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Article ; Online: Meta-analysis in clinical trials revisited.

DerSimonian, Rebecca / Laird, Nan

2015 Volume 45, Issue Pt A, Page(s) 139–145

Abstract: ... been widely used (with more than 12,000 citations to date) and the "DerSimonian and Laird method" is ...

Abstract	In this paper, we revisit a 1986 article we published in this Journal, Meta-Analysis in Clinical Trials, where we introduced a random-effects model to summarize the evidence about treatment efficacy from a number of related clinical trials. Because of its simplicity and ease of implementation, our approach has been widely used (with more than 12,000 citations to date) and the "DerSimonian and Laird method" is now often referred to as the 'standard approach' or a 'popular' method for meta-analysis in medical and clinical research. The method is especially useful for providing an overall effect estimate and for characterizing the heterogeneity of effects across a series of studies. Here, we review the background that led to the original 1986 article, briefly describe the random-effects approach for meta-analysis, explore its use in various settings and trends over time and recommend a refinement to the method using a robust variance estimator for testing overall effect. We conclude with a discussion of repurposing the method for Big Data meta-analysis and Genome Wide Association Studies for studying the importance of genetic variants in complex diseases.
MeSH term(s)	Clinical Trials as Topic/methods ; Genome-Wide Association Study/methods ; Humans ; Meta-Analysis as Topic ; Models, Statistical ; Research Design
Language	English
Publishing date	2015-09-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2182176-8
ISSN	1559-2030 ; 1551-7144
ISSN (online)	1559-2030
ISSN	1551-7144
DOI	10.1016/j.cct.2015.09.002
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Article: Random-effects model for meta-analysis of clinical trials: an update.

DerSimonian, Rebecca / Kacker, Raghu

Contemporary clinical trials

2007 Volume 28, Issue 2, Page(s) 105–114

Abstract: The random-effects model is often used for meta-analysis of clinical studies. The method explicitly accounts for the heterogeneity of studies through a statistical parameter representing the inter-study variation. We discuss several iterative and non- ... ...

Abstract	The random-effects model is often used for meta-analysis of clinical studies. The method explicitly accounts for the heterogeneity of studies through a statistical parameter representing the inter-study variation. We discuss several iterative and non-iterative alternative methods for estimating the inter-study variance and hence the overall population treatment effect. We show that the leading methods for estimating the inter-study variance are special cases of a general method-of-moments estimate of the inter-study variance. The general method suggests two new two-step methods. The iterative estimate is statistically optimal and it can be easily calculated on a spreadsheet program, such as Microsoft Excel, available on the desktop of most researchers. The two-step methods approximate the optimal iterative method better than the earlier one-step non-iterative methods.
MeSH term(s)	Algorithms ; Analysis of Variance ; Clinical Trials as Topic ; Computer Simulation ; Humans ; Meta-Analysis as Topic ; Models, Statistical ; Research Design
Language	English
Publishing date	2007-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2182176-8
ISSN	1559-2030 ; 1551-7144
ISSN (online)	1559-2030
ISSN	1551-7144
DOI	10.1016/j.cct.2006.04.004
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Article: Country of residence is associated with distinct inflammatory biomarker signatures in HIV-infected patients.

Manion, Maura / Andrade, Bruno B / DerSimonian, Rebecca / Gu, Wenjuan / Rupert, Adam / Musselwhite, Laura W / Sierra-Madero, Juan G / Belaunzaran-Zamudio, Pablo F / Sanne, Ian / Lederman, Michael M / Sereti, Irini

Journal of virus eradication

2017 Volume 3, Issue 1, Page(s) 24–33

Abstract: Background: Inflammation and coagulation biomarkers are independent predictors of morbidity and mortality in HIV-infected patients. The impact of country of residence on these biomarkers is unknown and was investigated in persons at similar stages of ... ...

