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ABSTRACT: BACKGROUND: SPRINT-2 demonstrated that boceprevir (BOC), an oral hepatitis C virus (HCV)- nonstructural 3 (NS3) protease inhibitor, added to peginterferon alfa-2b (P) and ribavirin (R) significantly increased sustained virologic response rates over PR alone in previously untreated adult patients with chronic HCV genotype 1. We estimated the long-term impact of triple therapy vs. dual therapy on the clinical burden of HCV and performed a cost-effectiveness evaluation. METHODS: A Markov model was used to estimate the incidence of liver complications, discounted costs (2010 US$), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) of three treatment strategies for treatment-naive patients with chronic HCV genotype 1. The model simulates the treatment regimens studied in SPRINT-2 in which PR was administered for 4 weeks followed by: 1) placebo plus PR for 44 weeks (PR48); 2) BOC plus PR using response guided therapy (BOC/RGT); and 3) BOC plus PR for 44 weeks (BOC/PR48) and makes projections within and beyond the trial. HCV-related state-transition probabilities, costs, and utilities were obtained from previously published studies. All costs and QALYs were discounted at 3%. RESULTS: The model projected approximately 38% and 43% relative reductions in the lifetime incidence of liver complications in the BOC/RGT and BOC/PR48 regimens compared with PR48; respectively. Treatment with BOC/RGT is associated with an incremental cost of $10,348 and an increase of 0.62 QALYs compared to treatment with PR48. Treatment with BOC/PR48 is associated with an incremental cost of $35,727 and an increase of 0.65 QALYs compared to treatment with PR48. The ICERs were $16,792/QALY and $55,162/QALY for the boceprevir-based treatment groups compared with PR48, respectively. The ICER for BOC/PR48 compared with BOC/RGT was $807,804. CONCLUSION: The boceprevir-based regimens used in the SPRINT-2 trial were projected to substantially reduce the lifetime incidence of liver complications and increase the QALYs in treatment-naive patients with hepatitis C genotype 1. It was also demonstrated that boceprevir-based regimens offer patients the possibility of experiencing great clinical benefit with a shorter duration of therapy. Both boceprevir-based treatment strategies were projected to be cost-effective at a reasonable threshold in the US when compared to treatment with PR48.
BMC Infectious Diseases 04/2013; 13(1):190. · 3.12 Impact Factor
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Christopher E McGowan,
Ali Monis,
Bruce R Bacon,
Josep Mallolas,
Fernando L Goncales,
Ioannis Goulis, Fred Poordad,
Nezam Afdhal,
Stefan Zeuzem,
Teerha Piratvisuth,
Patrick Marcellin,
Michael W Fried
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ABSTRACT: Background: Chronic infection with the hepatitis C virus (HCV) is a leading cause of global morbidity and mortality. While recent advances in antiviral therapy have led to significant improvements in treatment response rates, only a minority of infected patients is treated. Multiple barriers may impede the delivery of HCV therapy. Aim: To identify perceived barriers to care, knowledge, and opinions among a global sample of HCV treatment providers. Methods: An international, multidisciplinary survey of HCV treatment providers was conducted. Each physician responded to a series of 214 questions concerning his or her practice characteristics, opinions regarding the state of HCV care, knowledge regarding HCV treatment, and perception of treatment barriers. Results: 697 physicians from 29 countries completed the survey. Overall, physicians viewed patient-level barriers as most significant, including fear of side effects and concerns regarding treatment duration and cost. There were distinct regional variations, with Central and Eastern European physicians citing government barriers as most important. In Latin America, the Middle East, and Africa, payer-level barriers, including lack of treatment coverage, were prominent. Overall, the perception of barriers was strongly associated with physician knowledge, experience, and region of origin, with the fewest barriers reported by Nordic physicians and the most reported by Middle Eastern and African physicians. Globally, physicians demonstrated deficits in basic treatment principles, including the role of viral kinetics and the management of treatment non-responders. Two-thirds of surveyed physicians believed that patients do not have adequate access to providers in their community. Conclusion: Barriers to HCV treatment vary globally, though patient-level factors are viewed as most significant by treating physicians. Efforts to improve awareness, education, and specialist availability are needed. (HEPATOLOGY 2013.).
