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Background: Over the past decade, antiretroviral therapy (ART) regimens that include integrase strand inhibitors (INSTIs) have become the most commonly used for people with HIV starting ART. Although trials and observational studies have compared virological failure on INSTI-based with other regimens, few data are available on mortality in people with HIV treated with INSTIs in routine care. Therefore, we compared all-cause mortality between different INSTI-based and non-INSTI-based regimens in adults with HIV starting ART from 2013 to 2018. Methods: This cohort study used data on people with HIV in Europe and North America from the Antiretroviral Therapy Cohort Collaboration (ART-CC) and UK Collaborative HIV Cohort (UK CHIC). We studied the most common third antiretroviral drugs (additional to nucleoside reverse transcriptase inhibitor) used from 2013 to 2018: rilpivirine, darunavir, raltegravir, elvitegravir, dolutegravir, efavirenz, and others. Adjusted hazard ratios (aHRs; adjusted for clinical and demographic characteristics, comorbid conditions, and other drugs in the regimen) for mortality were estimated using Cox models stratified by ART start year and cohort, with multiple imputation of missing data. Findings: 62 500 ART-naive people with HIV starting ART (12 422 [19·9%] women; median age 38 [IQR 30-48]) were included in the study. 1243 (2·0%) died during 188 952 person-years of follow-up (median 3·0 years [IQR 1·6-4·4]). There was little evidence that mortality rates differed between regimens with dolutegravir, elvitegravir, rilpivirine, darunavir, or efavirenz as the third drug. However, mortality was higher for raltegravir compared with dolutegravir (aHR 1·49, 95% CI 1·15-1·94), elvitegravir (1·86, 1·43-2·42), rilpivirine (1·99, 1·49-2·66), darunavir (1·62, 1·33-1·98), and efavirenz (2·12, 1·60-2·81) regimens. Results were similar for analyses making different assumptions about missing data and consistent across the time periods 2013-15 and 2016-18. Rates of virological suppression were higher for dolutegravir than other third drugs. Interpretation: This large study of patients starting ART since the introduction of INSTIs found little evidence that mortality rates differed between most first-line ART regimens; however, raltegravir-based regimens were associated with higher mortality. Although unmeasured confounding cannot be excluded as an explanation for our findings, virological benefits of first-line INSTIs-based ART might not translate to differences in mortality. We would like to thank our funders (US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council) and all patients and the clinical teams associated with the participating cohort studies. The antiretroviral therapy cohort collaboration is funded by the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026209). UK Collaborative HIV Cohort is funded by the UK Medical Research Council (grant numbers G0000199, G0600337, G0900274, and M004236/1). JACS is funded by National Institute for Health Research Senior Investigator award (NF-SI-0611-10168). AT is funded by the Wellcome Trust under a Sir Henry Wellcome Postdoctoral Fellowship (222770/Z/21/Z). Funding for the individual antiretroviral therapy cohort collaboration cohorts included in this analysis was from Alberta Health, Gilead, National Agency for AIDS Research (France REcherche Nord&Sud Sida-hiv Hépatites), the French Ministry of Health, the Austrian Agency for Health and Food Safety, Stichting HIV Monitoring, the Dutch Ministry of Health, Welfare and Sport through the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment, the TP-HIV by the German Centre for Infection Research (NCT02149004), Instituto de Salud Carlos III (through the Red Temática de Investigación Cooperativa en Sida [RD06/006, RD12/0017/0018, and RD16/0002/0006]) as part of the Plan Nacional I + D + i. Other funders of the individual cohorts participating data for this analysis are ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional, ViiV Healthcare, Preben og Anna Simonsens Fond, ANRS-Maladies infectieuses émergentes, Institut National de la Santé et de la Recherche Médicale (INSERM), Bristol Myers Squibb, Janssen, Merck, the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026230), the Spanish Ministry of Health, the Swiss National Science Foundation (grant 33CS30_134277), Centers for AIDS Research Network of Integrated Clinical Systems (1R24 AI067039-1, P30-AI-027757), the US Department of Veterans Affairs, the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026224, U01-AA026209, U24-AA020794), the Veterans Health Administration Office of Research and Development, and the US National Institute of Allergy and Infectious Diseases (Tennessee Center for AIDS Research P30 AI110527). Sí

To assess the use of resources and the costs associated with following up patients infected with the human immunodeficiency virus after discontinuation of an antiretroviral treatment and initiation of a new one due to a lack of effectiveness or unacceptable toxicity, as compared to the costs involved in the routine follow-up of patients on antiretroviral treatment, from the Spanish National Health System perspective. Method: The use of resources (clinical tests, medical visits, and hospital pharmacy visits) associated with following three profiles of patients infected with the human immunodeficiency virus (stable ones, those discontinuing an existing antiretroviral treatment and being switched to a new one due to a lack of effectiveness, and those discontinuing an existing antiretroviral treatment and being switched to a new one due to unacceptable toxicity) was identified, based on clinical practice guidelines and the findings of a multidisciplinary expert panel (n = 5). The experts agreed on the main adverse events leading to discontinuation, classifying them into gastrointestinal, renal, osseous, musculoskeletal, dermatological, hepatic, lipid profile-related, neuropsychiatric and sexual alterations. Unit costs were identified from official healthcare costs databases. The cost (€, 2020) of following up each patient profile was estimated, excluding the cost of the antiretroviral treatment itself, with a time horizon of two years.The per-patient cost of following up stable patients over two years was estimated at €4,148 (tests: €2,293; visits: €1,855). Patient follow-up after discontinuation of an existing antiretroviral treatment and initiation of a different one due to a lack of effectiveness was estimated at €5,434 (tests: €2,777; visits: €2,657). The cost of follow-up after discontinuation of an existing regimen and initiation of a new one due to unacceptable toxicity varied according to the adverse event prompting the switch, ranging from €4,690 for lipid profile dysregulation, to €5,304, for musculoskeletal alterations. In this patient profile, the cost of tests ranged from €2,403 to €3,017, and that of visits from €2,287 to €2,842.The cost associated with following up of patients infected with the human immunodeficiency virus after discontinuation of an existing antiretroviral regimen and initiation of a new one is higher than that of routine follow-up, without taking the cost of drugs into account. The treatment discontinuation rate is a relevant factor when selecting the most appropriate therapy for each patient.Estimar el uso de recursos y costes asociados al seguimiento de pacientes con infección por el virus de la inmunodeficiencia humana tras discontinuación del tratamiento antirretroviral actual debido a falta de efectividad o toxicidad inaceptable y cambio a un nuevo tratamiento antirretroviral, comparado con el seguimiento habitual de los pacientes con tratamiento antirretroviral, desde la perspectiva del Sistema Nacional de Salud español.Método: Se identificó el uso de recursos (pruebas clínicas, visitas médicas, visitas a la farmacia hospitalaria) asociado al seguimiento de pacientes con infección por el virus de la inmunodeficiencia humana en tres perfiles de pacientes (estable, discontinuación y cambio por falta de efectividad, discontinuación y cambio por toxicidad inaceptable), a partir de las guías de práctica clínica y un panel de expertos multidisciplinar (n = 5). Los expertos consensuaron los principales eventos adversos que conducían a la discontinuación, agrupándolos en: alteraciones gastrointestinales, renales, óseas, musculoesqueléticas, dermatológicas, hepáticas y del perfil lipídico, trastornos neuropsiquiátricos y sexuales. Los costes unitarios se identificaron a partir de bases de datos oficiales assode costes sanitarios y de la literatura. Se estimó el coste (€, 2020) del seguimiento en cada perfil de paciente, sin incluir el coste derivado del tratamiento antirretroviral, en un horizonte temporal de dos años.El coste por paciente a dos años se estimó en 4.148 € (pruebas: 2.293 €; visitas: 1.855 €) para el seguimiento del paciente estable. El seguimiento del paciente tras discontinuación por falta de efectividad y cambio de tratamiento antirretroviral se estimó en 5.434 € (pruebas: 2.777 €; visitas: 2.657 €). El coste del seguimiento tras la discontinuación por toxicidad inaceptable y cambio de tratamiento antirretroviral varió en función del evento adverso que motivó el cambio, oscilando entre 4.690 € para las alteraciones del perfil lipídico, y 5.304 € para las alteraciones musculoesqueléticas. En este perfil de pacientes, las pruebas variaron entre 2.403 € y 3.017 € y las visitas entre 2.287 € y 2.842 €.El coste asociado al seguimiento del paciente con infección por el virus de la inmunodeficiencia humana tras discontinuación y cambio a un nuevo tratamiento antirretroviral es mayor comparado con el seguimiento habitual, sin tener en cuenta el coste farmacológico. La tasa de discontinuación del tratamiento antirretroviral es un factor relevante a la hora de seleccionar la terapia más adecuada para cada paciente.