Abstract	Background: Inflammation and coagulation biomarkers are independent predictors of morbidity and mortality in HIV-infected patients. The impact of country of residence on these biomarkers is unknown and was investigated in persons at similar stages of HIV infection. Methods: Cryopreserved plasma specimens were analysed from 267 ART-naive patients with CD4 cell counts <100 cells/μl from Mexico ( Results: Mexican patients were significantly different from South Africans with regard to age, gender, CD4 cell count, haemoglobin, presence of AIDS-defining illness and prevalence of active tuberculosis. After adjusting for baseline characteristics, patients from Mexico had higher levels of IFN-γ, IL-8, and CXCL-10 whereas patients from South Africa had higher levels of fibrinogen, LTB4, P-selectin, protein S, and sCD40 ligand. The effect of country on the profile of biomarker expression was stronger than gender differences and tuberculosis co-infection. Conclusion: Inflammation and coagulation biomarkers vary significantly by country. Further studies are needed to evaluate how these differences may contribute to HIV pathogenesis and prognosis in diverse populations and how they can be accounted for in studies using biomarkers as surrogate end points.
Language	English
Publishing date	2017-01-01
Publishing country	England
Document type	Editorial
ZDB-ID	2868549-0
ISSN	2055-6659 ; 2055-6640
ISSN (online)	2055-6659
ISSN	2055-6640
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Article ; Online: Selective expansion of polyfunctional pathogen-specific CD4(+) T cells in HIV-1-infected patients with immune reconstitution inflammatory syndrome.

Mahnke, Yolanda D / Greenwald, Jamieson H / DerSimonian, Rebecca / Roby, Gregg / Antonelli, Lis R V / Sher, Alan / Roederer, Mario / Sereti, Irini

Blood

2012 Volume 119, Issue 13, Page(s) 3105–3112

Abstract: Since the introduction of highly active antiretroviral therapies (ART), the prognosis for HIV-1 patients has improved immensely. However, approximately 25% of patients can experience a variety of inflammatory symptoms that are collectively known as ... ...

Abstract	Since the introduction of highly active antiretroviral therapies (ART), the prognosis for HIV-1 patients has improved immensely. However, approximately 25% of patients can experience a variety of inflammatory symptoms that are collectively known as immune reconstitution inflammatory syndrome (IRIS). Studying the etiology and immunopathology of IRIS has been hampered by the fact that the symptoms and associated opportunistic infections are highly varied. We hypothesized that there is a common mechanism underlying IRIS pathogenesis and investigated a patient group with IRIS related to different pathogens. Functional and phenotypic characterization of PBMC samples was performed by polychromatic flow cytometry after in vitro stimulation with relevant antigenic preparations. In most patients, IRIS events were characterized by the robust increase of preexisting polyfunctional, highly differentiated effector CD4(+) T-cell responses that specifically targeted the antigens of the underlying co-infection. T-cell responses to HIV-1 or other underlying infections were not affected and did not differ between IRIS and non-IRIS patients. These data suggest that patients with IRIS do not have a generalized T-cell dysfunction; instead, IRIS represents a dysregulated CD4(+) T-cell response against residual opportunistic infection antigen. These studies were registered at www.clinical-trials.gov as NCT00557570 and NCT00286767.
MeSH term(s)	AIDS-Related Opportunistic Infections/blood ; AIDS-Related Opportunistic Infections/etiology ; AIDS-Related Opportunistic Infections/immunology ; Adult ; CD4 Lymphocyte Count ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/pathology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/pathology ; Cell Proliferation ; Female ; HIV Infections/blood ; HIV Infections/complications ; HIV Infections/immunology ; HIV Infections/virology ; HIV-1/immunology ; HIV-1/pathogenicity ; HIV-1/physiology ; Humans ; Immune Reconstitution Inflammatory Syndrome/blood ; Immune Reconstitution Inflammatory Syndrome/etiology ; Immune Reconstitution Inflammatory Syndrome/immunology ; Immune Reconstitution Inflammatory Syndrome/virology ; Longitudinal Studies ; Male ; T-Cell Antigen Receptor Specificity/immunology ; Viral Load
Language	English
Publishing date	2012-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2011-09-380840
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Article ; Online: Country of residence is associated with distinct inflammatory biomarker signatures in HIV-infected patients

Maura Manion / Bruno B. Andrade / Rebecca DerSimonian / Wenjuan Gu / Adam Rupert / Laura W. Musselwhite / Juan G. Sierra-Madero / Pablo F. Belaunzaran-Zamudio / Ian Sanne / Michael M. Lederman / Irini Sereti

Journal of Virus Eradication, Vol 3, Iss 1, Pp 24-

2017 Volume 33

Abstract: Background: Inflammation and coagulation biomarkers are independent predictors of morbidity and mortality in HIV-infected patients. The impact of sa:country of residence on these biomarkers is unknown and was investigated in persons at similar stages of ... ...

