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1. Accessibility to SARS-CoV-2 swab test during the Covid-19 pandemic: Did age make the difference?

Author

Mauro Di Bari, Stefano Rusconi, Gabriele Pagani, Caterina Trevisan, Stefania Maggi, Raffaele Antonelli Incalzi, Andrea Giacomelli, Federica Prinelli, Fulvio Adorni, Claudio Pedone, Aleksandra Sojic, Marcello Tavio, Sabrina Molinaro, Fabrizio Bianchi, Marianna Noale, and Massimo Galli

Subjects
medicine.medical_specialty, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Ageism, Multimorbidity, COVID-19 diagnostic testing, Health Resources, Logistic regression, Article, NO, COVID-19 diagnostic testing, Ageism, COVID-19 Testing, Diagnostic Tests, Epidemiology, Health care, Pandemic, medicine, Humans, Routine, Medical history, Pandemics, Aged, Diagnostic Tests, Routine, SARS-CoV-2, business.industry, Health Policy, Confounding, Multimorbidity, COVID-19, Test (assessment), Health Resources, business, Demography
Abstract

Although COVID-19 affects older people more severely, health policies during the first wave of the pandemic often prioritized younger individuals. We investigated whether age had influenced the access to a diagnostic test for SARS-CoV-2 infection and whether clinical complexity and healthcare resources availability could have impacted such differences. This work included 126,741 Italian participants in the EPICOVID19 web-based survey, who reported having had contacts with known/suspected COVID-19 cases (epidemiological criterion) and/or COVID-19-like signs/symptoms (clinical criterion) from February to June 2020. Data on sociodemographic, medical history and access to SARS-CoV-2 nasopharyngeal swab (NPS) were collected. Logistic regressions estimated the probability of accessing NPS as a function of age and the possible modifying effect of chronic diseases' number and residential areas in such association. A total of 6136 (4.8%) participants had undergone an NPS. Older participants had lower NPS frequencies than the younger ones when reporting epidemiological (14.9% vs. 8.8%) or both epidemiological and clinical criteria (17.5% vs. 13.7%). After adjustment for potential confounders, including epidemiological and clinical criteria, the chance of NPS access decreased by 29% (OR=0.71, 95%CI:0.63-0.79) in older vs. younger individuals. Such disparity was accentuated in areas with greater healthcare resources. In conclusion, in the first wave of the pandemic, age may have affected the access to COVID-19 diagnostic testing, disadvantaging older people.

Published
2021

2. Five Years With Dolutegravir Plus Lamivudine as a Switch Strategy: Much More Than a Positive Finding

Author

Andrea Giacometti, Gabriella d'Ettorre, Amedeo Capetti, William Gennari, Stefano Rusconi, Gaetana Sterrantino, Andrea Giacomelli, Vanni Borghi, Gianmaria Baldin, Alessandra Latini, Andrea De Vito, Cristina Mussini, Arturo Ciccullo, Simona Di Giambenedetto, Giordano Madeddu, and Maria Vittoria Cossu

Subjects
Male, medicine.medical_specialty, HAART, Anti-HIV Agents, Pyridones, HIV Infections, 3-Ring, Settore MED/17 - MALATTIE INFETTIVE, Piperazines, chemistry.chemical_compound, Heterocyclic Compounds, Interquartile range, Internal medicine, HIV Seropositivity, Oxazines, medicine, Humans, Pharmacology (medical), Survival analysis, Retrospective Studies, business.industry, HIV, Lamivudine, Retrospective cohort study, Middle Aged, dolutegravir, Discontinuation, Regimen, Infectious Diseases, Tolerability, chemistry, Dolutegravir, RNA, Female, business, Heterocyclic Compounds, 3-Ring, medicine.drug
Abstract

BACKGROUND Results from clinical trials and observational studies suggest that dolutegravir plus lamivudine could be an effective and well-tolerated option for simplification in HIV-1-positive patients. We aimed to assess long-time efficacy and safety in our multicenter cohort. METHODS This was a retrospective study enrolling HIV-1-infected, virologically suppressed patients switching to dolutegravir + lamivudine. We performed survival analysis to evaluate time to virological failure (VF, defined by a single HIV-RNA ≥1000 copies/mL or by 2 consecutive HIV-RNA ≥ 50 copies/mL) and treatment discontinuation (defined as the interruption of either 3TC or dolutegravir), assessing predictors via Cox regression analyses. RESULTS Seven-hundred eighty-five patients were considered for the analysis: 554 were men (70.6%), with a median age of 52 years (interquartile range 45-58 years). Estimated probabilities of maintaining virological suppression at weeks 96, 144, and 240 were 97.7% (SD ±0.6), 96.9% (SD ±0.8), and 96.4% (SD ±0.9), respectively. A non-B HIV subtype (P = 0.014) and a previous VF (P = 0.037) resulted predictors of VF. We did not observe differences in probability of VF in people living with HIV with an M184V resistance mutation (P = 0.689); however, in a deeper analysis, M184V mutation was a predictor of VF (P = 0.038) in patients with time of virological suppression

Published
2021

3. Enhancing care for people living with HIV: current and future monitoring approaches

Author

Antonella Cingolani, Giordano Madeddu, Silvia Nozza, Stefano Rusconi, Renato Maserati, Alessandra Bandera, Paolo Maggi, Giulia Marchetti, Miriam Lichtner, Andrea Calcagno, Maurizio Zazzi, Nicola Gianotti, Sergio Lo Caputo, Marco Borderi, Anna Maria Cattelan, Antonio Di Biagio, Franco Maggiolo, Stefano Bonora, Maggiolo, F, Bandera, A, Bonora, S, Borderi, M, Calcagno, A, Cattelan, A, Cingolani, A, Gianotti, N, Lichtner, M, Lo Caputo, S, Madeddu, G, Maggi, P, Marchetti, Gc, Maserati, R, Nozza, S, Rusconi, S, Zazzi, M, and Di Biagio, A

Subjects
0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Anti-HIV Agents, antiretroviral therapy, 030106 microbiology, Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, surrogate markers, Microbiology, 03 medical and health sciences, 0302 clinical medicine, Quality of life (healthcare), Virology, HIV, patient Related Outcomes (PROs), surrogate endpoints, Humans, Medicine, 030212 general & internal medicine, Meaning (existential), Intensive care medicine, business.industry, Outcome measures, Viral Load, Antiretroviral therapy, CD4 Lymphocyte Count, Clinical Practice, Infectious Diseases, DNA, Viral, HIV-1, Quality of Life, Patient-reported outcome, business, Viral load
Abstract

Introduction Antiretroviral therapy (ART) is the most significant advance in the medical management of HIV-1 infection. Given the fact that HIV cannot be eradicated from the body, ART has to be indefinitely maintained. New approaches need to be defined for monitoring HIV-infected individuals (PLWHIV), including clinical, virologic, immunological parameters and also ways to collect individual points of view and quality of life. Areas covered We discuss which tests may be used to improve the management of PLWHIV and respond to a comprehensive health demand. Expert opinion Viral load and CD4 counts are well-validated outcome measures and we still need them, but they do not completely depict the health status of PLWHIV. We need to better understand and to apply to clinical practice what happens in sanctuaries, what is the role of HIV DNA, what is the meaning of low-level viremia. Most of these questions do not yet have a definitive response. Further, we need to understand how to modify these variables in order to improve outcomes. Similar points may be raised for immunological measures and for tests exploring the tolerability of drugs. The goal must be the evolution from a viro/immunologic-based to a comprehensive quality-of-health-based evaluation of PLWHIV.

Published
2020

4. Circulating endothelial progenitors are increased in COVID‐19 patients and correlate with SARS‐CoV‐2 RNA in severe cases

Author

Patrizia Mancuso, Luca Gusso, Antonio Gidaro, Francesco Bertolini, Jessica Quarna, Stefano Rusconi, Andrea Giacomelli, Paola Cremonesi, Sonia Caccia, Chiara Cogliati, Alessandro Raveane, and Giuliana Gregato

Subjects
Male, Endothelial cells, Apoptosis, Disease, 030204 cardiovascular system & hematology, Circulating Endothelial Progenitors, medicine.disease_cause, Polymerase Chain Reaction, Severity of Illness Index, Gastroenterology, SARS‐CoV‐2, 0302 clinical medicine, Endothelial Progenitor Cells, Coronavirus, Covid‐19, Aged, 80 and over, medicine.diagnostic_test, Brief Report, Liter, Hematology, Middle Aged, Viral Load, Flow Cytometry, COVID-19 Nucleic Acid Testing, Host-Pathogen Interactions, cardiovascular system, RNA, Viral, CD146, Female, Circulating Endothelial Cells, Adult, medicine.medical_specialty, CD146 Antigen, Flow cytometry, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Humans, Progenitor cell, Aged, SARS-CoV-2, business.industry, COVID-19, Cancer, medicine.disease, Kinetics, Case-Control Studies, Brief Reports, business, Biomarkers
Abstract

Background During the course of COVID-19, the disease caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), thrombotic phenomena and/or diffuse vascular damage are frequent, and viral elements have been observed within endothelial cells. Objectives CD146 + circulating endothelial cells (CD146 + CECs) and their progenitors (CEPs) are increased in cardiovascular, thrombotic, infectious, and cancer diseases. The present study was designed to investigate their kinetics in novel coronavirus (COVID-19) patients. Methods We used a validated flow cytometry procedure to enumerate viable and apoptotic CD146 + CECs and CEPs in COVID-19 patients during the course of the disease and in patients who recovered. Results Viable CEPs per milliliter were significantly increased in COVID-19 patients compared with healthy controls. This increase was observed in patients with mild symptoms and not further augmented in patients with severe symptoms. In patients who recovered, CEPs decreased, but were in a range still significantly higher than normal controls. Regarding mature CD146 + CECs, in COVID-19 patients, their absolute number was similar to those observed in healthy controls, but the viable/apoptotic CD146 + CEC ratio was significantly different. Both mild and severe COVID-19 patients had significantly less apoptotic CD146 + CECs compared with healthy controls. Patients who recovered had significantly less CD146 + CECs per milliliter when compared with controls as well as to mild and severe COVID-19 patients. A positive correlation was found between the copies of SARS-CoV-2 RNA in the cellular fraction and apoptotic CEPs per milliliter in severe COVID-19 patients. Conclusions CD146 + CECs and CEPs might be investigated as candidate biomarkers of endothelial damage in COVID-19 patients.

Published
2020

5. Sitagliptin Treatment at the Time of Hospitalization Was Associated With Reduced Mortality in Patients With Type 2 Diabetes and COVID-19: A Multicenter, Case-Control, Retrospective, Observational Study

Author

Marco Mirani, Riccardo Colombo, Ida Pastore, Rosalia Bellante, Francesca D'Addio, Angelo Corsico, Alessandro Roberto Dodesini, Cristiana Scaranna, Silvia Galliani, Sebastiano Bruno Solerte, Roberto Trevisan, Elisabetta Lovati, Giuseppe Lepore, Franco Folli, Emanuele Catena, Salvatore Endrio Oleandri, Marco Dell’Acqua, Antonio Rossi, Elio Ippolito, Francesca Geni, Antonio Di Sabatino, Carlo De Riva, Gian Vincenzo Zuccotti, Paolo Fiorina, Roberta Maria Fiorina, Reza Abdi, Massimo Galli, Joseph V. Bonventre, Stefano Rusconi, Solerte, S, D'Addio, F, Trevisan, R, Lovati, E, Rossi, A, Pastore, I, Acqua, M, Ippolito, E, Scaranna, C, Bellante, R, Galliani, S, Dodesini, A, Lepore, G, Geni, F, Fiorina, R, Catena, E, Corsico, A, Colombo, R, Mirani, M, Riva De, C, Oleandri, S, Abdi, R, Bonventre, J, Rusconi, S, Folli, F, Sabatino, A, Zuccotti, G, Galli, M, and Fiorina, P

Subjects
medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Coronaviru, Pneumonia, Viral, Population, 030209 endocrinology & metabolism, Type 2 diabetes, Dipeptidyl peptidase-4 inhibitor, Sitagliptin Phosphate, 03 medical and health sciences, 0302 clinical medicine, Retrospective Studie, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, 030212 general & internal medicine, education, Advanced and Specialized Nursing, education.field_of_study, Betacoronaviru, Pandemic, Emerging Therapies: Drugs and Regimens, SARS-CoV-2, Coronavirus Infection, business.industry, Hazard ratio, COVID-19, Retrospective cohort study, medicine.disease, Hospitalization, Italy, Diabetes Mellitus, Type 2, Sitagliptin, business, Human, medicine.drug
Abstract

OBJECTIVE Poor outcomes have been reported in patients with type 2 diabetes and coronavirus disease 2019 (COVID-19); thus, it is mandatory to explore novel therapeutic approaches for this population. RESEARCH DESIGN AND METHODS In a multicenter, case-control, retrospective, observational study, sitagliptin, an oral and highly selective dipeptidyl peptidase 4 inhibitor, was added to standard of care (e.g., insulin administration) at the time of hospitalization in patients with type 2 diabetes who were hospitalized with COVID-19. Every center also recruited at a 1:1 ratio untreated control subjects matched for age and sex. All patients had pneumonia and exhibited oxygen saturation RESULTS Of the 338 consecutive patients with type 2 diabetes and COVID-19 admitted in Northern Italy hospitals included in this study, 169 were on sitagliptin, while 169 were on standard of care. Treatment with sitagliptin at the time of hospitalization was associated with reduced mortality (18% vs. 37% of deceased patients; hazard ratio 0.44 [95% CI 0.29–0.66]; P = 0.0001), with an improvement in clinical outcomes (60% vs. 38% of improved patients; P = 0.0001) and with a greater number of hospital discharges (120 vs. 89 of discharged patients; P = 0.0008) compared with patients receiving standard of care, respectively. CONCLUSIONS In this multicenter, case-control, retrospective, observational study of patients with type 2 diabetes admitted to the hospital for COVID-19, sitagliptin treatment at the time of hospitalization was associated with reduced mortality and improved clinical outcomes as compared with standard-of-care treatment. The effects of sitagliptin in patients with type 2 diabetes and COVID-19 should be confirmed in an ongoing randomized, placebo-controlled trial.

Published
2020

6. The crosstalk between antiretrovirals pharmacology and HIV drug resistance

Author

Laura Pezzati, Stefano Rusconi, and Andrea Giacomelli

Subjects
Oncology, medicine.medical_specialty, Anti-HIV Agents, Human immunodeficiency virus (HIV), HIV Infections, Drug resistance, medicine.disease_cause, 030226 pharmacology & pharmacy, law.invention, 03 medical and health sciences, 0302 clinical medicine, Drug Development, law, Internal medicine, Drug Resistance, Viral, medicine, Antiretroviral treatment, Humans, Pharmacology (medical), General Pharmacology, Toxicology and Pharmaceutics, Clinical pharmacology, business.industry, virus diseases, General Medicine, Crosstalk (biology), 030220 oncology & carcinogenesis, Concomitant, HIV-1, Genotypic resistance, business, HIV drug resistance
Abstract

The clinical development of antiretroviral drugs has been followed by a rapid and concomitant development of HIV drug resistance. The development and spread of HIV drug resistance is due on the one hand to the within-host intrinsic HIV evolutionary rate and on the other to the wide use of low genetic barrier antiretrovirals.We searched PubMed and Embase on 31 January 2020, for studies reporting antiretroviral resistance and pharmacology. In this review, we assessed the molecular target and mechanism of drug resistance development of the different antiretroviral classes focusing on the currently approved antiretroviral drugs. Then, we assessed the main pharmacokinetic/pharmacodynamic of the antiretrovirals. Finally, we retraced the history of antiretroviral treatment and its interconnection with antiretroviral worldwide resistance development both in , and middle-income countries in the perspective of 90-90-90 World Health Organization target.Drug resistance development is an invariably evolutionary driven phenomenon, which challenge the 90-90-90 target. In high-income countries, the antiretroviral drug resistance seems to be stable since the last decade. On the contrary, multi-intervention strategies comprehensive of broad availability of high genetic barrier regimens should be implemented in resource-limited setting to curb the rise of drug resistance.

Published
2020

7. Overlooked cases of HIV infection: An Italian tale of missed diagnostic opportunities

Author

Alice Ranzani, Lorena van den Bogaart, Andrea Giacomelli, Spinello Antinori, Letizia Oreni, Mario Corbellino, Anna Lisa Ridolfo, Stefano Rusconi, and Massimo Galli

Subjects
Pediatrics, medicine.medical_specialty, Delayed Diagnosis, Constitutional symptoms, Human immunodeficiency virus (HIV), HIV Infections, Hiv testing, Primary care, Newly diagnosed, 030204 cardiovascular system & hematology, Logistic regression, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Acquired immunodeficiency syndrome (AIDS), Internal Medicine, medicine, Humans, 030212 general & internal medicine, Aged, Retrospective Studies, business.industry, Medical record, Middle Aged, medicine.disease, Early Diagnosis, Italy, business
Abstract

Background Late diagnoses are still a cause of increased HIV-related morbidity and mortality despite the availability of highly effective treatments. The aim of this study was to identify indicator conditions (ICs) in late presenters with HIV infection (LPs) that may represent missed opportunities of undertaking earlier HIV testing. Methods The medical records of LPs referred to a specialist clinic in Milan, Italy, between 2011 and 2017 were reviewed to assess the frequency of ICs during the five years preceding diagnosis. Logistic regression analysis was used to investigate the factors associated with missed opportunities of making an earlier diagnosis. Results The analysis considered 203 LPs (60.6% of the patients newly diagnosed as having HIV infection during the study period). Most had had ≥1 medical encounter in the five years before diagnosis, and 54 (26.6%) had been diagnosed as having ≥1 IC without undergoing HIV testing. The most frequent ICs were herpes zoster (19.8%), constitutional symptoms (17.4%) and lympho/thrombocytopenia (12.8%), and the missed opportunities for testing occurred in the settings of primary care (44.9%), specialist medical (38.2%) or surgical services (11.3%), and emergency departments (5.6%). Twenty-five (53.2%) of the 47 subjects with a non AIDS-defining IC had AIDS at the time of the diagnosis of HIV infection. Subjects aged >60 years were at increased risk of missed diagnostic opportunities (aOR 4.80, p = 0.008). Conclusion Implementing IC-guided HIV testing in non-specialist settings is an essential means of reducing late diagnoses of HIV infection even in the case of older subjects.

Published
2020

8. Effectiveness of Switching to Darunavir/Cobicistat in Virologically Suppressed HIV-Positive Patients Receiving Ritonavir-Boosted Protease Inhibitor–Based Regimen: The 'STORE' Study

Author

Alessandra Vergori, Elio Manzillo, Roberta Termini, Andrea Antinori, Diego Ripamonti, Antonella dʼArminio Monforte, Christof Stingone, Nicola Gianotti, Stefano Savinelli, Benedetto Maurizio Celesia, Francesco Castelli, Renato Maserati, Teresa Santantonio, Giancarlo Orofino, Barbara Menzaghi, Francesco Rucci, Maria Vittoria Cossu, Roberto Cauda, Gaetana Sterrantino, Anna Maria Cattelan, Alessia Uglietti, Andrea Gori, Stefano Rusconi, Daniela Mancusi, and Stefano Bonora

Subjects
Adult, Male, medicine.medical_specialty, Settore M-PSI/02 - PSICOBIOLOGIA E PSICOLOGIA FISIOLOGICA, Anti-HIV Agents, effectiveness, HIV Infections, 030312 virology, darunavir, cobicistat, ritonavir, HIV, STORE, virologically suppressed, Gastroenterology, 03 medical and health sciences, Internal medicine, HIV Seropositivity, medicine, Humans, darunavir/ritonavir, Pharmacology (medical), Prospective Studies, Adverse effect, Prospective cohort study, Darunavir, therapy, 0303 health sciences, Ritonavir, business.industry, Cobicistat, darunavir/cobicistat, HIV Protease Inhibitors, Middle Aged, Viral Load, Clinical Science, Regimen, Infectious Diseases, Tolerability, haart, HIV-1, RNA, Viral, Female, business, Viral load, medicine.drug
Abstract

Objective: This study investigates the effectiveness and tolerability of switching to a darunavir/cobicistat (DRV/c)-based antiretroviral regimen from a ritonavir-boosted protease inhibitor (PI/r)-based regimen in virologically suppressed HIV-positive patients. DRV trough values were also investigated. Setting: Prospective, multicenter, single-country, noninterventional cohort study. Methods: This study included patients on a PI/r-based ART for at least 12 months having plasma HIV-1 RNA

Published
2020

9. PD-1 blockade counteracts post–COVID-19 immune abnormalities and stimulates the anti–SARS-CoV-2 immune response

Author

Cristian Loretelli, Elio Ippolito, Laura Montefusco, Jun Yang, Emma Assi, Massimo Galli, Moufida Ben Nasr, Antonio Rossi, Mara Biasin, Vera Usuelli, Paolo Fiorina, Ahmed Abdelsalam, Andy Joe Seelam, Agostino Riva, Stefania Di Maggio, Maria Elena Lunati, Claudia Vanetti, Dejan Radovanovic, Andrea Mario Bolla, Ida Pastore, Spinello Antinori, Pierachille Santus, L. Loreggian, Gian Vincenzo Zuccotti, Francesca D'Addio, Anna Maestroni, Basset El Essawy, and Stefano Rusconi

Subjects
CD4-Positive T-Lymphocytes, Male, T-Lymphocytes, T cell, medicine.medical_treatment, Interleukin-1beta, Programmed Cell Death 1 Receptor, Immunology, CD8-Positive T-Lymphocytes, In Vitro Techniques, B7-H1 Antigen, Immunophenotyping, Post-Acute COVID-19 Syndrome, Immune system, Antigen, Humans, Medicine, Promoter Regions, Genetic, Immune Checkpoint Inhibitors, SARS-CoV-2, business.industry, Interleukin-8, COVID-19, General Medicine, Immunotherapy, DNA Methylation, Middle Aged, Immune checkpoint, Blockade, Interleukin 1 Receptor Antagonist Protein, MicroRNAs, medicine.anatomical_structure, Case-Control Studies, Anergy, Cytokines, Female, business, CD8, Ex vivo, Research Article
Abstract

A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19–related symptoms even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1+ T cells, as compared with healthy controls. Plasma levels of IL-1β, IL-1RA, and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1, as well as of PD1 promoter methylation and PD1-targeting miR–15-5p, in CD8+ T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post–COVID-19 immune abnormalities; indeed, we also noted an increased T cell–mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post–COVID-19 immune abnormalities and stimulates an anti–SARS-CoV-2 immune response.

Published
2021

10. HIV and COVID-19 pandemic collision: turning challenges into opportunity

Author

Andrea Giacomelli, Tiziana Formenti, Laura Pezzati, and Stefano Rusconi

Subjects
missed opportunities, retention in care, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), SARS-CoV-2, business.industry, pandemic, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Human immunodeficiency virus (HIV), HIV, outcomes, Retention in care, medicine.disease_cause, Virology, Editorial, Pandemic, Medicine, business
Published
2021

11. Has COVID-19 changed the approach to HIV diagnosis?

Author

Gianmaria Baldin, Giovanni Guaraldi, Carlo Torti, Bianca Candelaresi, Vanni Borghi, Gaetana Sterrantino, Cristina Mussini, Filippo Lagi, Simona Di Giambenedetto, Andrea Giacomelli, Roberto Cauda, Letizia Oreni, Arturo Ciccullo, Stefano Rusconi, Andrea De Vito, Oscar Cirioni, Barbara Rossetti, and Maria Mazzitelli

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Cross-sectional study, Observational Study, HIV Infections, Disease, Settore MED/17 - MALATTIE INFETTIVE, CD4 Lymphocyte Count, COVID-19, Cross-Sectional Studies, Delivery of Health Care, Female, Humans, Italy, Mass Screening, Middle Aged, Pandemics, Retrospective Studies, Risk Factors, SARS-CoV-2, Men who have sex with men, lockdown, Acquired immunodeficiency syndrome (AIDS), Health care, Pandemic, medicine, late presentation, Mass screening, business.industry, Incidence (epidemiology), virus diseases, HIV, General Medicine, medicine.disease, AIDS, business, Research Article
Abstract

The occurrence of COVID-19 pandemic had a significant negative effect on health care systems over the last year. Health care providers were forced to focus mainly on COVID-19 patients, neglecting in many cases equally important diseases, both acute and chronic. Therefore, also screening and diagnostic strategies for HIV could have been significantly impaired. This retrospective, multicenter, observational study aimed at assessing the number and characteristics of new HIV/AIDS diagnoses during COVID-19 pandemic in Italy and compared characteristics of people living with HIV at diagnosis between pre- and post-COVID-19 era (2019 vs 2020). Our results showed a significant reduction of HIV diagnoses during pandemic. By contrast, people living with HIV during pandemic were older and were diagnosed in earlier stage of disease (considering CD4+ T cell count) compared to those who were diagnosed the year before. Moreover, there was a significant decrease of new HIV diagnoses among men who have sex with men, probably for the impact of social distancing and restriction applied by the Italian Government. Late presentation incidence, if numbers in 2020 were lower than those in 2019, is still an issue. Routinely performing HIV testing in patients with suspected SARS-CoV-2 infection is identifying and linking to care underdiagnosed people living with HIV earlier. Thus, combined tests (HIV and SARS-CoV-2) should be implemented in patients with SARS-CoV-2 symptoms overlapping HIV's ones. Lastly, our results lastly showed how urgent implementation of a national policy for HIV screening is necessary.

