Similar incidence of coronavirus disease 2019 (COVID-19) in patients with rheumatic diseases with and without hydroxychloroquine therapy

Background Hydroxychloroquine is not efficacious as post-exposure prophylaxis against coronavirus disease 2019 (COVID-19). It is not known whether as pre-exposure prophylaxis it may prevent COVID-19. Objective To compare the incidence of COVID-19 in Spanish patients with autoimmune rheumatic diseases treated with and without hydroxychloroquine. Patients and methods Retrospective electronic record review, from February 27th to June 21st, 2020, of patients with autoimmune inflammatory diseases followed at two academic tertiary care hospitals in Seville, Spain. The cumulative incidence of confirmed COVID-19, by PCR or serology, was compared between patients with and without hydroxychloroquine as part of their treatment of autoimmune inflammatory diseases. Results Among 722 included patients, 290 (40%) were receiving hydroxychloroquine. During the seventeen-week study period, 10 (3.4% [95% CI: 1.7%-6.7%] cases of COVID-19 were registered among patients with hydroxychloroquine and 13 (3.0% [1.6%-5.1%]) (p = 0.565) in those without hydroxychloroquine. COVID-19 was diagnosed by PCR in four (1.4%, 95% CI 0.38%-3.5%) subject with hydroxychloroquine and six (1.4%, 95% CI 0.5%-3.0%) without hydroxychloroquine (p = 0.697). Three patients on hydroxychloroquine and four patients without hydroxychloroquine were admitted to the hospital, none of them required to be transferred to the intensive care unit and no patient died during the episode. Conclusions The incidence and severity of COVID-19 among patients with autoimmune rheumatic diseases with and without hydroxychloroquine was not significantly different.Instituto de Salud Carlos III I3SNSMinisterio de Ciencia, Innovación y Universidades CP18/0014

Incidence of and factors associated with SARS-CoV-2 infection among people living with HIV in Southern Spain after one year of pandemic

Whether people living with HIV (PLWH) are at greater risk of acquiring SARS-CoV-2 infection is currently unknown. Prospective serologic studies may allow seroincidence analyses, where all infections are accurately identified. Because of this, we evaluated the incidence of associated factors with and the clinical outcome of SARS-CoV-2 infection in PLWH in Southern Spain. This prospective cohort study included PLWH from a Tertiary University Hospital in Southern Spain. Patients were enrolled in the study if (1) they had attended as outpatients our Unit from 1 August 2019 to 8 February 2020 and (2) had two subsequent evaluations from 9 February 2020 to 4 March 2021. SARS-CoV-2 infections were diagnosed by PCR, antigen detection or serology. Seven hundred and nine PLWH were included in the study. Of them, 55 [7.8%, 95% confidence interval (95% CI) 5.9%-9.9%] patients developed SARS-CoV-2 infection. Between 18 May and 29 November 2020, the rate of seroconversion was 5.3% (95% CI: 3.1%-9.0%) for the general population in the area of Seville and 2.3% (95% CI: 1.3%-2.6%) for PLWH in this study (p = .001). After multivariable analysis, adjusted by age, sex, and risk factors for HIV infection, active tobacco use and CDC stage, active tobacco smoking was the only factor independently associated with lower risk of SARS-Cov-2 infection [Incidence rate ratio: 0.29 (95% CI 0.16-0.55) p < .001]. In conclusion, the incidence of SARS-CoV-2 infection among PLWH in Southern Spain during the ongoing pandemic was lower than that reported for the general population in the same area.This work was supported in part by the Instituto de Salud CarlosIII (Project ‘PI16/01443’), integrated in the national I+D+i 2013–2016andco-fundedbytheEuropeanUnion(ERDF/ESF,‘Investinginyour future’), by the Spanish Network for AIDS investigation (RIS)(www.red.es/redes/inicio)(RD16/0025/0010,RD16/0025/0040),asapartoftheNacionalI+D+I,ISCIIISubdirecciónGeneraldeEvaluaciónand the European Fund for Development of Regions (FEDER). JuanA.PinedareceivedaresearchextensiongrantfromtheProgramadeIntensificacióndelaActividaddeInvestigacióndelServicioNacionaldeSaludCarlosIII(I3SNS).FedericoGarciareceivedaresearchextensiongrantfromtheProgramadeIntensificacióndelaActividaddeInves-tigacióndelServicioAndaluzdeSalud.AnaïsCorma-GomezreceivedaRíoHortegagrantfromtheInstitutodeSaludCarlosIII(grantnum-ber CM19/00251). Funding for open access charge: Universidad deMálaga/CBU

