RESUMO
Approved direct-acting antiviral (DAA) regimens against hepatitis C virus (HCV) can cure nearly all patients; however, socioeconomic disparities may impact access and outcome. This study assesses socioeconomic factors, differences in insurance coverage and the drug prior authorization process in HCV-infected patients managed in community practices partnered with a dedicated pharmacy team with expertise in liver disease. This Institutional Review Board-approved, ongoing study captures data on a cohort of 2480 patients from community practices. Patients had chronic hepatitis C and were treated with DAA regimens selected by their physician. The HCV Health Outcomes Centers Network provides comprehensive patient management including a dedicated pharmacy support team with expertise in the prior authorization process. In this cohort, 60.1% were male, 49% were Hispanic Whites (HW), 37% were Non-Hispanic Whites (NHW), and 14% were Black/African American (BAA). Eighty-seven percent of patients were treatment-naïve, 74% were infected with genotype 1 virus and 63% had advanced fibrosis/cirrhosis (F3/F4 = 68.2% HW, 65.6% BAA, 55.4% NHW). Forty percent of patients were on disability with the highest percentage in the BAA group and less than one-third were employed full time, regardless of race/ethnicity. Medicare covered 42% of BAA patients versus 32% of HW and NHW. The vast majority of HW (80%) and BAA (75%) had a median income below the median income of Texas residents. Additionally, 75% of HW and 71% of BAA had median income below the poverty level in Texas. Despite the above socioeconomic factors, 92% of all prior authorizations were approved upon first submission and patients received DAAs an average of 17 days from prescription. DAA therapy resulted in cure in 95.3% of patients (sustained virologic response = 94.8% HW, 94.0% BAA, 96.5% NHW). Despite having more advanced diseases and more negative socioeconomic factors, >94% of HW and BAA patients were cured. Continued patient education and communication with the healthcare team can lead to high adherence and > 94% HCV cure rates regardless of race/ethnicity or underlying socioeconomic factors in the community setting.
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Hepatite C Crônica , Hepatite C , Farmácia , Idoso , Humanos , Masculino , Estados Unidos , Feminino , Hepatite C Crônica/tratamento farmacológico , Resposta Viral Sustentada , Antivirais , Medicare , Hepatite C/tratamento farmacológico , Hepacivirus/genética , Cirrose Hepática , Fatores Socioeconômicos , Resultado do TratamentoRESUMO
The aim of this study was to obtain real-world, US, observational data on the effect of baseline resistance-associated substitutions (RASs) on achieving sustained virologic response (SVR) in hepatitis C (HCV) patients treated with direct-acting antiviral (DAA) regimens; the need for long-term follow-up in post-SVR patients.It is uncertain if the presence of RASs limits efficacy to DAAs. Once SVR is achieved, society guidelines recommend long-term surveillance for hepatocellular carcinoma in certain patients. Real-world data are limited on these topics.Adult patients treated with DAAs at community hepatitis clinics between January 2015 and April 2017 were included in this study. Baseline resistance testing was performed before treatment. Per guidelines, post-SVR long-term monitoring was required in patients with F3 to F4 fibrosis before treatment or with elevated ALT levels (>19âU/L females; >30âU/L males).A total of 875 chronic, mostly GT1a (60%) HCV patients were treated with an approved DAA regimen. Average baseline AST and ALT were 75 and 67âU/L, respectively, and 47% had F3 to F4 fibrosis at baseline. SVR was achieved in 863 (98.6%) patients despite a high presence of baseline RASs (61%). Long-term monitoring was required post-SVR in 539 patients (62%).In a real-life, US cohort of HCV-infected patients, nearly all patients achieved SVR with available DAA regimens regardless of baseline RASs. Approximately two-thirds of these patients required long-term follow-up, despite viral eradication.