Published
2021

12. Durability of INI-containing regimens after switching from PI-containing regimens: a single-centre cohort of drug-experienced HIV-infected subjects

Author

Angelica Lupo, Letizia Oreni, Alice Ranzani, Stefano Rusconi, Andrea Giacomelli, Anna Lisa Ridolfo, Massimo Galli, and Elena Gervasi

Subjects
0301 basic medicine, medicine.medical_specialty, Anti-HIV Agents, Pyridones, protease inhibitors, Pharmaceutical Science, Integrase inhibitor, HIV Infections, Piperazines, lipids, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Interquartile range, Internal medicine, Raltegravir Potassium, Drug Discovery, Oxazines, medicine, Humans, HIV Integrase Inhibitors, Framingham, Original Research, Retrospective Studies, Pharmacology, Drug Design, Development and Therapy, Elvitegravir, business.industry, Hazard ratio, HIV, Raltegravir, Discontinuation, dolutegravir, Regimen, 030104 developmental biology, integrase inhibitors, chemistry, 030220 oncology & carcinogenesis, Dolutegravir, business, Heterocyclic Compounds, 3-Ring, medicine.drug
Abstract

Andrea Giacomelli, Alice Ranzani, Letizia Oreni, Elena Gervasi, Angelica Lupo, Anna Lisa Ridolfo, Massimo Galli, Stefano RusconiIII Infectious Disease Unit, Department of Biomedical and Clinical Sciences "L. Sacco", University of Milan, Milan, ItalyPurpose: Integrase inhibitor (INI)-containing regimens are increasingly replacing protease inhibitor(PI)-containing regimens in clinical practice. The aim of this study was to evaluate the determinants of the durability of INI-containing regimens after the switch.Patients and methods: We retrospectively analysed all of the people with HIV infection attending the University of Milan’s Infectious Diseases Unit at Luigi Sacco Hospital who were switched from a PI- to an INI-containing regimen between April 2008 and March 2017. The probability of remaining on an INI-containing regimen was estimated using Kaplan-Meier curves, and the baseline clinical predictors of INI-containing regimen durability were assessed using a multivariable Cox proportional hazard regression model.Results: Three hundred and twelve patients were included in the analysis. The median time of observation was 21months (interquartile range 10–36months). The main reasons for switching from a PI-containing regimen to an INI-containing regimen were toxicities (31.4%) and simplification (31.1%). Univariate analysis revealed no difference in the probability of INI discontinuation between the patients treated with raltegravir, dolutegravir or elvitegravir (p=0.060), but the multivariable Cox regression model showed that the patients treated with dolutegravir were at less risk of discontinuation than those treated with raltegravir (adjusted hazard ratio 0.49, 95% confidence interval 0.26–0.95; p=0.034).Conclusion: Switching from a PI- to an INI-containing regimen may be an option for patients under virological control. The patients switched to dolutegravir were less likely to discontinue the INI than those switched to raltegravir. Our findings support this therapeutic strategy and highlight the durability and efficacy of dolutegravir containing-regimens after switching from a PI-containing regimen.Keywords: HIV, protease inhibitors, integrase inhibitors, dolutegravir, lipids, Framingham

Published
2019

13. Impact of genotypic susceptibility score on cART outcomes during primary HIV infection

Author

Emanuele Focà, Silvia Nozza, Antonio Muscatello, Stefano Rusconi, Gabriella d'Ettorre, Alessandra Bandera, Ilaria De Benedetto, Andrea Giacomelli, Andrea Antinori, Benedetto Maurizio Celesia, Massimiliano Fabbiani, Giordano Madeddu, Cristina Mussini, and Giulia Marchetti

Subjects
Cart, medicine.medical_specialty, primary HIV, gss, hiv, primary hiv, adult, anti-hiv agents, drug therapy, combination, female, hiv infections, humans, male, middle aged, retrospective studies, Primary HIV infection, 03 medical and health sciences, 0302 clinical medicine, Virology, Internal medicine, Genotype, medicine, GSS, 030212 general & internal medicine, combination, Acute HIV infection, business.industry, HIV, Odds ratio, Antiretroviral therapy, Confidence interval, drug therapy, Regimen, Infectious Diseases, Drug Therapy, Combination, 030211 gastroenterology & hepatology, business
Abstract

To assess the impact of genotypic susceptibility score (GSS) on combined antiretroviral therapy (cART) outcomes during primary HIV infection (PHI) we retrospectively enrolled patients with PHI diagnosed between 2008 and 2015 at 9/24 Italian Network ACuTe HIV InfectiON centers. One hundred-seventy-six patients were enrolled. Of these, 55 (32.9%) patients started with more than three drugs and 11 (7.2%) started with a GSS

Published
2019

14. Durability of different initial regimens in HIV-infected patients starting antiretroviral therapy with CD4+ counts <200 cells/mm3 and HIV-RNA >5 log10 copies/mL

Author

Bruno Cacopardo, M. A. Ursitti, Claudio Maria Mastroianni, Emanuele Nicastri, R. Piolini, A. Antinori, Giustino Parruti, S. Truffa, Ivan Gentile, Giovanni Cassola, E. Girardi, I. Caramma, Andrea Calcagno, Laura Monno, A d'Arminio Monforte, R. Acinapura, Francesca Ceccherini-Silberstein, A. Di Biagio, Gabriella Verucchi, Alessandra Latini, Simone Marcotullio, Nicola Gianotti, C. Balotta, Camilla Tincati, M. C. Moioli, Alessandro Tavelli, Pietro Caramello, Carmen Rita Santoro, C. Abeli, A. Londero, F. Di Martino, R. Iardino, Stefano Bonora, M. Andreoni, A. Costantini, Raffaella Libertone, F. von Schloesser, G. Prota, Annalisa Saracino, Maria Grazia Cecchetto, Antonio Cristaudo, Mauro Zaccarelli, Carmela Pinnetti, Fabrizio Carletti, N. Abrescia, Andrea Giacometti, L. Gallo, Paolo Bonfanti, G. Angarano, E. Quiros Roldan, G. Pellizzer, F. Petrone, Giovanni Mazzarello, Silvia Nozza, R. Orlando, Franco Baldelli, Giovanni Guaraldi, Paola Meraviglia, Laura Sighinolfi, S. Carrara, D. Segala, Giuliano Rizzardini, C. Suardi, P. Piano, Mauro Sciandra, Daniela Francisci, A. De Luca, Patrizia Lorenzini, Paola Cinque, Tiziana Quirino, S. Graziano, Cristina Mussini, Massimo Galli, Giuseppe Ippolito, S. Lo Caputo, Benedetto Maurizio Celesia, C. Valeriani, Matteo Bassetti, Maria Rosaria Capobianchi, Claudio Viscoli, Vinicio Manfrin, Alessandro Chiodera, Alessandra Bandera, Guglielmo Borgia, Cinzia Puzzolante, Stefano Rusconi, Leonardo Calza, Valeria Belvisi, Francesca Vichi, Serena Quartu, Roberto Cauda, J. Vecchiet, Antonio Chirianni, A. Di Caro, P.E. Manconi, Stefania Cicalini, G. Magnani, M. Lichtner, Milensu Shanyinde, Stefano Savinelli, M. Puoti, Giulia Marchetti, Laura Carenzi, Carlo Federico Perno, Annalisa Ridolfo, G. Di Perri, F. Maggiolo, A Castagna, G. Orofino, Roberto Rossotti, Francesco Mazzotta, Gianmaria Baldin, Giovanni Lapadula, A. Rodano, V. Donati, Barbara Rossetti, F. Viviani, Adriana Ammassari, N. Bobbio, Adriano Lazzarin, C. Minardi, A. Alessandrini, Katia Falasca, Maria Stella Mura, Tamara Ursini, Andrea Gori, A. Cingolani, L. Maddaloni, Alessandro Cozzi-Lepri, Francesco Castelli, Iuri Fanti, Giordano Madeddu, E. Quiros, P. Viale, Marco Borderi, M. Capozzi, and Vincenzo Vullo

Subjects
Adult, Male, 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Anti-HIV Agents, Hepatitis C virus, Renal function, Integrase inhibitor, HIV Infections, medicine.disease_cause, Rate ratio, 03 medical and health sciences, 0302 clinical medicine, Antiretroviral Therapy, Highly Active, Internal medicine, Clinical endpoint, Humans, Medicine, Pharmacology (medical), Treatment Failure, 030212 general & internal medicine, Retrospective Studies, Pharmacology, AIDS-Related Opportunistic Infections, Coinfection, business.industry, Retrospective cohort study, Middle Aged, Viral Load, 030112 virology, CD4 Lymphocyte Count, Discontinuation, Treatment Outcome, Infectious Diseases, Cohort, Female, business
Abstract

ObjectivesOur aim was to investigate the durability of different initial regimens in patients starting ART with CD4+ counts 5 log10 copies/mL.MethodsThis was a retrospective study of HIV-infected patients prospectively followed in the ICONA cohort. Those who started ART with boosted protease inhibitors (bPIs), NNRTIs or integrase strand transfer inhibitors (InSTIs), with CD4+ 5 log10 copies/mL, were included. The primary endpoint was treatment failure (TF), a composite endpoint defined as virological failure (VF, first of two consecutive HIV-RNA >50 copies/mL after 6 months of treatment), discontinuation of class of the anchor drug or death. Independent associations were investigated by Poisson regression analysis in a model including age, gender, mode of HIV transmission, CDC stage, HCV and HBV co-infection, pre-treatment HIV-RNA, CD4+ count and CD4+/CD8+ ratio, ongoing opportunistic disease, fibrosis FIB-4 index, estimated glomerular filtration rate, haemoglobin, platelets, neutrophils, calendar year of ART initiation, anchor drug class (treatment group) and nucleos(t)ide backbone.ResultsA total of 1195 patients fulfilled the inclusion criteria: 696 started ART with a bPI, 315 with an InSTI and 184 with an NNRTI. During 2759 person-years of follow up, 642 patients experienced TF. Starting ART with bPIs [adjusted incidence rate ratio (aIRR) (95% CI) 1.62 (1.29–2.03) versus starting with NNRTIs; P ConclusionsIn patients starting ART with 5 log10 HIV-RNA copies/mL, the durability of regimens based on InSTIs was longer than that of NNRTI- and bPI-based regimens.

Published
2019

15. Cardiovascular adverse events during treatment with darunavir-based regimens in an Italian observational study

Author

Andrea Antinori, Teresa Bini, Stefano Rusconi, Nicola Gianotti, Daniela Mancusi, and Roberta Termini

Subjects
0301 basic medicine, Pharmacology, medicine.medical_specialty, Framingham Risk Score, business.industry, Pharmaceutical Science, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Blood pressure, 030220 oncology & carcinogenesis, Internal medicine, Drug Discovery, Propensity score matching, Cohort, medicine, In patient, Observational study, Adverse effect, business, Darunavir, medicine.drug
Abstract

Background: The protease inhibitor (PI) darunavir (DRV) has proven to be highly effective and well tolerated for HIV treatment. The DAD (Data collection on Adverse Effects of Anti-HIV Drugs) cohort showed an increased 5-year cumulative cardiovascular (CV) risk in patients given various PIs, including DRV, whereas two other recent studies found no association between DRV and CV diseases. Methods: We performed a post-hoc analysis of CV adverse events (CVAEs) in an Italian cohort, the TMC114-HIV4042 observational study, where 875 patients treated with ritonavir-boosted DRV-based regimens were followed for a total of 1,566 patient-years. Results: We observed 23 CVAEs of any type, including 17 [12 (95%CI, 7-19) per 1,000 patient-years] primary; 14 [10 (95%CI, 5-17) per 1,000 patient-years] were primary Framingham-type general CVAEs, close to what expected according to the Framingham algorithm based on traditional risk factors. Age and systolic blood pressure (SBP) at the time of study enrolment were the only relevant (p 0.05). Models that also adjusted for previous ARV exposure showed no statistically significant association between any-type CVAEs and either DRV doses, 1,200 or 800 mg/daily (as also suggested by propensity score stratification), or previous DRV exposure duration. Conclusion: We found no evidence of a relationship between DRV use and increased CV risk.

Published
2019

16. Clinical pharmacology in HIV cure research – what impact have we seen?

Author

Sonia de Rose, Andrea Giacomelli, and Stefano Rusconi

Subjects
Anti-HIV Agents, Human immunodeficiency virus (HIV), HIV Infections, Virus Replication, Bioinformatics, medicine.disease_cause, 030226 pharmacology & pharmacy, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, In vivo, Drug Discovery, Viral latency, Animals, Humans, Medicine, Pharmacology (medical), Molecular Targeted Therapy, General Pharmacology, Toxicology and Pharmaceutics, Clinical pharmacology, business.industry, Mechanism (biology), General Medicine, Antibodies, Neutralizing, Antiretroviral therapy, Virus Latency, 030220 oncology & carcinogenesis, Expert opinion, Fatal disease, Drug Therapy, Combination, business
Abstract

Introduction: Combined antiretroviral therapy (cART) has transformed an inexorably fatal disease into a chronic pathology, shifting the focus of research from the control of viral replication to the possibility of HIV cure. Areas covered: The present review assesses the principal pharmacological strategies that have been tested for an HIV cure starting from the in vitro proof of concept and the potential rationale of their in vivo applicability. We evaluated the possible pharmacological procedures employed during the early-stage HIV infection and the possibility of cART-free remission. We then analyzed the shock and kill approach from the single compounds in vitro mechanism of action, to the in vivo application of single or combined actions. Finally, we briefly considered the novel immunological branch through the discovery and development of broadly neutralizing antibodies in regard to the current and future in vivo therapeutic strategies aiming to verify the clinical applicability of these compounds. Expert opinion: Despite an incredible effort in HIV research cure, the likelihood of completely eradicating HIV is unreachable within our current knowledge. A better understanding of the mechanism of viral latency and the full characterization of HIV reservoir are crucial for the discovery of new therapeutic targets and novel pharmacological entities.

Published
2019

17. Author response: Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

Author

Diego Ripamonti, Sandro Panese, Agnese Verzuri, Giancarlo Bosio, Francesco Castelli, Leonardo Croci, Maurizio Spagnesi, Sergio Daga, Massimiliano Fabbiani, Barbara Rossetti, Silvia Cappelli, Giada Beligni, Gabriella Coiro, Antonio Di Biagio, Domenico A Coviello, Massimo Girardis, Pamela Raggi, Roberta Russo, Federico Franchi, Matteo Bassetti, Stefano Baratti, Gianfranco Parati, Francesca Montagnani, Marco Rizzi, Eugenia Quiros-Roldan, Francesca Fava, Tiziana Bachetti, Agostino Riva, Filippo Aucella, Francesca Gatti, Anna Canaccini, Anna Maria Pinto, Sandro Mancarella, Alessandra Renieri, Arianna Gabrieli, Mario Chiariello, Rossella Tita, Luca Guidelli, Sophie Venturelli, Ilaria Meloni, Luisa Tavecchia, Marta Corridi, Susanna Croci, Francesca Mari, Pierpaolo Parravicini, Andrea Tommasi, Carmelo Piscopo, Tullio Trotta, Miriana d'Alessandro, Maria Antonietta Mencarelli, Cristina Mussini, Simone Furini, Alessandra Vergori, Gen-Covid Multicenter Study, Margherita Baldassarri, Daniela Francisci, Giuseppe Fiorentino, Simona Sarzi-Braga, Mirella Bruttini, Sabino Scolletta, Mario Capasso, Melania Degli Antoni, Serafina Valente, Alice Donati, Maria Antonietta Mazzei, Maurizio Bussotti, Chiara Fallerini, Laura Di Sarno, Federico Anedda, Davide Romani, Katia Capitani, Gian Piero Caldarelli, Elisa Frullanti, Caterina Lo Rizzo, Bruno Frediani, Marco Castori, Arianna Emiliozzi, Andrea Cossarizza, Elena Desanctis, Luca Cantarini, Cesira Nencioni, Ottavia Spiga, Fabio Lena, Isabella Zanella, Genni Spargi, Francesco Paciosi, Pier Giorgio Scotton, Simona Dei, Marco Mandalà, Giacomo Zanelli, Alessia Giorli, Elena Bargagli, Maria Palmieri, Stefano Rusconi, Laura Bergantini, Ferdinando Giannattasio, David Bennett, Carmen Marciano, Chiara Spertilli, Maria Bandini, Serena Ludovisi, Enrico Martinelli, Edoardo Conticini, Valentina Anemoli, Nicola Iuso, Elisa Benetti, Matteo Siano, Achille Iolascon, Danilo Tacconi, Mario U. Mondelli, Sara Amitrano, Raffaele Scala, Paolo Piacentini, Lia Crotti, Maria Teresa La Rovere, Nicola Picchiotti, Patrizia Zucchi, Elisabetta Schiaroli, Immacolata Andolfo, Francesca Andretta, Gabriella Doddato, Annarita Giliberti, Stefano Busani, Simona Marcantonio, Antonella d'Arminio Monforte, Mary Ann Belli, Luca Masucci, Rita Perna, Chiara Gabbi, Gabriella Maria Squeo, Franco Maggiolo, Marco Feri, Susanna Guerrini, Paolo Cameli, Elisabetta Menatti, Maurizio Sanguinetti, Andrea Antinori, Lorenzo Salerni, Saverio Giuseppe Parisi, Stefania Mantovani, Floriana Valentino, Federica Gaia Miraglia, Agostino Ognibene, Marco Gori, Renzo Scaggiante, Matteo Della Monica, Giuseppe Merla, Massimo Vaghi, and Massimo Carella

Subjects
Toll-like receptor, Coronavirus disease 2019 (COVID-19), business.industry, Association (object-oriented programming), Nested case-control study, Immunology, Medicine, Disease, business
Published
2021

18. Unveiling the basis of antiretroviral therapy-induced osteopenia: the effects of Dolutegravir, Darunavir and Atazanavir on osteogenesis

Author

Jeanette A.M. Maier, Roberta Scrimieri, Stefano Rusconi, Alessandra Cazzaniga, and Massimo Galli

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Anti-HIV Agents, Pyridones, Immunology, Atazanavir Sulfate, Context (language use), HIV Infections, Piperazines, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Osteogenesis, Internal medicine, Oxazines, medicine, Immunology and Allergy, Humans, 030212 general & internal medicine, Darunavir, business.industry, Mesenchymal stem cell, virus diseases, medicine.disease, Antiretroviral therapy, Atazanavir, Osteopenia, Regimen, Bone Diseases, Metabolic, 030104 developmental biology, Infectious Diseases, chemistry, Dolutegravir, business, Heterocyclic Compounds, 3-Ring, medicine.drug
Abstract

Objectives Osteopenia is frequent in HIV-infected patients treated with antiretroviral therapy (ART) and has been linked to increased osteoclastogenesis. Little is known about the effects of ART on osteogenesis. Design We investigated the effect on human mesenchymal stem cells (hMSC) and osteoblasts of Darunavir and Dolutegravir, the most highly used as anchor drugs within a three-drug regimen, and Atazanavir, which was widely utilized in the past. Results We found that Atazanavir and Dolutegravir delay the osteogenic differentiation of hMSC, impair the activity of osteoblasts and inhibit their conversion into osteocytes, whereas Darunavir exerts no effect. Conclusion Atazanavir and Dolutegravir impair osteogenesis. It is essential to diagnose impaired osteogenesis early and to devise effective therapeutic interventions to preserve bone health in ART-treated HIV patients, putting it in the context of a correct antiretroviral combination.

Published
2021

19. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Author

François-Xavier Lescure, Hitoshi Honda, Robert A Fowler, Jennifer Sloane Lazar, Genming Shi, Peter Wung, Naimish Patel, Owen Hagino, Ignacio J. Bazzalo, Marcelo M. Casas, Sebastián A. Nuñez, Yael Pere, Carlos M. Ibarrola, Marco A. Solis Aramayo, Maria C. Cuesta, Andrea E. Duarte, Pablo M. Gutierrez Fernandez, Maria A. Iannantuono, Erica A. Miyazaki, Javier P. Silvio, Dario G. Scublinsky, Alessandra Bales, Daniela Catarino, Elie Fiss, Sara Mohrbacher, Victor Sato, Antonio Baylao, Adilson Cavalcante, Francini Correa, Celso A. de Andrade, Juvencio Furtado, Nelson Ribeiro Filho, Valéria Telles, Leopoldo T. Trevelin, Ricardo Vipich, Rodrigo Boldo, Paula Borges, Suzana Lobo, Graziela Luckemeyer, Luana Machado, Maysa B. Alves, Ana C. Iglessias, Marianna M. Lago, Daniel W. Santos, Hugo Chapdelaine, Emilia L. Falcone, Rahima Jamal, Me-Linh Luong, Madeleine Durand, Stephane Doucet, François-Martin Carrier, Bryan A. Coburn, Lorenzo Del Sorbo, Sharon L. Walmsley, Sara Belga, Luke Y. Chen, Allison D. Mah, Theodore Steiner, Alissa J. Wright, J. Hajek, Neill Adhikari, Robert A. Fowler, Nick Daneman, Kosar A. Khwaja, Jason Shahin, Carolina Gonzalez, Rafael Silva, Marcelo Lindh, Gabriel Maluenda, Patricia Fernandez, Maite Oyonarte, Martin Lasso, Alexandre Boyer, Didier Bronnimann, Hoang-Nam Bui, Charles Cazanave, Helene Chaussade, Arnaud Desclaux, Mailys Ducours, Alexandre Duvignaud, Denis Malvy, Lisa Martin, Didier Neau, Duc Nguyen, Thierry Pistone, Gaetane Soubrane-Wirth, Julie Leitao, Clotilde Allavena, Charlotte Biron, Sabelline Bouchez, Benjamin Gaborit, Antoine Gregoire, Paul Le Turnier, Anne-Sophie Lecompte, Raphael Lecomte, Maeva Lefebvre, Francois Raffi, David Boutoille, Pascale H. Morineau, Romain Guéry, Emmanuel Chatelus, Nathalie Dumoussaud, Renaud Felten, Florina Luca, Bernard Goichot, Francis Schneider, Marie-Caroline Taquet, Matthieu Groh, Mathilde Roumier, Mathilde Neuville, Antoine Bachelard, Valentina Isernia, F-Xavier Lescure, Bao-Chau Phung, Anne Rachline, Aurelie Sautereau, Dorothee Vallois, Yves Bleher, Delphine Boucher, Clémentine Coudon, Jean Esnault, Thomas Guimard, Sophie Leautez-Nainville, Dominique Merrien, Marine Morrier, Pauline Motte-Vincent, Romain Gabeff, Hélène Leclerc, Céline Cozic, Romain Decours, Ronan Février, Gwenhael Colin, Sophie Abgrall, Dorothee Vignes, Raluca Sterpu, Mira Kuellmar, Melanie Meersch-Dini, Raphael Weiss, Alexander Zarbock, Christiane Antony, Marc Berger, Thorsten Brenner, Christian Taube, Frank Herbstreit, Sebastian Dolff, Margarethe Konik, Karsten Schmidt, Markus Zettler, Oliver Witzke, Boris Boell, Jorge Garcia Borrega, Philipp Koehler, Thomas Zander, Fabian Dusse, Othman Al-Sawaf, Philipp Köhler, Dennis Eichenauer, Matthias Kochanek, Alexander Shimabukuro-Vornhagen, Sibylle Mellinghoff, Annika Claßen, Jan-Michel Heger, Charlotte Meyer-Schwickerath, Paul Liedgens, Katrin Heindel, Ana Belkin, Asaf Biber, Mayan Gilboa, Itzchak Levy, Vladislav Litachevsky, Galia Rahav, Anat Finesod Wiedner, Tal Zilberman-Daniels, Yonatan Oster, Jacob Strahilevitz, Sigal Sviri, Elena M. Baldissera, Corrado Campochiaro, Giulio Cavalli, Lorenzo Dagna, Giacomo De Luca, Emanuel Della Torre, Alessandro Tomelleri, Davide Bernasconi De Luca, Amedeo F. Capetti, Massimo Coen, Maria V. Cossu, Massimo Galli, Andrea Giacomelli, Guido A. Gubertini, Stefano Rusconi, Giulia J. Burastero, Margherita Digaetano, Giovanni Guaraldi, Marianna Meschiari, Cristina Mussini, Cinzia Puzzolante, Sara Volpi, Marina Aiello, Alarico Ariani, Alfredo A. Chetta, Annalisa Frizzelli, Andrea Ticinesi, Domenico Tuttolomondo, Stefano Aliberti, Francesco B. Blasi, Marta F. Di Pasquale, Sofia Misuraca, Tommaso Pilocane, Edoardo Simonetta, Alessio M. Aghelmo, Claudio Angelini, Enrico Brunetta, Giorgio W. Canonica, Michele Ciccarelli, Sara Dal Farra, Maria De Santis, Sebastian Ferri, Marco Folci, Giacomo M. Guidelli, Enrico M. Heffler, Ferdinando Loiacono, Giacomo Malipiero, Giovanni Paoletti, Rosa Pedale, Francesca A. Puggioni, Francesca Racca, Aurora Zumbo, Morihiko Satou, Tatyana Lisun, Denis Protsenko, Nikolay Rubtsov, Irina Beloglazova, Daria Fomina, Mariana Lysenko, Sofia Serdotetskova, Vitali Firstov, Ivan Gordeev, Ilia Kokorin, Ksenia Komissarova, Nina Lapochkina, Elena Luchinkina, Valentin Malimon, Sevinch Mamedguseyinova, Ksenia Polubatonova, Natalia Suvorova, Jose Arribas, Alberto M. Borobia Perez, Fernando de la Calle Prieto, Juan Carlos Figueira, Rocio Motejano Sanchez, Marta Mora-Rillo, Concepcion Prados Sanchez, Javier Queiruga Parada, Francisco Fernandez Arnalich, Maria Guerro Barrientos, Alejandro Bendala Estrada, Aranzazu Caballero Marcos, Maria E. Garcia Leoni, Rita García-Martínez, Ana María Collado, Patricia Munoz Garcia, Ana Torres do Rego, María V. Villalba García, Almudena Burrillo, Maricela Valerio Minero, Paloma Gijon Vidaurreta, Sonsoles Infante Herrero, Elena Velilla, Marina Machado, Maria Olmedo, Blanca Pinilla, Benito Almirante Gragera, Maria de la Esperanza Cañas Ruano, Sofia Contreras Medina, Alejandro Cortés Herrera, Vicenç Falcó Ferrer, Ricard Ferrer Roca, Xavier Nuvials Casals, Esteve Ribera Pascuet, Paula Suanzes Diez, Pedro Rebollo Castro, Felipe Garcia Alcaide, Alejandro Soriano, Aina Oliver Caldes, Ana González Cordón, Celia Cardozo, Lorena De la Mora Cañizo, Romina Pena López, Sandra Chamorro, Clara Crespillo-Andujar, Rosa Escudero Sanchez, Jesús Fortún-Abete, Begoña Monge-Maillo, Ana Moreno Zamora, Francesca Norman, Matilde Sanchez Conde, Sergio Serrano Villar, Pilar Vizcarra, Lescure, F. -X., Honda, H., Fowler, R. A., Lazar, J. S., Shi, G., Wung, P., Patel, N., Hagino, O., Bazzalo, I. J., Casas, M. M., Nunez, S. A., Pere, Y., Ibarrola, C. M., Solis Aramayo, M. A., Cuesta, M. C., Duarte, A. E., Gutierrez Fernandez, P. M., Iannantuono, M. A., Miyazaki, E. A., Silvio, J. P., Scublinsky, D. G., Bales, A., Catarino, D., Fiss, E., Mohrbacher, S., Sato, V., Baylao, A., Cavalcante, A., Correa, F., de Andrade, C. A., Furtado, J., Ribeiro Filho, N., Telles, V., Trevelin, L. T., Vipich, R., Boldo, R., Borges, P., Lobo, S., Luckemeyer, G., Machado, L., Alves, M. B., Iglessias, A. C., Lago, M. M., Santos, D. W., Chapdelaine, H., Falcone, E. L., Jamal, R., Luong, M. -L., Durand, M., Doucet, S., Carrier, F. -M., Coburn, B. A., Del Sorbo, L., Walmsley, S. L., Belga, S., Chen, L. Y., Mah, A. D., Steiner, T., Wright, A. J., Hajek, J., Adhikari, N., Daneman, N., Khwaja, K. A., Shahin, J., Gonzalez, C., Silva, R., Lindh, M., Maluenda, G., Fernandez, P., Oyonarte, M., Lasso, M., Boyer, A., Bronnimann, D., Bui, H. -N., Cazanave, C., Chaussade, H., Desclaux, A., Ducours, M., Duvignaud, A., Malvy, D., Martin, L., Neau, D., Nguyen, D., Pistone, T., Soubrane-Wirth, G., Leitao, J., Allavena, C., Biron, C., Bouchez, S., Gaborit, B., Gregoire, A., Le Turnier, P., Lecompte, A. -S., Lecomte, R., Lefebvre, M., Raffi, F., Boutoille, D., Morineau, P. H., Guery, R., Chatelus, E., Dumoussaud, N., Felten, R., Luca, F., Goichot, B., Schneider, F., Taquet, M. -C., Groh, M., Roumier, M., Neuville, M., Bachelard, A., Isernia, V., Phung, B. -C., Rachline, A., Sautereau, A., Vallois, D., Bleher, Y., Boucher, D., Coudon, C., Esnault, J., Guimard, T., Leautez-Nainville, S., Merrien, D., Morrier, M., Motte-Vincent, P., Gabeff, R., Leclerc, H., Cozic, C., Decours, R., Fevrier, R., Colin, G., Abgrall, S., Vignes, D., Sterpu, R., Kuellmar, M., Meersch-Dini, M., Weiss, R., Zarbock, A., Antony, C., Berger, M., Brenner, T., Taube, C., Herbstreit, F., Dolff, S., Konik, M., Schmidt, K., Zettler, M., Witzke, O., Boell, B., Garcia Borrega, J., Koehler, P., Zander, T., Dusse, F., Al-Sawaf, O., Kohler, P., Eichenauer, D., Kochanek, M., Shimabukuro-Vornhagen, A., Mellinghoff, S., Classen, A., Heger, J. -M., Meyer-Schwickerath, C., Liedgens, P., Heindel, K., Belkin, A., Biber, A., Gilboa, M., Levy, I., Litachevsky, V., Rahav, G., Finesod Wiedner, A., Zilberman-Daniels, T., Oster, Y., Strahilevitz, J., Sviri, S., Baldissera, E. M., Campochiaro, C., Cavalli, G., Dagna, L., De Luca, Giacomo., Della Torre, E., Tomelleri, A., Bernasconi De Luca, D., Capetti, A. F., Coen, M., Cossu, M. V., Galli, M., Giacomelli, A., Gubertini, G. A., Rusconi, S., Burastero, G. J., Digaetano, M., Guaraldi, G., Meschiari, M., Mussini, C., Puzzolante, C., Volpi, S., Aiello, M., Ariani, A., Chetta, A. A., Frizzelli, A., Ticinesi, A., Tuttolomondo, D., Aliberti, S., Blasi, F. B., Di Pasquale, M. F., Misuraca, S., Pilocane, T., Simonetta, E., Aghelmo, A. M., Angelini, C., Brunetta, E., Canonica, G. W., Ciccarelli, M., Dal Farra, S., De Santis, M., Ferri, S., Folci, M., Guidelli, G. M., Heffler, E. M., Loiacono, F., Malipiero, G., Paoletti, G., Pedale, R., Puggioni, F. A., Racca, F., Zumbo, A., Satou, M., Lisun, T., Protsenko, D., Rubtsov, N., Beloglazova, I., Fomina, D., Lysenko, M., Serdotetskova, S., Firstov, V., Gordeev, I., Kokorin, I., Komissarova, K., Lapochkina, N., Luchinkina, E., Malimon, V., Mamedguseyinova, S., Polubatonova, K., Suvorova, N., Arribas, J., Borobia Perez, A. M., de la Calle Prieto, F., Figueira, J. C., Motejano Sanchez, R., Mora-Rillo, M., Prados Sanchez, C., Queiruga Parada, J., Fernandez Arnalich, F., Guerro Barrientos, M., Bendala Estrada, A., Caballero Marcos, A., Garcia Leoni, M. E., Garcia-Martinez, R., Collado, A. M., Munoz Garcia, P., Torres do Rego, A., Villalba Garcia, M. V., Burrillo, A., Valerio Minero, M., Gijon Vidaurreta, P., Infante Herrero, S., Velilla, E., Machado, M., Olmedo, M., Pinilla, B., Almirante Gragera, B., Canas Ruano, M. D. L. E., Contreras Medina, S., Cortes Herrera, A., Falco Ferrer, V., Ferrer Roca, R., Nuvials Casals, X., Ribera Pascuet, E., Suanzes Diez, P., Rebollo Castro, P., Garcia Alcaide, F., Soriano, A., Oliver Caldes, A., Gonzalez Cordon, A., Cardozo, C., De la Mora Canizo, L., Pena Lopez, R., Chamorro, S., Crespillo-Andujar, C., Escudero Sanchez, R., Fortun-Abete, J., Monge-Maillo, B., Moreno Zamora, A., Norman, F., Sanchez Conde, M., Serrano Villar, S., and Vizcarra, P.

