Implementation of pre-exposure prophylaxis programme in Spain. Feasibility of four different delivery models

Infeccions pel VIH; Factors de risc mèdics; Profilaxi preexposicióInfecciones por VIH; Factores de riesgo médicos; Profilaxis preexposiciónHIV infections; Medical risk factors; Pre-exposure prophylaxisBackground Pre-exposure prophylaxis (PrEP) is an effective and cost-effective strategy for HIV prevention. Spain carried out an implementation study in order to assess the feasibility of implementing PrEP programmes within its heterogeneous health system. Methods Observational longitudinal study conducted on four different types of health-care setting: a community centre (CC), a sexually transmitted infections clinic (STIC), a hospital-based HIV unit (HBHIVU) and a hospital-based STI unit (HBSTIU). We recruited gay, bisexual and other men who have sex with men (GBSM) and transgender women at risk of HIV infections, gave them PrEP and monitored clinical, behavioural PrEP-related and satisfaction information for 52 weeks. We collected perceptions on PrEP implementation feasibility from health-care professionals participating in the study. Results A total of 321 participants were recruited, with 99.1% being GBMSM. Overall retention was 87.2% and it was highest at the CC (92.6%). Condom use decreased during the study period, while STIs did not increase consistently. The percentage of people who did not miss any doses of PrEP during the previous week remained at over 93%. No HIV seroconversions occurred. We observed overall decreases in GHB (32.5% to 21.8%), cocaine (27.5% to 21.4%), MDMA (25.7% to 14.3%), speed (11.4% to 5.7%) and mephedrone use (10.7% to 5.0%). The overall participant satisfaction with PrEP was 98.6%. Health-care professionals’ perceptions of PrEP feasibility were positive, except for the lack of personnel. Conclusions PrEP implementation is feasible in four types of health-care settings. Local specificities have to be taken into consideration while implementing PrEP.This study has been conducted with the resources from the National AIDS Programme ant those from the participating study centers. Gilead donated the drug administered in the study. Donors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Some authors are employed by BCN Checkpoint. BCN Checkpoint is a Community Centre run by an NGO. BCN Checkpoint did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of author PC. The specific roles of this author is articulated in the ‘author contributions’ section

HDAC inhibitors in acute myeloid leukemia

Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases (HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat, and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather in combination with other drugs. In this review, we discuss the rationale for the use of different HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are some encouraging data from treatment with the HDACi Pracinostat in combination with DNA demethylating agents

Towards the Improvement of the Software Quality: An Enterprise 2.0 Architecture for Distributed Software Developments.

Software development is tightly dependent on the tools available for supporting its processes. Organizational and sociotechnical peculiarities such as indefinition of roles, geographically distributed development teams, new business models and diverse cultural interactions steer these tools. Software development supported by web-based services, built on top of Web 2.0 technologies, is emerging as a new paradigm for distributed software development. New generation software forges (web-based development environments) such as EzForge are becoming the infrastructure that provides the required features for hosting collections of software development projects. They are composed of an integrated set of tools, interacting in a mashup-like environment, each one suited for a specific task, and therefore simple enough to keep total complexity low. An adequate selection of tools helps developers to focus on the implementation of the requirements, while at the same time they cope with complex information coming from many individuals and organizations. The complexity of distributed software development requires a controlled and a strong collaboration amongst developers, which has to be supported by the selected architecture. Moreover, an increased demand on quality assurance is required by the many organizations aiming to achieve a certain quality level. A new architecture based on the Web 2.0 core ideas and methods overcomes these challenges in software development, representing a cornerstone to achieve satisfactory results in this ambitious environment

Implementation of pre-exposure prophylaxis programme in Spain. Feasibility of four different delivery models.

