197 results on '"Samir K Gupta"'
Search Results
2. Insomnia symptoms and biomarkers of monocyte activation, systemic inflammation, and coagulation in HIV: Veterans Aging Cohort Study.
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Brittanny M Polanka, Suman Kundu, Kaku A So-Armah, Matthew S Freiberg, Samir K Gupta, Tamika C B Zapolski, Adam T Hirsh, Roger J Bedimo, Matthew J Budoff, Adeel A Butt, Chung-Chou H Chang, Stephen S Gottlieb, Vincent C Marconi, Julie A Womack, and Jesse C Stewart
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Medicine ,Science - Abstract
BackgroundInsomnia may be a risk factor for cardiovascular disease in HIV (HIV-CVD); however, mechanisms have yet to be elucidated.MethodsWe examined cross-sectional associations of insomnia symptoms with biological mechanisms of HIV-CVD (immune activation, systemic inflammation, and coagulation) among 1,542 people with HIV from the Veterans Aging Cohort Study (VACS) Biomarker Cohort. Past-month insomnia symptoms were assessed by the item, "Difficulty falling or staying asleep?," with the following response options: "I do not have this symptom" or "I have this symptom and…" "it doesn't bother me," "it bothers me a little," "it bothers me," "it bothers me a lot." Circulating levels of the monocyte activation marker soluble CD14 (sCD14), inflammatory marker interleukin-6 (IL-6), and coagulation marker D-dimer were determined from blood specimens. Demographic- and fully-adjusted (CVD risk factors, potential confounders, HIV-related factors) regression models were constructed, with log-transformed biomarker variables as the outcomes. We present the exponentiated regression coefficient (exp[b]) and its 95% confidence interval (CI).ResultsWe observed no significant associations between insomnia symptoms and sCD14 or IL-6. For D-dimer, veterans in the "Bothers a Lot" group had, on average, 17% higher D-dimer than veterans in the "No Difficulty Falling or Staying Asleep" group in the demographic-adjusted model (exp[b] = 1.17, 95%CI = 1.01-1.37, p = .04). This association was nonsignificant in the fully-adjusted model (exp[b] = 1.09, 95%CI = 0.94-1.26, p = .27).ConclusionWe observed little evidence of relationships between insomnia symptoms and markers of biological mechanisms of HIV-CVD. Other mechanisms may be responsible for the insomnia-CVD relationship in HIV; however, future studies with comprehensive assessments of insomnia symptoms are warranted.
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- 2021
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3. Hemoptysis: Beyond routine chest computed tomography and bronchoscopy
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Saurabh Mall, Rahul Kumar Sharma, Deepak Prajapat, Samir K Gupta, and Deepak Talwar
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Arteriovenous malformations ,Klippel-Trenaunay-Parkes-Weber syndrome ,Klippel-Trenaunay-Weber syndrome ,Parkes-Weber syndrome ,Diseases of the respiratory system ,RC705-779 - Abstract
Hemoptysis is considered as a medical emergency which requires urgent stabilization with identification and correction of underlying etiology. Diagnosis of the cause of hemoptysis is not always readily identified after bronchoscopy and conventional computed tomography (CT) chest. Arteriovenous malformation (AVM) is a rare but important cause of massive hemoptysis which can be easily picked up by the use of double turn contrast CT chest. We here report a rare congenital AVM anomaly called Klippel-Trenaunay-Parks-Weber syndrome as a cause of massive hemoptysis and utility of double turn CT in diagnosing AVM as a cause of hemoptysis.
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- 2017
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4. MASLD in persons with HIV is associated with high cardiometabolic risk as evidenced by altered advanced lipoprotein profiles and targeted metabolomics
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Kung-Hung Lin, Eduardo Vilar-Gomez, Kathleen E. Corey, Margery A. Connelly, Samir K. Gupta, Jordan E. Lake, Naga Chalasani, and Samer Gawrieh
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HIV ,MASLD ,Cardiovascular disease ,GlycA ,TMAO ,BCAA ,Nutritional diseases. Deficiency diseases ,RC620-627 - Abstract
Abstract Background Metabolic dysfunction associated steatotic liver disease (MASLD) is associated with increased cardiovascular disease (CVD) risk in persons with HIV (PWH). The lipidomic and metabolomic alterations contributing to this risk are poorly understood. We aimed to characterize the advanced lipoprotein and targeted metabolomic profiles in PWH and assess if the presence and severity of MASLD influence these profiles. Methods This is a cross-sectional analysis of a prospectively enrolled multicenter cohort. PWH without alcohol abuse or known liver disease underwent vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Lipidomic and metabolomic profiling was undertaken with nuclear magnetic resonance (NMR) spectroscopy. Hepatic steatosis was defined as CAP ≥ 263 dB/m and clinically significant fibrosis (CSF) as LSM ≥ 8 kPa. Logistic regression models assessed associations between MASLD, CSF and lipidomic and metabolic parameters. Results Of 190 participants (71% cisgender male, 96% on antiretroviral therapy), 58% had MASLD and 12% CSF. Mean (SD) age was 48.9 (12.1) years and body mass index (BMI) 29.9 (6.4) kg/m2. Compared to PWH without MASLD (controls), PWH with MASLD had lower HDL-C but higher total triglyceride, VLDL-C, branched-chain amino acids, GlycA, trimethylamine N-oxide levels, Lipoprotein-Insulin Resistance and Diabetes Risk Indices. There were no significant differences in these parameters between participants with MASLD with or without CSF. In a multivariable regression analysis, MASLD was independently associated with changes in most of these parameters after adjustment for age, gender, race/ethnicity, type 2 diabetes mellitus, BMI, and lipid lowering medications use. Conclusions MASLD in PWH is independently associated with altered advanced lipoprotein and targeted metabolic profiles, indicating a higher CVD risk in this population.
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- 2024
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5. Immune reconstitution in ART treated, but not untreated HIV infection, is associated with abnormal beta cell function.
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Emily K Sims, Grace Park, Kieren J Mather, Raghavendra G Mirmira, Ziyue Liu, and Samir K Gupta
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Medicine ,Science - Abstract
HIV infection has been associated with increased diabetes risk, but prior work has mostly focused on insulin resistance, as opposed to beta cell effects, or included patients on antiretroviral therapies (ART) directly linked to metabolic toxicity. In this analysis, we measured markers of glucose homeostasis and beta cell function, stress, and death in fasting sera from a cross section of HIV+ individuals off ART (n = 43), HIV+ individuals on ART (n = 23), and HIV- controls (n = 39). Markers included glucose, HOMA%S, HOMA%B, proinsulin:C-peptide ratio (PI:C ratio), and circulating preproinsulin (INS) DNA. We performed multiple linear regressions with adjustments for age, sex, race, BMI, and smoking status. Compared to HIV- controls, HIV+ participants off ART exhibited similar beta cell function and insulin sensitivity, without increases in markers of beta cell stress or death. Specifically, in HIV+ participants with CD4 counts
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- 2018
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6. HIV infection, antiretroviral therapy, and measures of endothelial function, inflammation, metabolism, and oxidative stress.
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Andrew Dysangco, Ziyue Liu, James H Stein, Michael P Dubé, and Samir K Gupta
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Medicine ,Science - Abstract
HIV-infected patients have an increased risk of cardiovascular disease (CVD). Impaired endothelial function is an early risk factor for CVD in the general population. It is presumed that HIV infection is associated with impaired endothelial function, but results have been inconsistent.Our objectives were to determine the relationships between HIV infection, virologic suppression with antiretroviral therapy (ART), in vivo measures of conduit artery and microvascular endothelial function, and circulating biomarkers of pathways associated with CVD.We performed a cross-sectional analysis of three prospectively enrolled groups from a single center: 28 were HIV-infected and virologically-suppressed on a regimen of FTC/TDF/EFV (HIV+ART+), 44 were HIV-infected but not on ART (HIV+ART-), and 39 were HIV-uninfected healthy volunteers (HIV-) matched to the HIV+ART- group for age, sex, smoking status, and height. None had diabetes, uncontrolled hypertension, known CVD, or other pro-inflammatory condition. Flow mediated dilation (FMD), nitroglycerin-mediated dilation (NTGMD), reactive hyperemia velocity time integral (RHVTI), and FMD/RHVTI of the brachial artery were measured, as well as circulating biomarkers of systemic inflammation, metabolism, oxidative stress, and endothelial activation.No significant differences were found amongst the three groups in FMD (P = 0.46), NTGMD (P = 0.42), RHVTI (P = 0.17), and FMD/RHVTI (P = 0.22) in unadjusted comparisons. Adjusted ANOVA models which included brachial artery diameter, demographics, and conventional CVD risk factors did not appreciably change these findings. In pairwise comparisons, the HIV+ART- group had significantly higher soluble tumor necrosis factor receptor II, soluble CD163, β-2 microglobulin, interferon-γ- induced protein-10, tissue inhibitor of metalloproteinase-1, and vascular cell adhesion molecule-1 compared to the other two groups (all p
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- 2017
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7. Fanconi syndrome accompanied by renal function decline with tenofovir disoproxil fumarate: a prospective, case-control study of predictors and resolution in HIV-infected patients.
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Samir K Gupta, Albert M Anderson, Ramin Ebrahimi, Todd Fralich, Hiba Graham, Valeska Scharen-Guivel, John F Flaherty, Claude Fortin, Robert C Kalayjian, Anita Rachlis, and Christina M Wyatt
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Medicine ,Science - Abstract
The predictors of Fanconi syndrome (FS) accompanied by renal function decline with use of the antiretroviral tenofovir disoproxil fumarate (TDF) have not been assessed. In addition, the natural history of renal recovery from FS after TDF discontinuation is not well-described.We prospectively enrolled HIV-infected patients receiving TDF with newly identified FS (defined as at least two markers of proximal tubulopathy and either a >25% decline in creatinine clearance (CrCl) from pre-TDF values or a CrCl 70% of pre-TDF values) although most participants had full normalization of proximal tubulopathy markers within two months of TDF discontinuation.FS, defined by specific CrCl decreases and markers of tubulopathy, is more likely in those who have received or are currently receiving concomitant lopinavir/ritonavir or who had lower CrCl prior to TDF initiation. Half of those with protocol-defined FS had CrCl recover to near pre-TDF values during the first year after TDF discontinuation.
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- 2014
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8. Transfer of intracellular HIV Nef to endothelium causes endothelial dysfunction.
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Ting Wang, Linden A Green, Samir K Gupta, Chul Kim, Liang Wang, Sharilyn Almodovar, Sonia C Flores, Igor A Prudovsky, Paul Jolicoeur, Ziyue Liu, and Matthias Clauss
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Medicine ,Science - Abstract
With effective antiretroviral therapy (ART), cardiovascular diseases (CVD) are emerging as a major cause of morbidity and death in the aging HIV-infected population. To address whether HIV-Nef, a viral protein produced in infected cells even when virus production is halted by ART, can lead to endothelial activation and dysfunction, we tested Nef protein transfer to and activity in endothelial cells. We demonstrated that Nef is essential for major endothelial cell activating effects of HIV-infected Jurkat cells when in direct contact with the endothelium. In addition, we found that Nef protein in endothelial cells is sufficient to cause apoptosis, ROS generation and release of monocyte attractant protein-1 (MCP-1). The Nef protein-dependent endothelial activating effects can be best explained by our observation that Nef protein rapidly transfers from either HIV-infected or Nef-transfected Jurkat cells to endothelial cells between these two cell types. These results are of in vivo relevance as we demonstrated that Nef protein induces GFP transfer from T cells to endothelium in CD4.Nef.GFP transgenic mice and Nef is present in chimeric SIV-infected macaques. Analyzing the signal transduction effects of Nef in endothelial cells, we found that Nef-induced apoptosis is mediated through ROS-dependent mechanisms, while MCP-1 production is NF-kB dependent. Together, these data indicate that inhibition of Nef-associated pathways may be promising new therapeutic targets for reducing the risk for cardiovascular disease in the HIV-infected population.
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- 2014
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9. Pentoxifylline, inflammation, and endothelial function in HIV-infected persons: a randomized, placebo-controlled trial.
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Samir K Gupta, Deming Mi, Michael P Dubé, Chandan K Saha, Raymond M Johnson, James H Stein, Matthias A Clauss, Kieren J Mather, Zeruesenay Desta, and Ziyue Liu
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Medicine ,Science - Abstract
Untreated HIV may increase the risk of cardiovascular events. Our preliminary in vitro and in vivo research suggests that pentoxifylline (PTX) reduces vascular inflammation and improves endothelial function in HIV-infected persons not requiring antiretroviral therapy.We performed a randomized, placebo-controlled trial of PTX 400 mg orally thrice daily for 8 weeks in 26 participants. The primary endpoint was change in flow-mediated dilation (FMD) of the brachial artery after 8 weeks. Nitroglycerin-mediated dilation (NTGMD) and circulating markers of inflammation, cellular immune activation, coagulation, and metabolism were also assessed.The difference in mean absolute change (SD) in FMD after 8 weeks between the placebo [-1.06 (1.45)%] and PTX [-1.93 (3.03)%] groups was not significant (P = 0.44). No differences in NTGMD were observed. The only significant between-group difference in the changes in biomarkers from baseline to week 8 was in soluble tumor necrosis factor receptor-1 (sTNFRI) [-83.2 pg/mL in the placebo group vs. +65.9 pg/mL in the PTX group; P = 0.03]. PTX was generally well-tolerated.PTX did not improve endothelial function and unexpectedly increased the inflammatory biomarker sTNFRI in HIV-infected participants not requiring antiretroviral therapy. Additional interventional research is needed to reduce inflammation and cardiovascular risk in this population.ClinicalTrials.gov NCT00796822.
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- 2013
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10. Relationship between microbial translocation and endothelial function in HIV infected patients.
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Emily Blodget, Changyu Shen, Grace Aldrovandi, Adrienne Rollie, Samir K Gupta, James H Stein, and Michael P Dubé
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Medicine ,Science - Abstract
BackgroundCirculating levels of microbial products are increased in HIV infection, and provoke endothelial dysfunction in other disease settings.Methodology/principal findingsWe examined data from a cross-sectional single site study at Indiana University (Indiana, N = 85) and a 24- week multicenter prospective study of antiretroviral therapy (ART) initiation (ACTG 5152s, N = 75). Brachial artery flow-mediated dilation (FMD) was measured by ultrasound. Plasma lipopolysaccharide (LPS) and soluble CD14 (sCD14) levels were measured from stored specimens and correlated with FMD values using Pearson correlations. The Indiana subjects were 63% male with a mean age of 39 years and a median CD4 count of 406 cells/mm(3) (388 not on ART, 464 on ART). The 5152s subjects were 92% were male with a mean age of 35 years and a median CD4 count of 251 cells/mm(3) at entry which increased to 396 cells/mm(3) on ART. When analyzing the two cohorts individually or in combination neither sCD14 nor LPS correlated significantly with FMD. In a pre-specified subgroup analysis of the Indiana subjects receiving ART (N = 46, mean ART duration 40 months) LPS was inversely correlated with FMD (r = -0.33, p = 0.02), but not sCD14 (r = -0.01, p = 0.9). Multivariate analysis confirmed LPS as an independent predictor of FMD in this subgroup (p = 0.02).Conclusions/significanceIn HIV-infected individuals on prolonged ART, higher LPS levels are associated with worse endothelial function but not in untreated subjects or at 24 weeks after ART initiation. Persistent microbial translocation may contribute to arterial dysfunction and the increased cardiovascular disease risk observed in individuals on long-term ART.
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- 2012
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11. Worsening endothelial function with efavirenz compared to protease inhibitors: a 12-month prospective study.
