Search

Objectives: Identifying profiles of hospitalized COVID-19 patients and explore their association with different degrees of severity of COVID-19 outcomes (i.e. in-hospital mortality, ICU assistance, and invasive mechanical ventilation). The findings of this study could inform the development of multiple care intervention strategies to improve patient outcomes. Methods: Prospective multicentre cohort study during four different waves of COVID-19 from March 1st, 2020 to August 31st, 2021 in four health consortiums within the southern Barcelona metropolitan region. From a starting point of over 292 demographic characteristics, comorbidities, vital signs, severity scores, and clinical analytics at hospital admission, we used both clinical judgment and supervised statistical methods to reduce to the 36 most informative completed covariates according to the disease outcomes for each wave. Patients were then grouped using an unsupervised semiparametric method (KAMILA). Results were interpreted by clinical and statistician team consensus to identify clinically-meaningful patient profiles. Results: The analysis included nw1 = 1657, nw2 = 697, nw3 = 677, and nw4 = 787 hospitalized-COVID-19 patients for each of the four waves. Clustering analysis identified 2 patient profiles for waves 1 and 3, while 3 profiles were determined for waves 2 and 4. Patients allocated in those groups showed a different percentage of disease outcomes (e.g., wave 1: 15.9% (Cluster 1) vs. 31.8% (Cluster 2) for in-hospital mortality rate). The main factors to determine groups were the patient’s age and number of obese patients, number of comorbidities, oxygen support requirement, and various severity scores. The last wave is also influenced by the massive incorporation of COVID-19 vaccines. Conclusion: Our study suggests that a single care model at hospital admission may not meet the needs of hospitalized-COVID-19 adults. A clustering approach appears to be appropriate for helping physicians to differe, "DF, NP, and GM have been supported by l’Agència de Gestio ´ d’Ajuts Universitaris i de Recerca (AGAUR) de la Generalitat de Catalunya (Spain) [2020PANDE00148] (https://agaur.gencat. cat/en/inici/index.html). DF and NP have been supported by the Ministerio de Ciencia e Innovacio ´n (Spain) [PID2019-104830RB-I00/ DOI (AEI): 10.13039/501100011033] (https://www.aei. gob.es/en/announcements/announcements-finder/ proyectos-idi-2019-modalidades-retosinvestigacion-generacion) and by grant 2021 SGR 01421 (GRBIO, https://agaur.gencat.cat/web/ shared/OVT/Departaments/REU/A_Universitats/ AGAUR/Documents/RECERCA/SGR/Resolucio_ definitiva_SGR-Cat_2021.pdf) administrated by the Departament de Recerca i Universitats de la Generalitat de Catalunya (Spain).", Peer Reviewed, Objectius de Desenvolupament Sostenible::3 - Salut i Benestar, Postprint (published version)

Introduction: Second-generation integrase strand transfer inhibitors (INSTIs) are preferred treatment options worldwide, and dolutegravir (DTG) is the treatment of choice in resource-limited settings. Nevertheless, in some resource-limited settings, these drugs are not always available. An analysis of the experience with the use of INSTIs in unselected adults living with HIV may be of help to make therapeutic decisions when second-generation INSTIs are not available. This study aimed to evaluate the real-life effectiveness and safety of dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), and raltegravir (RAL) in a large Spanish cohort of HIV-1-infected patients. Methods: Real-world study of adults living with HIV who initiated integrase INSTIs DTG, EVG/c, and RAL-based regimens in three settings (ART-naïve patients, ART-switching, and ART-salvage patients). The primary endpoint was the median time to treatment discontinuation after INSTI-based regimen initiation. Proportion of patients experiencing virological failure (VF) (defined as two consecutive viral loads (VL) =200 copies/mL at 24 weeks or as a single determination of VL =1,000 copies/mL while receiving DTG, EVG/c or RAL, and at least 3 months after INSTI initiation) and time to VF were also evaluated. Results: Virological effectiveness of EVG/c- and RAL-based regimens was similar to that of DTG when given as first-line and salvage therapy. Treatment switching for reasons other than virological failure was more frequent in subjects receiving EVG/c and, in particular, RAL. Naïve patients with CD4+ nadir <100 cells/µL were more likely to develop VF, particularly if they initiated RAL or EVG/c. In the ART switching population, initiation of RAL and EVG/c was associated with both VF and INSTI discontinuation. There were no differences in the time to VF and INSTI discontinuation between DTG, EVG/c and RAL. Immunological parameters improved in the three groups and for the three drugs assessed. Safety and tolerabil, Peer Reviewed, Postprint (published version)