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Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Farmacorresistência Viral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância da População , Estudos Prospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
Background and Aims: Approximately half of adults with hepatitis C in the United States do not know their infection status, and the majority of persons who know they are positive for hepatitis C virus (HCV) antibodies fail to receive care. We conducted a screening program in retail pharmacies and calculated the percentages of anti-HCV-positive individuals and how many subsequently entered a pathway to care. Methods: At 45 Walgreens retail pharmacies in 9 US cities, direct store advertising was used to recruit individuals for HCV antibody testing. Participants were at least 18 years old with at least 1 HCV risk factor, such as being born between 1945 and 1965. One day per week at each site, a phlebotomist obtained consent from interested participants and performed the testing. Within 3 business days, an HCV management specialist contacted anti-HCV-positive individuals and provided test results and a pathway for obtaining HCV RNA testing. During the following 21 to 28 days, the same HCV management specialist telephoned individuals to determine whether they underwent an HCV RNA test. Results: Between September 2015 and February 2016, 1298 individuals consented. Two patients withdrew consent after testing. In all, 8% (103/1296) were HCV antibody-positive; of them, 91 (88%) were contacted by an HCV management specialist. During the 21- to 28-day follow-up, 56 individuals (62%; 56/91) were reached by an HCV management specialist, and 29 (52%; 29/56) confirmed that an HCV RNA test was ordered. Conclusions: These results provide evidence in support of point-of-care HCV screening in retail pharmacies for at-risk individuals in the United States.
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BACKGROUND & AIMS: HCV-infected cirrhotics may urgently need therapy but are often under-represented in clinical trials resulting in limited data to guide their management. We performed a meta-analysis of well-compensated cirrhotic patients from five Phase 3 trials. METHODS: Patients received P/R (peginterferon/ribavirin; 4 weeks) followed by BOC (boceprevir)/P/R or P/R for 24, 32, or 44 weeks. Sustained virologic response (SVR) rates were calculated by Metavir score. Multivariate logistic regression (MLR) models identified baseline and on-treatment predictors of SVR. Safety was evaluated by adverse-event (AE) reporting and laboratory monitoring. RESULTS: Pooled meta-estimates for SVR rates (95% confidence interval) in 212 F4 (cirrhotic) patients were 55% (43, 66) with BOC/P/R vs.17% (0, 41) with P/R. MLR identified 4 predictors of SVR in F3/F4 patients: undetectable HCV-RNA at treatment week (TW) 8; ⩾ 1 log10 decline in HCV-RNA from baseline at TW4; male; and baseline HCV-RNA ⩽ 800,000 IU/ml. SVR rate was 89% (65/73) in F4 patients who were HCV-RNA undetectable at TW8. No F3 (0/5) or F4 (0/17) patients with <3 log10 decline and detectable HCV-RNA at TW8 achieved SVR. Anemia and diarrhea occurred more frequently in cirrhotic than non-cirrhotic patients. Serious AEs, discontinuations due to an AE, interventions to manage anemia, infections, and thrombocytopenia occurred more frequently in cirrhotics with BOC/P/R than P/R. Potential hepatic decompensation and/or sepsis were identified in 2 P/R and 3 BOC/P/R recipients. CONCLUSIONS: BOC/P/R appears to have a generally favorable benefit-risk profile in compensated cirrhotic patients. SVR rates were particularly high in cirrhotic patients with undetectable HCV-RNA at TW8.
Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/complicações , Interferon-alfa/administração & dosagem , Cirrose Hepática/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Prolina/análogos & derivados , Ribavirina/administração & dosagem , Adulto , Idoso , Ensaios Clínicos Fase III como Assunto , Quimioterapia Combinada , Feminino , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/etiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prolina/administração & dosagem , RNA Viral/análise , Proteínas Recombinantes/administração & dosagem , Estudos RetrospectivosRESUMO
BACKGROUND: Myelosuppression due to pegylated interferon (peg-IFN) is common during treatment for hepatitis C virus. The relationship between infection risk and decreases in leukocyte lines, however, is not well established. The objective of this analysis was to determine the incidence of and risk factors for infections during peg-IFN/ribavirin (RBV) therapy. METHODS: A total of 3070 treatment-naive, chronic hepatitis C genotype 1-infected patients were treated for up to 48 weeks with peg-IFN alfa-2b 1.5 µg/kg/week or 1 µg/kg/week, or peg-IFN alfa-2a 180 µg/week plus RBV. On-treatment leukocyte counts were obtained every 2-6 weeks. Dose reduction was required for a neutrophil count <0.75 × 10(9) cells/L, and treatment discontinuation was required for a neutrophil count <0.5 × 10(9) cells/L. Granulocyte colony-stimulating factor was prohibited. Data on infections were captured at each study visit and categorized according to MedDRA version 13.0. RESULTS: A total of 581 (19%) patients experienced moderate, severe, or life-threatening infections as assessed by the investigator; 648 (21%) patients had at least 1 neutrophil count <0.75 × 10(9) cells/L, but only 242 (8%) sustained an infection and had a neutrophil count <0.75 × 10(9) cells/L at any time while on treatment. Twelve patients had severe or life-threatening infection and grade 3/4 neutropenia, but only 4 had temporally related infections. In a multivariate logistic regression model, nadir lymphocyte count, history of depression, and female sex, but not nadir neutrophil count, were associated with moderate, severe, or life-threatening infection. CONCLUSIONS: Nadir lymphocyte count, not nadir neutrophil count, was independently associated with moderate, severe, or life-threatening infections in the IDEAL study. Clinicians should be aware of their patients' absolute lymphocyte counts during peg-IFN/RBV therapy; peg-IFN dose reductions may be a consideration in patients with significant lymphocytopenia (<0.5 × 10(9) cells/L).