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Samir K Gupta, Changyu Shen, Sharon M Moe, Lisa M Kamendulis, Mitchell Goldman, and Michael P Dubé
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Medicine ,Science - Abstract
Changes in endothelial function, measured as flow-mediated dilation (FMD) of the brachial artery, has not been systematically assessed beyond 6 months of initiation of antiretroviral therapy (ART) when drug-related effects might offset initial improvements with virologic control.We assessed 6 and 12 month changes in FMD [presented as median (quartile 1, quartile 3)] and circulating HIV and cardiovascular biomarkers in 23 subjects initiating ART.There were no significant changes in FMD at 6 or 12 months overall despite significant increases in CD4 cell count and HDL-C and reductions in HIV RNA level, MCP-1, IP-10, sVCAM-1, sTNFR2, and sCD14. However, there were significant differences (P = 0.04) in the changes in FMD between those receiving efavirenz [N = 12; -3.50% (-4.90%, 0.68%)] vs. protease inhibitors at 12 months [N = 11; 1.50% (-0.86%, 4.56%)]. The differences in changes in FMD between those receiving and not receiving emtricitabine/tenofovir/efavirenz were more pronounced and were significantly different at both 6 and 12 months (P
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- 2012
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12. Immunomodulators for immunocompromised patients hospitalized for COVID-19: a meta-analysis of randomized controlled trialsResearch in context
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Ilias I. Siempos, Andre C. Kalil, Drifa Belhadi, Viviane Cordeiro Veiga, Alexandre Biasi Cavalcanti, Westyn Branch-Elliman, Eleni Papoutsi, Konstantinos Gkirgkiris, Nikoleta A. Xixi, Anastasia Kotanidou, Olivier Hermine, Raphaël Porcher, Xavier Mariette, Philippe Ravaud, Serge Bureau, Maxime Dougados, Matthieu Resche-Rigon, Pierre-Louis Tharaux, Annick Tibi, Elie Azoulay, Jacques Cadranel, Joseph Emmerich, Muriel Fartoukh, Bertrand Guidet, Marc Humbert, Karine Lacombe, Matthieu Mahevas, Frédéric Pene, Valerie Pourchet-Martinez, Frédéric Schlemmer, Yazdan Yazdanpanah, Gabriel Baron, Elodie Perrodeau, Damien Vanhoye, Cécile Kedzia, Lauren Demerville, Anne Gysembergh-Houal, Alexandre Bourgoin, Nabil Raked, Lakhdar Mameri, Claire Montlahuc, Lucie Biard, St.phanie Alary, Samir Hamiria, Thinhinane Bariz, Hala Semri, Dhiaa Meriem Hai, Moustafa Benafla, Mohamed Belloul, Pernelle Vauboin, Saskia Flamand, Claire Pacheco, Anouk Walter-Petrich, Emilia Stan, Souad Benarab, Corine Nyanou, Robin Charreteur, Céline Dupre, Kévin Cardet, Blandine Lehmann, Kamyl Baghli, Claire Madelaine, Eric D'Ortenzio, Oriane Puéchal, Caroline Semaille, Laurent Savale, Anatole Harrois, Samy Figueiredo, Jacques Duranteau, Nadia Anguel, Arthur Pavot, Xavier Monnet, Christian Richard, Jean-Louis Teboul, Philippe Durand, Pierre Tissieres, Mitja Jevnikar, David Montani, Stephan Pavy, Gaétane Nocturne, Samuel Bitoun, Nicolas Noel, Olivier Lambotte, Lelia Escaut, Stephane Jauréguiberry, Elodie Baudry, Christiane Verny, Edouard Lefevre, Mohamad Zaidan, Domitille Molinari, Gaël Leprun, Alain Fourreau, Laurent Cylly, Lamiae Grimaldi, Myriam Virlouvet, Ramdane Meftali, Soléne Fabre, Marion Licois, Asmaa Mamoune, Yacine Boudali, Clotilde Le Tiec, Céline Verstuyft, Anne-Marie Roques, Sophie Georgin-Lavialle, Patricia Senet, Gilles Pialoux, Angele Soria, Antoine Parrot, Helene François, Nathalie Rozensztajn, Emmanuelle Blin, Pascaline Choinier, Juliette Camuset, Jean-Simon Rech, Antony Canellas, Camille Rolland-Debord, Nadege Lemarié, Nicolas Belaube, Marine Nadal, Martin Siguier, Camille Petit-Hoang, Julie Chas, Elodie Drouet, Matthieu Lemoine, Audrey Phibel, Lucie Aunay, Eliane Bertrand, Sylviane Ravato, Marie Vayssettes, Anne Adda, Celine Wilpotte, Pélagie Thibaut, Julie Fillon, Isabelle Debrix, Soraya Fellahi, Jean-Philippe Bastard, Guillaume Lefévre, Jacques-Eric Gottenberg, Yves Hansmann, Frédéric Blanc, Sophie Ohlmann-Caillard, Vincent Castelain, Emmanuel Chatelus, Eva Chatron, Olivier Collange, François Danion, Frédéric De Blay, Pierre Diemunsch, Sophie Diemunsch, Renaud Felten, Bernard Goichot, Valentin Greigert, Aurelien Guffroy, Bob Heger, Charlotte Kaeuffer, Loic Kassegne, Anne Sophie Korganow, Pierrick Le Borgne, Nicolas Lefebvre, Paul-Michel Mertes, Eric Noll, Mathieu Oberlin, Vincent Poindron, Julien Pottecher, Yvon Ruch, François Weill, Nicolas Meyer, Emmanuel Andres, Eric Demonsant, Hakim Tayebi, Gabriel Nisand, Stéphane Brin, Cédric Sublon, Guillaume Becker, Anne Hutt, Tristan Martin, Sophie Bayer, Catherine Metzger, Arsene Mekinian, Noémie Abisror, Amir Adedjouma, Diane Bollens, Marion Bonneton, Nathalie Bourcicaux, Anne Bourrier, Maria Chauchard Thibault Chiarabiani, Doroth.e Chopin, Jonathan Cohen, Ines Devred, Bruno Donadille, Olivier Fain, Geoffrey Hariri, Vincent Jachiet, Patrick Ingliz, Marc Garnier, Marc Gatfosse, Etienne Ghrenassia, Delphine Gobert, Jessica Krause le Garrec, Cecilia Landman, Jean Remy Lavillegrand, Benedicte Lefebvre, Thibault Mahevas, Sandie Mazerand, Jean Luc Meynard, Marjolaine Morgand, Zineb Ouaz.ne, Jerome Pacanowski, S.bastien Riviere, Philippe Seksik, Harry Sokol, Heithem Soliman, Nadia Valin, Thomas Urbina, Chloé McAvoy, Maria Pereira Miranda, Gladys Aratus, Laurence Berard, Tabassome Simon, Anne Daguenel Nguyen, Elise Girault, Cl.mentine Mayala-Kanda, Marie Antignac, Céline Leplay, Jean-Benoit Arlet, Jean-Luc Diehl, Florence Bellenfant, Anne Blanchard, Alexandre Buffet, Bernard Cholley, Antoine Fayol, Edouard Flamarion, Anne Godier, Thomas Gorget, Sophie-Rym Hamada, Caroline Hauw-Berlemont, Jean-Sébastien Hulot, David Lebeaux, Marine Livrozet, Adrien Michon, Arthur Neuschwander, Marie-Aude Pennet, Benjamin Planquette, Brigitte Ranque, Olivier Sanchez, Geoffroy Volle, Sandrine Briois, Mathias Cornic, Virginie Elisee, Jesuthasan Denis, Juliette Djadi-Prat, Pauline Jouany, Ramon Junquera, Mickael Henriques, Amina Kebir, Isabelle Lehir, Jeanne Meunier, Florence Patin, Val.rie Paquet, Anne Tréhan, Véronique Vigna, Brigitte Sabatier, Damien Bergerot, Charléne Jouve, Camille Knosp, Olivia Lenoir, Nassim Mahtal, Léa Resmini, Xavier Lescure, Jade Ghosn, Antoine Bachelard, Anne Rachline, Valentina Isernia, Bao-chau, Phung, Dorothée Vallois, Aurelie Sautereau, Catherine Neukrich, Antoine Dossier, Raphaël Borie, Bruno Crestani, Gregory Ducrocq, Philippe Gabriel Steg, Philippe Dieude, Thomas Papo, Estelle Marcault, Marhaba Chaudhry, Charléne Da Silveira, Annabelle Metois, Ismahan Mahenni, Meriam Meziani, Cyndie Nilusmas, Sylvie Le Gac, Awa Ndiaye, Fran.oise Louni, Malikhone Chansombat, Zelie Julia, Solaya Chalal, Lynda Chalal, Laura Kramer, Jeniffer Le Grand, Kafif Ouifiya, Valentine Piquard, Sarah Tubiana, Yann Nguyen, Vasco Honsel, Emmanuel Weiss, Anais Codorniu, Virginie Zarrouk, Victoire de Lastours, Matthieu Uzzan, Naura Gamany, Agathe Claveirole, Alexandre Navid, Tiffanie Fouque, Yonathan Cohen, Maya Lupo, Constance Gilles, Roza Rahli, Zeina Louis, David Boutboul, Lionel Galicier, Yaël Amara, Gabrielle Archer, Amira Benattia, Anne Bergeron, Louise Bondeelle, Nathalie de Castro, Melissa Clément, Michaël Darmon, Blandine Denis, Clairelyne Dupin, Elsa Feredj, Delphine Feyeux, Adrien Joseph, Etienne Lenglin, Pierre Le Guen, Geoffroy Liégeon, Gwenaël Lorillon, Asma Mabrouki, Eric Mariotte, Grégoire Martin de Frémont, Adrien Mirouse, Jean-Michel Molina, Régis Peffault de Latour, Eric Oksenhendler, Julien Saussereau, Abdellatif Tazi, Jean-Jacques Tudesq, Lara Zafrani, Isabelle Brindele, Emmanuelle Bugnet, Karine Celli Lebras, Julien Chabert, Lamia Djaghout, Catherine Fauvaux, Anne Lise Jegu, Ewa Kozakiewicz, Martine Meunier, Marie-Thérèse Tremorin, Claire Davoine, Isabelle Madelaine, Sophie Caillat-Zucman, Constance Delaugerre, Florence Morin, Damien Sène, Ruxandra Burlacu, Benjamin Chousterman, Bruno Mégarbanne, Pascal Richette, Jean-Pierre Riveline, Aline Frazier, Eric Vicaut, Laure Berton, Tassadit Hadjam, Miguel Alejandro Vazquez-Ibarra, Clément Jourdaine, Olivia Tran, Véronique Jouis, Aude Jacob, Julie Smati, Stéphane Renaud, Claire Pernin, Lydia Suarez, Luca Semerano, Sébastien Abad, Ruben B. nainous, Nicolas Bonnet, Celine Comparon, Yves Cohen, Hugues Cordel, Robin Dhote, Nathalie Dournon, Boris Duchemann, Nathan Ebstein, Thomas Gille, Benedicte Giroux-Leprieur, Jeanne Goupil de Bouille, Hilario Nunes, Johanna Oziel, Dominique Roulot, Lucile Sese, ClaireTantet, Yurdagul Uzunhan, Coralie Bloch-Queyrat, Vincent Levy, Fadhila Messani, Mohammed Rahaoui, Myléne Petit, Sabrina Brahmi, Vanessa Rathoin, Marthe Rigal, Nathalie Costedoat-Chalumeau, Liem Binh Luong, Zakaria Ait Hamou, Sarah Benghanem, Philippe Blanche, Nicolas Carlier, Benjamin Chaigne, Remy Gauzit, Hassan Joumaa, Mathieu Jozwiak, Marie Lachétre, Hélène Lafoeste, Odie Launay, Paul Legendre, Jonathan Marey, Caroline Morbieu, Lola-Jade Palmieri, Tali-Anne Szwebel, Hendy Abdoul, Alexandra Bruneau, Audrey Beclin-Clabaux, Charly Larrieu, Pierre Montanari, Eric Dufour, Ada Clarke, Catherine Le Bourlout, Nathalie Marin, Nathalie Menage, Samira Saleh-Mghir, Mamadou Salif Cisse, Kahina Cheref, Corinne Guerin, Jérémie Zerbit, Marc Michel, Sébastien Gallien, Etienne Crickx, Benjamin Le Vavasseur, Emmanuelle Kempf, Karim Jaffal, William Vindrios, Julie Oniszczuk, Constance Guillaud, Pascal Lim, Elena Fois, Giovanna Melica, Marie Matignon, Maud Jalabert, Jean-Daniel Lelièvre, David Schmitz, Marion Bourhis, Sylia Belazouz, Laetitia Languille, Caroline Boucle, Nelly Cita, Agnés Didier, Fahem Froura, Katia Ledudal, Thiziri Sadaoui, Alaki Thiemele, Delphine Le Febvre De Bailly, Muriel Carvhalo Verlinde, Julien Mayaux, Patrice Cacoub, David Saadoun, Mathieu Vautier, Héléne Bugaut, Olivier Benveniste, Yves Allenbach, Gaëlle Leroux, Aude Rigolet, Perrine Guillaume-Jugnot, Fanny Domont, Anne Claire Desbois, Chloé Comarmond, Nicolas Champtiaux, Segolene Toquet, Amine Ghembaza, Matheus Vieira, Georgina Maalouf, Goncalo Boleto, Yasmina Ferfar, Jean-Christophe Corvol, C.line Louapre, Sara Sambin, Louise-Laure Mariani, Carine Karachi, Florence Tubach, Candice Estellat, Linda Gimeno, Karine Martin, Aicha Bah, Vixra Keo, Sabrine Ouamri, Yasmine Messaoudi, Nessima Yelles, Pierre Faye, Sebastien Cavelot, Cecile Larcheveque, Laurence Annonay, Jaouad Benhida, Aida Zahrate-Ghoul, Soumeya Hammal, Ridha Belilita, Fanny Charbonnier, Claire Aguilar, Fanny Alby-Laurent, Carole Burger, Clara Campos-Vega, Nathalie Chavarot, Benjamin Fournier, Claire Rouzaud, Damien Vimpére, Caroline Elie, Prissile Bakouboula, Laure Choupeaux, Sophie Granville, Elodie Issorat, Christine Broissand, Marie-Alexandra Alyanakian, Guillaume Geri, Nawal Derridj, Naima Sguiouar, Hakim Meddah, Mourad Djadel, Héléne Chambrin-Lauvray, Jean-Charles Duclos-vallée, Faouzi Saliba, Sophie-Caroline Sacleux, Ilias Kounis, Sonia Tamazirt, Eric Rudant, Jean-Marie Michot, Annabelle Stoclin, Emeline Colomba, Fanny Pommeret, Christophe Willekens, Rosa Da Silva, Valérie Dejean, Yasmina Mekid, Ines Ben-Mabrouk, Florence Netzer, Caroline Pradon, Laurence Drouard, Valérie Camara-Clayette, Alexandre Morel, Gilles Garcia, Abolfazl Mohebbi, Férial Berbour, Mélanie Dehais, Anne-Lise Pouliquen, Alison Klasen, Loren Soyez-Herkert, Jonathan London, Younes Keroumi, Emmanuelle Guillot, Guillaume Grailles, Younes El amine, Fanny Defrancq, Hanane Fodil, Chaouki Bouras, Dominique Dautel, Nicolas Gambier, Thierno Dieye, Boris Bienvenu, Victor Lancon, Laurence Lecomte, Kristina Beziriganyan, Belkacem Asselate, Laure Allanic, Elena Kiouris, Marie-Héléne Legros, Christine Lemagner, Pascal Martel, Vincent Provitolo, Félix Ackermann, Mathilde Le Marchand, Aurélie Chan Hew Wai, Dimitri Fremont, Elisabeth Coupez, Mireille Adda, Frédéric Duée, Lise Bernard, Antoine Gros, Estelle Henry, Claire Courtin, Anne Pattyn, Pierre-Grégoire Guinot, Marc Bardou, Agnes Maurer, Julie Jambon, Amélie Cransac, Corinne Pernot, Bruno Mourvillier, Eric Marquis, Philippe Benoit, Damien Roux, Coralie Gernez, Cécile Yelnik, Julien Poissy, Mandy Nizard, Fanette Denies, Helene Gros, Jean-Jacques Mourad, Emmanuelle Sacco, Sophie Renet, F. Ader, Y. Yazdanpanah, F. Mentre, N. Peiffer-Smadja, F.X. Lescure, J. Poissy, L. Bouadma, J.F. Timsit, B. Lina, F. Morfin-Sherpa, M. Bouscambert, A. Gaymard, G. Peytavin, L. Abel, J. Guedj, C. Andrejak, C. Burdet, C. Laouenan, D. Belhadi, A. Dupont, T. Alfaiate, B. Basli, A. Chair, S. Laribi, J. Level, M. Schneider, M.C. Tellier, A. Dechanet, D. Costagliola, B. Terrier, M. Ohana, S. Couffin-Cadiergues, H. Esperou, C. Delmas, J. Saillard, C. Fougerou, L. Moinot, L. Wittkop, C. Cagnot, S. Le Mestre, D. Lebrasseur-Longuet, V. Petrov-Sanchez, A. Diallo, N. Mercier, V. Icard, B. Leveau, S. Tubiana, B. Hamze, A. Gelley, M. Noret, E. D’Ortenzio, O. Puechal, C. Semaille, T. Welte, J.A. Paiva, M. Halanova, M.P. Kieny, E. Balssa, C. Birkle, S. Gibowski, E. Landry, A. Le Goff, L. Moachon, C. Moins, L. Wadouachi, C. Paul, A. Levier, D. Bougon, F. Djossou, L. Epelboin, J. Dellamonica, C.H. Marquette, C. Robert, S. Gibot, E. Senneville, V. Jean-Michel, Y. Zerbib, C. Chirouze, A. Boyer, C. Cazanave, D. Gruson, D. Malvy, P. Andreu, J.P. Quenot, N. Terzi, K. Faure, C. Chabartier, V. Le Moing, K. Klouche, T. Ferry, F, Valour, B. Gaborit, E. Canet, P. Le Turnier, D. Boutoille, F. Bani-Sadr, F. Benezit, M. Revest, C. Cameli, A. Caro, MJ Ngo Um