Ovarian stimulation with corifollitropin alfa followed by hp-hMG compared to hp-hMG in patients at risk of poor ovarian response undergoing ICSI: A randomized controlled trial.

OBJECTIVE: To compare the results of two ovarian stimulation protocols for IVF in patients at risk of poor ovarian response: corifollitropin alfa followed by hp-hMG versus daily administration of hp-hMG. We intended to demonstrate the non-inferiority of the protocol with corifollitropin alfa. STUDY DESIGN: This is a prospective, randomized, non-inferiority, controlled study. We compared two ovarian stimulation protocols for IVF in 234 patients, under 40 years of age and at risk of poor ovarian response. First protocol was a single injection of 150 µg corifollitropin alfa and the second, a daily injection of 300 IU of hp-hMG during the first week of ovarian stimulation. In both groups, if necessary, a daily injection of 300 IU of hp-hMG was dispensed until the criteria for hCG administration are met. For the primary and secondary outcomes, results were analysed by using a one-sided chi-square test or a Fisher exact test, as appropriate, with a level of significance of 0.05. For continuous variables, parametric (independent t-test) or non-parametric (Mann-Whitney test) tests were used depending on the normality of the distribution. Statistical significance was set at P < 0.05. RESULTS: The ongoing pregnancy rate, live birth rate (15.2 vs 20.2) (P = 0.33), and the cumulative live birth rate (15.2 vs 22.0) (P = 0.19) per started cycle did not show significant differences between the corifollitropin alfa and hp-hMG groups, and the difference estimated between treatments was -5% [95% CI: (-15.1, 5.0)]. CONCLUSIONS: It was not possible to probe non-inferiority of the protocol with corifollitropin alfa followed by hp-hMG compared to hp-hMG in patients at risk of poor ovarian response undergoing ICSI.

Caracterización de la suplementación de folatos en el embarazo a partir de la combinación de sistemas de información sanitaria / Characterization of folate supplementation in pregnancy, based on a combination of health information systems

Objetivos: Explorar la utilidad de la combinación de los sistemas de información sanitaria de la Agencia Valenciana de Salud (AVS) para caracterizar la suplementación de folatos en la población de embarazadas de la Comunidad Valenciana.MétodosCohorte de todas las mujeres que parieron en hospitales de la AVS durante 2009, que fueron seguidas retrospectivamente en la historia clínica electrónica ABUCASIS y el sistema GAIA de gestión de la prescripción para identificar el consumo de folatos en los 3 meses previos y posteriores a la concepción.ResultadosDe los 38.069 partos realizados en 2009 en hospitales de la AVS, 37.040 (97,3%) pudieron incluirse en los análisis. Un 34,0% de las mujeres tenía registrada al menos la dispensación de un envase de folatos en la receta oficial durante el periodo periconcepcional (un 6,6% en el trimestre previo a la concepción). La dispensación con receta oficial se asoció a la mayor edad, la gratuidad de la prestación farmacéutica, haber nacido en España, tomar anticomiciales y al diagnóstico de diabetes. Un 8,0% de las mujeres (23,6% de las que tomaron folatos) recibieron tratamiento a dosis elevadas.ConclusionesLos sistemas de información sanitaria infrarregistran notablemente el consumo de folatos durante el embarazo debido a que la mayoría de las veces no se emplea la receta oficial para su prescripción y dispensación. La combinación de bases de datos informatizadas es una aproximación inadecuada para valorar la situación de la suplementación de folatos, monitorizarla o proponer medidas específicas de mejora (AU)

Objectives: To explore the utility of combining health information systems from the Valencia HealthAgency to characterize folate supplementation in pregnant women in the autonomous region of Valencia(Spain).Methods: The cohort comprised women who gave birth during 2009 in hospitals within the Valencian Health Agency. These women were retrospectively followed-up using ABUCASIS electronic medicalrecords and the GAIAelectronic prescription systemto identify folate consumption in the 3months beforeand after conception.Results: In 2009, there were 38,069 births in hospitals of the Valencian Health Agency, of which 37,040(97.3%) were included for analysis. In 34% of women, at least one folate dispensation was registered withan official prescription formwithin the periconceptional period (6.6%in the 3months prior to conception).Dispensation with an official prescription form was associated with older women, free pharmaceuticalprescriptions, birth in Spain, antiepileptic medications, and a diagnosis of diabetes. Eight percent ofwomen (23.6% of the folate-treated women) received folates at high doses.Conclusions: Folate consumption during pregnancy is systematically under-registered by healthcareinformation systems because health professionals do not use the official prescription form for prescription and dispensation. Database linkage is an inadequate approach to assess folic acid supplementationduring pregnancy (AU)

[Incidence of hospitalization for traumatic brain injury in children and adolescents (Valencia Community, Spain, 2002-2009)]. / Incidencia de la hospitalizacion por traumatismo craneoencefalico en la infancia y adolescencia (Comunidad Valenciana, 2002-2009).