Aims: To assess the potential direct effects of the integrase strand-transfer inhibitors (INsTIs) dolutegravir, bictegravir, and raltegravir, drugs used as treatment for people living with human immunodeficiency virus (PLWH), on human adipose cells. Main methods: Drugs were added to the differentiation medium of human Simpson-Golabi-Behmel syndrome (SGBS) adipose cells and morphological adipogenesis was monitored for 10 days. Also, adipocytes were exposed to drugs following differentiation (day 14). The gene expression levels of selected adipogenesis markers, adipocyte metabolism markers, adipokines, and cytokines were determined by quantitative-reverse transcription polymerase-chain reaction. The release of adiponectin and leptin into the culture medium was measured using specific enzyme-linked immunosorbent assay, and release of interleukin-6 and chemokine (CC motif) ligand-2 using Multiplex assays. Key findings: Overall morphological adipogenesis was unaltered by INsTIs. The expression of adipogenesis marker genes (peroxisome proliferator-activated receptor-Ɣ and lipoprotein lipase) was slightly reduced in dolutegravir-treated differentiating adipocytes. Bictegravir repressed gene expression and the release of pro-inflammatory cytokines in differentiating adipocytes. Dolutegravir and raltegravir increased interleukin-6 gene expression, but only dolutegravir increased interleukin-6 release. Dolutegravir repressed adiponectin expression and release in differentiating adipocytes and had a similar but milder effect on leptin. Drug treatment of mature adipocytes reduced adiponectin gene expression in response to dolutegravir. Significance: The INsTIs studied do not have a significant effect on human adipose cell differentiation but exert distinct effects on gene expression and secretion of adipokines and cytokines. These findings will help understand and manage the effects of INsTI-containing treatments on body weight and metabolic dysregulation in PLWH.

OBJECTIVE: To evaluate time trends in pregnancies and pregnancy outcomes among women with HIV in Europe. DESIGN: European multicentre prospective cohort study. METHODS: EuroSIDA has collected annual cross-sectional audits of pregnancies between 1996 and 2015. Pregnancy data were extracted and described. Odds of pregnancy were modelled, adjusting for potential confounders using logistic regression with generalized estimating equations. RESULTS: Of 5535 women aged 16 to

BackgroundThe pharmacokinetics of bictegravir (BIC) and its association with the decay of human immunodeficiency virus (HIV)–1 RNA in genital fluids and the rectum have not yet been addressed.MethodsWe conducted a prospective, multicenter study of antiretroviral-naive people living with HIV-1 and initiating BIC/emtricitabine (FTC)/tenofovir alafenamide (TAF). HIV-1 RNA was measured (limit of quantification, 40 copies/mL) in blood plasma (BP), seminal plasma (SP), rectal fluid (RF), and cervicovaginal fluid (CVF) at baseline; Days 3, 7, 14, and 28; and Weeks 12 and 24. Total and protein-unbound BIC concentrations at 24 hours postdose (C24h) were quantified in BP, SP, CVF and rectal tissue (RT) on Day 28 and Week 12 using a validated liquid chromatography-tandem mass spectrometry assay.ResultsThe study population comprised 15 males and 8 females. In SP, RF, and CVF, the baseline HIV-1 RNA was >40 copies/mL in 12/15, 13/15, and 4/8 individuals, respectively, with medians of 3.54 (2.41–3.79), 4.19 (2.98–4.70), and 2.56 (1.61–3.56) log10 copies/mL, respectively. The initial decay slope was significantly lower in SP than in RF and BP. The time to undetectable HIV-1 RNA was significantly shorter in SP and RF than in BP. All women achieved undetectable HIV-1 RNA in CVF at Day 14. The median total BIC concentrations in SP, RT, and CVF were 65.5 (20.1–923) ng/mL, 74.1 (6.0–478.5) ng/g, and 61.6 (14.4–1760.2) ng/mL, respectively, representing 2.7%, 2.6%, and 2.8% of the BP concentration, respectively, while the protein-unbound fractions were 51.1%, 44.6%, and 42.6%, respectively.ConclusionsBIC/FTC/TAF led to rapid decay of HIV-1 RNA in genital and rectal fluids. Protein-unbound BIC concentrations in SP, RT, and CVF highly exceeded the half-maximal effective concentration (EC50) value (1.1 ng/mL).Clinical Trials RegistrationEudraCT 2018-002310-12.

BackgroundTransmission of resistance mutations to integrase strand transfer inhibitors (INSTIs) in HIV-infected patients may compromise the efficacy of first-line antiretroviral regimens currently recommended worldwide. Continued surveillance of transmitted drug resistance (TDR) is thus warranted.ObjectivesWe evaluated the rates and effects on virological outcomes of TDR in a 96 week prospective multicentre cohort study of ART-naive HIV-1-infected subjects initiating INSTI-based ART in Spain between April 2015 and December 2016.MethodsPre-ART plasma samples were genotyped for integrase, protease and reverse transcriptase resistance using Sanger population sequencing or MiSeq™ using a ≥ 20% mutant sensitivity cut-off. Those present at 1%–19% of the virus population were considered to be low-frequency variants.ResultsFrom a total of 214 available samples, 173 (80.8%), 210 (98.1%) and 214 (100.0%) were successfully amplified for integrase, reverse transcriptase and protease genes, respectively. Using a Sanger-like cut-off, the overall prevalence of any TDR, INSTI-, NRTI-, NNRTI- and protease inhibitor (PI)-associated mutations was 13.1%, 1.7%, 3.8%, 7.1% and 0.9%, respectively. Only three (1.7%) subjects had INSTI TDR (R263K, E138K and G163R), while minority variants with integrase TDR were detected in 9.6% of subjects. There were no virological failures during 96 weeks of follow-up in subjects harbouring TDR as majority variants.ConclusionsTransmitted INSTI resistance remains rare in Spain and, to date, is not associated with virological failure to first-line INSTI-based regimens.

Two years after the appearance of the SARS-CoV-2 virus, the causal agent of the current global pandemic, it is time to analyze the evolution of the immune protection that infection and vaccination provide. Cellular immunity plays an important role in limiting disease severity and the resolution of infection. The early appearance, breadth and magnitude of SARS-CoV-2 specific T cell response has been correlated with disease severity and it has been thought that T cell responses may be sufficient to clear infection with minimal disease in COVID-19 patients with X-linked or autosomal recessive agammaglobulinemia. However, our knowledge of the phenotypic and functional diversity of CD8+ cytotoxic lymphocytes, CD4+ T helper cells, mucosal-associated invariant T (MAIT) cells and CD4+ T follicular helper (Tfh), which play a critical role in infection control as well as long-term protection, is still evolving. It has been described how CD8+ cytotoxic lymphocytes interrupt viral replication by secreting antiviral cytokines (IFN-γ and TNF-α) and directly killing infected cells, negatively correlating with stages of disease progression. In addition, CD4+ T helper cells have been reported to be key pieces, leading, coordinating and ultimately regulating antiviral immunity. For instance, in some more severe COVID-19 cases a dysregulated CD4+ T cell signature may contribute to the greater production of pro-inflammatory cytokines responsible for pathogenic inflammation. Here we discuss how cellular immunity is the axis around which the rest of the immune system components revolve, since it orchestrates and leads antiviral response by regulating the inflammatory cascade and, as a consequence, the innate immune system, as well as promoting a correct humoral response through CD4+ Tfh cells. This review also analyses the critical role of cellular immunity in modulating the development of high-affinity neutralizing antibodies and germinal center B cell differentiation in memory and long-lived antibody secreting cells. Finally, since there is currently a high percentage of vaccinated population and, in some cases, vaccine booster doses are even being administered in certain countries, we have also summarized newer approaches to long-lasting protective immunity and the cross-protection of cellular immune response against SARS-CoV-2.

Background Reports on the impact of some antiretrovirals against SARS-CoV-2 infection and disease severity are conflicting. Objectives We evaluated the effect of tenofovir as either tenofovir alafenamide/emtricitabine (TAF/FTC) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) against SARS-CoV-2 infection and associated clinical outcomes among people living with HIV (PLWH). Methods We conducted a propensity score-matched analysis in the prospective PISCIS cohort of PLWH (n = 14 978) in Catalonia, Spain. We used adjusted Cox regression models to assess the association between tenofovir and SARS-CoV-2 outcomes. Results After propensity score-matching, SARS-CoV-2 diagnosis rates were similar in TAF/FTC versus ABC/3TC recipients (11.6% versus 12.5%, P = 0.256); lower among TDF/FTC versus ABC/3TC recipients (9.6% versus 12.8%, P = 0.021); and lower among TDF/FTC versus TAF/FTC recipients (9.6% versus 12.1%, P = 0.012). In well-adjusted logistic regression models, TAF/FTC was no longer associated with reduced SARS-CoV-2 diagnosis [adjusted odds ratio (aOR) 0.90; 95% confidence interval (CI), 0.78–1.04] or hospitalization (aOR 0.93; 95% CI, 0.60–1.43). When compared with ABC/3TC, TDF/FTC was not associated with reduced SARS-CoV-2 diagnosis (aOR 0.79; 95% CI, 0.60–1.04) or hospitalization (aOR 0.51; 95% CI, 0.15–1.70). TDF/FTC was not associated with reduced SARS-CoV-2 diagnosis (aOR 0.79; 95% CI, 0.60–1.04) or associated hospitalization (aOR 0.33; 95% CI, 0.10–1.07) compared with TAF/FTC. Conclusions TAF/FTC or TDF/FTC were not associated with reduced SARS-CoV-2 diagnosis rates or associated hospitalizations among PLWH. TDF/FTC users had baseline characteristics intrinsically associated with more benign SARS-CoV-2 infection outcomes. Tenofovir exposure should not modify any preventive or therapeutic SARS-CoV-2 infection management.

