Clinical profile of Spanish hepatitisC virus-infected treatment-naïve patients with compensated cirrhosis in the CREST study. / Perfil clínico de los pacientes españoles con hepatitisC naïve con cirrosis compensada tratados en el estudio CREST.

BACKGROUND AND AIM OF THE STUDY: There are still patients with hepatitisC in Spain who have yet to be diagnosed, but their clinical profile is unclear. In 2021, 21.93% of patients diagnosed had cirrhosis and were mostly treatment-naïve. METHODS: This sub-analysis describes the clinical profile of the 60Spanish treatment-naïve patients with compensated cirrhosis who were included in the CREST study. MAJOR RESULTS: Sixty percent of patients were male, median age 56years, and 33% had a history of drug use. Almost three-quarters (71.3%) had more than one comorbidity and 78.3% took concomitant medication. At treatment initiation, median platelet count was 139×103/µL and FibroScan® 17kPa. No virological failure was observed and no patient discontinued treatment due to adverse events. No clinically significant changes were noted during or after treatment in the median platelet, albumin, bilirubin, and transaminase levels. CONCLUSIONS: Treatment with glecaprevir/pibrentasvir for 8weeks in this cohort of treatment-naïve patients with compensated cirrhosis in Spain was safe and effective. This information reinforces the use of this short antiviral regimen even when there is compensated cirrhosis, simplifying the approach to hepatitisC among those patients still to be diagnosed and treated in Spain.

Is the universal population Hepatitis C virus screening a cost-effective strategy? A systematic review of the economic evidence / ¿Es coste-efectivo realizar el cribado poblacional para la hepatitis C? Revisión sistemática de la evidencia farmacoeconómica

BACKGROUND: Efficient strategies are needed in order to achieve the objective of the WHO of eradicating Hepatitis C virus (HCV). Hepatitis C infection can be eliminated by a combination of direct acting antiviral (DAA). The problem is that many individuals remain undiagnosed. The objective is to conduct a systematic review of the evidence on economic evaluations that analyze the screening of HCV followed by treatment with DAAs. METHODS: Eleven databases were performed in a 2015-2018-systematic review. Inclusion criteria were economic evaluations that included incremental cost-effectiveness ratio (ICER) in terms of cost per life year gained or quality-adjusted life year. RESULTS: A total of 843 references were screened. Sixteen papers/posters meet the inclusion criteria. Ten of them included a general population screening. Other populations included were baby-boomer, people who inject drugs, prisoners or immigrants. Comparator was "standard of care", other high-risk populations or no-screening. Most of the studies are based on Markov model simulations and they mostly adopted a healthcare payer's perspective. ICER for general population screening plus treatment versus high-risk populations or versus routinely performed screening showed to be below the accepted willingness to pay thresholds in most studies and therefore screening plus DAAs strategy is highly cost-effective. CONCLUSION: This systematic review shows that screening programmes followed by DAAs treatment is cost-effective not only for high risk population but for general population too. Because today HCV can be easily cured and its long-term consequences avoided, a universal HCV screening plus DAAs therapies should be the recommended strategy to achieve the WHO objectives for HCV eradication by 2030

ANTECEDENTES: Para conseguir el objetivo de la Organización Mundial de la Salud (OMS) de erradicar la hepatitis C (VHC) se necesita estrategias eficientes. La infección por VHC puede ser eliminada por combinaciones de antivirales de acción directa (DAA). El problema es que muchos individuos permanecen sin diagnosticar. El objetivo es realizar una revisión sistemática de la evidencia de evaluaciones económicas que analicen el cribado del VHC (screening) seguido de tratamiento con DDA. MÉTODO: Realizamos una revisión sistemática de once bases de datos incluyendo 2015-2018. Los criterios de inclusión fueron evaluación económica que incluyera ratio de coste-efectividad incremental (ICER) en coste por año de vida ganado o año de vida ajustado por calidad. RESULTADOS: Extrajimos 843 referencias. Dieciséis pósters/artículos cumplieron criterio de inclusión. Diez de ellos valoraban cribado de población general. Otras poblaciones analizadas fueron "baby-boomer", usuarios de drogas parenterales, prisiones o inmigrantes. El comparador fue "práctica clínica habitual", otras poblaciones de alto riesgo o no hacer cribado. La mayoría de los estudios utilizaron simulaciones por modelo de Markov y la perspectiva del pagador. El ICER para cribado de población general + tratamiento DDA frente a poblaciones de alto riesgo o práctica rutinaria mostraron que está por debajo del umbral de la disponibilidad a pagar en la mayoría de los estudios y concluyen que la estrategia es altamente coste-eficaz y que está por debajo de los umbrales habituales de disposición a pagar. CONCLUSIÓN: Esta revisión sistemática muestra que los programas de detección seguidos de tratamiento con DDAs son coste-efectivos no sólo para poblaciones de alto riesgo sino también para población general. Dado que hoy el VHC puede ser fácilmente curado y evitadas sus consecuencias a largo plazo, el cribado universal seguido de tratamiento con combinaciones de DDA debería ser la estrategia recomendada para alcanzar el objetivo de la OMS de erradicar el VHC para 2030

Sociodemographic and clinical factors associated with the preference between NNRTIs and PIs for the initial treatment of HIV infection: Perfil-es study.