INTRODUCTION. Traumatic brain injuries (TBI) are a major cause of morbidity and mortality in children and adolescents but there are hardly any studies on the incidence and temporal evolution. AIM. To describe recent trends (2002-2009) in the incidence of hospitalization for TBI in children and adolescents in the region of Valencia. PATIENTS AND METHODS. Emergency admissions were identified in hospitals in the Valencian Health Agency from patients aged 0-19 years with a diagnosis of TBI (codes of the International Classification of Diseases 800, 801, 803, 804 and 850 to 854) during 2002 to 2009. The severity was classified using the fifth digit of these codes and the crude and standardized rates per 100,000 children were estimated stratified by age, sex and severity. RESULTS. From 2002 to 2009 a total of 5,504 TBI in children up to age of 19 years were hospitalized (mild: 92.9%; moderate to severe: 7.1%). In-hospital mortality was 0.6% for mild TBI and 15.7% for moderate-severe. Crude rates of mild head injury per 100,000 children fell from 85.9 to 55.4 in 2002-2009 (boys: 114.1 to 68.3, girls: 56.1 to 41.8), especially in the 15-19 years. For moderate-severe TBI, rates decreased from 5.73 to 2.78 per 100,000 in 2002-2009 (boys: 8.69 to 3.67; girls: 2.59 to 1.84). CONCLUSIONS. The incidence of pediatric TBI in the Valencia region has decreased significantly in the period 2002-2009, but their medical, legal, societal and family consequences still represents a substantial burden.

Incidencia de la hospitalización por traumatismo craneoencefálico en la infancia y adolescencia (Comunidad Valenciana, 2002-2009) / Incidence of hospitalization for traumatic brain injury in children and adolescents (Valencia Community, Spain, 2002-2009)

Introducción. Las lesiones cerebrales traumáticas son una de las causas más importantes de morbilidad y mortalidad en niños y adolescentes, pero apenas existen estudios sobre su incidencia y evolución temporal. bjetivo. Describir las tendencias recientes (2002-2009) en la incidencia de hospitalización por traumatismo craneoencefálico (TCE) en niños y adolescentes en la Comunidad Valenciana. Pacientes y métodos. Se identificaron los ingresos urgentes en hospitales de la Agencia Valenciana de Salud de pacientes de 0-19 años con un diagnóstico de TCE (códigos de la Clasificación Internacional de Enfermedades 800, 801, 803, 804 y 850 a 854) desde 2002 hasta 2009. La gravedad se clasificó utilizando el quinto dígito de estos códigos y se estimaron las tasas crudas y estandarizadas por 100.000 pacientes estratificadas por grupos de edad, sexo y gravedad. Resultados. Durante 2002-2009 se hospitalizaron 5.504 niños de 0-19 años por TCE (leves: 92,9%; moderados-graves: 7,1%). La mortalidad intrahospitalaria fue del 0,6% para los TCE leves y del 15,7% para los moderados-graves. Las tasas crudas de TCE leve por 100.000 niños descendieron de 85,9 a 55,4 en 2002-2009 (niños: de 114,1 a 68,3; niñas: de 56,1 a 41,8), especialmente en el grupo de 15-19 años. Para el TCE moderado-grave las tasas descendieron de 5,73 a 2,78 en 2002-2009 (niños: de 8,69 a 3,67; niñas: de 2,59 a 1,84). Conclusiones. La incidencia de TCE pediátrico en la Comunidad Valenciana ha disminuido considerablemente en el período 2002-2009, pero aún supone una elevada carga, con las consecuencias médicas, legales, sociales y familiares que conlleva (AU)

Introduction. Traumatic brain injuries (TBI) are a major cause of morbidity and mortality in children and adolescents but there are hardly any studies on the incidence and temporal evolution. Aim. To describe recent trends (2002-2009) in the incidence of hospitalization for TBI in children and adolescents in the region of Valencia. Patients and methods. Emergency admissions were identified in hospitals in the Valencian Health Agency from patients aged 0-19 years with a diagnosis of TBI (codes of the International Classification of Diseases 800, 801, 803, 804 and 850 to 854) during 2002 to 2009. The severity was classified using the fifth digit of these codes and the crude and standardized rates per 100,000 children were estimated stratified by age, sex and severity. Results. From 2002 to 2009 a total of 5,504 TBI in children up to age of 19 years were hospitalized (mild: 92.9%; moderate to severe: 7.1%). In-hospital mortality was 0.6% for mild TBI and 15.7% for moderate-severe. Crude rates of mild head injury per 100,000 children fell from 85.9 to 55.4 in 2002-2009 (boys: 114.1 to 68.3, girls: 56.1 to 41.8), especially in the 15-19 years. For moderate-severe TBI, rates decreased from 5.73 to 2.78 per 100,000 in 2002-2009 (boys: 8.69 to 3.67; girls: 2.59 to 1.84). Conclusions. The incidence of pediatric TBI in the Valencia region has decreased significantly in the period 2002-2009, but their medical, legal, societal and family consequences still represents a substantial burden (AU)

[Characterization of folate supplementation in pregnancy, based on a combination of health information systems]. / Caracterización de la suplementación de folatos en el embarazo a partir de la combinación de sistemas de información sanitaria.

OBJECTIVES: To explore the utility of combining health information systems from the Valencia Health Agency to characterize folate supplementation in pregnant women in the autonomous region of Valencia (Spain). METHODS: The cohort comprised women who gave birth during 2009 in hospitals within the Valencian Health Agency. These women were retrospectively followed-up using ABUCASIS electronic medical records and the GAIA electronic prescription system to identify folate consumption in the 3 months before and after conception. RESULTS: In 2009, there were 38,069 births in hospitals of the Valencian Health Agency, of which 37,040 (97.3%) were included for analysis. In 34% of women, at least one folate dispensation was registered with an official prescription form within the periconceptional period (6.6% in the 3 months prior to conception). Dispensation with an official prescription form was associated with older women, free pharmaceutical prescriptions, birth in Spain, antiepileptic medications, and a diagnosis of diabetes. Eight percent of women (23.6% of the folate-treated women) received folates at high doses. CONCLUSIONS: Folate consumption during pregnancy is systematically under-registered by healthcare information systems because health professionals do not use the official prescription form for prescription and dispensation. Database linkage is an inadequate approach to assess folic acid supplementation during pregnancy.