A significant proportion of people living with HIV (PLHIV) who successfully achieve virological suppression fail to recover CD4

Background: While much of the scientific focus thus far has been on cognitive sequelae in patients with severe COVID-19, subjective cognitive complaints are being reported across the spectrum of disease severity, with recent studies beginning to corroborate patients¿ perceived deficits. In response to this, the aims of this study were to (1) explore the frequency of impaired performance across cognitive domains in post-COVID patients with subjective complaints and (2) uncover whether impairment existed within a single domain or across multiple. Methods: Sixty-three patients with subjective cognitive complaints post-COVID were assessed with a comprehensive protocol consisting of various neuropsychological tests and mood measures. Cognitive test performance was transformed into T scores and classified based on recommended guidelines. After performing a principal component analysis to define cognitive domain factors, distributions of test scores within and across domains were analyzed. Results: Results revealed pervasive impact on attention abilities, both as the singularly affected domain (19% of single-domain impairment) as well as coupled with decreased performance in executive functions, learning, and long-term memory. These salient attentional and associated executive deficits were largely unrelated to clinical factors such as hospitalization, disease duration, biomarkers, or affective measures. Discussion: These findings stress the importance of comprehensive evaluation and intervention to address cognitive sequelae in post-COVID patients of varying disease courses, not just those who were hospitalized or experienced severe symptoms. Future studies should investigate to what extent these cognitive abilities are recuperated over time as well as employ neuroimaging techniques to uncover underlying mechanisms of neural damage.

Background GSK3640254 (GSK’254) is a next-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor with pharmacokinetics (PK) supporting once-daily therapy. Methods This phase IIa double-blind (sponsor-unblinded), randomized, placebo-controlled, adaptive study evaluated antiviral effect, safety, tolerability, and PK of once-daily GSK’254 monotherapy administered with food (moderate-fat meal) in HIV-1–positive, treatment-naive adults. In part 1, participants received GSK’254 10 or 200 mg for 10 days. In part 2, participants received GSK’254 40, 80, or 140 mg for 7 days, modified from 10 days by a protocol amendment to decrease potential for resistance-associated mutations (RAMs). The primary endpoint was maximum change from baseline in HIV-1 RNA. Results Maximum changes in HIV-1 RNA of −0.4, −1.2, −1.0, −1.5, and −2.0 log10 occurred with GSK’254 10, 40, 80, 140, and 200 mg, respectively. Regardless of dosing duration, doses ≥40 mg resulted in ≥1-log10 declines in HIV-1 RNA. Plasma PK was generally dose proportional to 140 mg but non-proportional between 140 and 200 mg. Four participants in the 200-mg group developed RAMs on day 11 in part 1, 1 with phenotypic resistance. No RAMs occurred in part 2. Adverse events (AEs) were reported by 22 (65%) participants; headache was the most common (n = 4). Two non–drug-related serious AEs occurred. All AEs were of mild-to-moderate intensity, except for 2 grade 3 non–drug-related AEs in 1 participant. Conclusions This monotherapy study established a dose–antiviral response relationship for GSK’254. No safety or tolerability concerns were noted. These results supported dose selection for the ongoing phase IIb study (ClinicalTrials.gov: NCT04493216). Clinical Trials Registration NCT03784079.

COVID-19 pathophysiology is currently not fully understood, reliable prognostic factors remain elusive, and few specific therapeutic strategies have been proposed. In this scenario, availability of biomarkers is a priority. MS-based Proteomics techniques were used to profile the proteome of 81 plasma samples extracted in four consecutive days from 23 hospitalized COVID-19 associated pneumonia patients. Samples from 10 subjects that reached a critical condition during their hospital stay and 10 matched non-severe controls were drawn before the administration of any COVID-19 specific treatment and used to identify potential biomarkers of COVID-19 prognosis. Additionally, we compared the proteome of five patients before and after glucocorticoids and tocilizumab treatment, to assess the changes induced by the therapy on our selected candidates. Forty-two proteins were differentially expressed between patients' evolution groups at 10% FDR. Twelve proteins showed lower levels in critical patients (fold-changes 1.20–3.58), of which OAS3 and COG5 found their expression increased after COVID-19 specific therapy. Most of the 30 proteins over-expressed in critical patients (fold-changes 1.17–4.43) were linked to inflammation, coagulation, lipids metabolism, complement or immunoglobulins, and a third of them decreased their expression after treatment. We propose a set of candidate proteins for biomarkers of COVID-19 prognosis at the time of hospital admission. The study design employed is distinctive from previous works and aimed to optimize the chances of the candidates to be validated in confirmatory studies and, eventually, to play a useful role in the clinical practice.

Lipodystrophy is a major disturbance in people living with HIV-1 (PLWH). Several systemic alterations in PLWH are reminiscent of those that occur in ageing. It is unknown whether the lipodystrophy in PLWH is the consequence of accelerated ageing in adipose tissue. We compared systemic and adipose tissue disturbances in PLWH with those in healthy elderly individuals (similar to 80 y old). We observed similarly enhanced expression of inflammation-related genes and decreased autophagy in adipose tissues from elderly individuals and PLWH. Indications of repressed adipogenesis and mitochondrial dysfunction were found specifically in PLWH, whereas reduced telomere length and signs of senesce were specific to elderly individuals. We conclude that ageing of adipose tissue accounts only partially for the alterations in adipose tissues of PLWH.

Background The aim of this study was to investigate whether switching from a ritonavir-boosted PI-based regimen to a dolutegravir-based regimen improved the atherogenic properties of LDL particles in patients with HIV. Methods This was a substudy of the NEAT022 study (ClinicalTrials.gov NCT02098837). Adults with HIV with a Framingham score >10% or aged >50 years and being treated with a stable boosted PI-based regimen were randomized to either switch to dolutegravir or continue with boosted PI. At baseline and Week 48, we assessed atherogenic LDL properties: LDL particle size and phenotype (A, intermediate, B), oxidized LDL (ox-LDL) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity. Results Eighty-six participants (dolutegravir 44; PI 42) were included. Participants had a median (IQR) age of 54 (51–57) years and 79.1% were male. In the dolutegravir arm, after 48 weeks, we observed: (1) an increase in LDL size [median 1.65 Å (IQR −0.60 to 4.20); P = 0.007], correlated with the decrease in triglyceride concentration [Spearman correlation = −0.352 (P = 0.001)], with a corresponding decrease of subjects with atherogenic LDL phenotype B (36.4% to 20.5%; P = 0.039); (2) a decrease in Lp-PLA2 activity [median 1.39 μmol/min/mL (IQR −2.3 to 0.54); P = 0.002]; and (3) a decrease in ox-LDL [median 14 U/L (IQR −102 to 13); P = 0.006]. In the PI arm, none of these favourable lipid modifications was observed. Conclusions Forty-eight weeks after switching from a PI-based to a dolutegravir-based regimen, patients with Framingham score >10% or aged >50 years showed improvement of several atherogenic lipid features, including LDL particle phenotype, ox-LDL and Lp-PLA2.

Background It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. Methods We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020—October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. Results Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83–2.45 with an I2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29–1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31–0.75], I2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40–0.68], I2 37%) were significantly lower for people with previous macrovascular disease. Conclusions This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup.

Background: The use of combination antiretroviral therapy has led to dramatic improvements in the life expectancy of HIV-infected persons. As result, the HIV population is aging and increasingly facing illnesses typically seen in the elderly, such as chronic kidney disease (CKD). Methods: A retrospective longitudinal study was conducted using data from years 2010 and 2014 in all HIV-infected persons enrolled at the Spanish VACH cohort. We analyzed the prevalence and the predictive factors for developing CKD (estimated glomerular filtration rate, eGFR

Summary Meningococcal disease was first clinically characterised by Gaspard Vieusseux in 1805, and its causative agent was identified by Anton Weichselbaum in 1887, who named it Diplococcus intracellularis menigitidis. From the beginning, the disease was dreaded because of its epidemic nature, predilection for previously healthy children and adolescents, and high mortality. In the last decade of the 19th century, the concept of serum therapy for toxin-related bacterial diseases was identified. This concept was applied to meningococcal disease therapy, in an independent way, by Wilhelm Kolle, August von Wasserman, and Georg Jochmann in Germany, and Simon Flexner in the USA, resulting in the first successful approach for the treatment of meningococcal disease. During the first three decades of the 20th century, serum therapy was the standard treatment for meningococcal disease. With the advent of sulphamides first and then antibiotics, serum therapy was abandoned. The great challenges that infectious diseases medicine is facing and the awaiting menaces in the future in terms of increasing antibiotic resistance, emergence of new pathogens, and re-emergence of old ones without effective therapy, make passive immunotherapy a promising tool. Acknowledging the achievements of our predecessors might teach us some lessons to bring light to our future.