The Perfil-es study demonstrated that, while non-nucleoside reverse transcriptase inhibitor (NNRTI)-based initial antiretroviral therapy (ART) is more frequently used in human immunodeficiency virus (HIV)-infected naïve patients, ritonavir-boosted protease inhibitors (PI/r)-based regimens are the preferred option in patients with advanced infectious stages or high baseline viral load. The present analysis focused on the second phase of the Perfil-es study, where sociodemographic and clinical data were retrospectively collected from patients starting NNRTI- or PI/r-based regimens in order to identify factors that could influence the choice of initial ART. Patients' characteristics were compared by both bivariate and multivariate analyses. A total of 642 patients were evaluated. The main transmission group was men who have sex with men (MSM) (48%), and 24% of patients were coinfected with hepatitis B or C. Patients with cardiovascular risk accounted for 56%, and 15% had a neuropsychiatric history. Anxiolytics (29%), antidepressants (18%) and methadone (18%) were the most frequent concomitant medications. The use of PI/r-based regimens was more frequent in older patients, childbearing potential women patients coinfected with hepatitis B or C, and those with cardiovascular risk and a neuropsychiatric history. The presence of a neuropsychiatric disorder (OR: 1.912; CI 95%: 1.146-3.191; p < .05) and the use of concomitant medication (OR: 1.736; CI 95%: 1.204-2.502; p < .01) were identified as independent factors associated with the selection of PI/r-based regimens. MSM sexual conduct was the only independent factor related to the selection of NNRTI-based ART (OR: 0.699; CI 95%: 0.504-0.970; p < .05). Neither the physicians' characteristics nor the geographical area where HIV patients were attended influenced the choice of ART. In conclusion, patients' comorbidity, pregnancy potential and lifestyle seem to influence the choice of ART. Neuropsychiatric comorbidity and concomitant medication, mainly related to this condition, appear to be associated with the use of PI/r-based initial ART while MSM seem more likely to receive NNRTI-based regimens in Spain.

Profiles and clinical management of hepatitis C patients in Spain: disHCovery study.

INTRODUCTION: To assess the clinical profile and management of patients with hepatitis C (HCV) infection in an observational study in Spanish hospitals. METHODS: The study included an initial cross-sectional phase (study phase I), in which investigators at 48 hospitals from 14 Spanish regions collected data from approximately 20 consecutive patients each (a total of 1,000 patients) to assess the general features of HCV-infected patients of any genotype. During the second phase (study phase II), data from 878 patients that were infected exclusively with genotype 1 HCV were assessed retrospectively. Eight pre-defined clinical profiles were established, in order to assess clinical and previous treatments characteristics. RESULTS: Among the HCV-infected individuals that were analysed during the first part, HCV genotype 1 was found to be predominant (with a prevalence of 76.6%), prevailing the subtype 1b (69.8%), with other significant groups infected by genotype 3 (12.3%) and 4 (7.4%). In the second part of the study, 44% of the HCV genotype 1-infected patients were at a F3/F4 fibrosis stage. 15.9% had never been treated, and previously unsuccessfully treated patients that were no longer receiving anti-HCV treatment accounted for 50.8% of cases. Individuals with a sustained virologic response (SVR) to previous dual therapies (based on Interferon and Ribavirin) were only 14.5% and patients under treatment during the study accounted for the remaining 18.8%. A total of 713 patients (81.2%) in the second phase were not receiving any type of therapy over the period analysed, mainly due to the anticipation of new anti-HCV drugs (41.8%), SVR achievement (17.8%) and unresponsiveness to therapies available at the time of the study (9.5%). CONCLUSIONS: HCV genotype 1, predominately 1b, is the most prevalent type in Spain. Advanced fibrosis or cirrhosis is frequent in this group, mainly patients not yet cured.