Subjects
Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Critical Care, International Cooperation, Population, Antibodies, Monoclonal, Humanized, Placebo, Severity of Illness Index, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Intensive care, Severity of illness, medicine, Clinical endpoint, Humans, Immunologic Factors, 030212 general & internal medicine, Mortality, education, Respiratory Distress Syndrome, education.field_of_study, Dose-Response Relationship, Drug, SARS-CoV-2, business.industry, Hazard ratio, COVID-19, Articles, Middle Aged, Receptors, Interleukin-6, Sarilumab, Treatment Outcome, 030228 respiratory system, Female, Drug Monitoring, Cytokine Release Syndrome, business
Abstract

Summary Background Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding Sanofi and Regeneron Pharmaceuticals.

Published
2021

20. Nucleoside Reverse-Transcriptase Inhibitor Resistance Mutations Predict Virological Failure in Human Immunodeficiency Virus-Positive Patients during Lamivudine plus Dolutegravir Maintenance Therapy in Clinical Practice

Author

Alberto Borghetti, Andrea Giacomelli, Arturo Ciccullo, Vanni Borghi, Alex Dusina, Massimiliano Fabbiani, Maurizio Zazzi, Stefano Rusconi, Cristina Mussini, and Simona Di Giambenedetto

Subjects
0301 basic medicine, resistance-associated mutations, 030106 microbiology, maintenance therapy, dolutegravir, HIV, lamivudine, Settore MED/17 - MALATTIE INFETTIVE, Nucleoside Reverse Transcriptase Inhibitor, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Maintenance therapy, Medicine, 030212 general & internal medicine, business.industry, Brief Report, Lamivudine, Resistance mutation, Virology, Clinical Practice, AcademicSubjects/MED00290, Infectious Diseases, Oncology, chemistry, Dolutegravir, Thymidine, business, Nucleoside, medicine.drug
Abstract

The TANGO trial demonstrated the efficacy of lamivudine plus dolutegravir in virologically suppressed patients without previous virological failures (VFs). In this dataset from clinical practice investigating the impact of past nucleoside reverse-transcriptase inhibitor resistance on this strategy, the combination of M184V/I plus at least 1 thymidine analog-associated mutation significantly increased the risk of VF.

Published
2021

21. Durability of Dolutegravir-Based Regimens: A 5-Year Prospective Observational Study

Author

Lucia, Taramasso, Andrea, De Vito, Elena Delfina, Ricci, Giancarlo, Orofino, Nicola, Squillace, Barbara, Menzaghi, Chiara, Molteni, Roberto, Gulminetti, Giuseppe Vittorio, De Socio, Giovanni Francesco, Pellicanò, Eleonora, Sarchi, Benedetto Maurizio, Celesia, Leonardo, Calza, Stefano, Rusconi, Laura, Valsecchi, Canio Vito, Martinelli, Antonio, Cascio, Paolo, Maggi, Francesca, Vichi, Goffredo, Angioni, Giuliana, Guadagnino, Giovanni, Cenderello, Chiara, Dentone, Alessandra, Bandera, Katia, Falasca, Paolo, Bonfanti, Antonio, Di Biagio, Giordano, Madeddu, M, Guastavigna, Taramasso, L., De Vito, A., Ricci, E. D., Orofino, G., Squillace, N., Menzaghi, B., Molteni, C., Gulminetti, R., De Socio, G. V., Pellicano, G. F., Sarchi, E., Celesia, B. M., Calza, L., Rusconi, S., Valsecchi, L., Martinelli, C. V., Cascio, A., Maggi, P., Vichi, F., Angioni, G., Guadagnino, G., Cenderello, G., Dentone, C., Bandera, A., Falasca, K., Bonfanti, P., Di Biagio, A., Madeddu, G., Taramasso L, De Vito A, Ricci ED, Orofino G, Squillace N, Menzaghi B, Molteni C, Gulminetti R, De Socio GV, Pellicanò GF, Sarchi E, Celesia BM, Calza L, Rusconi S, Valsecchi L, Martinelli CV, Cascio A, Maggi P, Vichi F, Angioni G, Guadagnino G, Cenderello G, Dentone C, Bandera A, Falasca K, Bonfanti P, Di Biagio A, Madeddu G, Taramasso L., De Vito A., Ricci E.D., Orofino G., Squillace N., Menzaghi B., Molteni C., Gulminetti R., De Socio G.V., Pellicano G.F., Sarchi E., Celesia B.M., Calza L., Rusconi S., Valsecchi L., Martinelli C.V., Cascio A., Maggi P., Vichi F., Angioni G., Guadagnino G., Cenderello G., Dentone C., Bandera A., Falasca K., Bonfanti P., Di Biagio A., Madeddu G., Taramasso, L, De Vito, A, Ricci, E, Orofino, G, Squillace, N, Menzaghi, B, Molteni, C, Gulminetti, R, De Socio, G, Pellicanò, G, Sarchi, E, Celesia, B, Calza, L, Rusconi, S, Valsecchi, L, Martinelli, C, Cascio, A, Maggi, P, Vichi, F, Angioni, G, Guadagnino, G, Cenderello, G, Dentone, C, Bandera, A, Falasca, K, Bonfanti, P, Di Biagio, A, and Madeddu, G

Subjects
adverse events, dolutegravir, durability, HIV, safety, toxicity, virolgical failure, Cohort Studies, Female, Heterocyclic Compounds, 3-Ring, Humans, Middle Aged, Oxazines, Piperazines, Prospective Studies, Pyridones, Anti-HIV Agents, HIV Infections, Pediatrics, medicine.medical_specialty, Settore MED/17 - Malattie Infettive, Oxazine, Human immunodeficiency virus (HIV), adverse event, Pyridone, medicine.disease_cause, 3-Ring, chemistry.chemical_compound, Heterocyclic Compounds, Antiretroviral treatment, Medicine, Adverse effect, Piperazine, business.industry, Public Health, Environmental and Occupational Health, Anti-HIV Agent, Discontinuation, Prospective Studie, Infectious Diseases, chemistry, Dolutegravir, Observational study, Cohort Studie, business, Human
Abstract

This study evaluates the frequency and causes of dolutegravir (DTG) discontinuation along 5 years of follow-up, in both antiretroviral treatment (ART)-naive and experienced people living with HIV (PLWH). This is a prospective multi-center cohort study enrolling PLWH on DTG from July 2014 until November 2020. DTG-durability was investigated using the Kaplan-Meier survival curve. The Cox proportional-hazards model was used for estimating the hazard ratio (HR) of DTG discontinuation for any cause, and for adverse events (AEs). Nine hundred sixty-three PLWH were included, 25.3% were women and 28.0% were ART-naive. Discontinuations for any causes were 10.1 [95% confidence interval (95% CI) 8.9-11.5] per 100 person-years, similar in most regimens, with the apparent exception of tenofovir alafenamide/emtricitabine+DTG (p