Tegue, Y. Le Tulzo, B. Laviolle, F. Laine, G. Thiery, F. Meziani, Y. Hansmann, W. Oulehri, C. Tacquard, F. Vardon-Bounes, B. Riu-Poulenc, M. Murris-Espin, L. Bernard, D. Garot, O. Hinschberger, M. Martinot, C. Bruel, B. Pilmis, O. Bouchaud, P. Loubet, C. Roger, X. Monnet, S. Figueiredo, V. Godard, J.P. Mira, M. Lachatre, S. Kerneis, J. Aboab, N. Sayre, F. Crockett, D. Lebeaux, A. Buffet, J.L. Diehl, A. Fayol, J.S. Hulot, M. Livrozet, A Mekontso- Dessap, C. Ficko, F. Stefan, J. Le Pavec, J. Mayaux, H. Ait-Oufella, J.M. Molina, G. Pialoux, M. Fartoukh, J. Textoris, M. Brossard, A. Essat, E. Netzer, Y. Riault, M. Ghislain, L. Beniguel, M. Genin, L. Gouichiche, C. Betard, L. Belkhir, A. Altdorfer, V Fraipont Centro, S. Braz, JM Ferreira Ribeiro, R Roncon Alburqueque, M. Berna, M. Alexandre, B. Lamprecht, A. Egle, R. Greil, M. Joannidis, Thomas F. Patterson, Philip O. Ponce, Barbara S. Taylor, Jan E. Patterson, Jason E. Bowling, Heta Javeri, LuAnn Larson, Angela Hewlett, Aneesh K. Mehta, Nadine G. Rouphael, Youssef Saklawi, Nicholas Scanlon, Jessica J. Traenkner, Ronald P. Trible, Jr., Emmanuel B. Walter, Noel Ivey, Thomas L. Holland, Guillermo M. Ruiz-Palacios, Alfredo Ponce de León, Sandra Rajme, Lanny Hsieh, Alpesh N. Amin, Miki Watanabe, Helen S. Lee, Susan Kline, Joanne Billings, Brooke Noren, Hyun Kim, Tyler D. Bold, Victor Tapson, Jonathan Grein, Fayyaz Sutterwala, Nicole Iovine, Lars K. Beattie, Rebecca Murray Wakeman, Matthew Shaw, Mamta K. Jain, Satish Mocherla, Jessica Meisner, Amneris Luque, Daniel A. Sweeney, Constance A. Benson, Farhana Ali, Robert L. Atmar, Hana M. El Sahly, Jennifer Whitaker, Ann R. Falsey, Angela R. Branche, Cheryl Rozario, Justino Regalado Pineda, José Arturo Martinez-Orozco, David Chien Lye, Sean WX. Ong, Po Ying Chia, Barnaby E. Young, Uriel Sandkovsky, Mezgebe Berhe, Clinton Haley, Emma Dishner, Valeria D. Cantos, Colleen F. Kelley, Paulina A. Rebolledo Esteinou, Sheetal Kandiah, Sarah B. Doernberg, Pierre-Cedric B. Crouch, Hannah Jang, Anne F. Luetkemeyer, Jay Dwyer, Stuart H. Cohen, George R. Thompson, 3rd, Hien H. Nguyen, Robert W. Finberg, Jennifer P. Wang, Juan Perez-Velazquez, Mireya Wessolossky, Patrick E.H. Jackson, Taison D. Bell, Miranda J. West, Babafemi Taiwo, Karen Krueger, Johnny Perez, Triniece Pearson, Catharine I. Paules, Kathleen G. Julian, Danish Ahmad, Alexander G. Hajduczok, Henry Arguinchona, Christa Arguinchona, Nathaniel Erdmann, Paul Goepfert, Neera Ahuja, Maria G. Frank, David Wyles, Heather Young, Myoung-don Oh, Wan Beom Park, Chang Kyung Kang, Vincent Marconi, Abeer Moanna, Sushma Cribbs, Telisha Harrison, Eu Suk Kim, Jongtak Jung, Kyoung-Ho Song, Hong Bin Kim, Seow Yen Tan, Humaira Shafi, MF Jaime Chien, Raymond KC. Fong, Daniel D. Murray, Jens Lundgren, Henrik Nielsen, Tomas Jensen, Barry S. Zingman, Robert Grossberg, Paul F. Riska, Otto O. Yang, Jenny Ahn, Rubi Arias, Rekha R. Rapaka, Naomi Hauser, James D. Campbell, William R. Short, Pablo Tebas, Jillian T. Baron, Susan L.F. McLellan, Lucas S. Blanton, Justin B. Seashore, C. Buddy Creech, Todd W. Rice, Shannon Walker, Isaac P. Thomsen, Diego Lopez de Castilla, Jason W. Van Winkle, Francis X. Riedo, Surinder Kaur Pada, Alvin DY. Wang, Li Lin, Michelle Harkins, Gregory Mertz, Nestor Sosa, Louis Yi Ann Chai, Paul Anantharajah Tambyah, Sai Meng Tham, Sophia Archuleta, Gabriel Yan, David A. Lindholm, Ana Elizabeth Markelz, Katrin Mende, Richard Mularski, Elizabeth Hohmann, Mariam Torres-Soto, Nikolaus Jilg, Ryan C. Maves, Gregory C. Utz, Sarah L. George, Daniel F. Hoft, James D. Brien, Roger Paredes, Lourdes Mateu, Cora Loste, Princy Kumar, Sarah Thornton, Sharmila Mohanraj, Noreen A. Hynes, Lauren M. Sauer, Christopher J. Colombo, Christina Schofield, Rhonda E. Colombo, Susan E. Chambers, Richard M. Novak, Andrea Wendrow, Samir K. Gupta, Tida Lee, Tahaniyat Lalani, Mark Holodniy, Aarthi Chary, Nikhil Huprikar, Anuradha Ganesan, Norio Ohmagari, Ayako Mikami, D. Ashley Price, Christopher J.A. Duncan, Kerry Dierberg, Henry J. Neumann, Stephanie N. Taylor, Alisha Lacour, Najy Masri, Edwin Swiatlo, Kyle Widmer, James D. Neaton, Mary Bessesen, David S. Stephens, Timothy H. Burgess, Timothy M. Uyeki, Robert Walker, G. Lynn Marks, Anu Osinusi, Huyen Cao, Anabela Cardoso, Stephanie de Bono, Douglas E. Schlichting, Kevin K. Chung, Jennifer L. Ferreira, Michelle Green, Mat Makowski, Michael R. Wierzbicki, Tom M. Conrad, Jill Ann El-Khorazaty, Heather Hill, Tyler Bonnett, Nikki Gettinger, Theresa Engel, Teri Lewis, Jing Wang, John H. Beigel, Kay M. Tomashek, Varduhi Ghazaryan, Tatiana Beresnev, Seema Nayak, Lori E. Dodd, Walla Dempsey, Effie Nomicos, Marina Lee, Rhonda Pikaart-Tautges, Mohamed Elsafy, Robert Jurao, Hyung Koo, Michael Proschan, Tammy Yokum, Janice Arega, Ruth Florese, Jocelyn D. Voell, Richard Davey, Ruth C. Serrano, Zanthia Wiley, Varun K. Phadke, Paul A. Goepfert, Carlos A. Gomez, Theresa A. Sofarelli, Laura Certain, Hannah N. Imlay, Cameron R. Wolfe, Emily R. Ko, John J. Engemann, Nora Bautista Felix, Claire R. Wan, Sammy T. Elmor, Laurel R. Bristow, Michelle S. Harkins, Nicole M. Iovine, Marie-Carmelle Elie-Turenne, Victor F. Tapson, Pyoeng Gyun Choe, Richard A. Mularski, Kevin S. Rhie, Rezhan H. Hussein, Dilek Ince, Patricia L. Winokur, Jin Takasaki, Sho Saito, Kimberly McConnell, PharmD, David L. Wyles, Ellen Sarcone, Kevin A. Grimes, Katherine Perez, Charles Janak, Jennifer A. Whitaker, Paulina A. Rebolledo, John Gharbin, Allison A. Lambert, Diego F. Zea, Emma Bainbridge, David C. Hostler, Jordanna M. Hostler, Brian T. Shahan, Evelyn Ling, Minjoung Go, Fleesie A. Hubbard, Melony Chakrabarty, Maryrose Laguio-Vila, Edward E. Walsh, Faheem Guirgis, Vincent C. Marconi, Christian Madar, Scott A. Borgetti, Corri Levine, Joy Nock, Keith Candiotti, Julia Rozman, Fernando Dangond, Yann Hyvert, Andrea Seitzinger, Kaitlyn Cross, Stephanie Pettibone, Seema U. Nayak, and Gregory A. Deye
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Acute respiratory distress syndrome ,Acute hypoxemic respiratory failure ,Pneumonia ,Critically ill ,Cancer ,Medicine (General) ,R5-920 - Abstract
Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.
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- 2024
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13. Effect of modernized collaborative care for depression on depressive symptoms and cardiovascular disease risk biomarkers: eIMPACT randomized controlled trial
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Jesse C. Stewart, Jay S. Patel, Brittanny M. Polanka, Sujuan Gao, John I. Nurnberger, Krysha L. MacDonald, Samir K. Gupta, Robert V. Considine, Richard J. Kovacs, Elizabeth A. Vrany, Jessica Berntson, Loretta Hsueh, Aubrey L. Shell, Bruce L. Rollman, and Christopher M. Callahan
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Behavioral Neuroscience ,Endocrine and Autonomic Systems ,Immunology - Published
- 2023
14. Lenacapavir administered every 26 weeks or daily in combination with oral daily antiretroviral therapy for initial treatment of HIV: a randomised, open-label, active-controlled, phase 2 trial
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Samir K, Gupta, Mezgebe, Berhe, Gordon, Crofoot, Paul, Benson, Moti, Ramgopal, James, Sims, Cheryl, McDonald, Peter, Ruane, William E, Sanchez, Anita, Scribner, Shan-Yu, Liu, Laurie A, VanderVeen, Hadas, Dvory-Sobol, Martin S, Rhee, Jared M, Baeten, and Ellen, Koenig
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Adult ,Anti-HIV Agents ,Epidemiology ,Adenine ,Immunology ,HIV Infections ,Viral Load ,Heterocyclic Compounds, 4 or More Rings ,Treatment Outcome ,Infectious Diseases ,Anti-Retroviral Agents ,Virology ,Oxazines ,Humans ,Emtricitabine ,RNA ,Tenofovir - Abstract
Antiretroviral agents with novel mechanisms and dosing intervals could expand treatment options for people with HIV. Lenacapavir, an inhibitor of capsid protein that makes use of a unique mechanism, can be administered orally or subcutaneously. We sought to explore the efficacy of lenacapavir in various combination regimens as initial and maintenance therapy for HIV.In a phase 2, randomised, open-label, ongoing study at 41 investigational sites in the USA and Dominican Republic, we randomly assigned adults with HIV who had not previously received antiretrovirals to four groups (2:2:2:1). Randomisation was stratified by plasma HIV-1 RNA load (≤100 000 or100 000 copies per mL) at screening. Groups 1 and 2 both received lenacapavir (927 mg) subcutaneously every 26 weeks (after 2 weeks of oral loading [600 mg on days 1 and 2, followed by 300 mg on day 8]) with oral daily emtricitabine (200 mg) and tenofovir alafenamide (25 mg) for 28 weeks followed by subcutaneous lenacapavir (927 mg) plus oral daily tenofovir alafenamide (25 mg, group 1) or bictegravir (75 mg, group 2). Group 3 received oral daily lenacapavir (600 mg on days 1 and 2, followed by 50 mg daily) with emtricitabine (200 mg) and tenofovir alafenamide (25 mg). Group 4 received oral daily bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants and investigators were not masked to group assignment. The primary endpoint was the percentage of participants with virological suppression (HIV-1 RNA50 copies per mL) at week 54, analysed in the full analysis set (all randomly assigned participants who received at least one dose of study drug) using only on-treatment data. The safety outcome measures were incidences of treatment-emergent adverse events and graded laboratory abnormalities, analysed in the full analysis set. This study is registered at ClinicalTrials.gov, NCT04143594.Between Nov 22, 2019, and Aug 27, 2020, 249 people with HIV were screened, 183 participants were randomly assigned and 182 received a dose of antiretroviral drugs (52 in group 1, 53 in group 2, 52 in group 3, and 25 in group 4). 22 participants did not complete the full study course (five in group 1, 12 in group 2, four in group 3, and one in group 4). At week 54, virological suppression was 90% (47 of 52 patients) for group 1 (difference vs group 4: -2·6%, 95% CI -18·4 to 13·2), 85% (45 of 53) for group 2 (-7·1%, -23·4 to 9·3), 85% (44 of 52) for group 3 (-7·2%, -23·5 to 9·1), and 92% (23 of 25) for group 4. The most frequent non-injection-site adverse events with lenacapavir (subcutaneous or oral) were headache (13%, 21 of 157) and nausea (13%, 21 of 157). The most common lenacapavir-related injection-site reactions were erythema (27%, 28 of 105), swelling (23%, 24 of 105), and pain (19%, 20 of 105), which were generally mild or moderate. No serious adverse event related to study treatment occurred. Three participants discontinued subcutaneous lenacapavir because of grade 1 injection-site reactions (two for induration and one for erythema or swelling).Lenacapavir warrants further investigation as a potential antiretroviral used orally and as injection in combination with other antiretroviral drugs.Gilead Sciences.
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- 2023
15. Weight Gain Among Treatment-Naïve Persons With HIV Receiving Dolutegravir in Kenya
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Kassem, Bourgi, Susan, Ofner, Beverly, Musick, Bradley, Griffith, Lameck, Diero, Kara, Wools-Kaloustian, Constantin T, Yiannoutsos, and Samir K, Gupta
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Male ,Pyridones ,HIV Infections ,Weight Gain ,Kenya ,Infectious Diseases ,Thinness ,Oxazines ,Humans ,Reverse Transcriptase Inhibitors ,Tuberculosis ,Female ,Pharmacology (medical) ,HIV Integrase Inhibitors ,Heterocyclic Compounds, 3-Ring - Abstract
Several recent studies have linked integrase strand transfer inhibitors (INSTI) with increased weight gain.The effects of sex on weight gain with dolutegravir (DTG)-based antiretroviral therapy (ART) among treatment-naïve participants in a lower-income, sub-Saharan population with high rates of pre-ART underweight and tuberculosis (TB) coinfection are unknown.Our analysis included treatment-naïve participants in Kenya and starting their first treatment regimen between January 1, 2015, and September 30, 2018. Participants were grouped into 2 cohorts based on the initial treatment regimen [DTG vs. nonnucleoside reverse transcriptase inhibitors (NNRTI)]. We modelled weight changes over time using a multivariable nonlinear mixed-effect model, with participant as a random effect. Logistic regression models were constructed to evaluate the association between different variables with extreme increase in body mass index (≥10% increase).Seventeen thousand forty-four participants met our inclusion criteria. Sixty-two percent of participants were women, 6% were receiving active TB therapy, and 97% were on NNRTI-based regimens. Participants starting DTG-based regimens were more likely to gain weight when compared with participants starting NNRTI-based regimens. Female participants starting DTG-based regimens experienced the highest weight gain compared with other participants (mean gain of 6.1 kgs at 18 months). Female participants receiving DTG-based regimens, along with participants with lower CD4 cell counts, underweight at baseline, and those receiving active TB therapy were also at higher risk for extreme body mass index increase.Our study in a lower-income sub-Saharan African population confirms higher weight gain with DTG-based regimens compared with traditional ART for treatment-naïve patients.