Profiles and clinical management of hepatitis C patients in Spain: disHCovery study / / Perfil clínico y seguimiento de los pacientes con hepatitis C crónica en hospitales españoles: Estudio disHCovery

Introduction. To assess the clinical profile and management of patients with hepatitis C (HCV) infection in an observational study in Spanish hospitals. Methods. The study included an initial cross-sectional phase (study phase I), in which investigators at 48 hospitals from 14 Spanish regions collected data from approximately 20 consecutive patients each (a total of 1,000 patients) to assess the general features of HCV-infected patients of any genotype. During the second phase (study phase II), data from 878 patients that were infected exclusively with genotype 1 HCV were assessed retrospectively. Eight pre-defined clinical profiles were established, in order to assess clinical and previous treatments characteristics. Results. Among the HCV-infected individuals that were analysed during the first part, HCV genotype 1 was found to be predominant (with a prevalence of 76.6%), prevailing the subtype 1b (69.8%), with other significant groups infected by genotype 3 (12.3%) and 4 (7.4%). In the second part of the study, 44% of the HCV genotype 1-infected patients were at a F3/F4 fibrosis stage. 15.9% had never been treated, and previously unsuccessfully treated patients that were no longer receiving anti-HCV treatment accounted for 50.8% of cases. Individuals with a sustained virologic response (SVR) to previous dual therapies (based on Interferon and Ribavirin) were only 14.5% and patients under treatment during the study accounted for the remaining 18.8%. A total of 713 patients (81.2%) in the second phase were not receiving any type of therapy over the period analysed, mainly due to the anticipation of new anti-HCV drugs (41.8%), SVR achievement (17.8%) and unresponsiveness to therapies available at the time of the study (9.5%). Conclusions. HCV genotype 1, predominately 1b, is the most prevalent type in Spain. Advanced fibrosis or cirrhosis is frequent in this group, mainly patients not yet cured (AU)

Introducción. Evaluar el perfil clínico y el manejo de los pacientes con infección por hepatitis C crónica (VHC) en un estudio observacional en hospitales españoles. Métodos. El estudio incluye una fase inicial de registro transversal de datos agregados (primera fase del estudio) en la cual investigadores de 48 hospitales en 14 regiones diferentes de España recopilaron datos de aproximadamente 20 pacientes atendidos consecutivamente en consulta (un total de 1.000 pacientes) en los que se analizó, en cada uno de ellos, las características generales de la infección por VHC de cualquier genotipo. Durante la segunda fase del estudio se realizó una evaluación retrospectiva de datos procedentes de 878 pacientes exclusivamente portadores del genotipo 1 del VHC. Se establecieron ocho perfiles clínicos predefinidos con el objetivo de evaluar las características tanto clínicas como de los tratamientos previos. Resultados. Entre los pacientes con infección por VHC que fueron analizados durante la primera parte del estudio, se observó que el genotipo 1 del VHC era el más frecuente (con una prevalencia del 76,6%), predominando el subtipo 1b (69,8%) seguido de los genotipo 3 (12,3%) y genotipo 4 (7,4%). En la segunda parte del estudio se observó que el 44% de los pacientes infectados por genotipo 1 del VHC presentaban un grado de fibrosis F3/F4. Un 15,9 % de los pacientes no habían sido previamente tratados y un 50,8% habían fracasado a un tratamiento previo y en ese momento no recibían ningún tratamiento. Un 14,5% de los pacientes habían presentado previamente respuesta viral sostenida (RVS) tras terapia con interferón y ribavirina y durante el punto de corte de estudio se encontraban bajo tratamiento el 18,8% de los pacientes en seguimiento. En la segunda fase, un total de 713 pacientes (81,2% de la población evaluada) no estaba recibiendo tratamiento, debido fundamentalmente a la previsión de llegada de nuevos fármacos (41,8%), a que ya estaban en RVS (17,8%) o a la ausencia de respuesta a las terapias disponibles en el momento del estudio (9,5%). Conclusiones. El genotipo más prevalente del VHC en España es el genotipo 1, predominantemente 1b. El perfil de paciente más frecuente fue el que presentaba fibrosis avanzadas o cirrosis, principalmente en pacientes aún no curados (AU)

Models and frameworks: a synergistic association for developing component-based applications.

The use of frameworks and components has been shown to be effective in improving software productivity and quality. However, the results in terms of reuse and standardization show a dearth of portability either of designs or of component-based implementations. This paper, which is based on the model driven software development paradigm, presents an approach that separates the description of component-based applications from their possible implementations for different platforms. This separation is supported by automatic integration of the code obtained from the input models into frameworks implemented using object-oriented technology. Thus, the approach combines the benefits of modeling applications from a higher level of abstraction than objects, with the higher levels of code reuse provided by frameworks. In order to illustrate the benefits of the proposed approach, two representative case studies that use both an existing framework and an ad hoc framework, are described. Finally, our approach is compared with other alternatives in terms of the cost of software development.