Background The potential role of the gut microbiome as a predictor of immune-mediated HIV-1 control in the absence of antiretroviral therapy (ART) is still unknown. In the BCN02 clinical trial, which combined the MVA.HIVconsv immunogen with the latency-reversing agent romidepsin in early-ART treated HIV-1 infected individuals, 23% (3/13) of participants showed sustained low-levels of plasma viremia during 32 weeks of a monitored ART pause (MAP). Here, we present a multi-omics analysis to identify compositional and functional gut microbiome patterns associated with HIV-1 control in the BCN02 trial. Results Viremic controllers during the MAP (controllers) exhibited higher Bacteroidales/Clostridiales ratio and lower microbial gene richness before vaccination and throughout the study intervention when compared to non-controllers. Longitudinal assessment indicated that the gut microbiome of controllers was enriched in pro-inflammatory bacteria and depleted in butyrate-producing bacteria and methanogenic archaea. Functional profiling also showed that metabolic pathways related to fatty acid and lipid biosynthesis were significantly increased in controllers. Fecal metaproteome analyses confirmed that baseline functional differences were mainly driven by Clostridiales. Participants with high baseline Bacteroidales/Clostridiales ratio had increased pre-existing immune activation-related transcripts. The Bacteroidales/Clostridiales ratio as well as host immune-activation signatures inversely correlated with HIV-1 reservoir size. Conclusions The present proof-of-concept study suggests the Bacteroidales/Clostridiales ratio as a novel gut microbiome signature associated with HIV-1 reservoir size and immune-mediated viral control after ART interruption., Peer Reviewed, Objectius de Desenvolupament Sostenible::3 - Salut i Benestar, Objectius de Desenvolupament Sostenible::10 - Reducció de les Desigualtats, Postprint (published version)

This is the peer reviewed version of the following article: Bonjoch, A. [et al.]. Prevalence, progression, and management of advanced chronic kidney disease in a cohort of people living with HIV. "HIV Medicine", 26 Abril 2022, vol. 23, núm. 10, p. 1078-1084, which has been published in final form at https://onlinelibrary.wiley.com/doi/10.1111/hiv.13317. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited, Peer Reviewed, Postprint (published version)

Integrase strand transfer inhibitors (INSTI) are a main component of the current antiretroviral regimens recommended for treatment of HIV infection. However, little is known about the impact of INSTI on neurocognition and neuroimaging. We developed a prospective observational trial to evaluate the effects of INSTI-based antiretroviral therapy on comprehensive brain outcomes (cognitive, functional, and imaging) according to the time since HIV-1 acquisition. We recruited men living with HIV who initiated antiretroviral therapy with INSTI < 3 months since the estimated date of HIV-1 acquisition (n = 12) and > 6 months since estimated date of HIV-1 acquisition (n = 15). We also recruited a group of matched seronegative individuals (n = 15). Assessments were performed at baseline (before initiation of therapy in HIV arms) and at weeks 4 and 48. Baseline cognitive functioning was comparable between the arms. At week 48, we did not find cognitive differences between starting therapy with INSTI earlier than 3 months or later than 6 months after acquisition of HIV-1 infection. Functional status was poorer in individuals diagnosed earlier. This effect recovered 48 weeks after initiation of therapy. Regarding brain imaging, we found that men living with HIV initiating antiretroviral therapy later experienced a greater decrease in medial orbitofrontal cortex over time, with expected negative repercussions for decision-making tasks., The study was supported by Fundació Lluita Contra la SIDA (FLS-ANT 2015-01). IMZ was supported by a P-FIS grant (FI17/00294) and CSM by a Miguel Servet contract (CPII16/00048) from the Instituto de Salud Carlos III. NPA was partially supported by grants MTM2015-64465-C2-1-R (MINECO/FEDER) and 2017 SGR 622 (GRBIO), Peer Reviewed, Postprint (published version)

El aprendizaje humano es autónomo debido a que tenemos un sistema de captación de información a través de los sentidos que es combinada usando las neuronas y permite generar conocimiento de nuestro entorno. Las redes neuronales artificiales son algoritmos que pretenden emular este comportamiento dando lugar a un proceso de aprendizaje automático. En este vídeo se explica la mecánica y el funcionamiento de estas redes a la vez que se muestran aplicaciones prácticas en diferentes disciplinas.