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- 2022
16. Examining Depression as a Risk Factor for Cardiovascular Disease in People with HIV: A Systematic Review
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Brittanny M Polanka, Samir K Gupta, Kaku A So-Armah, Matthew S Freiberg, Tamika C B Zapolski, Adam T Hirsh, and Jesse C Stewart
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Inflammation ,Psychiatry and Mental health ,Cross-Sectional Studies ,Cardiovascular Diseases ,Depression ,Risk Factors ,Humans ,HIV ,HIV Infections ,Risk Factors for Cardiovascular Disease ,General Psychology - Abstract
Background People with human immunodeficiency virus (HIV) have an increased risk of cardiovascular disease (CVD) not fully accounted for by traditional or HIV-specific risk factors. Successful management of HIV does not eliminate this excess risk. Thus, there is a need to identify novel risk factors for CVD among people with HIV (PWH). Purpose Our objective was to systematically review the literature on one such candidate CVD risk factor in PWH—depression. Methods A systematic literature search of PubMed, PsycINFO, EMBASE, Web of Science, and CINAHL was performed to identify published English-language studies examining associations of depression with clinical CVD, subclinical CVD, and biological mechanisms (immune activation, systemic inflammation, altered coagulation) among PWH between the earliest date and June 22, 2021. Results Thirty-five articles were included. For clinical CVD (k = 8), findings suggests that depression is consistently associated with an increased risk of incident CVD. For subclinical CVD (k = 5), one longitudinal analysis reported a positive association, and four cross-sectional analyses reported null associations. For immune activation (k = 13), systemic inflammation (k = 17), and altered coagulation (k = 5), findings were mixed, and there was considerable heterogeneity in sample characteristics and methodological quality across studies. Conclusions Depression may be an independent risk factor for CVD among PWH. Additional research is needed to confirm depression’s association with clinical CVD and to determine whether depression is consistently and meaningfully associated with subclinical CVD and biological mechanisms of CVD in HIV. We propose a research agenda for this emerging area.
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- 2023
17. Burden of fatty liver and hepatic fibrosis in persons with HIV: A diverse cross-sectional US multicenter study
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Samer Gawrieh, Jordan E. Lake, Paula Debroy, Julia A. Sjoquist, Montreca Robison, Mark Tann, Fatih Akisik, Surya S. Bhamidipalli, Chandan K. Saha, Kimon Zachary, Gregory K. Robbins, Samir K. Gupta, Raymond T. Chung, Naga Chalasani, and Kathleen E. Corey
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Hepatology - Published
- 2023
18. Urine Cell-Free Mitochondrial DNA as a Marker of Weight Loss and Body Composition in Older Adults With HIV
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Yuan-Shan Zhu, Michelle C. Rice, Carrie D Johnston, Mary E. Choi, Samir K. Gupta, Katie C. Hootman, Heather M Derry, Chelsie O Burchett, Eugenia L. Siegler, and Marshall J. Glesby
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Aging ,Frail Elderly ,Urinary system ,Physiology ,HIV Infections ,Urine ,Real-Time Polymerase Chain Reaction ,DNA, Mitochondrial ,Article ,chemistry.chemical_compound ,Weight loss ,Weight Loss ,Humans ,Medicine ,Pharmacology (medical) ,Geriatric Assessment ,Aged ,Creatinine ,Frailty ,business.industry ,Middle Aged ,Pathophysiology ,Cross-Sectional Studies ,Infectious Diseases ,chemistry ,Body Composition ,Albuminuria ,Biomarker (medicine) ,Female ,medicine.symptom ,business ,Cell-Free Nucleic Acids ,Viral load ,Biomarkers - Abstract
BACKGROUND Older adults with HIV (OAH) experience more comorbidities and geriatric syndromes than their HIV-negative peers, perhaps because of chronic inflammation. Cell-free mitochondrial DNA (cfmtDNA) released from cells undergoing necrosis-mediated cell death potentially acts as both a mediator and marker of inflammatory dysregulation. We hypothesized that urinary cfmtDNA would be associated with frailty, body composition, and fall history in OAH. METHODS OAH completed frailty testing, a psychosocial survey, body composition assessment, and measurement of urine cfmtDNA and urine albumin:creatinine in this cross-sectional study. Urine cfmtDNA was measured by quantative polymerase chain reaction and normalized to urinary creatinine. RESULTS Across 150 participants, the mean age was 61 years (SD 6 years), half identified as Black, one-third were women, and 93% had HIV-1 viral load
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- 2021
19. 1288. US Healthcare Provider Perspectives on the initiation of cabotegravir and rilpivirine long-acting (CAB+RPV LA) in an observational real-world study (BEYOND)
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Ricky K Hsu, John Phoenix, Gary I Sinclair, Samir K Gupta, Ana Puga, Kaitlin Nguyen, Catherine K Schubert, Deanna Merrill, David Richardson, Kate Nelson, Maria Reynolds, Laurie Zografos, Ashley Jean-Louis, and Cindy Garris
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Infectious Diseases ,Oncology - Abstract
Background CAB+RPV LA is a complete regimen for treatment of virologically suppressed people with HIV (PWH). As an injectable therapeutic administered by a healthcare provider (HCP), CAB+RPV LA may alleviate challenges with adherence to daily oral therapy and reduce fear of HIV status disclosure with oral treatment. Real world perspectives from HCPs and PWH are needed to enable successful delivery of this treatment in US healthcare settings. Methods BEYOND is a 2 year prospective, observational, real-world study of utilization, outcomes, and experience of PWH initiating CAB+RPV LA across 30 US sites. HCPs at participating sites (treaters, injectors, drug acquisition/reimbursement staff) completed surveys at site activation (Sep 2021-Feb 2022; with follow-up surveys planned at 6, 12, 24 months) evaluating experiences to date with implementation of CAB+RPV LA at their sites. Results HCPs from 24 sites responded to the initial survey (Table 1). 75% of HCPs estimated that ≥25% of their PWH are eligible for CAB+RPV LA, and 71% of sites are proactively discussing the regimen with ≥25% of PWH. The majority (79%) of treaters reported they were extremely/very positive about administering CAB+RPV LA. Over 90% of injectors reported a positive overall opinion about administering CAB+RPV LA, and 86% reported the injections were easy to administer. Most (87%) HCPs reported injection visits taking ≤45 minutes, including waiting time. Over 95% of sites have patient reminder systems; 86% will manually identify missed injections and all reported manual follow up by site staff. All sites utilizing the injection education video on the external HCP website (n=15/15) found it helpful and 94% (n=16/17) utilizing reimbursement specialists found them to be helpful. In their experience to date, most clinics reported only needing to increase coordination with the pharmacy team and add injection training to implement CAB+RPV LA. The most frequently reported benefits of implementing CAB+RPV LA by HCPs included assurance of patient adherence and patient engagement in their HIV treatment (Table 2). Conclusion Early real-world data from US HCPs in this study indicates interest in and anticipated uptake of CAB+RPV LA at their sites, positive overall opinion, and multiple benefits of administering the CAB+RPV LA regimen to PWH. Disclosures Ricky K. Hsu, MD, Gilead: Honoraria|Merck: Honoraria|ViiV: Advisor/Consultant|ViiV: Grant/Research Support|ViiV: Honoraria John Phoenix, MSN, APRN, FNP-C, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Honoraria|Gilead Sciences: speaker bureau, research funding|Janssen Pharmaceutical: Advisor/Consultant|Janssen Pharmaceutical: Honoraria|Lupin Pharmaceuticals: Advisor/Consultant|Lupin Pharmaceuticals: Honoraria|Napo pharmaceutical: Honoraria|Napo pharmaceutical: speaker bureau|Scinexis: Advisor/Consultant|Scinexis: Honoraria|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Honoraria|ViiV Healthcare: speaker bureau, clinical research funding Gary I. Sinclair, MD, ABBVIE: Grant/Research Support|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Janssen: Honoraria|Merck: Grant/Research Support|Thera: Grant/Research Support|Thera: Honoraria|ViiV/GSK: Advisor/Consultant|ViiV/GSK: Grant/Research Support|ViiV/GSK: Honoraria Samir K. Gupta, MD, Gilead Sciences: Advisor/Consultant|GSK/ViiV: Advisor/Consultant|GSK/ViiV: Grant/Research Support Ana Puga, MD, FAAP, AAHIVS, Care Resource: Healthcare provider (HCP)|ViiV Healthcare: Stocks/Bonds Kaitlin Nguyen, PharmD, AAHIVE, ViiV Healthcare: Stocks/Bonds Catherine K. Schubert, PharmD, ViiV Healthcare: Stocks/Bonds Deanna Merrill, PharmD, MBA, AAHIVP, ViiV Healthcare: Salaried employee|ViiV Healthcare: Stocks/Bonds David Richardson, BA, ViiV Healthcare: ViiV provided funding to RTI for the development of the study materials, the conduct of the study, and analysis & interpretation of study results. Kate Nelson, M.Ed, ViIV: ViiV provided funding to RTI for the development of the study materials, the conduct of the study, and analysis & interpretation of study results. Maria Reynolds, MStat, ViiV Healthcare: Viiv provided funding to RTI for the development of the study materials, the conduct of the study, and analysis & interpretation of study results. Laurie Zografos, BS, Viiv: ViiV provided funding to RTI for the development of the study materials, the conduct of the study, and analysis & interpretation of study results. Ashley Jean-Louis, MPH, ViiV Healthcare: (ViiV provided funding to RTI for the development of the study materials, the conduct of the study, and analysis & interpretation of study results.) Cindy Garris, MS, ViiV Healthcare: Employee|ViiV Healthcare: Stocks/Bonds.
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- 2022
20. A 58-Year-old Man With Multifocal Pulmonary Nodules
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Mitchell McClean, Samir K Gupta, and Ryan F Relich
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Microbiology (medical) ,Male ,Infectious Diseases ,Humans ,Multiple Pulmonary Nodules ,Middle Aged ,Tomography, X-Ray Computed - Published
- 2022
21. Associations of HIV and Depression with Incident Diabetes Mellitus: Veterans Aging Cohort Study
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Kassem Bourgi, Suman Kundu, Jesse C Stewart, Kaku So-Armah, Matthew Freiberg, and Samir K Gupta
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Microbiology (medical) ,Infectious Diseases - Abstract
Background Persons with HIV (PWH) are at increasingly higher risk for metabolic complications, including diabetes mellitus (DM). Additionally, depression is highly prevalent among PWH and has been associated with increased risk for DM in the general population. However, the association of HIV and depression with incident DM has not been well established. Methods Using the Veterans Aging Cohort Study (VACS), we selected adults with and without HIV who did not have DM at baseline. Prevalent depression was defined as having a Patient Health Questionnaire-9 (PHQ-9) score of ≥10. Incident DM was identified using validated Kelly’s criteria. Basic clinical and demographic characteristics were collected, and cox proportional hazards regression models were run to test the association between depression and incident DM stratified by HIV serostatus. Results A total of 5,722 participants were analyzed, 2,886 (53%) had HIV and 1,124 (20%) had depression at baseline. 1,235 (22%) participants developed incident DM during follow-up, with 26% of HIV-negative participants developing DM compared to 17% of participants with HIV. Depression was significantly associated with increased risk of incident DM among HIV-negative participants (adjusted HR [aHR] = 1.31; p-value 0.003), but not among participants with HIV (aHR 1.09; p-value 0.44). However, among participants with HIV with baseline viral load < 500 copies/mL, we noted a stronger association between depression and incident DM. Conclusions Incident DM in the VACS cohort is significantly higher for HIV-negative participants compared to veterans with HIV. A significant association between depression and incident DM was noted among HIV-negative participants but not among those with HIV.
- Published
- 2022
22. Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials
- Author
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David A. Wohl, Claudia Martorell, Amanda Clarke, Sean E Collins, Jason Flamm, Samir K. Gupta, Edwin DeJesus, Hans-Jürgen Stellbrink, Hal Martin, Daniel Podzamczer, Debbie Hagins, Jose R. Arribas, Diana M. Brainard, Franco Maggiolo, Cynthia Brinson, Gs-Us Investigators, Paul E. Sax, Rima Acosta, Gs-Us, Jeffrey L. Stephens, Melanie A. Thompson, Hailin Huang, and Chloe Orkin
- Subjects
Male ,0301 basic medicine ,Epidemiology ,HIV Infections ,Piperazines ,chemistry.chemical_compound ,0302 clinical medicine ,Abacavir ,Emtricitabine ,030212 general & internal medicine ,Alanine ,virus diseases ,Lamivudine ,Middle Aged ,Drug Combinations ,Treatment Outcome ,Infectious Diseases ,Dolutegravir ,RNA, Viral ,Female ,Heterocyclic Compounds, 3-Ring ,medicine.drug ,Adult ,medicine.medical_specialty ,Pyridones ,Immunology ,Fixed-dose combination ,Heterocyclic Compounds, 4 or More Rings ,Tenofovir alafenamide ,Drug Administration Schedule ,Young Adult ,03 medical and health sciences ,Double-Blind Method ,Virology ,Internal medicine ,Oxazines ,medicine ,Humans ,Tenofovir ,Aged ,Bictegravir ,business.industry ,Adenine ,030112 virology ,Dideoxynucleosides ,Regimen ,chemistry ,HIV-1 ,business - Abstract
Summary Background In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies. Methods We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov , NCT02607930 and NCT02607956 . Findings 629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and tenofovir alafenamide, 325 to dolutegravir, emtricitabine, tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference −2·6%, 95% CI −8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (difference −1·9%, −7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (−0·1 vs −0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study. Interpretation These long-term data support the use of bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance. Funding Gilead Sciences.
- Published
- 2020
23. Depression as a Risk Factor for Incident Ischemic Stroke Among HIV-Positive Veterans in the Veterans Aging Cohort Study
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Suman Kundu, Jason J. Sico, Adeel A. Butt, Stephen Crystal, Matthew S. Freiberg, Cynthia L. Gibert, Kaku So-Armah, Jesse C. Stewart, Vincent C. Marconi, Samir K. Gupta, Chung-Chou H. Chang, and Hilary A. Tindle
- Subjects
Adult ,Male ,medicine.medical_specialty ,Population ,Human immunodeficiency virus (HIV) ,combined antiretroviral therapy ,HIV Infections ,medicine.disease_cause ,Risk Assessment ,Stroke risk ,Cohort Studies ,Risk Factors ,Internal medicine ,medicine ,ischemic stroke ,Humans ,Risk factor ,education ,Stroke ,Depression (differential diagnoses) ,Proportional Hazards Models ,Veterans ,Original Research ,education.field_of_study ,Depressive Disorder, Major ,business.industry ,HIV ,Middle Aged ,medicine.disease ,stroke risk ,United States ,Ischemic stroke ,depression ,Female ,Cardiology and Cardiovascular Medicine ,business ,Cohort study - Abstract
Background HIV infection and depression are each associated with increased ischemic stroke risk. Whether depression is a risk factor for stroke within the HIV population is unknown. Methods and Results We analyzed data on 106 333 (33 528 HIV‐positive; 72 805 HIV‐negative) people who were free of baseline cardiovascular disease from an observational cohort of HIV‐positive people and matched uninfected veterans in care from April 1, 2003 through December 31, 2014. International Classification of Diseases, Ninth Revision ( ICD‐9 ) codes from medical records were used to determine baseline depression and incident stroke. Depression occurred in 19.5% of HIV‐positive people. After a median of 9.2 years of follow‐up, stroke rates were highest among people with both HIV and depression and lowest among those with neither condition. In Cox proportional hazard models, depression was associated with an increased risk of stroke for HIV‐positive people after adjusting for sociodemographic characteristics and cerebrovascular risk factors (hazard ratio [HR], 1.18; 95% CI: 1.03–1.34; 0.014). The depression‐stroke relationship was attenuated by alcohol use disorders, cocaine use, and baseline antidepressant use, and unaffected by combined antiretroviral therapy use or individual antiretroviral agents. A numerically higher HR of depression on stroke was found among those younger than 60 years. Conclusions Depression is associated with an increased risk of stroke among HIV‐positive people after adjusting for sociodemographic characteristics, traditional cerebrovascular risk factors, and HIV‐specific factors. Alcohol use disorders, cocaine use, and baseline antidepressant use accounted for some of the observed stroke risk. Depression may be a novel, independent risk factor for ischemic stroke in HIV, particularly among younger people.
- Published
- 2021
24. Elevated cardiac risk score by Atherosclerotic Cardiovascular Disease calculation is associated with albuminuria in older people living with HIV
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Chelsie O Burchett, Kene Chukwu C. Ifeagwu, Marshall J. Glesby, Samir K. Gupta, Eugenia L. Siegler, Carrie D Johnston, Mary E. Choi, Heather M Derry, and Michelle C. Rice
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Framingham Risk Score ,Atherosclerotic cardiovascular disease ,business.industry ,Immunology ,Human immunodeficiency virus (HIV) ,Disease ,urologic and male genital diseases ,medicine.disease_cause ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Infectious Diseases ,Internal medicine ,medicine ,Albuminuria ,Immunology and Allergy ,030212 general & internal medicine ,medicine.symptom ,Cardiac risk ,Older people ,business - Abstract
Globally, the proportion of older people living with HIV (PLWH) is growing and the burden of noncommunicable diseases, including cardiac and renal disease, is increasing. There are few studies of renal disease and cardiac risk in older PLWH. This study investigates the relationship between albuminuria and cardiac risk as estimated by the Atherosclerotic Cardiovascular Disease 10-year risk calculator. We report that albuminuria is associated with a higher Atherosclerotic Cardiovascular Disease risk score in both diabetic and nondiabetic older PLWH.