Prognostic value of non-invasive scores based on liver stiffness measurement, spleen diameter and platelets in HIV-infected patients

BACKGROUND AND AIMS: People living with HIV (PLWH) are at high risk for advanced chronic liver disease and related adverse outcomes. We aimed to validate the prognostic value of non-invasive scores based on liver stiffness measurement (LSM) and on markers of portal hypertension (PH), namely platelets and spleen diameter, in PLWH. METHODS: We combined data from eight international cohorts of PLWH with available non-invasive scores, including LSM and the composite biomarkers liver stiffness-spleen size-to-platelet ratio score (LSPS), LSM-to-Platelet ratio (LPR) and PH risk score. Incidence and predictors of all-cause mortality, any liver-related event and classical hepatic decompensation were determined by survival analysis, controlling for competing risks for the latter two. Non-invasive scores were assessed and compared using area under the receiver operating curve (AUROC). RESULTS: We included 1695 PLWH (66.8% coinfected with hepatitis C virus). During a median follow-up of 4.7 (interquartile range 2.8-7.7) years, the incidence rates of any liver-related event, all-cause mortality and hepatic decompensation were 13.7 per 1000 persons-year (PY) (95% confidence interval [CI], 11.4-16.3), 13.8 per 1000 PY (95% CI, 11.6-16.4) and 9.9 per 1000 PY (95% CI, 8.1-12.2), respectively. The AUROC of LSM was similar to that of the composite biomarkers, ranging between 0.83 and 0.86 for any liver-related event, 0.79-0.85 for all-cause mortality and 0.87-0.88 for classical hepatic decompensation. All individual non-invasive scores remained independent predictors of clinical outcomes in multivariable analysis. CONCLUSIONS: Non-invasive scores based on LSM, spleen diameter and platelets predict clinical outcomes in PLWH. Composite biomarkers do not achieve higher prognostic performance compared to LSM alone

Prognostic value of non-invasive scores based on liver stiffness measurement, spleen diameter and platelets in HIV-infected patients.

BACKGROUND AND AIMS People living with HIV (PLWH) are at high risk for advanced chronic liver disease and related adverse outcomes. We aimed to validate the prognostic value of non-invasive scores based on liver stiffness measurement (LSM) and on markers of portal hypertension (PH), namely platelets and spleen diameter, in PLWH. METHODS We combined data from eight international cohorts of PLWH with available non-invasive scores, including LSM and the composite biomarkers liver stiffness-spleen size-to-platelet ratio score (LSPS), LSM-to-Platelet ratio (LPR) and PH risk score. Incidence and predictors of all-cause mortality, any liver-related event and classical hepatic decompensation were determined by survival analysis, controlling for competing risks for the latter two. Non-invasive scores were assessed and compared using area under the receiver operating curve (AUROC). RESULTS We included 1695 PLWH (66.8% coinfected with hepatitis C virus). During a median follow-up of 4.7 (interquartile range 2.8-7.7) years, the incidence rates of any liver-related event, all-cause mortality and hepatic decompensation were 13.7 per 1000 persons-year (PY) (95% confidence interval [CI], 11.4-16.3), 13.8 per 1000 PY (95% CI, 11.6-16.4) and 9.9 per 1000 PY (95% CI, 8.1-12.2), respectively. The AUROC of LSM was similar to that of the composite biomarkers, ranging between 0.83 and 0.86 for any liver-related event, 0.79-0.85 for all-cause mortality and 0.87-0.88 for classical hepatic decompensation. All individual non-invasive scores remained independent predictors of clinical outcomes in multivariable analysis. CONCLUSIONS Non-invasive scores based on LSM, spleen diameter and platelets predict clinical outcomes in PLWH. Composite biomarkers do not achieve higher prognostic performance compared to LSM alone

Controlled attenuation parameter-insulin resistance (CIR) score to predict non-alcoholic steatohepatitis

The diagnosis of non-alcoholic steatohepatitis (NASH) requires liver biopsy. Patients with NASH are at risk of progression to advanced fibrosis and hepatocellular carcinoma. A reliable non-invasive tool for the detection of NASH is needed. We aimed at developing a tool to diagnose NASH based on a predictive model including routine clinical and transient hepatic elastography (TE) data. All subjects undergoing elective cholecystectomy in our center were invited to participate, if alcohol intake was < 30 g/d for men and < 15 g/d for women. TE with controlled attenuation parameter (CAP) was obtained before surgery. A liver biopsy was taken during surgery. Multivariate logistic regression models to predict NASH were constructed with the first 100 patients, the elaboration group, and the results were validated in the next pre-planned 50 patients. Overall, 155 patients underwent liver biopsy. In the elaboration group, independent predictors of NASH were CAP value [adjusted OR (AOR) 1.024, 95% confidence interval (95% CI) 1.002-1.046, p = 0.030] and HOMA value (AOR 1.847, 95% CI 1.203-2.835, p < 0.001). An index derived from the logistic regression equation to identify NASH was designated as the CAP-insulin resistance (CIR) score. The area under the receiver operating characteristic curve (95%CI) of the CIR score was 0.93 (0.87-0.99). Positive (PPV) and negative predictive values (NPV) of the CIR score were 82% and 91%, respectively. In the validation set, PPV was 83% and NPV was 88%. In conclusion, the CIR score, a simple index based on CAP and HOMA, can reliably identify patients with and without NASH.J.M. is recipient of an intensification grant from Consejería de Salud, Junta de Andalucía (grant number: A1-0060-2021). J.A.P. is recipient of an intensification grant from the Instituto de Salud Carlos III (grant number: I3SNS). A.G.S. is recipient of a Miguel Servet Research Contract from the Instituto de Salud Carlos III (CP18/00146). A.C.G. has received a Río Hortega grant from the Instituto de Salud Carlos III (grant number CM19/00251) and a research extension grant from Acciones para el refuerzo con recursos humanos de la actividad investigadora en las Unidades Clínicas del Servicio Andaluz de Salud 2021, acción B (Clínico-Investigadores) (grant number B-0061-2021).This work has been partially funded by the Instituto de Salud Carlos III (grant no: PI18/00606); co-funded by ERDF "A way to make Europe" and Consejería de Salud de la Junta de Andalucía (PI-0001/2017).Peer reviewe

Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Factores predictores de eventos clínicos tras la respuesta viral sostenida en pacientes con infección crónica por el virus de la hepatitis C y fibrosis hepática avanzada