This is an openaccessarticledistributedunderthe termsof theCreativeCommonsAttributionLicense,whichpermitsunrestricted use, distribution, andreproductionin any medium,providedthe originalauthorand sourceare credited., Objective Optimization of antiretroviral therapy and anti-inflammatory treatments, such as statins, are among the strategies aimed at reducing metabolic disorders, inflammation and immune activation in people living with HIV (PLWH). We evaluated the potential benefit of combining both strategies. Design Forty-two PLWH aged =40 years receiving a protease inhibitor (PI)-based regimen were randomized (1:1) to switch from PI to Raltegravir (n = 20), or to remain on PI (n = 22). After 24 weeks, all patients received atorvastatin 20mg/day for 48 weeks. Methods We analyzed plasma inflammatory as well as T-cell maturation, activation, exhaustion and senescence markers at baseline, 24 and 72 weeks, Results Plasma inflammatory markers remained unchanged. Furthermore, no major changes on T-cell maturation subsets, immunoactivation, exhaustion or immunosenescence markers in both CD4 and CD8 T cell compartments were observed. Only a modest decrease in the frequency of CD38+ CD8 T cells and an increase in the frequency of CD28-CD57+ in both CD4 and CD8 T-cell compartments were noticed in the Raltegravir-switched group. Conclusions The study combined antiretroviral switch to Raltegravir and Statin-based anti-inflammatory strategies to reduce inflammation and chronic immune activation in PLWH. Although this combination was safe and well tolerated, it had minimal impact on inflammatory and immunological markers. Clinical, Peer Reviewed, Ativle signat per 10 autors/es: Eugènia Negredo, Montse Jiménez, Jordi Puig, Cora Loste, Núria Pérez-Álvarez, Victor Urrea, Patricia Echeverría, Anna Bonjoch, Bonaventura Clotet, Julià Blanco, Postprint (published version)

Copyright © 2020 Rosás-Umbert, Ruiz-Riol, Fernández, Marszalek, Coll, Manzardo,Cedeño, Miró, Clotet, Hanke, Moltó, Mothe, Brander and the BCN02 study group.This is an open-access article distributed under the terms of the Creative CommonsAttribution License (CC BY). The use, distribution or reproduction in other forumsis permitted, provided the original author(s) and the copyright owner(s) are creditedand that the original publication in this journal is cited, in accordance with acceptedacademic practice. No use, distribution or reproduction ispermitted which does notcomply with these terms., Romidepsin (RMD) is a well-characterized histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma. in vitro and in vivo studies have demonstrated that it is able to induce HIV-1 gene expression in latently infected CD4+ T cells from HIV-1+ individuals on suppressive antiretroviral therapy. However, in vitro experiments suggested that RMD could also impair T-cell functionality, particularly of activated T cells. Thus, the usefulness of RMD in HIV-1 kick&kill strategies, that aim to enhance the immune system elimination of infected cells after inducing HIV-1 viral reactivation, may be limited. In order to address whether the in vitro observations are replicated in vivo, we determined the effects of RMD on the total and HIV-1-specific T-cell populations in longitudinal samples from the BCN02 kick&kill clinical trial (NCT02616874). BCN02 was a proof-of-concept study in 15 early treated HIV-1+ individuals that combined MVA.HIVconsv vaccination with three weekly infusions of RMD given as a latency reversing agent. Our results show that RMD induced a transient increase in the frequency of apoptotic T cells and an enhanced activation of vaccine-induced T cells. Although RMD reduced the number of vaccine-elicited T cells secreting multiple cytokines, viral suppressive capacity of CD8+ T cells was preserved over the RMD treatment. These observations have important implications for the design of effective kick&kill strategies for the HIV-1 cure., Peer Reviewed, Article signat per 13 autors/es i un grup de recerca: Miriam Rosás-Umbert,Marta Ruiz-Riol, Marco A. Fernández, Marta Marszalek, Pep Coll, Christian Manzardo, Samandhy Cedeño, José M. Miró, Bonaventura Clotet, Tomáš Hanke, José Moltó, Beatriz Mothe, Christian Brander, and the BCN02 study group, Postprint (published version)

A social network can be defined as a group of entities linked between each other by means of some relational tie. Several studies indicate the existence of an influence of social networks on job performance. This thesis is intended to assess such idea. More specifically, the objective is to examine the relationship between the position of the entities in a social network with their performances through time. To that purpose, an analysis with real data about a set of soldiers from an European country army is conducted by using the software R. Among others, it contains measures of the soldiers performance and the social networks that can be defined on them. In order to assess such influence, a multilevel model is considered as a proper tool to fit the data, which is characterized by its longitudinal and its hierarchical structure. Besides, the data is unbalanced. Thus, this study will cover the concept of social network and the theory around this matter, as well as the multilevel model theory and its estimation.

