelona, Spain. 3. St Vincent's Hospital, Sydney, NSW, Australia. 4. Allgemeines Krankenhaus der Stadt Wien, Wien, Austria. 5. Weill Cornell Medical College, New York, NY, United States. 6. Hopital Beaujon, Clichy, Paris, France. 7. Klinikum der Johann-Wolfgang-Goethe-Universität - Med. Klinik I, Frankfurt, Germany. 8. Tibotec BVBA, Beerse, Belgium. 9. Tibotec Inc., Titusville, NJ, United States.
k
Background and aim:
k
Background and aim:
TMC435, an oral investigational hepatitis C virus (HCV) NS3/4A protease inhibitor, has shown potent antiviral activity against genotype-1 (G1) HCV in Phase IIa. PILLAR (TMC435-C205; NCT00882908) is an ongoing international Phase IIb randomized, double-blind study to assess efficacy and safety of TMC435 in combination with peginterferon α-2a (PegIFN) and ribavirin (RBV) in treatment-naïve HCV G1 patients.
k
Methods:
Patients (n=386) were randomly assigned to 1 of 5 study arms: TMC435 (75 or 150mg qd)+PegIFN (180μg/wk)/RBV (1000-1200mg/day) for 12 weeks, followed by PegIFN/RBV for 12 weeks; TMC435 (75 or 150mg qd)+PegIFN/RBV for 24 weeks; or placebo+PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks. Patients in TMC435 arms who achieved HCV RNA less then 25iu/ml>
To evaluate the primary endpoint (SVR), HCV RNA was measured regularly after end of treatment up to Week 72. Results of a Week 24 interim analysis are reported. Secondary endpoints included assessment of antiviral activity, viral breakthrough, safety, and tolerability. IL-28B genotype was assessed in all consenting patients.
k
Results:
Between 79% and 86% of patients in TMC435 arms were able to end therapy at Week 24 as per protocol defined response criteria. Viral breakthrough was observed in 2.5%-7.8% of patients across different treatment arms. Addition of TMC435 to PegIFN/RBV increased response rates in all IL-28B genotypes.
Adverse events (AEs) did not differ substantially between TMC435 and placebo arms, and no differences were reported in frequency of rash, gastrointestinal events, or anemia. AEs leading to treatment discontinuation were reported in 7.1% of TMC435 arms and 7.8% of placebo arm.
Mild and reversible increases in bilirubin (direct and indirect) were noted in TMC435 150mg dose arms
.
Conclusions: This interim analysis demonstrates that TMC435 in addition to PegIFN/RBV achieves RVR and cEVR for the majority of patients. Available data indicate that high SVR12 rates are observed in patients who completed therapy. In this analysis TMC435 was well tolerated in all treatment arms.
k
GI-5005 Therapeutic Vaccine Plus Peg-IFN/Ribavirin Improves Sustained Virologic Response Versus Peg-IFN/Ribavirin In Prior Non-Responders With Genotype 1 Chronic HCV Infection
k
P. Pockros1; I. Jacobson2; T. D. Boyer3; E. R. Schiff4; G. T. Everson5; W. M. Lee6; J. M. Vierling7, 8; E. Lawitz9; M. Kugelmas10, 11; N. Tsai12; M. L. Shiffman13; R. S. Brown14; B. R. Armstrong15; A. Mattson16; T. C. Rodell16; D. Apelian16 1. Scripps Clinic, La Jolla, CA, United States. 2. Center for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY, United States. 3. Department of Medicine, University of Arizona College of Medicine, Tucson, AZ, United States. 4. Center for Liver Diseases, University of Miami School of Medicine, Miami, FL, United States. 5. Department of Medicine, University of Colorado Denver, Aurora, CO, United States. 6. Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States. 7. Department of Medicine and Surgery, Baylor College of Medicine, Houston, TX, United States. 8. St. Luke's Episcopal Hospital, Houston, TX, United States. 9. Alamo Medical Research, San Antonio, TX, United States. 10. South Denver Gastroenterology, PC, Englewood, CO, United States. 11. Center for Disease of the Liver and Pancreas, Swedish Medical Center, Englewood, CO, United States. 12. University of Hawaii, Honolulu, HI, United States. 13. Liver Institute of Virginia, Bon Secours Health System, Newport News, VA, United States. 14. Columbia University College of Physicians & Surgeons, New York, NY, United States. 15. QST Consultations, Allendale, MI, United States. 16. GlobeImmune, Louisville, CO, United States.