Background: The life expectancy of HIV-infected individuals has dramatically improved with potent antiretroviral therapies. However, organ-specific toxicities of some antiretrovirals and persistent inflammation and immune activation due to residual virus replication account for a high burden of age-associated comorbidities in the HIV population. Methods: The prevalence of overt cardiovascular, renal and bone diseases as well as their major risk factors were cross-sectionally examined during the year 2014 in the VACH cohort, a large nationwide population of HIV-infected individuals in Spain. Results: A total of 10,897 HIV-infected patients were examined. Seventy-one point four percent were male and the mean age was 48 years. Mean time since HIV diagnosis was 15.8 years and mean time on antiretroviral therapy was 13.1 years. The proportion of patients with undetectable viral load was 87.1%, whereas 65.7% had CD4 counts >500 cells/mm(3). Overall, cardiovascular, renal and bone disease were recorded in 4.7%, 5.9% and 2.8%, respectively. The prevalence of major risk factors was as follows: smoking 51.3%, alcohol abuse 7.8%, overweight/obesity 42.2%, diabetes 19.9%, dyslipidaemia 72.6%, hypertension 25.6%, and osteoporosis 11.1%. In the subset of patients older than 55 years-old (18%), all figures for overt disease and their major risk factors were significantly greater. Conclusion: Major age-related medical conditions and most of their risk factors are highly prevalent in HIV-infected individuals on long-term antiretroviral therapy in Spain. Preventive actions, including careful selection of antiretroviral agents, should be prioritized in the ageing HIV population. (C) 2018 Elsevier Espana, S.L.U. and Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica. All rights reserved.

The massive implementation of combination antiretroviral therapy (cART) has forever changed the landscape of HIV infection. This unprecedented success has turned HIV infection into a manageable chronic disease. The increased survival of people living with HIV is, however, shadowed by a high burden of aging-related comorbidities. The pathogenic basis underlying this excess of co-morbid conditions is most likely a persistent inflammatory and immune activation state, despite an optimal control of HIV replication, which in turn has largely been attributed to bacterial or bacterial products translocation from the gut. Area covered: This review is focused on the relationship between cART and the chronic inflammatory and immune activation status in otherwise virologically well-controlled people living with HIV (PLWH). Particular focus will be placed on the differences, if any, between distinct cART modalities, with emphasis on less-drug cART regimens, and especially on dual therapies. Expert opinion: Research to address the increased inflammatory and immune activation status of cART-treated, HIV-infected patients, should focus on adjuvant means of therapy, rather than on the cART regime itself. With current antiretrovirals, no difference between dual and triple regimens has been demonstrated, provided that virological and immunological outcomes be non-inferior.

Summary Background Factors affecting outcomes of SARS-CoV-2 infection in people living with HIV are unclear. We assessed the factors associated with SARS-CoV-2 diagnosis and severe outcomes among people living with HIV. Methods We did a retrospective cohort study using data from the PISCIS cohort of people with HIV in Catalonia (Spain) between March 1 and Dec 15, 2020. We linked PISCIS data with integrated health-care, clinical, and surveillance registries through the Public Data Analysis for Health Research and Innovation Program of Catalonia (PADRIS) to obtain data on SARS-CoV-2 diagnosis, chronic comorbidities, as well as clinical and mortality outcomes. Participants were aged at least 16 years in care at 16 hospitals in Catalonia. Factors associated with SARS-CoV-2 diagnoses and severe outcomes were assessed using univariable and multivariable Cox regression models. We estimated the effect of immunosuppression on severe outcomes (hospital admission for >24 h with dyspnoea, tachypnoea, hypoxaemia, asphyxia, or hyperventilation; or death) using Kaplan-Meier survival analysis. Findings We linked 20 847 (72·8%) of 28 666 participants in the PISCIS cohort with PADRIS data; 13 142 people had HIV. 749 (5·7%) people with HIV were diagnosed with SARS-CoV-2: their median age was 43·5 years (IQR 37·0–52·7), 131 (17·5%) were female, and 618 (82·5%) were male. 103 people with HIV (13·8%) were hospitalised, seven (0·9%) admitted to intensive care, and 13 (1·7%) died. SARS-CoV-2 diagnosis was more common among migrants (adjusted hazard ratio 1·55, 95% CI 1·31–1·83), men who have sex with men (1·42, 1·09–1·86), and those with four or more chronic comorbidities (1·46, 1·09–1·97). Age at least 75 years (5·2, 1·8–15·3), non-Spanish origin (2·1, 1·3–3·4), and neuropsychiatric (1·69, 1·07–2·69), autoimmune disease (1·92, 1·14–3·23), respiratory disease (1·84, 1·09–3·09), and metabolic disease (2·59, 1·59–4·23) chronic comorbidities were associated with increased risk of severe outcomes. A Kaplan-Meier estimator showed differences in the risk of severe outcomes according to CD4 cell count in patients with detectable HIV RNA (p=0·039) but no differences were observed in patients with undetectable HIV RNA (p=0·15). Interpretation People living with HIV with detectable HIV viraemia, chronic comorbidities, and some subpopulations could be at increased risk of severe outcomes from COVID-19. These groups should be prioritised in clinical management and SARS-CoV-2 vaccination programmes. Funding Fundacio "la Caixa". Translations For the Catalan, Spanish and Russian translations of the Summary see Supplementary Materials section.

Teràpia antiretroviral; Diagnòstic i gestió del VIH; Teràpia amb inhibidors de la proteasa Terapia antirretroviral; Diagnóstico y gestión del VIH; Terapia con inhibidores de la proteasa Antiretroviral therapy; HIV diagnosis and management; Protease inhibitor therapy Background Since 1996, the standard of care (SOC) therapy for HIV treatment has consisted of a backbone of two nucleoside analogue reverse transcriptase inhibitors (NRTI) paired with a third agent. Use of two-drug combinations (2DC) has been considered for selected patients to avoid toxicities associated with the use of NRTIs. This study aimed to compare the real-world outcomes of integrase strand transfer inhibitor (INSTI)-containing triple therapy (TT) to dolutegravir- (DTG) and/or boosted protease inhibitor (bPI)-based 2DC in a large Spanish cohort of HIV patients. Methods A retrospective analysis was performed using data from the VACH cohort, a prospective multicentre Spanish cohort of adult HIV patients. All treatment experienced patients initiating a TT of an INSTI combined with two NRTIs or a 2DC-containing DTG and/or a bPI between 01/01/2012 and 01/06/2017 were included. The unit of analysis was patient-regimens. The overall sample analysis was complemented with two sub-analyses. The first sub-analysis focused on patients treated with a backbone plus DTG compared to those treated with DTG+ one other antiretroviral. The second sub-analysis focused on patients with HIV RNA

Nuclear magnetic resonance (NMR)-based advanced lipoprotein tests have demonstrated that LDL and HDL particle numbers (LDL-P and HDL-P) are more powerful cardiovascular (CV) risk biomarkers than conventional cholesterol markers. Of interest, in people living with HIV (PLHIV), predictors of preclinical atherosclerosis and vascular dysfunction may be associated with impaired immune function. We previously stated that immunological non-responders (INR) were at higher CV risk than immunological responders (IR) before starting antiretroviral therapy (ART). Using Liposcale® tests, we characterized the lipoprotein profile from the same cohort of PLHIV at month 12 and month 36 after starting ART, intending to explore what happened with these indicators of CV risk during viral suppression. ART initiation dissipates the differences in lipoprotein-based CV risk markers between INR and IR, and only an increase in the number of HDL-P was found in INR + IR when compared to controls (p = 0.047). Interestingly, CD4+ T-cell counts negatively correlated with medium HDL-P concentrations at month 12 in all individuals (ρ = -0.335, p = 0.003). Longitudinal analyses showed an important increase in LDL-P and HDL-P at month 36 when compared to baseline values in both IR and INR. A proper balance between a proatherogenic and atherogenic environment may be related to the reconstitution of CD4+ T-cell count in PLHIV., This research was funded by the Fondo de Investigacion Sanitaria [PI16/00503, PI19/01337 and PI20/00326]-ISCIII-FEDER (co-funded by the European Regional Development Fund/European Social Fund; “A way to make Europe”/”Investing in your future”); Programa de Suport als Grups de Recerca AGAUR (2017SGR948), the SPANISH AIDS Research Network [RD16/0025/0006]-ISCIII-FEDER (Spain) and the Centro de Investigación Biomédica en Red de Enfermedades Infecciosas-ISCIII (CIBERINFEC) [CB21/13/00020], Madrid, Spain. JM is supported by the Universitat Rovira I Virgili under grant agreement “2019PMF-PIPF-18”, through the call “Martí Franquès Research Fellowship Programme”. FV is supported by grants from the Programa de Intensificación de Investigadores (INT20/00031)-ISCIII and by “Premi a la Trajectòria Investigadora dels Hospitals de l’ICS 2018”. AR is supported by a grant from IISPV through the project “2019/IISPV/05” (Boosting Young Talent), by GeSIDA through the “III Premio para Jóvenes Investigadores 2019” and by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CP19/00146” through the Miguel Servet Program.

Although the starting event in COVID-19 is a viral infection some patients present with an over-exuberant inflammatory response, leading to acute lung injury (ALI) and adult respiratory distress syndrome (ARDS). Since IL-6 plays a critical role in the inflammatory response, we assessed the efficacy and safety of tocilizumab (TCZ) in this single-centre, observational study in all Covid-19 in-patient with a proven SARS-CoV-2 rapidly progressing infection to prevent ALI and ARDS. 104 patients with COVID-19 treated with TCZ had a lower mortality rate (5·8%) compared with the regional mortality rate (11%), hospitalized patient's mortality (10%), and slightly lower than hospitalized patients treated with our standard of care alone (6%). We found that TCZ rapidly decreased acute phase reactants, ferritin and liver release of proteins. D-Dimer decreased slowly. We did not observe specific safety concerns. Early administration of IL6-R antagonists in COVID-19 patients with impending hyperinflammatory response, may be safe and effective treatment to prevent, ICU admission and further complications.

