Dynamics of HIV-1 transmission in Europe: a guidance for evidence-based prevention strategies

Introdução: Para controlar a pandemia de VIH a UNAIDS desenvolveu os objetivos 95- 95-95 para serem atingidos até 2030. A concretização destes objetivos pode ser dificultada pelo aparecimento de mutações de resistência devido ao uso intensivo da terapia antirretroviral ou também à existência de indivíduos com apresentação tardia (IAT) ao diagnóstico. Estes IAT não só impactam os resultados dos seus próprios tratamentos como são também uma ameaça para alcançar os objetivos da UNAIDS, uma vez que podem potenciar, de forma inconsciente, a transmissão do VIH. Objetivos: Primeiro, identificar as caraterísticas sociodemográficas e clínicas dos indivíduos infetados com VIH-1, bem como identificar os determinantes da apresentação tardia em Portugal e na Europa. Segundo, descrever os padrões de resistência transmitida (TDR) e de resistência adquirida (ADR) em indivíduos infetados com VIH-1 seguidos na Europa, comparar os seus padrões de resistência IAT e indivíduos com apresentação nãotardia (IANT) e analisar as mutações de resistência aos antirretrovirais nos diferentes subtipos de VIH-1. Para finalizar, descrever e caraterizar os clusters de transmissão (CT) de VIH-1 na Europa e comparar o papel dos IAT com os IANT nos CT do VIH-1. Metodologia: No primeiro estudo, a base de dados utilizada incluiu dados clínicos e sociodemográficos de indivíduos infetados com VIH-1 seguidos no Hospital Egas Moniz, Centro Hospitalar de Lisboa Ocidental (CHLO), Lisboa, Portugal, entre1984 e 2017. Nos outros estudos, utilizou-se a EuResist Integrated Database (EIDB) que inclui dados sociodemográficos, clínicos e genómicos de indivíduos infetados com VIH-1 seguidos na Europa (Portugal, Espanha, Alemanha, Luxemburgo, Rússia, Reino Unido e Itália) entre 1981 e 2019. Para a análise dos CTs, foram utilizadas informações de indivíduos infetados pelos subtipos mais prevalentes (B, A e G). Resultados: No primeiro estudo, 68,7% dos indivíduos infetados com VIH-1 eram homens com uma mediana de idade de 37 anos (IQR 30–47). 50,6% destes indivíduos tinham apresentação tardia (AT) e desses 61,9% tinham apresentação tardia com doença avançada. Os determinantes associados à AT foram idade ao diagnóstico superior a 30 anos e origem em países da África subsaariana. No segundo estudo, entre os indivíduos incluídos na análise a mediana de idade foi igual a 33 anos (IQR: 27,0–41,0) e 74,4% eram homens. 50,4% destes indivíduos tinham AT e os determinantes associados foram idade acima de 56 anos, heterossexuais, indivíduos com origem em países africanos e com carga viral abaixo de 4,1cópias/mL. No terceiro estudo, a mediana de idades obtida foi igual a 37 anos (IQR: 27,0–45,0) e 72,2% eram homens. 71,9% dos indivíduos tinham sido infetados pelo subtipo B e 54,8% foram classificados com AT. Para AT e apresentação não-tardia (ANT) a prevalência de TDR foi 12,3% e 12,6% respetivamente, e a de ADR foi de 69,9% e de 68,2% respetivamente. As mutações mais prevalentes observadas em IAT e IANT foram K103N/S, T215rev, T215FY, M184I/V, M41I/L, M46I/L e L90M. No quarto estudo, o subtipo mais prevalente nos indivíduos infetados com VIH-1 foi o subtipo B (84,7%) seguido do subtipo G (9,4%) e subtipo A (5,9%). A idade mediana foi de 33 anos (IQR: 26,0-41,0) e 75,5% eram homens. 51,4% dos indivíduos infetados com VIH-1 tinham AT e 21,6% estavam dentro de CTs. As análises filogenéticas demonstraram que apenas 17,6% dos IAT estavam dentro de CTs comparados com 20,2% dos IANT. Para os subtipos A e B, verificou-se que os IAT dentro de CTs foram caracterizados por uma menor percentagem de homens e por uma maior percentagem de indivíduos mais velhos comparativamente aos IANT. Para os subtipos B e G, os IAT dentro de CTs apresentaram maior percentagem de tratados comparativamente com os IANT. No subtipo G, os IAT dentro de CTs, eram maioritariamente utilizadores de drogas intravenosas comparativamente com os IANT. Analisando o tamanho dos CTs, verificou-se que os IANT pertenciam a grandes CTs (>8 indivíduos) comparativamente aos IAT. Conclusão: A AT é considerada um dos grandes obstáculos para travar a epidemia do VIH e uma ameaça à transmissão do mesmo. Os nossos resultados apresentam as características sociodemográficas e clínicas dos IAT na Europa e indicam que estes não contribuem, de forma significativa, para