k
Background and aims:
k
Background and aims:
The GI-5005 therapeutic vaccine has been shown to improve sustained virologic response in naïve subjects with the greatest effect observed in IL28B T/T subjects. We now report the sustained virologic response (SVR) data from prior IFN/ribavirin non-responders (NR). Methods: HCV genotype 1 patients were randomized 1:1, and stratified by prior treatment status; Arm 1- GI-5005 monotherapy run-in of five weekly followed by 2 monthly subcutaneous (SC) doses of 40YU (1 YU = 107 yeast) GI-5005 over 12 weeks, followed by triple therapy of monthly 40YU GI-5005 doses plus 48 weeks pegIFN α-2a/ribavirin (SOC), Arm 2- SOC alone. NRs received 72 weeks of triple therapy versus SOC. Prior NRs were defined as poor responders (> 1 log10 and <> 2 log10 reduction without clearance at any time during therapy). Prior null response, relapse, and breakthrough were exclusionary.
k
Results:
Triple therapy was well tolerated with an equivalent number of discontinuations due to adverse events in each group; Triple 8/68(11.8%) and SOC 8/65(12.3%). Improvement in end of treatment response (ETR) (Triple 6/18 [33%] vs SOC 2/19 [11%]) and SVR (Triple 3/18[17%] vs SOC 1/19[5%]) was observed in NR patients. Due to the small number of patients in each treatment arm, these differences were not statistically significant (see table). SVR in NRs occurred only in IL28B C/T subjects (Triple 3/13[23%] vs SOC 1/13[8%]). In summary, GI-5005 triple therapy delivered improved ETR and SVR (Δ ranging from 10-22%) in all patient subgroups (see table).
k
Conclusions:
GI-5005 plus SOC is well tolerated and improved SVR rates compared to SOC in genotype 1 NR patients. ETR and SVR rates were improved by GI-5005 triple therapy for all subgroups (all, naïve, and NR). These data support further investigation of GI-5005 triple therapy in naïve and NR patients as well as novel combination strategies for GI-5005 with other HCV inhibitory agents in larger numbers of patients.
l
Dual, Triple, and Quadruple Combination Treatment with a Protease Inhibitor (GS-9256) and a Polymerase Inhibitor (GS-9190) alone and in Combination with Ribavirin (RBV) or PegIFN/RBV for up to 28 days in Treatment Naïve, Genotype 1 HCV Subjects
Dual, Triple, and Quadruple Combination Treatment with a Protease Inhibitor (GS-9256) and a Polymerase Inhibitor (GS-9190) alone and in Combination with Ribavirin (RBV) or PegIFN/RBV for up to 28 days in Treatment Naïve, Genotype 1 HCV Subjects
.
S. Zeuzem1; P. Buggisch2; K. Agarwal3; M. P. Manns4; P. Marcellin5; G. R. Foster6; D. Sereni7; H. Klinker8; C. Moreno9; J. H. Zarski10; M. J. Shelton11; S. West11; J. Zong11; J. Harris11; J. G. McHutchison11; W. Lee11; W. E. Delaney11; D. Oldach 11 1. J.W. Goethe University Hospital, Frankfurt, Germany. 2. ifi-Studien und Projekte GmbH an der Asklepios Klinik St, Georg Haus K, Hamburg, Germany. 3. Institute of Liver Studies, London, United Kingdom. 4. Medizinische Hochschule Hannover, Hannover, Germany. 5. Hospital Beaujon, Clichy, France. 6. Barts and The London NHS Trust, London, United Kingdom. 7. Hôspital Saint-Louis, Paris, France. 8. Universitätsklinikum Würzburg, Würzburg, Germany. 9. Hôspital Erasme, Bruxelles, Belgium. 10. CHU de Grenoble - Hospital Michallon, La Tronche, France. 11. Gilead Sciences, Foster City, CA, United States.
.
Background and Aims:
.
Background and Aims:
Available data on combinations of direct-acting HCV agents are limited to 14 days of dual treatment. We sought to evaluate combinations of novel protease and polymerase inhibitors for up to 28 days.
l
Methods: Part A subjects were randomized to receive 9256/9190 (n=16) or 9256/9190/RBV (n=15) for up to 28 days. Part B is evaluating 9256/9190/PegIFN/RBV. Doses were 9256 75 mg BID, 9190 40 mg BID, RBV 1000-1200 mg/day divided BID, and PegIFN 180 μg QW. PegIFN ± RBV was started prior to Day 28 for suboptimal response or breakthrough (Part A).