Estudios de cohortes; VIH; Pérdida de seguimiento Cohort studies; HIV; Lost to follow-up Estudis de cohorts; VIH; Pèrdua del seguiment Background Despite remarkable achievements in antiretroviral therapy (ART), losses to follow-up (LTFU) might prevent the long-term success of HIV treatment and might delay the achievement of the 90–90-90 objectives. This scoping review is aimed at the description and analysis of the strategies used in high-income countries to reengage LTFU in HIV care, their implementation and impact. Methods A scoping review was done following Arksey & O′Malley’s methodological framework and recommendations from Joanna Briggs Institute. Peer reviewed articles were searched for in Pubmed, Scopus and Web of Science; and grey literature was searched for in Google and other sources of information. Documents were charted according to the information presented on LTFU, the reengagement procedures used in HIV units in high-income countries, published during the last 15 years. In addition, bibliographies of chosen articles were reviewed for additional articles. Results Twenty-eight documents were finally included, over 80% of them published in the United States later than 2015. Database searches, phone calls and/or mail contacts were the most common strategies used to locate and track LTFU, while motivational interviews and strengths-based techniques were used most often during reengagement visits. Outcomes like tracing activities efficacy, rates of reengagement and viral load reduction were reported as outcome measures. Conclusions This review shows a recent and growing trend in developing and implementing patient reengagement strategies in HIV care. However, most of these strategies have been implemented in the United States and little information is available for other high-income countries. The procedures used to trace and contact LTFU are similar across reviewed studies, but their impact and sustainability are widely different depending on the country studied. The project leading to these results (PISCIS Cohort) has received funding from “la Caixa” Banking Foundation under the project code LCF/PR/PR17/51120008. This work is supported by a grant from the Foundation Marató TV3 (project code 239/C/2018) aimed at the analysis of the LTFU patients of the PISCIS Cohort. The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Background Antiretroviral therapy has significantly improved prognosis in treatment against HIV infection, however, prolonged exposure is associated to cardiovascular diseases, lipodystrophy, type 2 diabetes, insulin resistance, metabolic alteration, as obesity which includes the accumulation of oxidative stress in adipose tissue. FGF21 is a peptide hormone that is known to regulate glucose and lipid metabolism. FGF21 is expressed and secreted primarily in the liver and adipose tissue, promoting oxidation of glucose/fatty acids and insulin sensitivity. Alterations in FGF21 may be associated with the development of insulin resistance, metabolic syndrome and cardiovascular disease. We hypothesized that FGF21 protein levels are associated with metabolic abnormalities, placing special attention to the alterations in relation to the concurrence of overweight/obesity in people living with HIV (PLWH). Design Serum FGF21 was analyzed in 241 subjects, 160 PLWH and 81 unrelated HIV-uninfected subjects as a control group. Clinical records were consulted to obtain CD4+ cell counting and number of viral RNA copies. Serum FGF21 levels were tested for correlation with anthropometric and metabolic parameters; glucose, cholesterol, HDL, LDL, VLDL, triglycerides, insulin and indexes of atherogenesis and insulin resistance (HOMA). Results The participants were classified into four groups: (i) PLWH with normal weight, (ii) PLWH with overweight/obesity, (iii) HIV-uninfected with normal weight, and (iv) HIV-uninfected with overweight/obesity. Insulin levels were higher in normal-weight PLWH than in the HIV-uninfected group but not statistically significant, however, for the overweight/obesity PLWH group, insulin levels were significantly higher in comparison with the other three groups (p In HIV-infected subjects, FGF21 levels showed a strong positive correlation with triglycerides, insulin levels and insulin resistance with a p-value Conclusion Insulin resistance and FGF21 elevations were observed in overweight-obese PLWH. FGF21 elevation could be viewed as a compensation mechanism as, in the control group, FGF21 correlations appeared to be confined to weight and waist circumference. This can be explained based on the action of FGF21 promoting the uptake of glucose in adipose tissue. In PLWH, FGF21 was low, possibly as a result of a change in adiposity leading to a metabolic disruption.

AimThis study’s objective was to assess the risk of severe in-hospital complications of patients admitted for COVID-19 and diabetes mellitus (DM).DesignThis was a cross-sectional study.SettingsWe used pseudonymised medical record data provided by six general hospitals from the HM Hospitales group in Spain.Outcome measuresMultiple logistic regression analyses were used to identify variables associated with mortality and the composite of mortality or invasive mechanical ventilation (IMV) in the overall population, and stratified for the presence or absence of DM. Spline analysis was conducted on the entire population to investigate the relationship between glucose levels at admission and outcomes.ResultsOverall, 1621 individuals without DM and 448 with DM were identified in the database. Patients with DM were on average 5.1 years older than those without. The overall in-hospital mortality was 18.6% (N=301), and was higher among patients with DM than those without (26.3% vs 11.3%; p65 years, male sex and pre-existing chronic kidney disease. We observed a non-linear relationship between blood glucose levels at admission and risk of in-hospital mortality and death or IMV. The highest probability for each outcome (around 50%) was at random glucose of around 550 mg/dL (30.6 mmol/L), and the risks flattened above this value.ConclusionThe results confirm the high burden associated with DM in patients hospitalised with COVID-19 infection, particularly among men, the elderly and those with impaired kidney function. Moreover, hyperglycaemia on admission was strongly associated with poor outcomes, suggesting that personalised optimisation could help to improve outcome during the hospital stay.

Objective: We aimed to assess differences in patients' profiles in the first two surges of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in Barcelona, Spain. Methods: We prospectively collected data from all adult patients with SARS-CoV-2 infection diagnosed at the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. All the patients were diagnosed through nasopharyngeal swab PCR. The first surge spanned from 1st March to 13th August 2020, while surge two spanned from 14th August to 8th December 2020. Results: There were 2479 and 852 patients with microbiologically proven SARS-CoV-2 infection in surges one and two, respectively. Patients from surge two were significantly younger (median age 52 (IQR 35) versus 59 (40) years, respectively, p < 0.001), had fewer comorbidities (379/852, 44.5% versus 1237/2479, 49.9%, p 0.007), and there was a shorter interval between onset of symptoms and diagnosis (median 3 (5) versus 4 (5) days, p < 0.001). All-cause in-hospital mortality significantly decreased for both the whole population (24/852, 2.8% versus 218/2479, 8.8%, p < 0.001) and hospitalized patients (20/302, 6.6% versus 206/1570,13.1%, p 0.012). At adjusted logistic regression analysis, predictors of in-hospital mortality were older age (per year, adjusted odds ratio (aOR) 1.079, 95%CI 1.063-1.094), male sex (aOR 1.476, 95%CI 1.079-2.018), having comorbidities (aOR 1.414, 95%CI 0.934-2.141), ICU admission (aOR 3.812, 95%CI 1.875-7.751), mechanical ventilation (aOR 2.076, 95%CI 0.968-4.454), and coronavirus disease 2019 (COVID-19) during surge one (with respect to surge two) (aOR 2.176, 95%CI 1.286-3.680). Conclusions: First-wave SARS-CoV-2-infected patients had a more than two-fold higher in-hospital mortality than second-wave patients. The causes are likely multifactorial. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

REIPI-SEIMC COVID-19 group and COVID@HULP group., [Background] The clinical presentation of COVID-19 in patients admitted to hospital is heterogeneous. We aimed to determine whether clinical phenotypes of patients with COVID-19 can be derived from clinical data, to assess the reproducibility of these phenotypes and correlation with prognosis, and to derive and validate a simplified probabilistic model for phenotype assignment. Phenotype identification was not primarily intended as a predictive tool for mortality., [Methods] In this study, we used data from two cohorts: the COVID-19@Spain cohort, a retrospective cohort including 4035 consecutive adult patients admitted to 127 hospitals in Spain with COVID-19 between Feb 2 and March 17, 2020, and the COVID-19@HULP cohort, including 2226 consecutive adult patients admitted to a teaching hospital in Madrid between Feb 25 and April 19, 2020. The COVID-19@Spain cohort was divided into a derivation cohort, comprising 2667 randomly selected patients, and an internal validation cohort, comprising the remaining 1368 patients. The COVID-19@HULP cohort was used as an external validation cohort. A probabilistic model for phenotype assignment was derived in the derivation cohort using multinomial logistic regression and validated in the internal validation cohort. The model was also applied to the external validation cohort. 30-day mortality and other prognostic variables were assessed in the derived phenotypes and in the phenotypes assigned by the probabilistic model., [Findings] Three distinct phenotypes were derived in the derivation cohort (n=2667)—phenotype A (516 [19%] patients), phenotype B (1955 [73%]) and phenotype C (196 [7%])—and reproduced in the internal validation cohort (n=1368)—phenotype A (233 [17%] patients), phenotype B (1019 [74%]), and phenotype C (116 [8%]). Patients with phenotype A were younger, were less frequently male, had mild viral symptoms, and had normal inflammatory parameters. Patients with phenotype B included more patients with obesity, lymphocytopenia, and moderately elevated inflammatory parameters. Patients with phenotype C included older patients with more comorbidities and even higher inflammatory parameters than phenotype B. We developed a simplified probabilistic model (validated in the internal validation cohort) for phenotype assignment, including 16 variables. In the derivation cohort, 30-day mortality rates were 2·5% (95% CI 1·4–4·3) for patients with phenotype A, 30·5% (28·5–32·6) for patients with phenotype B, and 60·7% (53·7–67·2) for patients with phenotype C (log-rank test p, [Interpretation] Patients admitted to hospital with COVID-19 can be classified into three phenotypes that correlate with mortality. We developed and validated a simplified tool for the probabilistic assignment of patients into phenotypes. These results might help to better classify patients for clinical management, but the pathophysiological mechanisms of the phenotypes must be investigated., [Funding] Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA., Funding: Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA.