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Hepatite C/tratamento farmacológico , Infecções/epidemiologia , Interferon-alfa/efeitos adversos , Polietilenoglicóis/efeitos adversos , Ribavirina/efeitos adversos , Adolescente , Adulto , Idoso , Feminino , Hepatite C/complicações , Humanos , Incidência , Infecções/complicações , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Contagem de Linfócitos , Linfopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neutrófilos/efeitos dos fármacos , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND & AIMS: Boceprevir with peginterferon/ribavirin (BOC/PR) leads to significantly higher sustained virological response (SVR) rates in patients with chronic hepatitis C and partial response or relapse after prior treatment with peginterferon/ribavirin. We studied the efficacy of BOC/PR in patients with prior treatment failure, including those with a null response (<2-log10 decline in HCV RNA), to peginterferon/ribavirin. METHODS: Patients in the control arms of boceprevir Phase 2/3 studies who did not achieve SVR were re-treated with BOC/PR for up to 44 weeks. Patients enrolling >2 weeks after end-of-treatment in the prior study received PR for 4 weeks before adding boceprevir. RESULTS: Of 168 patients enrolled, four discontinued from the PR lead-in and 164 received BOC/PR. Baseline viral load was >800,000 IU/ml in 77% of patients; 62% had HCV genotype 1a, and 10% were cirrhotic. In the ITT analysis (all 168 patients), SVR was achieved in 20 (38%) of 52 patients with prior null response, 57 (67%) of 85 with prior partial response, and 27 (93%) of 29 with prior relapse. In the mITT analysis (164 BOC/PR-treated patients), SVR rates were 41% (20/49), 67% (57/85), and 96% (27/28), respectively. SVR was achieved by 48% of patients with <1-log10 decline in HCV-RNA after lead-in and 76% of those with ⩾ 1-log10 decline or undetectable HCV-RNA after lead-in. The most common adverse events were anemia (49%), fatigue (48%), and dysgeusia (35%); 8% of patients discontinued due to adverse events. CONCLUSIONS: Re-treatment with BOC/PR improved SVR rates in all patient subgroups, including those with prior null response.
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Antivirais/administração & dosagem , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Prolina/análogos & derivados , Ribavirina/administração & dosagem , Adulto , Idoso , Antivirais/efeitos adversos , Farmacorresistência Viral/genética , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/classificação , Hepacivirus/efeitos dos fármacos , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Prolina/administração & dosagem , Prolina/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Ribavirina/efeitos adversos , Falha de Tratamento , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
BACKGROUND: Baseline viral load is a predictor of treatment outcome in patients with hepatitis C virus (HCV) infection receiving peginterferon and ribavirin. The impact of baseline viral load on sustained virologic response (SVR) after boceprevir-based therapy is unknown. METHODS: This retrospective analysis included patients with chronic HCV genotype 1 infection who were previously untreated or were previous treatment failures. Virologic response was assessed according to baseline viral load (≤1 million IU/mL, >1 to ≤5 million IU/mL, >5 to ≤10 million IU/mL, and >10 million IU/mL). RESULTS: SVR was higher in patients receiving boceprevir plus peginterferon and ribavirin than in those receiving peginterferon and ribavirin alone, regardless of baseline viral load. Patients with a baseline viral load ≤1 million IU/mL had the highest SVR (boceprevir plus peginterferon and ribavirin, 78% to 83%; peginterferon and ribavirin, 33% to 63%). Among patients with baseline viral load >1 million IU/mL, SVR rates were 57% to 68% in patients receiving boceprevir plus peginterferon and ribavirin, and 11% to 41% in patients receiving peginterferon and ribavirin. Relapse was higher in patients receiving peginterferon and ribavirin (previously untreated, 12% to 40%; previous treatment failures, 17% to 67%) than in those receiving boceprevir plus peginterferon and ribavirin (previously untreated, 3% to 12%; previous treatment failure, 9% to 16%), irrespective of baseline viral load. CONCLUSIONS: The efficacy of boceprevir plus peginterferon and ribavirin was unaffected by baseline viral loads >1 million IU/mL, whereas viral burden >1 million IU/mL was associated with lower SVR with peginterferon and ribavirin. Relapse rates were lower with boceprevir plus peginterferon and ribavirin than with peginterferon and ribavirin, and were unaffected by baseline viral load.