Pre-exposure prophylaxis (PrEP) is an effective and cost-effective strategy for HIV prevention. Spain carried out an implementation study in order to assess the feasibility of implementing PrEP programmes within its heterogeneous health system. Observational longitudinal study conducted on four different types of health-care setting: a community centre (CC), a sexually transmitted infections clinic (STIC), a hospital-based HIV unit (HBHIVU) and a hospital-based STI unit (HBSTIU). We recruited gay, bisexual and other men who have sex with men (GBSM) and transgender women at risk of HIV infections, gave them PrEP and monitored clinical, behavioural PrEP-related and satisfaction information for 52 weeks. We collected perceptions on PrEP implementation feasibility from health-care professionals participating in the study. A total of 321 participants were recruited, with 99.1% being GBMSM. Overall retention was 87.2% and it was highest at the CC (92.6%). Condom use decreased during the study period, while STIs did not increase consistently. The percentage of people who did not miss any doses of PrEP during the previous week remained at over 93%. No HIV seroconversions occurred. We observed overall decreases in GHB (32.5% to 21.8%), cocaine (27.5% to 21.4%), MDMA (25.7% to 14.3%), speed (11.4% to 5.7%) and mephedrone use (10.7% to 5.0%). The overall participant satisfaction with PrEP was 98.6%. Health-care professionals' perceptions of PrEP feasibility were positive, except for the lack of personnel. PrEP implementation is feasible in four types of health-care settings. Local specificities have to be taken into consideration while implementing PrEP.This study has been conducted with the resources from the National AIDS Programme ant those from the participating study centers. Gilead donated the drug administered in the study. Donors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Some authors are employed by BCN Checkpoint. BCN Checkpoint is a Community Centre run by an NGO. BCN Checkpoint did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of author PC. The specific roles of this author is articulated in the ‘author contributions’ section.S

Incidence and clearance of anal high-risk human papillomavirus in HIV-positive men who have sex with men: Estimates and risk factors

Background: To estimate incidence and clearance of high-risk human papillomavirus (HR-HPV), and their risk factors, in men who have sex with men (MSM) recently infected by HIV in Spain; 2007-2013. Methods: Multicenter cohort. HR-HPV infection was determined and genotyped with linear array. Two-state Markov models and Poisson regression were used. Results: We analysed 1570 HR-HPV measurements of 612 MSM over 13 608 person-months (p-m) of follow-up. Median (mean) number of measurements was 2 (2.6), median time interval between measurements was 1.1 years (interquartile range: 0.89-1.4). Incidence ranged from 9.0 [95% confidence interval (CI) 6.8-11.8] per 1000 p-m for HPV59 to 15.9 (11.7-21.8) per 1000 p-m for HPV51. HPV16 and HPV18 had slightly above average incidence: 11.9/1000 p-m and 12.8/1000 p-m. HPV16 showed the lowest clearance for both 'prevalent positive' (15.7/1000 p-m; 95% CI 12.0-20.5) and 'incident positive' infections (22.1/1000 p-m; 95% CI 11.8-41.1). More sexual partners increased HR-HPV incidence, although it was not statistically significant. Age had a strong effect on clearance (P-value < 0.001) due to the elevated rate in MSM under age 25; the effect of HIV-RNA viral load was more gradual, with clearance rate decreasing at higher HIV-RNA viral load (P-value 0.008). Conclusion: No large variation in incidence by HR-HPV type was seen. The most common incident types were HPV51, HPV52, HPV31, HPV18 and HPV16. No major variation in clearance by type was observed, with the exception of HPV16 which had the highest persistence and potentially, the strongest oncogenic capacity. Those aged below 25 or with low HIV-RNA- viral load had the highest clearanceThis work was supported by grants from the Fondo de Investigacio´n Sanitaria [PI06/0372, PS09/2181], Red de Investigacio´n en SIDA (RIS) [RD06/006/0026 and RD12/0017/0018 to C.G.] and CIBERESP [group 54A-CB06/02/1009

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p &lt; 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Eibartik Zuberoara, euskalkietan barrena : Koldo Zuazori gorazarre

International audienc

Synergistic effect of novel HDAC inhibitors with chemotherapy drugs in acute myeloid leukemia