- Published
- 2020
25. HIV-Nef Protein Transfer to Endothelial Cells Requires Rac1 Activation and Leads to Endothelial Dysfunction Implications for Statin Treatment in HIV Patients
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Matthias Clauss, Paul Jolicoeur, Bradley W. Ellis, Sarvesh Chelvanambi, Bernhard Maier, Samir K. Gupta, Pinar Zorlutuna, Xingjuan Chen, Tyler M. Colbert, Jithin Kuriakose, and Alexander G. Obukhov
- Subjects
Adult ,Male ,rac1 GTP-Binding Protein ,0301 basic medicine ,Statin ,Physiology ,medicine.drug_class ,Human immunodeficiency virus (HIV) ,HIV Infections ,Mice, Transgenic ,RAC1 ,medicine.disease_cause ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Human Umbilical Vein Endothelial Cells ,medicine ,Animals ,Humans ,nef Gene Products, Human Immunodeficiency Virus ,030212 general & internal medicine ,Endothelial dysfunction ,Gene ,Aged ,business.industry ,Endothelial Cells ,virus diseases ,Middle Aged ,Statin treatment ,medicine.disease ,Treatment Outcome ,030104 developmental biology ,Apoptosis ,Immunology ,Hiv patients ,Female ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Cardiology and Cardiovascular Medicine ,business - Abstract
Rationale:Even in antiretroviral therapy-treated patients, HIV continues to play a pathogenic role in cardiovascular diseases. A possible cofactor may be persistence of the early HIV response gene Nef, which we have demonstrated recently to persist in the lungs of HIV+ patients on antiretroviral therapy. Previously, we have reported that HIV strains with Nef, but not Nef-deleted HIV strains, cause endothelial proinflammatory activation and apoptosis.Objective:To characterize mechanisms through which HIV-Nef leads to the development of cardiovascular diseases using ex vivo tissue culture approaches as well as interventional experiments in transgenic murine models.Methods and Results:Extracellular vesicles derived from both peripheral blood mononuclear cells and plasma from HIV+ patient blood samples induced human coronary artery endothelial cells dysfunction. Plasma-derived extracellular vesicles from antiretroviral therapy+ patients who were HIV-Nef+ induced significantly greater endothelial apoptosis compared with HIV-Nef-plasma extracellular vesicles. Both HIV-Nef expressing T cells and HIV-Nef-induced extracellular vesicles increased transfer of cytosol and Nef protein to endothelial monolayers in a Rac1-dependent manner, consequently leading to endothelial adhesion protein upregulation and apoptosis. HIV-Nef induced Rac1 activation also led to dsDNA breaks in endothelial colony forming cells, thereby resulting in endothelial colony forming cell premature senescence and endothelial nitric oxide synthase downregulation. These Rac1-dependent activities were characterized by NOX2-mediated reactive oxygen species production. Statin treatment equally inhibited Rac1 inhibition in preventing or reversing all HIV-Nef-induction abnormalities assessed. This was likely because of the ability of statins to block Rac1 prenylation as geranylgeranyl transferase inhibitors were effective in inhibiting HIV-Nef-induced reactive oxygen species formation. Finally, transgenic expression of HIV-Nef in endothelial cells in a murine model impaired endothelium-mediated aortic ring dilation, which was then reversed by 3-week treatment with 5 mg/kg atorvastatin.Conclusions:These studies establish a mechanism by which HIV-Nef persistence despite antiretroviral therapy could contribute to ongoing HIV-related vascular dysfunction, which may then be ameliorated by statin treatment.
- Published
- 2019
26. Depression and all‐cause mortality risk in HIV‐infected and HIV‐uninfected US veterans: a cohort study
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Matthew J. Budoff, Kaku So-Armah, Cynthia L. Gibert, Samir K. Gupta, Chung Chou Chang, Maria C. Rodriguez-Barradas, Matthew S. Freiberg, Roger Bedimo, Jesse C. Stewart, Adeel A. Butt, Stephen Crystal, Suman Kundu, Jason J. Sico, Joseph L. Goulet, and Vincent C. Marconi
- Subjects
Male ,0301 basic medicine ,Human immunodeficiency virus (HIV) ,HIV Infections ,medicine.disease_cause ,0302 clinical medicine ,Pharmacology (medical) ,Longitudinal Studies ,Prospective Studies ,030212 general & internal medicine ,Aetiology ,Depression (differential diagnoses) ,Veterans ,Depression ,Health Policy ,Mortality rate ,Hazard ratio ,Middle Aged ,Mental Health ,Infectious Diseases ,HIV/AIDS ,Major depressive disorder ,Female ,Infection ,Cohort study ,Adult ,medicine.medical_specialty ,Clinical Sciences ,Article ,03 medical and health sciences ,Clinical Research ,Virology ,Internal medicine ,Behavioral and Social Science ,medicine ,Humans ,Mortality ,Depressive Disorder, Major ,Depressive Disorder ,business.industry ,Prevention ,Major ,HIV ,medicine.disease ,030112 virology ,United States ,Confidence interval ,Brain Disorders ,Patient Health Questionnaire ,Good Health and Well Being ,Case-Control Studies ,business ,2.4 Surveillance and distribution - Abstract
ObjectivesThe contribution of depression to mortality in adults with and without HIV infection is unclear. We hypothesized that depression increases mortality risk and that this association is stronger among those with HIV infection.MethodsVeterans Aging Cohort Study (VACS) data were analysed from the first clinic visit on or after 1 April 2003 (baseline) to 30 September 2015. Depression definitions were: (1) major depressive disorder defined using International Classification of Diseases, Ninth Revision (ICD-9) codes; (2) depressive symptoms defined as Patient Health Questionnaire (PHQ)-9 scores ≥10. The outcome was all-cause mortality. Covariates were demographics, comorbid conditions and health behaviours.ResultsAmong 129140 eligible participants, 30% had HIV infection, 16% had a major depressive disorder diagnosis, and 24% died over a median follow-up time of 11years. The death rate was 25.3 [95% confidence interval (CI) 25.0-25.6] deaths per 1000 person-years. Major depressive disorder was associated with mortality [hazard ratio (HR) 1.04; 95% CI1.01, 1.07]. This association was modified by HIV status (interaction P-value=0.02). In HIV-stratified analyses, depression was significantly associated with mortality among HIV-uninfected veterans but not among those with HIV infection. Among those with PHQ-9 data (n=7372), 50% had HIV infection, 22% had PHQ-9 scores ≥10, and 28% died over a median follow-up time of 12years. The death rate was 27.3 (95% CI 26.1-28.5) per 1000 person-years. Depressive symptoms were associated with mortality (HR 1.16; 95% CI 1.04, 1.28). This association was modified by HIV status (interaction P-value=0.05). In HIV-stratified analyses, depressive symptoms were significantly associated with mortality among veterans with HIV infection but not among those without HIV infection.ConclusionsDepression was associated with all-cause mortality. This association was modified by HIV status and method of depression ascertainment.
- Published
- 2019
27. Women have enhanced bone loss associated with phosphaturia and CD4+ cell restoration during initial antiretroviral therapy
- Author
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Robert C. Kalayjian, Jeffrey M. Albert, Serge Cremers, Samir K. Gupta, Grace A. McComsey, Karin L. Klingman, Carl J. Fichtenbaum, Todd T. Brown, and Babafemi O. Taiwo
- Subjects
Adult ,Male ,musculoskeletal diseases ,0301 basic medicine ,medicine.medical_specialty ,Randomization ,Adolescent ,Sustained Virologic Response ,030106 microbiology ,Immunology ,Urology ,Renal function ,HIV Infections ,Article ,law.invention ,Excretion ,Young Adult ,03 medical and health sciences ,Absorptiometry, Photon ,Immune Reconstitution ,0302 clinical medicine ,N-terminal telopeptide ,Randomized controlled trial ,Bone Density ,law ,Antiretroviral Therapy, Highly Active ,medicine ,Humans ,Immunology and Allergy ,030212 general & internal medicine ,Pelvic Bones ,Hypophosphatemia, Familial ,Randomized Controlled Trials as Topic ,Bone mineral ,business.industry ,Area under the curve ,Middle Aged ,Viral Load ,Spine ,CD4 Lymphocyte Count ,Bone Diseases, Metabolic ,Treatment Outcome ,Infectious Diseases ,Anti-Retroviral Agents ,Female ,business ,Viral load - Abstract
OBJECTIVE We compared bone mineral density (BMD) changes and their correlates, between men and women participating in two randomized trials of initial [antiretroviral therapy (ART)] regimens, with or without tenofovir disoproxil fumarate (TDF). METHODS Covariates in linear regression models of 48-week hip and spine %BMD changes, by dual energy X-ray absorptiometry, included baseline and 48-week changes in plasma viral load, CD4 cells, plasma C-terminal telopeptide, procollagen 1 N-terminal propeptide and glomerular filtration rates, and the 48-week area under the curve of fractional excretion of phosphate. RESULTS Despite overall hip and spine BMD declines of 2.8 and 2.9%, respectively, plasma viral load suppression to less than 50 vs. at least 50 copies/ml was associated 1.0% (P = 0.02) and 0.8% (P = 0.01) less BMD decline. Women had lower baseline spine (P = 0.04; n = 59 women, 418 men) and hip BMD (P = 0.01) in adjusted models, with 1.7% more hip decline on ART than men (P = 0.001). Serum phosphate was positively associated with baseline spine BMD in women (P = 0.03) but not men, and area under the curve of fractional excretion of phosphate was negatively associated with spine BMD changes, particularly in women randomized to TDF regimens (P = 0.03 and 0.054 for interactions by sex, and randomization to TDF vs. non-TDF regimens, respectively; n = 44 women, 326 men). Women also had 0.6% (P = 0.004) more hip BMD decline than men associated with each 100 CD4 cells/μl increase on ART (P = 0.02; n = 49 women, 379 men). CONCLUSION Women randomized to TDF-containing ART had accentuated spine loss associated with phosphaturia, and accentuated hip loss associated with CD4 restoration, regardless of TDF exposure. Viral load suppression reduced bone loss.
- Published
- 2018
28. Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis
- Author
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Jennifer M. Weiss, Robert Hüneburg, Frank A. Sinicrope, Paul E. Wise, Fiona Lalloo, R. Lim, Frank G.J. Kallenberg, Gregory G. Ginsberg, Carol A. Burke, N. Jewel Samadder, Field F. Willingham, Elena M. Stoffel, Patrick M. Lynch, Evelien Dekker, Eric van Cutsem, Alfred Cohen, Robert Gryfe, William M. Grady, Samir K. Gupta, John Burn, Sapna Syngal, Alex Henderson, Victorine H. Roos, Molly Ford, James M. Church, Priyanka Kanth, Christian P. Strassburg, Steven Gallinger, Francesc Balaguer, Anil K. Rustgi, Antoni Castells, Gastroenterology and Hepatology, CCA - Cancer Treatment and Quality of Life, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, APH - Methodology, APH - Personalized Medicine, and APH - Quality of Care
- Subjects
Drug ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Eflornithine ,Combination therapy ,media_common.quotation_subject ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,law.invention ,Familial adenomatous polyposis ,03 medical and health sciences ,0302 clinical medicine ,Pharmacotherapy ,Sulindac ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,media_common ,business.industry ,General Medicine ,medicine.disease ,digestive system diseases ,Intention to Treat Analysis ,Clinical trial ,Treatment Outcome ,Adenomatous Polyposis Coli ,Disease Progression ,Drug Therapy, Combination ,Female ,business ,medicine.drug - Abstract
BACKGROUND: The efficacy and safety of combination therapy with eflornithine and sulindac, as compared with either drug alone, in delaying disease progression in patients with familial adenomatous polyposis are unknown. METHODS: We evaluated the efficacy and safety of the combination of eflornithine and sulindac, as compared with either drug alone, in adults with familial adenomatous polyposis. The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status; the strata were precolectomy (shortest projected time to disease progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time). The patients were then randomly assigned in a 1:1:1 ratio to receive 750 mg of eflornithine, 150 mg of sulindac, or both once daily for up to 48 months. The primary end point, assessed in a time-to-event analysis, was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or pouch, or progression of duodenal disease. RESULTS: A total of 171 patients underwent randomization. Disease progression occurred in 18 of 56 patients (32%) in the eflornithine-sulindac group, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio of 0.71 (95% confidence interval [CI], 0.39 to 1.32) for eflornithine-sulindac as compared with sulindac (P = 0.29) and 0.66 (95% CI, 0.36 to 1.24) for eflornithine-sulindac as compared with eflornithine. Among 37 precolectomy patients, the corresponding values in the treatment groups were 2 of 12 patients (17%), 6 of 13 (46%), and 5 of 12 (42%) (hazard ratios, 0.30 [95% CI, 0.07 to 1.32] and 0.20 [95% CI, 0.03 to 1.32]); among 34 patients with rectal or ileal pouch polyposis, the values were 4 of 11 patients (36%), 2 of 11 (18%), and 5 of 12 (42%) (hazard ratios, 2.03 [95% CI, 0.43 to 9.62] and 0.84 [95% CI, 0.24 to 2.90]); and among 100 patients with duodenal polyposis, the values were 12 of 33 patients (36%), 14 of 34 (41%), and 13 of 33 (39%) (hazard ratios, 0.73 [95% CI, 0.34 to 1.52] and 0.76 [95% CI, 0.35 to 1.64]). Adverse and serious adverse events were similar across the treatment groups. CONCLUSIONS: In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone. (Funded by Cancer Prevention Pharmaceuticals; ClinicalTrials.gov number, NCT01483144; EudraCT number, 2012-000427-41.).
- Published
- 2020
29. Effects of Internet Cognitive-Behavioral Therapy on Depressive Symptoms and Surrogates of Cardiovascular Risk in Human Immunodeficiency Virus: A Pilot, Randomized, Controlled Trial
- Author
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Samir K. Gupta, Brittanny M. Polanka, Ziyue Liu, James E. Slaven, Matthew S. Freiberg, and Jesse C. Stewart
- Subjects
medicine.medical_specialty ,cognitive-behavioral therapy ,medicine.medical_treatment ,Human immunodeficiency virus (HIV) ,Disease ,030204 cardiovascular system & hematology ,medicine.disease_cause ,law.invention ,Major Articles ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,endothelial function ,law ,Internal medicine ,medicine.artery ,medicine ,Clinical endpoint ,030212 general & internal medicine ,Brachial artery ,Depressive symptoms ,business.industry ,HIV ,Patient Health Questionnaire ,Cognitive behavioral therapy ,Infectious Diseases ,AcademicSubjects/MED00290 ,Oncology ,inflammation ,depression ,business - Abstract
Background Depression is associated with an increased risk of cardiovascular disease in human immunodeficiency virus (HIV). We hypothesized that reducing depressive symptoms would improve HIV-related cardiovascular risk. Methods We conducted a single-center, randomized (1:1), controlled, parallel-group, assessor-blinded, pilot trial comparing Beating the Blues US (BtB)—an evidence-based, 8-session, internet cognitive-behavioral therapy for depression—with usual care (UC) in HIV-positive participants receiving virologically suppressive antiretroviral therapy and with Patient Health Questionnaire (PHQ)-9 scores ≥10. The primary endpoint was change in brachial artery flow-mediated dilation (FMD) at 12 weeks. Secondary endpoints were FMD change at 24 weeks and inflammation, coagulation, and metabolic biomarker changes at 12 and 24 weeks. Results Fifty-four participants were randomized (27 in each arm). Mean reductions in PHQ-9 scores were significantly greater with BtB versus UC at 12 weeks (−5.60 vs −1.52; P = .007) and 24 weeks (−6.00 vs −1.38; P = .008); reductions in the Hopkins Symptom Checklist Depression Scale-20 scores were also significantly greater with BtB versus UC at 24 weeks (−0.72 vs −0.35; P = .029). Changes in FMD between arms were not significantly different at 12 or 24 weeks. Significantly larger reductions in soluble (s)CD14 and sCD163 with BtB versus UC were found at 12 and 24 weeks, respectively. Conclusions Compared with UC, internet cognitive-behavioral therapy using BtB resulted in greater improvements in depressive symptoms and monocyte activation markers but did not improve FMD in this pilot trial. These data support performing larger studies to determine the potential salutatory effects of behavioral therapies for depression on HIV-related inflammation., In this pilot randomized trial, we found that internet cognitive-behavioral therapy, compared with usual care, improved depressive symptoms and monocyte activation, but not endothelial function, in HIV-positive patients.