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Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Prolina/análogos & derivados , Adulto , Idoso , Antivirais/administração & dosagem , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Prolina/administração & dosagem , Prolina/uso terapêutico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Recidiva , Estudos Retrospectivos , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Falha de Tratamento , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND & AIMS: Triple therapy with peginterferon/ribavirin (PR) plus an NS3 protease inhibitor has emerged as the standard-of-care for patients with chronic hepatitis C genotype-1. We provide a detailed safety analysis comparing PR to boceprevir plus PR (BOC/PR) across three phase 2/3 studies. METHODS: SPRINT-1 was an open-label phase 2 study in 595 treatment-naive patients. In the two phase 3 studies, 1500 patients (1097 treatment-naive, SPRINT-2; 403 treatment-failure, RESPOND-2) were randomized to receive PR alone, or one of two regimens where BOC was added to PR after a 4-wk PR lead-in. In this analysis, the respective BOC/PR and PR arms were combined for all three trials. The benefit of shortened duration of treatment using response-guided therapy (RGT) was also explored in the SPRINT-2 trial. RESULTS: Only two adverse events, anaemia and dysgeusia, occurred 20% more often with the BOC-containing regimens compared with PR. Nausea, diarrhoea and neutropenia were the only other common events with an incidence of at least 5% greater when BOC was added to the PR backbone. The proportions of patients reporting serious adverse events (AE), life-threatening AEs, and study drug discontinuation because of an AE were similar in the PR and BOC/PR arms. In treatment-naive patients, RGT generally did not result in a lower frequency of common AEs; however, RGT led to decreased exposure to all 3 study drugs and to a decrease in the mean duration of several clinically relevant AEs such as anaemia, neutropenia, fatigue and depression, as well as earlier normalization of haemoglobin and neutrophil counts. CONCLUSIONS: The safety profile of BOC combination therapy largely reflects the known profile of peginterferon and ribavirin, with incremental haematolgical effects and dysgeusia. Shorter treatment duration with RGT significantly reduced the duration of AEs.
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Antivirais/efeitos adversos , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/efeitos adversos , Polietilenoglicóis/efeitos adversos , Prolina/análogos & derivados , Ribavirina/efeitos adversos , Adolescente , Adulto , Idoso , Quimioterapia Combinada , Feminino , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Prolina/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Adulto JovemRESUMO
INTRODUCTION: Pharmacogenomic testing is important in developing individualized therapeutic approaches. In the phase 3 IDEAL (Individualized Dosing to Assess Optimal Pegylated Interferon Therapy) clinical trial, a subset of patients receiving peginterferon and ribavirin for treatment of chronic hepatitis C agreed to provide blood samples for genetic testing. Genome-wide association studies subsequently identified associations between IL28B polymorphism and sustained virologic response, and ITPA polymorphism and ribavirin-associated anemia. OBJECTIVE: To characterize the groups of patients who accepted or declined pharmacogenomic testing in the IDEAL study. METHODS: Clinical and demographic factors and treatment outcomes were compared at all sites that had approved pharmacogenomic testing. Differences between patients who consented to and declined pharmacogenomic testing were analyzed using Student's t-test and χ²-test. RESULTS: In total, 109 of 118 sites participated in the pharmacogenomic substudy, and 1674 of 2949 (57%) patients enrolled at these sites consented to pharmacogenomic testing. More patients treated in academic medical centers than in community centers (60 vs. 52%, P<0.001) provided consent. More men than women (58 vs. 54%, P=0.04) consented to pharmacogenomic testing. There was no significant difference in pharmacogenomic participation between patients from different racial groups, including whites and African Americans (58 vs. 54%, P=0.07). Treatment outcomes were also similar according to pharmacogenomic participation. CONCLUSION: In the IDEAL study, patient consent to pharmacogenomic testing did not introduce selection bias. Treatment at an academic center and male sex were associated with higher rates of pharmacogenomic testing consent. Efficacy and safety outcomes were similar in patients who accepted and declined pharmacogenomic testing.
