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1. Do people living with HIV experience greater age advancement than their HIV-negative counterparts?

Author

De Francesco, Davide, Wit, Ferdinand W., Burkle, Alexander, Oehlke, Sebastian, Kootstra, Neeltje A., Winston, Alan, Franceschi, Claudio, Garagnani, Paolo, Pirazzini, Chiara, Libert, Claude, Grune, Tilman, Weber, Daniela, Jansen, Eugene H. J. M., Sabin, Caroline A., Reiss, Peter, Reiss, P., Winston, A., Wit, F. W., Prins, M., van der Loeff, M. F. Schim, Schouten, J., Schmand, B., Geurtsen, G. J., Sharp, D. J., Caan, M. W. A., Majoie, C., Villaudy, J., Berkhout, B., Kootstra, N. A., Gisslen, M., Pasternak, A., Sabin, C. A., Guaraldi, G., Burkle, A., Libert, C., Franceschi, C., Kalsbeek, A., Fliers, E., Hoeijmakers, J., Pothof, J., van der Valk, M., Bisschop, P. H., Portegies, P., Zaheri, S., Burger, D., Cole, J. H., Biirkle, A., Zikkenheiner, W., Janssen, F. R., Underwood, J., Kooij, K. W., van Zoest, R. A., Doyle, N., van der Loeff, M. Schim, Schmand, B. A., Verheij, E., Verboeket, S. O., Elsenga, B. C., Hillebregt, M. M. J., Ruijs, Y. M. C., Benschop, D. P., Tembo, L., McDonald, L., Stott, M., Legg, K., Lovell, A., Erlwein, O., Kingsley, C., Norsworthy, P., Mullaney, S., Kruijer, T., del Grande, L., Olthof, V, Visser, G. R., May, L., Verbraak, F., Demirkaya, N., Visser, I, Majoie, C. B. L. M., Su, T., Leech, R., Huguet, J., Frankin, E., van der Kuyl, A., Weijer, K., Siteur-Van Rijnstra, E., Harskamp-Holwerda, A. M., Maurer, I, Ruiz, M. M. Mangas, Girigorie, A. F., Boeser-Nunnink, B., Kals-Beek, A., Bisschop, P. H. L. T., de Graaff-Teulen, M., Dewaele, S., Garagnani, P., Pirazzini, C., Capri, M., Dall'Olio, F., Chiricolo, M., Salvioli, S., Fuchs, D., Zetterberg, H., Weber, D., Grune, T., Jansen, E. H. J. M., De Francesco, D., Sindlinger, T., Oehlke, S., Global Health, AII - Infectious diseases, APH - Aging & Later Life, Experimental Immunology, ANS - Neurodegeneration, AMS - Restoration & Development, Medical Psychology, and APH - Mental Health

Subjects
Male, 0301 basic medicine, CYTOMEGALOVIRUS, HIV Infections, DISEASE, 0302 clinical medicine, Biomarkers of aging, Medicine and Health Sciences, Immunology and Allergy, 030212 general & internal medicine, the Co-morBidity in Relation to AIDS (COBRA) Collaboration, POPULATION, Immunodeficiency, education.field_of_study, premature aging, virus diseases, 11 Medical And Health Sciences, Middle Aged, Hepatitis B, SOUTH-AFRICA, Infectious Diseases, Anti-Retroviral Agents, Cohort, Female, Life Sciences & Biomedicine, medicine.drug, Adult, Premature aging, medicine.medical_specialty, BIOMARKERS, Immunology, Population, biomarkers of aging, 17 Psychology And Cognitive Sciences, 03 medical and health sciences, Acquired immunodeficiency syndrome (AIDS), Virology, ddc:570, Internal medicine, medicine, Humans, accelerated aging, education, Aged, accelerated aging, aging, biological age, biomarkers of aging, HIV, premature aging, Science & Technology, business.industry, aging, Biology and Life Sciences, HIV, 06 Biological Sciences, medicine.disease, COMORBIDITIES, biological age, INFECTED INDIVIDUALS, IMMUNOGLOBULIN-G ANTIBODY, PROTEASE INHIBITORS, Cross-Sectional Studies, 030104 developmental biology, RISK-FACTORS, business, Saquinavir
Abstract