Tratamiento antirretroviral de inicio en pacientes infectados por el virus de la inmunodeficiencia humana en España: decisiones con relación a características inmunovirológicas específicas (estudio PERFIL-es) / Initial antiretroviral treatment in human immunodeficiency virus-infected patients in Spain: Decisions made in relation to particular immunovirological characteristics (PERFIL-es study)

INTRODUCCIÓN: El objetivo del estudio Perfil-es era conocer, en la práctica clínica, la proporción de TARV de inicio basado en ITINAN o IP/r e identificar los factores implicados en la decisión terapéutica. Métodos Estudio observacional, retrospectivo en 65 hospitales. Resultados Se iniciaron 1.687 TARV: un 53% basado en ITINAN y un 42% en IP/r. Se analizaron 642 pacientes. El 72% presentaba un recuento de CD4 < 350 células/μl. Conclusión En España el TARV de inicio sigue siendo tardío. Los ITINAN son la elección más frecuente aunque los IP/r desempeñan un importante papel

INTRODUCTION: The purpose of Perfil-es study was to identify the proportion of patients starting ARV treatment based on NNRTIs or PI/r, and to identify the variables involved in the therapeutic decision-makingin standard clinical practice. METHODS: An observational restrospective study performed in 65 Spanish hospitals. RESULTS: Was a total of 1,687 starts: 53% with NNRTI-based regimen and 42% with PI/r, and of the642 patients analyzed, 72% had a CD4 count < 350 cells/l. CONCLUSION: The initiation of ARV treatment is still late in Spain. NNRTIs are the more frequent choice, although PI/r plays an important role

[Initial antiretroviral treatment in human immunodeficiency virus-infected patients in Spain: Decisions made in relation to particular immunovirological characteristics (PERFIL-es study)]. / Tratamiento antirretroviral de inicio en pacientes infectados por el virus de la inmunodeficiencia humana en España: decisiones con relación a características inmunovirológicas específicas (estudio PERFIL-es).

INTRODUCTION: The purpose of Perfil-es study was to identify the proportion of patients starting ARV treatment based on NNRTIs or PI/r, and to identify the variables involved in the therapeutic decision-making in standard clinical practice. METHODS: An observational retrospective study performed in 65 Spanish hospitals. RESULTS: Was a total of 1,687 starts: 53% with NNRTI-based regimen and 42% with PI/r, and of the 642 patients analyzed, 72% had a CD4 count<350 cells/µl. CONCLUSION: The initiation of ARV treatment is still late in Spain. NNRTIs are the more frequent choice, although PI/r plays an important role.

Análisis comparativo de coste-eficacia entre darunavir/ritonavir y otros inhibidores de la proteasa en el tratamiento de la infección por el virus de la inmunodeficiencia humana de tipo 1 en pacientes naïve en España / Comparative cost-effectiveness analysis between darunavir/ritonavir and other protease inhibitors in treatment-naive human immunodeficiency syndrome type 1-infected patients in Spain

INTRODUCCIÓN: Las guías GESIDA proponen pautas preferentes de inicio de tratamiento antirretroviral en pacientes infectados por el VIH. El objetivo de este análisis es comparar los costes y la eficacia de darunavir/r QD frente a otros inhibidores de la proteasa (IP) potenciados recomendados por GESIDA en pacientes naďve. MÉTODOS: Mediante un modelo de coste-eficacia se compararon los IP/r recomendados como pautas preferentes o alternativas en pacientes naďve, junto con un tratamiento de base con 2 ITIAN. La eficacia se midió mediante la respuesta virológica (carga viral < 50 copias/ml) a las 48 semanas ajustada por los niveles basales de carga viral y recuentos de CD4. Para generar la «frontera de eficiencia» y ratios de coste-eficacia se utilizaron los costes espańoles y las tasas de eficacia a las 48 semanas. RESULTADOS: El modelo estimó que el inicio del tratamiento en naďve con darunavir/r QD se mostró como la opción preferente basada en un IP/r más coste-eficaz. El coste medio del TARGA por paciente respondedor era menor para darunavir/r (13.420 €) que para atazanavir/r (14.000 €) o lopinavir/r (13.815 €). Se estimó que darunavir/r sería el IP preferente más eficiente, mientras que atazanavir/r QD y lopinavir/r BID resultarían opciones «dominadas», situándose fuera de la frontera de la eficiencia. Partiendo de un presupuesto fijo de 10 millones de €, se estimó que la pauta de inicio con darunavir/r QD conseguiría un mayor número de pacientes respondedores (745) que con atazanavir/r QD (714) o lopinavir/r BID (724). Al mismo tiempo, darunavir/r QD reduciría el número de pacientes que fracasarían al tratamiento (150) en comparación con atazanavir/r QD (172) o lopinavir/r (286). CONCLUSIONES: Según este modelo, darunavir/r QD es el IP/r preferente más coste-efectivo para el tratamiento de la infección por el VIH-1 basado en IP/r en pacientes naďve en Espańa