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Antivirais/administração & dosagem , Testes Genéticos , Hepatite C Crônica/genética , Interferon-alfa/administração & dosagem , Interleucinas/genética , Polietilenoglicóis/administração & dosagem , Pirofosfatases/genética , Ribavirina/administração & dosagem , Adolescente , Adulto , Idoso , Anemia/genética , Antivirais/uso terapêutico , Quimioterapia Combinada , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Hepacivirus/metabolismo , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Consentimento Livre e Esclarecido , Interferon-alfa/uso terapêutico , Interferons , Masculino , Pessoa de Meia-Idade , Farmacogenética , Polietilenoglicóis/uso terapêutico , Polimorfismo Genético , Medicina de Precisão , Grupos Raciais/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Caracteres Sexuais , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND & AIMS: Treatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety. METHODS: Patients (n = 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251). RESULTS: Rates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total milligrams of ribavirin assigned by the protocol had a significantly lower rate of SVR (P < .0001) than those who received ≥50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported in 9 of 295 patients who received erythropoietin, compared with 1 of 392 patients who did not receive erythropoietin. CONCLUSIONS: Reduction of ribavirin dosage can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dosage throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (milligrams) of ribavirin assigned by response-guided therapy. ClinicalTrials.gov number, NCT01023035.
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Anemia/prevenção & controle , Eritropoetina/uso terapêutico , Genótipo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Prolina/análogos & derivados , Ribavirina/uso terapêutico , Algoritmos , Anemia/induzido quimicamente , Anemia/epidemiologia , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Gerenciamento Clínico , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Eritropoetina/efeitos adversos , Feminino , Humanos , Incidência , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Prolina/efeitos adversos , Prolina/uso terapêutico , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Ribavirina/efeitos adversos , Resultado do TratamentoRESUMO
GOALS: To evaluate differences in metrics of quality and site performance in academic and community sites participating in a multicenter study. BACKGROUND: In the Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy study, the participation of 76 academic-based and 42 community-based US centers provided an opportunity to evaluate various metrics of quality and site performance. STUDY: A secondary data analysis of the Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy study was performed. There were 3070 treatment-naive, hepatitis C virus genotype 1 infected patients were included. We retrospectively evaluated rates of screen failure, completion, and discontinuation of treatment and follow-up, treatment adherence, and virologic response by site type. RESULTS: Of the patients screened, 63% and 37% were in academic and community centers, respectively. Screen failure rates were similar (30% to 32%). End-of-treatment response, relapse, and sustained virologic response (SVR) rates in academic and community centers did not differ. SVR was achieved in 40% of patients at academic sites and 39% at community sites. Adherence to ≥80% of peginterferon-α and ribavirin dosing for ≥80% assigned duration was also similar (46% in academic and 47% in community centers). In both academic and community centers, 54% of patients completed treatment; there were similar discontinuation rates for treatment failure and adverse events. CONCLUSIONS: There were no significant differences in adherence, adverse events, rates of discontinuation, on-treatment virologic response, and SVR when comparing academic and community sites. The performance of academic-based and experienced community-based sites in clinical trials is largely similar for the treatment of chronic hepatitis C.
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Centros Médicos Acadêmicos/normas , Centros Comunitários de Saúde/normas , Hepatite C/tratamento farmacológico , Qualidade da Assistência à Saúde , Centros Médicos Acadêmicos/métodos , Adulto , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Indicadores de Qualidade em Assistência à Saúde , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Falha de Tratamento , Resultado do TratamentoRESUMO
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 pegylated interferon-α2b plus ribavirin (PR). Plasma samples collected at protocol-specified visits were analysed by population sequencing for detection of BOC-associated resistance-associated variants (RAVs). RESULTS: A total of 17/24 (71%) patients randomized to BOC with baseline RAVs achieved sustained virological response (SVR). V55A/I (n=14), Q41H (n=11) and T54S (n=9) were the most frequently detected polymorphisms at baseline. Seven non-SVR patients with baseline RAVs had V55A (relapse, n=3; breakthrough, n=1; and non-response, n=1) and/or R155K (non-response, n=2). In total, 63/144 (44%) patients with sequenced post-baseline samples (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 virological response: 90%, 67%, 27% and 37% of breakthrough, incomplete virological response, relapse and non-responder patients, respectively, had post-baseline RAVs present. Similar RAVs were identified in both the PR lead-in and no-lead-in arms and the frequency of post-baseline 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 post-baseline RAVs.