Published
2021

22. Genetic mechanisms of critical illness in COVID-19

Author

Pairo-Castineira, Erola, Clohisey, Sara, Klaric, Lucija, Bretherick, Andrew D, Rawlik, Konrad, Pasko, Dorota, Walker, Susan, Parkinson, Nick, Fourman, Max Head, Russell, Clark D, Furniss, James, Richmond, Anne, Gountouna, Elvina, Wrobel, Nicola, Harrison, David, Wang, Bo, Yang, Wu, Meynert, Alison, Griffiths, Fiona, Oosthuyzen, Wilna, Kousathanas, Athanasios, Moutsianas, Loukas, Yang, Zhijian, Zhai, Ranran, Zheng, Chenqing, Grimes, Graeme, Beale, Rupert, Millar, Jonathan, Shih, Barbara, Keating, Sean, Zechner, Marie, Haley, Chris, Porteous, David J, Hayward, Caroline, Yang, Jian, Knight, Julian, Summers, Charlotte, Shankar-Hari, Manu, Klenerman, Paul, Turtle, Lance, Antonia, Ho, Moore, Shona C, Hinds, Charles, Horby, Peter, Nichol, Alistair, Maslove, David, Ling, Lowell, Mcauley, Danny, Montgomery, Hugh, Walsh, Timothy, Pereira, Alexandre C, Renieri, Johnny, Millar, Alistair, Nichol, Tim, Walsh, Manu, Shankar-Hari, Chris, Ponting, Jen, Meikle, Paul, Finernan, Ellie, Mcmaster, Andy, Law, J Kenneth Baillie, Trevor, Paterson, Tony, Wackett, Ruth, Armstrong, Richard, Clark, Audrey, Coutts, Lorna, Donnelly, Tammy, Gilchrist, Katarzyna, Hafezi, Louise, Macgillivray, Alan, Maclean, Sarah, Mccafferty, Kirstie, Morrice, Jane, Weaver, Ceilia, Boz, Ailsa, Golightly, Mari, Ward, Hanning, Mal, Helen, Szoor-McElhinney, Adam, Brown, Ross, Hendry, Andrew, Stenhouse, Louise, Cullum, Dawn, Law, Sarah, Law, Rachel, Law, Maaike, Swets, Nicky, Day, Filip, Taneski, Esther, Duncan, Nicholas, Parkinson, Collier, D, Wood, S, Zak, A, Borra, C, Matharu, M, May, P, Alldis, Z, Mitchelmore, O, Bowles, R, Easthope, A, Bibi, F, Lancoma-Malcolm, I, Gurasashvili, J, Pheby, J, Shiel, J, Bolton, M, Patel, M, Taylor, M, Zongo, O, Ebano, P, Harding, P, Astin-Chamberlain, R, Choudhury, Y, Cox, A, Kallon, D, Burton, M, Hall, R, Blowes, S, Prime, Z, Biddle, J, Prysyazhna, O, Newman, T, Tierney, C, Kassam, J, Shankar-Hari, M, Ostermann, M, Campos, S, Bociek, A, Lim, R, Grau, N, O Jones, T, Whitton, C, Marotti, M, Arbane, G, Bonner, S, Hugill, K, Reid, J, Welters, I, Waugh, V, Williams, K, Shaw, D, J Fernandez Roman, M Lopez Martinez, Johnson, E, Waite, A, Johnston, B, Hamilton, D, Mulla, S, Mcphail, M, Smith, J, K Baillie, J, Barclay, L, Hope, D, Mcculloch, C, Mcquillan, L, Clark, S, Singleton, J, Priestley, K, Rea, N, Callaghan, M, Campbell, R, Andrew, G, Marshall, L, Mckechnie, S, Hutton, P, Bashyal, A, Davidson, N, Summers, C, Polgarova, P, Stroud, K, Pathan, N, Elston, K, Agrawal, S, Battle, C, Newey, L, Rees, T, Harford, R, Brinkworth, E, Williams, M, Murphy, C, White, I, Croft, M, Bandla, N, Gellamucho, M, Tomlinson, J, Turner, H, Davies, M, Quinn, A, Hussain, I, Thompson, C, Parker, H, Bradley, R, Griffiths, R, Scriven, J, Nilsson, A, Bates, M, Dasgin, J, Gill, J, Puxty, A, Cathcart, S, Salutous, D, Turner, L, Duffy, K, Puxty, K, Joseph, A, Herdman-Grant, R, Simms, R, Swain, A, Naranjo, A, Crowe, R, Sollesta, K, Loveridge, A, Baptista, D, Morino, E, Davey, M, Golden, D, Jones, J, J Moreno Cuesta, Haldeos, A, Bakthavatsalam, D, Vincent, R, Elhassan, M, Xavier, K, Ganesan, A, Purohit, D, Abdelrazik, M, Morgan, J, Akeroyd, L, Bano, S, Lawton, T, Warren, D, Bromley, M, Sellick, K, Gurr, L, Wilkinson, B, Nagarajan, V, Szedlak, P, Cupitt, J, Stoddard, E, Benham, L, Preston, S, Laha, S, Slawson, N, Bradshaw, Z, Brown, J, Caswell, M, Melling, S, Bamford, P, Faulkner, M, Cawley, K, Jeffrey, H, London, E, Sainsbury, H, Nagra, I, Nasir, F, Dunmore, C, Jones, R, Abraheem, A, Al-Moasseb, M, Girach, R, Padden, G, Egan, J, Brantwood, C, Alexander, P, Bradley-Potts, J, Allen, S, Felton, T, Manna, S, Farnell-Ward, S, Leaver, S, Queiroz, J, Maccacari, E, Dawson, D, C Castro Delgado, R Pepermans Saluzzio, Ezeobu, O, Ding, L, Sicat, C, Kanu, R, Durrant, G, Texeira, J, Harrison, A, Samakomva, T, Willis, H, Hopkins, B, Thrasyvoulou, L, Jackson, M, Zaki, A, Tibke, C, Bennett, S, Woodyatt, W, Kent, A, Goodwin, E, Brandwood, C, Clark, R, Smith, L, Rooney, K, Thomson, N, Rodden, N, Hughes, E, Mcglynn, D, Clark, C, Clark, P, Abel, L, Sundaram, R, Gemmell, L, Brett, M, Hornsby, J, Macgoey, P, Price, R, Digby, B, O'Neil, P, Mcconnell, P, Henderson, P, Henderson, S, Sim, M, Kennedy-Hay, S, Mcparland, C, Rooney, L, Baxter, N, Pogson, D, Rose, S, Daly, Z, Brimfield, L, K Phull, M, Hussain, M, Pogreban, T, Rosaroso, L, Salciute, E, Grauslyte, L, Brealey, D, Raith, E, Maccallum, N, Bercades, G, Hass, I, Smyth, D, Reyes, A, Martir, G, D Clement, I, Webster, K, Hays, C, Gulati, A, Hodgson, L, Margarson, M, Gomez, R, Baird, Y, Thirlwall, Y, Folkes, L, Butler, A, Meadows, E, Moore, S, Raynard, D, Fox, H, Riddles, L, King, K, Kimber, S, Hobden, G, Mccarthy, A, Cannons, V, Balagosa, I, Chadbourn, I, Gardner, A, Horner, D, Mclaughlanv, D, Charles, B, Proudfoot, N, Marsden, T, Mcmorrow, L, Blackledge, B, Pendlebury, J, Harvey, A, Apetri, E, Basikolo, C, Catlow, L, Doonan, R, Knowles, K, Lee, S, Lomas, D, Lyons, C, Perez, J, Poulaka, M, Slaughter, M, Slevin, K, Thomas, V, Walker, D, Harris, J, Drummond, A, Tully, R, Dearden, J, Philbin, J, Munt, S, Rishton, C, O'Connor, G, Mulcahy, M, Dobson, E, Cuttler, J, Edward, M, Norris, J, Hanson, K, Poole, A, Rose, A, Sloan, B, Buckley, S, Brooke, H, Smithson, E, Charlesworth, R, Sandhu, R, Thirumaran, M, Wagstaff, V, J Cebrian Suarez, Kaliappan, A, Vertue, M, Nicholson, A, Riches, J, Solesbury, A, Kittridge, L, Forsey, M, Maloney, G, Cole, J, Davies, R, Hill, H, Thomas, E, Williams, A, Duffin, D, Player, B, Radhakrishnan, J, Gibson, S, Lyle, A, Mcneela, F, Patel, B, Gummadi, M, Sloane, G, Dormand, N, Salmi, S, Farzad, Z, Cristiano, D, Liyanage, K, Thwaites, V, Varghese, M, Meredith, M, Mills, G, Willson, J, Harrington, K, Lenagh, B, Cawthron, K, Masuko, S, Raithatha, A, Bauchmuller, K, Wiles, M, Ahmad, N, Barker, J, Jackson, Y, Kibutu, F, Bird, S, Watson, G, Martin, J, Bevan, E, C Wrey Brown, Trodd, D, English, K, Bell, G, Wilcox, L, Katary, A, Gopal, S, Lake, V, Harris, N, Metherell, S, Radford, E, Moore, F, Bancroft, H, Daglish, J, Sangombe, M, Carmody, M, Rhodes, J, Bellamy, M, Garg, A, Kuravi, A, Virgilio, E, Ranga, P, Butler, J, Botfield, L, Dexter, C, Fletcher, J, Shanmugasundaram, P, Hambrook, G, Burn, I, Manso, K, Thornton, D, Tebbutt, J, Penn, R, Hulme, J, Hussain, S, Maqsood, Z, Joseph, S, Colley, J, Hayes, A, Ahmed, C, Haq, R, Clamp, S, Kumar, R, Purewal, M, Baines, B, Frise, M, Jacques, N, Coles, H, Caterson, J, S Gurung Rai, Brunton, M, Tilney, E, Keating, L, Walden, A, Antcliffe, D, Brett, S, Gordon, A, Templeton, M, Rojo, R, Banach, D, S Sousa Arias, Fernandez, Z, Coghlan, P, Williams, D, Jardine, C, Bewley, J, Sweet, K, Grimmer, L, Johnson, R, Garland, Z, Gumbrill, B, Phillips, C, L Ortiz-Ruiz de Gordoa, Peasgood, E, Tridente, A, Shuker, K, Greer, S, Lynch, C, Pothecary, C, Roche, L, Deacon, B, Turner, K, Singh, J, G Sera Howe, Paul, P, Gill, M, Wynter, I, Ratnam, V, Shelton, S, Naisbitt, J, Melville, J, Baruah, R, Morrison, S, Mcgregor, A, Parris, V, Mpelembue, M, Srikaran, S, Dennis, C, Sukha, A, Verlander, M, Holding, K, Riches, K, Downes, C, Swan, C, Rostron, A, Roy, A, Woods, L, Cornell, S, Wakinshaw, F, Creagh-Brown, B, Blackman, H, Salberg, A, Smith, E, Donlon, S, Mtuwa, S, Michalak-Glinska, N, Stone, S, Beazley, C, Pristopan, V, Nikitas, N, Lankester, L, Wells, C, S Raj, A, Fletcher, K, Khade, R, Tsinaslanidis, G, Macmahon, M, Fowler, S, Coventry, T, Stewart, R, Wren, L, Mwaura, E, Mew, L, Scaletta, D, Williams, F, Inweregbu, K, Lancaster, N, Cunningham, M, Daniels, A, Harrison, L, Hope, S, Jones, S, Crew, A, Wray, G, Matthews, J, Crawley, R, Carter, J, Birkinshaw, I, Ingham, J, Scott, Z, Pearson, H, Howard, K, Joy, R, Roche, S, Clark, M, Purvis, S, Morrison, A, Strachan, D, Clements, S, Black, K, Parmar, C, Altabaibeh, A, Simpson, K, Mostoles, L, Gilbert, K, L, Ma, Alvaro, A, Thomas, M, Faulkner, B, Worner, R, Hayes, K, Gendall, E, Blakemore, H, Borislavova, B, Goff, E, Vuylsteke, A, Mwaura, L, Zamikula, J, Garner, L, Mitchell, A, Mepham, S, Cagova, L, Fofano, A, Holcombe, H, Praman, K, Szakmany, T, E Heron, A, Cherian, S, Cutler, S, Roynon-Reed, A, Randell, G, Convery, K, Stammers, K, Fottrell-Gould, D, Hudig, L, Keshet-Price, J, Peters, M, O'Neill, L, Ray, S, Belfield, H, Mchugh, T, Jones, G, Akinkugbe, O, Tomas, A, Abaleke, E, Beech, E, Meghari, H, Yussuf, S, Bamford, A, Hairsine, B, Dooks, E, Farquhar, F, Packham, S, Bates, H, Armstrong, L, Kaye, C, Allan, A, Medhora, J, Liew, J, Botello, A, Anderson, F, Cusack, R, Golding, H, Prager, K, Williams, T, Leggett, S, Golder, K, Male, M, Jones, O, Criste, K, Marani, M, Anumakonda, V, Amin, V, Karthik, K, Kausar, R, Anastasescu, E, Reid, K, Smith, M, Hormis, A, Walker, R, Duncan, T, Uriel, A, Ustianowski, A, T-Michael, H, Bruce, M, Connolly, K, Smith, K, Partridge, R, Griffin, D, Mupudzi, M, Muchenje, N, Martin, D, Filipe, H, Eastgate, C, Jackson, C, Gratrix, A, Foster, L, Martinson, V, Stones, E, Caroline, Abernathy, Parkinson, P, Reed, A, Prendergast, C, Rogers, P, Woodruff, M, Shokkar, R, Kaul, S, Barron, A, Collins, C, Beavis, S, Whileman, A, Dale, K, Hawes, J, Pritchard, K, Gascoyne, R, Stevenson, L, Jha, R, Lim, L, Krishnamurthy, V, Parker, R, Turner-Bone, I, Wilding, L, Reddy, A, Whiteley, S, Wilby, E, Howcroft, C, Aspinwall, A, Charlton, S, Ogg, B, Menzies, D, Pugh, R, Allan, E, Lean, R, Davies, F, Easton, J, Qiu, X, Kumar, S, Darlington, K, Houston, G, O'Brien, P, Geary, T, Allan, J, Meikle, A, Hughes, G, Balasubramaniam, M, Latham, S, Mckenna, E, Flanagan, R, Sathe, S, Davies, E, Chablani, M, Kirkby, A, Netherton, K, Archer, S, Yates, B, Ashbrook-Raby, C, Cole, S, Casey, M, Cabrelli, L, Chapman, S, Hutcheon, A, Whyte, C, Almaden-Boyle, C, Pattison, N, Cruz, C, Vochin, A, Kent, H, Thomas, A, Murdoch, S, David, B, Penacerrada, M, Lubimbi, G, Bastion, V, Wulandari, R, Lorusso, R, Valentine, J, Clarke, D, Serrano-Ruiz, A, Hierons, S, Eckbad, C, Ramos, L, Demetriou, C, Mitchard, S, White, K, White, N, Pitts, S, Branney, D, Frankham, J, Watters, M, Langton, H, Prout, R, Page, V, Varghes, T, Cowton, A, Kay, A, Potts, K, Birt, M, Kent, M, Wilkinson, A, B Jude, E, Turner, V, Savill, H, Mccormick, J, Coulding, M, Siddiqui, S, Mercer, O, Rehman, H, Potla, D, Capps, N, Donaldson, D, Button, H, Martin, T, Hard, K, Agasou, A, Tonks, L, Arden, T, Boyle, P, Carnahan, M, Strickley, J, Adams, C, Childs, D, Rikunenko, R, Leigh, M, Breekes, M, Wilcox, R, Bowes, A, Tiveran, H, Hurford, F, Summers, J, Carter, A, Hussain, Y, Ting, L, Javaid, A, Motherwell, N, Moore, H, Millward, H, Jose, S, Schunki, N, Noakes, A, Clulow, C, Sadera, G, Jacob, R, Jones, C, Blunt, M, Coton, Z, Curgenven, H, S Mohamed Ally, Beaumont, K, Elsaadany, M, Fernandes, K, I Ali Mohamed Ali, Rangarajan, H, Sarathy, V, Selvanayagam, S, Vedage, D, White, M, Truman, N, Chukkambotla, S, Keith, S, Cockerill-Taylor, J, Ryan-Smith, J, Bolton, R, Springle, P, Dykes, J, Thomas, J, Khan, M, T Hijazi, M, Massey, E, Croston, G, Reschreiter, H, Camsooksai, J, Patch, S, Jenkins, S, Humphrey, C, Wadams, B, Msiska, M, Adanini, O, Attwood, B, Parsons, P, Tatham, K, Jhanji, S, Black, E, A Dela Rosa, Howle, R, Thomas, B, Bemand, T, Raobaikady, R, Saha, R, Staines, N, Daniel, A, Finn, J, Hutter, J, Doble, P, Shovelton, C, Pawley, C, Kannan, T, Hill, M, Combes, E, Monnery, S, Joefield, T, Popescu, M, Thankachen, M, Oblak, M, Little, J, Mcivor, S, Brady, A, Whittle, H, Prady, H, Chan, R, Ahmed, A, Morris, A, Gibson, C, Gordon, E, Keenan, S, Quinn, H, Benyon, S, Marriott, S, Zitter, L, Park, L, Baines, K, Lyons, M, Holland, M, Keenan, N, Young, M, Garrioch, S, Dawson, J, Tolson, M, Scholefield, B, R, Bi, Richardson, N, Schumacher, N, Cosier, T, Millen, G, Higham, A, Turki, S, Allen, L, Crisp, N, Hazleton, T, Knight, A, Deery, J, Price, C, Turney, S, Tilbey, S, Beranova, E, Wright, D, George, L, Twiss, S, Wadd, S, Postlethwaite, K, Gondo, P, Masunda, B, Kayani, A, Hadebe, B, Whiteside, J, Clarke, N, Donnison, P, Trim, F, Leadbitter, I, Butcher, D, O'Sullivan, S, Purewal, B, Bell, S, Rivers, V, O'Leary, R, Birch, J, Collins, E, Anderson, S, Hammerton, K, Andrews, E, Burns, K, Edmond, I, Todd, A, Donnachie, J, Turner, P, Prentice, L, Symon, L, Runciman, N, Auld, F, Halkes, M, Mercer, P, Thornton, L, Debreceni, G, Wilkins, J, Brown, A, Crickmore, V, Subramanian, G, Marshall, R, Jennings, C, Latif, M, Bunni, L, Spivey, M, Bean, S, Burt, K, Linnett, V, Ritzema, J, Sanderson, A, Mccormick, W, Bokhari, M, Kapoor, R, Loader, D, Ayers, A, Harrison, W, North, J, Belagodu, Z, Paramsothy, R, Olufuwa, O, Gherman, A, Fuller, B, Stuart, C, Kelsall, O, Davis, C, Wild, L, Wood, H, Thrush, J, Durie, A, Austin, K, Archer, K, Anderson, P, Vigurs, C, Thorpe, C, Knights, E, Boyle, N, Price, A, Kubisz-Pudelko, A, Wood, D, Lewis, A, Board, S, Pippard, L, Perry, J, Beesley, K, Rattray, A, Lee, E, Lennon, L, Douglas, K, Bell, D, Boyle, R, Glass, L, M Nauman Akhtar, Dent, K, Potoczna, D, Pearson, S, Horsley, E, Spencer, S, Mullan, D, Skinner, D, Gaylard, J, Barber, R, Hewitt, C, Hilldrith, A, Shepardson, S, Wills, M, Jackson-Lawrence, K, Gupta, A, Timlick, E, Gorman, C, Otahal, I, Gales, A, Coetzee, S, Sell, C, Raj, M, Peiu, M, Quaid, S, Watson, E, Elliott, K, Mallinson, J, Chandler, B, Turnbull, A, Finch, C, Holl, C, Cooper, J, Evans, A, Khaliq, W, Collins, A, E Treus Gude, Love, N, L van Koutrik, Hunt, J, Kaye, D, Fisher, E, Brayne, A, Tuckey, V, Jackson, P, Parkin, J, Tariq, A, Houlden, H, Tucci, A, Hardy, J, Moncur, E, Highgate, J, Cowley, A, Mitra, A, Stead, R, Behan, T, Burnett, C, Newton, M, Heeney, E, Pollard, R, Hatton, J, Patel, A, Kasipandian, V, Allibone, S, M Genetu, R, O'Brien, L, Omar, Z, Perkins, E, Davies, K, Tetla, D, Shelley, B, Irvine, V, Williams, S, Williams, P, Goodsell, J, Tutton, R, Bough, L, Winter-Goodwin, B, Kitson, R, Pinnell, J, Wilson, A, Nortcliffe, T, Wood, T, Home, M, Holdroyd, K, Robinson, M, Shaw, R, Greig, J, Brady, M, Haigh, A, Matupe, L, Usher, M, Mellor, S, Dale, S, Gledhill, L, Shaw, L, Turner, G, Kelly, D, Anwar, B, Riley, H, Sturgeon, H, Ali, A, Thomis, L, Melia, D, Dance, A, Humphreys, S, Frost, I, Gopal, V, Godden, J, Holden, A, Swann, S, Smith, T, Clapham, M, Poultney, U, Harper, R, Rice, P, Reece-Anthony, R, Gurung, B, Moultrie, S, Odam, M, Mayer, A, Bellini, A, Pickard, A, Bryant, J, Roe, N, Sowter, J, Lang, K, Taylor, J, Barry, P, Hobrok, M, Tench, H, Wolf-Roberts, R, Mcguinness, H, Loosley, R, Hawcutt, D, Rad, L, O'Malley, L, Saunderson, P, Seddon, G, Anderson, T, Rogers, N, Ruddy, J, Harkins, M, Beith, C, Mcalpine, A, Ferguson, L, Grant, P, Macfadyen, S, Mclaughlin, M, Baird, T, Rundell, S, Welsh, B, Hamill, R, Fisher, F, Gregory, J, Campbell, A, Smuts, S, Gail, Carson, Beatrice, Alex, Benjamin, Bach, Wendy, S Barclay, Debby, Bogaert, Meera, Chand, Graham, S Cooke, Annemarie, B Docherty, Jake, Dunning, Ana da Silva Filipe, Tom, Fletcher, Christoper, A Green, Ewen, M Harrison, Julian, A Hiscox, Antonia Ying Wai Ho, Peter, W Horby, Samreen, Ijaz, Saye, Khoo, Paul, Klenerman, Wei Shen Lim, Alexander, J Mentzer, Laura, Merson, Alison, M Meynert, Mahdad, Noursadeghi, Shona, C Moore, Massimo, Palmarini, William, A Paxton, Georgios, Pollakis, Nicholas, Price, Andrew, Rambaut, David, L Robertson, Vanessa, Sancho-Shimizu, Janet, T Scott, Thushan de Silva, Louise, Sigfrid, Tom, Solomon, Shiranee, Sriskandan, David, Stuart, Richard, S Tedder, Emma, C Thomson, A Roger Thompson, A, Ryan, S Thwaites, Lance C, W Turtle, Maria, Zambon, Hayley, Hardwick, Chloe, Donohue, Ruth, Lyons, Lisa, Norman, Riinu, Pius, Thomas, M Drake, Cameron, J Fairfield, Stephen, R Knight, Kenneth, A Mclean, Derek, Murphy, Catherine, A Shaw, Dalton, Jo, Michelle, Girvan, Egle, Saviciute, Stephanie, Roberts, Janet, Harrison, Laura, Marsh, Marie, Connor, Sophie, Halpin, Clare, Jackson, Carrol, Gamble, Gary, Leeming, Murray, Wham, William, Greenhalf, Victoria, Shaw, Sara, Mcdonald, Seán, Keating, Andrea, Ganna, Patrick, Sulem, David, A van Heel, Mattia, Cordioli, Gardar, Sveinbjornsson, Mari E, K Niemi, Janie, F Shelton, Anjali, J Shastri, Chelsea, Ye, Catherine, H Weldon, Teresa, Filshtein-Sonmez, Daniella, Coker, Antony, Symons, Jorge, Esparza-Gordillo, Stella, Aslibekyan, Adam, Auton, Jose, E Krieger, Emmanuelle, Marques, Cinthia, E Jannes, Mari, Francesca, Daga, Sergio, Baldassarri, Margherita, Benetti, Elisa, Simone, Furini, Fallerini, Chiara, Fava, Francesca, Floriana, Valentino, Gabriella, Doddato, Annarita, Giliberti, Tita, Rossella, Amitrano, Sara, Bruttini, Mirella, Croci, Susanna, Meloni, Ilaria, Pinto, ANNA MARIA, Frullanti, Elisa, Mencarelli, MARIA ANTONIETTA, LO RIZZO, Caterina, Montagnani, Francesca, DI SARNO, Laura, Tommasi, Andrea, Palmieri, Maria, Emiliozzi, Arianna, Fabbiani, Massimiliano, Rossetti, Barbara, Zanelli, Giacomo, Bargagli, Elena, Bergantini, Laura, D'Alessandro, Miriana, Cameli, Paolo, David, Bennet, Anedda, Federico, Marcantonio, Simona, Scolletta, Sabino, Franchi, Federico, Mazzei, MARIA ANTONIETTA, Guerrini, Susanna, Conticini, Edoardo, Cantarini, Luca, Frediani, Bruno, Danilo, Tacconi, SPERTILLI RAFFAELLI, Chiara, Marco, Feri, Alice, Donati, Scala, Raffaele, Luca, Guidelli, Genni, Spargi, Marta, Corridi, Cesira, Nencioni, Croci, Leonardo, Gian Piero Caldarelli, Maurizio, Spagnesi, Paolo, Piacentini, Maria, Bandini, Elena, Desanctis, Cappelli, Silvia, Anna, Canaccini, Verzuri, Agnese, Valentina, Anemoli, Agostino, Ognibene, Massimo, Vaghi, Antonella D'Arminio Monforte, Esther, Merlini, Mario, U Mondelli, Stefania, Mantovani, Serena, Ludovisi, Massimo, Girardis, Sophie, Venturelli, Marco, Sita, Andrea, Cossarizza, Andrea, Antinori, Alessandra, Vergori, Stefano, Rusconi, Matteo, Siano, Arianna, Gabrieli, Agostino, Riva, Daniela, Francisci, Elisabetta, Schiaroli, Pier Giorgio Scotton, Francesca, Andretta, Sandro, Panese, Renzo, Scaggiante, Francesca, Gatti, Saverio Giuseppe Parisi, Francesco, Castelli, Maria Eugenia Quiros-Roldan, Paola, Magro, Isabella, Zanella, Matteo Della Monica, Carmelo, Piscopo, Mario, Capasso, Roberta, Russo, Immacolata, Andolfo, Achille, Iolascon, Giuseppe, Fiorentino, Massimo, Carella, Marco, Castori, Giuseppe, Merla, Filippo, Aucella, Pamela, Raggi, Carmen, Marciano, Rita, Perna, Matteo, Bassetti, Antonio Di Biagio, Maurizio, Sanguinetti, Luca, Masucci, Valente, Serafina, Marco, Mandalà, Giorli, Alessia, Salerni, Lorenzo, Patrizia, Zucchi, Pierpaolo, Parravicini, Elisabetta, Menatti, Stefano, Baratti, Tullio, Trotta, Ferdinando, Giannattasio, Gabriella, Coiro, Fabio, Lena, Domenico, A Coviello, Cristina, Mussini, Giancarlo, Bosio, Enrico, Martinelli, Sandro, Mancarella, Luisa, Tavecchia, Lia, Crotti, Nicola, Picchiotti, Marco, Gori, Chiara, Gabbi, Maurizio, Sanarico, Stefano, Ceri, Pietro, Pinoli, Francesco, Raimondi, Filippo, Biscarini, Alessandra, Stella, Alessandra, Shen, Xia, Ponting, Chris P, Fawkes, Angie, Tenesa, Albert, Caulfield, Mark, Scott, Richard, Rowan, Kathy, Murphy, Lee, Openshaw, Peter J M, Semple, Malcolm G, Law, Andrew, Vitart, Veronique, Wilson, James F, Baillie, J Kenneth, Pairo-Castineira, E, Clohisey, S, Klaric, L, Bretherick, A, Rawlik, K, Pasko, D, Walker, S, Parkinson, N, Fourman, M, Russell, C, Furniss, J, Richmond, A, Gountouna, E, Wrobel, N, Harrison, D, Wang, B, Wu, Y, Meynert, A, Griffiths, F, Oosthuyzen, W, Kousathanas, A, Moutsianas, L, Yang, Z, Zhai, R, Zheng, C, Grimes, G, Beale, R, Millar, J, Shih, B, Keating, S, Zechner, M, Haley, C, Porteous, D, Hayward, C, Yang, J, Knight, J, Summers, C, Shankar-Hari, M, Klenerman, P, Turtle, L, Ho, A, Moore, S, Hinds, C, Horby, P, Nichol, A, Maslove, D, Ling, L, Mcauley, D, Montgomery, H, Walsh, T, Pereira, A, Renieri, A, Ponting, C, Meikle, J, Finernan, P, Mcmaster, E, Law, A, Baillie, J, Paterson, T, Wackett, T, Armstrong, R, Clark, R, Coutts, A, Donnelly, L, Gilchrist, T, Hafezi, K, Macgillivray, L, Maclean, A, Mccafferty, S, Morrice, K, Weaver, J, Boz, C, Golightly, A, Ward, M, Mal, H, Szoor-McElhinney, H, Brown, A, Hendry, R, Stenhouse, A, Cullum, L, Law, D, Law, S, Law, R, Swets, M, Day, N, Taneski, F, Duncan, E, Collier, D, Wood, S, Zak, A, Borra, C, Matharu, M, May, P, Alldis, Z, Mitchelmore, O, Bowles, R, Easthope, A, Bibi, F, Lancoma-Malcolm, I, Gurasashvili, J, Pheby, J, Shiel, J, Bolton, M, Patel, M, Taylor, M, Zongo, O, Ebano, P, Harding, P, Astin-Chamberlain, R, Choudhury, Y, Cox, A, Kallon, D, Burton, M, Hall, R, Blowes, S, Prime, Z, Biddle, J, Prysyazhna, O, Newman, T, Tierney, C, Kassam, J, Ostermann, M, Campos, S, Bociek, A, Lim, R, Grau, N, Jones, T, Whitton, C, Marotti, M, Arbane, G, Bonner, S, Hugill, K, Reid, J, Welters, I, Waugh, V, Williams, K, Shaw, D, Roman, J, Martinez, M, Johnson, E, Waite, A, Johnston, B, Hamilton, D, Mulla, S, Mcphail, M, Smith, J, Barclay, L, Hope, D, Mcculloch, C, Mcquillan, L, Clark, S, Singleton, J, Priestley, K, Rea, N, Callaghan, M, Campbell, R, Andrew, G, Marshall, L, Mckechnie, S, Hutton, P, Bashyal, A, Davidson, N, Polgarova, P, Stroud, K, Pathan, N, Elston, K, Agrawal, S, Battle, C, Newey, L, Rees, T, Harford, R, Brinkworth, E, Williams, M, Murphy, C, White, I, Croft, M, Bandla, N, Gellamucho, M, Tomlinson, J, Turner, H, Davies, M, Quinn, A, Hussain, I, Thompson, C, Parker, H, Bradley, R, Griffiths, R, Scriven, J, Nilsson, A, Bates, M, Dasgin, J, Gill, J, Puxty, A, Cathcart, S, Salutous, D, Turner, L, Duffy, K, Puxty, K, Joseph, A, Herdman-Grant, R, Simms, R, Swain, A, Naranjo, A, Crowe, R, Sollesta, K, Loveridge, A, Baptista, D, Morino, E, Davey, M, Golden, D, Jones, J, Moreno Cuesta, J, Haldeos, A, Bakthavatsalam, D, Vincent, R, Elhassan, M, Xavier, K, Ganesan, A, Purohit, D, Abdelrazik, M, Morgan, J, Akeroyd, L, Bano, S, Lawton, T, Warren, D, Bromley, M, Sellick, K, Gurr, L, Wilkinson, B, Nagarajan, V, Szedlak, P, Cupitt, J, Stoddard, E, Benham, L, Preston, S, Laha, S, Slawson, N, Bradshaw, Z, Brown, J, Caswell, M, Melling, S, Bamford, P, Faulkner, M, Cawley, K, Jeffrey, H, London, E, Sainsbury, H, Nagra, I, Nasir, F, Dunmore, C, Jones, R, Abraheem, A, Al-Moasseb, M, Girach, R, Padden, G, Egan, J, Brantwood, C, Alexander, P, Bradley-Potts, J, Allen, S, Felton, T, Manna, S, Farnell-Ward, S, Leaver, S, Queiroz, J, Maccacari, E, Dawson, D, Delgado, C, Saluzzio, R, Ezeobu, O, Ding, L, Sicat, C, Kanu, R, Durrant, G, Texeira, J, Harrison, A, Samakomva, T, Willis, H, Hopkins, B, Thrasyvoulou, L, Jackson, M, Zaki, A, Tibke, C, Bennett, S, Woodyatt, W, Kent, A, Goodwin, E, Brandwood, C, Smith, L, Rooney, K, Thomson, N, Rodden, N, Hughes, E, Mcglynn, D, Clark, C, Clark, P, Abel, L, Sundaram, R, Gemmell, L, Brett, M, Hornsby, J, Macgoey, P, Price, R, Digby, B, O'Neil, P, Mcconnell, P, Henderson, P, Henderson, S, Sim, M, Kennedy-Hay, S, Mcparland, C, Rooney, L, Baxter, N, Pogson, D, Rose, S, Daly, Z, Brimfield, L, Phull, M, Hussain, M, Pogreban, T, Rosaroso, L, Salciute, E, Grauslyte, L, Brealey, D, Raith, E, Maccallum, N, Bercades, G, Hass, I, Smyth, D, Reyes, A, Martir, G, Clement, I, Webster, K, Hays, C, Gulati, A, Hodgson, L, Margarson, M, Gomez, R, Baird, Y, Thirlwall, Y, Folkes, L, Butler, A, Meadows, E, Raynard, D, Fox, H, Riddles, L, King, K, Kimber, S, Hobden, G, Mccarthy, A, Cannons, V, Balagosa, I, Chadbourn, I, Gardner, A, Horner, D, Mclaughlanv, D, Charles, B, Proudfoot, N, Marsden, T, Mcmorrow, L, Blackledge, B, Pendlebury, J, Harvey, A, Apetri, E, Basikolo, C, Catlow, L, Doonan, R, Knowles, K, Lee, S, Lomas, D, Lyons, C, Perez, J, Poulaka, M, Slaughter, M, Slevin, K, Thomas, V, Walker, D, Harris, J, Drummond, A, Tully, R, Dearden, J, Philbin, J, Munt, S, Rishton, C, O'Connor, G, Mulcahy, M, Dobson, E, Cuttler, J, Edward, M, Norris, J, Hanson, K, Poole, A, Rose, A, Sloan, B, Buckley, S, Brooke, H, Smithson, E, Charlesworth, R, Sandhu, R, Thirumaran, M, Wagstaff, V, Suarez, J, Kaliappan, A, Vertue, M, Nicholson, A, Riches, J, Solesbury, A, Kittridge, L, Forsey, M, Maloney, G, Cole, J, Davies, R, Hill, H, Thomas, E, Williams, A, Duffin, D, Player, B, Radhakrishnan, J, Gibson, S, Lyle, A, Mcneela, F, Patel, B, Gummadi, M, Sloane, G, Dormand, N, Salmi, S, Farzad, Z, Cristiano, D, Liyanage, K, Thwaites, V, Varghese, M, Meredith, M, Mills, G, Willson, J, Harrington, K, Lenagh, B, Cawthron, K, Masuko, S, Raithatha, A, Bauchmuller, K, Wiles, M, Ahmad, N, Barker, J, Jackson, Y, Kibutu, F, Bird, S, Watson, G, Martin, J, Bevan, E, Brown, C, Trodd, D, English, K, Bell, G, Wilcox, L, Katary, A, Gopal, S, Lake, V, Harris, N, Metherell, S, Radford, E, Moore, F, Bancroft, H, Daglish, J, Sangombe, M, Carmody, M, Rhodes, J, Bellamy, M, Garg, A, Kuravi, A, Virgilio, E, Ranga, P, Butler, J, Botfield, L, Dexter, C, Fletcher, J, Shanmugasundaram, P, Hambrook, G, Burn, I, Manso, K, Thornton, D, Tebbutt, J, Penn, R, Hulme, J, Hussain, S, Maqsood, Z, Joseph, S, Colley, J, Hayes, A, Ahmed, C, Haq, R, Clamp, S, Kumar, R, Purewal, M, Baines, B, Frise, M, Jacques, N, Coles, H, Caterson, J, Rai, S, Brunton, M, Tilney, E, Keating, L, Walden, A, Antcliffe, D, Brett, S, Gordon, A, Templeton, M, Rojo, R, Banach, D, Arias, S, Fernandez, Z, Coghlan, P, Williams, D, Jardine, C, Bewley, J, Sweet, K, Grimmer, L, Johnson, R, Garland, Z, Gumbrill, B, Phillips, C, Ortiz-Ruiz de Gordoa, L, Peasgood, E, Tridente, A, Shuker, K, Greer, S, Lynch, C, Pothecary, C, Roche, L, Deacon, B, Turner, K, Singh, J, Howe, G, Paul, P, Gill, M, Wynter, I, Ratnam, V, Shelton, S, Naisbitt, J, Melville, J, Baruah, R, Morrison, S, Mcgregor, A, Parris, V, Mpelembue, M, Srikaran, S, Dennis, C, Sukha, A, Verlander, M, Holding, K, Riches, K, Downes, C, Swan, C, Rostron, A, Roy, A, Woods, L, Cornell, S, Wakinshaw, F, Creagh-Brown, B, Blackman, H, Salberg, A, Smith, E, Donlon, S, Mtuwa, S, Michalak-Glinska, N, Stone, S, Beazley, C, Pristopan, V, Nikitas, N, Lankester, L, Wells, C, Raj, A, Fletcher, K, Khade, R, Tsinaslanidis, G, Macmahon, M, Fowler, S, Coventry, T, Stewart, R, Wren, L, Mwaura, E, Mew, L, Scaletta, D, Williams, F, Inweregbu, K, Lancaster, N, Cunningham, M, Daniels, A, Harrison, L, Hope, S, Jones, S, Crew, A, Wray, G, Matthews, J, Crawley, R, Carter, J, Birkinshaw, I, Ingham, J, Scott, Z, Pearson, H, Howard, K, Joy, R, Roche, S, Clark, M, Purvis, S, Morrison, A, Strachan, D, Clements, S, Black, K, Parmar, C, Altabaibeh, A, Simpson, K, Mostoles, L, Gilbert, K, Ma, L, Alvaro, A, Thomas, M, Faulkner, B, Worner, R, Hayes, K, Gendall, E, Blakemore, H, Borislavova, B, Goff, E, Vuylsteke, A, Mwaura, L, Zamikula, J, Garner, L, Mitchell, A, Mepham, S, Cagova, L, Fofano, A, Holcombe, H, Praman, K, Szakmany, T, Heron, A, Cherian, S, Cutler, S, Roynon-Reed, A, Randell, G, Convery, K, Stammers, K, Fottrell-Gould, D, Hudig, L, Keshet-Price, J, Peters, M, O'Neill, L, Ray, S, Belfield, H, Mchugh, T, Jones, G, Akinkugbe, O, Tomas, A, Abaleke, E, Beech, E, Meghari, H, Yussuf, S, Bamford, A, Hairsine, B, Dooks, E, Farquhar, F, Packham, S, Bates, H, Armstrong, L, Kaye, C, Allan, A, Medhora, J, Liew, J, Botello, A, Anderson, F, Cusack, R, Golding, H, Prager, K, Williams, T, Leggett, S, Golder, K, Male, M, Jones, O, Criste, K, Marani, M, Anumakonda, V, Amin, V, Karthik, K, Kausar, R, Anastasescu, E, Reid, K, Smith, M, Hormis, A, Walker, R, Duncan, T, Uriel, A, Ustianowski, A, T-Michael, H, Bruce, M, Connolly, K, Smith, K, Partridge, R, Griffin, D, Mupudzi, M, Muchenje, N, Martin, D, Filipe, H, Eastgate, C, Jackson, C, Gratrix, A, Foster, L, Martinson, V, Stones, E, Abernathy, C, Parkinson, P, Reed, A, Prendergast, C, Rogers, P, Woodruff, M, Shokkar, R, Kaul, S, Barron, A, Collins, C, Beavis, S, Whileman, A, Dale, K, Hawes, J, Pritchard, K, Gascoyne, R, Stevenson, L, Jha, R, Lim, L, Krishnamurthy, V, Parker, R, Turner-Bone, I, Wilding, L, Reddy, A, Whiteley, S, Wilby, E, Howcroft, C, Aspinwall, A, Charlton, S, Ogg, B, Menzies, D, Pugh, R, Allan, E, Lean, R, Davies, F, Easton, J, Qiu, X, Kumar, S, Darlington, K, Houston, G, O'Brien, P, Geary, T, Allan, J, Meikle, A, Hughes, G, Balasubramaniam, M, Latham, S, Mckenna, E, Flanagan, R, Sathe, S, Davies, E, Chablani, M, Kirkby, A, Netherton, K, Archer, S, Yates, B, Ashbrook-Raby, C, Cole, S, Casey, M, Cabrelli, L, Chapman, S, Hutcheon, A, Whyte, C, Almaden-Boyle, C, Pattison, N, Cruz, C, Vochin, A, Kent, H, Thomas, A, Murdoch, S, David, B, Penacerrada, M, Lubimbi, G, Bastion, V, Wulandari, R, Lorusso, R, Valentine, J, Clarke, D, Serrano-Ruiz, A, Hierons, S, Eckbad, C, Ramos, L, Demetriou, C, Mitchard, S, White, K, White, N, Pitts, S, Branney, D, Frankham, J, Watters, M, Langton, H, Prout, R, Page, V, Varghes, T, Cowton, A, Kay, A, Potts, K, Birt, M, Kent, M, Wilkinson, A, Jude, E, Turner, V, Savill, H, Mccormick, J, Coulding, M, Siddiqui, S, Mercer, O, Rehman, H, Potla, D, Capps, N, Donaldson, D, Button, H, Martin, T, Hard, K, Agasou, A, Tonks, L, Arden, T, Boyle, P, Carnahan, M, Strickley, J, Adams, C, Childs, D, Rikunenko, R, Leigh, M, Breekes, M, Wilcox, R, Bowes, A, Tiveran, H, Hurford, F, Summers, J, Carter, A, Hussain, Y, Ting, L, Javaid, A, Motherwell, N, Moore, H, Millward, H, Jose, S, Schunki, N, Noakes, A, Clulow, C, Sadera, G, Jacob, R, Jones, C, Blunt, M, Coton, Z, Curgenven, H, Ally, S, Beaumont, K, Elsaadany, M, Fernandes, K, Ali Mohamed Ali, I, Rangarajan, H, Sarathy, V, Selvanayagam, S, Vedage, D, White, M, Truman, N, Chukkambotla, S, Keith, S, Cockerill-Taylor, J, Ryan-Smith, J, Bolton, R, Springle, P, Dykes, J, Thomas, J, Khan, M, Hijazi, M, Massey, E, Croston, G, Reschreiter, H, Camsooksai, J, Patch, S, Jenkins, S, Humphrey, C, Wadams, B, Msiska, M, Adanini, O, Attwood, B, Parsons, P, Tatham, K, Jhanji, S, Black, E, Dela Rosa, A, Howle, R, Thomas, B, Bemand, T, Raobaikady, R, Saha, R, Staines, N, Daniel, A, Finn, J, Hutter, J, Doble, P, Shovelton, C, Pawley, C, Kannan, T, Hill, M, Combes, E, Monnery, S, Joefield, T, Popescu, M, Thankachen, M, Oblak, M, Little, J, Mcivor, S, Brady, A, Whittle, H, Prady, H, Chan, R, Ahmed, A, Morris, A, Gibson, C, Gordon, E, Keenan, S, Quinn, H, Benyon, S, Marriott, S, Zitter, L, Park, L, Baines, K, Lyons, M, Holland, M, Keenan, N, Young, M, Garrioch, S, Dawson, J, Tolson, M, Scholefield, B, Bi, R, Richardson, N, Schumacher, N, Cosier, T, Millen, G, Higham, A, Turki, S, Allen, L, Crisp, N, Hazleton, T, Knight, A, Deery, J, Price, C, Turney, S, Tilbey, S, Beranova, E, Wright, D, George, L, Twiss, S, Wadd, S, Postlethwaite, K, Gondo, P, Masunda, B, Kayani, A, Hadebe, B, Whiteside, J, Clarke, N, Donnison, P, Trim, F, Leadbitter, I, Butcher, D, O'Sullivan, S, Purewal, B, Bell, S, Rivers, V, O'Leary, R, Birch, J, Collins, E, Anderson, S, Hammerton, K, Andrews, E, Burns, K, Edmond, I, Todd, A, Donnachie, J, Turner, P, Prentice, L, Symon, L, Runciman, N, Auld, F, Halkes, M, Mercer, P, Thornton, L, Debreceni, G, Wilkins, J, Crickmore, V, Subramanian, G, Marshall, R, Jennings, C, Latif, M, Bunni, L, Spivey, M, Bean, S, Burt, K, Linnett, V, Ritzema, J, Sanderson, A, Mccormick, W, Bokhari, M, Kapoor, R, Loader, D, Ayers, A, Harrison, W, North, J, Belagodu, Z, Paramsothy, R, Olufuwa, O, Gherman, A, Fuller, B, Stuart, C, Kelsall, O, Davis, C, Wild, L, Wood, H, Thrush, J, Durie, A, Austin, K, Archer, K, Anderson, P, Vigurs, C, Thorpe, C, Knights, E, Boyle, N, Price, A, Kubisz-Pudelko, A, Wood, D, Lewis, A, Board, S, Pippard, L, Perry, J, Beesley, K, Rattray, A, Lee, E, Lennon, L, Douglas, K, Bell, D, Boyle, R, Glass, L, Nauman Akhtar, M, Dent, K, Potoczna, D, Pearson, S, Horsley, E, Spencer, S, Mullan, D, Skinner, D, Gaylard, J, Barber, R, Hewitt, C, Hilldrith, A, Shepardson, S, Wills, M, Jackson-Lawrence, K, Gupta, A, Timlick, E, Gorman, C, Otahal, I, Gales, A, Coetzee, S, Sell, C, Raj, M, Peiu, M, Quaid, S, Watson, E, Elliott, K, Mallinson, J, Chandler, B, Turnbull, A, Finch, C, Holl, C, Cooper, J, Evans, A, Khaliq, W, Collins, A, Gude, E, Love, N, van Koutrik, L, Hunt, J, Kaye, D, Fisher, E, Brayne, A, Tuckey, V, Jackson, P, Parkin, J, Tariq, A, Houlden, H, Tucci, A, Hardy, J, Moncur, E, Highgate, J, Cowley, A, Mitra, A, Stead, R, Behan, T, Burnett, C, Newton, M, Heeney, E, Pollard, R, Hatton, J, Patel, A, Kasipandian, V, Allibone, S, Genetu, R, O'Brien, L, Omar, Z, Perkins, E, Davies, K, Tetla, D, Shelley, B, Irvine, V, Williams, S, Williams, P, Goodsell, J, Tutton, R, Bough, L, Winter-Goodwin, B, Kitson, R, Pinnell, J, Wilson, A, Nortcliffe, T, Wood, T, Home, M, Holdroyd, K, Robinson, M, Shaw, R, Greig, J, Brady, M, Haigh, A, Matupe, L, Usher, M, Mellor, S, Dale, S, Gledhill, L, Shaw, L, Turner, G, Kelly, D, Anwar, B, Riley, H, Sturgeon, H, Ali, A, Thomis, L, Melia, D, Dance, A, Humphreys, S, Frost, I, Gopal, V, Godden, J, Holden, A, Swann, S, Smith, T, Clapham, M, Poultney, U, Harper, R, Rice, P, Reece-Anthony, R, Gurung, B, Moultrie, S, Odam, M, Mayer, A, Bellini, A, Pickard, A, Bryant, J, Roe, N, Sowter, J, Lang, K, Taylor, J, Barry, P, Hobrok, M, Tench, H, Wolf-Roberts, R, Mcguinness, H, Loosley, R, Hawcutt, D, Rad, L, O'Malley, L, Saunderson, P, Seddon, G, Anderson, T, Rogers, N, Ruddy, J, Harkins, M, Beith, C, Mcalpine, A, Ferguson, L, Grant, P, Macfadyen, S, Mclaughlin, M, Baird, T, Rundell, S, Welsh, B, Hamill, R, Fisher, F, Gregory, J, Campbell, A, Smuts, S, Kenneth Baillie, J, Carson, G, Alex, B, Bach, B, Barclay, W, Bogaert, D, Chand, M, Cooke, G, Docherty, A, Dunning, J, da Silva Filipe, A, Fletcher, T, Green, C, Harrison, E, Hiscox, J, Ijaz, S, Khoo, S, Lim, W, Mentzer, A, Merson, L, Noursadeghi, M, Palmarini, M, Paxton, W, Pollakis, G, Price, N, Rambaut, A, Robertson, D, Sancho-Shimizu, V, Scott, J, de Silva, T, Sigfrid, L, Solomon, T, Sriskandan, S, Stuart, D, Tedder, R, Thomson, E, Thompson, A, Thwaites, R, Zambon, M, Hardwick, H, Donohue, C, Lyons, R, Norman, L, Pius, R, Drake, T, Fairfield, C, Knight, S, Mclean, K, Murphy, D, Shaw, C, Dalton, J, Girvan, M, Saviciute, E, Roberts, S, Harrison, J, Marsh, L, Connor, M, Halpin, S, Gamble, C, Leeming, G, Wham, M, Greenhalf, W, Shaw, V, Mcdonald, S, Ganna, A, Sulem, P, van Heel, D, Cordioli, M, Sveinbjornsson, G, Niemi, M, Shelton, J, Shastri, A, Ye, C, Weldon, C, Filshtein-Sonmez, T, Coker, D, Symons, A, Esparza-Gordillo, J, Aslibekyan, S, Auton, A, Krieger, J, Marques, E, Jannes, C, Mari, F, Daga, S, Baldassarri, M, Benetti, E, Furini, S, Fallerini, C, Fava, F, Valentino, F, Doddato, G, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Pinto, A, Frullanti, E, Mencarelli, M, Rizzo, C, Montagnani, F, Di Sarno, L, Tommasi, A, Palmieri, M, Emiliozzi, A, Fabbiani, M, Rossetti, B, Zanelli, G, Bargagli, E, Bergantini, L, D'Alessandro, M, Cameli, P, Bennet, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Caldarelli, G, Spagnesi, M, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, Vaghi, M, D'Arminio Monforte, A, Merlini, E, Mondelli, M, Mantovani, S, Ludovisi, S, Girardis, M, Venturelli, S, Sita, M, Cossarizza, A, Antinori, A, Vergori, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Scotton, P, Andretta, F, Panese, S, Scaggiante, R, Gatti, F, Parisi, S, Castelli, F, Quiros-Roldan, M, Magro, P, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Valente, S, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Baratti, S, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, D, Mussini, C, Bosio, G, Martinelli, E, Mancarella, S, Tavecchia, L, Crotti, L, Picchiotti, N, Gori, M, Gabbi, C, Sanarico, M, Ceri, S, Pinoli, P, Raimondi, F, Biscarini, F, Stella, A, Shen, X, Fawkes, A, Tenesa, A, Caulfield, M, Scott, R, Rowan, K, Murphy, L, Openshaw, P, Semple, M, Vitart, V, Wilson, J, Pairo-Castineira, Erola [0000-0002-2423-3090], Klaric, Lucija [0000-0003-3105-8929], Bretherick, Andrew D [0000-0001-9258-3140], Rawlik, Konrad [0000-0002-0010-370X], Walker, Susan [0000-0002-5016-6426], Fourman, Max Head [0000-0001-7381-2278], Russell, Clark D [0000-0002-9873-8243], Gountouna, Elvina [0000-0001-7870-2780], Wang, Bo [0000-0002-1580-797X], Wu, Yang [0000-0002-0128-7280], Kousathanas, Athanasios [0000-0001-6265-6521], Moutsianas, Loukas [0000-0001-5453-345X], Zhai, Ranran [0000-0002-5834-9120], Beale, Rupert [0000-0002-6705-8560], Keating, Sean [0000-0001-8552-5604], Haley, Chris [0000-0002-9811-0210], Porteous, David J [0000-0003-1249-6106], Hayward, Caroline [0000-0002-9405-9550], Yang, Jian [0000-0003-2001-2474], Knight, Julian [0000-0002-0377-5536], Summers, Charlotte [0000-0002-7269-2873], Shankar-Hari, Manu [0000-0002-5338-2538], Turtle, Lance [0000-0002-0778-1693], Moore, Shona C [0000-0001-8610-2806], Hinds, Charles [0000-0001-5094-8324], McAuley, Danny [0000-0002-3283-1947], Montgomery, Hugh [0000-0001-8797-5019], Renieri, Alessandra [0000-0002-0846-9220], Shen, Xia [0000-0003-4390-1979], Ponting, Chris P [0000-0003-0202-7816], Tenesa, Albert [0000-0003-4884-4475], Caulfield, Mark [0000-0001-9295-3594], Rowan, Kathy [0000-0001-8217-5602], Murphy, Lee [0000-0001-6467-7449], Openshaw, Peter JM [0000-0002-7220-2555], Semple, Malcolm G [0000-0001-9700-0418], Law, Andrew [0000-0003-1868-2364], Vitart, Veronique [0000-0002-4991-3797], Wilson, James F [0000-0001-5751-9178], Baillie, J Kenneth [0000-0001-5258-793X], Apollo - University of Cambridge Repository, Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A. D., Rawlik, K., Pasko, D., Walker, S., Parkinson, N., Fourman, M. H., Russell, C. D., Furniss, J., Richmond, A., Gountouna, E., Wrobel, N., Harrison, D., Wang, B., Wu, Y., Meynert, A., Griffiths, F., Oosthuyzen, W., Kousathanas, A., Moutsianas, L., Yang, Z., Zhai, R., Zheng, C., Grimes, G., Beale, R., Millar, J., Shih, B., Keating, S., Zechner, M., Haley, C., Porteous, D. J., Hayward, C., Yang, J., Knight, J., Summers, C., Shankar-Hari, M., Klenerman, P., Turtle, L., Ho, A., Moore, S. C., Hinds, C., Horby, P., Nichol, A., Maslove, D., Ling, L., Mcauley, D., Montgomery, H., Walsh, T., Pereira, A. C., Renieri, A., Ponting, C., Meikle, J., Finernan, P., Mcmaster, E., Law, A., Baillie, J. K., Paterson, T., Wackett, T., Armstrong, R., Clark, R., Coutts, A., Donnelly, L., Gilchrist, T., Hafezi, K., Macgillivray, L., Maclean, A., Mccafferty, S., Morrice, K., Weaver, J., Boz, C., Golightly, A., Ward, M., Mal, H., Szoor-McElhinney, H., Brown, A., Hendry, R., Stenhouse, A., Cullum, L., Law, D., Law, S., Law, R., Swets, M., Day, N., Taneski, F., Duncan, E., Collier, D., Wood, S., Zak, A., Borra, C., Matharu, M., May, P., Alldis, Z., Mitchelmore, O., Bowles, R., Easthope, A., Bibi, F., Lancoma-Malcolm, I., Gurasashvili, J., Pheby, J., Shiel, J., Bolton, M., Patel, M., Taylor, M., Zongo, O., Ebano, P., Harding, P., Astin-Chamberlain, R., Choudhury, Y., Cox, A., Kallon, D., Burton, M., Hall, R., Blowes, S., Prime, Z., Biddle, J., Prysyazhna, O., Newman, T., Tierney, C., Kassam, J., Ostermann, M., Campos, S., Bociek, A., Lim, R., Grau, N., Jones, T. O., Whitton, C., Marotti, M., Arbane, G., Bonner, S., Hugill, K., Reid, J., Welters, I., Waugh, V., Williams, K., Shaw, D., Roman, J. F., Martinez, M. L., Johnson, E., Waite, A., Johnston, B., Hamilton, D., Mulla, S., Mcphail, M., Smith, J., Barclay, L., Hope, D., Mcculloch, C., Mcquillan, L., Clark, S., Singleton, J., Priestley, K., Rea, N., Callaghan, M., Campbell, R., Andrew, G., Marshall, L., Mckechnie, S., Hutton, P., Bashyal, A., Davidson, N., Polgarova, P., Stroud, K., Pathan, N., Elston, K., Agrawal, S., Battle, C., Newey, L., Rees, T., Harford, R., Brinkworth, E., Williams, M., Murphy, C., White, I., Croft, M., Bandla, N., Gellamucho, M., Tomlinson, J., Turner, H., Davies, M., Quinn, A., Hussain, I., Thompson, C., Parker, H., Bradley, R., Griffiths, R., Scriven, J., Nilsson, A., Bates, M., Dasgin, J., Gill, J., Puxty, A., Cathcart, S., Salutous, D., Turner, L., Duffy, K., Puxty, K., Joseph, A., Herdman-Grant, R., Simms, R., Swain, A., Naranjo, A., Crowe, R., Sollesta, K., Loveridge, A., Baptista, D., Morino, E., Davey, M., Golden, D., Jones, J., Moreno Cuesta, J., Haldeos, A., Bakthavatsalam, D., Vincent, R., Elhassan, M., Xavier, K., Ganesan, A., Purohit, D., Abdelrazik, M., Morgan, J., Akeroyd, L., Bano, S., Lawton, T., Warren, D., Bromley, M., Sellick, K., Gurr, L., Wilkinson, B., Nagarajan, V., Szedlak, P., Cupitt, J., Stoddard, E., Benham, L., Preston, S., Laha, S., Slawson, N., Bradshaw, Z., Brown, J., Caswell, M., Melling, S., Bamford, P., Faulkner, M., Cawley, K., Jeffrey, H., London, E., Sainsbury, H., Nagra, I., Nasir, F., Dunmore, C., Jones, R., Abraheem, A., Al-Moasseb, M., Girach, R., Padden, G., Egan, J., Brantwood, C., Alexander, P., Bradley-Potts, J., Allen, S., Felton, T., Manna, S., Farnell-Ward, S., Leaver, S., Queiroz, J., Maccacari, E., Dawson, D., Delgado, C. C., Saluzzio, R. P., Ezeobu, O., Ding, L., Sicat, C., Kanu, R., Durrant, G., Texeira, J., Harrison, A., Samakomva, T., Willis, H., Hopkins, B., Thrasyvoulou, L., Jackson, M., Zaki, A., Tibke, C., Bennett, S., Woodyatt, W., Kent, A., Goodwin, E., Brandwood, C., Smith, L., Rooney, K., Thomson, N., Rodden, N., Hughes, E., Mcglynn, D., Clark, C., Clark, P., Abel, L., Sundaram, R., Gemmell, L., Brett, M., Hornsby, J., Macgoey, P., Price, R., Digby, B., O'Neil, P., Mcconnell, P., Henderson, P., Henderson, S., Sim, M., Kennedy-Hay, S., Mcparland, C., Rooney, L., Baxter, N., Pogson, D., Rose, S., Daly, Z., Brimfield, L., Phull, M. K., Hussain, M., Pogreban, T., Rosaroso, L., Salciute, E., Grauslyte, L., Brealey, D., Raith, E., Maccallum, N., Bercades, G., Hass, I., Smyth, D., Reyes, A., Martir, G., Clement, I. D., Webster, K., Hays, C., Gulati, A., Hodgson, L., Margarson, M., Gomez, R., Baird, Y., Thirlwall, Y., Folkes, L., Butler, A., Meadows, E., Moore, S., Raynard, D., Fox, H., Riddles, L., King, K., Kimber, S., Hobden, G., Mccarthy, A., Cannons, V., Balagosa, I., Chadbourn, I., Gardner, A., Horner, D., Mclaughlanv, D., Charles, B., Proudfoot, N., Marsden, T., Mcmorrow, L., Blackledge, B., Pendlebury, J., Harvey, A., Apetri, E., Basikolo, C., Catlow, L., Doonan, R., Knowles, K., Lee, S., Lomas, D., Lyons, C., Perez, J., Poulaka, M., Slaughter, M., Slevin, K., Thomas, V., Walker, D., Harris, J., Drummond, A., Tully, R., Dearden, J., Philbin, J., Munt, S., Rishton, C., O'Connor, G., Mulcahy, M., Dobson, E., Cuttler, J., Edward, M., Norris, J., Hanson, K., Poole, A., Rose, A., Sloan, B., Buckley, S., Brooke, H., Smithson, E., Charlesworth, R., Sandhu, R., Thirumaran, M., Wagstaff, V., Suarez, J. C., Kaliappan, A., Vertue, M., Nicholson, A., Riches, J., Solesbury, A., Kittridge, L., Forsey, M., Maloney, G., Cole, J., Davies, R., Hill, H., Thomas, E., Williams, A., Duffin, D., Player, B., Radhakrishnan, J., Gibson, S., Lyle, A., Mcneela, F., Patel, B., Gummadi, M., Sloane, G., Dormand, N., Salmi, S., Farzad, Z., Cristiano, D., Liyanage, K., Thwaites, V., Varghese, M., Meredith, M., Mills, G., Willson, J., Harrington, K., Lenagh, B., Cawthron, K., Masuko, S., Raithatha, A., Bauchmuller, K., Wiles, M., Ahmad, N., Barker, J., Jackson, Y., Kibutu, F., Bird, S., Watson, G., Martin, J., Bevan, E., Brown, C. 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S., Fernandez, Z., Coghlan, P., Williams, D., Jardine, C., Bewley, J., Sweet, K., Grimmer, L., Johnson, R., Garland, Z., Gumbrill, B., Phillips, C., Ortiz-Ruiz de Gordoa, L., Peasgood, E., Tridente, A., Shuker, K., Greer, S., Lynch, C., Pothecary, C., Roche, L., Deacon, B., Turner, K., Singh, J., Howe, G. S., Paul, P., Gill, M., Wynter, I., Ratnam, V., Shelton, S., Naisbitt, J., Melville, J., Baruah, R., Morrison, S., Mcgregor, A., Parris, V., Mpelembue, M., Srikaran, S., Dennis, C., Sukha, A., Verlander, M., Holding, K., Riches, K., Downes, C., Swan, C., Rostron, A., Roy, A., Woods, L., Cornell, S., Wakinshaw, F., Creagh-Brown, B., Blackman, H., Salberg, A., Smith, E., Donlon, S., Mtuwa, S., Michalak-Glinska, N., Stone, S., Beazley, C., Pristopan, V., Nikitas, N., Lankester, L., Wells, C., Raj, A. S., Fletcher, K., Khade, R., Tsinaslanidis, G., Macmahon, M., Fowler, S., Coventry, T., Stewart, R., Wren, L., Mwaura, E., Mew, L., Scaletta, D., Williams, F., Inweregbu, K., Lancaster, N., Cunningham, M., Daniels, A., Harrison, L., Hope, S., Jones, S., Crew, A., Wray, G., Matthews, J., Crawley, R., Carter, J., Birkinshaw, I., Ingham, J., Scott, Z., Pearson, H., Howard, K., Joy, R., Roche, S., Clark, M., Purvis, S., Morrison, A., Strachan, D., Clements, S., Black, K., Parmar, C., Altabaibeh, A., Simpson, K., Mostoles, L., Gilbert, K., Ma, L., Alvaro, A., Thomas, M., Faulkner, B., Worner, R., Hayes, K., Gendall, E., Blakemore, H., Borislavova, B., Goff, E., Vuylsteke, A., Mwaura, L., Zamikula, J., Garner, L., Mitchell, A., Mepham, S., Cagova, L., Fofano, A., Holcombe, H., Praman, K., Szakmany, T., Heron, A. E., Cherian, S., Cutler, S., Roynon-Reed, A., Randell, G., Convery, K., Stammers, K., Fottrell-Gould, D., Hudig, L., Keshet-Price, J., Peters, M., O'Neill, L., Ray, S., Belfield, H., Mchugh, T., Jones, G., Akinkugbe, O., Tomas, A., Abaleke, E., Beech, E., Meghari, H., Yussuf, S., Bamford, A., Hairsine, B., Dooks, E., Farquhar, F., Packham, S., Bates, H., Armstrong, L., Kaye, C., Allan, A., Medhora, J., Liew, J., Botello, A., Anderson, F., Cusack, R., Golding, H., Prager, K., Williams, T., Leggett, S., Golder, K., Male, M., Jones, O., Criste, K., Marani, M., Anumakonda, V., Amin, V., Karthik, K., Kausar, R., Anastasescu, E., Reid, K., Smith, M., Hormis, A., Walker, R., Duncan, T., Uriel, A., Ustianowski, A., T-Michael, H., Bruce, M., Connolly, K., Smith, K., Partridge, R., Griffin, D., Mupudzi, M., Muchenje, N., Martin, D., Filipe, H., Eastgate, C., Jackson, C., Gratrix, A., Foster, L., Martinson, V., Stones, E., Abernathy, C., Parkinson, P., Reed, A., Prendergast, C., Rogers, P., Woodruff, M., Shokkar, R., Kaul, S., Barron, A., Collins, C., Beavis, S., Whileman, A., Dale, K., Hawes, J., Pritchard, K., Gascoyne, R., Stevenson, L., Jha, R., Lim, L., Krishnamurthy, V., Parker, R., Turner-Bone, I., Wilding, L., Reddy, A., Whiteley, S., Wilby, E., Howcroft, C., Aspinwall, A., Charlton, S., Ogg, B., Menzies, D., Pugh, R., Allan, E., Lean, R., Davies, F., Easton, J., Qiu, X., Kumar, S., Darlington, K., Houston, G., O'Brien, P., Geary, T., Allan, J., Meikle, A., Hughes, G., Balasubramaniam, M., Latham, S., Mckenna, E., Flanagan, R., Sathe, S., Davies, E., Chablani, M., Kirkby, A., Netherton, K., Archer, S., Yates, B., Ashbrook-Raby, C., Cole, S., Casey, M., Cabrelli, L., Chapman, S., Hutcheon, A., Whyte, C., Almaden-Boyle, C., Pattison, N., Cruz, C., Vochin, A., Kent, H., Thomas, A., Murdoch, S., David, B., Penacerrada, M., Lubimbi, G., Bastion, V., Wulandari, R., Lorusso, R., Valentine, J., Clarke, D., Serrano-Ruiz, A., Hierons, S., Eckbad, C., Ramos, L., Demetriou, C., Mitchard, S., White, K., White, N., Pitts, S., Branney, D., Frankham, J., Watters, M., Langton, H., Prout, R., Page, V., Varghes, T., Cowton, A., Kay, A., Potts, K., Birt, M., Kent, M., Wilkinson, A., Jude, E. B., Turner, V., Savill, H., Mccormick, J., Coulding, M., Siddiqui, S., Mercer, O., Rehman, H., Potla, D., Capps, N., Donaldson, D., Button, H., Martin, T., Hard, K., Agasou, A., Tonks, L., Arden, T., Boyle, P., Carnahan, M., Strickley, J., Adams, C., Childs, D., Rikunenko, R., Leigh, M., Breekes, M., Wilcox, R., Bowes, A., Tiveran, H., Hurford, F., Summers, J., Carter, A., Hussain, Y., Ting, L., Javaid, A., Motherwell, N., Moore, H., Millward, H., Jose, S., Schunki, N., Noakes, A., Clulow, C., Sadera, G., Jacob, R., Jones, C., Blunt, M., Coton, Z., Curgenven, H., Ally, S. M., Beaumont, K., Elsaadany, M., Fernandes, K., Ali Mohamed Ali, I., Rangarajan, H., Sarathy, V., Selvanayagam, S., Vedage, D., White, M., Truman, N., Chukkambotla, S., Keith, S., Cockerill-Taylor, J., Ryan-Smith, J., Bolton, R., Springle, P., Dykes, J., Thomas, J., Khan, M., Hijazi, M. T., Massey, E., Croston, G., Reschreiter, H., Camsooksai, J., Patch, S., Jenkins, S., Humphrey, C., Wadams, B., Msiska, M., Adanini, O., Attwood, B., Parsons, P., Tatham, K., Jhanji, S., Black, E., Dela Rosa, A., Howle, R., Thomas, B., Bemand, T., Raobaikady, R., Saha, R., Staines, N., Daniel, A., Finn, J., Hutter, J., Doble, P., Shovelton, C., Pawley, C., Kannan, T., Hill, M., Combes, E., Monnery, S., Joefield, T., Popescu, M., Thankachen, M., Oblak, M., Little, J., Mcivor, S., Brady, A., Whittle, H., Prady, H., Chan, R., Ahmed, A., Morris, A., Gibson, C., Gordon, E., Keenan, S., Quinn, H., Benyon, S., Marriott, S., Zitter, L., Park, L., Baines, K., Lyons, M., Holland, M., Keenan, N., Young, M., Garrioch, S., Dawson, J., Tolson, M., Scholefield, B., Bi, R., Richardson, N., Schumacher, N., Cosier, T., Millen, G., Higham, A., Turki, S., Allen, L., Crisp, N., Hazleton, T., Knight, A., Deery, J., Price, C., Turney, S., Tilbey, S., Beranova, E., Wright, D., George, L., Twiss, S., Wadd, S., Postlethwaite, K., Gondo, P., Masunda, B., Kayani, A., Hadebe, B., Whiteside, J., Clarke, N., Donnison, P., Trim, F., Leadbitter, I., Butcher, D., O'Sullivan, S., Purewal, B., Bell, S., Rivers, V., O'Leary, R., Birch, J., Collins, E., Anderson, S., Hammerton, K., Andrews, E., Burns, K., Edmond, I., Todd, A., Donnachie, J., Turner, P., Prentice, L., Symon, L., Runciman, N., Auld, F., Halkes, M., Mercer, P., Thornton, L., Debreceni, G., Wilkins, J., Crickmore, V., Subramanian, G., Marshall, R., Jennings, C., Latif, M., Bunni, L., Spivey, M., Bean, S., Burt, K., Linnett, V., Ritzema, J., Sanderson, A., Mccormick, W., Bokhari, M., Kapoor, R., Loader, D., Ayers, A., Harrison, W., North, J., Belagodu, Z., Paramsothy, R., Olufuwa, O., Gherman, A., Fuller, B., Stuart, C., Kelsall, O., Davis, C., Wild, L., Wood, H., Thrush, J., Durie, A., Austin, K., Archer, K., Anderson, P., Vigurs, C., Thorpe, C., Knights, E., Boyle, N., Price, A., Kubisz-Pudelko, A., Wood, D., Lewis, A., Board, S., Pippard, L., Perry, J., Beesley, K., Rattray, A., Lee, E., Lennon, L., Douglas, K., Bell, D., Boyle, R., Glass, L., Nauman Akhtar, M., Dent, K., Potoczna, D., Pearson, S., Horsley, E., Spencer, S., Mullan, D., Skinner, D., Gaylard, J., Barber, R., Hewitt, C., Hilldrith, A., Shepardson, S., Wills, M., Jackson-Lawrence, K., Gupta, A., Timlick, E., Gorman, C., Otahal, I., Gales, A., Coetzee, S., Sell, C., Raj, M., Peiu, M., Quaid, S., Watson, E., Elliott, K., Mallinson, J., Chandler, B., Turnbull, A., Finch, C., Holl, C., Cooper, J., Evans, A., Khaliq, W., Collins, A., Gude, E. T., Love, N., van Koutrik, L., Hunt, J., Kaye, D., Fisher, E., Brayne, A., Tuckey, V., Jackson, P., Parkin, J., Tariq, A., Houlden, H., Tucci, A., Hardy, J., Moncur, E., Highgate, J., Cowley, A., Mitra, A., Stead, R., Behan, T., Burnett, C., Newton, M., Heeney, E., Pollard, R., Hatton, J., Patel, A., Kasipandian, V., Allibone, S., Genetu, R. M., O'Brien, L., Omar, Z., Perkins, E., Davies, K., Tetla, D., Shelley, B., Irvine, V., Williams, S., Williams, P., Goodsell, J., Tutton, R., Bough, L., Winter-Goodwin, B., Kitson, R., Pinnell, J., Wilson, A., Nortcliffe, T., Wood, T., Home, M., Holdroyd, K., Robinson, M., Shaw, R., Greig, J., Brady, M., Haigh, A., Matupe, L., Usher, M., Mellor, S., Dale, S., Gledhill, L., Shaw, L., Turner, G., Kelly, D., Anwar, B., Riley, H., Sturgeon, H., Ali, A., Thomis, L., Melia, D., Dance, A., Humphreys, S., Frost, I., Gopal, V., Godden, J., Holden, A., Swann, S., Smith, T., Clapham, M., Poultney, U., Harper, R., Rice, P., Reece-Anthony, R., Gurung, B., Moultrie, S., Odam, M., Mayer, A., Bellini, A., Pickard, A., Bryant, J., Roe, N., Sowter, J., Lang, K., Taylor, J., Barry, P., Hobrok, M., Tench, H., Wolf-Roberts, R., Mcguinness, H., Loosley, R., Hawcutt, D., Rad, L., O'Malley, L., Saunderson, P., Seddon, G., Anderson, T., Rogers, N., Ruddy, J., Harkins, M., Beith, C., Mcalpine, A., Ferguson, L., Grant, P., Macfadyen, S., Mclaughlin, M., Baird, T., Rundell, S., Welsh, B., Hamill, R., Fisher, F., Gregory, J., Campbell, A., Smuts, S., Kenneth Baillie, J., Carson, G., Alex, B., Bach, B., Barclay, W. S., Bogaert, D., Chand, M., Cooke, G. S., Docherty, A. B., Dunning, J., da Silva Filipe, A., Fletcher, T., Green, C. A., Harrison, E. M., Hiscox, J. A., Ho, A. Y. W., Horby, P. W., Ijaz, S., Khoo, S., Lim, W. S., Mentzer, A. J., Merson, L., Meynert, A. M., Noursadeghi, M., Palmarini, M., Paxton, W. A., Pollakis, G., Price, N., Rambaut, A., Robertson, D. L., Sancho-Shimizu, V., Scott, J. T., de Silva, T., Sigfrid, L., Solomon, T., Sriskandan, S., Stuart, D., Tedder, R. S., Thomson, E. C., Thompson, A. A. R., Thwaites, R. S., Turtle, L. C. W., Zambon, M., Hardwick, H., Donohue, C., Lyons, R., Norman, L., Pius, R., Drake, T. M., Fairfield, C. J., Knight, S. R., Mclean, K. A., Murphy, D., Shaw, C. A., Dalton, J., Girvan, M., Saviciute, E., Roberts, S., Harrison, J., Marsh, L., Connor, M., Halpin, S., Gamble, C., Leeming, G., Wham, M., Greenhalf, W., Shaw, V., Mcdonald, S., Ganna, A., Sulem, P., van Heel, D. A., Cordioli, M., Sveinbjornsson, G., Niemi, M. E. K., Shelton, J. F., Shastri, A. J., Ye, C., Weldon, C. H., Filshtein-Sonmez, T., Coker, D., Symons, A., Esparza-Gordillo, J., Aslibekyan, S., Auton, A., Krieger, J. E., Marques, E., Jannes, C. E., Mari, F., Daga, S., Baldassarri, M., Benetti, E., Furini, S., Fallerini, C., Fava, F., Valentino, F., Doddato, G., Giliberti, A., Tita, R., Amitrano, S., Bruttini, M., Croci, S., Meloni, I., Pinto, A. M., Frullanti, E., Mencarelli, M. A., Rizzo, C. L., Montagnani, F., Di Sarno, L., Tommasi, A., Palmieri, M., Emiliozzi, A., Fabbiani, M., Rossetti, B., Zanelli, G., Bargagli, E., Bergantini, L., D'Alessandro, M., Cameli, P., Bennet, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, F., Mazzei, M. A., Guerrini, S., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Spertilli, C., Feri, M., Donati, A., Scala, R., Guidelli, L., Spargi, G., Corridi, M., Nencioni, C., Croci, L., Caldarelli, G. P., Spagnesi, M., Piacentini, P., Bandini, M., Desanctis, E., Cappelli, S., Canaccini, A., Verzuri, A., Anemoli, V., Ognibene, A., Vaghi, M., D'Arminio Monforte, A., Merlini, E., Mondelli, M. U., Mantovani, S., Ludovisi, S., Girardis, M., Venturelli, S., Sita, M., Cossarizza, A., Antinori, A., Vergori, A., Rusconi, S., Siano, M., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Scotton, P. G., Andretta, F., Panese, S., Scaggiante, R., Gatti, F., Parisi, S. G., Castelli, F., Quiros-Roldan, M. E., Magro, P., Zanella, I., Della Monica, M., Piscopo, C., Capasso, M., Russo, R., Andolfo, I., Iolascon, A., Fiorentino, G., Carella, M., Castori, M., Merla, G., Aucella, F., Raggi, P., Marciano, C., Perna, R., Bassetti, M., Di Biagio, A., Sanguinetti, M., Masucci, L., Valente, S., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Baratti, S., Trotta, T., Giannattasio, F., Coiro, G., Lena, F., Coviello, D. A., Mussini, C., Bosio, G., Martinelli, E., Mancarella, S., Tavecchia, L., Crotti, L., Picchiotti, N., Gori, M., Gabbi, C., Sanarico, M., Ceri, S., Pinoli, P., Raimondi, F., Biscarini, F., Stella, A., Shen, X., Ponting, C. P., Fawkes, A., Tenesa, A., Caulfield, M., Scott, R., Rowan, K., Murphy, L., Openshaw, P. J. M., Semple, M. G., Vitart, V., and Wilson, J. F.