Objectives: Despite successful antiretroviral (ARV) therapy, people living with HIV (PLWH) may show signs of premature/accentuated aging. We compared established biomarkers of aging in PLWH, appropriately-chosen HIV-negative individuals, and blood donors, and explored factors associated with biological age advancement.Design: Cross-sectional analysis of 134 PLWH on suppressive ARV therapy, 79 lifestyle-comparable HIV-negative controls aged ≥45 years from the Co-morBidity in Relation to AIDS (COBRA) cohort, and 35 age-matched blood donors (BD).Methods: Biological age was estimated using a validated algorithm based on ten biomarkers. Associations between ‘age advancement’ (biological minus chronological age) and HIV status/parameters, lifestyle, cytomegalovirus (CMV), hepatitis B (HBV) and hepatitis C virus (HCV) infections were investigated using linear regression.Results: The average (95% CI) age advancement was greater in both HIV-positive [13.2 (11.6, 14.9) years] and HIV-negative [5.5 (3.8, 7.2) years] COBRA participants compared to BD [-7.0 (-4.1, -9.9) years, both p's < 0.001)], but also in HIV-positive compared to HIV-negative participants (p < 0.001). Chronic HBV, higher anti-CMV IgG titer and CD8+ T-cell count were each associated with increased age advancement, independently of HIV-status/group. Among HIV-positive participants, age advancement was increased by 3.5 (0.1, 6.8) years among those with nadir CD4+ < 200 cells/μL and by 0.1 (0.06, 0.2) years for each additional month of exposure to saquinavir.Conclusions: Both treated PLWH and lifestyle-comparable HIV-negative individuals show signs of age advancement compared to BD, to which persistent CMV, HBV co-infection and CD8+ T-cell activation may have contributed. Age advancement remained greatest in PLWH and was related to prior immunodeficiency and cumulative saquinavir exposure. published