Assuntos
Substituição de Aminoácidos , Farmacorresistência Viral/genética , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Prolina/análogos & derivados , Ribavirina/uso terapêutico , Quimioterapia Combinada , Genótipo , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Prolina/administração & dosagem , Prolina/uso terapêutico , RNA Viral , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Recidiva , Ribavirina/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: The addition of boceprevir to therapy with peginterferon alfa-2b and ribavirin results in significantly higher rates of sustained virologic response (SVR) in previously treated patients with chronic hepatitis C virus (HCV) genotype-1 infection, compared with peginterferon alfa-2b and ribavirin 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) and 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 end point was SVR 24 weeks after therapy ended. RESULTS: The addition of boceprevir after 4 weeks of 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 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 BOC/PEG2a/R group developed anemia (hemoglobin <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.
Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Prolina/análogos & derivados , Ribavirina/administração & dosagem , Adulto , Idoso , Método Duplo-Cego , Feminino , Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Prolina/administração & dosagem , RNA Viral/sangue , Proteínas Recombinantes/administração & dosagem , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND & 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 of 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 × 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 improves 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.
Assuntos
Antivirais/administração & dosagem , Hepacivirus/classificação , Hepatite C/tratamento farmacológico , Interferon-alfa/administração & dosagem , Cirrose Hepática/virologia , Polietilenoglicóis/administração & dosagem , Prolina/análogos & derivados , Ribavirina/administração & dosagem , Adulto , Método Duplo-Cego , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Hepatite C/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Prolina/administração & dosagem , Prolina/efeitos adversos , RNA Viral/sangue , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Ribavirina/efeitos adversosRESUMO
UNLABELLED: 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. A total of 1,097 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]<10 g/dL) included RBV dose reduction and/or erythropoietin (EPO) use. A total of 1,080 patients had ≥1 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 affected 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 (AEs) and discontinuations due to AEs among BOC-treated patients did not differ by EPO use. CONCLUSION: With BOC/PR therapy, SVR rates in patients with incident anemia were higher than nonanemic patients and did not vary significantly according to the investigator-selected approach for anemia management. Prospective studies are needed to confirm this observation.
Assuntos
Anemia/induzido quimicamente , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/efeitos adversos , Polietilenoglicóis/efeitos adversos , Prolina/análogos & derivados , Ribavirina/efeitos adversos , Inibidores de Serina Proteinase/efeitos adversos , Adulto , Anemia/tratamento farmacológico , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Quimioterapia Combinada/efeitos adversos , Eritropoetina/administração & dosagem , Eritropoetina/efeitos adversos , Feminino , Hematínicos/administração & dosagem , Hematínicos/efeitos adversos , Hemoglobinas/metabolismo , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Masculino , Placebos , Polietilenoglicóis/administração & dosagem , Prolina/administração & dosagem , Prolina/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Ribavirina/administração & dosagem , Inibidores de Serina Proteinase/administração & dosagem , Resultado do TratamentoRESUMO
GOALS: To evaluate the safety and efficacy of peginterferon-α-2b plus ribavirin in patients with recurrent hepatitis C after orthotopic liver transplant. BACKGROUND: Reinfection of liver allografts in hepatitis C virus -infected transplant recipients begins immediately after transplantation. Treatment of these patients is challenging because of poor tolerability. STUDY: A multicenter, open-label study enrolling patients with persistent viremia after primary orthotopic liver transplant for cirrhosis related to hepatitis C virus infection. Patients received peginterferon-α-2b (1.5 µg/kg/wk) plus ribavirin (400 to 1200 mg/d administered using a dose-escalating regimen and according to body weight) for 48 weeks. The primary endpoint was sustained virologic response (SVR). RESULTS: In total, 125 patients started treatment and 58.4% completed 48 weeks. SVR rate was 28.8% (G1, 23.8%; G2/3, 55.0%), end-of-treatment response rate was 40.8%, and relapse rate was 18.2%. SVR was 55% among patients who completed treatment. Genotype 2/3 infection, male sex, baseline hemoglobin>14 g/dL, 80:80:80 compliance, rapid virologic response (RVR), and complete early virologic response (cEVR) were predictors of SVR. SVR was higher among patients with RVR compared with those without RVR (83.3% vs. 25.7%; P=0.0098), and among patients with cEVR compared with those without EVR (66.7% vs. 1.8%; P<0.0001). Thirty-eight patients discontinued because of an adverse event and 69 required dose reduction or interruption. Anemia (74%) and neutropenia (30%) were common, and rejection was low (3.2%). CONCLUSIONS: SVR was low in this study. Anemia was a particular challenge in achieving maximal ribavirin therapeutic exposure and may account in part for the lower SVR.