Subjects
0301 basic medicine, Male, CCR2, Chromosomes, Human, Pair 21, Genome-wide association study, Receptor, Interferon alpha-beta, Disease, Bioinformatics, Genome-wide association studies, 23andMe Investigators, Interferon alpha-beta, 0302 clinical medicine, Receptors, 2',5'-Oligoadenylate Synthetase, Pair 12, genetics, Lung, BRACOVID Investigators, Multidisciplinary, GenOMICC Investigators, Tyrosine kinase 2, 030220 oncology & carcinogenesis, Multigene Family, Medical genetics, Female, Dipeptidyl-Peptidases and Tripeptidyl-Peptidase, 5'-Oligoadenylate Synthetase, Human, Receptor, medicine.medical_specialty, Critical Care, Receptors, CCR2, General Science & Technology, Critical Illness, Chromosomes, 03 medical and health sciences, Intensive care, Mendelian randomization, Immunogenetics, medicine, Humans, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Gen-COVID Investigators, Inflammation, TYK2 Kinase, Chromosomes, Human, Pair 12, Pair 19, SARS-CoV-2, business.industry, Drug Repositioning, COVID-19, United Kingdom, COVID-19 Human Genetics Initiative, 030104 developmental biology, Viral infection, Chromosomes, Human, Pair 19, Genome-Wide Association Study, Pharmacogenomics, ISARICC Investigators, Pair 21, 2', business
Abstract