Background Pre-exposure prophylaxis (PrEP) is a promising strategy to break COVID-19 transmission. Although hydroxychloroquine was evaluated for treatment and post-exposure prophylaxis, it is not evaluated for COVID-19 PrEP yet. The aim of this study was to evaluate the efficacy and safety of PrEP with hydroxychloroquine against placebo in healthcare workers at high risk of SARS-CoV-2 infection during an epidemic period. Methods We conducted a double-blind placebo-controlled randomized clinical trial in three hospitals in Barcelona, Spain. From 350 adult healthcare workers screened, we included 269 participants with no active or past SARS-CoV-2 infection (determined by a negative nasopharyngeal SARS-CoV-2 PCR and a negative serology against SARS-CoV-2). Participants allocated in the intervention arm (PrEP) received 400 mg of hydroxychloroquine daily for the first four consecutive days and subsequently, 400 mg weekly during the study period. Participants in the control group followed the same treatment schedule with placebo tablets. Results 52.8% (142/269) of participants were in the hydroxychloroquine arm and 47.2% (127/269) in the placebo arm. Given the national epidemic incidence decay, only one participant in each group was diagnosed with COVID-19. The trial was stopped due to futility and our study design was deemed underpowered to evaluate any benefit regarding PrEP efficacy. Both groups showed a similar proportion of participants experiencing at least one adverse event (AE) (p=0.548). No serious AEs were reported. Almost all AEs (96.4%, 106/110) were mild. Only mild gastrointestinal symptoms were significantly higher in the hydroxychloroquine arm compared to the placebo arm (27.4% (39/142) vs 15.7% (20/127), p=0.041). Conclusions Although the efficacy of PrEP with hydroxychloroquine for preventing COVID-19 could not be evaluated, our study showed that PrEP with hydroxychloroquine at low doses is safe. Trial registration ClinicalTrials.govNCT04331834. Registered on April 2, 2020.

Blocking IL-6 pathways with sarilumab, a fully human anti-IL-6R antagonist may potentially curb the inflammatory storm of SARS-CoV2. In the present emergency scenario, we used "off-label"" sarilumab in 5 elderly patients in life-threatening condition not candidates to further active measures. We suggest that sarilumab can modulate severe COVID-19-associated Cytokine Release Syndrome."

Aim: The study aim was to assess the association of vitamin D supplementation before hospital admission and severe outcomes in subjects admitted for COVID-19.Methods: We performed a cross-sectional analysis of pseudonymised medical record data from subjects admitted to the Hospital de la Santa Creu i Sant Pau (Barcelona, Spain) for COVID-19 during March and April 2020. The composite primary study outcome was defined as death and/or invasive mechanical ventilation (IMV). Association between risk factors and study outcomes was evaluated by bivariate analysis, followed by logistic regression analysis.Results: In total, 1,267 persons were hospitalised during the observation period. Overall, 14.9% of the subjects were on active vitamin D supplementation treatment before admission. The subjects in the vitamin D group were significantly older than subjects without vitamin D supplementation. We observed higher rates of the primary outcome (death and/or IMV) among the persons with previous use of vitamin D (30.1 vs. 22.9% in those not receiving treatment). In the bivariate analysis, previous use of vitamin D was positively associated with death and/or IMV [odds ratio (OR): 1.45 95% CI: 1.03; 2.04]; however, after adjustment for other risk factors this association disappeared (OR: 1.09 95%CI: 0.65; 1.81).Conclusion: We did not find an association between vitamin D supplementation before hospital admission and death and/or IMV in subjects admitted for COVID-19. The age and the burden of age-associated comorbidities were independently associated with the in-hospital events.

Altres ajuts: Gilead Sciences (GLD14/293, GLD17/00299, GLD19/00008) Altres ajuts: European Regional Development Fund (FEDER) Introduction: When coronavirus infectious disease-2019 (COVID-19) blew up, ill-fated auguries on the collision between COVID-19 and the human immunodeficiency virus (HIV) epidemics loomed. Areas covered: Data from observational studies suggest similar incidence attacks of SARS-CoV-2 infection in people living with HIV (PLWH) and HIV-uninfected populations. The mortality rate of COVID-19 is similar in both populations too. The authors discuss the role of combination antiretroviral therapy (cART) in preventing infection or reducing COVID-19 severity. They also discuss the pharmacological interventions for COVID-19 in PLWH. Expert opinion: Management of COVID-19 in PLWH is no different from the general population. It should be based on careful supportive care, emphasizing lung-protective ventilation, and wise pharmacological interventions. The antiviral drug remdesivir and dexamethasone are the only pharmacological interventions with clinical benefit for COVID-19, whereas anticoagulation may prevent thrombotic complications. The experience with using these drugs in PLWH is limited, which prevents from rendering well-founded conclusions. Until more data on COVID-19 in PLWH become available, the best weapons within our reach are sound supportive care and sensible use of RDV and dexamethasone, bearing in mind the potential for drug-drug interactions of most corticosteroids and antiretroviral drugs.

Summary Background Simplified antiretroviral therapy (ART) regimens are desirable for people with HIV. We investigated the efficacy and safety of switching from triple ART to dual dolutegravir plus lamivudine therapy. Methods DOLAM is a phase 4, randomised, open-label, non-inferiority trial, done at six HIV clinics in Catalonia, Spain. Adults with HIV-1 receiving a triple ART regimen, aged 18 years or older, with virological suppression, a CD4 nadir of at least 200 cells per μL, who were HBsAg-negative, and without previous viral failure or resistance mutations to study drugs were eligible. Participants underwent computer-generated randomisation, stratified by the class of the third drug, and were assigned (1:1) to switch to oral dolutegravir 50 mg and lamivudine 300 mg once daily or to continue triple ART for 48 weeks. The primary endpoint was the proportion of people with an HIV RNA value of at least 50 copies per mL at week 48 (US Food and Drug Administration snapshot algorithm, 8% non-inferiority margin). Both the primary and safety outcomes were evaluated in the intention-to-treat exposed population. The study is completed and was registered with EudraCT 201500027435. Findings Between July 7, 2015, and Oct 31, 2018, 265 participants were randomly assigned to switch to dolutegravir plus lamivudine (n=131) or to maintain triple ART (n=134) and all received at least one dose. Nine (7%) participants in the dual therapy group and ten (7%) in the triple therapy group were excluded before 48 weeks, mostly due to treatment discontinuations or virological failure. Participants were predominantly male (116 [87%] of 134 in the triple ART group and 111 [85%] of 131 in the dolutegravir plus lamivudine group). The difference in the proportion of participants with HIV RNA values of at least 50 copies per mL at 48 weeks between the dual therapy group (three [2%] of 131) and triple therapy group (two [1%] of 134) was 0·8 percentage points (95% CI –3·3 to 5·2), showing non-inferiority of dolutegravir plus lamivudine dual therapy compared with triple ART. 73 (56%) of 131 participants allocated to dual therapy had 150 adverse effects, compared with 78 (58%) of 134 participants allocated to triple therapy who also had 150 adverse events (p=0·68). Drug discontinuation due to adverse effects occurred in four people in the triple therapy group and three people in the dual therapy group. Interpretation Our findings show the efficacy and safety of dolutegravir plus lamivudine as a simplified therapy switch option for selected people with HIV with virological suppression on triple ART. Funding Instituto de Salud Carlos III, Red de Investigacion en Sida, and ViiV Healthcare.

Introduction: Cardiovascular disease (CVD) continues to be an essential cause of morbidity and mortality among people living with human immunodeficiency virus infection (PLWH). Since the bulk of ca...