Acute myeloid leukemia (AML) is a highly heterogeneous malignant disease characterized by uncontrolled proliferation, differentiation arrest and accumulation of immature myeloid progenitors. Despite recent developments and the approval of new therapeutic agents in the last few years, outcome remains poor for most patients, particularly in elderly patients, being an urgent unmet need for therapeutic improvements. After rigorous studies, our group identified and characterized two novel HDACi (histone deacetylases inhibitors), CM-444 and CM-1758, exhibiting higher capacity to promote in vitro and in vivo myeloid differentiation in all subtypes of AML at low non-cytotoxic doses in comparison with commercial HDACi. The acetylome analysis after CM-444 and CM-1758 treatment showed the modulation of a specific non-histone protein acetylation pattern in AML cells. CM-444 and CM-1758 led to acetylation of bromodomain proteins (BRDs), especially BRD4 and BRD1, and other non-histone proteins involved in the enhancer-promoter chromatin regulatory complex. This is essential to enhance the expression of key transcription factors that induce myeloid differentiation and play a very important role in the differentiation therapy exerted by CM-444 or CM-1758 in AML cells. Interestingly, the complete transcriptome analysis after CM-444 and CM-1758 treatment showed changes in genes implicated in chemo-sensitivity, suggesting that CM-444 and CM-1758 could also enhance the efficacy of conventional chemotherapy for AML treatment. CM-444 and CM-1758 led to promising synergistic effect in combination with Doxorubicin and 5-AZA agents in vitro. Moreover, a slight improvement on Doxorubicin treatment was obtained in those AML cells that were previously induced to overexpress the chemo-sensitive gene ALOX5. Proposing that ALOX5 overexpression induced by CM-444 and CM-1758 is one of the possible molecular mechanisms underlying the synergistic effect previously obtained between HDACi (CM-444 and CM-1758) and Doxorubicin or 5-AZA. In summary, on the one hand these new epigenetic compounds might be an effective differentiation-based therapy with a novel mechanism to be tested in AML. And on the other hand, these novels HDACi could also be combined with therapeutic agents to improve their therapeutic effect, in part due to chemo-sensitive gene expression induced by the compounds themselves.La leucemia mieloide aguda (LMA) es una enfermedad clonal heterogénea caracterizada por una rápida proliferación de precursores mieloides que han perdido su capacidad de diferenciación. A pesar de los recientes avances y la aprobación de nuevos agentes terapéuticos en los últimos años, el pronóstico sigue siendo pobre para la mayoría de los pacientes, especialmente para aquellos de edad avanzada, lo que supone una necesidad urgente de mejoras terapéuticas. En este sentido, tras realizar una serie de estudios, nuestro grupo identificó y caracterizó dos nuevos HDACi (inhibidores de las desacetilasas de histonas), el CM-444 y el CM-1758, que presentan una mayor capacidad para promover la diferenciación mieloide in vitro e in vivo en todos los subtipos de LMA a dosis bajas no citotóxicas en comparación con los HDACi comerciales. El análisis del acetiloma tras el tratamiento con CM-444 y CM-1758 mostró la modulación de un patrón específico de acetilación de proteínas no histónicas en las células de la LMA. El CM-444 y el CM-1758 provocaron la acetilación de e bromodominios (BRD), especialmente BRD4 y BRD1, y de otras proteínas no histónicas implicadas en el complejo regulador potenciador-promotor de la cromatina. Esto es esencial para potenciar la expresión de factores de transcripción clave que inducen la diferenciación mieloide y desempeñan un papel muy importante en la terapia de diferenciación ejercida por el CM-444 o el CM-1758 en las células de la LMA. De forma interesante, el análisis completo del transcriptoma tras el tratamiento con CM-444 y CM-1758 mostró cambios en los genes implicados en la quimiosensibilidad celular, lo que sugiere que CM-444 y CM-1758 también podrían mejorar la eficacia de la quimioterapia convencional para el tratamiento de la LMA. El CM-444 y el CM-1758 provocaron in vitro un prometedor efecto sinérgico en combinación con los agentes Doxorubicina y 5-AZA. Además, se obtuvo una ligera mejora en el tratamiento con Doxorrubicina en aquellas células de LMA a las que se les indujo previamente la sobreexpresión del gen quimiosensible ALOX5. Lo que propone que la sobreexpresión de ALOX5 inducida por CM-444 y CM-1758 es uno de los posibles mecanismos moleculares que subyacen al efecto sinérgico obtenido previamente entre los HDACi (CM-444 y CM-1758) y la Doxorrubicina o 5-AZA. En resumen, por un lado, estos nuevos compuestos epigenéticos podrían ser una terapia eficaz basada en la terapia de diferenciación con un mecanismo novedoso para ser probados en la LMA. Y por otro lado, estos novedosos HDACi también podrían combinarse con agentes terapéuticos para mejorar su efecto terapéutico, en parte debido a la expresión génica quimiosensible inducida por los propios compuestos

Synergistic effect of novel HDAC inhibitors with chemotherapy drugs in acute myeloid leukemia