INTRODUCTION: GESIDA (AIDS Study Group) has proposed preferred regimens of antiretroviral treatment as initial therapy in HIV infected patients. The objective of this analysis is to compare the costs and effectiveness of darunavir/r QD and other ritonavir-boosted (/r) protease inhibitors (PIs) currently recommended in GESIDA guidelines for treatment-naďve patients. METHODS: A cost-efficacy model compared the boosted PIs recommended as preferred or alternative treatment choices, each used with a nucleoside reverse transcriptase inhibitor backbone. Efficacy was measured by 48-week virological response (viral load < 50 copies/mL) adjusted by baseline viral load and CD4 cell count. To generate efficiency frontiers and cost-efficacy ratios, one-year antiretroviral therapy costs in Spain, and 48-week efficacy values were used. Results The model estimated that starting treatment with darunavir/r QD was the most cost-effective choice compared with the other preferred PI/r based therapies. The average cost per patient with a virological response was lower for darunavir/r QD (13,420€) than for atazanavir/r QD (14,000€), or lopinavir/r BID (13,815€). Among the preferred PI/r-based therapies, darunavir/r QD also was estimated to be the most efficient option for treatment-naďve patients. Atazanavir/r QD and lopinavir/r BID were found to be «dominated» by darunavir/r) and, consequently, were outside the efficiency frontier of PI/r-based first-line treatment. Given a fixed budget of 10 million euros for PI/r-based first-line therapy, the model estimated that darunavir/r QD would yield more responders (745) than atazanavir/r QD (714), or lopinavir/r BID (724). At the same time, darunavir/r QD would reduce the number of individuals failing treatment (150) compared with atazanavir/r QD (172) and lopinavir/r BID (286). CONCLUSIONS: In this model, darunavir/r QD was found to be the most cost-effective choice, among the preferred PI/r-based therapies recommended in the Spanish guidelines for treatment-naïve patients

[Reasons for the introduction of darunavir in the antirretroviral treatment in HIV-infected patients]. / Motivos de introducción de darunavir en un régimen antirretroviral en pacientes infectados por el virus de la inmunodeficiencia adquirida.

INTRODUCTION: In 2009 a deep change in ARV treatment took place in Spain with the introduction of new ARV drugs. The principal objective of the study was to determine the clinical situation of the patients in which DRV/r was introduced in the ARV therapy. METHODS: Observational, cross sectional and multicentre study in which 91 reference hospitals participated. Patient's enrollment was carried out between 2008 and 2009. Data were collected retrospectively considering standard clinical practice. RESULTS: 719 medical records were reviewed. Patients had a different clinical situation compared to nowadays with predominance of multiresistant virus which leaded to virologic failure. The principal reason for introducing DRV/r in the ARV regimen was the virologic failure (54.2%). CONCLUSIONS: Considering this situation, DRV/r became a therapeutic option which represented a change in the ARV paradigm in that period.

Motivos de introducción de darunavir en un régimen antirretroviral en pacientes infectados por el virus de la inmunodeficiencia adquirida / Reasons for the introduction of darunavir in the antirretroviral treatment in HIV-infected patients

Introducción. En el año 2009 se produjo un cambio muy sustancial en el tratamiento antirretroviral (ARV) de nuestro país con la introducción de nuevos fármacos antiretrovirales. El objetivo fue conocer la situación clínica de los pacientes en los que se introducía darunavir (DRV/r) en el tratamiento antirretroviral. Métodos. Estudio observacional, transversal y retrospectivo, en el que participaron 91 centros españoles de referencia. El periodo de reclutamiento del estudio se llevó a cabo entre 2008 y 2009. Se recogieron datos relacionados con la práctica clínica habitual. Resultados. Se revisaron 719 historias clínicas. La situación clínica prevalente entre los pacientes que necesitaban un ajuste al tratamiento antirretroviral era diferente a la actual con predominio de multirresistencias que llevaban a fracaso. El motivo principal por el que se había incluido DRV/r en la pauta fue el fracaso virológico (54,2%). Conclusiones. En esa situación, DRV/r constituyó una opción terapéutica que supuso un cambio en el paradigma del tratamiento antirretroviral de la época(AU)

Introduction. In 2009 a deep change in ARV treatment took place in Spain with the introduction of new ARV drugs. The principal objective of the study was to determine the clinical situation of the patients in which DRV/r was introduced in the ARV therapy. Methods. Observational, cross sectional and multicentre study in which 91 reference hospitals participated. Patient’s enrolment was carried out between 2008 and 2009. Data were collected retrospectively considering standard clinical practice. Results. 719 medical records were reviewed. Patients had a different clinical situation compared to nowadays with predominance of multiresistant virus which leaded to virologic failure. The principal reason for introducing DRV/r in the ARV regimen was the virologic failure (54.2%). Conclusions. Considering this situation, DRV/r became a therapeutic option which represented a change in the ARV paradigm in that period(AU)