This is a pre-copyedited, author-produced PDF of an article accepted for publication in Journal of antimicrobial chemotherapy following peer review. The version of record Negredo, E., Langohr, K., Bonjoch, A., Perez, N., Estany, C., Puig, J., Echevarría, P., Clotet, B., Gómez Melis, G. High risk and probability of progression to osteoporosis at 10 years in HIV-infected individuals: the role of PIs. "Journal of antimicrobial chemotherapy", 1 Setembre 2018, vol. 73, núm. 9, p. 2452-2459 is available online at: https://academic.oup.com/jac/article-abstract/73/9/2452/5026321., Peer Reviewed, Postprint (author's final draft)

En este trabajo hemos analizado un estudio de cohorte de pacientes de VIH, se ha realizado todo el proceso de gestión de datos y estadístico necesario. Se han realizado análisis descriptivos, análisis de supervivencia y ajustados modelos lineales mixtos, así como modelos multivariantes longitudinales.

Extensively pretreated subjects with virological failure (VF) may receive salvage regimens containing NRTIs with only residual or no activity. Once virological suppression is achieved, their contribution remains elusive. This was a multicentre, randomized, prospective study. Subjects with at least one prior VF, HIV-1 RNA < 50 copies/mL for a parts per thousand yen6 months and receiving a regimen with at least two active drugs (one of them a boosted PI) were randomized 1:1 to stop (experimental arm) or maintain (control arm) NRTIs. EudraCT: 2012-000198-21. Ninety subjects were randomized (experimental, naEuroS=aEuroS45; and control, naEuroS=aEuroS45). The mean age was 50 years, 80% were male, the mean CD4+ cell count was 542 cells/mm(3) and the median number of prior VFs was 3. Seventy-four subjects (82%) harboured the mutation M184V/I and the median number of thymidine-associated mutations was 3 (IQR: 0-4). In the experimental arm, thirty-two (71%) subjects removed one NRTI and 13 (29%) subjects removed two. Twenty-two of 45 (49%) discontinued tenofovir disoproxil fumarate. Forty-one of 45 (91.1%, experimental arm) and 44 of 45 (97.8%, control arm) had HIV-1 RNA < 50 copies/mL at 48 weeks (difference: -6.7%; 95% CI: -17.4, 4.1). In a post-hoc analysis allowing NRTI reintroduction, efficacy rates were 95.6% and 97.8%, respectively (difference: -2.2%; 95% CI: -7.2, 2.7). Rates of discontinuation at 48 weeks were 2% in both arms. One subject developed a late VF with resistance selection. In patients receiving a successful multidrug salvage regimen with at least two active drugs (one a boosted PI), the withdrawal of inactive NRTIs was safe, rates of VF were low and drug resistance was uncommon at 48 weeks in this small study. This strategy could potentially prevent long-term toxicities, reduce the number of drugs and reduce costs if non-inferiority was met in a fully powered trial., Peer Reviewed, Postprint (published version)

Kidney injury (defined as the presence of albuminuria, proteinuria, glycosuria [without hyperglycemia], hematuria, and/or renal hypophosphatemia) is an emerging problem in human immunodeficiency virus (HIV)-infected patients, although few data are available on the role of protease inhibitors (PIs) in this condition. To determine the time to kidney injury in a cohort of HIV-infected patients receiving a PI-containing regimen. We report the results of a subanalysis of a published cross-sectional study. The subanalysis included only patients receiving PI-containing regimens for more than 6 months (377 of the overall 970 patients). We determined associated factors and constructed receiver operating characteristic curves to estimate time to kidney injury depending on the PI used. The percentage of patients with kidney injury was 27.7% for darunavir, 27.9% for lopinavir, and 30% for atazanavir. Time to kidney injury was as follows: 229 days for atazanavir/ritonavir (area under the curve [AUC], 0.639; sensitivity, 0.89; specificity, 0.41); 332 days for atazanavir/ritonavir plus tenofovir (AUC, 0.603; sensitivity, 0.75; and specificity, 0.29); 318 days for nonboosted atazanavir (AUC, 0.581; sensitivity, 0.89; and specificity, 0.29); 478 days for lopinavir/ritonavir (AUC, 0.566; sensitivity, 0.864; and specificity, 0.44); 1339 days for lopinavir/ritonavir plus tenofovir (AUC, 0.667; sensitivity, 0.86; and specificity, 0.77); 283 days for darunavir/ritonavir (AUC, 0.523; sensitivity, 0.80; and specificity, 0.261); and 286 days for darunavir/ritonavir plus tenofovir (AUC, 0.446; sensitivity, 0.789; and specificity, 0.245). The use of lopinavir/ritonavir without tenofovir was a protective factor (odds ratio = 1.772; 95% CI, 1.070-2.93; P = 0.026). For all PIs, the percentage of patients with kidney injury exceeded 27%, irrespective of tenofovir use. The longest time to kidney injury was recorded with lopinavir/ritonavir. These results demonstrate the need for renal monitoring, Peer Reviewed, Postprint (published version)