l
Results:
In Part A, median maximal declines in HCV RNA were 4.1 and 5.1 log10 IU/mL for the 2- and 3-drug regimens, respectively. RBV enhanced the antiviral activity of 9256/9190 and delayed/reduced virologic breakthrough. Most subjects with breakthrough had HCV isolates with NS3 (D168V/E/N, and/or R155K) plus NS5B (Y448H) resistance mutations. To date, 5/15 planned subjects have enrolled in Part B and completed 7-21 days on treatment. All subjects on treatment for 14 days achieved HCV RNA ≤ 25 IU/mL, without breakthrough. Treatments were generally well-tolerated. Most AEs were Grade 1 or 2 in severity, resolving with continued study drug dosing. Indirect bilirubin elevations occurred in 29% of subjects, resolving with continued dosing (maximal value: 3.2 mg/dL). In Part B, one serious AE (hospitalization for gastroenteritis) has been reported.
l
Conclusions:
9256/9190/RBV produced substantial viral suppression, demonstrating the important contribution of RBV to a PegIFN-free regimen. 9256/9190/PegIFN/RBV achieved rapid complete viral suppression, strongly supporting further development of GS-9256 + GS-9190 + PegIFN/RBV.
Telaprevir in Combination with Peginterferon Alfa2a and Ribavirin for 24 or 48 weeks in Treatment-Naïve Genotype 1 HCV Patients who Achieved an Extended Rapid Viral Response: Final Results of Phase 3 ILLUMINATE Study
K. E. Sherman1; S. L. Flamm2; N. H. Afdhal3; D. R. Nelson4; M. S. Sulkowski5; G. T. Everson6; M. W. Fried7; K. Kleber8; M. Martin8; A. J. Sankoh8; R. S. Kauffman8; S. George8; C. I. Wright8; F. Poordad9 1. University of Cincinnati College of Medicine, Cincinnati, OH, United States. 2. Northwestern University, Chicago, IL, United States. 3. Beth Israel Deaconess Medical Center, Boston, MA, United States. 4. University of Florida , Gainesville, FL, United States. 5. Johns Hopkins University School of Medicine, Baltimore, MD, United States. 6. University of Colorado Denver, Aurora, CO, United States. 7. University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. 8. Vertex Pharmaceuticals Incorporated, Cambridge , MA, United States. 9. Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Background:
Background:
The Phase 3 open-label study, ILLUMINATE, evaluated patients randomized to two durations of therapy among those who achieved extended rapid viral response (eRVR).
l
Methods:
HCV genotype 1 treatment-naïve patients (pts) were treated with telaprevir (T; 12 weeks (wk), 750 mg po q8h) with peginterferon alfa2a (P; 180 μg/week) and ribavirin (R; 1000-1200 mg/day). Pts who achieved eRVR (undetectable HCV RNA at Wks 4 and 12) were randomized at Wk 20 to continue receiving PR for 24 or 48 wks of total treatment. Pts not achieving eRVR were assigned 48 wks of treatment. Pts who failed to achieve a 2log10 drop at 12 wks or had detectable HCV RNA by 24 wks were discontinued as virologic failures. The primary endpoint was the proportion of randomized pts achieving SVR 24 wks after planned treatment completion. The study was powered to rule out non-inferiority (NI) of 24-wk to 48-wk treatment among randomized pts with an NI of -10.5%. Analyses were based on the intent-to-treat (ITT) randomized population.
lo
Results:
540 pts were treated at 74 sites: 60.2% male, 79.1% Caucasian, 13.5% Black, median HCV RNA log10 6.5 IU/ml, 11.3% cirrhosis. Efficacy: 72% (n=389) of pts achieved RVR; 65.2% (n=352) of pts achieved eRVR. 322 (59.6%) pts were randomized (1:1) to either a 24-wk or 48-wk arm. SVR was 92% among pts randomized to 24 wks (n=162).
SVR was 87.5% (Δ4.5%, 2-sided 95% C.I. = -2.1% to +11.1%) among pts randomized to 48 wks (n=160).
Overall, SVR was 71.9% (ITT analysis). 36 pts (6.7%) discontinued treatment due to virologic failure.
lo
Safety:
94 pts (17.4%) had permanent discontinuation of all study drugs (D/C) for AEs. Fatigue (n=22) and anemia (n=12) were the most common AEs leading to D/C. AEs led to treatment D/C after Wk 20 in 1 (0.6%) and 20 (12.5%) of eRVR+ pts randomized to 24 wks and 48 wks of treatment, respectively.
Treatment D/C due to anemia and rash were 3 (0.6%) and 6 (1.1%) pts, respectively, during the telaprevir treatment phase. Conclusions: Among patients who achieved eRVR, a 24-week telaprevir-based regimen was non-inferior to 48-week telaprevir-based regimen (92% SVR compared to 87.5%).