Acute myeloid leukemia (AML) is a highly heterogeneous malignant disease characterized by uncontrolled proliferation, differentiation arrest and accumulation of immature myeloid progenitors. Despite recent developments and the approval of new therapeutic agents in the last few years, outcome remains poor for most patients, particularly in elderly patients, being an urgent unmet need for therapeutic improvements. After rigorous studies, our group identified and characterized two novel HDACi (histone deacetylases inhibitors), CM-444 and CM-1758, exhibiting higher capacity to promote in vitro and in vivo myeloid differentiation in all subtypes of AML at low non-cytotoxic doses in comparison with commercial HDACi. The acetylome analysis after CM-444 and CM-1758 treatment showed the modulation of a specific non-histone protein acetylation pattern in AML cells. CM-444 and CM-1758 led to acetylation of bromodomain proteins (BRDs), especially BRD4 and BRD1, and other non-histone proteins involved in the enhancer-promoter chromatin regulatory complex. This is essential to enhance the expression of key transcription factors that induce myeloid differentiation and play a very important role in the differentiation therapy exerted by CM-444 or CM-1758 in AML cells. Interestingly, the complete transcriptome analysis after CM-444 and CM-1758 treatment showed changes in genes implicated in chemo-sensitivity, suggesting that CM-444 and CM-1758 could also enhance the efficacy of conventional chemotherapy for AML treatment. CM-444 and CM-1758 led to promising synergistic effect in combination with Doxorubicin and 5-AZA agents in vitro. Moreover, a slight improvement on Doxorubicin treatment was obtained in those AML cells that were previously induced to overexpress the chemo-sensitive gene ALOX5. Proposing that ALOX5 overexpression induced by CM-444 and CM-1758 is one of the possible molecular mechanisms underlying the synergistic effect previously obtained between HDACi (CM-444 and CM-1758) and Doxorubicin or 5-AZA. In summary, on the one hand these new epigenetic compounds might be an effective differentiation-based therapy with a novel mechanism to be tested in AML. And on the other hand, these novels HDACi could also be combined with therapeutic agents to improve their therapeutic effect, in part due to chemo-sensitive gene expression induced by the compounds themselves.La leucemia mieloide aguda (LMA) es una enfermedad clonal heterogénea caracterizada por una rápida proliferación de precursores mieloides que han perdido su capacidad de diferenciación. A pesar de los recientes avances y la aprobación de nuevos agentes terapéuticos en los últimos años, el pronóstico sigue siendo pobre para la mayoría de los pacientes, especialmente para aquellos de edad avanzada, lo que supone una necesidad urgente de mejoras terapéuticas. En este sentido, tras realizar una serie de estudios, nuestro grupo identificó y caracterizó dos nuevos HDACi (inhibidores de las desacetilasas de histonas), el CM-444 y el CM-1758, que presentan una mayor capacidad para promover la diferenciación mieloide in vitro e in vivo en todos los subtipos de LMA a dosis bajas no citotóxicas en comparación con los HDACi comerciales. El análisis del acetiloma tras el tratamiento con CM-444 y CM-1758 mostró la modulación de un patrón específico de acetilación de proteínas no histónicas en las células de la LMA. El CM-444 y el CM-1758 provocaron la acetilación de e bromodominios (BRD), especialmente BRD4 y BRD1, y de otras proteínas no histónicas implicadas en el complejo regulador potenciador-promotor de la cromatina. Esto es esencial para potenciar la expresión de factores de transcripción clave que inducen la diferenciación mieloide y desempeñan un papel muy importante en la terapia de diferenciación ejercida por el CM-444 o el CM-1758 en las células de la LMA. De forma interesante, el análisis completo del transcriptoma tras el tratamiento con CM-444 y CM-1758 mostró cambios en los genes implicados en la quimiosensibilidad celular, lo que sugiere que CM-444 y CM-1758 también podrían mejorar la eficacia de la quimioterapia convencional para el tratamiento de la LMA. El CM-444 y el CM-1758 provocaron in vitro un prometedor efecto sinérgico en combinación con los agentes Doxorubicina y 5-AZA. Además, se obtuvo una ligera mejora en el tratamiento con Doxorrubicina en aquellas células de LMA a las que se les indujo previamente la sobreexpresión del gen quimiosensible ALOX5. Lo que propone que la sobreexpresión de ALOX5 inducida por CM-444 y CM-1758 es uno de los posibles mecanismos moleculares que subyacen al efecto sinérgico obtenido previamente entre los HDACi (CM-444 y CM-1758) y la Doxorrubicina o 5-AZA. En resumen, por un lado, estos nuevos compuestos epigenéticos podrían ser una terapia eficaz basada en la terapia de diferenciación con un mecanismo novedoso para ser probados en la LMA. Y por otro lado, estos novedosos HDACi también podrían combinarse con agentes terapéuticos para mejorar su efecto terapéutico, en parte debido a la expresión génica quimiosensible inducida por los propios compuestos