Background. Prospective studies about the reversibility of tenofovir disoproxil fumarate- (TDF-) related renal impairment remain scarce. Methods. This is an observational prospective study including all patients that presented at our HIV Unit who interrupted TDF owing to nephrotoxicity. We assessed the evolution of renal parameters after discontinuation of this drug. Results. We included 59 patients, who were followed up for 72 weeks. Most were male (41, 69.5%), median (IQR) age was 53 (44; 58) years, and median time receiving TDF-containing regimens was 55.4 (28; 87.7) months. Most patients were receiving PI-based treatments (67%). At the final visit, most of the subjects showed complete recovery (35, 59.3%) or improvement (13 subjects, 22%). Significant improvements were observed in creatinine levels (from 84.9 [73.8; 97.5] to 78 [69.6; 91] mu mol/L, p = 0.013), estimated glomerular filtration rate (eGFR, CKD EPI equation, from 87.7 [67; 99] to 89.9 [73.6; 99.3] mL/min/1.73 m(2), p = 0.017), and number of patients with eGFR <60 mL/min/1.73 m(2) (from 9 [15.3%] to 1 [1.7%], p = 0.031). A trend toward significance was observed in abnormal urine proteinuria/creatinine ratio (from 22 [37%] to 8 [13.6%], p = 0.057). Conclusions. Our results corroborate the high frequency of complete or partial renal recovery in patients receiving TDF-containing regimens who discontinued therapy owing to nephrotoxicity., Peer Reviewed, Postprint (published version)

Non-invasive in vivo diffuse optical characterization of human bone opens a new possibility of diagnosing bone related pathologies. We present an in vivo characterization performed on seventeen healthy subjects at six different superficial bone locations: radius distal, radius proximal, ulna distal, ulna proximal, trochanter and calcaneus. A tailored diffuse optical protocol for high penetration depth combined with the rather superficial nature of considered tissues ensured the effective probing of the bone tissue. Measurements were performed using a broadband system for Time-Resolved Diffuse Optical Spectroscopy (TRS) to assess mean absorption and reduced scattering spectra in the 600–1200 nm range and Diffuse Correlation Spectroscopy (DCS) to monitor microvascular blood flow. Significant variations among tissue constituents were found between different locations; with radius distal rich of collagen, suggesting it as a prominent location for bone related measurements, and calcaneus bone having highest blood flow among the body locations being considered. By using TRS and DCS together, we are able to probe the perfusion and oxygen consumption of the tissue without any contrast agents. Therefore, we predict that these methods will be able to evaluate the impairment of the oxygen metabolism of the bone at the point-of-care., Peer Reviewed, Postprint (published version)

Background: Data on the efficacy of simplifying therapy using darunavir/ritonavir and lopinavir/ritonavir monotherapy in clinical practice remain limited.; Methods: A retrospective single-centre study including patients initiating darunavir/ritonavir or lopinavir/ritonavir monotherapy with a plasma HIV-1 viral load (pVL) <50 copies/mL and at least one subsequent follow-up visit. The primary endpoint was the percentage of patients remaining free of virological failure (VF; defined as a confirmed pVL >50 copies/mL or as any change in the regimen after a single determination with a pVL >50 copies/mL) during the follow-up. We also evaluated the percentage of patients remaining free of treatment failure (TF; defined as VF or the early discontinuation of monotherapy for any reason) and compared the effectiveness of the two regimens. Effectiveness was evaluated using cumulative survival analysis (at Weeks 48 and 96). Factors associated with VF and TF were analysed using Cox regression.; Results: A total of 522 patients were included (309 receiving lopinavir/ritonavir and 213 receiving darunavir/ritonavir). The median follow-up was 64.3 (30.5-143.0) weeks. The percentage of patients free of VF and TF was 94% (95% CI 91%-96%) and 79% (95% CI 75%-82%) at 48 weeks, respectively, and 86% (95% CI 81%-89%) and 62% (95% CI 57%-67%) at 96 weeks, respectively. The risk of VF was similar for the two regimens (HR = 1.0, 95% CI 0.6-1.8; P = 0.962). Lopinavir/ritonavir monotherapy was associated with a 1.5-fold greater risk of TF (95% CI 1.1-2.1; P = 0.012) and a 2.3-fold greater risk of discontinuation of therapy due to adverse events (95% CI 1.3-3.9; P = 0.003).; Conclusions: The virological efficacy of darunavir/ritonavir and lopinavir/ritonavir monotherapy is high in clinical practice. Treatment discontinuation due to safety issues is more frequent with lopinavir/ritonavir., This study was supported in part by grants from Lluita contra la SIDA Foundation (Barcelona, Spain), the Spanish AIDS Network ‘Red Temática Cooperativa de Investigación en SIDA’ (RIS, RD06/0006), NEAT (European AIDS Treatment Network), Ministerio de Economía y Competitividad of Spain (MTM2012-38067-C02-01) and GRBIO (Grup de Recerca en Bioestadística i Bioinformàtica; 2014 SGR 464). The funders had no role in study design, data collection and analysis, the decision to publish or drafting of the manuscript., Peer Reviewed, Postprint (published version)