a transmissão dos VIH-1. Os resultados encontrados podem contribuir para o desenvolvimento de medidas de prevenção e para uma melhor compreensão das mutações de resistência e falhas terapêuticas nesta população de indivíduos. Palavras-Background: To control the HIV pandemic, the UNAIDS set the 95-95-95 targets to be reached by 2030. These targets can be more difficult to achieve, whether due to the appearance of drug resistance mutations regarding the increasing use of antiretroviral therapy (ART) or due to individuals who present late at diagnosis (late presenters-LP). These individuals can not only impact treatment outcomes, but also threat UNAIDS goals, as well as potentiate the spread of HIV. Aims: First, to identify clinical and sociodemographic characteristics of HIV-1 infected patients, as well as to identify determinants of late presentation in Portugal and in Europe. Second, to describe the patterns of transmitted drug resistance (TDR) and acquired drug resistance (ADR) in HIV-1 infected patients followed in Europe (Portugal, Spain, Germany, Luxembourg, United Kingdom, Russia and Italy), to compare its patterns in late presenters (LP) vs non-late presenters (NLP), and to analyze the most prevalent drug resistance mutations among HIV-1 subtypes. And finally, to describe and characterize HIV-1 transmission clusters in Europe and to compare the role of LP vs NLP populations on HIV-1 transmission clusters (TC). Methods: For the first study, the database included clinical and sociodemographic information from HIV-1-infected patients followed in Hospital Egas Moniz, Centro Hospitalar de Lisboa Ocidental (CHLO), Lisbon, Portugal, between 1984 and 2017. For the other studies, the EuResist Integrated Database (EIDB) included socio-demographic, clinical, and genomic information from HIV-1 infected patients followed between 1981 and 2019. For the analysis of TC, information from patients infected with the most prevalent subtypes B, A and G was analyzed. Results: In the first study, 68.7% of patients were males and the median age was 37 years (IQR 30–47). 50.6% patients were LP and, of those, 61.9% were late presenters with advanced disease (LPAD). The determinants associated with LP were age at diagnosis higher than 30 years and origin from sub-Saharan Africa. In the second study, among the HIV-1 infected patients included in the analysis, the median age was 33 (IQR: 27.0–41.0) years and 74.4% were males. 50.4% were late presenters and the determinants associated with late presentation were older patients (>56), heterosexuals, patients originated from Africa and patients presenting with log VL >4.1. In the third study, the median age of HIV-1 infected individuals was 37 (IQR: 27.0–45.0) years old and 72.6% were males. 71.9% of patients were infected by subtype B and 54.8% of patients were classified as LP. For LP and NLP, the TDR prevalence was 12.3% and 12.6%, respectively, while ADR, was 69.9% and 68.2%, respectively. The most prevalent TDR drug resistance mutations, in both LP and NLP, were K103N/S, T215rev, T215FY, M184I/V, M41I/L, M46I/L, and L90M. In the fourth study, the most prevalent subtype among those infected with HIV-1 was subtype B (84.7%), followed by subtype G (9.4%) and subtype A (5.9%). The median age was 33 (IQR: 26.0-41.0) years old and 75.5% of patients were males. 51.4% of patients were classified as LP and 21.6% of patients were inside TCs.Phylogenetic analyses showed that only 17.6% of LPs were inside clusters compared to 20.2% of NLPs. For subtypes A and B, we found that LP inside clusters were less frequently males and were older than NLPs. For subtypes B and G, LP inside clusters were more frequently treated than NLP. In subtype G, LP inside clusters more frequently had IDU transmission route than NLP. Finally, when analyzing cluster size, we found that NLP more frequently belonged to large clusters (>8 patients) when compared to LP. Conclusion: Late presentation is a major obstacle to halt the HIV epidemic and could be a threat to HIV-1 transmission. Our results characterize the socio-demographic and clinical characteristics of LPs in Europe and, all together, indicate that LPs are not important contributors to forward HIV-1 transmission. These results help to direct prevention measures for this population and to better understand drug resistance mutations and therapeutic failure in this population of patients