Educational level and HIV disease progression before and after the introduction of HAART: a cohort study in 989 HIV seroconverters in Spain.

OBJECTIVES: To analyse the effect of educational level on the progression from HIV seroconversion to highly active antiretroviral therapy (HAART) requirement, HAART initiation, AIDS and death from any cause at different periods of the HIV epidemic in Spain. METHODS: Open, prospective, multicentre cohort of HIV seroconverters set up in 1983. The risk of progression was calculated by the multiple decrements method. Effect of educational level was estimated by Fine and Gray model, adjusting for sex, HIV transmission category, age and method to estimate seroconversion. Calendar period was introduced as a variable that could change over time (<1997; 1997-2003; >2003). RESULTS: Up to 2009, 989 HIV seroconverters with information on educational level were identified. Some 52% and 48% had a low and a high educational level respectively. Persons with higher education had 32% lower risk of death (HR: 0.68; 95% CI 0.45 to 1.03). Regarding progression to AIDS, educational level had no effect in the pre-HAART era (HR: 1.47; 95% CI 0.91 to 2.38), but did show an effect in the period 1997-2003 (HR: 0.58; 95% CI 0.34 to 0.99), which was accentuated after 2004 (HR: 0.26; 95% CI 0.10 to 0.68). No difference was found in time to HAART requirement or initiation. CONCLUSIONS: Results suggest that, despite similar access to HAART, persons with low educational level are at increased risk of HIV disease progression, highlighting the impact of social inequities on health. The availability of more effective treatments over time will strengthen the protective effect of higher education on the development of AIDS.

Adherence to and appropriateness of anti-osteoporotic treatments in patients aged 50 and over in the Valencia Region (Spain). The ESOSVAL-AD study.

BACKGROUND: A study to evaluate the adherence to and appropriateness of anti-osteoporotic treatments in a cohort of men and women aged 50 and over participating in the ESOSVAL-R study. DESIGN: An observational, longitudinal, prospective cohort study; STUDY SUBJECTS: Men and women aged 50 and over living in the Valencia Region (Spain) who initiated treatment between June 15, 2009, and June 15, 2011, in primary healthcare centers with electronic medical records; DATA SOURCES: The main data source will be electronic medical records. Measurement of results: Degree of compliance with and persistence of anti-osteoporotic treatments, and the proportion of patients with appropriate anti-osteoporotic treatment in accordance with the most relevant and high impact recommendations with clearly defined treatment algorithms in Spain (the Spanish National Health System guide (2010), the General Practitioners' Society (2007) and the General Directorate for Pharmacy and Medical Products of Madrid (2007)), and with the National Osteoporosis Foundation (NOF, 2010), and the International Osteoporosis Foundation guidelines (IOF, 2008); ANALYSIS: 1.) Descriptive analysis of patients undergoing treatment and the treatments prescribed; 2.) Descriptive analysis of compliance with and persistence of anti-osteoporotic treatments; 3.) ANALYSIS of factors associated with compliance with and persistence of treatments by Cox proportional hazard regression models, 4.) Descriptive analysis of appropriateness of treatment; 5.) ANALYSIS of factors associated with the appropriateness of treatment by multilevel models (4 levels: patient, doctor, Basic Healthcare Zone/Primary Healthcare Center, and Health Area variables). DISCUSSION: ESOSVAL-AD will provide information regarding adherence to osteoporosis treatments and the factors associated with a higher or lower adherence (including the appropriateness of the treatment) in the Spanish context. A better understanding of this phenomenon and the interventions needed to address it would contribute to the increased effectiveness of therapeutic measures, a reduction in morbidity and mortality, and a corresponding reduction in healthcare costs.

Efectividad del tratamiento antirretroviral combinado de gran actividad en eventos recurrentes de sida en una cohorte de seroconvertores al virus de la inmunodeficiencia humana / Effectiveness of combined antiretroviral therapy on multiple aids-defining illnesses in an hiv seroconverter cohort

Introducción La efectividad del tratamiento antirretroviral de gran actividad (TARGA) en la reducción del tiempo al primer evento definitorio de sida ha sido demostrada por diversos estudios observacionales, pero el efecto en eventos recurrentes de sida no es tan evidente. Material y métodos Se dispone de 1.938 sujetos seroconvertores al VIH de la cohorte GEMES. Se ha utilizado una extensión del modelo de Cox para analizar el tiempo desde la seroconversión a cada evento sida, que tiene en cuenta el tiempo entre sucesivos eventos y que permite que el riesgo de referencia cambie con el número de paciente con sida previos. El calendario se dividió en tres períodos coincidiendo con la disponibilidad de diferentes regímenes de terapia antirretroviral. Resultados Durante el seguimiento 1.524 (78,6%), 259(13,4%), 83 (4,3%) y 72 (3,7%) sujetos desarrollaron 0, 1, 2 y 3 o más eventos definitorios de sida, respectivamente. Después de ajustar por sexo, edad a la seroconversión y categoría de exposición, el riesgo de sida para el período TARGA fue RR=0,38 (IC del 95%, 0,30-0,48) en comparación con el período 1992–1995.Teniendo en cuenta el número de sujetos con sida previos, se observó un RR de 0,40 (IC del95%, 0,32-0,50) para el primer evento sida, RR=0,27 (IC del 95%, 0,15-0,50) para el segundo y 0,41 (IC del 95%, 0,18-0,96) para el tercero. Considerando todos los eventos de sida, se obtiene un riesgo RR=0,32 (IC del 95%, 0,125-0,40). Los usuarios de drogas por vía parenteral tienen un riesgo mayor de desarrollar un primer episodio de sida que los homosexuales, RR=2,14 (IC del 95%, 1,48-3,10).Conclusiones Los resultados obtenidos muestran un efecto protector de la terapia al primer sida, manteniéndose el efecto para posteriores eventos. La inclusión en el análisis de todos los eventos recurrentes de sida permite obtener estimaciones del riesgo más precisas (AU)