Response-guided treatment led to 71.9% SVR overall and nearly two-thirds of the patients were eligible for shorter duration of treatment. Permanent discontinuation of all study drugs due to adverse events occurred in 17.4% of patients. Among eRVR randomized patients, there were more adverse events and adverse event-related treatment discontinuations in the 48-week versus 24-week arm. These results support response-guided therapy for telaprevir-based regimens in treatment-naïve patients.
Telaprevir in Combination with Peginterferon and Ribavirin in Genotype 1 HCV Treatment-Naïve Patients: Final Results of Phase 3 ADVANCE Study
I. M. Jacobson1; J. G. McHutchison2; G. M. Dusheiko3; A. M. Di Bisceglie4; R. Reddy5; N. H. Bzowej6; P. Marcellin7; A. J. Muir2; L. Bengtsson8; A. Dunne8; N. Adda8; S. George8; R. S. Kauffman8; S. Zeuzem9 1. Weill Cornell Medical College, New York, NY, United States. 2. Duke University Medical Center, Durham, NC, United States. 3. Royal Free and University College, London, United Kingdom. 4. Saint Louis University School of Medicine, Saint Louis, MO, United States. 5. University of Pennsylvania School of Medicine, Philadelphia, PA, United States. 6. California Pacific Medical Center, San Francisco, CA, United States. 7. Hôpital Beaujon, Paris, France. 8. Vertex Pharmaceuticals Incorporated, Cambridge, MA, United States. 9. Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany.
Background:
Background:
The ADVANCE study is a 3-arm double-blind, randomized, placebo-controlled Phase 3 study assessing efficacy and safety of two telaprevir (TVR, T)-based response-guided regimens compared with peginterferon alfa-2a 180 µg/week and ribavirin 1000-1200 mg/day (PR) in treatment-naïve patients with chronic genotype 1 HCV infection.
;
Methods:
Treatment arms were (a) T 750 mg q8h in combination with PR for 8 weeks, followed by additional weeks of PR; (b) T 750 mg q8h in combination with PR for 12 weeks, followed by additional weeks of PR; (c) PR for 48 weeks (control arm).
Patients in T arms achieving an extended rapid viral response (eRVR, undetectable HCV RNA at weeks 4 and 12) received a total of 24 weeks of therapy while those who did not received a total of 48 weeks of therapy. Randomization was 1:1:1 and patients were stratified by HCV RNA (less then 800,000>
The primary endpoint was SVR (undetectable HCV RNA 24 weeks after last planned dose of treatment). The primary analysis was based on the Full Analysis (intention-to-treat) dataset. Safety is presented for TVR/Placebo duration phase.
\
Results:
Of 1088 patients, 839 (77%) had HCV RNA ≥800,000 IU/mL, 631 (58%) were genotype 1a, 636 (58%) male, 94 (9%) black, 117 (11%) Latino/Hispanic, 231 (21%) had bridging fibrosis or compensated cirrhosis. The most common (>25%) AEs in the T arms were fatigue, pruritus, nausea, headache, anemia, rash, influenza-like illness, insomnia, pyrexia, and diarrhea. Discontinuation of treatment due to AEs occurred in 8% in T8PR, 7% in T12PR and 4% in PR48; due to rash occurred in 0.5%, 1.4% and 0.0% and due to anemia occurred in 3.3%, 0.8% and 0.6% in T8PR, T12PR and control arms, respectively.
'
Conclusions:
A significantly greater proportion of patients achieved SVR with 12-week and 8-week telaprevir-based combination regimens (75% and 69%, respectively) compared with PR48 control arm (44%, Patients less then 0.0001). The safety and tolerability profile of telaprevir in the ADVANCE trial was consistent with the profile previously reported, with an improvement in treatment discontinuation rates due to adverse events, including rash and anemia. These first Phase 3 results confirm the clinical benefit previously reported in Phase 2.
Long-term Follow-up of Patients with Chronic Hepatitis C Treated with Telaprevir in Combination with Peginterferon Alfa-2a and Ribavirin: Interim Analysis of the EXTEND Study
S. Zeuzem1; M. S. Sulkowski2; F. Zoulim3; K. E. Sherman4; A. Alberti5; L. J. Wei6; B. van Baelen7; J. Sullivan8; T. L. Kieffer8; S. De Meyer7; G. Picchio9; F. Tomaka9; C. S. Graham8; J. G. McHutchison10 1. Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany. 2. Johns Hopkins University School of Medicine, Baltimore, MD, United States. 3. INSERM Unit 871, Lyon, France. 4. University of Cincinnati College of Medicine, Cincinnati, OH, United States. 5. University of Padova, Padova, Italy. 6. Harvard School of Public Health, Boston, MA, United States. 7. Tibotec BVBA, Mechelen, Belgium. 8. Vertex Pharmaceuticals Incorporated, Cambridge, MA, United States. 9. Tibotec Inc., Titusville, NJ, United States. 10. Duke University Medical Center, Durham, NC, United States.