Published
2019

2. Validation of a Novel Multivariate Method of Defining HIV-Associated Cognitive Impairment

Author

Underwood, Jonathan, De Francesco, Davide, Cole, James H, Caan, Matthan W A, van Zoest, Rosan A, Schmand, Ben A, Sharp, David J, Sabin, Caroline A, Reiss, Peter, Winston, Alan Coolaboratori: Reiss P, Wit FWNM, Schouten J, Kooij KW, van Zoest RA, Elsenga BC, Janssen FR, Heidenrijk M, Zikkenheiner W, van der Valk M, Kootstra NA, Harskamp-Holwerda AM, Maurer I, Mangas Ruiz MM, Girigorie AF, Villaudy J, Frankin E, Pasternak A, Berkhout B, van der Kuyl T, Portegies P, Schmand BA, Geurtsen GJ, Ter Stege JA, Klein Twennaar M, Majoie CBLM, Caan MWA, Su T, Weijer K, Bisschop PHLT, Kalsbeek A, Wezel M, Visser I, Ruhé HG, Franceschi C, Garagnani P, Pirazzini C, Capri M, Dall'Olio F, Chiricolo M, Salvioli S, Hoeijmakers J, Pothof J, Prins M, Martens M, Moll S, Berkel J, Totté M, Kovalev S, Gisslén M, Fuchs D, Zetterberg H, Winston A, Underwood J, McDonald L, Stott M, Legg K, Lovell A, Erlwein O, Doyle N, Kingsley C, Sharp DJ, Leech R, Cole JH, Zaheri S, Hillebregt MMJ, Ruijs YMC, Benschop DP, Burger D, de Graaff-Teulen M, Guaraldi G, Bürkle A, Sindlinger T, Moreno-Villanueva M, Keller A, Sabin C, de Francesco D, Libert C, Dewaele S, Boffito M, Mallon P, Post F, Sachikonye M, Anderson J, Asboe D, Garvey L, Pozniak A, Vera J, Williams I, Campbell L, Yurdakul S, Okumu S, Pollard L, Otiko D, Phillips L, Laverick R, Fisher M, Clarke A, Bexley A, Richardson C, Macken A, Ghavani-Kia B, Maher J, Byrne M, Flaherty A, Mguni S, Clark R, Nevin-Dolan R, Pelluri S, Johnson M, Ngwu N, Hemat N, Jones M, Carroll A, Whitehouse A, Burgess L, Babalis D, Higgs C, Seah E, Fletcher S, Anthonipillai M, Moyes A, Deats K, Syed I, Matthews C., Underwood, Jonathan, De Francesco, Davide, Cole, James H, Caan, Matthan W A, van Zoest, Rosan A, Schmand, Ben A, Sharp, David J, Sabin, Caroline A, Reiss, Peter, Winston, Alan Coolaboratori: Reiss P, Wit FWNM, Schouten J, Kooij KW, van Zoest RA, Elsenga BC, Janssen FR, Heidenrijk M, Zikkenheiner W, van der Valk M, Kootstra NA, Harskamp-Holwerda AM, Maurer I, Mangas Ruiz MM, Girigorie AF, Villaudy J, Frankin E, Pasternak A, Berkhout B, van der Kuyl T, Portegies P, Schmand BA, Geurtsen GJ, Ter Stege JA, Klein Twennaar M, Majoie CBLM, Caan MWA, Su T, Weijer K, Bisschop PHLT, Kalsbeek A, Wezel M, Visser I, Ruhé HG, Franceschi C, Garagnani P, Pirazzini C, Capri M, Dall'Olio F, Chiricolo M, Salvioli S, Hoeijmakers J, Pothof J, Prins M, Martens M, Moll S, Berkel J, Totté M, Kovalev S, Gisslén M, Fuchs D, Zetterberg H, Winston A, Underwood J, McDonald L, Stott M, Legg K, Lovell A, Erlwein O, Doyle N, Kingsley C, Sharp DJ, Leech R, Cole JH, Zaheri S, Hillebregt MMJ, Ruijs YMC, Benschop DP, Burger D, de Graaff-Teulen M, Guaraldi G, Bürkle A, Sindlinger T, Moreno-Villanueva M, Keller A, Sabin C, de Francesco D, Libert C, Dewaele S, Boffito M, Mallon P, Post F, Sabin C, Sachikonye M, Winston A, Anderson J, Asboe D, Boffito M, Garvey L, Mallon P, Post F, Pozniak A, Sabin C, Sachikonye M, Vera J, Williams I, Winston A, Post F, Campbell L, Yurdakul S, Okumu S, Pollard L, Williams I, Otiko D, Phillips L, Laverick R, Fisher M, Clarke A, Vera J, Bexley A, Richardson C, Mallon P, Macken A, Ghavani-Kia B, Maher J, Byrne M, Flaherty A, Anderson J, Mguni S, Clark R, Nevin-Dolan R, Pelluri S, Johnson M, Ngwu N, Hemat N, Jones M, Carroll A, Whitehouse A, Burgess L, Babalis D, Winston A, Garvey L, Underwood J, Stott M, McDonald L, Boffito M, Asboe D, Pozniak A, Higgs C, Seah E, Fletcher S, Anthonipillai M, Moyes A, Deats K, Syed I, Matthews C., Molecular Genetics, Biomedical Engineering and Physics, Radiology and Nuclear Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Diabetes & metabolism, ACS - Microcirculation, AMS - Restoration & Development, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neurovascular Disorders, Graduate School, AII - Infectious diseases, APH - Aging & Later Life, Medical Psychology, Amsterdam Neuroscience - Neurodegeneration, Global Health, Infectious diseases, APH - Mental Health, APH - Methodology, Commission of the European Communities, Imperial College Healthcare NHS Trust- BRC Funding, and National Institute for Health Research