Hepatology 01/2013; · 11.66 Impact Factor
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Savino Bruno,
John M Vierling,
Rafael Esteban,
Lisa M Nyberg,
Hugo Tanno,
Zachary Goodman, Fred Poordad,
Bruce Bacon,
Keith Gottesdiener,
Lisa D Pedicone,
Janice K Albrecht,
Clifford A Brass,
Seth Thompson,
Margaret H Burroughs
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ABSTRACT: BACKGROUND AND AIMS: We assessed the safety and efficacy of boceprevir (BOC) plus peginterferon-ribavirin (PR) in patients with HCV-G1 infection and advanced fibrosis/cirrhosis (Metavir F3/F4). METHODS: In two randomized controlled studies in previously untreated and previous treatment-failures, patients received a 4-week lead-in of PR followed by PR plus placebo for 44 weeks (PR48); PR plus BOC using response guided therapy (BOC/RGT); or PR plus BOC for 44 weeks (BOC/PR48). RESULTS: The trials enrolled 178 patients with F3/4. HCV-RNA levels at week 4 and 8 were highly predictive of response. No patient with F3/4 in the PR48 arm with a <1-log(10) decline in HCV-RNA at week 4 achieved SVR, whereas those randomized to BOC/RGT or BOC/PR48 had SVR rates of 11-33% (F3) and 10-14% (F4). In these latter groups, patients with high baseline viral load (>2 X 10(6) IU/mL) had an overall SVR rate of 6% (2/33). For patients with a ⩾1-log(10) decline at week 4, SVR rates in the BOC/PR48 arm of SPRINT-2 and RESPOND-2, respectively, were 77% and 87% vs. 18% and 50% for PR48; SVR rates in early responders (undetectable HCV RNA at week 8) were 90-93% in the BOC/PR48 arm. Neutropenia and thrombocytopenia were more common in cirrhotics than non-cirrhotics. CONCLUSIONS: BOC improved SVR rates in patients with F3/4, and longer treatment duration provides the most benefit. With triple therapy, SVR rates are modest in F4 patients with a <1-log(10) decline at week 4, thus the 4-week PR lead-in aids in the assessment of early futility.
Journal of Hepatology 11/2012; · 9.26 Impact Factor
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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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Ira M Jacobson,
Patrick Marcellin,
Stefan Zeuzem,
Mark S Sulkowski,
Rafael Esteban, Fred Poordad,
Savino Bruno,
Margaret H Burroughs,
Lisa D Pedicone,
Navdeep Boparai,
Weiping Deng,
Mark J DiNubile,
Keith M Gottesdiener,
Clifford A Brass,
Janice K Albrecht,
Jean-Pierre Bronowicki
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ABSTRACT: In comparison with peginterferon/ribavirin alone, boceprevir with peginterferon/ribavirin significantly improves sustained virological response (SVR) rates in patients with chronic hepatitis C virus (HCV) genotype 1 infections, but treatment failure remains a significant problem. Using phase 3 trial databases, we sought to develop stopping rules for patients destined to fail boceprevir-based combination therapy in order to minimize drug toxicity, resistance, and costs in the face of ultimate futility. Exploratory post hoc analyses using data from the Serine Protease Inhibitor Therapy 2 (SPRINT-2) study (treatment-naive patients) and the Retreatment With HCV Serine Protease Inhibitor Boceprevir and Pegintron/Rebetol 2 (RESPOND-2) study (treatment-experienced patients) were undertaken to determine whether protocol-specified stopping rules (detectable HCV RNA at week 24 for SPRINT-2 and at week 12 for RESPOND-2) could be refined and harmonized. In SPRINT-2, a week 12 rule with an HCV RNA cutoff of ≥ 100 IU/mL would have discontinued therapy in 65 of 195 failures (sensitivity = 33%) without sacrificing a single SVR among 475 successes (specificity = 100%). Viral variants emerged after week 12 in 36 of the 49 evaluable patients (73%) who would have discontinued at week 12 using a ≥ 100 IU/mL stopping rule. In RESPOND-2, five of six patients with week 12 HCV RNA levels between the lower limit of detection (9.3 IU/mL) and the lower limit of quantification (25 IU/mL) who continued therapy despite the protocol-stipulated futility rule achieved SVR; one additional patient with a week 12 HCV RNA level of 148 IU/mL also continued therapy, had undetectable HCV RNA at week 16, and attained SVR. CONCLUSION: Although a stopping rule of detectable HCV RNA at week 12 would have forfeited some SVR cases, week 12 HCV RNA levels ≥ 100 IU/mL almost universally predicted a failure to achieve SVR in both treatment-naive and treatment-experienced patients. In boceprevir recipients, the combination of 2 stopping rules-an HCV RNA level ≥ 100 IU/mL at week 12 and detectable HCV RNA at week 24--maximized the early discontinuation of futile therapy and minimized premature treatment discontinuation.