A composite endpoint (CE) is a single outcome that combines various outcomes and measures the number of patients who present at least one of the individual components. The objective of this Master Thesis is to learn about the use of CE and develop a methodology to decide between a dichotomous primary endpoint and a composite one in terms of the asymptotic relative efficiency (ARE). A bibliographic research will be accomplished with the aim of seeing the use of Combined endpoints in HIV during 2012 to then, develop a statistical theoretical framework to get an expression for the ARE. Based on its values, statistical recommendations are given in the area of HIV to decide whether to expand a study primary endpoint to the composite, as well as preliminary results in other areas.

Background: Etravirine (ETR) was approved for patients with virological failure and antiretroviral resistance mutations. It has also shown antiviral efficacy in antiretroviral-naive patients. However, data on the switching from protease inhibitors (PI) to ETR are lacking.; Methods: HIV-1-infected patients with suppressed viral load (VL) during a PI-containing regimen (>12 months) and no previous virological failure were randomized to switch from the PI to ETR (400 mg/day, dissolved in water) (ETR group, n = 22) or to continue with the same regimen (control group, n = 21). Percentage of patients with VL <= 50 copies/mL were assessed at week 48, as well as changes in CD4 T-cell counts and metabolic profile.; Results: We included 43 patients [72.9% male, 46.3 (42.2; 50.6) years]. Two patients receiving ETR (grade-1 diarrhea and voluntary discontinuation) and another in the control group (simplification) discontinued therapy early. No patients presented virological failure (two consecutive VL>50 copies/mL); treatment was successful in 95.2% of the control group and 90.9% of the ETR group (intention-to-treat analysis, missing = failure) (p = 0.58). CD4+ T-cell counts did not significantly vary [+49 cells/mu L in the ETR group (p = 0.25) and -4 cells/mu L in the control group (p = 0.71)]. The ETR group showed significant reductions in cholesterol (p<0.001), triglycerides (p=<0.001), and glycemia (p = 0.03) and higher satisfaction (0-10 scale) (p = 0.04). Trough plasma concentrations of ETR were similar to observed in studies using ETR twice daily.; Conclusion: Switch from a PI-based regimen to a once-daily combination based on ETR maintained undetectable VL during 48 weeks in virologically suppressed HIV-infected patients while lipid profile and patient satisfaction improved significantly., Peer Reviewed, Postprint (published version)

Currently, resources that may be spent in health care are limited so it is necessary to rationalize their consumption and prioritise their allocation to the options with higher health outcome and economic sustainability. It is for that reason that economic analyses are increasingly included in medicine research as an instrument for evaluating different therapeutic strategies. In this thesis, both cost and health outcome are separately and jointly evaluated to compare different therapeutic strategies to treat diseases in different and specific health areas. The challenge was adapting and implementing the methods to reflect the assessed health issue. The analyses require data, and the main sources to obtain them are clinical studies (prospective or retrospective), or simulation models. The use of simulations avoids to experiment directly to the system of interest, these methods imply a smaller time consumption and cost, and any danger can be caused by the experimentation performance. However, the simulated data always is going to be an approximation of real data. Real data of a clinical trial was used in the assessment of the adherence to antiretroviral treatment promotion program in HIV infected patients. A decision tree was used to study the cost per health gain, measured by means of clinical and health related quality of life outcomes. The simulation of a Spanish cohort of postmenopausal women and their possible osteoporotic fractures was done to assess the performance of two treatments for the prevention of vertebral and non-vertebral fractures in terms of cost-effectiveness. Simulation by means of a Markov model required that the disease evolution and the related events were simplified using a finite number of health states and the probabilities of moving from one state to another as the time go on. Markov models were adapted to reflect that the risk of suffering an event can change over time. This analytical model was applied to elucidate whether co-receptors te, Actualment, els recursos destinats a la salut són limitats i es fa necessari racionalitzar-ne el seu consum; cal prioritzar la despesa en opcions que reportin un major benestar i que siguin sostenibles econòmicament. És per aquest motiu, que cada cop hi ha més estudis clínics que inclouen paràmetres econòmics com a instrument per triar entre diferents estratègies terapèutiques. En aquesta tesi, tant el cost com la resposta de salut s'estudien per separat i conjuntament per a comparar diferents estratègies per al tractament de malalties de diferent àrees de salut. El repte es troba en adaptar i implementar la metodologia necessària per a dur a terme el seguiment d'aquests problemas de salut. Les anàlisis requereixen dades i la majoria d'elles provenen d'estudis clínics, ja siguin prospectius o retrospectius, o bé de models de simulació. L'ús de dades simulades evita experimentar directament amb el sistema d'interès, implicant un temps menor, un cost més econòmic i un decreixement del risc d'experimentació necessaris per a l'obtenció de resultats. Per contrapartida, la simulació és una aproximació de les dades reals. D'una banda, l'avaluació d'un programa de promoció de l'adherència al tractament antiretroviral per pacients VIH+ es du a terme amb dades reals recollides en el marc d'un assaig clínic. El cost per unitat de guany en salut, mesurat amb paràmetres clínics i en qualitat de vida, es representa mitjançant un arbre de decisió. A continuació, la simulació d'una cohort de dones espanyoles post menopàusiques i les seves possibles fractures òssies permet comparar, en termes de cost-efectivitat, dos tractaments usats en la prevenció de fractures vertebrals i no vertebrals. Els models de Markov permeten simular el curs de la malaltia fent servir un nombre finit d'esdeveniments que representen els possibles estats de salut i la probabilitat de que un pacient canviï d'estat amb l'adaptació dels models de Markov per permetre que el risc de patir un esdeveniment variï e, Postprint (published version)