Subjects
Multivariate statistics, medicine.medical_specialty, COmorBidity in Relation to AIDS (COBRA) Collaboration and the Pharmacokinetic and clinical Observations in PePle over fiftY (POPPY) Study Group, Immunology, Human immunodeficiency virus (HIV), Audiology, medicine.disease_cause, Microbiology, 03 medical and health sciences, 0302 clinical medicine, multivariate, SDG 3 - Good Health and Well-being, Neuroimaging, Medicine and Health Sciences, medicine, Major Article, OLDER-PEOPLE, 030212 general & internal medicine, VALIDITY, Cognitive impairment, cognitive impairment, Science & Technology, neuroimaging, SCORES, business.industry, Biology and Life Sciences, HIV, MEN, Cognition, Mental health, White matter microstructure, PREVALENCE, 3. Good health, Infectious Diseases, Oncology, REGISTRATION, business, Life Sciences & Biomedicine, Neurocognitive, 030217 neurology & neurosurgery
Abstract

Background The optimum method of defining cognitive impairment in virally suppressed people living with HIV is unknown. We evaluated the relationships between cognitive impairment, including using a novel multivariate method (NMM), patient– reported outcome measures (PROMs), and neuroimaging markers of brain structure across 3 cohorts. Methods Differences in the prevalence of cognitive impairment, PROMs, and neuroimaging data from the COBRA, CHARTER, and POPPY cohorts (total n = 908) were determined between HIV-positive participants with and without cognitive impairment defined using the HIV-associated neurocognitive disorders (HAND), global deficit score (GDS), and NMM criteria. Results The prevalence of cognitive impairment varied by up to 27% between methods used to define impairment (eg, 48% for HAND vs 21% for NMM in the CHARTER study). Associations between objective cognitive impairment and subjective cognitive complaints generally were weak. Physical and mental health summary scores (SF-36) were lowest for NMM-defined impairment (P < .05). There were no differences in brain volumes or cortical thickness between participants with and without cognitive impairment defined using the HAND and GDS measures. In contrast, those identified with cognitive impairment by the NMM had reduced mean cortical thickness in both hemispheres (P < .05), as well as smaller brain volumes (P < .01). The associations with measures of white matter microstructure and brain-predicted age generally were weaker. Conclusion Different methods of defining cognitive impairment identify different people with varying symptomatology and measures of brain injury. Overall, NMM-defined impairment was associated with most neuroimaging abnormalities and poorer self-reported health status. This may be due to the statistical advantage of using a multivariate approach., We have previously described a novel multivariate method (NMM) with theoretical statistical advantages over existing methods, which we assessed here in 3 cohorts of people living with HIV. Overall, NMM-defined impairment was associated with most neuroimaging abnormalities and poorer self-reported health status.

Published
2019

8. Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell- associated HIV RNA and DNA levels compared to protease inhibitor-based therapy

Author

O Erlwein, A Winston, Peter Reiss, J Villaudy, B Berkhout, M. van der Valk, DP Benschop, A Kalsbeek, Ben Berkhout, M Martens, C Kingsley, T Booiman, Neeltje A. Kootstra, M Wezel, M Moreno-Villanueva, Paolo Garagnani, N Doyle, S Salvioli, BC Elsenga, JA ter Stege, T van der Kuyl, T Su, FR Janssen, BA Schmand, MM Mangas Ruiz, T Sindlinger, I Maurer, A Bürkle, M Capri, W Zikkenheiner, C Libert, M Chiricolo, Robert Leech, Ferdinand Wnm Wit, J Pothof, Caroline A. Sabin, Cblm Majoie, M Gisslén, A Lovell, Mmj Hillebregt, S Zaheri, I Visser, Claudio Franceschi, M de Graaff-Teulen, Alexander O. Pasternak, S Kovalev, M Prins, M Totté, NA Kootstra, H Zetterberg, D de Francesco, JH Cole, K Legg, Mwa Caan, J Schouten, M Klein Twennaar, Jelmer Vroom, J Berkel, AF Girigorie, P Reiss, S Moll, S Dewaele, K Weijer, D Fuchs, Marijn de Bruin, Alan Winston, Chiara Pirazzini, R.A. van Zoest, F Dall'Olio, Davide De Francesco, David J. Sharp, A Keller, AM Harskamp-Holwerda, J Underwood, F. W. Wit, GJ Geurtsen, P Portegies, Ymc Ruijs, M Stott, Margreet Bakker, M Heidenrijk, KW Kooij, Phlt Bisschop, G Guaraldi, L McDonald, C Sabin, AO Pasternak, J Hoeijmakers, Jan M. Prins, HG Ruhé, E Frankin, D Burger, Commission of the European Communities, National Institute for Health Research, and Pasternak AO, Vroom J, Kootstra NA, Wit FW, de Bruin M, De Francesco D, Bakker M, Sabin CA, Winston A, Prins JM, Reiss P, Berkhout B. Collaboratori C Franceschi, P Garagnani, C Pirazzini, M Capri, F Dall'Olio, M Chiricolo, S Salvioli