Hepatology 05/2012; 56(2):567-75. · 11.66 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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ABSTRACT: Hepatic encephalopathy (HE) represents a continuum of transient and reversible neurologic and psychiatric dysfunction. It is a reversible state of impaired cognitive function or altered consciousness in patients with liver disease or portosystemic shunting. Over the last several years, high-quality studies have been conducted on various pharmacologic therapies for HE; as more data emerge, it is hoped that HE will become a more easily treated complication of decompensated liver disease. In the interim, it is important that physicians continue to screen for minimal HE and treat patients early in addition to continuing to provide current treatments of overt HE.
Clinics in liver disease 05/2012; 16(2):301-20.
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ABSTRACT: Hepatic encephalopathy (HE) is a potentially reversible state of impaired cognitive function or altered consciousness in patients with liver disease or portosystemic shunting. Overt HE is a particularly pressing problem. Given the many targets of treatment and lack of a clear singular cause of overt HE, there is no consensus on a single best treatment. Over the past several years, high-quality studies have been conducted on the various pharmacologic therapies for HE and, as more data emerge, hopefully HE will become a much more easily treated complication of decompensated liver disease.
Clinics in liver disease 02/2012; 16(1):73-89.
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ABSTRACT: Thrombocytopenia (TCP), defined as platelet counts <150,000/µL, is a common complication of severe chronic liver disease (CLD). This retrospective study estimated the prevalence of thrombocytopenia in a large population of CLD patients and compared medical resource utilization and medical care costs by TCP status.
A retrospective analysis was conducted on a longitudinal administrative claims database from a large US commercial health plan. Patients assigned CLD diagnosis codes from January 1, 2000-December 31, 2003 were identified; annual ambulatory visits, ER visits, inpatient stays, and general and CLD-related medical care costs for patients with vs without TCP (identified using diagnosis codes and platelet count data if available) were compared.
Of 56,445 patients with an ICD-9-CM diagnosis for CLD, 1289 (2.3%) had a diagnosis for TCP. CLD patients with vs without a TCP diagnosis had >2.5-times the annual number of liver disease-related ambulatory visits (3.6 vs 1.4; odds ratio [OR] = 2.6, p < 0.01); were 13-times more likely to have a liver-related inpatient stay (OR = 13.0, p < 0.01); were nearly 4-times more likely to have a liver-related ER visit (OR = 3.9, p < 0.01); had 3.5-fold greater mean annual overall medical care costs ($43,560 vs $12,270, p < 0.01); and had 7-fold greater annual liver disease-related medical care costs ($9940 vs $1420, p < 0.01). Similar results were seen for patients with platelet count data indicating TCP.
CLD and TCP are not always diagnosed, nor is diagnosis uniform or standardized; administrative claims data are subject to coding errors, and individuals covered are not necessarily representative of the general US population. The number of CLD patients in this study with TCP (n = 1289) is small relative to that expected in the general US population.
In this analysis, CLD patients with TCP used significantly more medical resources and incurred significantly higher medical care costs than those without TCP.