Para a compreensão do contributo da epigenética na doença de Alzheimer

Dissertação para obtenção do grau de Mestre no Instituto Superior de Ciências da Saúde Egas MonizA doença do Alzheimer (DA) é uma das doenças mais complexas entre as patologias do foro neurodegenerativo. Esta é caracterizada como uma doença lenta, progressiva e irreversível que se manifesta através da perda de cognição e memória. A DA é responsável por cerca de 50% a 70% dos casos de demência. A incidência e a prevalência da doença aumentam exponencialmente com a idade, principalmente em idades acima dos 65 anos. Para esta doença são conhecidas duas formas, o Alzheimer de início tardio e o Alzheimer de início precoce. Estudos recentes sugerem que alterações de natureza epigenética estão associadas à DA. Esta nova área de estudo associa a influência do ambiente sobre a expressão génica, ou seja a capacidade de fatores ambientais induzirem alterações no fenótipo sem afectarem a sequência de ADN. As principais alterações epigenéticas que afetam o fenótipo são a nível da metilação do ADN, modificação de histonas, modificação da cromatina e regulação do RNA não codificante. A terapia na DA tem como objetivos a terapêutica específica, a terapêutica profilática e o tratamento sintomático. Os fármacos disponíveis para o tratamento são a tacrina, o donepezilo, a galantamina, a rivastigmina e a memantina. Para a DA o único objetivo da utilização destes fármacos é retardar a sua progressão. Tem também vindo a ser estudada a hipótese da utilização de terapia epigenética para o seu tratamento. As classes mais desenvolvidas neste âmbito são as dos inibidores das DNMT e inibidores das HDACs. Estas classes são usadas com o objetivo de reverter as alterações epigenéticas. O tema abordado neste trabalho é relativamente recente, sendo uma área em desenvolvimento. Com isto, é essencial que a investigação desta doença continue no âmbito de se encontrar uma cura e diminuir assim a taxa de mortalidade

Determinants of HIV late presentation among men who have sex with men in Portugal (2014–2019): who’s being left behind?

IntroductionHIV late presentation (LP) remains excessive in Europe. We aimed to analyze the factors associated with late presentation in the MSM population newly diagnosed with HIV in Portugal between 2014 and 2019.MethodsWe included 391 newly HIV-1 diagnosed Men who have Sex with Men (MSM), from the BESTHOPE project, in 17 countrywide Portuguese hospitals. The data included clinical and socio-behavioral questionnaires and the viral genomic sequence obtained in the drug resistance test before starting antiretrovirals (ARVs). HIV-1 subtypes and epidemiological surveillance mutations were determined using different bioinformatics tools. Logistic regression was used to estimate the association between predictor variables and late presentation (LP).ResultsThe median age was 31 years, 51% had a current income between 501–1,000 euros, 28% were migrants. 21% had never been tested for HIV before diagnosis, with 42.3% of MSM presenting LP. 60% were infected with subtype B strains. In the multivariate regression, increased age at diagnosis, higher income, lower frequency of screening, STI ever diagnosed and higher viral load were associated with LP.ConclusionOur study suggests that specific subgroups of the MSM population, such older MSM, with higher income and lower HIV testing frequency, are not being targeted by community and clinical screening services. Overall, targeted public health measures should be strengthened toward these subgroups, through strengthened primary care testing, expanded access to PrEP, information and promotion of HIV self-testing and more inclusive and accessible health services

Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype

Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, and ABCG8), polygenic hypercholesterolemia, and hyperlipoprotein (a) [Lp(a)] can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical FH phenotype. Biochemical and genetic study was performed in 1,005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A next-generation sequencing panel, covering eight genes and eight SNPs to determine LDL-C polygenic risk score and LPA genetic score, was validated, and used in this study. FH was genetically confirmed in 417 index cases: 408 heterozygotes and 9 homozygotes. Cascade screening increased the identification to 1,000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype positive and genotype negative) have Lp(a) >50 mg/dl (30%), high polygenic risk score (16%), other monogenic lipid metabolism disorders (1%), and heterozygous pathogenic variants in FH-phenocopy genes (2%). Heterozygous variants of uncertain significance were identified in primary genes (12%) and phenocopy genes (7%). Overall, 42% of our cohort was genetically confirmed with FH. In the remaining individuals, other causes for high LDL-C were identified in 68%. Hyper-Lp(a) or polygenic hypercholesterolemia may be the cause of the clinical FH phenotype in almost half of FH-negative individuals. A small part has pathogenic variants in ABCG5/ABCG8 in heterozygosity that can cause hypercholesterolemia and should be further investigated. This extended next-generation sequencing panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person’s treatment according to the affected pathway

Ciência, Crise e Mudança. 3.º Encontro Nacional de História das Ciências e da Tecnologia. ENHCT2012

III Encontro Nacional de História das Ciências e da Tecnologia. O Centro de Estudos de História e Filosofia da Ciência, organiza o 3.º Encontro Nacional de História da Ciência e da Técnica, sob o tema «Ciência, Crise e Mudança» que tem lugar na Universidade de Évora, nos dias 26, 27 e 28 de Setembro de 2012. O Primeiro Encontro Nacional de História da Ciência teve lugar em 21 e 22 Julho de 2009, no seguimento do programa de estímulo ao de¬senvolvimento da História da Ciência em Portugal e de valorização do património cultural e científico do País, lançado pelo Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) em 31 de Janeiro desse ano. A sua organização coube a investigadores do Instituto de História Contemporânea (IHC), da FCSH da UNL, e do Centro Científico e Cultural de Macau (CCCM), em cujas instalações se realizou. De en¬tre as conclusões do Encontro, destacou-se a de realizar periodicamen¬te novos Encontros Nacionais, a serem organizados de forma rotativa por diferentes centros e núcleos de investigadores. Na sequência deste Primeiro Encontro, o Centro Interuniversitário de História das Ciências e da Tecnologia (CIUHCT) organizou, entre 26 e 28 de Julho de 2010, o II Encontro, dedicado ao tema “Comunicação das Ciências e da Tecnologia em Portugal: Agentes, Meios e Audiências”. Cabe agora ao CEHFCi cumprir o que foi decidido no final deste Encontro. Na situação económica e política que hoje vivemos torna-se particularmente urgente aprofundar o estudo e o debate sobre a interação entre a Sociedade, a Ciência e a sua História. Coordenação Científica e Executiva do encontro estiveram a cargo de dois investigadores CEHFCi: Maria de Fátima Nunes, José Pedro Sousa Dia

Data_Sheet_1_Determinants of HIV late presentation among men who have sex with men in Portugal (2014–2019): who’s being left behind?.docx