- Published
- 2020
30. Associations of Total, Cognitive/Affective, and Somatic Depressive Symptoms and Antidepressant Use with Cardiovascular Disease-Relevant Biomarkers in HIV: Veterans Aging Cohort Study
- Author
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Samir K. Gupta, Matthew S. Freiberg, Brittanny M. Polanka, Chung-Chou H. Chang, Jesse C. Stewart, Suman Kundu, Kaku So-Armah, and Jessica R. White
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,medicine.drug_class ,Serotonin reuptake inhibitor ,Lipopolysaccharide Receptors ,Tricyclic antidepressant ,HIV Infections ,Disease ,Cardiovascular System ,Article ,Monocytes ,Cohort Studies ,Fibrin Fibrinogen Degradation Products ,03 medical and health sciences ,0302 clinical medicine ,Cognition ,Risk Factors ,Internal medicine ,Medicine ,Humans ,Applied Psychology ,Depression (differential diagnoses) ,Aged ,Veterans ,chemistry.chemical_classification ,Inflammation ,business.industry ,Depression ,Interleukin-6 ,Confounding ,Middle Aged ,Antidepressive Agents ,030227 psychiatry ,Psychiatry and Mental health ,chemistry ,Cardiovascular Diseases ,Antidepressant ,Female ,business ,030217 neurology & neurosurgery ,Biomarkers ,Tricyclic ,Cohort study - Abstract
Objective We sought to determine the associations of total, cognitive/affective, and somatic depressive symptoms and antidepressant use with biomarkers of processes implicated in cardiovascular disease in HIV (HIV-CVD). Methods We examined data from 1546 HIV-positive and 843 HIV-negative veterans. Depressive symptoms were assessed using the Patient Health Questionnaire-9, and past-year antidepressant use was determined from Veterans Affair pharmacy records. Monocyte (soluble CD14 [sCD14]), inflammatory (interleukin-6 [IL-6]), and coagulation (D-dimer) marker levels were determined from previously banked blood specimens. Linear regression models with multiple imputation were run to estimate the associations between depression-related factors and CVD-relevant biomarkers. Results Among HIV-positive participants, greater somatic depressive symptoms were associated with higher sCD14 (exp[b] = 1.02, 95% confidence interval [CI] = 1.00-1.03) and D-dimer (exp[b] = 1.06, 95% CI = 1.00-1.11) after adjustment for demographics and potential confounders. Further adjustment for antidepressant use and HIV factors slightly attenuated these relationships. Associations were also detected for antidepressant use, as selective serotonin reuptake inhibitor use was related to lower sCD14 (exp[b] = 0.95, 95% CI = 0.91-1.00) and IL-6 (exp[b] = 0.86, 95% CI = 0.76-0.96), and tricyclic antidepressant use was related to higher sCD14 (exp[b] = 1.07, 95% CI = 1.03-1.12) and IL-6 (exp[b] = 1.14, 95% CI = 1.02-1.28). Among HIV-negative participants, total, cognitive/affective, and somatic depressive symptoms were associated with higher IL-6, and tricyclic antidepressant use was related to higher sCD14. Conclusions Our novel findings suggest that a) monocyte activation and altered coagulation may represent two pathways through which depression increases HIV-CVD risk and that b) tricyclic antidepressants may elevate and selective serotonin reuptake inhibitors may attenuate HIV-CVD risk by influencing monocyte and inflammatory activation.
- Published
- 2020
31. Inhibitory Effects of Probenecid on Pharmacokinetics of Tenofovir Disoproxil Fumarate and Emtricitabine for On-Demand HIV Pre-exposure Prophylaxis
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Richard F. Bergstrom, Stephanie N. Liu, Samir K. Gupta, Brandon T. Gufford, Peter L. Anderson, Lane R. Bushman, Jessica Bo Li Lu, and Zeruesenay Desta
- Subjects
Adult ,Male ,Tenofovir ,Adolescent ,Anti-HIV Agents ,Human immunodeficiency virus (HIV) ,Pharmacology ,medicine.disease_cause ,Emtricitabine ,030226 pharmacology & pharmacy ,Peripheral blood mononuclear cell ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Pharmacokinetics ,Medicine ,Humans ,Pharmacology (medical) ,Drug Interactions ,Cross-Over Studies ,business.industry ,Probenecid ,Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination ,Middle Aged ,Crossover study ,Regimen ,030220 oncology & carcinogenesis ,Area Under Curve ,Leukocytes, Mononuclear ,Pre-Exposure Prophylaxis ,business ,medicine.drug - Abstract
In a randomized, cross-over study in healthy volunteers (N=14), 2 g probenecid (PRO)-boosted pharmacokinetics of single dose 600 mg tenofovir disoproxil fumarate (TDF) / 400 mg emtricitabine (FTC) (Treatment, T +PRO) was compared with the current On-Demand HIV Pre-Exposure Prophylaxis (PrEP) from the IPERGAY study (a 600 mg TDF/400 mg FTC on day 1 and 300 mg TDF/200 mg FTC on days 2 and 3) (Control, C IPERGAY). PRO increased mean single dose plasma AUC(0−∞) of TFV and FTC by 64% and 62%, respectively. The 24-hour TFV-diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMC) were significantly higher (~30%) in T +PRO compared to C IPERGAY and remained nearly unchanged (on average over 20 fmol/10(6)cells) for 72 hours, suggesting prolonged exposure by PRO. The interaction between FTC and PRO was unexpected and novel. Although further study is needed, PRO-boosted TDF/FTC may allow simpler dosing and improved adherence to HIV PrEP.
- Published
- 2019
32. GCH1 haplotypes and cardiovascular risk in HIV
- Author
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Ziyue Liu, James H. Stein, Samir K. Gupta, David W Haas, Todd T. Brown, and James E. Slaven
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Immunology ,Human immunodeficiency virus (HIV) ,HIV Infections ,Inflammation ,Systemic inflammation ,medicine.disease_cause ,Risk Assessment ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Genetic Predisposition to Disease ,cardiovascular diseases ,030212 general & internal medicine ,GTP Cyclohydrolase ,Extramural ,business.industry ,Racial Groups ,Haplotype ,Middle Aged ,Antiretroviral therapy ,United States ,030104 developmental biology ,Infectious Diseases ,Haplotypes ,Cardiovascular Diseases ,Cohort ,Female ,medicine.symptom ,business - Abstract
Heightened systemic inflammation contributes to cardiovascular (CVD) events in people living with HIV (PLWH), although not all PLWH develop CVD, thus suggesting a genetic modifying role. We examined GCH1 polymorphisms, which have been associated with reduced endothelial function in European populations with CVD and increased inflammation, in a racially diverse cohort of US PLWH initiating antiretroviral therapy (ART). GCH1 polymorphisms differed by race and were not associated with flow-mediated dilation or carotid intima-media thickness before or after 48 weeks of ART.
- Published
- 2019
33. Bone mineral density reductions after tenofovir disoproxil fumarate initiation and changes in phosphaturia: a secondary analysis of ACTG A5224s
- Author
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Samir K. Gupta, Charles S. Venuto, Belinda Ha, Douglas Kitch, Todd T. Brown, Gene D. Morse, Grace A. McComsey, Kathleen Melbourne, and Eunice Yeh
- Subjects
Adult ,Male ,musculoskeletal diseases ,0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,Efavirenz ,Bone density ,Anti-HIV Agents ,Urology ,Renal function ,HIV Infections ,Phosphates ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Bone Density ,immune system diseases ,Abacavir ,medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Tenofovir ,skin and connective tissue diseases ,Hypophosphatemia, Familial ,Original Research ,Pharmacology ,Bone mineral ,Hip ,business.industry ,virus diseases ,Middle Aged ,medicine.disease ,030112 virology ,Virology ,Dideoxynucleosides ,Spine ,Atazanavir ,Infectious Diseases ,chemistry ,Female ,Ritonavir ,sense organs ,business ,Hypophosphatemia ,Glomerular Filtration Rate ,medicine.drug - Abstract
Background It is unknown if the greater reductions in bone mineral density (BMD) associated with initiation of tenofovir disoproxil fumarate compared with abacavir in previously untreated HIV-infected participants in the ACTG A5224s clinical trial were associated with potentially worsening tenofovir-related phosphaturia. Methods We correlated changes in BMD at the hip and spine with changes in phosphaturia [transtubular reabsorption of phosphorus (TRP) and tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR)] from entry through week 96 in those initiating tenofovir ( n = 134) versus abacavir ( n = 135) with efavirenz or atazanavir/ritonavir in A5224s. We also correlated changes in BMD with tenofovir AUC measured between weeks 4 and 24. Results Changes in TRP and TmP/GFR through week 96 between the tenofovir and abacavir arms were not significantly different (both P ≥ 0.70) and did not differ with use of efavirenz versus atazanavir/ritonavir. There were no significant correlations between changes in either TRP or TmP/GFR and with either hip or spine BMD in the tenofovir arms. Tenofovir AUC was significantly correlated with changes in hip BMD, but not spine BMD, at week 24 ( r = -0.22, P = 0.028) and week 48 ( r = -0.26, P = 0.010), but not at week 96 ( r = -0.14, P = 0.18). Conclusions Changes in phosphaturia were not different between the tenofovir and abacavir arms in A5224s. Changes in hip and spine BMD with tenofovir were not related to changes in phosphaturia. However, tenofovir exposure was weakly associated with changes in hip BMD through week 48.
- Published
- 2017
34. Pharmacokinetic-Pharmacodynamic Correlations of Benzodiazepines
- Author
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Samir K. Gupta and Everett H. Ellinwood
- Subjects
business.industry ,Pharmacokinetic pharmacodynamic ,Medicine ,Pharmacology ,business - Published
- 2019
35. Insomnia as an Independent Predictor of Incident Cardiovascular Disease in HIV: Data From the Veterans Aging Cohort Study
- Author
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Adeel A. Butt, Suman Kundu, Roger Bedimo, Kaku So-Armah, Stephen S. Gottlieb, Brittanny M. Polanka, Chung-Chou H. Chang, Matthew S. Freiberg, Matthew J. Budoff, Samir K. Gupta, Julie A. Womack, Vincent C. Marconi, and Jesse C. Stewart
- Subjects
Adult ,Male ,medicine.medical_specialty ,Population ,MEDLINE ,HIV Infections ,Disease ,Article ,Risk Factors ,Internal medicine ,Sleep Initiation and Maintenance Disorders ,mental disorders ,medicine ,Insomnia ,Humans ,Pharmacology (medical) ,Prospective cohort study ,education ,Veterans ,Sleep disorder ,education.field_of_study ,business.industry ,Middle Aged ,medicine.disease ,United States ,nervous system diseases ,Infectious Diseases ,Cardiovascular Diseases ,Cohort ,Female ,medicine.symptom ,business ,Cohort study - Abstract
Insomnia is associated with increased cardiovascular disease (CVD) risk in the general population and is highly prevalent in people with HIV. The CVD risk conferred by insomnia in the HIV population is unknown.Using the Veterans Aging Cohort Study Survey Cohort, insomnia symptoms were measured and dummy coded with the item, "Difficulty falling or staying asleep?" (5-point scale from no difficulty to bothers a lot). Incident CVD event ICD-9 codes (acute myocardial infarction, stroke, or coronary artery revascularization) were identified with the Department of Veterans Affairs (VA) and Medicare administrative data and VA fee-for-service data. Those with baseline CVD were excluded.HIV-infected (N = 3108) veterans had a median follow-up time of 10.8 years, during which 267 CVD events occurred. Compared to HIV-infected veterans with no difficulty falling or staying asleep, HIV-infected veterans bothered a lot by insomnia symptoms had an increased risk of incident CVD after adjusting for demographics [hazard ratio (HR) = 1.64, 95% confidence interval (CI): 1.16 to 2.31, P = 0.005], CVD risk factors (HR = 1.62, 95% CI: 1.14 to 2.30, P = 0.007), additional potential confounders (hepatitis C infection, renal disease, anemia, alcohol use, and cocaine use; HR = 1.70, 95% CI: 1.19 to 2.43, P = 0.003), and HIV-specific factors (HIV-1 RNA, CD4 T-cell count, and antiretroviral therapy; HR = 1.66, 95% CI: 1.16 to 2.37, P = 0.005). Additional adjustment for nonbenzodiazepine sleep medication (HR = 1.62, 95% CI: 1.13 to 2.32, P = 0.009) did not attenuate the association; however, it fell short of significance at P0.01 after adjustment for depressive symptoms (HR = 1.51, 95% CI: 0.98 to 2.32, P = 0.060) or antidepressant medication (HR = 1.51, 95% CI: 1.04 to 2.19, P = 0.031).Highly bothersome insomnia symptoms were significantly associated with incident CVD in HIV-infected veterans, suggesting that insomnia may be a novel, modifiable risk factor for CVD in HIV.
- Published
- 2019
36. Beetroot supplementation in women enjoying exercise together (BEE SWEET): Rationale, design and methods
- Author
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Andrew R. Coggan, Samir K. Gupta, John S. Raglin, Marissa N. Baranauskas, Cody A. Altherr, Stephen J. Carter, and Allison H. Gruber
- Subjects
medicine.medical_specialty ,Disease ,Beetroot Juice ,Article ,law.invention ,03 medical and health sciences ,Social support ,0302 clinical medicine ,Randomized controlled trial ,law ,Dietary Nitrate ,medicine ,030212 general & internal medicine ,Adverse effect ,Vascular health ,Pharmacology ,lcsh:R5-920 ,business.industry ,Dietary nitrate ,Nitric oxide ,General Medicine ,Cardiovascular disease ,medicine.disease ,Menopause ,Physical therapy ,Postmenopausal ,lcsh:Medicine (General) ,business ,Exercise prescription ,030217 neurology & neurosurgery - Abstract
Background Postmenopausal women exhibit higher rates of disability and cardiovascular disease (CVD) with aging compared to men. Whereas habitual exercise training is a known strategy to enhance physiologic function in men and premenopausal women, exercise-related adaptations are often modest in postmenopausal women. We propose dietary nitrate (beetroot juice) administered prior to exercise training may be a feasible approach to improve mobility and cardio-metabolic health outcomes in postmenopausal women. Methods Our randomized, placebo-controlled study aims to determine preliminary effects sizes for changes in functional mobility and endothelium-dependent vasodilation across three study arms: exercise only (EX), exercise + placebo (EX + PL), and exercise + beetroot (EX + BR). Thirty-six postmenopausal women are recruited in small cohorts wherein group exercise is implemented to facilitate social support and adherence to an 8-week training progression. Participants are randomized to one of three study arms (n = 12 per group) following baseline assessments. Post-intervention assessments are used to determine pre-post changes in outcome measures including distance covered during a 6 min walk test, walking economy, muscle speed and power, and endothelial-dependent vasodilation as determined by flow-mediated dilation. Measures of feasibility include recruitment, retention, adherence to exercise prescription, perceived exercise session difficulty, and adverse event rates. Discussion Evidence-based, translational strategies are needed to optimize exercise training-related adaptations in postmenopausal women. Findings will inform larger randomized clinical trials to determine if pre-exercise consumption of beetroot juice is an efficacious strategy to promote mobility and attenuate CVD disease risk.
- Published
- 2021
37. Staging laparoscopy for assessing inoperability in gastrointestinal malignancies: Is it useful?
- Author
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Samir K Gupta, Shrirang Vasant Kulkarni, Manish K Sondhi, and Alok J Bhalla
- Subjects
Curative resection ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Aortocaval lymph node ,General Medicine ,Malignancy ,medicine.disease ,Tertiary care ,Predictive value ,Laparotomy ,medicine ,Statistical analysis ,Staging laparoscopy ,Radiology ,business - Abstract
Background: Despite the availability of modern cross-sectional diagnostic staging modalities, preoperative assessment of operability in intra-abdominal malignancy is often inadequate, especially in patients being considered for potential curative resection, resulting in many unnecessary laparotomies. Staging laparoscopy (SL) is usually undertaken in tertiary care centers, but the same has not been widely studied in India. The aim of the present study was to find out the possibility of diagnosing inoperability on SL and to study whether SL can prevent unnecessary laparotomy in cases of clinically diagnosed potentially resectable abdominal malignancies. Methods: This prospective diagnostics study was conducted in consecutive patients with gastrointestinal malignancies. All eligible patients were subjected to a thorough SL to look for inoperability before a therapeutic laparotomy. Statistical analysis of SL as a diagnostic modality was performed and the results were noted. Results: A total of 88 such patients were studied. The SL demonstrated inoperability in 24 out of the 88 (27.3%) patients. However, it failed to predict inoperability in 11 (12.5%) patients, yielding a sensitivity of 68.57% and specificity of 100%. The positive predictive value (PPV) of SL was 100%, whereas the negative predictive value (NPV) was 82.81% with efficacy of 87.5%. Conclusions: The specificity, PPV, NPV, and accuracy of SL to rule out inoperability in clinically diagnosed potentially resectable intra-abdominal gastrointestinal malignancies are noteworthy. The sensitivity of SL for the same purpose, though relatively low, may be augmented with practices such as liberal use of frozen section biopsy and intraoperative ultrasound. However, SL still fails to demonstrate unresectability due to locoregional advancement and aortocaval lymph node mets.