© 2020 The Authors., [Background]: The underlying mechanisms of incomplete immune reconstitution in treated HIV-positive patients are very complex and may be multifactorial, but perturbation of chemokine secretion could play a key role in CD4+ T-cell turnover., [Methods]: We evaluated the circulating baseline and 48-week follow-up concentrations of SDF-1/CXCL12, fractalkine/CX3CL1, MCP-1/CCL2, MIP-α/CCL3, MIP-β/CCL4 and RANTES/CCL5, and we estimated their association with CXCL12, CX3CR1, CCR2, CCL5 and CCR5 single nucleotide polymorphisms (SNPs) to investigate multiple chemokine-chemokine receptor signatures associated with immune dysregulation preceding poor immune recovery., [Findings]: The circulating concentrations and gene expression patterns of SDF-1/CXCL12 (CXCL12 rs1801157) and MCP-1/CCL2 (CCR2 rs1799864_814) were associated with immune recovery status. CCR2 rs1799864_814 and CCR5 rs333_814 (Δ32) determine the baseline plasma RANTES and MIP-α concentrations, respectively, in participants with poor immune response., [Interpretation]: SDF-1/CXCL12 and MCP-1/CCL2 could be considered prognostic markers of immune failure despite suppressive antiretroviral therapy. The strong linkage disequilibrium (LD) between CCR2 rs1799864_814 and CCR5 rs1800024 indicated that the alleles of each gene are inherited together more often than would be expected by chance., This work was supported by the Fondo de Investigacion Sanitaria [PI10/02635, PI13/0796, PI14/ 0063, PI14/0700, PI16/00503, PI17/0420, PI17/0498, PI18/01216, PI19/01337 and PI20/00326]-ISCIII-FEDER (co-funded by the European Regional Development Fund/European Social Fund; “A way to make Europe”/”Investing in your future”); Programa de Suport als Grups de Recerca AGAUR (2014SGR250, 2017SGR948); Gilead Fellowship Program GLD14/293and GLD19/00,008; and The SPANISH AIDS Research Network [RD12/0017/0005, RD16/0025/0002, RD16/0025/0006, RD16/0025/0019]-ISCIII-FEDER (Spain). FV is supported by grants from the Programa de Intensificación de Investigadores (INT20/00031)-ISCIII. PD is supported by grants from the Programa de Intensificación de Investigadores (INT19/00036)-ISCIII. YMP is supported by the Servicio Andaluz de Salud through Programa Nicolás Monardes (C-0013/17). JVG is supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “FI19/00330″ through the program “Contratos Predoctorales de Formación en Investigación en Salud”. EY is supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “FI20/00118″ through the program “Contratos Predoctorales de Formación en Investigación en Salud”. LR is supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CD20/00105″ through the program “Sara Borrell”. AR is supported by a grant from the Acció Instrumental d'incorporació de científics i tecnòòlegs (PERIS SLT002/16/00,101), Departament de Salut, Generalitat de Catalunya, by IISPV through the project “2019/IISPV/05″ (Boosting Young Talent), by GeSIDA through the "III Premio para Jóvenes Investigadores 2019″ and by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CP19/00,146″ through the Miguel Servet Program.

Linezolid has good penetration to the meninges and could be an alternative for treatment ofRetrospective multicenter cohort study of 26 adults treated with linezolid, derived from a cohort of 350 cases ofThere were 15 males (58%) and mean age was 47.3 years. Meningitis was postoperative in 21 (81%) patients. The infection was nosocomial in 23 (88%) cases, and caused by methicillin-resistantLinezolid appears to be effective and safe for therapy of

Background Switching from boosted PIs to dolutegravir in virologically suppressed HIV-infected patients with high cardiovascular risk significantly decreased total cholesterol and other proatherogenic lipid fractions at 48 weeks. The impact of this strategy on subclinical cardiovascular disease is unknown. Methods NEAT022 is a European, multicentre, open-label, randomized, non-inferiority trial. HIV-infected adults aged >50 years or with a Framingham score >10% were eligible if plasma HIV RNA was 24 weeks on a boosted PI-based regimen. Patients were randomized 1:1 to switch from boosted PIs to dolutegravir or to continue on boosted PIs. Common carotid arteries intima–media thickness (CIMT) and pulse wave velocity (PWV) were measured following a standardized protocol in a subgroup of NEAT022 study participants at baseline and at Week 48. Results One hundred and fifty-six patients participated in the ultrasonography and arterial stiffness substudies, respectively. In each substudy, population characteristics did not differ between arms and matched those of the main study. At 48 weeks, patients who switched to dolutegravir had lower mean progression of both right (+4 versus +14.6 μm) and left (−6.1 versus +1.6 μm) CIMT and also a smaller increase in mean PWV (+0.18 versus +0.39 m/s) than patients continuing on boosted PIs, although differences were not statistically significant. CIMT trends were consistent across Framingham score, age and country. Inconsistent effects were seen in arterial stiffness. Conclusions Relative to continuing on boosted PIs, switching to dolutegravir in virologically suppressed patients with high cardiovascular risk showed consistent favourable although non-significant trends on CIMT progression at 48 weeks.

It is not well understood why diabetic individuals are more prone to develop severe COVID-19. To this, we here established a human kidney organoid model promoting early hallmarks of diabetic kidney disease development. Upon SARS-CoV-2 infection, diabetic-like kidney organoids exhibited higher viral loads compared with their control counterparts. Genetic deletion of the angiotensin-converting enzyme 2 (ACE2) in kidney organoids under control or diabetic-like conditions prevented viral detection. Moreover, cells isolated from kidney biopsies from diabetic patients exhibited altered mitochondrial respiration and enhanced glycolysis, resulting in higher SARS-CoV-2 infections compared with non-diabetic cells. Conversely, the exposure of patient cells to dichloroacetate (DCA), an inhibitor of aerobic glycolysis, resulted in reduced SARS-CoV-2 infections. Our results provide insights into the identification of diabetic-induced metabolic programming in the kidney as a critical event increasing SARS-CoV-2 infection susceptibility, opening the door to the identification of new interventions in COVID-19 pathogenesis targeting energy metabolism.

Objectives: To analyse lipid changes and tolerability in a cohort of HIV-infected patients who switched their anti- retroviral regimens to rilpivirine/emtricitabine/tenofovir (RPV/FTC/TDF) in a real-world setting. Methods: PRO-STR is a 48 week prospective observational post-authorization study in 25 hospitals. Patients with a viral load

This article belongs to the Special Issue Adipokines in Health and Diseases., A significant proportion of people living with HIV (PLHIV) who successfully achieve virological suppression fail to recover CD4+ T-cell counts. Since adipose tissue has been discovered as a key immune organ, this study aimed to assess the role of adipokines in the HIV immunodiscordant response. This is a multicenter prospective study including 221 PLHIV starting the first antiretroviral therapy (ART) and classified according to baseline CD4+ T-cell counts/µL (controls > 200 cells/µL and cases ≤ 200 cells/µL). Immune failure recovery was considered when cases did not reach more than 250 CD4+ T cells/µL at 144 weeks (immunological nonresponders, INR). Circulating adipokine concentrations were longitudinally measured using enzyme-linked immunosorbent assays. At baseline, apelin receptor (APLNR) and zinc-alpha-2-glycoprotein (ZAG) concentrations were significantly lower in INRs than in immunological responders (p = 0.043 and p = 0.034), and they remained lower during all ART follow-up visits (p = 0.044 and p = 0.028 for APLNR, p = 0.038 and p = 0.010 for ZAG, at 48 and 144 weeks, respectively). ZAG levels positively correlated with retinol-binding protein 4 (RBP4) levels (p < 0.01), and low circulating RBP4 concentrations were related to a low CD4+ T-cell gain (p = 0.018 and p = 0.039 at 48 and 144 weeks, respectively). Multiple regression adjusted for clinical variables and adipokine concentrations confirmed both low APLNR and RBP4 as independent predictors for CD4+ T cells at 144 weeks (p < 0.001). In conclusion, low APLNR and RBP4 concentrations were associated with poor immune recovery in treated PLHIV and could be considered predictive biomarkers of a discordant immunological response., This research was funded by the Fondo de Investigacion Sanitaria (PI16/00503, PI18/01216, PI19/01337, and PI20/00326)-ISCIII-FEDER (co-funded by the European Regional Development Fund/European Social Fund; “A way to make Europe”/”Investing in your future”); Programa de Suport als Grups de Recerca AGAUR (2017SGR948), the SPANISH AIDS Research Network (RD12/0017/0005, RD12/0025/0001, RD16/0025/0006)-ISCIII-FEDER (Spain) and the Centro de Investigación Biomédica en Red de Enfermedades Infecciosas-ISCIII (CIBERINFEC) (CB21/13/00020), Madrid, Spain. E.Y. is supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “FI20/00118” through the program “Contratos Predoctorales de Formación en Investigación en Salud”. Y.M.P. is supported by Nicolás Monarde from the Consejería de Salud del Servicio Andaluz de Salud (C-0013-2017). F.V. is supported by grants from the Programa de Intensificación de Investigadores (INT20/00031)-ISCIII and by “Premi a la Trajectòria Investigadora dels Hospitals de l’ICS 2018”. A.R. is supported by a grant from IISPV through the project “2019/IISPV/05” (Boosting Young Talent), by GeSIDA through the “III Premio para Jóvenes Investigadores 2019”, and by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CP19/00146” through the Miguel Servet Program.