IntroductionHIV late presentation (LP) remains excessive in Europe. We aimed to analyze the factors associated with late presentation in the MSM population newly diagnosed with HIV in Portugal between 2014 and 2019.MethodsWe included 391 newly HIV-1 diagnosed Men who have Sex with Men (MSM), from the BESTHOPE project, in 17 countrywide Portuguese hospitals. The data included clinical and socio-behavioral questionnaires and the viral genomic sequence obtained in the drug resistance test before starting antiretrovirals (ARVs). HIV-1 subtypes and epidemiological surveillance mutations were determined using different bioinformatics tools. Logistic regression was used to estimate the association between predictor variables and late presentation (LP).ResultsThe median age was 31 years, 51% had a current income between 501–1,000 euros, 28% were migrants. 21% had never been tested for HIV before diagnosis, with 42.3% of MSM presenting LP. 60% were infected with subtype B strains. In the multivariate regression, increased age at diagnosis, higher income, lower frequency of screening, STI ever diagnosed and higher viral load were associated with LP.ConclusionOur study suggests that specific subgroups of the MSM population, such older MSM, with higher income and lower HIV testing frequency, are not being targeted by community and clinical screening services. Overall, targeted public health measures should be strengthened toward these subgroups, through strengthened primary care testing, expanded access to PrEP, information and promotion of HIV self-testing and more inclusive and accessible health services.</p

Data_Sheet_1_Determinants of HIV late presentation among men who have sex with men in Portugal (2014–2019): who’s being left behind?.docx

IntroductionHIV late presentation (LP) remains excessive in Europe. We aimed to analyze the factors associated with late presentation in the MSM population newly diagnosed with HIV in Portugal between 2014 and 2019.MethodsWe included 391 newly HIV-1 diagnosed Men who have Sex with Men (MSM), from the BESTHOPE project, in 17 countrywide Portuguese hospitals. The data included clinical and socio-behavioral questionnaires and the viral genomic sequence obtained in the drug resistance test before starting antiretrovirals (ARVs). HIV-1 subtypes and epidemiological surveillance mutations were determined using different bioinformatics tools. Logistic regression was used to estimate the association between predictor variables and late presentation (LP).ResultsThe median age was 31 years, 51% had a current income between 501–1,000 euros, 28% were migrants. 21% had never been tested for HIV before diagnosis, with 42.3% of MSM presenting LP. 60% were infected with subtype B strains. In the multivariate regression, increased age at diagnosis, higher income, lower frequency of screening, STI ever diagnosed and higher viral load were associated with LP.ConclusionOur study suggests that specific subgroups of the MSM population, such older MSM, with higher income and lower HIV testing frequency, are not being targeted by community and clinical screening services. Overall, targeted public health measures should be strengthened toward these subgroups, through strengthened primary care testing, expanded access to PrEP, information and promotion of HIV self-testing and more inclusive and accessible health services.</p

Data_Sheet_1_Determinants of HIV late presentation among men who have sex with men in Portugal (2014–2019): who’s being left behind?.docx

IntroductionHIV late presentation (LP) remains excessive in Europe. We aimed to analyze the factors associated with late presentation in the MSM population newly diagnosed with HIV in Portugal between 2014 and 2019.MethodsWe included 391 newly HIV-1 diagnosed Men who have Sex with Men (MSM), from the BESTHOPE project, in 17 countrywide Portuguese hospitals. The data included clinical and socio-behavioral questionnaires and the viral genomic sequence obtained in the drug resistance test before starting antiretrovirals (ARVs). HIV-1 subtypes and epidemiological surveillance mutations were determined using different bioinformatics tools. Logistic regression was used to estimate the association between predictor variables and late presentation (LP).ResultsThe median age was 31 years, 51% had a current income between 501–1,000 euros, 28% were migrants. 21% had never been tested for HIV before diagnosis, with 42.3% of MSM presenting LP. 60% were infected with subtype B strains. In the multivariate regression, increased age at diagnosis, higher income, lower frequency of screening, STI ever diagnosed and higher viral load were associated with LP.ConclusionOur study suggests that specific subgroups of the MSM population, such older MSM, with higher income and lower HIV testing frequency, are not being targeted by community and clinical screening services. Overall, targeted public health measures should be strengthened toward these subgroups, through strengthened primary care testing, expanded access to PrEP, information and promotion of HIV self-testing and more inclusive and accessible health services.</p

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved