RESUMEN
BACKGROUND: The timely publication of findings in peer-reviewed journals is a primary goal of clinical research. In clinical trials, the processes leading to publication can be complex from choice and prioritization of analytic topics through to journal submission and revisions. As little literature exists on the publication process for multicenter trials, we describe the development, implementation, and effectiveness of such a process in a multicenter trial. METHODS: The Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial included a data coordinating center (DCC) and clinical centers that recruited and followed more than 1,000 patients. Publication guidelines were approved by the steering committee, and the publications committee monitored the publication process from selection of topics to publication. RESULTS: A total of 73 manuscripts were published in 23 peer-reviewed journals. When manuscripts were closely tracked, the median time for analyses and drafting of manuscripts was 8 months. The median time for data analyses was 5 months and the median time for manuscript drafting was 3 months. The median time for publications committee review, submission, and journal acceptance was 7 months, and the median time from analytic start to journal acceptance was 18 months. CONCLUSIONS: Effective publication guidelines must be comprehensive, implemented early in a trial, and require active management by study investigators. Successful collaboration, such as in the HALT-C trial, can serve as a model for others involved in multidisciplinary and multicenter research programs. TRIAL REGISTRATION: The HALT-C Trial was registered with clinicaltrials.gov (NCT00006164).
Asunto(s)
Comités de Monitoreo de Datos de Ensayos Clínicos/normas , Interpretación Estadística de Datos , Adhesión a Directriz/normas , Guías como Asunto/normas , Manuscritos Médicos como Asunto , Publicaciones Periódicas como Asunto/normas , Proyectos de Investigación/normas , Antivirales/uso terapéutico , Quimioterapia Combinada , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Humanos , Difusión de la Información , Interferón-alfa/uso terapéutico , Revisión de la Investigación por Pares/normas , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Proyectos de Investigación/estadística & datos numéricos , Ribavirina/uso terapéutico , Factores de Tiempo , Resultado del Tratamiento , Estados UnidosRESUMEN
UNLABELLED: Chronic hepatitis C virus infection can cause chronic liver disease, cirrhosis and liver cancer. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was a prospective, randomized controlled study of long-term, low-dose peginterferon therapy in patients with advanced chronic hepatitis C who failed to respond to a previous course of optimal antiviral therapy. The aim of this follow-up analysis is to describe the frequency and causes of death among this cohort of patients. Deaths occurring during and after the HALT-C Trial were reviewed by a committee of investigators to determine the cause of death and to categorize each death as liver- or nonliver-related and as related or not to complications of peginterferon. Rates of liver transplantation were also assessed. Over a median of 5.7 years, 122 deaths occurred among 1,050 randomized patients (12%), of which 76 were considered liver-related (62%) and 46 nonliver-related (38%); 74 patients (7%) underwent liver transplantation. At 7 years the cumulative mortality rate was higher in the treatment compared to the control group (20% versus 15%, P = 0.049); the primary difference in mortality was in patients in the fibrosis compared to the cirrhosis stratum (14% versus 7%, P = 0.01); comparable differences were observed when liver transplantation was included. Excess mortality, emerging after 3 years of treatment, was related largely to nonliver-related death; liver-related mortality was similar in the treatment and control groups. No specific cause of death accounted for the excess mortality and only one death was suspected to be a direct complication of peginterferon. CONCLUSION: Long-term maintenance peginterferon in patients with advanced chronic hepatitis C is associated with an excess overall mortality, which was primarily due to nonliver-related causes among patients with bridging fibrosis.
Asunto(s)
Antivirales/efectos adversos , Hepatitis C Crónica/mortalidad , Interferón-alfa/efectos adversos , Cirrosis Hepática/mortalidad , Polietilenglicoles/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Causas de Muerte , Progresión de la Enfermedad , Femenino , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Interferón alfa-2 , Cirrosis Hepática/tratamiento farmacológico , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Ribavirina/uso terapéuticoRESUMEN
UNLABELLED: Retrospective studies suggest that subjects with chronic hepatitis C and advanced fibrosis who achieve a sustained virological response (SVR) have a lower risk of hepatic decompensation and hepatocellular carcinoma (HCC). In this prospective analysis, we compared the rate of death from any cause or liver transplantation, and of liver-related morbidity and mortality, after antiviral therapy among patients who achieved SVR, virologic nonresponders (NR), and those with initial viral clearance but subsequent breakthrough or relapse (BT/R) in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) Trial. Laboratory and/or clinical outcome data were available for 140 of the 180 patients who achieved SVR. Patients with nonresponse (NR; n = 309) or who experienced breakthrough or relapse (BT/R; n = 77) were evaluated every 3 months for 3.5 years and then every 6 months thereafter. Outcomes included death, liver-related death, liver transplantation, decompensated liver disease, and HCC. Median follow-up for the SVR, BT/R, and NR groups of patients was 86, 85, and 79 months, respectively. At 7.5 years, the adjusted cumulative rate of death/liver transplantation and of liver-related morbidity/mortality in the SVR group (2.2% and 2.7%, respectively) was significantly lower than that of the NR group (21.3% and 27.2%, P < 0.001 for both) but not the BT/R group (4.4% and 8.7%). The adjusted hazard ratio (HR) for time to death/liver transplantation (HR = 0.17, 95% confidence interval [CI] = 0.06-0.46) or development of liver-related morbidity/mortality (HR = 0.15, 95% CI = 0.06-0.38) or HCC (HR = 0.19, 95% CI = 0.04-0.80) was significant for SVR compared to NR. Laboratory tests related to liver disease severity improved following SVR. CONCLUSION: Patients with advanced chronic hepatitis C who achieved SVR had a marked reduction in death/liver transplantation, and in liver-related morbidity/mortality, although they remain at risk for HCC.
Asunto(s)
Antivirales/uso terapéutico , Progresión de la Enfermedad , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Carcinoma Hepatocelular/epidemiología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Hepatitis C Crónica/mortalidad , Humanos , Interferón alfa-2 , Hígado/patología , Neoplasias Hepáticas/epidemiología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Proteínas Recombinantes , Recurrencia , Factores de Riesgo , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: In patients with chronic hepatitis C who do not have a response to antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain. METHODS: We conducted a randomized, controlled trial of peginterferon alfa-2a at a dosage of 90 microg per week for 3.5 years, as compared with no treatment, in 1050 patients with chronic hepatitis C and advanced fibrosis who had not had a response to previous therapy with peginterferon and ribavirin. The patients, who were stratified according to stage of fibrosis (622 with noncirrhotic fibrosis and 428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsy at 1.5 and 3.5 years after randomization. The primary end point was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points. RESULTS: We randomly assigned the patients to receive peginterferon (517 patients) or no therapy (533 patients) for 3.5 years. The level of serum aminotransferases, the level of serum hepatitis C virus RNA, and histologic necroinflammatory scores all decreased significantly (P<0.001) with treatment, but there was no significant difference between the groups in the rate of any primary outcome (34.1% in the treatment group and 33.8% in the control group; hazard ratio, 1.01; 95% confidence interval, 0.81 to 1.27; P=0.90). The percentage of patients with at least one serious adverse event was 38.6% in the treatment group and 31.8% in the control group (P=0.07). CONCLUSIONS: Long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin. (ClinicalTrials.gov number, NCT00006164.)
Asunto(s)
Antivirales/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Alanina Transaminasa/sangre , Antivirales/efectos adversos , Antivirales/uso terapéutico , Carcinoma Hepatocelular/etiología , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/sangre , Hepatitis C Crónica/mortalidad , Hepatitis C Crónica/patología , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Interferón-alfa/uso terapéutico , Estimación de Kaplan-Meier , Hígado/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/virología , Neoplasias Hepáticas/etiología , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , ARN Viral/sangre , Proteínas Recombinantes , Resultado del TratamientoRESUMEN
UNLABELLED: Treatment of chronic hepatitis C with pegylated interferon (peginterferon) and ribavirin can cause or exacerbate depression but its effects on cognitive function are largely unknown. The aim of this study was to determine whether treatment with peginterferon and ribavirin adversely impacts cognitive function in patients with chronic hepatitis C. Prior nonresponders to interferon were retreated with peginterferon alfa-2a and ribavirin for 24 (n=177) or 48 weeks (n=57) in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial. Cognitive function was prospectively assessed using a battery of 10 standardized neuropsychological tests at weeks 0, 24, 48, and 72. Cognitive impairment was defined based upon a global deficit score. The Beck Depression Inventory and Brief Symptom Inventory were used to assess mood status. The 57 subjects who completed 48 weeks of antiviral therapy reported significant increases in difficulty concentrating, emotional distress, and symptoms of depression, all of which improved after cessation of therapy [P<0.0001, analysis of variance (ANOVA)]. Nonetheless, the frequency of cognitive impairment did not increase during the first 24 weeks of treatment in 177 patients (34% versus 32%, P=0.64) nor in the 57 patients completing 48 weeks of treatment (P=0.48, ANOVA). CONCLUSION: Retreatment of prior non-responders with peginterferon and ribavirin was not associated with objective evidence of cognitive impairment as measured by a comprehensive battery of neuropsychological tests. The lack of cognitive impairment is reassuring and suggests that self-reported symptoms of cognitive dysfunction are more likely related to the systemic and psychiatric side effects of antiviral treatment rather than measurable changes in cognition.