Background:
Background:
Telaprevir (TVR) is a potent, specific hepatitis C virus (HCV) protease inhibitor that in combination with pegylated interferon alfa-2a (P) and ribavirin (R) led to higher sustained virologic response (SVR) rates than PR alone in both treatment-naïve and treatment-experienced genotype 1 HCV patients in Phase 2 clinical trials. EXTEND is a 3-year virology follow-up study on some of these patients. Here, we report an interim analysis of durability of virologic response in patients who had achieved SVR as well as changes in HCV variants in patients who had not achieved SVR.
Methods:
Methods:
867 patients who received at least one dose of TVR in PROVE1, PROVE2, PROVE3 or Study 107 and from whom baseline HCV sequences were available were eligible for enrollment; 202 entered the study. Patients who achieved SVR (n=123) were observed for a median time of 22 months (range: 5-35) post-SVR. Patients who did not achieve an SVR as defined in previous studies (n=79) were observed for a median time of 25 months (range: 7-36) after the end of the prior study. HCV RNA levels were assessed with the COBAS TaqMan® HCV Test (version 2.0). Viral sequence was determined by nested RT-PCR followed by population sequencing of the NS3 protease (detecting variants present in >~20% of viral population). Amino acid (AA) positions 36, 54, 155, and 156 that are associated with decreased susceptibility to TVR in genotype 1 HCV patients were analyzed. We report on patients who possessed identified variants with decreased susceptibility to TVR at time of treatment failure.
Results:
Results:
Ninety-nine percent (122/123) of patients maintained SVR during follow-up; one patient from PROVE2 experienced a late relapse 47 weeks after early discontinuation from study dosing, as previously presented. Variants were no longer detectable in 89% (50/56) of patients who had NS3 variants after failing to achieve an SVR. NS3 variants in each of the four AA positions associated with decreased susceptibility to TVR were no longer detectable in 88-100% of patients. In this cohort, there was no evidence to suggest that the time to undetectability of variants varied as a function of treatment arm, duration of TVR dosing, or non-response type (e.g., virologic breakthrough on treatment versus relapse).
Conclusions:
Conclusions:
In this interim analysis, SVR after telaprevir-based therapy was durable, with 122 of 123 subjects maintaining HCV RNA undetectable during a median 22 months follow-up. Amongst patients who did not achieve SVR after telaprevir-based therapy variants associated with decreased sensitivity to telaprevir were no longer detectable in 89% of patients within the study period.
k
Boceprevir (BOC) Combined with Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype (G) 1: SPRINT-2 Final Results
k
F. Poordad1; J. McCone2; B. R. Bacon3; S. Bruno4; M. P. Manns5; M. S. Sulkowski6; I. M. Jacobson7; K. Reddy8; N. Boparai9; V. Sniukiene9; C. A. Brass9; J. K. Albrecht9; J. Bronowicki10 1. Cedars-Sinai Medical Center, Los Angeles, CA, United States. 2. Gastroenterology/Hepatology/Certified Endoscopy Centers, Alexandria, VA, United States. 3. St. Louis University School of Medicine, St. Louis, MO, United States. 4. University of Milan, Milan, Italy. 5. Medical School of Hannover, Hannover, Germany. 6. Johns Hopkins School of Medicine, Baltimore, MD, United States. 7. The Joan Sanford I. Weill Medical College of Cornell University, New York, NY, United States. 8. University of Pennsylvania, Philadelphia, PA, United States. 9. Merck, North Wales, PA, United States. 10. Centre Hospitalier Universitaire de Nancy-Brabois, Vandoeuvre-lès-Nancy, France.
k k
Background:
k k
Background:
Sustained virologic responses (SVR) have been less then 50%>
k
Methods:
This Phase 3 international double-blind randomized study compared a 4-wk lead-in (LI) treatment period with P/R, followed by (1) P/R plus placebo for 44 wks (48P/R); (2) response-guided therapy (RGT): BOC plus P/R for 24 wks, with an additional 20 wks of P/R only if detectable HCV RNA during Wk 8-24 (LI+24 BOC/P/R±20 P/R); or (3) BOC plus P/R for 44 wks (LI+44 BOC/P/R). P was dosed 1.5 μg/kg SC weekly, R dose was weight-based (600-1400 mg/day) PO divided BID, & the BOC dose was 800 mg PO TID. Patients with detectable HCV RNA at Wk 24 were discontinued for futility. The primary efficacy endpoint was SVR 24 wks post-therapy in all randomized patients treated with ≥1 dose of any study medication. Non-black (Cohort 1) & black (Cohort 2) patients were enrolled & analyzed separately per protocol.