- Published
- 2021
38. A pilot trial of pentoxifylline on endothelial function and inflammation in HIV-infected patients initiating antiretroviral therapy
- Author
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James H. Stein, Matthias Clauss, Ziyue Liu, Michael P. Dubé, and Samir K. Gupta
- Subjects
Adult ,Male ,Vasculitis ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Vasodilator Agents ,Immunology ,HIV Infections ,Pilot Projects ,Inflammation ,Vasodilation ,Article ,Pentoxifylline ,03 medical and health sciences ,0302 clinical medicine ,Antiretroviral Therapy, Highly Active ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Hiv infected patients ,030212 general & internal medicine ,business.industry ,Pilot trial ,medicine.disease ,Antiretroviral therapy ,030104 developmental biology ,Infectious Diseases ,Vasodilator agents ,Physical therapy ,Female ,Endothelium, Vascular ,medicine.symptom ,business ,Biomarkers ,medicine.drug - Published
- 2016
39. Endothelial Colony-Forming Cell Function Is Reduced During HIV Infection
- Author
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Ziyue Liu, Mervin C. Yoder, Laura S. Haneline, Samir K. Gupta, Emily Sims, and Matthew J. Repass
- Subjects
0301 basic medicine ,Cyclopropanes ,Male ,Lipopolysaccharide Receptors ,Monocytes ,Plasma ,0302 clinical medicine ,HIV Seropositivity ,Immunology and Allergy ,030212 general & internal medicine ,Prospective Studies ,Endothelial dysfunction ,Chemokine CCL5 ,medicine.diagnostic_test ,Stem Cells ,Middle Aged ,Fetal Blood ,Flow Cytometry ,Infectious Diseases ,medicine.anatomical_structure ,Cord blood ,Alkynes ,Female ,medicine.symptom ,Adult ,Endothelium ,Anti-HIV Agents ,CD14 ,Neovascularization, Physiologic ,Vascular Cell Adhesion Molecule-1 ,Inflammation ,CD16 ,GPI-Linked Proteins ,Flow cytometry ,03 medical and health sciences ,Major Articles and Brief Reports ,HIV Seronegativity ,medicine ,Humans ,Cell Proliferation ,Vascular Endothelial Growth Factor Receptor-1 ,business.industry ,Monocyte ,Receptors, IgG ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,Benzoxazines ,030104 developmental biology ,Immunology ,business - Abstract
BACKGROUND: Human immunodeficiency virus (HIV) may be related to cardiovascular disease through monocyte activation–associated endothelial dysfunction. METHODS: Blood samples from 15 HIV-negative participants (the uninfected group), 8 HIV-positive participants who were not receiving antiretroviral therapy (ART) (the infected, untreated group), and 15 HIV-positive participants who were receiving ART (the infected, treated group) underwent flow cytometry of endothelial colony-forming cells (ECFCs) and monocyte proportions. IncuCyte live cell imaging of 8 capillary proliferative capacity parameters were obtained from cord blood ECFCs treated with participant plasma. RESULTS: The ECFC percentage determined by flow cytometry was not different between the study groups; however, values of the majority of capillary proliferative capacity parameters (ie, cell area, network length, network branch points, number of networks, and average tube width uniformity) were significantly lower in infected, untreated participants as compared to values for uninfected participants or infected, treated participants (P < .00625 for all comparisons). CD14(+)CD16(+) intermediate monocytes and soluble CD163 were significantly and negatively correlated with several plasma-treated, cord blood ECFC proliferative capacity parameters in the combined HIV-positive groups but not in the uninfected group. CONCLUSIONS: Cord blood ECFC proliferative capacity was significantly impaired by plasma from infected, untreated patients, compared with plasma from uninfected participants and from infected, treated participants. Several ECFC functional parameters were adversely associated with monocyte activation in the HIV-positive groups, thereby suggesting a mechanism by which HIV-related inflammation may impair vascular reparative potential and consequently increase the risk of cardiovascular disease during HIV infection.
- Published
- 2018
40. Long-term kidney function, proteinuria, and associated risks among HIV-infected and uninfected men
- Author
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Joseph B. Margolick, Xiuhong Li, Frank J. Palella, Lawrence A. Kingsley, Michelle M. Estrella, John P. Phair, Lisa P. Jacobson, Roger Detels, and Samir K. Gupta
- Subjects
0301 basic medicine ,Male ,Kidney Disease ,HIV Infections ,Cardiovascular ,Medical and Health Sciences ,0302 clinical medicine ,Risk Factors ,Antiretroviral Therapy, Highly Active ,Prevalence ,Immunology and Allergy ,030212 general & internal medicine ,Longitudinal Studies ,Prospective Studies ,Didanosine ,Proteinuria ,virus diseases ,Hepatitis C ,Biological Sciences ,Middle Aged ,longitudinal glomerular filtration rate ,Infectious Diseases ,Anti-Retroviral Agents ,6.1 Pharmaceuticals ,HIV/AIDS ,HIV serostatus differences ,medicine.symptom ,Infection ,medicine.drug ,Glomerular Filtration Rate ,Adult ,medicine.medical_specialty ,Immunology ,Renal and urogenital ,Antiretroviral Therapy ,Emtricitabine ,Article ,03 medical and health sciences ,Young Adult ,Clinical Research ,Internal medicine ,Virology ,medicine ,Humans ,Highly Active ,Aged ,business.industry ,Psychology and Cognitive Sciences ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,030112 virology ,Atazanavir ,Nelfinavir ,Good Health and Well Being ,Ritonavir ,business ,Saquinavir ,risks - Abstract
BackgroundFactors affecting kidney function and proteinuria among HIV-positive (HIV+) and HIV-negative (HIV-) persons need better characterization.MethodsWe evaluated estimated glomerular filtration rate (eGFR, ml/min per 1.73 m) changes, proteinuria prevalence (a urine protein-to-creatinine ratio of ≥0.2 at two consecutive visits) and associated factors among HIV+ and HIV- men.ResultsThere were 917 HIV+ men receiving HAART, 159 HIV+ men not receiving HAART, and 1305 HIV- men seen from October 2003 to September 2014. Median annual eGFR change was -0.5, -0.8% for HIV+ and -0.3% for HIV- men (P
- Published
- 2018
41. Abstract 111: Depression as a Risk Factor for Incident Ischemic Stroke Among HIV-infected Veterans
- Author
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Suman Kundu, Joyce Chang, Kaku So-Armah, Jason J. Sico, Jesse C. Stewart, Samir K. Gupta, and Matthew S. Freiberg
- Subjects
medicine.medical_specialty ,business.industry ,Human immunodeficiency virus (HIV) ,virus diseases ,medicine.disease_cause ,medicine.disease ,behavioral disciplines and activities ,Increased risk ,Hiv infected ,Internal medicine ,Ischemic stroke ,medicine ,Major depressive disorder ,Risk factor ,Cardiology and Cardiovascular Medicine ,business ,Stroke ,Depression (differential diagnoses) - Abstract
Background: HIV infection (HIV+) and major depressive disorder (MDD) are each associated with an increased risk of ischemic stroke. While depressive disorders are common among HIV+ people, it is not known if MDD is a risk factor for ischemic stroke in the HIV population. Methods and Results: We analyzed data on 106,363 (33,544 HIV+; 72,819 HIV-) participants who were free of baseline cardiovascular disease from the Veterans Aging Cohort Study, an observational cohort of HIV+ and matched uninfected veterans in care from April 1 st , 2003 through September 30, 2012. International Classification of Diseases, Ninth Revision codes from medical records were used to determine baseline MDD and the primary outcome, incident ischemic stroke. The prevalence of MDD was similar for HIV+ and HIV- veterans (20.0% and 18.8%, respectively). After a median of 9.2 years of follow-up, stroke rates per 1000 person-years were highest among HIV+/MDD+ veterans (5.8; 95% CI:5.2-6.5), followed by HIV+/MDD- veterans (5.3; 95% CI:5.0-5.6), HIV-/MDD+ (5.1; 95% CI: 4.7-5.5), and HIV-/MDD- (4.8; 95% CI: 4.6-5.0). In Cox proportional hazard models, MDD was associated with an increased risk of ischemic stroke for both HIV+ and HIV- veterans, even after adjusting for sociodemographic adjusting for sociodemographic characteristics and cerebrovascular risk factors (Table). The risk persisted among HIV+ people after further adjusting for HIV factors (Table). These associations were modestly attenuated with the addition of cocaine and alcohol abuse/dependence. Conclusions: In the VACS, MDD was associated with an increased risk of ischemic stroke in HIV+ veterans after adjustment for sociodemographic characteristics, traditional cerebrovascular risk factors, and HIV factors; however, this association was modestly attenuated after adjustment for cocaine and alcohol abuse/dependence. Future research is necessary to: (a) fully elucidate the relationships among MDD, cocaine/alcohol use, and stroke risk and (b) determine whether intervening on MDD reduces stroke risk in HIV+ and HIV- people. Clinical providers should be aware of the increased stroke risk among HIV+ adults with MDD.
- Published
- 2018
42. Immune reconstitution in ART treated, but not untreated HIV infection, is associated with abnormal beta cell function
- Author
-
Grace Park, Emily K. Sims, Samir K. Gupta, Kieren J. Mather, Ziyue Liu, and Raghavendra G. Mirmira
- Subjects
Male ,HIV Infections ,Pathology and Laboratory Medicine ,Biochemistry ,Body Mass Index ,Endocrinology ,0302 clinical medicine ,Immunodeficiency Viruses ,Homeostasis ,Insulin ,Medicine ,Glucose homeostasis ,lcsh:Science ,education.field_of_study ,DNA methylation ,C-Peptide ,Organic Compounds ,Chemical Reactions ,Fasting ,Chromatin ,3. Good health ,Nucleic acids ,Medical Microbiology ,Viral Pathogens ,Physical Sciences ,Infectious diseases ,Epigenetics ,Chromatin modification ,Chromosome biology ,Proinsulin ,medicine.medical_specialty ,Preproinsulin ,Endocrine Disorders ,Carbohydrates ,Microbiology ,Methylation ,03 medical and health sciences ,Diabetes Mellitus ,Genetics ,Humans ,Protein Precursors ,education ,Microbial Pathogens ,lcsh:R ,Organisms ,Chemical Compounds ,Biology and Life Sciences ,DNA ,medicine.disease ,Hormones ,Glucose ,Case-Control Studies ,lcsh:Q ,Gene expression ,Physiological Processes ,Biomarkers ,RNA viruses ,Blood Glucose ,Physiology ,lcsh:Medicine ,Immune Reconstitution ,Antiretroviral Therapy, Highly Active ,Insulin-Secreting Cells ,Medicine and Health Sciences ,030212 general & internal medicine ,Multidisciplinary ,Monosaccharides ,Smoking ,Age Factors ,Middle Aged ,Chemistry ,Viruses ,Toxicity ,Female ,Pathogens ,Beta cell ,DNA modification ,Cell-Free Nucleic Acids ,Research Article ,Adult ,Cell biology ,Diabetes risk ,Anti-HIV Agents ,Population ,030209 endocrinology & metabolism ,Viral diseases ,Sex Factors ,Insulin resistance ,Internal medicine ,Retroviruses ,Diabetic Endocrinology ,business.industry ,Lentivirus ,Organic Chemistry ,HIV ,CD4 Lymphocyte Count ,Metabolic Disorders ,Insulin Resistance ,business - Abstract
HIV infection has been associated with increased diabetes risk, but prior work has mostly focused on insulin resistance, as opposed to beta cell effects, or included patients on antiretroviral therapies (ART) directly linked to metabolic toxicity. In this analysis, we measured markers of glucose homeostasis and beta cell function, stress, and death in fasting sera from a cross section of HIV+ individuals off ART (n = 43), HIV+ individuals on ART (n = 23), and HIV- controls (n = 39). Markers included glucose, HOMA%S, HOMA%B, proinsulin:C-peptide ratio (PI:C ratio), and circulating preproinsulin (INS) DNA. We performed multiple linear regressions with adjustments for age, sex, race, BMI, and smoking status. Compared to HIV- controls, HIV+ participants off ART exhibited similar beta cell function and insulin sensitivity, without increases in markers of beta cell stress or death. Specifically, in HIV+ participants with CD4 counts
- Published
- 2018
43. Blockage of CD59 Function Restores Activities of Neutralizing and Nonneutralizing Antibodies in Triggering Antibody-Dependent Complement-Mediated Lysis of HIV-1 Virions and Provirus-Activated Latently Infected Cells
- Author
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Nicole Shepherd, Corlin Jewell, Ningjie Hu, Kai Yang, Daniel Byrd, Jimin Gao, Samir K. Gupta, Yanyan Xing, Jie Lan, Carole Kounga, Qigui Yu, and Tohti Amet
- Subjects
Male ,Immunology ,CD59 Antigens ,HIV Infections ,CD59 ,HIV Antibodies ,Biology ,Microbiology ,Immune system ,Proviruses ,Immunity ,Virology ,Virus latency ,medicine ,Humans ,Antibody-Dependent Cell Cytotoxicity ,Virion ,Complement System Proteins ,Provirus ,medicine.disease ,Antibodies, Neutralizing ,Virus Latency ,Complement system ,Insect Science ,HIV-1 ,biology.protein ,Pathogenesis and Immunity ,Female ,Antibody ,Complement membrane attack complex - Abstract
Both HIV-1 virions and infected cells use their surface regulators of complement activation (RCA) to resist antibody-dependent complement-mediated lysis (ADCML). Blockage of the biological function of RCA members, particularly CD59 (a key RCA member that controls formation of the membrane attack complex at the terminal stage of the complement activation cascades via all three activation pathways), has rendered both HIV-1 virions and infected cells sensitive to ADCML mediated by anti-Env antibodies (Abs) or sera/plasma from patients at different stages of viral infection. In the current study, we used the well-characterized anti-HIV-1 neutralizing Abs (nAbs), including 2G12, 2F5, and 4E10, and non-nAbs, including 2.2C, A32, N5-i5, and N12-i15, to investigate whether the enhancement of ADCML by blockage of CD59 function is mediated by nAbs, non-nAbs, or both. We found that all nAbs and two non-nAbs (N5-i5 and A32) strongly reacted to three HIV-1 laboratory strains (R5, X4, and R5/X4), six primary isolates, and provirus-activated ACH-2 cells examined. In contrast, two non-nAbs, 2.2C and N12-i15, reacted weakly and did not react to these targets, respectively. After blockage of CD59 function, the reactive Abs, regardless of their neutralizing activities, significantly enhanced specific ADCML of HIV-1 virions (both laboratory strains and primary isolates) and provirus-activated latently infected cells. The ADMCL efficacy positively correlated with the enzyme-linked immunosorbent assay-reactive intensity of those Abs with their targets. Thus, blockage of RCA function represents a novel approach to restore activities of both nAbs and non-nAbs in triggering ADCML of HIV-1 virions and provirus-activated latently infected cells. IMPORTANCE There is a renewed interest in the potential role of non-nAbs in the control of HIV-1 infection. Our data, for the first time, demonstrated that blockage of the biological function of RCA members rendered both HIV-1 virions and infected cells sensitive to ADCML mediated by not only nAbs but also non-nAbs. Our results are significant in developing novel immune-based approaches to restore the functions of nAbs and non-nAbs in the circulation of HIV-1-infected individuals to specifically target and clear HIV-1 virions and infected cells. Our data also provide new insights into the mechanisms by which HIV-1 virions and infected cells escape Ab-mediated immunity and could aid in the design and/or development of therapeutic HIV-1 vaccines. In addition, a combination of antiretroviral therapy with RCA blockage, provirus activators, and therapeutic vaccines may represent a novel approach to eliminate HIV-1 reservoirs, i.e., the infected cells harboring replication-competent proviruses and residual viremia.