[Comparative cost-effectiveness analysis between darunavir/ritonavir and other protease inhibitors in treatment-naive human immunodeficiency syndrome type 1-infected patients in Spain]. / Análisis comparativo de coste-eficacia entre darunavir/ritonavir y otros inhibidores de la proteasa en el tratamiento de la infección por el virus de la inmunodeficiencia humana de tipo 1 en pacientes naïve en España.

INTRODUCTION: GESIDA (AIDS Study Group) has proposed preferred regimens of antiretroviral treatment as initial therapy in HIV infected patients. The objective of this analysis is to compare the costs and effectiveness of darunavir/r QD and other ritonavir-boosted (/r) protease inhibitors (PIs) currently recommended in GESIDA guidelines for treatment-naïve patients. METHODS: A cost-efficacy model compared the boosted PIs recommended as preferred or alternative treatment choices, each used with a nucleoside reverse transcriptase inhibitor backbone. Efficacy was measured by 48-week virological response (viral load < 50 copies/mL) adjusted by baseline viral load and CD4 cell count. To generate efficiency frontiers and cost-efficacy ratios, one-year antiretroviral therapy costs in Spain, and 48-week efficacy values were used. RESULTS: The model estimated that starting treatment with darunavir/r QD was the most cost-effective choice compared with the other preferred PI/r based therapies. The average cost per patient with a virological response was lower for darunavir/r QD (13,420€) than for atazanavir/r QD (14,000€), or lopinavir/r BID (13,815€). Among the preferred PI/r-based therapies, darunavir/r QD also was estimated to be the most efficient option for treatment-naïve patients. Atazanavir/r QD and lopinavir/r BID were found to be «dominated¼ by darunavir/r) and, consequently, were outside the efficiency frontier of PI/r-based first-line treatment. Given a fixed budget of 10 million euros for PI/r-based first-line therapy, the model estimated that darunavir/r QD would yield more responders (745) than atazanavir/r QD (714), or lopinavir/r BID (724). At the same time, darunavir/r QD would reduce the number of individuals failing treatment (150) compared with atazanavir/r QD (172) and lopinavir/r BID (286). CONCLUSIONS: In this model, darunavir/r QD was found to be the most cost-effective choice, among the preferred PI/r-based therapies recommended in the Spanish guidelines for treatment-naïve patients.

Real-Time PCR Quantification of Peronospora arborescens, the Opium Poppy Downy Mildew Pathogen, in Seed Stocks and Symptomless Infected Plants.

In this study, we developed a reliable, quick, and accurate quantitative polymerase chain reaction (qPCR) assay based on the MIQE (Minimum Information for publication of Quantitative Real-Time PCR Experiments) guidelines for the quantification of Peronospora arborescens in infected downy mildew-symptomless opium poppy (Papaver somniferum) tissues and commercial seed stocks. The protocol was highly reproducible and allowed accurate quantification of pathogen DNA up to 10 fg in different plant DNA backgrounds without losing specificity and efficiency. Moreover, to further overcome difficulties conferred by the strict biotrophy of this pathogen, we developed dilution series of DNA extracted from a plasmid with the target pathogen DNA as a cloned insert. This facilitated the demonstration of the robustness of the protocol in different laboratories with different qPCR equipment and reagents, which may help in its use on a broad scale. Finally, we validated the usefulness of the qPCR protocol for quarantine purposes and downy mildew resistance screening by quantifying P. arborescens in complex, naturally infested opium poppy samples. Thus, a pathogen biomass of 0.0003 to 0.007‰ or of 0.110 to 5,557 ppm was quantified in symptomless capsules in commercial seed stocks, or in stem samples from symptomless opium poppy plants systemically infected by the pathogen, respectively.

A nested-polymerase chain reaction protocol for detection and population biology studies of Peronospora arborescens, the downy mildew pathogen of opium poppy, using herbarium specimens and asymptomatic, fresh plant tissues.