Introduction: Several observational studies support the protective effect of combined antiretroviral therapy (cART) on time to first AIDS-defining event, but the effect on multiple AIDS defining illnesses remains unclear. The aim of this study is to analyse whether the protective effect of cART persists beyond the first AIDS-defining illness. Material and methods: A total of 1938 subjects from GEMES seroconverter cohort have been included. Toanalyse cART effectiveness, calendar time has been divided into three periods according to antiretroviral availability. A population-averaged proportional hazard model with staggered entries that counted the gap time, and had event-specific baseline risks, was fitted. Results: During follow-up, 1524 (78.6%), 259 (13.4%), 83 (4.3%) and 72 (3.7%) subjects incurred 0, 1, 2,and 3 or more AIDS-defining illnesses, respectively. After adjustment for sex, age at seroconversion and exposure category, the Relative Risk (RR) of AIDS in the cART period was 0.38 (95%CI 0.30-0.48) compared with the 1992-95 period. The RR of the first, second and third AIDS-defining illness in the cART period were0.40 (95% CI: 0.32-0.50), 0.27 (95% CI: 0.15-0.50) and 0.41 (95% CI: 0.18-0.96) respectively, relative to the reference calendar period when we allowed the odds ratios to vary by the number of prior AIDS-defining events. The relative risk of AIDS, taking all events into account, was 0.32 (95% CI: 0.25-0.40). Intravenous drug users have a higher risk of developing a first episode of AIDS than homosexuals, RR: 2.14 (95% CI:1.48-3.10).Conclusions: Results indicate that the relative effect of cART appears to be both protective and stable over multiple AIDS-defining illnesses. Analysis of multiple AIDS-defining illnesses improves the precision of the estimated relative risk (AU)

[Effectiveness of combined antiretroviral therapy on multiple AIDS-defining illnesses in an HIV seroconverter cohort]. / Efectividad del tratamiento antirretroviral combinado de gran actividad en eventos recurrentes de sida en una cohorte de seroconvertores al virus de la inmunodeficiencia humana.

INTRODUCTION: Several observational studies support the protective effect of combined antiretroviral therapy (cART) on time to first AIDS-defining event, but the effect on multiple AIDS defining illnesses remains unclear.The aim of this study is to analyse whether the protective effect of cART persists beyond the first AIDS-defining illness. MATERIAL AND METHODS: A total of 1938 subjects from GEMES seroconverter cohort have been included. To analyse cART effectiveness, calendar time has been divided into three periods according to antiretroviral availability. A population-averaged proportional hazard model with staggered entries that counted the gap time, and had event-specific baseline risks, was fitted. RESULTS: During follow-up, 1524 (78.6%), 259 (13.4%), 83 (4.3%) and 72 (3.7%) subjects incurred 0, 1, 2, and 3 or more AIDS-defining illnesses, respectively. After adjustment for sex, age at seroconversion and exposure category, the Relative Risk (RR) of AIDS in the cART period was 0.38 (95%CI 0.30-0.48) compared with the 1992-95 period. The RR of the first, second and third AIDS-defining illness in the cART period were 0.40 (95% CI: 0.32-0.50), 0.27 (95% CI: 0.15-0.50) and 0.41 (95% CI: 0.18-0.96) respectively, relative to the reference calendar period when we allowed the odds ratios to vary by the number of prior AIDS-defining events. The relative risk of AIDS, taking all events into account, was 0.32 (95% CI: 0.25-0.40). Intravenous drug users have a higher risk of developing a first episode of AIDS than homosexuals, RR: 2.14 (95% CI: 1.48-3.10). CONCLUSIONS: Results indicate that the relative effect of cART appears to be both protective and stable over multiple AIDS-defining illnesses. Analysis of multiple AIDS-defining illnesses improves the precision of the estimated relative risk.

Development and validation of a population-based prediction scale for osteoporotic fracture in the region of Valencia, Spain: the ESOSVAL-R study.

BACKGROUND: Today, while there are effective drugs that reduce the risk of osteoporotic fracture, yet there are no broadly accepted criteria that can be used to estimate risks and decide who should receive treatment. One of the actual priorities of clinical research is to develop a set of simple and readily-available clinical data that can be used in routine clinical practice to identify patients at high risk of bone fracture, and to establish thresholds for therapeutic interventions. Such a tool would have high impact on healthcare policies. The main objective of the ESOSVAL-R is to develop a risk prediction scale of osteoporotic fracture in adult population using data from the Region of Valencia, Spain. STUDY DESIGN: An observational, longitudinal, prospective cohort study, undertaken in the Region of Valencia, with an initial follow-up period of five years; SUBJECTS: 14,500 men and women over the age of 50, residing in the Region and receiving healthcare from centers where the ABUCASIS electronic clinical records system is implanted; SOURCES OF DATA: The ABUCASIS electronic clinical record system, complemented with hospital morbidity registers, hospital Accidents & Emergency records and the Regional Ministry of Health's mortality register; Measurement of results: Incident osteoporotic fracture (in the hip and/or major osteoporotic fracture) during the study's follow-up period. Independent variables include clinical data and complementary examinations; ANALYSIS: 1) Descriptive analysis of the cohorts' baseline data; 2) Upon completion of the follow-up period, analysis of the strength of association between the risk factors and the incidence of osteoporotic fracture using Cox's proportional hazards model; 3) Development and validation of a model to predict risk of osteoporotic fracture; the validated model will serve to develop a simplified scale that can be used during routine clinical visits. DISCUSSION: The ESOSVAL-R study will establish a prediction scale for osteoporotic fracture in Spanish adult population. This scale not only will constitute a useful prognostic tool, but also it will allow identifying intervention thresholds to support treatment decision-making in the Valencia setting, based mainly on the information registered in the electronic clinical records.