- Published
- 2015
44. A randomized, controlled trial of the effect of rilpivirine versus efavirenz on cardiovascular risk in healthy volunteers
- Author
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Ziyue Liu, Samir K. Gupta, Lisa M. Kamendulis, and James E. Slaven
- Subjects
Cyclopropanes ,Microbiology (medical) ,medicine.medical_specialty ,Time Factors ,Efavirenz ,Anti-HIV Agents ,Pharmacology ,Cardiovascular System ,Gastroenterology ,law.invention ,chemistry.chemical_compound ,Pre-exposure prophylaxis ,Insulin resistance ,Randomized controlled trial ,law ,Internal medicine ,Humans ,Medicine ,Pharmacology (medical) ,Adverse effect ,Original Research ,F2-Isoprostanes ,biology ,business.industry ,Rilpivirine ,C-reactive protein ,virus diseases ,Bilirubin ,medicine.disease ,Cardiotoxicity ,Healthy Volunteers ,Benzoxazines ,Clinical trial ,Oxidative Stress ,Infectious Diseases ,chemistry ,Cardiovascular Diseases ,Alkynes ,biology.protein ,business ,Biomarkers - Abstract
OBJECTIVES The HIV NNRTI rilpivirine is being evaluated as a possible agent for HIV pre-exposure prophylaxis. We have recently shown that the NNRTI efavirenz may impair endothelial function assessed as flow-mediated dilation (FMD), but whether this impairment is also found with rilpivirine is unknown. We sought to compare cardiovascular risk profiles between efavirenz and rilpivirine in healthy volunteers. METHODS We performed a prospective, randomized, open-label trial in 40 HIV-uninfected healthy volunteers who were randomized 1: 1 to either efavirenz or rilpivirine. Vascular indices, metabolic parameters, inflammatory biomarkers and oxidative stress were measured before and after 4 weeks of treatment. This study is registered at ClinicalTrials.gov (NCT01585038). RESULTS There were no significant differences in 4 week mean (SD) changes in FMD between efavirenz and rilpivirine [0.089 (3.65)% versus 0.63 (2.42)%; P = 0.77]. There were also no significant differences in 4 week changes in high-sensitivity C-reactive protein, IL-6, soluble vascular cell adhesion molecule-1, HDL-cholesterol, triglycerides or homeostasis model assessment-insulin resistance. However, efavirenz led to significant increases in total cholesterol [19.39 (23.9) versus -5.78 (16.5) mg/dL; P < 0.001], LDL-cholesterol [13.29 (19.5) versus -2.24 (13.4) mg/dL; P = 0.009] and F2-isoprostanes [92.7 (178.6) versus -101.4 (215.7) pg/mL; P = 0.019] compared with rilpivirine. Two participants from each study group discontinued prematurely for adverse events. CONCLUSIONS There were no significant differences in the changes in endothelial function over 1 month between the efavirenz and rilpivirine groups, although efavirenz had worse lipid changes compared with rilpivirine. Longer-term studies are required for confirmation.
- Published
- 2015
45. Markers of renal disease and function are associated with systemic inflammation in HIV infection
- Author
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Belinda Ha, Douglas Kitch, Grace A. McComsey, Kathleen Melbourne, Camlin Tierney, and Samir K. Gupta
- Subjects
medicine.medical_specialty ,Creatinine ,Proteinuria ,business.industry ,Health Policy ,Renal function ,Inflammation ,urologic and male genital diseases ,Systemic inflammation ,medicine.disease ,Gastroenterology ,Nephropathy ,chemistry.chemical_compound ,Infectious Diseases ,chemistry ,Internal medicine ,Immunology ,Albuminuria ,medicine ,Pharmacology (medical) ,medicine.symptom ,business ,Kidney disease - Abstract
Objectives Both renal disease and systemic inflammation predict non-AIDS-defining events and overall mortality in HIV-infected patients. Here, we sought to determine the relationships between renal disease and circulating inflammation markers. Methods We performed a secondary analysis of AIDS Clinical Trials Group Study A5224s to determine if markers of renal disease [urine protein:creatinine ratio (uPCR), urine albumin:creatinine ratio (uACR), and estimated glomerular filtration rate (eGFR), using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine and cystatin C-creatinine] were associated with markers of systemic inflammation [high-sensitivity C-reactive protein, interleukin-6, tumour necrosis factor (TNF)-α, soluble TNF-α receptor I (sTNFRI), sTNFRII, and soluble vascular cellular and intercellular adhesion molecules]. We correlated these renal and inflammatory markers prior to antiretroviral initiation and after 96 weeks of therapy. Results We found that eGFR (estimated using CKD-EPI cystatin C-creatinine), uPCR, and uACR were significantly correlated with most assessed markers of systemic inflammation prior to antiretroviral initiation. uPCR and eGFR (using CKD-EPI cystatin C-creatinine), but not uACR, remained significantly correlated with most of the assessed inflammatory markers after 96 weeks of antiretroviral therapy (ART). Most of these correlations, although statistically significant, were
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- 2015
46. Brief Report
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Ziyue Liu, Jamie Case, David A. Ingram, Samir K. Gupta, Travis R. Hays, and Julie A. Mund
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Adult ,Male ,CD14 ,Human immunodeficiency virus (HIV) ,Flow mediated dilation ,Cell Count ,HIV Infections ,CD16 ,Biology ,medicine.disease_cause ,Endothelial progenitor cell ,Monocytes ,Article ,Young Adult ,medicine ,Humans ,Pharmacology (medical) ,Prospective Studies ,Endothelial Progenitor Cells ,Monocyte ,virus diseases ,Middle Aged ,Antiretroviral therapy ,Cross-Sectional Studies ,Infectious Diseases ,medicine.anatomical_structure ,Immunology ,Female - Abstract
The relationships between HIV infection, monocyte activation, and endothelial colony forming cells (ECFCs) are unknown. We compared ECFC, intermediate monocytes (CD14+CD16+), and non-classical monocytes (CD14dimCD16++) levels in HIV-infected participants virologically-suppressed on antiretroviral therapy, HIV-infected treatment-naïve participants, and HIV-uninfected healthy controls. ECFC levels were significantly higher in the HIV-infected, virologically-suppressed group compared to the uninfected controls. CD14+CD16+ percentages (but not CD14dimCD16++ cells) were significantly higher in both HIV-infected groups vs uninfected controls. In the HIV-infected groups, ECFCs and CD14+CD16+ intermediate monocytes were significantly and inversely correlated. Lower availability of ECFCs may partly explain the relationship between greater intermediate monocytes and atherosclerosis in HIV.
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- 2015
47. A two-week regimen of high-dose integrase inhibitors does not cause nephrotoxicity in mice
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Hongji Zhang, Takashi Hato, Zeruesenay Desta, Todd C. Skaar, Samir K. Gupta, Michael T. Eadon, and Pierre C. Dagher
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Pyridones ,Short Communications ,Administration, Oral ,Renal function ,Integrase inhibitor ,HIV Integrase ,Biology ,Pharmacology ,Kidney ,Piperazines ,Nephrotoxicity ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Raltegravir Potassium ,Oxazines ,medicine ,Animals ,HIV Integrase Inhibitors ,Creatinine ,Dose-Response Relationship, Drug ,Molecular Structure ,Macrophages ,General Medicine ,Raltegravir ,Integrase ,Mice, Inbred C57BL ,Regimen ,chemistry ,Dolutegravir ,biology.protein ,Heterocyclic Compounds, 3-Ring ,medicine.drug - Abstract
BackgroundThe integrase inhibitors, raltegravir and dolutegravir, are nucleoside reverse transcriptase inhibitor-sparing agents which may be used as part of first-line antiretroviral therapy for HIV. These drugs inhibit creatinine secretion through organic cation transporters, thus elevating serum creatinine without affecting glomerular filtration. We sought to determine whether subtle signs of nephrotoxicity could be observed in mice administered a two-week regimen of high-dose integrase inhibitors.MethodsC57BL/6 mice were fed standard water (CTRL, n = 6), raltegravir-containing water (40 mg/kg/day, n = 6), or dolutegravir-containing water (2.7 mg/kg/day, n = 6) for two weeks and sacrificed. Endpoints were assessed including urine microalbumin, kidney injury molecule-1 renal tissue gene expression, renal histopathology, serum creatinine, and blood urea nitrogen.ResultsThe results are NOT consistent with a direct nephrotoxic effect of the integrase inhibitors in mice. Serum creatinine was significantly elevated in raltegravir and dolutegravir mice (p ConclusionThese studies are consistent with integrase inhibitors competitively inhibiting creatinine secretion. While no evidence of direct nephrotoxicity was observed after two weeks of high-dose drug administration, additional studies may be performed to understand whether these drugs lead to chronic nephropathy.
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- 2015
48. Substantial Effect of Efavirenz Monotherapy on Bilirubin Levels in Healthy Volunteers
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Troy C. Quigg, Anne T. Nguyen, Samir K. Gupta, David A. Flockhart, John T. Callaghan, Colleen K. Stevens, Ingrid F. Metzger, Zeruesenay Desta, Abdulateef O. Aregbe, Nancy Thong, and Noam Epstein
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Drug ,Efavirenz ,Bilirubin ,Anemia ,media_common.quotation_subject ,Pharmacology ,chemistry.chemical_compound ,Pharmacokinetics ,bilirubin disposition ,medicine ,neutropenia ,Pharmacology (medical) ,media_common ,Original Research ,business.industry ,lcsh:RM1-950 ,virus diseases ,efavirenz ,drug interactions ,medicine.disease ,anemia ,3. Good health ,Atazanavir ,lcsh:Therapeutics. Pharmacology ,chemistry ,monotherapy ,Hemoglobin ,business ,medicine.drug ,Blood sampling - Abstract
Background: Efavirenz exhibits multiple interactions with drug-metabolizing enzymes and transporters, and for this reason efavirenz-based HIV therapy is associated with altered pharmacokinetics of coadministered drugs. Probably by the same mechanism, efavirenz-based HIV therapy affects the disposition of endogenous compounds, but this effect is difficult to directly link with efavirenz because it is used in combination with other drugs. Objectives: To explore the effect of efavirenz monotherapy on biochemical laboratory values in a clinical trial of healthy volunteers. Methods: Men and women (aged 18–49 years) with body mass index r32 who were assessed to be healthy based on medical history, physical examination, and standard laboratory screening received a single (600 mg) and multiple doses (600 mg/d for 17 days) of efavirenz orally. This trial was designed to determine the pharmacokinetics and drug interactions of efavirenz. As part of this study, analysis of serum chemistries that were measured at study entry (screening) and 1 week after completion of the multiple dose study (exit) is reported. Results: Data from 60 subjects who fully completed and 13 subjects who partially completed the study are presented. Total bilirubin was substantially reduced at exit (by � 30%, with large intersubject variability) compared with screening values (P o 0.0001). The percent changes were in part explained by the intersubject differences in baseline total bilirubin because there was a significant correlation between baseline (screening) values and percent change at exit (r ¼ 0.50; P o 0.0001). Hemoglobin and absolute neutropenia were also substantially decreased at exit compared with screening, but this may be due to intensive blood sampling rather than direct effect of efavirenz on these parameters. No significant correlation was found between percent change in hemoglobin versus percent change in bilirubin, indicating the effect of efavirenz on bilirubin is independent of its effects on hemoglobin. Conclusions: Efavirenz monotherapy significantly lowers plasma total bilirubin concentration in healthy volunteers independent of its effect on hemoglobin, probably through its effects on bilirubin metabolism and transport (uptake and efflux). These findings help explain reversal by efavirenz of hyperbilirubinemia induction observed by some protease inhibitor antiretroviral drugs (eg, atazanavir). Besides its welldocumented role on drug interactions, efavirenz may alter the disposition of endogenous compounds relevant in physiologic homeostasis through its interaction with drug metabolizing enzymes and/or drug transporters. ClinicalTrials.gov identifier: NCT00668395. & 2014. The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
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- 2014
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49. BCL6 represses antiviral resistance in follicular T helper cells
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Luis J. Montaner, Young Min Son, Samir K. Gupta, Tohti Amet, In Su Cheon, Li Jiang, Jie Sun, Alexander L. Dent, Su Huang, and Qigui Yu
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0301 basic medicine ,Chromatin Immunoprecipitation ,Immunology ,Blotting, Western ,HIV Infections ,GTPase ,Real-Time Polymerase Chain Reaction ,Cell Line ,03 medical and health sciences ,Mice ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Follicular phase ,Immunology and Allergy ,Animals ,Humans ,Gene ,Disease Resistance ,biology ,Cell growth ,Cell Biology ,T-Lymphocytes, Helper-Inducer ,BCL6 ,Host Defense & Pathophysiology ,Flow Cytometry ,Transmembrane protein ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,biology.protein ,HIV-1 ,Proto-Oncogene Proteins c-bcl-6 ,Antibody ,Function (biology) ,030215 immunology - Abstract
Follicular Th (Tfh) cells are a distinct subset of Th cells that help B cells produce class-switched antibodies. Studies have demonstrated that Tfh cells are highly prone to HIV infection and replication. However, the molecular mechanisms underlying this phenomenon are largely unclear. Here, we show that murine and human Tfh cells have diminished constitutive expression of IFN-stimulated genes (ISGs) inclusive of antiviral resistance factor MX dynamin-like GTPase 2 (MX2) and IFN-induced transmembrane 3 (IFITM3) compared with non-Tfh cells. A lower antiviral resistance in Tfh was consistent with a higher susceptibility to retroviral infections. Mechanistically, we found that BCL6, a master regulator of Tfh cell development, binds to ISG loci and inhibits the expression of MX2 and IFITM3 in Tfh cells. We demonstrate further that inhibition of the BCL6 BR-C, ttk, and bab (BTB) domain function increases the expression of ISGs and suppresses HIV infection and replication in Tfh cells. Our data reveal a regulatory role of BCL6 in inhibiting antiviral resistance factors in Tfh cells, thereby promoting the susceptibility Tfh cells to viral infections. Our results indicate that the modulation of BCL6 function in Tfh cells could be a potential strategy to enhance Tfh cell resistance to retroviral infections and potentially decrease cellular reservoirs of HIV infection.
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- 2017
50. MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders
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Sushmita Rane, Samir K. Gupta, Yanyan Xing, Shanxiang Zhang, Wei Li, Jie Lan, Nicole Shepherd, Jun Dong, and Qigui Yu
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0301 basic medicine ,Adult ,Male ,Chemokine ,AIDS Dementia Complex ,Immunology ,Neurocognitive Disorders ,Endogeny ,Matrix metalloproteinase ,Blood–brain barrier ,Article ,Proinflammatory cytokine ,Pathogenesis ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,Cerebrospinal fluid ,medicine ,Humans ,Tissue Inhibitor of Metalloproteinase-2 ,Tissue Inhibitor of Metalloproteinase-1 ,biology ,Endocrine and Autonomic Systems ,business.industry ,Monocyte ,Tissue Inhibitor of Metalloproteinases ,Middle Aged ,Matrix Metalloproteinases ,030104 developmental biology ,medicine.anatomical_structure ,Matrix Metalloproteinase 9 ,Blood-Brain Barrier ,biology.protein ,HIV-1 ,Matrix Metalloproteinase 2 ,Female ,business ,030217 neurology & neurosurgery - Abstract
HIV-1-associated neurocognitive disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of combined antiretroviral therapy (cART). Growing evidence suggests that an imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs) contributes to the pathogenesis of HAND. In our present study, we examined protein levels and enzymatic activities of MMPs and TIMPs in both plasma and cerebrospinal fluid (CSF) samples from HIV-1 patients with or without HAND and HIV-1-negative controls. Imbalances between MMPs and TIMPs with distinct patterns were revealed in both the peripheral blood and CSF of HIV-1 patients, especially those with HAND. In the peripheral blood, the protein levels of MMP-2, MMP-9, TIMP-1, TIMP-2, and the enzymatic activities of MMP-2 and MMP-9 were increased in HIV-1 patients with or without HAND when compared with HIV-1-negative controls. The enzymatic activity of MMP-2, but not MMP-9, was further increased in plasma samples of HAND patients than that of HIV-1 patients without HAND. Notably, the ratio of MMP-2/TIMP-2 in plasma was significantly increased in HAND patients, not in patients without HAND. In the CSF, MMP-2 activity was increased, but the ratio of MMP-2/TIMP-2 was not altered. De novo induction and activation of MMP-9 in the CSF of HAND patients was particularly prominent. The imbalances between MMPs and TIMPs in the blood and CSF were related to the altered profiles of inflammatory cytokines/chemokines and monocyte activation in these individuals. In addition, plasma from HIV-1 patients directly induced integrity disruption of an in vitro blood-brain barrier (BBB) model, leading to increased BBB permeability and robust transmigration of monocytes/-macrophages. These results indicate that imbalances between MMPs and TIMPs are involved in BBB disruption and are implicated in the pathogenesis of neurological disorders such as HAND in HIV-1 patients.
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- 2017
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