Subjects
Life Sciences & Biomedicine - Other Topics, DYNAMICS, Male, PROVIRUSES PRODUCE, medicine, Time Factors, Co-morBidity in Relation to Aids (COBRA) Collaboration, HIV Infections, Virus Replication, 0601 Biochemistry and Cell Biology, Nucleoside Reverse Transcriptase Inhibitor, chemistry.chemical_compound, Transcription (biology), virus infection, Biology (General), Randomized Controlled Trials as Topic, INFECTED PATIENTS, Reverse-transcriptase inhibitor, General Neuroscience, virus diseases, General Medicine, Middle Aged, Viral Load, Europe, Treatment Outcome, viru, RNA, Viral, Reverse Transcriptase Inhibitors, Drug Therapy, Combination, Female, Life Sciences & Biomedicine, medicine.drug, Adult, antiviral drug, Nevirapine, Efavirenz, QH301-705.5, RALTEGRAVIR INTENSIFICATION, Science, infectious disease, VIREMIA, virus, General Biochemistry, Genetics and Molecular Biology, Virus, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], antiviral drugs, All institutes and research themes of the Radboud University Medical Center, Humans, Protease inhibitor (pharmacology), Biology, Science & Technology, General Immunology and Microbiology, business.industry, PERSISTENCE, microbiology, RNA, HIV, HIV Protease Inhibitors, Virology, IMMUNE ACTIVATION, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Cross-Sectional Studies, chemistry, REPLICATION, DNA, Viral, RESERVOIR, business, DECAY
Abstract

Background:It remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress human immunodeficiency virus (HIV) replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI).Methods:CA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n = 100, n = 124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either an NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4+ count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically measured adherence to ART.Results:In both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho = 0.70 and rho = 0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (padj = 0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (padj = 0.048 and padj = 0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals.Conclusions:All current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size.Funding:This work was supported by ZonMw (09120011910035) and FP7 Health (305522).

Published
2021

9. Hierarchical modeling of indoor radon concentration: how much do geology and building factors matter?

Author

Davide De Francesco, Nikos Tzavidis, Daniela de Bartolo, Riccardo Borgoni, Borgoni, R, De Francesco, D, DE BARTOLO, D, and Tzavidis, N

Subjects
Pollution, Health, Toxicology and Mutagenesis, media_common.quotation_subject, chemistry.chemical_element, Radon, Soil, Natural gas, Floor effect, Environmental Chemistry, Waste Management and Disposal, Background radiation, media_common, Hierarchical modeling, business.industry, Construction Materials, Soil gas, Environmental engineering, Floor level, General Medicine, Indoor radon concentration, Models, Theoretical, Building factor, Residential radon, Construction Material, Hierarchical mixed model, chemistry, Italy, Air Pollutants, Radioactive, Air Pollution, Indoor, Housing, business, Geology
Abstract

Radon is a natural gas known to be the main contributor to natural background radiation exposure and only second to smoking as major leading cause of lung cancer. The main concern is in indoor environments where the gas tends to accumulate and can reach high concentrations. The primary contributor of this gas into the building is from the soil although architectonic characteristics, such as building materials, can largely affect concentration values. Understanding the factors affecting the concentration in dwellings and workplaces is important both in prevention, when the construction of a new building is being planned, and in mitigation when the amount of Radon detected inside a building is too high. In this paper we investigate how several factors, such as geologic typologies of the soil and a range of building characteristics, impact on indoor concentration focusing, in particular, on how concentration changes as a function of the floor level. Adopting a mixed effects model to account for the hierarchical nature of the data, we also quantify the extent to which such measurable factors manage to explain the variability of indoor radon concentration.

Published
2014

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