[Effect of distinct sociodemographic variables on progression of HIV infection in a cohort of drug users]. / Efecto de diferentes variables sociodemográficas en la progresión de la infección por el virus de la inmunodeficiencia humana en una cohorte de usuarios de drogas.

OBJECTIVE: To analyze whether the effectiveness of combined antiretroviral therapy in delaying progression to AIDS and death is affected by social inequities in a cohort of HIV-positive injecting drug users (IDUs). METHODS: A cohort of 3,122 HIV-positive IDUs identified in the AIDS Information and Prevention Centers of the autonomous region of Valencia was analyzed, with further follow-up in 1,876. Progression to AIDS and death after seroconversion were calculated by Kaplan-Meier estimation according to sociodemographic variables (age, sex, education, marital status, length of addiction). Cox regression models were also fitted. RESULTS: No significant differences were observed according to the variables considered when analyzing time to AIDS development. Evaluation of survival time revealed that individuals with further follow-up showed an excess of mortality (HR = 1.35; 95%CI: 0.20-1.54). For individuals without follow-up, mortality risk was reduced in those with secondary school education (HR = 0.51; 95%CI: 0.35-0.74) and with university education (HR = 0.41; 95%CI: 0.18-0.93) compared with those with no education. When individuals with follow-up were analyzed, the differences lost significance for those with secondary school education (HR = 0.92; 95%CI: 0.72-1.19) and university education (HR = 0.62; 95%CI: 0.35-1.11). CONCLUSIONS: The mortality excess found in IDUs with lower educational levels, especially among those not seeking healthcare in the initial period after being identified as HIV-positive, highlights the need for interventions aimed at facilitating access to health systems, especially among the socially disadvantaged.

Efecto de diferentes variables sociodemográficas en la progresión de la infección por el virus de la inmunodeficiencia humana en una cohorte de usuarios de drogas / Effect of distinct sociodemographic variables on progression of HIV infection in a cohort of drug users

Objetivos: Analizar si la efectividad de la terapia antirretroviralcombinada (cART) en la progresión a sida y muerte seve afectada por diferencias sociodemográficas en una cohortede usuarios de drogas intravenosas, infectados por el virusde la inmunodeficiencia humana (VIH).Métodos: Se analiza la cohorte formada por 3.122 VIH+ identificadosen los Centros de Información y Prevención del sidade la Comunidad Valenciana, con un seguimiento posterioren 1.876. Se calcula la progresión a sida y muerte desde laseroconversión por medio de curvas de Kaplan-Meier en funciónde las variables sociodemográficas (edad, sexo, estudios,estado civil y tiempo desde la primera inyección). Posteriormente,se ajustan modelos de regresión de Cox.Resultados: No se observaron diferencias significativas paralas variables consideradas al evaluar el tiempo hasta la apariciónde sida. Al evaluar la supervivencia se encuentra un excesode mortalidad entre los sujetos para los que se disponede seguimiento (hazard ratio [HR] = 1,35; intervalo deconfianza del 95% [IC95%]: 0,20-1,54). En los individuos sinseguimiento se observa una disminución del riesgo de muerteen los que tienen estudios secundarios (HR = 0,51; IC95%:0,35-0,74) y universitarios (HR = 0,41; IC95%: 0,18-0,93), frentea aquellos sin estudios. En los individuos en que se ha efectuadoel seguimiento, las diferencias se atenúan y pierden lasignificación en los sujetos con estudios secundarios (HR =0,92; IC95%: 0,72-1,19) y universitarios (HR = 0,62; IC95%:0,35-1,11).Conclusiones: El exceso de mortalidad encontrado en sujetosde niveles educativos bajos, sobre todo entre los queno acudieron al sistema sanitario en los momentos inicialesde haber sido identificado como VIH+, refuerza la necesidadde efectuar intervenciones que favorezcan el acceso al sistemasanitario, sobre todo entre los socialmente más desfavorecidos(AU)

Objective: To analyze whether the effectiveness of combinedantiretroviral therapy in delaying progression to AIDS anddeath is affected by social inequities in a cohort of HIV-positiveinjecting drug users (IDUs).Methods: A cohort of 3,122 HIV-positive IDUs identified inthe AIDS Information and Prevention Centers of the autonomousregion of Valencia was analyzed, with further follow-upin 1,876. Progression to AIDS and death after seroconversionwere calculated by Kaplan-Meier estimation according to sociodemographicvariables (age, sex, education, marital status,length of addiction). Cox regression models were also fitted.Results: No significant differences were observed accordingto the variables considered when analyzing time to AIDS development.Evaluation of survival time revealed that individualswith further follow-up showed an excess of mortality (HR = 1.35;95%CI: 0.20-1.54). For individuals without follow-up, mortalityrisk was reduced in those with secondary school education(HR = 0.51; 95%CI: 0.35-0.74) and with university education(HR = 0.41; 95%CI: 0.18-0.93) compared with thosewith no education. When individuals with follow-up were analyzed,the differences lost significance for those with secondaryschool education (HR = 0.92; 95%CI: 0.72-1.19) and universityeducation (HR = 0.62; 95%CI: 0.35-1.11).Conclusions: The mortality excess found in IDUs with lowereducational levels, especially among those not seeking healthcarein the initial period after being identified as HIV-positive,highlights the need for interventions aimed at facilitatingaccess to health systems, especially among the sociallydisadvantaged(AU)

The shifting pattern of cause-specific mortality in a cohort of human immunodeficiency virus-infected and non-infected injecting drug users.