Challenges and new opportunities for the integration of biostatisticians in multidisciplinary teams are a major concern in the field. New forms of broader training in the life sciences, collaborations with other scientists, and strategic partnerships in research, all appear as essential means towards success for young professionals in Biostatistics. This article is novel in that it provides a young biostatisticians perspective on what many experienced colleagues have been discussing for years, i.e., what the future will bring to the profession and how we will be best trained to face it. The vision emerged from a unique forum comprising six authors with completely different backgrounds and work experience in the field, and is complemented by the discussion generated in a roundtable., Peer Reviewed, Postprint (published version)

Algorithms for bone mineral density (BMD) management in HIV-infected patients are lacking. Our objective was to assess how often a dual-energy x-ray absorptiometry (DXA) scan should be performed by assessing time of progression to osteopenia/osteoporosis. Methods: All DXA scans performed between 2000 and 2009 from HIV-infected patients with at least two DXA were included. Time to an event (osteopenia and osteoporosis) was assessed using the Kaplan–Meier method. Strata (tertiles) were defined using baseline minimum T scores. Differences between strata in time to an event were compared with the log-rank test. Results: Of 391 patients (1,639 DXAs), 49.6% had osteopenia and 21.7% osteoporosis at their first DXA scan. Of the 112 (28.6%) with normal BMD, 35.7% progressed to osteopenia; median progression time was 6.7 years. These patients were stratified: “low-risk" (baseline minimum T score >−0.2 SD), “middle-risk" (between −0.2 and −0.6 SD), and “high-risk" (from −0.6 to −1 SD); median progression time to osteopenia was 8.7, >7.2, and 1.7 years, respectively (p<0.0001). Of patients with osteopenia, 23.7% progressed to osteoporosis; median progression time was >8.5 years. Progression time was >8.2 years in “low-risk" tertile (T score between −1.1 and −1.6 SD), >8.5 years in “middle-risk" (between −1.6 and −2), and 3.2 years in “high-risk" (from −2 to −2.4) (p<0.0001). Conclusions: Our results may help to define the BMD testing interval. The lowest T score tertiles would suggest recommending a subsequent DXA in 1–2 years; in the highest tertiles, ≥6 years. Early intervention in patients with bone demineralization could reduce fracture–related morbidity/mortality., Peer Reviewed, Postprint (published version)

There is a need to plan an appropriate statistical analysis of missing data for researchers working in clinical trials in HIV. Based on it, the main objectives of this thesis are: - Review the different typologies of missing data in clinical trials in HIV. - Explore the most important methods used to handle missing data, describe the advantages and disadvanteges, apply some of these methods to the Lluta Fundacio' study and implement in the R environment one of the new approaches. - Generate some guidelines that should be followed by researchers working in clinical trials (in particular in the Lluita Fundacio') and give some recommendation when it would be better to use a method instead of another according to the estimates and confidence intervals., El projecte que s'ofereix té com a principal motivació desenvolupar un pla per a la correcta anàlisi estadística de dades en presència de valors mancants o missings. S'aplicarà i estudiarà en el contexte dels estudis clínics que es desenvolupen a la Fundació de Lluita contra la SIDA (http://www.flsida.org). Es donen dades mancants per moltes causes i la problemàtica es dona tant en estudis longitudinals com transversals, observacionals o experimentals. L'estudiant haurà d¿abordar els següents aspectes: Determinar quin tipus de dades mancants afecten als estudis de recerca en VIH que es duen a terme a la FLS, tant a les covariants fixes (basals i retrospectives) com a les longitudinals. S¿estudiarà la metodologia més rellevant per fer inferència amb dades mancants. S'aplicaran algunes d'aquestes metodologies a alguns dels estudis de la FLS distingint les anàlisis segons el tipus d¿estudi i el patró per les dades mancants.