A sensitive nested-polymerase chain reaction (PCR) protocol was developed using either of two primer pairs that improves the in planta detection of Peronospora arborescens DNA. The new protocol represented an increase in sensitivity of 100- to 1,000-fold of detection of the oomycete in opium poppy tissue compared with the detection limit of single PCR using the same primer pairs. The new protocol allowed amplification of 5 to 0.5 fg of Peronospora arborescens DNA mixed with Papaver somniferum DNA. The protocol proved useful for amplifying Peronospora arborescens DNA from 96-year-old herbarium specimens of Papaver spp. and to demonstrate that asymptomatic, systemic infections by Peronospora arborescens can occur in wild Papaver spp. as well as in cultivated opium poppy. Also, the increase in sensitivity of the protocol made possible the detection of seedborne Peronospora arborescens in commercial opium poppy seed stocks in Spain with a high frequency, which poses a threat for pathogen spread. Direct sequencing of purified amplicons allowed alignment of a Peronospora arborescens internal transcribed spacer (ITS) ribosomal DNA (rDNA) sequence up to 730-bp long when combining the sequences obtained with the two primer sets. Maximum parsimony analysis of amplified Peronospora arborescens ITS rDNA sequences from specimens of Papaver dubium, P. hybridum, P. rhoeas, and P. somniferum from different countries indicated for the first time that a degree of host specificity may exist within populations of Peronospora arborescens. The reported protocol will be useful for epidemiological and biogeographical studies of downy mildew diseases as well as to unravel misclassification of Peronospora arborescens and Peronospora cristata, the reported causal agents of the opium poppy downy mildew disease.

Phylogenetic Analysis of Downy Mildew Pathogens of Opium Poppy and PCR-Based In Planta and Seed Detection of Peronospora arborescens.

ABSTRACT Severe downy mildew diseases of opium poppy (Papaver somniferum) can be caused by Peronospora arborescens and P. cristata, but differentiating between the two pathogens is difficult because they share morphological features and a similar host range. In Spain, where severe epidemics of downy mildew of opium poppy have occurred recently, the pathogen was identified as P. arborescens on the basis of morphological traits. In this current study, sequence homology and phylogenetic analyses of the internal transcribed spacer regions (ITS) of the ribosomal DNA (rDNA) were carried out with DNA from P. arborescens and P. cristata from diverse geographic origins, which suggested that only P. arborescens occurs in cultivated Papaver somniferum in Spain. Moreover, analyses of the rDNA ITS region from 27 samples of downy-mildew-affected tissues from all opium-poppy-growing regions in Spain showed that genetic diversity exists within P. arborescens populations in Spain and that these are phylogenetically distinct from P. cristata. P. cristata instead shares a more recent, common ancestor with a range of Peronospora species that includes those found on host plants that are not members of the Papaveraceae. Species-specific primers and a PCR assay protocol were developed that differentiated P. arborescens and P. cristata and proved useful for the detection of P. arborescens in symptomatic and asymptomatic opium poppy plant parts. Use of these primers demonstrated that P. arborescens can be transmitted in seeds and that commercial seed stocks collected from crops with high incidence of the disease were frequently infected. Field experiments conducted in microplots free from P. arborescens using seed stocks harvested from infected capsules further demonstrated that transmission from seedborne P. arborescens to opium poppy plants can occur. Therefore, the specific-PCR detection protocol developed in this study can be of use for epidemiological studies and diagnosing the pathogen in commercial seed stocks; thus facilitating the sanitary control of the disease and avoidance of the pathogen distribution in seeds.

[Therapy with antipsychotic drugs as a risk factor for diabetes in schizophrenia: a case-control study]. / Evaluación del tratamiento antipsicótico como factor de riesgo de diabetes en la esquizofrenia: estudio de casos y controles.

BACKGROUND AND OBJECTIVES: Atypical antipsychotics have been related with hyperglycaemia, diabetes mellitus, weight gain and lipid alterations in some patients. This study analyzed whether continuous treatment with risperidone, olanzapine, or clozapine entails a risk of glucose or lipid metabolism alterations in schizophrenic patients. PATIENTS AND METHOD: Patients included in this study were schizophrenics who had received mono-therapeutic with clozapine, olanzapine or risperidone for a period of 1 to 3 years. Those schizophrenic patients who were diagnosed as diabetic during psychiatric treatment and those who showed fasting glycemia greater than or equal to 126 mg/dl in two consecutive measurements were considered cases. The remaining schizophrenic patients who were receiving treatment and did not show these alterations were considered controls. RESULTS: In the adjusted analysis (multivariate logistic regression) of the effect of antipsychotic treatment on the presence of diabetes, which also assessed age and body-mass index, the adjusted odds ratio (OR) for olanzapine relative to risperidone was 2.22 (95% confidence interval [CI], 1.12-4.22), (p = 0.0228); and that for clozapine relative to risperidone was 2.87 (95% CI, 1.19, 6.93), (p = 0.0192). Both results reveal a significantly greater risk for the appearance of diabetes mellitus in patients treated with olanzapine or clozapine than in those treated with risperidone. There were significant differences in the risk of increase in triglycerides in patients receiving olanzapine (OR = 1.34; p = 0.0075) and clozapine (OR = 1.58; p = 0.0028). CONCLUSIONS: The risk of the appearance of diabetes mellitus in patients treated with olanzapine is twice as high as that in patients treated with risperidone, and the risk in patients treated with clozapine is nearly triple as high as that found in patients treated with risperidone. Risperidone appears to be a safer antipsychotic drug in the long term, with regard to the risk of alterations in glucose and lipid metabolism.