k
Results:
938 non-black & 159 black patients were enrolled: 92% >400,000 IU/mL HCV RNA & 9% biopsy-proven F3/4. SVR in non-black patients was 40% for 48P/R & significantly higher (p<.0001) in both BOC arms: RGT (67%) & LI+44 BOC/P/R (68%); corresponding SVR in black patients were 23%, 42% (p=.044) & 53% (p=.004) (Table). For non-black patients receiving ≥1 dose of BOC or placebo, respective SVR were 42%, 70% & 71%. At the end of LI period, a high percent (25%) of patients had less then 1>
HCV RESPOND-2 Final Results: High Sustained Virologic Response Among Genotype 1 Previous Non-Responders and Relapsers to Peginterferon/Ribavirin when Re-Treated with Boceprevir Plus PEGINTRON (Peginterferon alfa-2b)/Ribavirin
Clinical, Virological, Biochemical Outcomes After 20 Years of Sustained Virological Response (SVR) in Chronic Hepatitis C: The NIH Experience.
Discontinuation for adverse events occurred in 16%, 12% & 16% in the 3 arms, respectively. Anemia was reported in 29% of controls vs. 49% in the BOC arms, leading to dose reduction in 13% & 21% & discontinuation in 1% & 2%, respectively
.
Conclusions: BOC/P/R significantly increased SVR in both the RGT & 48-wk treatment arms over standard of care by ~70%. BOC was well tolerated; although reported more often in BOC recipients, anemia rarely led to treatment discontinuation. Compared to 44 wks of triple therapy after the LI period, RGT with LI+24BOC/P/R±20P/R produced comparable SVR.
HCV RESPOND-2 Final Results: High Sustained Virologic Response Among Genotype 1 Previous Non-Responders and Relapsers to Peginterferon/Ribavirin when Re-Treated with Boceprevir Plus PEGINTRON (Peginterferon alfa-2b)/Ribavirin
B. R. Bacon1; S. C. Gordon2; E. Lawitz3; P. Marcellin4; J. M. Vierling5; S. Zeuzem6; F. Poordad7; N. Boparai8; M. Burroughs8; C. A. Brass8; J. K. Albrecht8; R. Esteban9 1. Saint Louis University School of Medicine, St. Louis, MS, United States. 2. Henry Ford Hospital, Detroit, MI, United States. 3. Alamo Medical Research, San Antonio, TX, United States. 4. University Paris 7-Hôpital Beaujon, Clichy, France. 5. Baylor College of Medicine, Houston, TX, United States. 6. Universitätsklinikum des Saarlandes, Homburg/Saar, Germany. 7. Cedars-Sinai Medical Center, Los Angeles, CA, United States. 8. Merck, Whitehouse Station, NJ, United States. 9. Hospital General Universitario Vall d'Hebron, Barcelona, Spain.
Background:
Background:
Boceprevir (BOC) is an oral inhibitor of HCV-NS3 protease. RESPOND-2 assessed the safety and efficacy of BOC plus PEGINTRON (P) and Ribavirin (R) in the re-treatment of previous non-responders (NRs) and relapsers to Peginterferon/R therapy.
m
Methods:
In this double-blind placebo controlled trial, 403 genotype 1 Peginterferon/R treatment failure patients from the US, Canada and Europe were randomized 1:2:2 (table) to receive either P/R control (Arm 1), 4 wks of P/R (lead-in) then response guided therapy (RGT) with P/R + 800 mg BOC TID (Arm 2), or P/R lead-in for 4 wks followed by 44 weeks of P/R + 800 mg BOC TID (Arm 3). All patients with detectable HCV-RNA at wk 12 were discontinued for futility. The primary endpoint was sustained virologic response (SVR) at 24 wks post-treatment (Roche TaqMan LLD less then 15 IU/mL).
l
Results:
Patient distribution was 67% male, 12% black, and 12% cirrhotic. The addition of BOC following a 4 wk lead-in with P/R significantly increased SVR over control by 37% (Arm 2; 59% vs 21%) and 45% (Arm 3; 67% vs 21%). For all arms, previous relapsers had higher SVR than previous NRs. The highest SVR (80%) was observed in patients with a ≥1 log decline at wk 4 following the 4 wk P/R lead-in (non-null) who were then treated with 800 mg BOC TID for 44 wks. Notably, SVR in Arms 2 and 3 was significantly higher than Arm 1 for the ‘null’ responders who represented ~28% of the population in Arms 2/3. Discontinuation due to adverse events was reported in 3%, 8% and 12% of patients in Arms 1, 2 and 3, respectively, with none related to rash. The most common reason for discontinuation was lack of response at wk 12.
