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Eric Lawitz,
Alessandra Mangia,
David Wyles,
Maribel Rodriguez-Torres,
Tarek Hassanein, Stuart C Gordon,
Michael Schultz,
Mitchell N Davis,
Zeid Kayali,
K Rajender Reddy, [......],
Robert H Hyland,
Sarah Arterburn,
Deyuan Jiang,
John McNally,
Diana Brainard,
William T Symonds,
John G McHutchison,
Aasim M Sheikh,
Zobair Younossi,
Edward J Gane
[show abstract]
[hide abstract]
ABSTRACT: Background In phase 2 trials, the nucleotide polymerase inhibitor sofosbuvir was effective in previously untreated patients with chronic hepatitis C virus (HCV) genotype 1, 2, or 3 infection. Methods We conducted two phase 3 studies in previously untreated patients with HCV infection. In a single-group, open-label study, we administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4). In a noninferiority trial, 499 patients with HCV genotype 2 or 3 infection were randomly assigned to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks. In the two studies, the primary end point was a sustained virologic response at 12 weeks after the end of therapy. Results In the single-group study, a sustained virologic response was reported in 90% of patients (95% confidence interval, 87 to 93). In the noninferiority trial, a sustained response was reported in 67% of patients in both the sofosbuvir-ribavirin group and the peginterferon-ribavirin group. Response rates in the sofosbuvir-ribavirin group were lower among patients with genotype 3 infection than among those with genotype 2 infection (56% vs. 97%). Adverse events (including fatigue, headache, nausea, and neutropenia) were less common with sofosbuvir than with peginterferon. Conclusions In a single-group study of sofosbuvir combined with peginterferon-ribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks. In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%). Adverse events were less frequent with sofosbuvir than with peginterferon. (Funded by Gilead Sciences; FISSION and NEUTRINO ClinicalTrials.gov numbers, NCT01497366 and NCT01641640 , respectively.).
New England Journal of Medicine 04/2013; · 53.30 Impact Factor
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Ira M Jacobson, Stuart C Gordon,
Kris V Kowdley,
Eric M Yoshida,
Maribel Rodriguez-Torres,
Mark S Sulkowski,
Mitchell L Shiffman,
Eric Lawitz,
Gregory Everson,
Michael Bennett, [......],
Di An,
Ming Lin,
John McNally,
Diana Brainard,
William T Symonds,
John G McHutchison,
Keyur Patel,
Jordan Feld,
Stephen Pianko,
David R Nelson
[show abstract]
[hide abstract]
ABSTRACT: Background Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment with peginterferon is not an option, or who have not had a response to prior interferon treatment, currently have no approved treatment options. In phase 2 trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection. Methods We conducted two randomized, phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection. In one trial, patients for whom treatment with peginterferon was not an option received oral sofosbuvir and ribavirin (207 patients) or matching placebo (71) for 12 weeks. In a second trial, patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks (103 patients) or 16 weeks (98). The primary end point was a sustained virologic response at 12 weeks after therapy. Results Among patients for whom treatment with peginterferon was not an option, the rate of a sustained virologic response was 78% (95% confidence interval [CI], 72 to 83) with sofosbuvir and ribavirin, as compared with 0% with placebo (P<0.001). Among previously treated patients, the rate of response was 50% with 12 weeks of treatment, as compared with 73% with 16 weeks of treatment (difference, -23 percentage points; 95% CI, -35 to -11; P<0.001). In both studies, response rates were lower among patients with genotype 3 infection than among those with genotype 2 infection and, among patients with genotype 3 infection, lower among those with cirrhosis than among those without cirrhosis. The most common adverse events were headache, fatigue, nausea, and insomnia; the overall rate of discontinuation of sofosbuvir was low (1 to 2%). Conclusions In patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon and ribavirin was not an option, 12 or 16 weeks of treatment with sofosbuvir and ribavirin was effective. Efficacy was increased among patients with HCV genotype 2 infection and those without cirrhosis. In previously treated patients with genotype 3 infection, 16 weeks of therapy was significantly more effective than 12 weeks. (Funded by Gilead Sciences; POSITRON and FUSION ClinicalTrials.gov numbers, NCT01542788 and NCT01604850 , respectively.).