Evaluación del tratamiento antipsicótico como factor de riesgo de diabetes en la esquizofrenia: estudio de casos y controles / Therapy wit antipsychotic drugs as a risk factor for diabetes in schizophrenia: a case-control study

Fundamento y objetivos: Los antipsicóticos atípicos se han relacionado en los últimos años con la hiperglucemia, la diabetes mellitus, el aumento de peso y las alteraciones de lípidos en algunos pacientes. El objetivo de este estudio es analizar si el tratamiento continuado con risperidona, olanzapina o clozapina altera el metabolismo de los lípidos y la glucosa en los pacientes esquizofrénicos. Pacientes y método: Este estudio incluyó a pacientes esquizofrénicos que habían recibido tratamiento psiquiátrico en monoterapia con clozapina, olanzapina o risperidona durante un período de 1-3 años. Los pacientes diagnosticados de diabetes durante el tratamiento psiquiátrico y los que presentaron cifras de glucemia en ayunas >= 126 mg/dl en dos determinaciones consecutivas constituyeron el grupo de casos. Los demás pacientes esquizofrénicos en tratamiento que no presentaron estas alteraciones fueron incluidos en el grupo control. Resultados: Según el análisis ajustado de regresión logística multivariante para determinar el efecto del tratamiento antipsicótico sobre la presencia de diabetes ­que incluyó también como factores de evaluación la edad y el índice de masa corporal­ la odds ratio (OR) para olanzapina respecto de risperidona fue de 2,22 (intervalo de confianza [IC] del 95%, 1,12-4,22; p = 0,0228); y para clozapina en relación con risperidona, de 2,87 (IC del 95%, 1,19-6,93; p = 0,0192). Ambos resultados muestran que los pacientes tratados con olanzapina o clozapina presentan un riesgo de diabetes mellitus significativamente superior en comparación con los pacientes tratados con risperidona. El riesgo de aumento de triglicéridos varió significativamente en los pacientes tratados con olanzapina (OR = 1,34; p = 0,0075) o clozapina (OR = 1,58; p = 0,0028). Conclusiones: El riesgo de diabetes mellitus en los pacientes tratados con olanzapina es dos veces veces más elevado que el de los tratados con risperidona y, en el caso de los tratados con clozapina, el riesgo es práticamente tres veces superior al de risperidona. La risperidona ofrece al parecer un mejor perfil de seguridad a largo plazo respecto al riesgo de alteraciones del metabolismo de los lípidos y la glucosa

Background and objectives: Atypical antipsychotics have been related with hyperglycaemia, diabetes mellitus, weight gain and lipid alterations in some patients. This study analyzed whether continuous treatment with risperidone, olanzapine, or clozapine entails a risk of glucose or lipid metabolism alterations in schizophrenic patients. Patients and method: Patients included in this study were schizophrenics who had received mono-therapeutic with clozapine, olanzapine or risperidone for a period of 1 to 3 years. Those schizophrenic patients who were diagnosed as diabetic during psychiatric treatment and those who showed fasting glycemia greater than or equal to 126 mg/dl in two consecutive measurements were considered cases. The remaining schizophrenic patients who were receiving treatment and did not show these alterations were considered controls. Results: In the adjusted analysis (multivariate logistic regression) of the effect of antipsychotic treatment on the presence of diabetes, which also assessed age and body-mass index, the adjusted odds ratio (OR) for olanzapine relative to risperidone was 2.22 (95% confidence interval [CI], 1.12-4.22), (p = 0.0228); and that for clozapine relative to risperidone was 2.87 (95% CI, 1.19, 6.93), (p = 0.0192). Both results reveal a significantly greater risk for the appearance of diabetes mellitus in patients treated with olanzapine or clozapine than in those treated with risperidone. There were significant differences in the risk of increase in triglycerides in patients receiving olanzapine (OR = 1.34; p = 0.0075) and clozapine (OR = 1.58; p = 0.0028). Conclusions: The risk of the appearance of diabetes mellitus in patients treated with olanzapine is twice as high as that in patients treated with risperidone, and the risk in patients treated with clozapine is nearly triple as high as that found in patients treated with risperidone. Risperidone appears to be a safer antipsychotic drug in the long term, with regard to the risk of alterations in glucose and lipid metabolism