'
Conclusions:
Boceprevir added to P/R leads to high SVR rates in genotype 1 previous non-responders and relapsers to Peginterferon/R therapy, with significant but lower response rates in ‘null’ responders. This therapy was generally well tolerated, and offers substantial benefit to patients who failed prior Peginterferon/R therapy.
Other Presentations
Clinical, Virological, Biochemical Outcomes After 20 Years of Sustained Virological Response (SVR) in Chronic Hepatitis C: The NIH Experience.
C. Koh1; T. Heller1; V. Haynes-Williams1; K. Hara1; J. Feld1; Y. Rotman1; M. G. Ghany1; T. Liang1; J. H. Hoofnagle1 1. Liver Diseases Branch, NIH-NIDDK, Bethesda, MD, United States.
Introduction:
Introduction:
The short-term goal of therapy of hepatitis C is viral eradication; but the long-term goal is prevention of liver-related disability or death. Although the short-term benefits of an SVR after therapy are established, the long-term clinical benefits are less defined.
Aims:
To assess changes in non-invasive markers of disease activity and fibrosis in a cohort of pts followed for up to 22 yrs after SVR.
l
Methods:
The first 103 patients (pts) to achieve SVR after being treated at the National Institutes of Health, starting in 1984, using standard or peginterferon with or without ribavirin were evaluated. Serum markers of hepatic inflammation, synthetic function and fibrosis before treatment and at the last visit were compared. Pts evaluated since 2007 underwent transient elastography.
Results:
Three of the 103 pts relapsed; 0.7, 6.4 and 6.5 years after therapy (10-year relapse rate of 5.7% by Kaplan-Meier analysis).
The 100 remaining pts included 56 men; 88 whites, 4 African Americans, 8 Asians; average age at last visit 56 years (range 17 - 84); HCV genotype 1 in 45%, 2 and 3 in 53%, other in 2%.
Pretreatment liver histology (99 pts) showed mild fibrosis (Ishak score 0-2) in 64, moderate (3-4) in 25, and cirrhosis (5-6) in 10.
After SVR, pts were followed for 0.5 to 22 (median = 7.6) yrs.
There were no cases of hepatic decompensation or liver cancer. Serum markers improved in all long-term responders, including mean ALT (from 152 to 27 U/L), AST (86 to 24 U/L), alkaline phosphatase (78 to 69 U/L), globulin (3.2 to 2.8 gm/dL), IgG (1462 to 1113 mg/dL), alpha fetoprotein (4.6 to 2.9 ng/mL), GGT (47 to 28 U/L), rheumatoid factor (38% to 19% positive), platelet count (208,000 to 239,000/ μL) and AST-platelet ratio index (APRI: 0.99 to 0.25)
Maintenance peginterferon (pegIFN) therapy to prevent hepatocellular carcinoma (HCC) in patients (pts) with advanced chronic hepatitis C (CHC): extended follow-up results from the HALT-C Trial
Transient elastography was successful in 75 pts and was normal (<> 13.8) in 9%. Of 7 pts with cirrhosis before therapy, 6 had abnormal elastography at follow up. Elastography readings but not serum markers at the time of last follow up correlated with pre-treatment liver fibrosis (p= less then 0.001).
'
Conclusions:
In long-term follow up, 97% of patients with an SVR maintained a virological response. No patients died of liver-related causes. Despite long-term SVR, patients with pre-existing cirrhosis still had evidence of hepatic fibrosis by transient elastography. Noninvasive markers of liver disease all improve over time. In chronic hepatitis C, SVR is associated with both short term and long-term benefits.
Maintenance peginterferon (pegIFN) therapy to prevent hepatocellular carcinoma (HCC) in patients (pts) with advanced chronic hepatitis C (CHC): extended follow-up results from the HALT-C Trial
,
A. S. Lok1; J. E. Everhart2; E. C. Wright2; T. R. Morgan3; A. M. Di Bisceglie4; H. Kim5 1. Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, MI, United States. 2. NIDDK, NIH, Bethesda, MD, United States. 3. VA Med Ctr, Long Beach, CA, United States. 4. Saint Louis Univ, Saint Louis, MO, United States. 5. NERI, Watertown, MA, United States.