Assuntos
Antivirais , Hepatite C/prevenção & controle , Interferon-alfa , Transplante de Fígado/efeitos adversos , Polietilenoglicóis , Ribavirina/uso terapêutico , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Quimioterapia Combinada , Feminino , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Ribavirina/efeitos adversos , Prevenção Secundária , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Prolina/análogos & derivados , Adulto , Biomarcadores/sangue , Canadá , Quimioterapia Combinada , Europa (Continente) , Feminino , Genótipo , Hepacivirus/genética , Hepacivirus/crescimento & desenvolvimento , Hepatite C/diagnóstico , Hepatite C/genética , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Interferons , Interleucinas/genética , Modelos Logísticos , Masculino , Análise Multivariada , Razão de Chances , Fenótipo , Polietilenoglicóis/uso terapêutico , Polimorfismo de Nucleotídeo Único , Prolina/uso terapêutico , Estudos Prospectivos , RNA Viral/sangue , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Carga ViralRESUMO
BACKGROUND: Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impacts remain to be determined. AIM: We sought to validate these associations and to explore their impact on treatment response to peginterferon and ribavirin therapy. METHODS: A total of 972 G1 HCV-infected Caucasian patients were genotyped for the SNPs rs12979860 (IL28B) and rs2896019 (PNPLA3). Multivariable analysis tested IL28B and PNPLA3 for association with the presence of any steatosis (>0 %); clinically significant steatosis (>5 %); steatosis severity (grade 0-3/4); and the interacting associations of the SNPs and hepatic steatosis to sustained viral response (SVR). RESULTS: IL28B and PNPLA3 polymorphisms were associated with the presence of any steatosis (rs12979860, p = 1.87 × 10(-7); rs2896019, p = 7.56 × 10(-4)); clinically significant steatosis (rs12979860, p = 1.82 × 10(-3); rs2896019, p = 1.27 × 10(-4)); and steatosis severity (rs12979860, p = 2.05 × 10(-8); rs2896019, p = 2.62 × 10(-6)). Obesity, hypertriglyceridemia, hyperglycemia, liver fibrosis, and liver inflammation were all independently associated with worse steatosis. Hepatic steatosis was associated with lower SVR, and this effect was attenuated by IL28B. PNPLA3 had no independent association with SVR. CONCLUSIONS: IL28B and PNPLA3 are associated with hepatic steatosis prevalence and severity in Caucasians with G1 HCV, suggesting differing potential genetic risk pathways to steatosis. IL28B attenuates the association between steatosis and SVR. Remediable metabolic risk factors remain important, independently of these polymorphisms, and remain key therapeutic goals to achieve better outcomes for patients with HCV-associated hepatic steatosis.
Assuntos
Fígado Gorduroso/genética , Hepatite C Crônica/complicações , Interleucinas/genética , Lipase/genética , Proteínas de Membrana/genética , Adulto , Idoso , Fígado Gorduroso/virologia , Feminino , Genótipo , Hepatite C Crônica/genética , Hepatite C Crônica/virologia , Humanos , Interferons , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Análise de Regressão , Fatores de RiscoRESUMO
UNLABELLED: 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.
Assuntos
Monitoramento de Medicamentos/métodos , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Prolina/análogos & derivados , Ribavirina/efeitos adversos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Bases de Dados Factuais , Quimioterapia Combinada , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Polietilenoglicóis/efeitos adversos , Prolina/administração & dosagem , Prolina/efeitos adversos , RNA Viral/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Estudos Retrospectivos , Ribavirina/administração & dosagem , Falha de TratamentoRESUMO
BACKGROUND & AIMS: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.