A pesar de las altas tasas de curación de la infección por el virus de la hepatitis C (VHC) a partir de la reciente introducción de los antivirales de acción directa (AAD), incluso en los escenarios más complicados, la carga de la enfermedad hepática residual a esta infección sigue siendo un importante problema de salud pública. Los factores asociados a una evolución clínica desfavorable son de sobra conocidos en el contexto de la infección por el VHC activa. Sin embargo, la información relativa a la evolución clínica y al manejo adecuado de las complicaciones que pueden surgir tras la respuesta viral sostenida (RVS) de los pacientes al tratamiento erradicador, es limitada. Por ello, la presente Tesis Doctoral se ha centrado en evaluar los factores que se asocian a evolución clínica en este contexto específico de pacientes. Más concretamente, dado que el VIH modifica sustancialmente la historia natural de la enfermedad hepática durante la infección activa por el VHC, es razonable pensar que, tras la consecución de la RVS con AAD siga teniendo un impacto negativo. Por otro lado, a pesar de que la rigidez hepática, evaluada mediante elastografía hepática de transición con vibración controlada (ETVC), ha demostrado ser un potente predictor de eventos clínicos en pacientes con infección activa, su valor predictivo después de la curación no ha sido analizado. Específicamente, un valor de rigidez hepática por debajo de 21 KPa identifica a los individuos cirróticos con bajo riesgo de desarrollar sangrado de varices esofágicas (VE) por hipertensión portal, durante la infección activa por el VHC. Sin embargo, el rendimiento diagnóstico de esta técnica con dicha finalidad no se ha evaluado tras la RVS. El objetivo global de la presente Tesis Doctoral fue por valor predictivo de varios factores en el desarrollo de eventos clínicos después de lograr respuesta viral sostenida en pacientes infectados con fibrosis avanzada previa al tratamiento. Los tres estudios que componen este trabajo se llevaron a cabo en la cohorte GEHEP-011 (clinicaltrials.gov ID: NCT04460157). Se trata de una cohorte multicéntrica en la que participan unidades de Enfermedades Infecciosas de 18 hospitales españoles. En ella se incluyen pacientes monoinfectados por el VHC y coinfectados por el VIH/VHC que cumplen los siguientes criterios: 1) Haber recibido un régimen terapéutico con al menos un AAD, ya fuera libre de IFN o no; 2) Presentar una RH, medida por ETVC, previa al tratamiento ≥9,5 KPa; 3) Haber alcanzado RVS después de la finalización del tratamiento, definida como una PCR negativa para ARN del VHC en sangre en ese momento; y 4) Disponer de una medición de la RH por ETVC válida en el momento de la RVS. Los pacientes con HBsAg sérico positivo son excluidos del estudio. En primer lugar, se evaluó el impacto de la coinfección por VIH sobre el riesgo de desarrollar eventos hepáticos en pacientes con infección crónica por el VHC y fibrosis avanzada, que alcanzan la RVS con regímenes basados en AAD. Este objetivo concreto se abordó en el trabajo “HIV infection does not increase the risk of liver complications in hepatitis C virus-infected patient with advanced fibrosis, after sustained virological response with direct-acting antivirals”. Se puso de manifiesto que, al contrario de lo que ocurre durante la infección por VHC activa, la coinfección por el VIH no tiene un impacto negativo en la progresión de la enfermedad hepática, en estos pacientes tras la curación del VHC. En segundo lugar, se determinó el valor predictivo de la rigidez hepática, medida por ETVC, en el momento de la RVS, para la aparición de complicaciones hepáticas en pacientes con infección por VIH e infección crónica por VHC y fibrosis avanzada previa al tratamiento, tratados con AAD. Este objetivo se cumplió en el trabajo “Liver Stiffness at the time of sustained virological response predicts the clinical outcome in people living with human immunodeficiency virus and hepatitis C virus with advanced fibrosis treated with direct-acting antivirals”. En éste se concluyó que la RH, evaluada por ETVC, en el momento de la curación, fue capaz de identificar por sí sola a aquellos pacientes con un bajo riesgo de desarrollar complicaciones hepáticas tras la RVS. Estos individuos podrían ser potencialmente excluidos de los programas de cribado de complicaciones hepáticas de forma segura, después de la RVS. Además, la RH en RVS también resultó ser un factor predictor de muerte por cualquier causa en estos individuos. Por último, se validaron marcadores basados en la rigidez hepática previamente descritos, medidos en el momento de la RVS, para predecir el sangrado digestivo por varices esofágicas en pacientes con infección crónica por VHC en fase de cirrosis hepática, coinfectados o no por VIH, que alcanzan la RVS con regímenes basados en AAD. Este objetivo se acometió en el trabajo “Liver stiffness-based strategies predict absence of variceal bleeding in cirrhotic HCV-infected patients with and without HIV-coinfection after sustained virological response”. Se demostró que las estrategias de cribado de VE basadas en la RH y validadas durante la infección activa por VHC también presentan un buen rendimiento después de la consecución de la RVS, en pacientes con cirrosis hepática por VHC. Los criterios HEPAVIR, VIH/cirrosis y BAVENO VI expandido evaluados en el momento de la RVS son de gran utilidad para identificar a aquellos individuos cirróticos con bajo riesgo de presentar un sangrado por VE tras la curación de la infección por VHC. Concretamente, el criterio VIH/cirrosis es capaz de identificar al máximo número de pacientes en los que podrían interrumpirse las medidas de vigilancia de VE, sin que se produzcan eventos hemorrágicos en individuos no cribados