New England Journal of Medicine 04/2013; · 53.30 Impact Factor
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Kris V Kowdley,
Eric Lawitz,
Israel Crespo,
Tarek Hassanein,
Mitchell N Davis,
Michael Demicco,
David E Bernstein,
Nezam Afdhal,
John M Vierling, Stuart C Gordon,
Jane K Anderson,
Robert H Hyland,
Hadas Dvory-Sobol,
Di An,
Robert G Hindes,
Efsevia Albanis,
William T Symonds,
M Michelle Berrey,
David R Nelson,
Ira M Jacobson
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. METHODS: For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800 000 IU/mL vs ≥800 000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978. RESULTS: We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug-anaemia and neutropenia-were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event. INTERPRETATION: Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. FUNDING: Gilead Sciences.
The Lancet 03/2013; · 38.28 Impact Factor
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Robert A Ogert,
John A Howe,
John M Vierling,
Paul Y Kwo,
Eric J Lawitz,
Jonathan McCone,
Eugene R Schiff,
David Pound,
Mitchell N Davis, Stuart C Gordon, [......],
Ira M Jacobson,
Robert Ralston,
Eirum Chaudhri,
Ping Qiu,
Lisa D Pedicone,
Clifford A Brass,
Janice K Albrecht,
Richard Jo Barnard,
Daria J Hazuda,
Anita Ym Howe
[show abstract]
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ABSTRACT: BACKGROUND: Resistance to direct-acting antivirals represents a new challenge in the treatment of chronic hepatitis C. METHODS: SPRINT-1 was a randomized study of treatment-naive patients with genotype (G) 1 hepatitis C infection (N=595) that evaluated the safety and efficacy of boceprevir (BOC) when added to peginterferon alfa 2b plus ribavirin (PR). Plasma samples collected at protocol-specified visits were analyzed by population sequencing for detection of BOC associated resistance-associated variants (RAVs). RESULTS: 17/24 (71%) patients randomized to BOC with baseline RAVs achieved sustained virologic response (SVR). V55A/I (n=13), Q41H (n=11), and T54S (n=9) were the most frequently detected polymorphisms at baseline. 7 Non-SVR patients with baseline RAVs had V55A (relapse, n=3; breakthrough, n=1; and nonresponse, n=1) and/or R155K (nonresponse, n=2). In total, 63/144 (44%) patients having postbaseline samples sequenced (2 SVR, 61 non-SVR) had detectable RAVs after BOC treatment (G1a: R155K [39/49; 80%], V36M [37/49; 76%], and T54S [24/49; 49%]; G1b: T54S [3/11; 27%], T54A [4/11; 35%], A156S [2/11; 18%], and V170A [2/11; 18%]. RAV frequency varied according to the virologic response: 90%, 67%, 27%, and 37% of breakthrough, incomplete virologic response, relapse, and nonresponder patients, respectively had postbaseline RAVs present. Similar RAVs were identified in both the PR lead-in and no-lead-in arms and the frequency of postbaseline RAVs was highest in the low-dose ribavirin arm. CONCLUSIONS: SVR rates were not compromised among patients with RAVs at baseline; however, a lower starting mg/kg dose of ribavirin was associated with a higher frequency of postbaseline RAVs.
Antiviral therapy 02/2013; · 3.16 Impact Factor
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Eric J Lawitz,
John M Hill,
Thomas Marbury,
Michael P Demicco,
William Delaney,
Jenny Yang,
Lisa Moorehead,
Anita Mathias,
Hongmei Mo,
John G McHutchison,
Maribel Rodriguez-Torres, Stuart C Gordon
[show abstract]
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ABSTRACT: BACKGROUND: GS-9451 is a novel inhibitor of the hepatitis C virus (HCV) NS3/4A protease and demonstrates potent in vitro suppression of HCV genotype 1 replicons. METHODS: The safety, pharmacokinetics, and antiviral efficacy of GS-9451 were evaluated in a Phase 1 study in treatment-naïve, HCV genotype 1 infected patients. Patients were randomized to 3 days of once-daily dosing with placebo (n=8) or GS-9451 60 mg (n=8 genotype 1a), 200 mg (n=8 genotype 1a; n=8 genotype 1b), or 400 mg (n=9 genotype 1a). Plasma samples were collected through Day 14 for pharmacokinetic evaluation, serum HCV RNA quantitation, and NS3 sequencing. RESULTS: No patients interrupted or discontinued dosing due to an adverse event. The median (range) maximal HCV RNA reductions from baseline were -0.88 (-1.24, -0.64), -3.19 (-3.31, -2.94), and -3.64 (-4.08, -3.54) log(10) IU/mL in genotype 1a patients receiving 60, 200, and 400 mg/d GS-9451, respectively, and -3.48 (-3.54, -3.03) log(10) IU/mL in genotype 1b patients receiving GS-9451 200 mg/d. Median half-life ranged from 14-17 hours. Day 3 mean C(tau) was 5.5- and 17-fold above protein-binding adjusted mean EC(50) in 200- and 400-mg cohorts, respectively. No resistance mutations were detected with GS-9451 60 mg/d. In the 200 mg/d or 400 mg/d groups, predominant mutations were NS3 R155 (R155K) in genotype 1a patients and D168 (D168E, D168V and D168G) in genotype 1b patients. CONCLUSIONS: GS-9451 was well tolerated. During 3 days of monotherapy, GS-9451 200 mg/d or 400 mg/d demonstrated potent antiviral activity in both HCV genotype 1a and 1b infected patients. GS-9451 is currently being evaluated in combination regimens with and without peginterferon alfa.
Antiviral therapy 09/2012; · 3.16 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
[show abstract]
[hide abstract]
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
[show abstract]
[hide abstract]
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
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Andrew J Muir,
Mitchell L Shiffman,
Atif Zaman,
Boris Yoffe,
Andrew de la Torre,
Steven Flamm, Stuart C Gordon,
Paul Marotta,
John M Vierling,
Juan Carlos Lopez-Talavera,
Kelly Byrnes-Blake,
David Fontana,
Jeremy Freeman,
Todd Gray,
Diana Hausman,
Naomi N Hunder,
Eric Lawitz
[show abstract]
[hide abstract]
ABSTRACT: Interferon lambda 1 (IFN-lambda1) is a type III IFN that produces intracellular responses similar to those of IFN-alpha but in fewer cell types because of differences in the receptor distribution pattern, and this could potentially result in an improved safety profile. This was an open-label three-part study of patients with chronic hepatitis C virus (HCV) genotype 1 infection. Part 1 evaluated single-agent pegylated interferon lambda (PEG-IFN-lambda) at 1.5 or 3.0 microg/kg administered every 2 weeks or weekly for 4 weeks in patients who had relapsed after previous IFN-alpha-based treatment. Part 2 evaluated weekly doses of PEG-IFN-lambda ranging from 0.5 to 2.25 microg/kg in combination with ribavirin (RBV) for 4 weeks in treatment-relapse patients. Part 3 evaluated weekly PEG-IFN-lambda at 1.5 microg/kg in combination with RBV for 4 weeks in treatment-naive patients. Fifty-six patients were enrolled: 24 patients in part 1, 25 patients in part 2, and 7 patients in part 3. Antiviral activity was observed at all PEG-IFN-lambda dose levels (from 0.5 to 3.0 microg/kg). Two of seven treatment-naive patients (29%) achieved rapid virological response. Treatment was well tolerated with minimal flu-like symptoms and no significant hematologic changes other than RBV-associated decreases in hemoglobin. The most common adverse events were fatigue (29%), nausea (12%), and myalgia (11%). Six patients experienced increases in aminotransferases that met protocol-defined criteria for dose-limiting toxicity (DLT) or temporarily holding therapy with PEG-IFN-lambda. Most DLT occurred in patients with high PEG-IFN-lambda exposure. CONCLUSION: Weekly PEG-IFN-lambda with or without daily RBV for 4 weeks is well tolerated with minimal adverse events and hematologic effects and is associated with clear antiviral activity across a broad range of doses in patients with chronic HCV.
Hepatology 09/2010; 52(3):822-32. · 11.66 Impact Factor
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Paul Y Kwo,
Eric J Lawitz,
Jonathan McCone,
Eugene R Schiff,
John M Vierling,
David Pound,
Mitchell N Davis,
Joseph S Galati, Stuart C Gordon,
Natarajan Ravendhran,
Lorenzo Rossaro,
Frank H Anderson,
Ira M Jacobson,
Raymond Rubin,
Kenneth Koury,
Lisa D Pedicone,
Clifford A Brass,
Eirum Chaudhri,
Janice K Albrecht
[show abstract]
[hide abstract]
ABSTRACT: Peginterferon plus ribavirin achieves sustained virological response (SVR) in fewer than half of patients with genotype 1 chronic hepatitis C virus infection treated for 48 weeks. We tested the efficacy of boceprevir, an NS3 hepatitis C virus oral protease inhibitor, when added to peginterferon alfa-2b and ribavirin.
In part 1 of this trial, undertaken in 67 sites in the USA, Canada, and Europe, 520 treatment-naive patients with genotype 1 hepatitis C virus infection were randomly assigned to receive peginterferon alfa-2b 1.5 mug/kg plus ribavirin 800-1400 mg daily for 48 weeks (PR48; n=104); peginterferon alfa-2b and ribavirin daily for 4 weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg three times a day for 24 weeks (PR4/PRB24; n=103) or 44 weeks (PR4/PRB44; n=103); or peginterferon alfa-2b, ribavirin, and boceprevir three times a day for 28 weeks (PRB28; n=107) or 48 weeks (PRB48; n=103). In part 2, 75 patients were randomly assigned to receive either PRB48 (n=16) or low-dose ribavirin (400-1000 mg) plus peginterferon alfa-2b and boceprevir three times a day for 48 weeks (low-dose PRB48; n=59). Randomisation was by computer-generated code, and study personnel and patients were not masked to group assignment. The primary endpoint was SVR 24 weeks after treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00423670.
Patients in all four boceprevir groups had higher rates of SVR than did the control group (58/107 [54%, 95% CI 44-64], p=0.013 for PRB28; 58/103 [56%, 44-66], p=0.005 for PR4/PRB24; 69/103 [67%, 57-76], p<0.0001 for PRB48; and 77/103 [75%, 65-83], p<0.0001 for PR4/PRB44; vs 39/104 [38%, 28-48] for PR48 control). Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 [27%]), and a rate of relapse (six of 27 [22%]) similar to control (12/51 [24%]). Boceprevir-based groups had higher rates of anaemia (227/416 [55%] vs 35/104 [34%]) and dysgeusia (111/416 [27%] vs nine of 104 [9%]) than did the control group.
In patients with untreated genotype 1 chronic hepatitis C infection, the addition of the direct-acting antiviral agent boceprevir to standard treatment with peginterferon and ribavirin after a 4-week lead-in seems to have the potential to double the sustained response rate compared with that recorded with standard treatment alone.
Merck.
The Lancet 08/2010; 376(9742):705-16. · 38.28 Impact Factor
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Vinod K Rustgi,
William M Lee,
Eric Lawitz, Stuart C Gordon,
Nezam Afdhal,
Fred Poordad,
Herbert L Bonkovsky,
Leif Bengtsson,
Gurudatt Chandorkar,
Matthew Harding,
Lindsay McNair,
Molly Aalyson,
John Alam,
Robert Kauffman,
Shahin Gharakhanian,
John G McHutchison
[show abstract]
[hide abstract]
ABSTRACT: Merimepodib (MMPD) is an orally administered, inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C (CHC) when combined with pegylated interferon alfa 2a (Peg-IFN-alfa-2a) and ribavirin (RBV). We conducted a randomized, double-blind, multicenter, phase 2b study to evaluate the antiviral activity, safety, and tolerability of MMPD in combination with Peg-IFN-alfa-2a and RBV in patients with genotype 1 CHC who were nonresponders to prior therapy with Peg-IFN and RBV. Patients received 50 mg MMPD, 100 mg MMPD, or placebo every 12 hours, in addition to Peg-IFN-alfa-2a and RBV, for 24 weeks. Patients with a 2-log or more decrease from baseline or undetectable hepatitis C virus (HCV) RNA levels at week 24 were then eligible to continue Peg-IFN-alfa-2a and RBV for a further 24 weeks, followed by 24 weeks of follow-up. The primary efficacy endpoint was sustained virological response (SVR) rate at week 72 in all randomized patients who received at least one dose of study drug and had a history of nonresponse to standard therapy. A total of 354 patients were randomized to treatment (117 to placebo; 119 to 50 mg MMPD; 118 to 100 mg MMPD), and 286 completed the core study. The proportion of patients who achieved SVR was similar among the treatment groups: 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P = 0.8431). Adverse-event profiles for the MMPD combination groups were similar to that for Peg-IFN-alfa and RBV alone. Nausea, arthralgia, cough, dyspnea, neutropenia, and anemia were more common in patients taking MMPD. CONCLUSION: The addition of MMPD to Peg-IFN-alfa-2a and RBV combination therapy did not increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR.
Hepatology 08/2009; 50(6):1719-26. · 11.66 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Current therapy for chronic hepatitis C virus (HCV) infection is effective in less than 50% of patients infected with HCV genotype 1. Telaprevir, a protease inhibitor specific to the HCV nonstructural 3/4A serine protease, rapidly reduced HCV RNA levels in early studies.
We randomly assigned patients infected with HCV genotype 1 to one of three telaprevir groups or to the control group. The control group (called the PR48 group) received peginterferon alfa-2a (180 microg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 48 weeks, plus telaprevir-matched placebo for the first 12 weeks (75 patients). The telaprevir groups received telaprevir (1250 mg on day 1 and 750 mg every 8 hours thereafter) for 12 weeks, as well as peginterferon alfa-2a and ribavirin (at the same doses as in the PR48 group) for the same 12 weeks (the T12PR12 group, 17 patients) or for a total of 24 weeks (the T12PR24 group, 79 patients) or 48 weeks (the T12PR48 group, 79 patients). The primary outcome was a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy).
The rate of sustained virologic response was 41% (31 of 75 patients) in the PR48 group, as compared with 61% (48 of 79 patients) in the T12PR24 group (P=0.02), 67% (53 of 79 patients) in the T12PR48 group (P=0.002), and 35% (6 of 17 patients) in the T12PR12 group (this group was exploratory and not compared with the control group). Viral breakthrough occurred in 7% of patients receiving telaprevir. The rate of discontinuation because of adverse events was higher in the three telaprevir-based groups (21%, vs. 11% in the PR48 group), with rash the most common reason for discontinuation.
Treatment with a telaprevir-based regimen significantly improved sustained virologic response rates in patients with genotype 1 HCV, albeit with higher rates of discontinuation because of adverse events. (ClinicalTrials.gov number, NCT00336479.)
New England Journal of Medicine 05/2009; 360(18):1827-38. · 53.30 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Bioelectrical impedance analysis (BIA) is a non-invasive technique that measures electrical resistance (R) and reactance (Xc), which are then used to calculate phase angle (PA). The aim of this pilot study was to assess whether BIA can differentiate between minimal and advanced hepatic fibrosis in patients with chronic hepatitis C (HCV) infection. Twenty patients with HCV participated in this study, and were divided into minimal (Metavir 1) and advanced (Metavir 3 or 4) fibrosis groups. We obtained BIA measurements (R and Xc) in several axes and calculated PA from each pair of measurements. We found no statistically significant differences between the two groups with respect to PA, R, or Xc for the whole body, the trunk or the right upper quadrant measurements in any axis. Mean whole body PA was 7.0 and 7.1 (P = 0.9) in the minimal and advanced fibrosis groups, respectively. Bioelectrical impedance analysis did not demonstrate the ability to distinguish between minimal and advanced degrees of hepatic fibrosis in patients with chronic HCV infection.
Digestive Diseases and Sciences 08/2008; 53(7):1957-60. · 2.12 Impact Factor
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John G McHutchison,
Geoffrey Dusheiko,
Mitchell L Shiffman,
Maribel Rodriguez-Torres,
Samuel Sigal,
Marc Bourliere,
Thomas Berg, Stuart C Gordon,
Fiona M Campbell,
Dickens Theodore,
Nicole Blackman,
Julian Jenkins,
Nezam H Afdhal
[show abstract]
[hide abstract]
ABSTRACT: Eltrombopag is a new, orally active thrombopoietin-receptor agonist that stimulates thrombopoiesis. We evaluated its ability to increase platelet counts and facilitate treatment for hepatitis C virus (HCV) infection in patients with thrombocytopenia associated with HCV-related cirrhosis.
Seventy-four patients with HCV-related cirrhosis and platelet counts of 20,000 to less than 70,000 per cubic millimeter were randomly assigned to receive eltrombopag (30, 50, or 75 mg daily) or placebo daily for 4 weeks. The primary end point was a platelet count of 100,000 per cubic millimeter or more at week 4. Peginterferon and ribavirin could then be initiated, with continuation of eltrombopag or placebo for 12 additional weeks.
At week 4, platelet counts were increased to 100,000 per cubic millimeter or more in a dose-dependent manner among patients for whom these data were available: in 0 of the 17 patients receiving placebo, in 9 of 12 (75%) receiving 30 mg of eltrombopag, in 15 of 19 (79%) receiving 50 mg of eltrombopag, and in 20 of 21 (95%) receiving 75 mg of eltrombopag (P<0.001). Antiviral therapy was initiated in 49 patients (in 4 of 18 patients receiving placebo, 10 of 14 receiving 30 mg of eltrombopag, 14 of 19 receiving 50 mg of eltrombopag, and 21 of 23 receiving 75 mg of eltrombopag) while the administration of eltrombopag or placebo was continued. Twelve weeks of antiviral therapy, with concurrent receipt of eltrombopag or placebo, were completed by 36%, 53%, and 65% of patients receiving 30 mg, 50 mg, and 75 mg of eltrombopag, respectively, and by 6% of patients in the placebo group. The most common adverse event during the initial 4 weeks was headache; thereafter, the adverse events were those expected with interferon-based therapy.
Eltrombopag therapy increases platelet counts in patients with thrombocytopenia due to HCV-related cirrhosis, thereby permitting the initiation of antiviral therapy. (ClinicalTrials.gov number, NCT00110799.)
New England Journal of Medicine 12/2007; 357(22):2227-36. · 53.30 Impact Factor
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John G McHutchison,
Bruce R Bacon, Stuart C Gordon,
Eric Lawitz,
Mitchell Shiffman,
Nezam H Afdhal,
Ira M Jacobson,
Andrew Muir,
Mohammed Al-Adhami,
Mary L Morris,
Julie A Lekstrom-Himes,
Susan M Efler,
Heather L Davis
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ABSTRACT: CPG 10101, a synthetic oligodeoxynucleotide (ODN), is a toll-like receptor 9 (TLR9) agonist with antiviral and immunomodulatory properties that could potentially influence chronic infection with HCV. In this multicenter Phase 1b trial, 60 HCV-positive patients (50 genotype 1 HCV) were randomized and received either placebo or CPG 10101 at 0.25, 1, 4, 10, or 20 mg subcutaneously (SC) twice weekly for 4 weeks or at 0.5 or 0.75 mg/kg SC once weekly for 4 weeks. Dose-dependent cytokine induction was observed after administration of CPG 10101. At 24 hours after administering the highest dose of 0.75 mg/kg CPG 10101, interferon (IFN)-gamma-inducible protein 10 (IP-10) had a mean increase over baseline levels (+/-SD) of 15,057 (+/-9769) pg/ml (P < 0.01, compared to placebo); IFN-alpha had a 106 (+/-63.3) pg/ml increase (P < 0.01); and 2'5'-oligoadenylate synthetase (OAS) had a 163 (+/-120.6) pmol/dl increase (P < 0.01). Decreases in HCV RNA also were dose-dependent, with the greatest group geometric mean maximum reduction of 1.69 +/- 0.618 log(10) (P < 0.05) observed in the 0.75 mg/kg dose group. Decreases >/=1 log(10) were seen in 22 of 40 patients who received >/=1 mg CPG 10101, with 3 patients exceeding a 2.5-log(10) reduction. CPG 10101 was well tolerated, and adverse events were consistent with CPG 10101's mechanism of action. Conclusion: In this Phase 1 study, CPG 10101 was associated with dose-dependent increases in markers of immune activation and decreases in HCV RNA levels. The data support further clinical studies of CPG 10101 for treating chronic HCV infection.
Hepatology 11/2007; 46(5):1341-9. · 11.66 Impact Factor
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ABSTRACT: The aims of this study were to determine the effect of pretreatment hepatic iron concentration (HIC) on response to combination therapy with interferon and ribavirin, and to examine the change in HIC associated with this treatment.
Patients with hepatitis C who underwent liver biopsy before and after combination therapy were studied retrospectively. HIC was measured from paired pre- and posttreatment liver biopsy specimens, and histologic grade and stage were recorded.
Sixty of 112 (54%) patients achieved sustained virologic response (SVR); response varied by genotype (genotype 1 (44%), genotype 2 or 3 (85%)). There was no difference in pretreatment median HIC between responders and nonresponders (404 microg/g and 394 microg/g, respectively; p= 0.31); patients with HIC > or = 500 microg/g were not less likely to achieve SVR (OR = 1.1; 95% CI 0.5-2.3). In a multivariate analysis, factors associated with SVR included genotype 2 or 3 (OR = 12.2; 95% CI 3.1-47.8) and viral load < 2 million copies/ml (OR = 3.6; 95% CI 1.3-10.0). HIC > or = 500 microg/g did not decrease the likelihood of SVR (OR = 0.8; 95% CI 0.3-2.1). There was no significant change in HIC after combination therapy (median increase in HIC = 29.5 microg/g), and the change in HIC did not differ between responders and nonresponders (p= 0.73).