Altres ajuts: GLD13/00168 Altres ajuts: GLD14/293 Altres ajuts: PERIS/SLT002-16-00101 Poor immunological recovery in treated HIV-infected patients is associated with greater morbidity and mortality. To date, predictive biomarkers of this incomplete immune reconstitution have not been established. We aimed to identify a baseline metabolomic signature associated with a poor immunological recovery after antiretroviral therapy (ART) to envisage the underlying mechanistic pathways that influence the treatment response. This was a multicentre, prospective cohort study in ART-naive and a pre-ART low nadir (

Supplemental Digital Content is available in the text, Objective: To compare the efficacy, safety, and impact on lipid fractions of switching from a ritonavir-boosted protease inhibitor (PI/r) to a dolutegravir (DTG) regimen. Methods: HIV type 1-infected adults more than 50 years or with a Framingham score more than 10% were eligible if plasma HIV RNA less than 50 copies per ml for at least 24 weeks while on a PI/r regimen. Patients were randomized to switch to DTG or to remain on PI/r. Primary endpoints were: proportion maintaining HIV RNA less than 50 copies per ml and percentage change from baseline of total cholesterol at week 48. Results: In total, 415 patients (32 sites in six European countries) were randomized: 205 to DTG and 210 to continue PI/r. About 89% were men, 87% more than 50 years, 74% had a Framingham score more than 10%, with a median CD4+ cell count of 617 cells per μl and suppressed viremia for a median of 5 years. At week 48, in the intent-to-treat analysis, treatment success rate was 93.1% in DTG group and 95.2% in PI/r group (difference −2.1%, 95% confidence interval −6.6 to 2.4, noninferiority demonstrated). There were four virological failures with DTG and one with PI/r with no emergent resistance mutations. There was no significant difference in severe adverse events or grade 3 or 4 adverse events or treatment modifying adverse events. Total cholesterol and other lipid fractions (except high-density lipoprotein cholesterol) improved significantly (P < 0.001) in the DTG group regardless of PI/r at baseline. Conclusion: Switching to a DTG regimen in virologically suppressed HIV type 1 patients with high cardiovascular disease risk was noninferior, and significantly improved lipid profiles.

Background: To evaluate long term outcomes in patients maintaining a NVP based regimen for more than 10 years. Materials and methods: Retrospective, multicenter, cohort study including virologically suppressed patients, currently receiving a NVP-based regimen that had been started at least 10 years previously. Demographic, clinical, and analytical variables were recorded. Results: Two hundred and seventy four subjects were included. Median (IQR) follow up was 17.1 (13.8-18.5) years. Dyslipidemia (29.9%), hypertension (11.4%) and diabetes (8%) were the most common reported co-morbidities. After a median of 17 years of follow-up we observed a significant increase in general health markers such as hemoglobin and CD4 cells (all p50

Early in the HIV epidemic, lipodystrophy, characterized by subcutaneous fat loss (lipoatrophy), with or without central fat accumulation (lipohypertrophy), was recognized as a frequent condition among people living with HIV (PLWH) receiving combination antiretroviral therapy. The subsequent identification of thymidine analogue nucleoside reverse transcriptase inhibitors as the cause of lipoatrophy led to the development of newer antiretroviral agents; however, studies have demonstrated continued abnormalities in fat and/or lipid storage in PLWH treated with newer drugs (including integrase inhibitor-based regimens), with fat gain due to restoration to health in antiretroviral therapy-naive PLWH, which is compounded by the rising rates of obesity. The mechanisms of fat alterations in PLWH are complex, multifactorial and not fully understood, although they are known to result in part from the direct effects of HIV proteins and antiretroviral agents on adipocyte health, genetic factors, increased microbial translocation, changes in the adaptive immune milieu after infection, increased tissue inflammation and accelerated fibrosis. Management includes classical lifestyle alterations with a role for pharmacological therapies and surgery in some patients. Continued fat alterations in PLWH will have an important effect on lifespan, healthspan and quality of life as patients age worldwide, highlighting the need to investigate the critical uncertainties regarding pathophysiology, risk factors and management. HIV and antiretroviral therapy-related fat alterations are frequent in people living with HIV and include fat loss, fat gain and obesity. This Primer discusses the changing epidemiology, mechanisms, diagnosis and treatment of these alterations.

Background The combination of boosted darunavir plus rilpivirine, once daily, could be a convenient, effective and well-tolerated two-drug regimen to achieve HIV suppression in HIV-infected patients. Methods Multicentre, retrospective cohort study in nine hospitals in Spain. All HIV-infected subjects starting boosted darunavir plus rilpivirine were included, irrespective of their viral load (VL). The primary objective was the percentage of patients with VL Results Eighty-one of 84 patients reached Week 48. Fifty-nine (70.2%) patients had VL Conclusions The combination of boosted darunavir plus rilpivirine has shown good effectiveness and tolerability in this cohort of pretreated patients with a long-lasting HIV infection, exposure to multiple antiretroviral regimens and prior HIV resistance.

Osteoporosis has become an emerging comorbid condition in people living with HIV (PLWH). The increase in survival and the progressive aging of PLWH will make this complication more frequent in the near future. In addition to the traditional risk factors affecting the general population, factors directly or indirectly associated with HIV infection, including antiretroviral therapy, can increase the risk of osteoporosis. The present article is an executive summary of the document that updates the previous recommendations on the prevention and treatment of osteoporosis in PLWH. This document is intended for all professionals who work in clinical practice in the field of HIV infection. (C) 2017 Elsevier Espana, S.L.U. and Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica. All rights reserved.

A relationship between polymorphisms in genes encoding interleukin 7 (IL-7) and its cellular receptor (IL-7R) and antiretroviral therapy (ART)-associated immune recovery in HIV subjects has been previously reported. However, details of this relationship remain unclear, and the association of these polymorphisms with circulating IL-7/IL-7R levels is scarce. Here, we explored whether IL-7/IL-7R axis was associated with quantitative CD4+ T-cell recovery in HIV-infected subjects. IL-7/IL-7R polymorphisms were assessed by genotyping, and multiple inheritance models were used to estimate both, their association with low pre-ART CD4+ T-cell counts and incomplete immune recovery status after 48 weeks of suppressive ART. Integrated data from genetic variants association and soluble plasma IL-7/IL-7R quantification suggest that IL-7/IL-7R genotype expression could alter the homeostatic balance between soluble and membrane-bound receptors. The haplotype analyses indicates that allele combinations impacts pre-ART circulating CD4+ T-cell counts, immune recovery status and the absolute increment of CD4+ T-cell counts. The knowledge about how IL-7/IL-7R axis is related to quantitative CD4+ T-cell recovery and immune recovery status after initiating ART could be useful regarding T-cell reservoirs investigations in HIV subjects., This work was supported by the Fondo de Investigacion Sanitaria [PI10/02635, PI13/0796, PI14/1693, PI16/00503, PI16/00684, PI19/01337]-ISCIII-FEDER; Programa de Suport als Grups de Recerca AGAUR (2014SGR250, 2017SGR948); Gilead Fellowship Program GLD14/293 and GLD17/00299; The SPANISH AIDS Research Network [RD12/0017/0005, RD16/0025/0002, RD16/0025/0006, RD16/0025/0019, RD16/0025/0020]-ISCIII-FEDER (Spain) and Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (Proyecto de Investigación de Excelencia; CTS2593). FV is supported by grants from the Programa de Intensificación de Investigadores (INT15/226)-ISCIII. YMP and ERM are supported by the Servicio Andaluz de Salud through Programa Nicolás Monardes (C-0013/17 and C-0032/17, respectively). E.R-M was also supported by Programa Miguel Servet ISCIII, FEDER, CPII014/00025. AR is supported by a grant from the Acció Instrumental d’incorporació de científics i tecnòlegs (PERIS SLT002/16/00101), Departament de Salut, Generalitat de Catalunya and Agencia Estatal de Investigación (Acciones de carácter internacional “Europa Investigación”; EUIN2017-89297), Ministry of Economy and Competitiveness. We are also grateful to GESIDA for ‘‘Premio para Jóvenes Investigadores 2019’’ to AR.

Exposure to some antiretroviral drugs, especially integrase strand transfer inhibitors (INsTI)-based combination antiretroviral therapy (cART) has been associated with weight gain in people living with HIV (PLWH) exceeding what would be a "return to health" phenomenon. Notwithstanding the fact that weight gain and obesity are multifactorial, the common epidemiological link in PLWH is INsTI-based cART. Here, we postulate that interference with the melanocortin system (MCS) functioning by INsTI plays an essential role in excess weight gain and obesity in PLWH, similar to disturbances caused by melanocortin receptor (MCR) mutations in the general population and by antipsychotic therapy in psychiatric patients.

Introduction: Drug-drug interactions (DDI) between antiretroviral drugs and drugs for the treatment of metabolic disturbances in people living with human immunodeficiency virus (HIV) (PLWH) have represented a problem of paramount importance in the recent times. The problem has been mainly driven by sharing common metabolizing pathways. This problem has classically been worsened by the frequent use of pharmacokinetic boosters to enhance protease inhibitors and some integrase inhibitors plasma levels. Areas covered: This article focuses on the interactions between antiretroviral drugs and those drugs used to treat metabolic disturbances which frequently appear in PLWH. These include dyslipidemia, diabetes mellitus, hyperuricemia, and finally, drugs for the treatment of overweight and clinical obesity. References from PubMed, Embase, or Web of Science, among others, were reviewed. Expert opinion: The advent of safer drugs, in terms of DDI, in the antiretroviral and the metabolic field,such as non-boosted antiretrovirals and drugs with divergent metabolizing paths. Besides, learning by the caregivers on how to decrease and manage DDI, together with the extensive use of online updated DDI databases, has undoubtedly minimized the problem. The foreseeable increase in the burden of HIV-associated comorbidities and their associated treatments anticipates further complexities in the management of DDI in PLWH.