Journal of Medical Economics 01/2012; 15(1):112-24.
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ABSTRACT: Hepatitis C is a virus affecting millions worldwide and is a major health risk. With the potentially severe adverse event profile of the current backbone of therapy, interferon, there is an impetus to discover interferon free treatment regimens. With the development of new oral direct acting antivirals, interferon free regimens may be available in the next few years. This article discusses some of the preliminary data from interferon free studies.
Current Gastroenterology Reports 11/2011; 14(1):74-7.
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Kenneth E Sherman,
Steven L Flamm,
Nezam H Afdhal,
David R Nelson,
Mark S Sulkowski,
Gregory T Everson,
Michael W Fried,
Michael Adler,
Hendrik W Reesink,
Marie Martin,
Abdul J Sankoh,
Nathalie Adda,
Robert S Kauffman,
Shelley George,
Christopher I Wright, Fred Poordad
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ABSTRACT: Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often need 48 weeks of peginterferon-ribavirin treatment for a sustained virologic response. We designed a noninferiority trial (noninferiority margin, -10.5%) to compare rates of sustained virologic response among patients receiving two treatment durations.
We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 μg per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon-ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48.
Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, -2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001).
In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon-ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number, NCT00758043.).
New England Journal of Medicine 09/2011; 365(11):1014-24. · 53.30 Impact Factor
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ABSTRACT: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is rarely curable. However, in view of the advent of new treatments, it is critical that patients at high risk for recurrence are identified.
Patients undergoing LT for HCC at a single centre between 2002 and 2010 were reviewed and data on clinical parameters and explant pathology were analysed to determine factors associated with HCC recurrence. All necrotic and viable tumour nodules were included in explant staging. All patients underwent LT according to the United Network for Organ Sharing (UNOS) Model for End-stage Liver Disease (MELD) tumour exception policies.
Liver transplantation was performed in 122 patients with HCC during this period. Rates of recurrence-free survival in the entire cohort at 1 year and 3 years were 95% and 89%, respectively. Thirteen patients developed HCC recurrence at a median of 14 months post-LT. In univariate analysis the factors associated with HCC recurrence were bilobar tumours, vascular invasion, and stage exceeding either Milan or University of California San Francisco (UCSF) Criteria. Multivariate analysis showed pathology outside UCSF Criteria was the major predictor of recurrence; when pathology outside UCSF Criteria was found in combination with vascular invasion, the predicted 3-year recurrence-free survival was only 26%.
Explant pathology can be used to predict the risk for recurrent HCC after LT, which may allow for improved adjuvant and management strategies.
HPB 09/2011; 13(9):626-32. · 1.60 Impact Factor
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Fred Poordad
Clinics in liver disease 08/2011; 15(3):xiii-xiv.
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Alexander J Thompson,
Paul J Clark,
Abanish Singh,
Dongliang Ge,
Jacques Fellay,
Mingfu Zhu,
Qianqian Zhu,
Thomas J Urban,
Keyur Patel,
Hans L Tillmann, [......],
Paul Y Kwo,
Kevin V Shianna,
Stephanie Noviello,
Lisa D Pedicone,
Clifford A Brass,
Janice K Albrecht,
Mark S Sulkowski,
David B Goldstein,
John G McHutchison,
Andrew J Muir
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ABSTRACT: Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia.
1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ≥80×10(9)/L and an absolute neutrophil count (ANC) ≥1500/mm(3). Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n=1294).
6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p=10(-10)). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction (p=10(-12), p=10(-7)) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r=-0.28, p=10(-17)) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia.
Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified.
Journal of Hepatology 05/2011; 56(2):313-9. · 9.26 Impact Factor
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Fred Poordad,
Jonathan McCone,
Bruce R Bacon,
Savino Bruno,
Michael P Manns,
Mark S Sulkowski,
Ira M Jacobson,
K Rajender Reddy,
Zachary D Goodman,
Navdeep Boparai,
Mark J DiNubile,
Vilma Sniukiene,
Clifford A Brass,
Janice K Albrecht,
Jean-Pierre Bronowicki
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ABSTRACT: Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.