Pretreatment HIC is not an independent predictor of response to therapy with interferon and ribavirin. Combination therapy does not significantly change HIC regardless of baseline histology or virologic response.
The American Journal of Gastroenterology 03/2005; 100(2):332-7. · 7.28 Impact Factor
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ABSTRACT: We examined 46 nonalcoholic steatohepatitis (NASH) and 52 hepatitis C virus (HCV) biopsy specimens to determine the magnitude of fibrosis heterogeneity and minimum length for accurate fibrosis staging. Three fibrosis scores were recorded: lowest regional, highest regional, and most common overall. Mean specimen lengths were 1.6 and 1.8 cm in NASH and HCV, respectively (P = .283). Mean (highest minus lowest) fibrosis heterogeneity scores (highest regional fibrosis - lowest regional fibrosis) were 3.7 and 2.0 in NASH and HCV, respectively (P < .001). Of 36 NASH specimens longer than 1.0 cm, 31 (86%) had the highest regional fibrosis in the deepest sampled parenchyma. Shorter specimens were associated significantly with greater fibrosis heterogeneity in NASH (coefficient, -1.3; P < .001) but not in HCV (P = .901). NASH specimens longer than 1.6 cm had significantly lower mean heterogeneity scores than specimens 1.6 cm or shorter (1.2 vs 3.4; P = .012). In NASH, fibrosis heterogeneity can be substantial and is greater than in HCV, and parenchymal injury, fibrosis, and healing might vary in different regions of the liver. The fibrosis stage in patients with NASH might not be assessed accurately in short specimens. Individual needle cores should be longer than 1.6 cm in NASH for accurate fibrosis staging.
American Journal of Clinical Pathology 03/2005; 123(3):382-7. · 2.60 Impact Factor
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ABSTRACT: Inhibition of inosine monophosphate dehydrogenase (IMPDH) is one of several proposed mechanisms of action for ribavirin (RBV), a critical component of the current treatment for chronic hepatitis C (CHC). This study was a double-blind, placebo-controlled dose-escalation study of a novel, selective, orally active small molecule inhibitor of IMPDH, merimepodib (VX-497 or MMPD) in combination with standard interferon-alpha (IFN-alpha). Fifty-four treatment-naive patients with genotype-1 CHC were randomized to receive IFN-alpha 3 MIU subcutaneously three times a week, alone or in combination with 100 mg or 300 mg (every 8 h) of MMPD for 4 weeks. At the end of 4 weeks, all patients were offered 48 weeks of treatment with IFN-alpha/RBV. The objectives of the study were to evaluate the tolerability of the IFN-alpha/MMPD combination and to evaluate whether MMPD had an on-treatment effect on HCV-RNA, similar to RBV when added to IFN-alpha. The drug combination was generally well tolerated; one patient at the higher dose discontinued because of elevated alanine aminotransferase levels. No pharmacokinetic interactions were evident between the two drugs. Analysis of covariance that adjusted for a baseline imbalance in HCV-RNA in the intent-to-treat population did not show any significant differences between the treatment groups, or between MMPD plus IFN-alpha compared with IFN-alpha alone. However, the per-protocol primary efficacy analysis based on treatment-compliant patients demonstrated a greater reduction in mean HCV-RNA in the combination of 100 mg MMPD plus IFN-alpha compared with IFN-alpha alone (-1.78 log vs -0.86 log, P=0.037). In conclusion, the addition of a selective IMPDH inhibitor to IFN-alpha was well tolerated. In a low-dose range, the addition of MMPD may have the potential to add to the antiviral efficacy of IFN-alpha. Larger, longer duration trials incorporating pegylated IFN would be required to determine whether this combination, alone or with RBV, would increase either early or sustained virological response rates.
Antiviral therapy 02/2005; 10(5):635-43. · 3.16 Impact Factor
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ABSTRACT: There are limited data regarding the frequency and proportionality of drug-induced hepatotoxicity in the United States. We sought to determine the scope of nonfulminant drug-induced hepatitis as seen in a community-based hepatology referral service.
From a population of 4,039 outpatients referred for evaluation of acute (n = 96) and chronic (n = 3,943) liver disease over a 10-year period, we reviewed the records of those patients diagnosed with acute bona fide drug-induced hepatitis.