Asunto(s)
Antivirales/uso terapéutico , Cognición/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/psicología , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Afecto/efectos de los fármacos , Antivirales/efectos adversos , Trastornos del Conocimiento/inducido químicamente , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Masculino , Persona de Mediana Edad , Polietilenglicoles/efectos adversos , Proteínas Recombinantes , Ribavirina/efectos adversosRESUMEN
BACKGROUND/AIMS: Although the antiviral and histological benefits of peginterferon/ribavirin therapy are well established, the effects on health-related quality of life (HRQOL) and sexual health are less certain. This study assessed HRQOL and sexual health in patients with advanced fibrosis or cirrhosis in the HALT-C Trial. METHODS: Subjects completed SF-36 and sexual health questionnaires prior to and after 24 weeks of peginterferon/ribavirin therapy (n=1144). Three hundred and seventy-three (33%) subjects were HCV RNA negative at week 20 and continued therapy through week 48; 258 were seen at week 72. One hundred and eighty achieved sustained virological responses (SVR) and 78 relapsed. RESULTS: At baseline, patients had poorer scores for all eight SF-36 domains compared to healthy controls. Patients with cirrhosis had lower HRQOL scores than those with bridging fibrosis, as did patients with higher depression scores. SVR patients had significant improvements in seven domains, whereas relapsers had significant worsening in one domain. Sexual scores improved in SVR patients and decreased in relapsers (p=0.03). In multivariate analyses, improvements in HRQOL and sexual scores were significantly associated with SVR but were less striking in patients with lower depression scores. CONCLUSIONS: Achievement of SVR after peginterferon/ribavirin therapy improves HRQOL and sexual health in chronic hepatitis C patients with advanced fibrosis or cirrhosis.
Asunto(s)
Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/psicología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/psicología , Calidad de Vida/psicología , Adulto , Antivirales/uso terapéutico , Progresión de la Enfermedad , Quimioterapia Combinada , Femenino , Estado de Salud , Encuestas Epidemiológicas , Hepatitis C Crónica/complicaciones , Humanos , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Proteínas Recombinantes , Ribavirina/uso terapéutico , Conducta Sexual/psicología , Disfunciones Sexuales Psicológicas/etiología , Resultado del TratamientoRESUMEN
Mild neuropsychological impairment has previously been reported in chronic hepatitis C (CHC) patients. The aim of this study was to assess the presence and severity of cognitive impairment among a cohort of CHC patients with advanced fibrosis using clinician ratings compared to classification based upon statistical methods. In addition, we set out to determine the relationship between cognitive scores and functional status. Two experienced neuropsychologists provided "clinician ratings" on a battery of 10 neuropsychological tests performed in 100 randomly selected patients participating in the HALT-C clinical trial. The overall kappa between the 2 graders on level of impairment was 0.59. Clinician ratings (the gold standard) were similarly sensitive to identifying cognitive impairment as was classification based on standard scores (44% vs. 40%). Global Deficit Scores (GDS), derived from pooling standard scores, also identified 44% of patients as having mild impairment and were highly correlated with clinician ratings (r = .81 p = < 0.0001). Neither clinician ratings nor deficit scores correlated with SF-36 subscale or summary scores but did correlate with depression scores (p < .0007). In summary, clinician ratings and deficit scores identified a similar prevalence of cognitive impairment amongst CHC patients with advanced fibrosis. There was a significant correlation between cognitive impairment and self-reported depression.
Asunto(s)
Cognición/fisiología , Fibrosis/complicaciones , Hepatitis C/complicaciones , Pruebas Neuropsicológicas/estadística & datos numéricos , Adulto , Trastornos del Conocimiento/etiología , Demografía , Femenino , Humanos , Pruebas de Inteligencia/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Curva ROC , Índice de Severidad de la Enfermedad , Estadística como AsuntoRESUMEN
PURPOSE: The relationships between reproductive risk factors, including use of hormone replacement therapy and oral contraceptives and severity of age-related maculopathy (ARM) among postmenopausal women were evaluated. We hypothesized that exposure to endogenous or exogenous estrogens would be associated with a reduced risk of advanced ARM. DESIGN: Cross-sectional study. METHODS: The 394 subjects were postmenopausal women with ARM. Logistic regression analysis was used to compare the effects of several reproductive factors across two groups: 193 subjects with nonadvanced ARM and 201 subjects with advanced ARM. RESULTS: Women with ARM who had used postmenopausal estrogen therapy in the past had significantly lower odds of advanced ARM than nonusers, after controlling for other known and potential risk factors (odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.30 to 0.98). Older age at menarche was associated with increased odds of advanced ARM (OR = 1.16, 95% CI = 1.00 to 1.35). CONCLUSIONS: These findings suggest that exposure to exogenous estrogens may have a beneficial effect of reducing the risk of advanced types of ARM in postmenopausal women with ARM. Few therapeutic or preventive measures currently exist for ARM; therefore, these results deserve further evaluation.