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079,P=1.65×10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1,OAS2andOAS3); on chromosome 19p13.2 (rs74956615,P=2.3×10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069,P=3.98× 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757,P=4.99×10−8) in the interferon receptor geneIFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression ofIFNAR2, or high expression ofTYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptorCCR2is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.

Published
2020
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23. Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection

Author

Stefano Rusconi, Paola Morpurgo, Anna Maestroni, Enrica Chebat, Franco Folli, Emma Assi, Cristian Loretelli, Roberta Maria Fiorina, Andrea Mario Bolla, Francesca D'Addio, Andy Joe Seelam, Giuseppe Daniele, Manuela Nebuloni, Marco Dell’Acqua, Moufida Ben Nasr, Paolo Fiorina, Ahmed Abdelsalam, Reza Abdi, Vera Usuelli, Maria Elena Lunati, Ida Pastore, Laura Montefusco, Giovanna Finzi, Agostino Riva, Domenico Corradi, Joseph V. Bonventre, Massimo Galli, Elio Ippolito, Pierachille Santus, Gian Vincenzo Zuccotti, and Antonio Rossi

Subjects
Blood Glucose, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Context (language use), Disease, Gastroenterology, Article, Cohort Studies, Insulin resistance, Physiology (medical), Internal medicine, Diabetes mellitus, Insulin-Secreting Cells, Internal Medicine, medicine, Glucose homeostasis, Humans, business.industry, SARS-CoV-2, COVID-19, Cell Biology, medicine.disease, Cytokine, Hyperglycemia, Cohort, Insulin Resistance, business, Cohort study
Abstract

Patients with coronavirus disease 2019 (COVID-19) are reported to have a greater prevalence of hyperglycaemia. Cytokine release as a consequence of severe acute respiratory syndrome coronavirus 2 infection may precipitate the onset of metabolic alterations by affecting glucose homeostasis. Here we describe abnormalities in glycometabolic control, insulin resistance and beta cell function in patients with COVID-19 without any pre-existing history or diagnosis of diabetes, and document glycaemic abnormalities in recovered patients 2 months after onset of disease. In a cohort of 551 patients hospitalized for COVID-19 in Italy, we found that 46% of patients were hyperglycaemic, whereas 27% were normoglycaemic. Using clinical assays and continuous glucose monitoring in a subset of patients, we detected altered glycometabolic control, with insulin resistance and an abnormal cytokine profile, even in normoglycaemic patients. Glycaemic abnormalities can be detected for at least 2 months in patients who recovered from COVID-19. Our data demonstrate that COVID-19 is associated with aberrant glycometabolic control, which can persist even after recovery, suggesting that further investigation of metabolic abnormalities in the context of long COVID is warranted.

Published
2020

24. Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males

Author

Sergio Daga, Alessandra Renieri, Margherita Baldassarri, Francesca Fava, Elisa Frullanti, Francesca Mari, Elisa Benetti, Francesco Castelli, Matteo Siano, Simone Furini, Nicola Picchiotti, Stefania Mantovani, Agatha Schlüter, Gen-Covid Multicenter Study, Maria Eugenia Quiros-Roldan, Chiara Fallerini, Maria Bandini, Jesús Troya, Aurora Pujol, Massimo Vaghi, Stefano Rusconi, Mario U. Mondelli, Serena Ludovisi, and Laura Planas-Serra

Subjects
business.industry, Immunology, Cohort, IRF7, Missense mutation, Medicine, Disease, medicine.symptom, business, Peripheral blood mononuclear cell, Gene, Phenotype, Asymptomatic
Abstract

BackgroundCOVID-19 clinical presentation ranges from asymptomatic to fatal outcome. This variability is due in part to host genome specific mutations. Recently, two families in which COVID-19 segregates like an X-linked recessive monogenic disorder environmentally conditioned by SARS-CoV-2 have been reported leading to identification of loss-of-function variants in TLR7.ObjectiveWe sought to determine whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients.MethodsWe compared male subjects with extreme phenotype selected from the Italian GEN-COVID cohort of 1178 SARS-CoV-2-infected subjects (TLR7 as the most important susceptibility gene.ResultsRare TLR7 missense variants were predicted to impact on protein function in severely affected males and in none of the asymptomatic subjects. We then investigated a similar white European cohort in Spain, confirming the impact of TRL7 variants. A gene expression profile analysis in peripheral blood mononuclear cells after stimulation with TLR7 agonist demonstrated a reduction of mRNA level of TLR7, IRF7, ISG15, IFN-□ and IFN-γ in COVID-19 patients compared with unaffected controls demonstrating an impairment in type I and II INF responses.ConclusionYoung males with TLR7 loss-of-function mutations and severe COVID-19 in the two reported families represent only a fraction of a broader and complex host genome situation. Specifically, missense mutations in the X-linked recessive TLR7 disorder may significantly contribute to disease susceptibility in up to 4% of severe COVID-19.Clinical ImplicationIn this new yet complex scenario, our observations provide the basis for a personalized interferon-based therapy in patients with rare TLR7 variants.CAPSULE SUMMARYOur results in large cohorts from Italy and Spain showed that X-linked recessive TLR7 disorder may represent the cause of disease susceptibility to COVID-19 in up to 4% of severely affected young male cases.

Published
2020

25. Research news in clinical context

Author

Rayner Kay Jin Tan, Chen Xiang-Sheng, Stefano Rusconi, and Kristine Shields

Subjects
medicine.medical_specialty, viruses, Population, Context (language use), Dermatology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, 030212 general & internal medicine, education, Disease burden, Hepatitis B virus, Hepatitis, education.field_of_study, 030505 public health, business.industry, virus diseases, Hepatitis C, medicine.disease, Hepatitis D, Infectious Diseases, Attributable risk, 0305 other medical science, business
Abstract

Hepatitis delta virus (HDV) co-infection is known to accelerate disease progression in people with chronic hepatitis B. This case-control study used real-world insurance claims data from 2011 to 2014 to characterise the healthcare cost of HDV in USA. Nearly 3000 cases with HDV and Hepatitis B Virus (HBV) were matched by sociodemographic characteristics and comorbidities to HBV-only controls. Cases had higher rates of cirrhosis and hepatic decompensation and significantly more healthcare claims and annual healthcare costs. People with HDV also had higher prevalence of substance abuse and higher rates of hepatitis C and STIs. Excess disease burden warrants improved control strategies targeting vulnerable populations at risk of dual HBV and HDV infection. Elsaid MI, Li Y, John T, et al Economic and healthcare burdens of hepatitis delta: a study of commercially insured adults in the United States. Hepatology 2019; doi:10.1002/hep.31055. This systematic review estimated the population attributable fraction of herpes simplex virus type 2 (HSV-2) seropositivity to HIV acquisition. Globally, of the 1.4 million sexually-acquired HIV infections that occurred in individuals aged 15–49 years in 2016, nearly a third (30%) were attributable to HSV-2. The effect of HSV-2 was prominent in the African region (37%), women (35%) …

Published
2020
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26. Correlation between continuous Positive end-expiratory pressure (PEEP) values and occurrence of Pneumothorax and Pneumomediastinum in SARS-CoV2 patients during non-invasive ventilation with Helmet

Author

Anna Maria Brambilla, Antonio Gidaro, Chiara Cogliati, Marco Schiuma, Cecilia Bonino, Stella Ingrassia, Stefano Rusconi, Jaqueline Curra, Antonio Brucato, Viola Cupiraggi, Francesco Banfi, Andrea Giacomelli, Federica Samartin, and Emanuele Salvi

Subjects
Original Article: Clinical Research, medicine.medical_treatment, Population, Pneumomediastinum, CPAP, Medicine, Continuous positive airway pressure, education, PEEP, education.field_of_study, business.industry, Mortality rate, Pneumothorax, COVID-19, respiratory system, medicine.disease, respiratory tract diseases, Pneumonia, Anesthesia, SARS-CoV2, Breathing, business, Complication, circulatory and respiratory physiology
Abstract

Background Acute Hypoxemic Respiratory Failure (AHRF) is a common complication of Covid-19 related pneumonia, for which non-invasive ventilation (NIV) with Helmet Continuous Positive Airway Pressure (CPAP) is widely used. During past epidemics of SARS and MERS pneumomediastinum (PNM) and pneumothorax (PNX) were common complications (respectively 1.7-12% and 16,4%) either spontaneous or associated to ventilation. Methods Aim of our retrospective study was to investigate the incidence of PNX/PNM in COVID-19 pneumonia patients treated with CPAP. Moreover, we examined the correlation between PNX/PNM and Positive end-expiratory pressure (PEEP) values. We collected data from patients admitted to “Luigi Sacco” University Hospital of Milan from 21/02/2020 to 06/05/2020 with COVID-19 pneumonia requiring CPAP. Results One-hundred-fifty-four patients were enrolled. During hospitalization 3 PNX and 2 PNM occurred (3.2%). Out of these five patients 2 needed invasive ventilation after PNX, two died. In the overall population, 42 patients (27%) were treated with High-PEEP (>10 cmH2O), and 112 with Low-PEEP (≤10 cmH2O). All the PNX/PNM occurred in the High-PEEP group (5/37 vs 0/112, p Conclusion The incidence of PNX appears to be lower in COVID-19 than SARS and MERS, but their occurrence is accompanied by high mortality and worsening of clinical conditions. Considering the association of PNX/PNM with high PEEP we suggest using the lower PEEP as possible to prevent these complications. “Key messages” box Section 1: What is already known on this subject Elevated incidence of pneumomediastinum (PNM) and pneumothorax (PNX) occurring during SARS and MERS pneumonia (respectively 1.7-12%9,10 and 16,4%11), either spontaneous or associated to ventilation.Conversely, these complications have not been reported when NIV was used for the treatment of common pneumonia patients6,7. Some cases of PNX and PNM have been recently reported in patients with COVID-19 pneumonia, most of them spontaneous12-14, in some cases related to NIV15,16 or endotracheal intubation (ETI)17,18. Section 2: What this study adds Incidence of PNX/PNM is lower in COVID19 pneumonia patients during CPAP (3,2%) than SARS and MERS. Considering mortality rate and need of ETI, occurrence of PNX/PNM worsens prognosis. All the PNX/PNM occurred in the High-PEEP (>10 cmH2O) group (5/37 vs 0/112, p Considering the association of high PEEP (>10 cmH2O) with PNX/PNM, the use of low PEEP values has to be taken into consideration.

Published
2020

27. 30-day mortality in patients hospitalized with COVID-19 during the first wave of the Italian epidemic: A prospective cohort study

Author

Massimo Galli, Agostino Riva, Roberto Rech, Matteo Passerini, Cecilia Bonazzetti, Marco Schiuma, Letizia Oreni, Laura Milazzo, Andrea Giacomelli, Luca Meroni, Alessandro Torre, Anna Maria Brambilla, Dario Bernacchia, Antonio Castelli, Alice Covizzi, Spinello Antinori, Matteo Siano, Giuliano Rizzardini, Massimo Coen, Chiara Cogliati, Riccardo Colombo, Anna Lisa Ridolfo, Guido Gubertini, Stefano Rusconi, and Marco Piscaglia

Subjects
0301 basic medicine, Pharmacology, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, Hazard ratio, Disease, medicine.disease, Obesity, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Interquartile range, 030220 oncology & carcinogenesis, Internal medicine, Intensive care, Pandemic, medicine, Prospective cohort study, business
Abstract

BackgroundItaly was the first European country hit by the COVID-19 pandemic and has the highest number of recorded COVID-19 deaths in Europe.MethodsThis prospective cohort study of the correlates of the risk of death in COVID-19 patients was conducted at the Infectious Diseases and Intensive Care units of Luigi Sacco Hospital, Milan, Italy. The clinical characteristics of all the COVID-19 patients hospitalised in the early days of the epidemic (21 February -19 March 2020) were recorded upon admission, and the time-dependent probability of death was evaluated using the Kaplan-Meier method (censored as of 20 April 2020). Cox proportional hazard models were used to assess the factors independently associated with the risk of death.ResultsForty-eight (20.6%) of the 233 patients followed up for a median of 40 days (interquartile range 33-47) died during the follow-up. Most were males (69.1%) and their median age was 61 years (IQR 50-72). The time-dependent probability of death was 19.7% (95% CI 14.6-24.9%) 30 days after hospital admission. Age (adjusted hazard ratio [aHR] 2.08, 95% CI 1.48-2.92 per ten years more) and obesity (aHR 3.04, 95% CI 1.42-6.49) were independently associated with an increased risk of death, which was also associated with critical disease (aHR 8.26, 95% CI 1.41-48.29), C-reactive protein levels (aHR 1.17, 95% CI 1.02-1.35 per 50 mg/L more) and creatinine kinase levels above 185 U/L (aHR 2.58, 95% CI 1.37-4.87) upon admission.ConclusionsCase-fatality rate of patients hospitalized with COVID-19 in the early days of the Italian epidemic was about 20%. Our study adds evidence to the notion that older age, obesity and more advanced illness are factors associated to an increased risk of death among patients hospitalized with COVID-19.

Published
2020
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28. Simplification to High Genetic Barrier 2-Drug Regimens in People Living With HIV Harboring 4-Class Resistance Enrolled in the PRESTIGIO Registry

Author

Maria Mercedes Santoro, Laura Galli, Antonella Castagna, Diana Canetti, Leonardo Calza, Micol Ferrara, Nicola Gianotti, Sara Modica, Stefano Rusconi, Maurizio Zazzi, Giovanni Cenderello, Roberta Gagliardini, Anna Celotti, Canetti D, Galli L, Gianotti N, Celotti A, Calza L, Gagliardini R, Rusconi S, Modica S, Cenderello G, Ferrara M, Santoro MM, Zazzi M, Castagna A, Canetti, D., Galli, L., Gianotti, N., Celotti, A., Calza, L., Gagliardini, R., Rusconi, S., Modica, S., Cenderello, G., Ferrara, M., Santoro, M. M., Zazzi, M., and Castagna, A.

Subjects
Drug, medicine.medical_specialty, Class (computer programming), business.industry, Anti-HIV Agents, media_common.quotation_subject, Human immunodeficiency virus (HIV), MEDLINE, Resistance (psychoanalysis), HIV Infections, medicine.disease_cause, Settore MED/07, Infectious Diseases, Internal medicine, Non disponibili, Drug Resistance, Viral, HIV-1, Medicine, Humans, Pharmacology (medical), Registries, business, media_common, Retrospective Studies
Abstract

Non disponibile.

Published
2020

29. Darunavir does not prevent SARS-CoV-2 infection in HIV patients

Author

Cristina Gervasoni, Laura Pezzati, Angelica Lupo, Federico Conti, Salvatore Sollima, Dario Bernacchia, Stefania Merli, Matteo Siano, Dario Cattaneo, Agostino Riva, and Stefano Rusconi

Subjects
Pharmacology, biology, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Lopinavir, medicine.disease, biology.organism_classification, Virology, Pneumonia, Pandemic, Hiv patients, Medicine, Ritonavir, business, Betacoronavirus, Darunavir, medicine.drug
Published
2020
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30. Early administration of lopinavir/ritonavir plus hydroxychloroquine does not alter the clinical course of SARS-COV-2 infection: a retrospective cohort study

Author

Simone Passerini, Riccardo Colombo, Anna Lisa Ridolfo, Valentina Morena, Spinello Antinori, Elisa Ceriani, Letizia Oreni, Stefano Rusconi, Lucia Bradanini, Cristina Gervasoni, Giacomo Casalini, Federico Conti, Gabriele Pagani, Cinzia Bassoli, Laura Pezzati, Massimo Galli, Chiara Cogliati, Giuliano Rizzardini, Andrea Giacomelli, and Dario Cattaneo

Subjects
Male, medicine.medical_specialty, hydroxychloroquine, antiviral treatment, Lopinavir/ritonavir, Antiviral Agents, Lopinavir, early, COVID‐19, Virology, Internal medicine, medicine, Humans, Adverse effect, Research Articles, Aged, Retrospective Studies, Ritonavir, SARS-CoV-2, business.industry, Retrospective cohort study, Hydroxychloroquine, Odds ratio, Middle Aged, mortality, Confidence interval, COVID-19 Drug Treatment, Drug Combinations, Infectious Diseases, Italy, Female, business, Research Article, medicine.drug
Abstract

As it has been shown that lopinavir (LPV) and hydroxychloroquine (HCQ) have in vitro activity against coronaviruses, they were used to treat COVID-19 during the first wave of the epidemic in Lombardy, Italy.The aim of this retrospective intent-to-treat analysis of the hospitalized patients who started off-label treatment with LPV/ritonavir (LPV/r)+HCQ between 21 February and 20 March 2020 was to compare the rate of clinical improvement between those who started the treatment within five days of symptom onset (early treatment, ET) and those who started later (delayed treatment, DT). The association between the timing of treatment and the probability of 30-day mortality was also assessed using uni- and multivariable logistic models.The study involved 172 patients: 43 (25%) in the ET and 129 (75%) in the DT group. The rate of clinical improvement increased over time to 73.3% on day 30, without any significant difference between the two groups (Gray’s test P = 0.213). After adjusting for potentially relevant clinical variables, there was no significant association between the timing of the start of treatment and the probability of 30-day mortality (adjusted odds ratio [aOR] ET vs DT = 1.45, 95% confidence interval 0.50-4.19). Eight percent of the patients discontinued the treatment because of severe gastrointestinal disorders attributable to LPV/r.The timing of the start of LPV/r+HCQ treatment does not seem to affect the clinical course of hospitalised patients with COVID-19. Together with the severe adverse events attributable to LPV/r, this raises concerns about the benefit of using this combination to treat COVID-19.