Thirty-two patients presented with self-limited acute drug-induced hepatitis, representing 0.8% of all hepatology patients and 33% of those patients presenting with acute liver injury. Antibiotics (amoxicillin/clavulanic acid, minocycline, nitrofurantoin, an investigational ketolide antibiotic, trimethoprim-sulfamethoxazole, and trovafloxacin) were the class of drugs most frequently implicated (14 of 32; 44%), while amiodarone was the single agent most commonly associated with liver injury (7 of 32; 22%). The mean age of affected patients was 52.2 years, and we found a male predominance (18 of 32; 56%). The mean time to biochemical resolution after discontinuation of the offending agent was 14.1 weeks.
Drug-induced hepatitis is an uncommon entity in clinical hepatology but does represent a significant proportion of acute self-limited liver disease in the United States. Antibiotics and amiodarone were the most common drug culprits in our population. Time to resolution following the discontinuation of the offending agent may be protracted. Prospective studies are needed to further assess the burden of drug-induced liver injury.
Journal of Clinical Gastroenterology 02/2005; 39(1):64-7. · 3.16 Impact Factor
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ABSTRACT: In chronic hepatitis C (CHC) infection, a liver biopsy provides important information that guides treatment decisions, but is invasive, expensive and associated with possible complications. Extracellular matrix remodeling proteins may be useful non-invasive markers of fibrosis. The aim of this study was to evaluate the diagnostic accuracy of a panel of these markers in CHC patients, develop a predictive algorithm that differentiates no/mild (METAVIR F0-F1) from moderate/severe (F2-F4) fibrosis, and validate the model in external cohorts.
A combination of matrix markers were initially evaluated and optimized in 294 CHC patients from a single center, and validated in an external cohort of 402 patients.
Hyaluronic acid, TIMP-1 and alpha2-macroglobulin were selected as having the best predictive accuracy for F2-F4 fibrosis (combined AUROC = 0.831). At an index cut-off >0.36 and prevalence for F2-F4 of 52%, results in all 696 patients indicated positive and negative predictive values of 74.3 and 75.8% with an accuracy of 75%.
The three-marker panel may reliably differentiate CHC patients with moderate/severe fibrosis from those with no/mild fibrosis, although accurate delineation between stages was not possible. Prospective studies are required to determine the potential utility of the marker panel in guiding treatment decisions and following disease progression.
Journal of Hepatology 01/2005; 41(6):935-42. · 9.26 Impact Factor
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Elizabeth D Morrison,
David J Brandhagen,
Pradyumna D Phatak,
James C Barton,
Edward L Krawitt,
Hashem B El-Serag, Stuart C Gordon,
Mark V Galan,
Bruce Y Tung,
George N Ioannou,
Kris V Kowdley
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ABSTRACT: DNA-based HFE gene testing can confirm hereditary hemochromatosis in most people of Northern European descent. However, liver biopsy is important to detect cirrhosis.
To develop noninvasive criteria to predict the presence or absence of advanced hepatic fibrosis or cirrhosis in Americans with hemochromatosis.
Cross-sectional study.
Six tertiary care referral clinics.
182 patients with phenotypically defined hemochromatosis.
Liver histopathology and serum ferritin, aspartate aminotransferase, and alanine aminotransferase levels. Multivariate logistic regression analysis was used to examine factors associated with cirrhosis (defined as bridging fibrosis or unequivocal cirrhosis on biopsy).
Cirrhosis was present in 40 of 182 (22%) patients in the overall group and in 35 of 147 (24%) of C282Y homozygotes. Only 1 of 93 patients with a serum ferritin level less than 1000 microg/L had cirrhosis compared with 39 of 89 patients with serum ferritin levels greater than 1000 microg/L (P < 0.001). No C282Y homozygotes or C282Y/H63D compound heterozygotes with serum ferritin levels less than 1000 microg/L had cirrhosis. Elevated serum aminotransferase levels (P = 0.001) and serum ferritin levels greater than 1000 microg/L (P = 0.001), but not age older than 40 years (P = 0.2), were independently associated with cirrhosis. In a multivariate model, the probability of cirrhosis was 7.4% among patients with serum ferritin levels less than 1000 microg/L compared with 72% among patients with serum ferritin levels greater than 1000 microg/L after adjustment for age and elevated serum liver enzyme levels.
Patients with hemochromatosis and serum ferritin levels less than 1000 microg/L are unlikely to have cirrhosis. Liver biopsy to screen for cirrhosis may be unnecessary in such patients, regardless of age or serum liver enzyme levels.
Annals of internal medicine 04/2003; 138(8):627-33. · 16.73 Impact Factor