We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned 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 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.
A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.
The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).
New England Journal of Medicine 03/2011; 364(13):1195-206. · 53.30 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
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ABSTRACT: The current standard of care for patients with chronic hepatitis C virus (HCV) infection is pegylated interferon alfa in combination with ribavirin. Treatment duration and efficacy depend heavily on HCV genotype. A sustained virologic response (SVR) is achieved only in approximately 40% of patients. Side effects of the current standard of care often make adherence to therapy difficult, further reducing the chance for an SVR. Numerous patient-related and virus-related factors can determine response to treatment. Nonresponders are a large proportion of the current HCV-infected population, and the number of patients with HCV infection is growing, necessitating newer therapies with higher efficacy and potentially fewer side effects. A new era of direct acting antiviral (DAA) compounds has emerged. The first 2 protease inhibitors for HCV infection, telaprevir and boceprevir, are coming to market in 2011. Other protease compounds in development include TMC-435, vaniprevir, BI-201335, BMS-650032, and danoprevir. The numerous other therapies that have potential in the treatment of HCV infection include nucleoside inhibitors, non-nucleoside inhibitors, NS5A inhibitors, DAA combinations, therapeutic vaccines, human monoclonal antibodies, immune modifiers, and interferon lambda.
The American journal of managed care 03/2011; 17 Suppl 4:S123-30. · 2.46 Impact Factor
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ABSTRACT: Thrombocytopenia is a significant risk for patients with chronic HCV infection and a common side-effect of treatment with pegylated (PEG) interferon (IFN). Thrombocytopenia predisposes patients to bleeding and requirements for platelet transfusions, and may thus place an increased burden on patients and on medical resource utilisation.
In a retrospective analysis of an integrated, longitudinal database of medical and pharmacy claims and laboratory results in a US commercial health (insurance) plan, patients with chronic hepatitis C viral (HCV) infection were identified by reviewing ICD-9-CM HCV-, chronic liver disease-, and cirrhosis-related diagnoses. Medical resource utilisation and laboratory results were evaluated during the year following the HCV diagnosis index date as well as during the baseline year prior to that index date. Medical resource utilisation was determined by comparing outpatient visits, emergency department (ER) visits, and inpatient hospital stays for HCV patients with or without thrombocytopenia.
HCV patients diagnosed with thrombocytopenia had a greater incidence of bleeding events (27.3 vs. 9.9%), platelet transfusions (8.5 vs. <1%), liver disease-related ambulatory visits (10.4 vs. 4.4; odds ratio [OR] = 2.3; p < 0.001), ER visits (OR = 8.6; p < 0.01), and inpatient hospital stays (OR = 17.7; p < 0.01) during the study period compared with HCV patients without a thrombocytopenia diagnosis. HCV patients with thrombocytopenia had significantly higher overall healthcare costs ($37,924 vs. $12,174; p < 0.001) and liver disease-related costs ($14,569 vs. $4107; p < 0.001) than patients without thrombocytopenia.
Administrative claims data are subject to coding errors; additionally, the patient population may not be completely representative of the general chronic HCV population.
Diagnosis of thrombocytopenia in patients with HCV is associated with increased incidence of certain comorbidities, complications, and medical interventions, and significantly increased medical resource utilisation.
Journal of Medical Economics 02/2011; 14(2):194-206.
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Fred Poordad
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ABSTRACT: The story of hepatitis C virus (HCV) therapy is about to add one of its biggest chapters. From the serendipitous beginnings in the 1980s when investigators noted that interferon improves liver enzymes in non-A, non-B hepatitis, to the discovery and naming of the hepatitis virus, to the addition of ribavirin, to the pegylation of interferon, and now to the first direct-acting antivirals (DAA), the history of HCV is an intriguing one that continues to unfold. Along with the first DAAs, other important findings have helped explain long-observed differences between various ethnic groups, as well as new predictive information that can be gleaned from some of the observed adverse events.
Current Gastroenterology Reports 11/2010; 13(1):72-7.