Published
2020

31. Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and Non-ICU patients: Clinical outcome and differences in post_treatment hospitalisation status

Author

Roberto Rech, Spinello Antinori, Giuliano Rizzardini, Martina Pellicciotta, Letizia Oreni, Gabriele Pagani, Riccardo Giorgi, Beatrice Borghi, Maria Rita Gismondo, Riccardo Colombo, Massimo Galli, Antonio Castelli, Stefano Rusconi, Mario Corbellino, Massimo Coen, Carlo Alberto Magni, Luca Meroni, Stefania Vimercati, Davide Mileto, Andrea Giacomelli, Cecilia Bonazzetti, Anna Lisa Ridolfo, Laura Milazzo, Alessandro Torre, Maria Vittoria Cossu, Guido Gubertini, and Elena Angeli

Subjects
0301 basic medicine, Compassionate Use Trials, Male, medicine.medical_specialty, Activities of daily living, medicine.medical_treatment, Pneumonia, Viral, Remdesivir, Antiviral Agents, Article, law.invention, 03 medical and health sciences, Betacoronavirus, 0302 clinical medicine, law, SARS-Cov2, medicine, Humans, Adverse effect, Pandemics, Transaminases, ComputingMethodologies_COMPUTERGRAPHICS, Aged, Pharmacology, Mechanical ventilation, Alanine, business.industry, SARS-CoV-2, Acute kidney injury, COVID-19, Acute Kidney Injury, Middle Aged, medicine.disease, Early warning score, Intensive care unit, Adenosine Monophosphate, Hospitalization, Pneumonia, Intensive Care Units, 030104 developmental biology, Treatment Outcome, 030220 oncology & carcinogenesis, Emergency medicine, Female, business, Coronavirus Infections
Abstract

Graphical abstract, SARS-CoV-2 is causing an increasing number of deaths worldwide because no effective treatment is currently available. Remdesivir has shown in vitro activity against coronaviruses and is a possible antiviral treatment for SARS-CoV-2 infection. This prospective (compassionate), open-label study of remdesivir, which was conducted at Luigi Sacco Hospital, Milan, Italy, between February 23 and March 20, 2020, involved patients with SARS-CoV-2 pneumonia aged ≥18 years undergoing mechanical ventilation or with an oxygen saturation level of ≤94% in air or a National Early Warning Score 2 of ≥4. The primary outcome was the change in clinical status based on a 7-category ordinal scale (1 = not hospitalised, resuming normal daily activities; 7 = deceased). The 35 patients enrolled from February 23 to March 20, 2020, included 18 in intensive care unit (ICU), and 17 in our infectious diseases ward (IDW). The 10-day course of remdesivir was completed by 22 patients (63%) and discontinued by 13, of whom eight (22.8%) discontinued because of adverse events. The median follow-up was 39 days (IQR 25-44). At day 28, 14 (82.3%) patients from IDW were discharged, two were still hospitalized and one died (5.9%), whereas in ICU 6 (33.3%) were discharged, 8 (44.4%) patients died, three (16.7%) were still mechanically ventilated and one (5.6%) was improved but still hospitalized. Hypertransaminasemia and acute kidney injury were the most frequent severe adverse events observed (42.8% and 22.8% of the cases, respectively). Our data suggest that remdesivir can benefit patients with SARS-CoV-2 pneumonia hospitalised outside ICU where clinical outcome was better and adverse events are less frequently observed. Ongoing randomised controlled trials will clarify its real efficacy and safety, who to treat, and when.

Published
2020

32. Self-reported Olfactory and Taste Disorders in Patients With Severe Acute Respiratory Coronavirus 2 Infection: A Cross-sectional Study

Author

Anna Lisa Ridolfo, Stefano Rusconi, Cristina Gervasoni, Massimo Galli, Giuliano Rizzardini, Matteo Siano, Spinello Antinori, Letizia Oreni, Laura Pezzati, Federico Conti, Dario Bernacchia, and Andrea Giacomelli

Subjects
Microbiology (medical), medicine.medical_specialty, China, Cross-sectional study, Pneumonia, Viral, medicine.disease_cause, Betacoronavirus, Taste Disorders, Internal medicine, Medicine, Humans, In patient, Respiratory system, Pandemics, Coronavirus, biology, business.industry, SARS-CoV-2, COVID-19, Ageusia, biology.organism_classification, medicine.disease, Pneumonia, Cross-Sectional Studies, Infectious Diseases, Taste disorder, Self Report, medicine.symptom, business, Coronavirus Infections
Published
2020
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33. Predictors of incomplete viral response and virologic failure in patients with acute and early HIV infection. Results of Italian Network of ACuTe HIV InfectiON (INACTION) cohort

Author

Elena Bruzzesi, Giorgio Bozzi, Antonio Muscatello, Emanuele Focà, Maria Licinia Campus, Andrea Gori, Giordano Madeddu, A. Antinori, Nicola Squillace, Alessandra Bandera, Andrea Calcagno, Lucia Taramasso, Lucio Cosco, Eugenia Quiros-Roldan, Giuseppe Tambussi, A. Di Biagio, Silvia Nozza, Cristina Mussini, Stefano Rusconi, Micol Ferrara, Andrea Mastrangelo, A. Cingolani, Benedetto Maurizio Celesia, I. De Benedetto, Roberto Gulminetti, Carmela Pinnetti, Giulia Marchetti, G. Orofino, Diego Ripamonti, A. Franco, Gabriella d'Ettorre, Carlo Torti, and Massimiliano Fabbiani

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Anti-HIV Agents, incomplete viral response, acute HIV infection, blip, early antiretroviral treatment, virologic failure, HIV Infections, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Central Nervous System Diseases, Risk Factors, Internal medicine, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Treatment Failure, Retrospective Studies, Proportional hazards model, business.industry, Health Policy, Hazard ratio, Retrospective cohort study, Middle Aged, Viral Load, Raltegravir, 030112 virology, CD4 Lymphocyte Count, Infectious Diseases, Italy, Cohort, Acute Disease, HIV-1, RNA, Viral, Regression Analysis, Ritonavir, Female, business, Cohort study, medicine.drug
Abstract

The aim of this study was to evaluate the factors that can influence an incomplete viral response (IVR) after acute and early HIV infection (AEHI).This was a retrospective, observational study including patients with AEHI (Fiebig stages I-V) diagnosed between January 2008 and December 2014 at 20 Italian centres. IVR was defined by: (1) viral blip (51-1000 HIV-1 RNA copies/mL after achievement of 50 HIV-1 RNA copies/mL); (2) virologic failure [ 1000 copies/mL after achievement of 200 copies/mL, or ≥ 200 copies/mL after 24 weeks on an antiretroviral therapy (ART)]; (3) suboptimal viral response ( 50 copies/mL after 48 weeks on ART or two consecutive HIV-1 RNA levels with ascending trend during ART). Cox regression analysis was used to calculate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for IVR.In all, 263 patients were studied, 227 (86%) males, with a median [interquartile range (IQR)] age of 38 (30-46) years. During a median follow-up of 13.0 (5.7-31.1) months, 38 (14.4%) had IVR. The presence of central nervous system (CNS) symptoms was linked to a higher risk of IVR (HR = 4.70, 95% CI: 1.56-14.17), while a higher CD4/CD8 cell count ratio (HR = 0.13, 95% CI: 0.03-0.51 for each point increase) and first-line ART with three-drug regimens recommended by current guidelines (HR = 0.40, 95% CI: 0.18-0.91 compared with other regimens including four or five drugs, older drugs or non-standard backbones) were protective against IVR.Patients with lower CD4/CD8 ratio and CNS symptoms could be at a higher risk of IVR after AEHI. The use of recommended ART may be relevant for improving short-term viral efficacy in this group of patients.

Published
2020

34. 96-week results of a dual therapy with darunavir/ritonavir plus rilpivirine once a day vs triple therapy in patients with suppressed viraemia: virological success and non-HIV related morbidity evaluation

Author

C. Abeli, Giuseppe Bruno, Marco Annovazzi Lodi, Valentina Di Cristo, Maria Vittoria Cossu, Paolo Maggi, Maria Letizia Oreni, Paola Vitiello, Elisa Colella, Anna Volpe, Fulvio Adorni, Stefano Bonora, Stefano Rusconi, Renato Maserati, and Micol Ferrara

Subjects
Oncology, endocrine system, medicine.medical_specialty, Dual therapy, Darunavir+Ritonavir, Immunovirological success, business.industry, Rilpivirine, Limiting, chemistry.chemical_compound, Infectious Diseases, chemistry, Internal medicine, Toxicity, medicine, HIV-1, Pharmacology (medical), In patient, Safety, business, Darunavir, medicine.drug
Abstract

Antiretroviral therapies have been tested with the goal of maintaining virological suppression with a particular attention in limiting drug-related toxicity. With this aim we designed the DUAL study: a randomized, open-label, multicenter, 96 weeks-long pilot exploratory study in virologically suppressed HIV-1+ patients with the aim of evaluating the immunovirological success and the impact on non-HIV related morbidity of switching to a dual therapy with darunavir-ritonavir (DRV/r) and rilpivirine (RPV). We recruited patients who received a PI/r-containing HAART for >=6 months, HIV-RNA < 50 cp/mL for >=3 months, eGFR > 60 mL/min/1,73m2, without DRV or RPV RAMs. We randomized patients in arm A: RPV + DRV/r QD or arm B: ongoing triple therapy. The primary endpoint has been defined as the percentage of patients with HIV-RNA < 50 cp/mL at week 48 (ITT). VACS index, Framingham CVD risk (FRS) and urinary RBP (uRBP) were calculated. We used Chi-square or Fisher statistics for categorical variables and Mann-Whitney U for continuous ones. Forty-one patients were enrolled (22 in arm A, 14 in arm B, plus 5 screening failures): 30 patients reached 96 weeks: 100% had HIV-RNA < 50 cp/mL in arm A versus 91.7% in arm B. Similar changes were observed in median CD4/mL between baseline and week 96 (+59 versus - 31, p: n.s.). Thirty-one in arm A and 23 in arm B adverse events took place, whereas only 1 was serious (arm A: turbinate hypertrophy, unrelated to HAART). Among the 6 discontinuations (3 in A, 3 in B), only 1 was related to adverse event (arm A: G3 depression, insomnia, weakness). VACS index, median FRS and median uRBP values did not vary from baseline to week 96. At 96-weeks all patients switched to a QD 2-drug regimen based on DRV/r + RPV maintained HIV-RNA suppression, but a single patient who showed a virological failure at week 4. CD4 counts increased overtime without significant differences between the two arms. The novel dual regimen was well tolerated with the same amount of discontinuation as the control arm. VACS index, FRS and uRBP did not differ between arms at week 96.

Published
2020

35. Self-Reported Symptoms of SARS-CoV-2 Infection in a Nonhospitalized Population in Italy: Cross-Sectional Study of the EPICOVID19 Web-Based Survey

Author

Luca Bastiani, Massimo Galli, Stefania Maggi, Caterina Trevisan, Nithiya Jesuthasan, Federica Prinelli, Sabrina Molinaro, Raffaele Antonelli Incalzi, Andrea Giacomelli, Dario Bernacchia, Fulvio Adorni, Massimo Andreoni, Aleksandra Sojic, Fabrizio Bianchi, Loredana Fortunato, Carla Pettenati, Marcello Tavio, Claudio Maria Mastroianni, Marianna Noale, Stefano Rusconi, and Gabriele Pagani

Subjects
myalgia, Male, Cross-sectional study, Health Status, Severe Acute Respiratory Syndrome, 0302 clinical medicine, 80 and over, Odds Ratio, Prevalence, voluntary respondents, Viral, 030212 general & internal medicine, Young adult, Aged, 80 and over, 0303 health sciences, education.field_of_study, Middle Aged, Taste disorder, Italy, Area Under Curve, Population Surveillance, Female, Public aspects of medicine, RA1-1270, medicine.symptom, Coronavirus Infections, Adult, medicine.medical_specialty, cross-sectional, Adolescent, Population, Pneumonia, Viral, Health Informatics, Context (language use), Asymptomatic, NO, 03 medical and health sciences, Betacoronavirus, Young Adult, Internal medicine, medicine, Humans, education, Pandemics, 030304 developmental biology, Aged, Original Paper, web-based survey, business.industry, SARS-CoV-2, Public Health, Environmental and Occupational Health, COVID-19, COVID-19, Web-based survey, Voluntary respondents, Self-reported symptom, SARS-CoV-2, Nasopharyngeal swab testing, Cross-sectional, Pneumonia, Odds ratio, Health Surveys, nasopharyngeal swab testing, self-reported symptom, Coronavirus, Cross-Sectional Studies, ROC Curve, Self Report, Settore MED/17, business
Abstract

Background Understanding the occurrence of symptoms resembling those of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a large nonhospitalized population at the peak of the epidemic in Italy is of paramount importance; however, data are currently scarce. Objective The aims of this study were to evaluate the association of self-reported symptoms with SARS-CoV-2 nasopharyngeal swab (NPS) test results in nonhospitalized individuals and to estimate the occurrence of symptoms associated with coronavirus disease (COVID-19) in a larger nontested population. Methods EPICOVID19 is a self-administered cross-sectional voluntary web-based survey of adults throughout Italy who completed an anonymous questionnaire in the period of April 13 to 21, 2020. The associations between symptoms potentially related to SARS-CoV-2 infection and NPS results were calculated as adjusted odds ratios (aORs) with 95% CIs by multiple logistic regression analysis controlling for age, sex, education, smoking habits, and number of comorbidities. Thereafter, for each symptom and for combinations of the symptoms, we calculated the sensitivity, specificity, accuracy, and areas under the curve (AUCs) in a receiver operating characteristic (ROC) analysis to estimate the occurrence of COVID-19–like infection in the nontested population. Results A total of 171,310 people responded to the survey, of whom 102,543 (59.9%) were women; mean age 47.4 years. Out of the 4785 respondents with known NPS test results, 4392 were not hospitalized. Among the 4392 nonhospitalized respondents, those with positive NPS tests (856, 19.5%) most frequently reported myalgia (527, 61.6%), olfactory and taste disorders (507, 59.2%), cough (466, 54.4%), and fever (444, 51.9%), whereas 7.7% were asymptomatic. Multiple regression analysis showed that olfactory and taste disorders (aOR 10.3, 95% CI 8.4-12.7), fever (aOR 2.5, 95% CI 2.0-3.1), myalgia (aOR 1.5, 95% CI 1.2-1.8), and cough (aOR 1.3, 95% CI 1.0-1.6) were associated with NPS positivity. Having two to four of these symptoms increased the aOR from 7.4 (95% CI 5.6-9.7) to 35.5 (95% CI 24.6-52.2). The combination of the four symptoms showed an AUC of 0.810 (95% CI 0.795-0.825) in classifying positive NPS test results and then was applied to the nonhospitalized and nontested sample (n=165,782). We found that 7739 to 20,103 of these 165,782 respondents (4.4% to 12.1%) had experienced symptoms suggestive of COVID-19 infection. Conclusions Our results suggest that self-reported symptoms are reliable indicators of SARS-CoV-2 infection in a pandemic context. A nonnegligible number of symptomatic respondents (up to 12.1%) were undiagnosed and potentially contributed to the spread of the infection. Trial Registration ClinicalTrials.gov NCT04471701; https://clinicaltrials.gov/ct2/show/NCT04471701

Published
2020
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36. Shall we dance? Extending tango's results to clinical practice

Author

Vanni Borghi, Gianmaria Baldin, Alberto Borghetti, William Gennari, Amedeo Capetti, Cristina Mussini, Simona Di Giambenedetto, Stefano Rusconi, Gaetana Sterrantino, and Arturo Ciccullo

Subjects
Microbiology (medical), Medical education, Models, Statistical, Dance, business.industry, MEDLINE, hiv, dual therapy, Settore MED/17 - MALATTIE INFETTIVE, Clinical Practice, Infectious Diseases, AcademicSubjects/MED00290, Correspondence, Medicine, Cluster Analysis, Humans, Dancing, business, Online Only Articles
Published
2020

37. Efficacy and safety of switching to dolutegravir plus emtricitabine/tenofovir disoproxil fumarate (TDF) or elvitegravir/cobicistat/emtricitabine/TDF in virologically suppressed HIV-infected patients in clinical practice: results from a multicentre, observ

Author

Alessandra Latini, Maria Vittoria Cossu, S Di Giambenedetto, Gaetana Sterrantino, Arturo Ciccullo, Paola Bagella, Gianmaria Baldin, Andrea Giacomelli, Filippo Lagi, Giordano Madeddu, Amedeo Capetti, Stefano Rusconi, and A. De Luca

Subjects
Male, 0301 basic medicine, efficacy, HIV Infections, Quinolones, elvitegravir/cobicistat/tenofovir/emtricitabine, Piperazines, chemistry.chemical_compound, 0302 clinical medicine, Emtricitabine, Pharmacology (medical), 030212 general & internal medicine, Elvitegravir, Health Policy, Cobicistat, dolutegravir, safety, tenofovir/emtricitabine, Middle Aged, Viral Load, Infectious Diseases, Tolerability, Dolutegravir, RNA, Viral, Drug Therapy, Combination, Female, Heterocyclic Compounds, 3-Ring, Viral load, medicine.drug, Adult, medicine.medical_specialty, Pyridones, Settore MED/17 - MALATTIE INFETTIVE, 03 medical and health sciences, Internal medicine, Oxazines, medicine, Humans, Tenofovir, Adverse effect, Retrospective Studies, business.industry, 030112 virology, Discontinuation, chemistry, HIV-1, business
Abstract

OBJECTIVES The aim of the study was to compare the efficacy and tolerability of switching antiretroviral therapy to dolutegravir + emtricitabine/tenofovir disoproxil fumarate (TDF) with those of switching to elvitegravir/cobicistat/emtricitabine/TDF in clinical practice. METHODS In a multicentre real-life observational study, we analysed data for HIV-infected patients on antiretroviral treatment with viral load < 50 HIV-1 RNA copies/mL switching to dolutegravir + emtricitabine/TDF (dolutegravir group) or elvitegravir/cobicistat/emtricitabine/TDF (elvitegravir group). Follow-up was censored at 48 weeks. RESULTS The 48-week estimated proportion maintaining virological efficacy was 96.1% with dolutegravir (n = 123) and 95.4% with elvitegravir (n = 186; P = 0.941). Patients in the dolutegravir group showed more treatment discontinuations, but these were mainly as a result of simplification. The elvitegravir group showed more discontinuations because of renal adverse events (2.7% versus 0% with dolutegravir). Interestingly, no difference was observed between the two regimens in central nervous system toxicity-related discontinuations. Switching to dolutegravir was associated with a better blood lipid profile. CONCLUSIONS Switching to dolutegravir + emtricitabine/TDF was associated with similar efficacy and tolerability to switching to elvitegravir/cobicistat/emtricitabine/TDF in virologically suppressed patients in clinical practice, although reasons for discontinuation showed differences between regimens. These results should be interpreted with caution, as this is a nonrandomized comparison.

Published
2018

38. Durability of dolutegravir plus boosted darunavir as salvage or simplification of salvage regimens in HIV-1 infected, highly treatment-experienced subjects

Author

Niccolò Riccardi, Fosca Niero, Maria Vittoria Cossu, Anna Maria Cattelan, Giuseppe Vittorio De Socio, Giorgio Barbarini, Stefano Rusconi, Amedeo Capetti, Giuliano Rizzardini, Gaetana Sterrantino, Benedetto Maurizio Celesia, Gian M Baldin, Giovanni Cenderello, and Alessandro Soria

Subjects
Adult, Male, 0301 basic medicine, Oncology, endocrine system, medicine.medical_specialty, Pyridones, 030106 microbiology, Human immunodeficiency virus (HIV), Salvage therapy, HIV Infections, medicine.disease_cause, Piperazines, Treatment experienced, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Oxazines, Salvage regimen, medicine, Humans, Pharmacology (medical), HIV Integrase Inhibitors, 030212 general & internal medicine, Darunavir, Aged, Salvage Therapy, business.industry, Reproducibility of Results, HIV Protease Inhibitors, Middle Aged, Infectious Diseases, Italy, chemistry, Dolutegravir, HIV-1, Female, business, Heterocyclic Compounds, 3-Ring, medicine.drug
Abstract

Dolutegravir (DTG) plus boosted darunavir (bDRV) is a compact, adherence-friendly salvage regimen with the highest genetic barrier to HIV-1 resistance.Aim of the present study is to assess the long term (96-week) safety and efficacy of DTG + bDRV in a of multidrug-experienced HIV-1 infected patients, simplifying or building rescue regimens.All HIV-1-infected subjects from eleven Italian centers switched to DTG + bDRV between March 2014 and September 2015 were included and followed for minimum 96 weeks.The cohort comprises 130 subjects, switched from 42 different, complex or at least twice-daily regimens, mainly for simplification (44.6%), viral failure (30.0%) or toxicity (16.6%). At baseline 118 had documented resistance to 1-5 antiretroviral classes and 12 lacked genotypic results either for historical reasons or for problems with primer annealing; 52 (40%) had uncontrolled viral replication, three above 500.000 copies/mL. At week 96 two showed ≥50 HIV-1 RNA copies/mL, 23 had 1-49 copies/mL and 101 had no virus detected. The proportion of subjects presenting abnormal values at baseline significantly decreased for serum glucose, creatinine, AST, total cholesterol and triglycerides.These long-term data confirm the reliability of the two-drug regimen consisting of bDRV plus DTG in salvage settings in HIV-1 infection.

Published
2018

39. Cohort profile: The Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE)

Author

Francesca Vignale, Cristina Mussini, Simona Di Giambenedetto, Sibilla Restelli, Manuela Colafigli, Gianmaria Baldin, Amedeo Capetti, Luigi Celani, Alex Dusina, Maria Vittoria Cossu, Giordano Madeddu, Alessandra Latini, Arturo Ciccullo, Vanni Borghi, Barbara Rossetti, Gaetana Sterrantino, Alberto Borghetti, William Gennari, Lucia Brescini, Stefano Rusconi, Andrea Giacomelli, and Filippo Lagi

Subjects
Male, Integrase inhibitor, HIV Infections, Piperazines, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, 030212 general & internal medicine, Lamivudine, General Medicine, cohort, Middle Aged, dolutegravir, Treatment Outcome, Tolerability, Anti-Retroviral Agents, Italy, Rilpivirine, Dolutegravir, Cohort, HIV/AIDS, Drug Therapy, Combination, Female, antiretroviral therapy, HIV, INI, Heterocyclic Compounds, 3-Ring, medicine.drug, Adult, medicine.medical_specialty, Pyridones, Settore MED/17 - MALATTIE INFETTIVE, 03 medical and health sciences, Internal medicine, Oxazines, medicine, Humans, Cohort Profile, business.industry, Discontinuation, CD4 Lymphocyte Count, Regimen, chemistry, business, 030217 neurology & neurosurgery
Abstract

PurposeThe Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE) cohort was established in Italy in 2016 to evaluate the overall efficacy and tolerability of dolutegravir (DTG)-based antiretroviral (ARV) regimens in clinical practice.ParticipantsThe ODOACRE cohort enrols all adult HIV-1-infected patients, both treatment-naïve and treatment-experienced, starting a DTG-based ARV regimen, in 11 clinical centres in Italy from 2014.Findings to dateIn recent years, various works by the ODOACRE cohort have been produced, demonstrating the high efficacy and tolerability of DTG-based ARV regimens in clinical practice, both in ART-naïve (in the setting of acute HIV-1 infection and late presenters patient) and experienced patients. We confirmed the virological efficacy of DTG-based regimens and we evaluated predictors of virological failure. We investigated cause of discontinuation and evaluated tolerability and metabolic profile of the regimens. Within these investigations, we explored particularly the use of DTG in simplification in two-drug regimen with either rilpivirine or lamivudine. We also compared DTG-based regimens with other integrase inhibitors in clinical practice.Future plansTo continue to study long-term efficacy and tolerability of DTG-based regimens is the purpose of the ODOACRE cohort.

Published
2019

40. Dolutegravir (DTG)-containing regimens after receiving raltegravir (RAL) or elvitegravir (EVG): Durability and virological response in a large Italian HIV drug resistance network (ARCA)

Author

Valeria Micheli, Stefania Paolucci, Paola Meraviglia, Daniela Francisci, Bianca Bruzzone, Renato Maserati, Pamela Tau, Monica Pecorari, Stefano Rusconi, Fulvio Adorni, Alessandro Mancon, Vanni Borghi, Arca, A. Di Biagio, Laura Monno, Grazia Punzi, and Maurizio Zazzi

Subjects
Male, 0301 basic medicine, Oncology, Sustained Virologic Response, Dolutegravir, Drug resistance, Durability, Genotype, Human immunodeficiency virus type 1, Virological response, Adult, Anti-HIV Agents, Cohort Studies, Female, HIV Infections, HIV-1, Heterocyclic Compounds, 3-Ring, Humans, Middle Aged, Quinolones, RNA, Viral, Raltegravir Potassium, Retrospective Studies, Young Adult, Drug Resistance, Multiple, Viral, Drug Resistance, Piperazines, chemistry.chemical_compound, 0302 clinical medicine, Heterocyclic Compounds, Viral, 030212 general & internal medicine, Virology, Infectious Diseases, biology, Elvitegravir, Integrase, Multiple, HIV drug resistance, medicine.drug, medicine.medical_specialty, Pyridones, 030106 microbiology, 3-Ring, 03 medical and health sciences, Internal medicine, Oxazines, HIV1, medicine, business.industry, Raltegravir, Discontinuation, Regimen, chemistry, biology.protein, RNA, business
Abstract

Background: Dolutegravir (DTG) is a next-generation HIV integrase inhibitor (INI) with an increased genetic barrier to resistance with respect to raltegravir (RAL) or elvitegravir (EVG). Few data are available on the durability of DTG-containing regimens. Objectives: We aimed at investigating the duration of the DTG-containing regimen, the occurrence of an HIV-1 RNA blip, and factors associated with DTG virological response. Study design: From the Antiviral Response Cohort Analysis database, we selected 89 HIV-1-positive four-class-experienced subjects who started DTG after receiving RAL or EVG. Factors associated with durability and virological response were analysed by logistic regression. Results: After a median duration of 18.8 [0.4-76.2] months, 79/89 (88.8%) subjects were still on DTG. All subjects remaining on DTG at the end of follow-up had undetectable HIV-1 RNA, compared to 5/10 subjects who discontinued DTG. DTG discontinuation was less frequent in patients who had experienced >=10 regimens (HR 0.11, p = 0.040). The probability of having an HIV-1 RNA positive value at the last follow-up significantly increased in patients with non-B HIV-1 subtype (HR 5.77, p 200/?L (HR 0.29, p = 0.038), with more than 10 previous regimens (HR 0.27, p = 0.040), and who harbored virus with IN mutations (HR 0.12, p = 0.023) at DTG start. Conclusions: After previous exposure to first-generation INIs, treatment with DTG showed long durability and did not show virological rebound after virological suppression. Subjects infected with a non-B HIV-1 subtype had a greater risk of having detectable HIV-1 RNA at the last observation.