AIMS: To monitor changes in cause-specific mortality before and after 1997 according to human immunodeficiency virus (HIV) serological status in a cohort of injecting drug users (IDUs) observed for a 17-year period (1987--2004). DESIGN: Community-based prospective cohort study of IDUs recruited in three acquired immunodeficiency virus (AIDS) prevention centres (1987--96) and followed-up until to 2004. METHODS: We obtained annual overall mortality rates and mortality rates by specific causes according to HIV status. Poisson regression models were adjusted to compare mortality rates between calendar periods. Significant changes in slope trends were evaluated by join-point regression. Disease-specific mortality rates were estimated using competing risk models. FINDINGS: From 7186 IDUs recruited (80677.218 person-years), 1589 deaths were observed with an overall mortality rate of 19.7 per 1000 person-years (95% CI, 18.8-20.7). This rate decreased from 22.9 per 1000 (95% CI, 21.4-24.7) before 1997 to 17.4 per 1000 (95% CI, 16.3-18.6) after 1997 [relative risk (RR) 0.83; 95% confidence interval (CI), 0.75-0.92]. Risk of death for HIV-positive was four times higher than for HIV-negative (RR 4.08; 95% CI, 3.63-4.58). Among HIV-positive individuals a significantly decreased change point in trend was found in 1997 for both total and AIDS mortality. HIV-negative individuals showed a similar pattern for drug overdose, suicide and accident mortality. Both groups showed an increase in proportional mortality by liver-related causes, cardiovascular diseases and cancer. Furthermore, a progressively increasing trend was observed for the three causes. However, there were no significant differences according to serological groups. CONCLUSIONS: Cardiovascular and cancer mortality are increasing among IDUs, but the increases are not related to HIV infection. We have not found a link between highly active antiretroviral therapy (HAART) introduction and increases in mortality for specific causes.

Changes in the incidence of tuberculosis in a cohort of HIV-seroconverters before and after the introduction of HAART.

OBJECTIVE: To analyse incidence and determinants of tuberculosis in HIV-seroconverters before and after the introduction of HAART. METHODS: Data from a multicenter cohort study of 2238 HIV-seroconverters between the 1980s and 2004 were analysed and censored by December 2004. Calendar year at risk intervals were pre-1992, 1992-1996 and 1997-2004. Incident tuberculosis was calculated as cases per 1000 person-years (p-y). Survival analyses using Kaplan-Meier and multivariate Cox regression allowing for late-entry were used. Proportional hazards assumptions were checked with tests based on Schoenfeld residuals. RESULTS: Overall, 173 (7.7%) patients developed tuberculosis over 23 698 p-y at a rate of 7.3 cases per 1000 p-y [95% confidence interval (CI), 6.3-8.5]. Incident tuberculosis was higher in intravenous drug-users (IDUs), 12.3 per 1000 p-y compared with persons infected sexually, 3.8 per 1000 p-y (P < 0.001), and persons with clotting disorders (PCD), 2.7 per 1000 p-y (P < 0.001). A decreasing tuberculosis incidence trend was observed from 1995 in all categories. Highest tuberculosis rates, 44 per 1000 p-y, were observed prior to 1997 in IDUs infected with HIV for 11 years. In multivariable analyses women were less likely to develop tuberculosis [relative hazard (RH), 0.62; 95% CI, 0.41-0.96; P < 0.05) and IDUs were more likely to develop tuberculosis (RH, 3.0; 95% CI, 1.72-5.26, P < 0.001). In the HAART era, the hazard of developing tuberculosis was 70% lower (RH, 0.31; 95% CI, 0.17-0.54; P < 0.001). Before 1997, the risk of tuberculosis increased with time since HIV seroconversion, whereas it remained nearly constant in the HAART era. CONCLUSIONS: Since the mid-1990s important decreases in tuberculosis have been observed in HIV-seroconverters that probably reflect the impact of both HAART and tuberculosis control programmes.

[Marginal structural models application to estimate the effects of antiretroviral therapy in 5 cohorts of HIV seroconverters]. / Aplicación de modelos estructurales marginales para estimar los efectos de la terapia antirretroviral en 5 cohortes de seroconvertores al virus de la inmunodeficiencia humana.

OBJECTIVES: Standard methods to evaluate population effectiveness of treatments in observational studies have important limitations to appropriately adjust for time-dependent confounders. In this paper, we describe a recently developed methodological approach, marginal structural models (MSM), and use it to estimate the effectiveness of highly active antiretroviral therapy (HAART) on AIDS or death incidence. SUBJECTS AND METHODS: We analyzed all subjects followed after 1997 as part of the GEMES project (comprised by several cohorts of HIV seroconverters in Spain) and who had not used HAART before the start of follow-up. To estimate the effect of HAART on AIDS or death incidence, we estimated the parameters of a marginal structural Cox model by fitting an inverse probability weighted logistic regression model. The estimation of the weights was based on CD4 count, time since seroconversion, sex, age, transmission category and previous treatment. RESULTS: 917 eligible subjects were followed for an average of 3.4 years and we observed 139 events. 42.1% of the participants received HAART during the study. The estimated rate ratio was 1.01 (95% confidence interval [CI], 0.68-1.49) using a Cox model without covariates and 0.90 (95% CI, 0.61-1.32) using a Cox model with time-dependent covariates. The causal rate ratio estimated for MSM was 0.74, (95% CI, 0.49-1.12). CONCLUSIONS: The beneficial effect of HAART estimated by the MSM, but largely missed by conventional methods, is consistent with the findings of previous randomized studies. The MSM appropriately adjusted for the time-dependent covariate CD4 count, which is both a time-varying confounder and is affected by prior treatment.

Aplicación de modelos estructurales marginales para estimar los efectos de la terapia antirretroviral en 5 cohortes de seroconvertores al virus de la inmunodeficiencia humana / Marginal structural models application to estimate the effects of antiretroviral therapy in 5 cohorts of HIV seroconverters

Objetivos: Los métodos convencionales tienen limitaciones para ajustar por factores de confusión dependientes del tiempo para evaluar la efectividad poblacional de tratamientos en estudios observacionales. En este trabajo se muestra un nuevo tipo de metodología, los modelos estructurales marginales (MEM), y se estima la efectividad de la terapia antirretroviral de gran actividad (TARGA) sobre la incidencia de sida o muerte. Sujetos y métodos: Se identificaron los sujetos sin TARGA seguidos a partir de 1997 en las cohortes de seroconvertores al virus de la inmunodeficiencia humana (VIH) del proyecto GEMES (Grupo de Estudio Multicéntrico Español de Seroconvertores). Para estimar el efecto sobre la incidencia de sida o muerte, se obtuvieron los parámetros de un MEM mediante una regresión logística ponderada por probabilidad inversa. La estimación de los pesos se basó en el recuento de CD4, el tiempo desde la seroconversión, el sexo, la edad, la categoría de trasmisión y el tratamiento previo. Resultados: Los 917 sujetos elegibles se siguieron durante una media de 3,4 años, durante los cuales se observaron 139 desenlaces de interés. El 42,1% de los participantes recibió TARGA durante el estudio. La tasa relativa fue de 1,01 (intervalo de confianza [IC] del 95%, 0,68-1,49) mediante un modelo de Cox convencional sin covariables, y de 0,90 (IC del 95%, 0,61-1,32) mediante un modelo de Cox convencional con covariables cambiantes en el tiempo. La tasa relativa causal estimada por un MEM fue de 0,74 (IC del 95%, 0,49-1,12). Conclusiones: El efecto beneficioso del TARGA encontrado por los MEM está bien establecido, pero los modelos convencionales no pudieron detectarlo. El uso de un MEM permitió ajustar apropiadamente por la variable CD4, que es a la vez una variable de confusión dependiente del tiempo y está afectada por el uso previo de tratamiento

Objectives: Standard methods to evaluate population effectiveness of treatments in observational studies have important limitations to appropriately adjust for time-dependent confounders. In this paper, we describe a recently developed methodological approach, marginal structural models (MSM), and use it to estimate the effectiveness of highly active antiretroviral therapy (HAART) on AIDS or death incidence. Subjects and methods: We analyzed all subjects followed after 1997 as part of the GEMES project (comprised by several cohorts of HIV seroconverters in Spain) and who had not used HAART before the start of follow-up. To estimate the effect of HAART on AIDS or death incidence, we estimated the parameters of a marginal structural Cox model by fitting an inverse probability weighted logistic regression model. The estimation of the weights was based on CD4 count, time since seroconversion, sex, age, transmission category and previous treatment. Results: 917 eligible subjects were followed for an average of 3.4 years and we observed 139 events. 42.1% of the participants received HAART during the study. The estimated rate ratio was 1.01 (95% confidence interval [CI], 0.68-1.49) using a Cox model without covariates and 0.90 (95% CI, 0.61-1.32) using a Cox model with time-dependent covariates. The causal rate ratio estimated for MSM was 0.74, (95% CI, 0.49-1.12). Conclusions: The beneficial effect of HAART estimated by the MSM, but largely missed by conventional methods, is consistent with the findings of previous randomized studies. The MSM appropriately adjusted for the time-dependent covariate CD4 count, which is both a time-varying confounder and is affected by prior treatment

Trends in AIDS and mortality in HIV-infected subjects with hemophilia from 1985 to 2003: the competing risks for death between AIDS and liver disease.

OBJECTIVE: To study trends in progression to AIDS, all-cause mortality, and cause-specific mortality (AIDS-related, liver disease, and hemorrhagic complications) over calendar periods with different exposure to highly active antiretroviral therapy (HAART) in a cohort of hemophiliacs in Spain, taking into account the competing risks of the causes of death. METHODS: Multicenter cohort of HIV-infected hemophiliacs. HIV seroconversion was estimated using mathematic techniques for interval-censored data from 1979 through 1985. Rates of AIDS and cause-specific death were calculated by Poisson regression, allowing for late entry, for the periods 1985 through 1992, 1993 through 1996, 1997 through 2000 (early HAART), and 2001 through 2003 (late HAART), also allowing for competing risks. RESULTS: Of 585 subjects, 44% were younger than 15 years of age, 82% had severe hemophilia, 86% had type A hemophilia, and the median seroconversion date was October 1982. Calendar period and age at HIV seroconversion strongly influenced AIDS and death rates. Compared with 1993 through 1996, decreases of 75% (relative risk [RR] = 0.25, 95% confidence interval [CI]: 0.14 to 0.43) and 72% (RR = 0.28, 95% CI: 0.12 to 0.63) in the RR of AIDS were observed in early and late HAART. For all-cause mortality, 72% (RR = 0.28, 95% CI: 0.18 to 0.42) and 83% (RR = 0.17, 95% CI: 0.09 to 0.33) decreases were observed by 1997 through 2000 and 2001 through 2003. For liver-related deaths, increases were observed in the late-HAART period (RR = 2.80, 95% CI: 0.94 to 8.36) compared with 1993 through 1996, but using competing risks, this RR was substantially reduced (RR = 1.70, 95% CI: 0.57 to 5.04). DISCUSSION: Major reductions in AIDS and death rates were observed from 1997 to 2003 in hemophiliacs. These survival improvements are largely attributable to decreases in AIDS-related deaths and have been accompanied by increases in liver disease death rates, which are overestimated if competing risks are not taken into account.

Impact of hepatitis C infection on long-term mortality of injecting drug users from 1990 to 2002: differences before and after HAART.

OBJECTIVE: To assess the impact of HIV and hepatitis C virus (HCV) infection on long-term mortality in injecting drug users (IDU). DESIGN: Community-based prospective cohort study. METHODS: Mortality data from follow-up in clinical sites and the Mortality Registry by December 2002 were collected for 3247 IDU who attended three centres for voluntary counselling and testing for HIV/AIDS, HCV and hepatitis B virus (HBV) in 1990-1996. Mortality rates by Poisson regression were adjusting for age, sex, duration of drug use, education, HBV and calendar period (1990-1997 and 1998-2002). RESULTS: Overall, 11.2% were HIV/HCV negative, 43.7% positive only for HCV and 45.1% positive for both. During 26 772 person-years of follow-up, 585 deaths were detected (2.19/100 person-years). Before 1997, HIV/HCV-positive subjects had a five-fold increase in risk of death [relative risk (RR), 5.4; 95% confidence interval (CI), 2.5-11.4] compared with those negative for both; after 1997, a three-fold increase was observed (RR, 2.7; 95% CI, 1.7-4.2). Being HCV positive/HIV negative was not associated with an increase in the risk of death either before (RR, 1.3; 95% CI, 0.6-2.9) or after (RR, 1.2; 95% CI, 0.8-1.9) 1997 compared with HCV/HIV negative. While increases in mortality were seen in those HCV/HIV negative (RR, 1.6; 95% CI, 0.7-3.7) and those only positive for HCV (RR, 1.5; 95% CI, 1.0-2.1), a 20% reduction among coinfected IDUs was observed after 1997 (interaction P = 0.033). CONCLUSIONS: HCV/HIV coinfection has had a large impact on mortality in IDU. After 1997, mortality increased in HIV negative/HCV positive subjects and decreased in HIV positive/HCV positive.

Gender differences in progression to AIDS and death from HIV seroconversion in a cohort of injecting drug users from 1986 to 2001.

BACKGROUND: Although the consensus is that gender does not influence HIV progression, its relevance may depend on the setting. AIM: To study gender differences in HIV progression to AIDS and death from 1986 to 2001 in a cohort of injecting drug user (IDU) seroconverters in Spain. METHODS: Risk of AIDS and death in persons infected for the same length of time were compared through Kaplan-Meier, allowing for late entry, and Cox regression adjusting for gender, age, and calendar period (before 1992, 1992-1995, 1996-1998, 1999-2001) fitted as time dependent covariates. RESULTS: Of 929 IDU, 24.7% were women. Median seroconversion year was 1993.3 for men and women. 44% of women and 34% of men received antiretroviral therapy. Risk of AIDS was lower in women in univariate (hazard ratio (HR) 0.72; 95%CI:0.51 to 1.01) and multivariate analyses (HR 0.73 95%CI:0.52 to 1.03). A 46% reduction in risk of AIDS for period 1999-2001 compared with 1992-1995 was seen in both men and women (HR: 0.56 (95%CI:0.36 to 0.87). As for mortality, women's risk of death was lower univariately (HR 0.67 95%CI:0.45 to 0.99) although compared with 1992-95, men experienced a 34% reduction in mortality during 1999-2001 (HR 0.66 95%CI:0.40 to 1.01), which was not statistically significant in women. CONCLUSIONS: HIV progression was lower in female IDU before and after 1997 and their uptake of antiretroviral therapy was higher than male IDU. The inability to detect a reduction in mortality for women during 1999-2001 is probably attributable to lack of power. Differences in severity of addiction, drug using patterns, and competing causes of death may explain these findings.

[Determination of the beginning of follow-up in longitudinal studies applied to HIV infections]. / Imputación del instante de inicio de seguimiento en estudios longitudinales: aplicación a la infección por VIH.

BACKGROUND: In cohort or longitudinal studies, subjects are recruited some time after the beginning of the problem, as in HIV infection. The aim of this paper is to show several imputation techniques of the beginning of follow up and evaluate its use in the framework of a study of HIV progression. METHODS: Three subcohorts of HIV+ subjects recruited in Valencia and Castellón CIPS up to 1996 are available. Seroconversion date was estimated for 244 Seroincidents, 887 seroprevalents with CD4 measurements and 337 without CD4 measurements. For seroincidents midpoint between last HIV- and first HIV+ visits was considered. For prevalent with CD4 serocon version date was imputed from 5 random samples of a progression model of infection to a CD4 level. For prevalent without CD4 seroconversion date was imputed from 5 random samples of HIV incidence density obtained from the other subcohorts. The imputation was repeated 500 times, assigning the seroconversion date as the median of imputations and obtaining confidence limits from 5 and 95 percentiles. Imputation validity was tested comparing time to AIDS and death for each one of the 3 groups. RESULTS: 443 and 405 deaths were observed among the 1468 subjects. Median of seroconversion was January 1993 for incidents, January 1991 for prevalents with CD4 and November 1988 for prevalents without CD4. The latest group showed a worse survival and AIDS free time compared to the other two cohorts. CONCLUSIONS: The imputation tools used showed their usefulness to reduce the survival bias in observational studies. Their generalization depends on the viability of incident cohorts, the availability of a progression marker or a origin on time.