Background:
Background:
IFN has been reported to decrease the incidence of HCC in pts with CHC. Earlier reports of the HALT-C trial found that maintenance pegIFN did not reduce clinical outcomes during the first 4 yr but the follow-up may have been too short to observe a chemopreventive effect on HCC. Aim: To determine whether pegIFN decreased the incidence of HCC in the HALT-C cohort with longer follow-up.
l
Methods:
1050 pts with CHC and Ishak fibrosis ≥3, who failed to achieve SVR after pegIFN and ribavirin therapy, were randomized to receive pegIFN 90 μg/wk x 3.5 yrs or no treatment. Pts were followed q 3 mos x 3.5 yrs then q 6 mos until the end of the study.
/
Results:
After a median follow-up of 6.1 yrs (max 8.7), 88 (68 definite and 20 presumed) pts met predefined criteria of HCC: 37/515 (7.2%) pegIFN-treated and 51/533 (9.6%) control pts (p=0.24). PegIFN was associated with a significantly lower incidence of HCC among pts with cirrhosis at baseline but not those with fibrosis; cumulative incidence at 8 yrs was 11% vs. 24.2%, HR 0.45 (95% CI 0.24-0.83, p=0.01) for pts with cirrhosis, and 10.1% vs. 9.8%; HR 1.44 (95% CI 0.77-2.69, p=0.26) for those with fibrosis. Among pts with cirrhosis at baseline, the cumulative rate of HCC in the two treatment groups did not diverge until after yr 4. A beneficial effect of pegIFN among pts with cirrhosis at baseline persisted when presumed HCC cases were excluded and when the analysis was limited to pts at risk after yr 4. Treated pts who had a decrease in histologic activity index (HAI) by ≥2 points on follow-up biopsy had a lower incidence of HCC than those with unchanged or increase in HAI: 2.9% vs. 9.4% (p=0.03).
l
Conclusions:
Extended follow-up of the HALT-C cohort showed a modest benefit of long-term pegIFN in decreasing the incidence of HCC. This effect was mainly observed in pts with established cirrhosis and took several yrs to become apparent.
Impact of sustained virologic response to pegylated interferon/ribavirin on all-cause mortality by HCV genotype in a large real-world cohort: the US Department of Veterans Affairs’ experience
;
L. Backus1; D. B. Boothroyd1; B. R. Phillips1; L. A. Mole1 1. Center for Quality Management in Public Health, Palo Alto VA, Palo Alto, CA, United States.
Background:
Background:
The goal of HCV antiviral treatment is a sustained virologic response (SVR) with the intent to slow liver disease progression and ultimately reduce mortality. The mortality impact of SVR has not been well documented by genotype or in populations in routine medical practice that have substantial competing risk.
;
Methods:
From the United States Department of Veterans Affairs’ (VA) Clinical Case Registry (CCR) we identified all HCV infected patients with HCV genotype (GT) 1, 2 or 3 without HIV coinfection or a diagnosis of hepatocellular carcinoma prior to pegylated interferon/ribavirin treatment who started treatment by June 30th 2007, stopped treatment by June 30th 2008, and had a post-treatment HCV RNA test that identified the virologic response as SVR or no SVR. Mortality data were available from the VA and Social Security Administration through December 31, 2009. We fitted univariate and multivariate proportional hazards survival models within genotype to assess survival in patients with and without SVR.
l
Results:
We identified 21,836 patients (75% GT1, 15% GT2 and 10% GT3) meeting all inclusion criteria except a post-treatment HCV RNA test; their intention to treat SVR rate was 34% (26% GT1, 62% GT2 and 52% GT3). The cohort of 16,864 patients with a post-treatment HCV RNA test had a SVR rate of 44% (35% GT1, 72% GT2, and 62% GT3). The cohort had high rates of comorbidities that impact survival including histories of tobacco use (52%) hypertension (52%), diabetes (20%), COPD (15%), coronary artery disease (12%) and recent diagnoses within 12 months before treatment of depression (36%), alcohol abuse (24%) and hard drug use (12%). These comorbidities were not equally distributed among patients with and without SVR. During a mean follow-up of 3.7 years after the post-treatment HCV RNA test, 1,535 patients died (1,119 GT1, 220 GT2 and 196 GT3). In unadjusted analyses, SVR was associated with significantly reduced mortality for GT1, 2 and 3 patients (table). In multivariate models controlling for age, sex, race, BMI, albumin, ALT, AST, bilirubin, creatinine clearance, hemoglobin, platelets, sodium, HBV coinfection, comorbidities, treatment duration, and year of starting treatment, SVR independently and significantly reduced mortality risk for each genotype (table). Conclusion: SVR is associated with improved survival among HCV genotypes 1, 2 and 3 and in patients in routine medical practice with substantial competing risk.
;
;
To review all presentations
No comments:
Post a Comment