Published
2018

41. Dolutegravir Plus Rilpivirine as a Switch Option in cART-Experienced Patients: 96-Week Data

Author

Giuseppe Vittorio De Socio, Gaetana Sterrantino, Amedeo Capetti, Gian Carlo Orofino, Barbara Argenteri, Giorgio Barbarini, Giuliano Rizzardini, Simona Di Giambenedetto, Stefano Rusconi, Antonio Di Biagio, Benedetto Maurizio Celesia, and Maria Vittoria Cossu

Subjects
Male, 0301 basic medicine, HIV Infections, Piperazines, chemistry.chemical_compound, 0302 clinical medicine, pharmacoeconomics, Heterocyclic Compounds, adverse drug reactions, antiretrovirals, drug utilization, HIV/AIDS, metabolism, Adult, Anti-HIV Agents, Cholesterol, HDL, Cholesterol, LDL, Drug Substitution, Drug Therapy, Combination, Female, HIV-1, Heterocyclic Compounds, 3-Ring, Humans, Middle Aged, RNA, Viral, Rilpivirine, Pharmacology (medical), Viral, 030212 general & internal medicine, Cholesterol, Combination, Dolutegravir, Drug Utilization, Cart, medicine.medical_specialty, HDL, Pyridones, 030106 microbiology, 3-Ring, LDL, 03 medical and health sciences, Pharmacoeconomics, Drug Therapy, Acquired immunodeficiency syndrome (AIDS), Internal medicine, Oxazines, medicine, business.industry, medicine.disease, chemistry, RNA, business
Abstract

Background: Data from clinical studies confirm the efficacy of switching to dolutegravir (DTG) plus rilpivirine (RPV) in selected patients. Objective: The primary objective is to report the 96-week virological suppression in our cohort, assessing the durability of this strategy in complicated situations. The secondary objective is to describe the safety and metabolic profile. Methods: All patients who had switched to DTG plus RPV between October 1, 2014, and September 30, 2015, were analyzed using a retrospective-prospective design, approved by ethics committees. Routine metabolic, immunological, and virological data were regularly sent to the coordinating center. Viral control was classified as HIV-1 RNA ≥50 copies/mL, 1 to 49 copies/mL, or undetectable (no virus detected [NVD]). Results: We followed 145 patients for a median of 101 weeks. The median age was 52 years; 31.7% were women, and 9.6% non-Caucasian; 50.3% had failed at least 1 antiretroviral regimen; and 15% had ≥50 copies/mL at baseline. The reasons for switching were as follows: simplification (51.7%), toxicity (36.5%), drug-drug interactions (6.9%), persistent low-level viremia (3.0%), nonadherence (2.1%), and viral failure (1.4%). By week 96, seven patients dropped out. At week 96, none had ≥50 HIV-1 RNA copies/mL, 138 (95.2%) had

Published
2018

42. Use of quantitative ultrasound as bone mineral density evaluation in an Italian female population living with HIV: A real-life experience

Author

Chiara Gabrielli, Paola Vitiello, Lucia Taramasso, Paolo Maggi, Barbara Menzaghi, Giuseppe Vittorio De Socio, Antonio Di Biagio, Elena Ricci, Alessandro Tebini, Stefano Rusconi, Canio Martinelli, Katia Falasca, Valentina Di Cristo, Vitiello, P, Taramasso, L, Ricci, E, Maggi, P, Martinelli, C, Gabrielli, C, Vittorio De Socio, G, Di Cristo, V, Rusconi, S, Falasca, K, Menzaghi, B, Tebini, A, and Di Biagio, A

Subjects
musculoskeletal diseases, medicine.medical_specialty, Heel, Osteoporosis, Human immunodeficiency virus (HIV), vitamin D, HIV Infections, medicine.disease_cause, Gender Studies, Osteopenia, osteoporosis, QUS, Sahara, women living with HIV, Bone Density, Risk Factors, medicine, Vitamin D and neurology, Humans, Aged, Ultrasonography, Female population, Bone mineral, business.industry, Obstetrics, HIV, Middle Aged, medicine.disease, Quantitative ultrasound, Bone Diseases, Metabolic, Calcaneus, Cross-Sectional Studies, medicine.anatomical_structure, Italy, Female, Geriatrics and Gerontology, business
Abstract

This is a multicenter cross-sectional study where we aimed to detect the rate of osteopenia/osteoporosis in an HIV female population (WLWHIV) by means of "heel quantitative ultrasound" (QUS) measurement. We enrolled 273 patients, mean age 48.1 years, 36% menopausal, 96% on combination antiretroviral therapy (cART). Calcaneal measure of bone mass index by QUS revealed osteopenia and osteoporosis in 76 (27.8%) and 16 (5.9%) WLWHIV. Our data underline the correlation between low QUS parameters and traditional risk factors for osteoporosis rather than with cART exposure, thus suggesting the crucial importance of detection and correction of traditional risk factors for osteoporosis in WLWHIV.

Published
2018

43. Marked decrease in acquired resistance to antiretrovirals in latest years in Italy

Author

Simona Di Giambenedetto, Claudia Balotta, Alessia Lai, Nicola Gianotti, Marco Franzetti, Saverio Giuseppe Parisi, Maria Mercedes Santoro, Sergio Lo Caputo, Antonio Di Biagio, Franco Maggiolo, Stefano Rusconi, Francesco Saladini, Bianca Bruzzone, and Annalisa Bergna

Subjects
Male, 0301 basic medicine, Multivariate analysis, Predictors of resistance, Drug Resistance, HIV Infections, Drug resistance, Settore MED/07, 0302 clinical medicine, Risk Factors, Genotype, ART regimens, Medicine, Viral, Treatment Failure, 030212 general & internal medicine, prescription guidelines, Antiretrovirals, General Medicine, Middle Aged, HIV-1, acquired resistance, new cART regimens, non-B subtypes, Infectious Diseases, Anti-Retroviral Agents, Italy, Female, Adult, Microbiology (medical), medicine.medical_specialty, 030106 microbiology, Temporal trends, Settore MED/17 - MALATTIE INFETTIVE, Acquired resistance, 03 medical and health sciences, Acquired immunodeficiency syndrome (AIDS), Internal medicine, Drug Resistance, Viral, Humans, Potency, In patient, business.industry, medicine.disease, Integrase strand transfer inhibitor, Mutation, business
Abstract

Objectives The aim of this study was to evaluate acquired drug resistance in Italy in the 2009–2018 period. Methods We analysed 3094 patients from the Italian ARCA database who had failed antiretroviral treatment and who had received a genotypic test after 6 months of treatment. Drug resistance mutations were identified using International AIDS Society (IAS)-USA tables and the Stanford HIVdb algorithm. The global burden of acquired resistance was calculated among all subjects with antiretroviral failure. Time trends and correlates of resistance were analysed using standard statistical tests. Results Patients of non-European origin and non-B subtypes increased significantly from 11.5% (103/896) to 19.2% (33/172) and from 13.1% (141/1079) to 23.8% (53/223), respectively, over time. Overall, 14.5% (448/3094), 12.1% (374/3094) and 37.8% (1169/3094) of patients failed first, second and later lines, respectively. According to both IAS and HIVdb, in the study period resistance to any class, nucleoside reverse inhibitor, non-nucleoside reverse inhibitor, and protease inhibitors (PIs) declined significantly. Integrase strand transfer inhibitor (INSTI) resistance declined significantly from 31% (36/116) to 20.8% (41/197) according to HIVdb but not to IAS. Divergent data were highlighted regarding the proportion of non-European patients carrying any, PI and INSTI resistance using IAS tables compared with the Stanford HIVdb algorithm, as the former failed to detect a decrease in resistance while the latter indicates a reduction of 1.6-, 5- and 1.8-fold resistance for such drug classes. In the multivariate analysis, the risk of resistance increased in patients with a larger number of treatment lines and higher viraemia and decreased in those starting therapy in the last biennium of the study. Discussion A marked reduction in drug resistance was observed over 10 years, compatible with higher genetic barrier and potency of new antiretrovirals. Nonetheless, concerns remain for subjects with non-B subtypes when using mutation lists instead of interpretation systems because of the extensive polymorphism of the protease region.

Published
2021

44. Effect of Legal Status on the Early Treatment Outcomes of Migrants Beginning Combined Antiretroviral Therapy at an Outpatient Clinic in Milan, Italy

Author

Chiara Resnati, Giorgio Bozzi, Stefano Rusconi, Paolo Vassalini, Letizia Oreni, Spinello Antinori, Laura Milazzo, Anna Lisa Ridolfo, and Massimo Galli

Subjects
Adult, Male, 0301 basic medicine, Cart, Pediatrics, medicine.medical_specialty, Latin Americans, Anti-HIV Agents, Ethnic group, HIV Infections, Ambulatory Care Facilities, Health Services Accessibility, 03 medical and health sciences, 0302 clinical medicine, Humans, Outpatient clinic, Medicine, Pharmacology (medical), 030212 general & internal medicine, Transients and Migrants, Legal status, business.industry, fungi, virus diseases, Health Status Disparities, Odds ratio, Middle Aged, 030112 virology, Antiretroviral therapy, CD4 Lymphocyte Count, Regimen, Infectious Diseases, Italy, Female, Lost to Follow-Up, business, Demography
Abstract

OBJECTIVE In a setting of free access to HIV care, we compared the early treatment outcomes of HIV-infected undocumented migrants (UMs), documented migrants (DMs), and Italian subjects. METHODS The clinical data of 640 Italians and 245 migrants who started combined antiretroviral therapy (cART) at an HIV clinic in Milan, Italy, were reviewed. The migrants were mainly Latin Americans (83 DMs and 56 UMs) or sub-Saharan Africans (52 DMs and 11 UMs), but a minority were of other origin (33 DMs and 10 UMs). Retention in follow-up and HIV suppression were compared between UMs, DMs, and natives 12 months ± 90 days after start of cART. RESULTS There were no significant between-group differences in the stage of HIV infection at the start of cART or the type of regimen received. The Latin American DMs and UMs included a higher proportion of transgender women than the other ethnic groups (P < 0.001). The UMs were less frequently followed up after 12 months than the DMs and natives (P = 0.004) and were more frequently permanently lost to follow-up (P < 0.001). UM status was an independent predictor of lost to follow-up (adjusted odds ratio 8.05, P < 0.001). The DMs and UMs were less frequently HIV suppressed after 12 months than the natives (78% and 80.7% vs 90.5%, P = 0.001), and Latin American migrants were significantly less likely to be virologically suppressed than the natives (adjusted odds ratio 0.30, P = 0.001). CONCLUSIONS Despite their free access to cART, subgroups of migrants facing multiple levels of vulnerability still have difficulties in gaining optimal HIV care.

Published
2017

45. Impact of NRTI resistance mutations on virological effectiveness of antiretroviral regimens containing elvitegravir: a multi-cohort study

Author

Barbara Rossetti, Emanuela Giombini, Annapaola Callegaro, D. Redi, Maurizio Zazzi, Manuela Colafigli, Gaetana Sterrantino, Andrea De Luca, Domenico Di Carlo, Andrea Costantini, Sergio Ferrara, Stefano Rusconi, Nicola Gianotti, Roberta Gagliardini, Maria Rita Gismondo, Franco Maggiolo, Alberto Borghetti, Antonia Bezenchek, Francesca Lombardi, Damiano Farinacci, and Sara Modica

Subjects
0301 basic medicine, Microbiology (medical), Adult, Male, medicine.medical_specialty, Databases, Factual, HIV Infections, Drug resistance, Quinolones, Emtricitabine, Tenofovir alafenamide, Gastroenterology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antiretroviral Therapy, Highly Active, Drug Resistance, Viral, medicine, Clinical endpoint, Humans, Pharmacology (medical), 030212 general & internal medicine, Pharmacology, business.industry, Elvitegravir, Cobicistat, Middle Aged, Viral Load, 030112 virology, Regimen, Infectious Diseases, Treatment Outcome, Anti-Retroviral Agents, Italy, Mutation, HIV-1, Drug Therapy, Combination, Female, business, Viral load, medicine.drug
Abstract

BackgroundAntiretroviral drug resistance mutations remain a major cause of treatment failure.ObjectivesTo evaluate the impact of NRTI resistance mutations on virological effectiveness of elvitegravir-containing regimens.Materials and methodsWe selected treatment-experienced HIV-1-infected patients starting elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), with at least one protease/reverse transcriptase genotype available before switching and at least one HIV-1 RNA viral load (VL) measurement during follow-up. The primary endpoint was virological failure (VF), defined as one VL value of ≥1000 copies/mL or two consecutive VL values of >50 copies/mL.ResultsWe included 264 ART regimens: 75.6% male, median (IQR) age 47 years (39–53), 7 years (3–16) of HIV infection, nadir CD4+ 247 cells/mm3 (105–361), 81.5% with VL ≤50 copies/mL and 11.7% with at least one NRTI mutation at baseline. Eleven (5.2%) VFs occurred in virologically suppressed patients versus eight (15.1%) in viraemic patients. The estimated probability of VF at 48 weeks with versus without any NRTI mutation was 7.4% (95% CI 2.3–12.5) versus 3.8% (2.1–5.5) in virologically suppressed patients and 66.7% (39.5–93.9) versus 11.2% (6.5–15.9) (PConclusionsA switch to E/C/F/TDF or E/C/F/TAF is safe for virologically suppressed patients without documented NRTI resistance, but not recommended in viraemic patients with a history of NRTI resistance. Although we did not detect a detrimental effect of past NRTI resistance in virologically suppressed patients, a fully active regimen remains preferred in this setting due to possible rebound of drug-resistant virus in the long term.

Published
2019

46. Switch to dolutegravir and unboosted atazanavir in HIV-1 infected patients with undetectable viral load and long exposure to antiretroviral therapy

Author

Andrea Poli, Agostino Riva, Simona Di Giambenedetto, Roberto Gulminetti, Antonella Castagna, Sinibaldo Carosella, Giovanni Mazzola, Stefano Bonora, Anna Maria Cattelan, Stefano Rusconi, Laura Galli, Maria Eugenia Quiros-Roldan, Giuseppe Vittorio De Socio, Maurizio Mena, Nicoletta Ladisa, Castagna, A., Rusconi, S., Gulminetti, R., Bonora, S., Mazzola, G., Quiros-Roldan, M. E., De Socio, G. V., Ladisa, N., Carosella, S., Cattelan, A., Di Giambenedetto, S., Mena, M., Poli, A., Galli, L., and Riva, A.

Subjects
0301 basic medicine, Male, HIV Infections, Kaplan-Meier Estimate, Piperazines, chemistry.chemical_compound, 0302 clinical medicine, Antiretroviral Therapy, Highly Active, Immunology and Allergy, Medicine, Pharmacology (medical), 030212 general & internal medicine, Drug Substitution, Health Policy, virus diseases, Middle Aged, Viral Load, dolutegravir, Treatment Outcome, Infectious Diseases, Dolutegravir, RNA, Viral, Drug Therapy, Combination, Female, Viral load, Heterocyclic Compounds, 3-Ring, medicine.drug, medicine.medical_specialty, Pyridones, Immunology, Atazanavir Sulfate, antiretroviral therapy, switch strategy, Settore MED/17 - MALATTIE INFETTIVE, 03 medical and health sciences, Pharmacotherapy, Internal medicine, Oxazines, Humans, HIV Integrase Inhibitors, dual therapy, business.industry, Antiretroviral therapy, Discontinuation, Atazanavir, CD4 Lymphocyte Count, Regimen, 030104 developmental biology, chemistry, HIV-1, business
Abstract

We evaluated the efficacy and safety of a two-drug regimen including dolutegravir (DTG) and unboosted atazanavir (uATV) in 151 HIV-1 infected patients with HIV-RNA of more than 50 copies/ml. During a median follow-up of 62 (42-97) weeks, two virological failures (1%) and 13 treatment discontinuations (9%) occurred; the 48-week probability of virological failure was 0.8% (95% confidence interval 0.2-5.6%). Switch to DTG + uATV may represent a boosting and transcriptase reverse inhibitors sparing otion in individuals with long exposure to antiretroviral therapy and risk of cardiovascular disease.

Published
2019

47. Statins and aspirin in the prevention of cardiovascular disease among HIV-positive patients between controversies and unmet needs: Review of the literature and suggestions for a friendly use

Author

A. Di Biagio, Vincenzo Spagnuolo, M. D’Abbraccio, Laura Sighinolfi, Gabriella d'Ettorre, Nicola Squillace, Paolo Maggi, Stefano Rusconi, G. V. De Socio, Giuseppe Nunnari, Stefania Cicalini, Canio Martinelli, Maggi, P., De Socio, G. V., Cicalini, S., D'Abbraccio, M., Dettorre, G., Di Biagio, A., Martinelli, C., Nunnari, G., Rusconi, S., Sighinolfi, L., Spagnuolo, V., Squillace, N., Maggi, P, De Socio, Gv, Cicalini, S, D'Abbraccio, M, Dettorre, G, Di Biagio, A, Martinelli, C, Nunnari, G, Rusconi, S, Sighinolfi, L, and Spagnuolo, V

Subjects
lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Drug, Adult, medicine.medical_specialty, Statin, medicine.drug_class, media_common.quotation_subject, Atorvastatin, 030106 microbiology, Population, HIV Infections, Disease, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Virology, medicine, Humans, Pharmacology (medical), Rosuvastatin, 030212 general & internal medicine, Intensive care medicine, education, media_common, Aged, education.field_of_study, Aspirin, business.industry, Methodology, Antiplatelet agents, Statins, HIV, Middle Aged, Cardiovascular disease, Oral anticoagulants, United States, Primary Prevention, Cardiovascular Diseases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Practice Guidelines as Topic, Molecular Medicine, Position paper, lcsh:RC581-607, business, medicine.drug
Abstract

Background As in non-infected subjects, statins and aspirin have a pivotal preventive role in reducing the cardiovascular related morbidity and mortality in HIV infected patients. The persistence of immune activation in these subjects, could contribute to accelerate atherosclerosis, therefore, these treatments that reduce inflammation could provide additional cardiovascular protection. However the current guidelines for the use of these drugs in general population are dissimilar, with important differences between American and European ones. Aim of the present position paper is to provide recommendations aimed to overcome the actual differences and limitations among the current ones and to adapt them to the needs of HIV infected patients. Results We propose to adopt the new ACC/AHA guidelines, simple to use and cost effective, to use the ASCVD score that seems to estimate more accurately the cardiovascular risk among these patients. We suggest to start statin therapy in all patients with a calculated 10-year risk of a cardiovascular event of 10% or greater. Rosuvastatin and atorvastatin should be preferred. LDL-C target may be adopted. Aspirin should be always associated with a statin, in secondary prevention, while in primary prevention it should be reserved only to patients with ≥ 20% 10-year risk particularly adherent to treatments, and with low risk of bleeding. We suggest to start with a dose of 100 mg/day. Finally, management of antiplatelet agents or novel oral anticoagulants may include selecting antiretrovirals with a lower potential for drug interactions or choosing agents least likely to interact with antiretrovirals. Conclusions As demonstrated in surveys, HIV physicians are generally highly committed regarding CVD and autonomous in prescribing statins and ASA. Consequently, in the light of the previously discussed discrepancies among the different guidelines and of the incomplete indications regarding HIV-positive persons, the present suggestions could overcome the actual differences and limitations among the current ones.

Published
2019

48. No impact of previous NRTIs resistance in HIV positive patients switched to DTG+2NRTIs under virological control: Time of viral suppression makes the difference

Author

Francesca Lombardi, Giacomo Magnani, Vanni Borghi, Stefania Paolucci, Ilaria Vicenti, Alessia Lai, Luciana Lepore, Franco Maggiolo, Stefano Rusconi, Andrea Giacomelli, Laura Monno, Marco Franzetti, Simona Di Giambenedetto, Monica Pecorari, and Daniela Francisci

Subjects
0301 basic medicine, Oncology, Male, Genes, Viral, HIV Infections, Piperazines, chemistry.chemical_compound, Abacavir, Antiretroviral Therapy, Highly Active, virus diseases, Lamivudine, Middle Aged, Viral Load, Resistance mutation, Drug Combinations, Anti-Retroviral Agents, Dolutegravir, Female, M184V/I, Heterocyclic Compounds, 3-Ring, medicine.drug, Adult, medicine.medical_specialty, Pyridones, 030106 microbiology, Lower risk, Emtricitabine, Settore MED/17 - MALATTIE INFETTIVE, Tenofovir alafenamide, 03 medical and health sciences, Virology, Internal medicine, Drug Resistance, Viral, Oxazines, medicine, Drug resistance, Genotypic resistance test, NNRTIs, Humans, Tenofovir, Retrospective Studies, Pharmacology, business.industry, Dideoxynucleosides, Regimen, 030104 developmental biology, chemistry, Mutation, HIV-1, business
Abstract

The accumulation of drug-resistance mutations on combined antiretroviral regimens (ART) backbone could affect the virological efficacy of the regimen. Our aim was to assess the impact of previous drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) on the probability of virological failure (VF) in patients, under virological control, who switched to dolutegravir (DTG)+2NRTIs regimens. All HIV-1 positive drug-experienced patients who started a regimen composed by DTG+2NRTIs [abacavir/lamivudine or tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)/emtricitabine (FTC)] in the ARCA collaborative group with HIV-RNA50 cp/mL were included in the analysis. Patients with a previous VF to integrase inhibitors were excluded. The impact of single and combined NRTIs mutations on the probability of VF (defined as 2 consecutive HIV-RNA50 copies/mL or one HIV-RNA1000 copies/mL) was assessed by Kaplan Meier curves. A multivariable Cox regression analysis was constructed to assess factors potentially related to VF. Five hundred and eighty-eight patients were included in the analysis with a median time of viral suppression before the switch of 37 months (IQR 12-78), of whom 148 (25.2%) had at least one previous NRTIs resistance mutation. In the multivariable model no association was observed between NRTIs mutations and VF. Conversely, the duration of viral suppression before switch resulted associated with a lower risk of VF (for 1 month increase, adjusted Hazard Ratio 0.98, 95%CI 0.96-0.99; p=0.024). Previous NRTIs mutations appeared to have no impact on the risk of VF in patients switched to DTG+2NRTIs, whereas a longer interval on a controlled viremia decreased significantly the risk of VF.

Published
2019

49. Long-term data on the efficacy and tolerability of lamivudine plus dolutegravir as a switch strategy in a multi-centre cohort of HIV-1-infected, virologically suppressed patients

Author

Amedeo Capetti, Alberto Borghetti, Gabriella d'Ettorre, Maria Vittoria Cossu, Manuela Colafigli, Gaetana Sterrantino, Stefano Rusconi, William Gennari, Vanni Borghi, Andrea Giacometti, Gianmaria Baldin, Arturo Ciccullo, Cristina Mussini, and Simona Di Giambenedetto

Subjects
Adult, Male, 0301 basic medicine, Microbiology (medical), HIV, dual therapy, two-drug regimen, ART, simplification, lamivudine, dolutegravir, medicine.medical_specialty, Anti-HIV Agents, Pyridones, 030106 microbiology, HIV Infections, Settore MED/17 - MALATTIE INFETTIVE, Piperazines, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Oxazines, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Survival analysis, Retrospective Studies, Proportional hazards model, business.industry, Repeated measures design, Lamivudine, General Medicine, Dolutegravir, Simplification, Two-drug regimen, Middle Aged, Discontinuation, Infectious Diseases, chemistry, Tolerability, Cohort, HIV-1, Female, business, Heterocyclic Compounds, 3-Ring, medicine.drug
Abstract

Background Results from clinical trials and observational studies suggest that lamivudine plus dolutegravir (3TC+DTG) could be an effective and tolerated option for simplification in human immunodeficiency virus (HIV)-1-positive patients. Materials and methods This observational study enrolled HIV-1-infected, virologically suppressed patients switching to 3TC+DTG. Kaplan–Meyer survival analysis was performed to evaluate time to virological failure (VF; defined by a single HIV-RNA determination ≥1000 copies/mL or by two consecutive HIV-RNA determinations ≥50 copies/mL) and time to treatment discontinuation (TD; defined as interruption of either 3TC or DTG), Cox regression was performed to assess predictors, and linear mixed model was performed for repeated measures to measure changes in immunological and metabolic parameters. Results Five hundred and fifty-six patients were eligible for analysis. Their median CD4+ count at baseline was 668 cells/mm3 and median time of virological suppression was 88 months. Estimated probabilities of maintaining virological suppression at 96 and 144 weeks of follow-up were 97.5% [standard deviation (SD) 0.8] and 96.5% (SD 1.0), respectively. Years since HIV diagnosis was the only predictor of VF. In patients with time of virological suppression Conclusions These findings confirm the efficacy and tolerability of 3TC+DTG in virologically suppressed patients.

Published
2019

50. Impact of circulating resistance-associated mutations on HIV pre-exposure prophylaxis (PrEP) efficacy: Modeling from antiretroviral resistance cohort analysis (ARCA) national database

Author

Maurizio Zazzi, Ilaria Vicenti, Roberto Rossotti, Valeria Micheli, Maria Rita Gismondo, Vanni Borghi, Anna Paola Callegaro, Bianca Bruzzone, Grazia Colao, Stefano Rusconi, and Giovanni Penco

Subjects
HIV, MSM, PrEP, Resistance-associated mutations, Infectious Diseases, Virology, Adult, Male, Risk, 0301 basic medicine, medicine.medical_specialty, 030106 microbiology, Population, Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, Cohort Studies, 03 medical and health sciences, Pre-exposure prophylaxis, 0302 clinical medicine, Antiretroviral Therapy, Highly Active, Internal medicine, Drug Resistance, Viral, Epidemiology, medicine, Emtricitabine, Humans, 030212 general & internal medicine, Homosexuality, Male, Tenofovir, education, education.field_of_study, business.industry, Number needed to harm, Middle Aged, Anti-Retroviral Agents, Relative risk, Mutation, Immunology, HIV-1, Female, Pre-Exposure Prophylaxis, National database, business, Cohort study
Abstract

Background PrEP with FTC/TDF has shown great efficacy in preventing new HIV infections but issues remain (low adherence, high costs, toxicity and resistance development). No data are available about the impact of circulating Resistance-Associated Mutations (RAMs) on its efficacy. Objectives describe the prevalence of FTC and/or TDF-related RAMs in Italian HIV-infected population and their potential impact on PrEP efficacy. Study design ARCA is a national database that collects data about RAMs and epidemiological correlates from sites throughout Italy; it was queried about the prevalence of these RAMs in the last decade. PrEP efficacy was adjusted for a dynamic score based on RAMs prevalence. Absolute and relative risk increases (ARI and RRI) and number needed to harm (NNH) were calculated after this score. Results the query retrieved 3579 HAART-naive and 5781 experienced subjects. Resistance to TDF is low and more common among naive MSM in the area of Milan (where it topped to 14.3%), without other significant differences. If good adherence is not attained, RRI for receptive anal sex increases by 16% (in naive) and 93.4% (in experienced MSM). NNH is largely above 10000 except for having receptive anal sex with a HAART-experienced MSM on a failing treatment (970). Conclusions according to this model, PrEP may be introduced in Italy without general concerns, but efficacy may be partly reduced in young MSM having sex in Rome and Milan.

Published
2016

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