BACKGROUND: Although antiretroviral therapy improves immune response, some human immunodeficiency virus-infected patients present unsatisfactory CD4 T cell recovery despite achieving viral suppression, resulting in increased morbidity and mortality. METHODS: Cross-sectional, case-control study to characterize the mechanism and to identify predictive factors of poor immune response. We included 230 patients who were receiving highly active antiretroviral therapy and who had a viral load <50 copies/mL for >2 years; 95 were "discordant" (case patients; CD4 T cell count always <350 cells/microL), and 135 were "concordant" (control subjects). Activation markers, CD4 T cell death (necrosis, intrinsic apoptosis, and extrinsic apoptosis), and caspase-3 were measured. Clinical parameters, particularly antiretroviral combinations, were correlated with immune recovery. RESULTS: Discordant patients showed higher levels of activation markers, mainly in CD4 T cells (p < .001), and higher rates of spontaneous cell death (P < .001). Rates of activation and rates of CD4 T cell death (mainly by intrinsic apoptosis) were the best predictive factors for immune recovery, along with nadir CD4 T cell count. Patients who were receiving a protease inhibitor-based regimen were more likely to be discordant and showed higher rates of activation (P= .011), higher rates of CD4 T cell death (P = .033), and a lower nadir CD4 T cell count (P < .001). Multivariate analysis, however, ruled out any effect of protease inhibitors on immune recovery. No differences were observed between the use of tenofovir-emtricitabine (Truvada) and the use of abacavir-lamivudine (Kivexa). CONCLUSIONS: CD4 T cell apoptosis by the intrinsic pathway represents the determinant mechanism of the unsatisfactory immune recovery and should be targeted to manage therapy for discordant patients. The predictive value of low nadir CD4 T cell count for a poor immune recovery led us to consider starting antiretroviral therapy earlie, Postprint (published version)

Because interruptions of antiretroviral treatment may entail clinical risks for human immunodeficiency virus (HIV)-infected individuals, we investigated their impact on neurocognitive functioning. Cross-sectional study was carried out, comparing HIV-infected persons who had interrupted antiretroviral therapy in the past (interruption group, IG) with persons who had never discontinued therapy (noninterruption group, NIG). Interruption was defined as the discontinuation of highly active antiretroviral therapy (HAART) for more than 15 days after previous treatment of at least 15 days. All the participants were on therapy. Demographic, clinical, and neurocognitive variables were assessed. The primary end point was the percentage of people with neurocognitive impairment. The score in different neurocognitive domains was a secondary end point. A total of 83 subjects participated in the study (IG: n = 27; NIG: n = 56). Demographic and clinical characteristics were balanced between the groups, except for years since HIV diagnosis (IG, 13.8; NIG, 10.2 [P = .003]). The percentage of people with neurocognitive impairment was significantly higher in the IG group (IG, 59.25%; NIG, 33.92% [P = 0.02]). As for scores in neurocognitive domains, individuals in the IG showed worse neurocognitive functioning, and significant differences in attention/working memory and information processing speed were found. The adjusted analysis supported the unadjusted analysis. In this study, a higher prevalence of neurocognitive impairment was detected in HIV-infected persons who had interrupted antiretroviral therapy in the past. Additionally, neurocognitive functioning was observed to be more impaired in the same individuals. Further studies should examine the potential negative effects of antiretroviral therapy interruptions on neurocognitive functioning., Postprint (published version)

Postprint (published version)

El estudio de los factores relacionados con la reducción de la densidad minenal ósea en pacientes VIH son de interes.Es disposa d'una base de dades de més de 1800 DEXAs pertanyent a 700 pacients. Les variables recollides fan referència a: DEXAs, Dades basals i demogràfiques , Marcadors del VIH i biològics mesurats longitudinalment. Els objectius del projecte són: Fer una descripció de l'estat de la salut òssia de la població VIH+ de la unitat Fer el modelatge de les mesures repetides de DEXAs. Tenint en compte el seguiment heterogeni per pacients, la presència de covariables mesurades longitudinalment i covariables mesurades basalment; de manera que s'obtingui un model que permeti identificar les característiques dels pacients amb mes risc de patir dolències òssies.

Postprint (published version)