Abstract	Background: Inflammation and coagulation biomarkers are independent predictors of morbidity and mortality in HIV-infected patients. The impact of sa:country of residence on these biomarkers is unknown and was investigated in persons at similar stages of HIV infection. Methods: Cryopreserved plasma specimens were analysed from 267 ART-naive patients with CD4 cell counts <100 cells/μl from Mexico (n=124) and South Africa (n=143). Biomarkers were compared and dimension reduction analyses were performed to highlight biosignatures according to nationality, gender and tuberculosis co-infection. Results: Mexican patients were significantly different from South Africans with regard to age, gender, CD4 cell count, haemoglobin, presence of AIDS-defining illness and prevalence of active tuberculosis. After adjusting for baseline characteristics, patients from Mexico had higher levels of IFN-γ, IL-8, and CXCL-10 whereas patients from South Africa had higher levels of fibrinogen, LTB4, P-selectin, protein S, and sCD40 ligand. The effect of sa:country on the profile of biomarker expression was stronger than gender differences and tuberculosis co-infection. Conclusion: Inflammation and coagulation biomarkers vary significantly by sa:country. Further studies are needed to evaluate how these differences may contribute to HIV pathogenesis and prognosis in diverse populations and how they can be accounted for in studies using biomarkers as surrogate end points.
Keywords	HIV ; nationality ; inflammation ; biomarkers ; Microbiology ; QR1-502 ; Public aspects of medicine ; RA1-1270
Subject code	310
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Clinically Indicated Corticosteroids Do Not Affect Bone Turnover During Immune Restoration of Severely Lymphopenic HIV-Infected Patients.

Grant, Philip M / Sheikh, Virginia / DerSimonian, Rebecca / Rupert, Adam / Roby, Gregg / Pau, Alice / Sneller, Michael C / Rico, Sheryl-Vi / Brown, Todd T / Sereti, Irini

AIDS research and human retroviruses

2015 Volume 31, Issue 7, Page(s) 739–744

Abstract: Unlabelled: Lymphopenia, corticosteroids, antiretroviral therapy (ART), and inflammation negatively impact bone turnover and decrease bone mineral density, but their combined effect has not been evaluated. We examined the association between ... ...

Abstract	Unlabelled: Lymphopenia, corticosteroids, antiretroviral therapy (ART), and inflammation negatively impact bone turnover and decrease bone mineral density, but their combined effect has not been evaluated. We examined the association between corticosteroids on bone turnover markers in severely lymphopenic HIV-infected patients initiating ART. Levels of osteocalcin (bone formation marker) and C-terminal telopeptide (CTX; bone resorption marker) were measured at baseline, weeks 4, 12, and 48 of ART in individuals with severe lymphopenia and opportunistic infection (OI) who received (n=28) or did not receive corticosteroids (n=30) during the first year of ART, and in a control group with CD4 >200 (n=15). Wilcoxon tests were used to compare median values of variables between groups. Correlations between plasma interleukin (IL)-6 and tumor necrosis factor (TNF) levels with bone turnover marker levels were performed using Spearman's coefficient. Individuals given corticosteroids received a median of 21 days at a 35 mg prednisone-equivalent daily dose. Individuals with severe lymphopenia had lower osteocalcin levels at baseline and week 4 and higher CTX levels at ART initiation vs. Controls: Bone turnover markers did not differ in severely lymphopenic persons according to corticosteroid receipt. In those with severe lymphopenia, higher IL-6 was associated with higher CTX levels at ART initiation only. HIV-infected patients with severe lymphopenia and OI had lower levels of bone formation and higher levels of bone resorption than those initiating ART at higher CD4. Corticosteroid use, as prescribed during OI, was not associated with bone turnover. In contrast, higher markers of systemic inflammation prior to ART were associated with greater bone resorption.
MeSH term(s)	Adrenal Cortex Hormones/adverse effects ; Adrenal Cortex Hormones/therapeutic use ; Adult ; Anti-Inflammatory Agents/adverse effects ; Anti-Inflammatory Agents/therapeutic use ; Bone Remodeling/drug effects ; Bone and Bones/physiology ; Collagen Type I/blood ; Female ; HIV Infections/complications ; HIV Infections/drug therapy ; Humans ; Male ; Osteocalcin/blood ; Peptides/blood ; Prospective Studies ; Treatment Outcome
Chemical Substances	Adrenal Cortex Hormones ; Anti-Inflammatory Agents ; Collagen Type I ; Peptides ; collagen type I trimeric cross-linked peptide ; Osteocalcin (104982-03-8)
Language	English
Publishing date	2015-07
Publishing country	United States
Document type	Clinical Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	639130-8
ISSN	1931-8405 ; 0889-2229
ISSN (online)	1931-8405
ISSN	0889-2229
DOI	10.1089/AID.2015.0028
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Article ; Online: Graves' disease as immune reconstitution disease in HIV-positive patients is associated with naive and primary thymic emigrant CD4(+) T-cell recovery.

Sheikh, Virginia / Dersimonian, Rebecca / Richterman, Aaron G / Porter, Brian O / Natarajan, Ven / Burbelo, Peter D / Rupert, Adam / Santich, Brian H / Kardava, Lela / Mican, JoAnn M / Moir, Susan / Sereti, Irini

AIDS (London, England)

2014 Volume 28, Issue 1, Page(s) 31–39

Abstract: Objective: Immune restoration disease (IRD) can develop in HIV-infected patients following antiretroviral therapy (ART) initiation as unmasking or paradoxical worsening of opportunistic infections and, rarely, autoimmune phenomena. Although IRD usually ... ...

Abstract	Objective: Immune restoration disease (IRD) can develop in HIV-infected patients following antiretroviral therapy (ART) initiation as unmasking or paradoxical worsening of opportunistic infections and, rarely, autoimmune phenomena. Although IRD usually occurs in the first months of ART during memory CD4 T-cell recovery, Graves' disease occurs as a distinctive late-onset IRD and its pathogenesis is unclear. Design: Seven patients who developed Graves' disease following ART initiation from the primary HIV care clinic at the National Institutes of Health were retrospectively identified and each was matched with two HIV-infected controls based on age, sex, and baseline CD4 T-cell count. Laboratory evaluations on stored cryopreserved samples were performed. Methods: Immunophenotyping of peripheral blood mononuclear cells (PBMCs), T-cell receptor excision circle (TREC) analysis in PBMCs, measurement of serum cytokines, and luciferase immunoprecipitation systems (LIPS) analysis for autoimmune antibodies were performed on stored samples for cases and controls at baseline and longitudinally following ART initiation. TSH/thyrotropin receptor (TSH-R) antibody testing was performed on serum from cases. Data were analyzed using nonparametric testing. Results: In comparison with controls, the proportion of naive CD4 T cells increased significantly (P = 0.0027) in the Graves' disease-IRD patients. TREC/10 PBMCs also increased significantly following ART in Graves' disease-IRD patients compared with controls (P = 0.0071). Similarly, LIPS analysis demonstrated increases in nonthyroid-related autoantibody titers over time following ART in cases compared with controls. Conclusion: Our data suggest that Graves' disease-IRD, in contrast to early-onset IRD, is associated with naive and primary thymic emigrant CD4 T-cell recovery and inappropriate autoantibody production.
MeSH term(s)	Adult ; Anti-Retroviral Agents/therapeutic use ; Autoantibodies/blood ; CD4-Positive T-Lymphocytes/immunology ; Case-Control Studies ; Cytokines/blood ; Graves Disease/immunology ; Graves Disease/pathology ; HIV Infections/complications ; HIV Infections/drug therapy ; Humans ; Immune Reconstitution Inflammatory Syndrome/immunology ; Immune Reconstitution Inflammatory Syndrome/pathology ; Immunophenotyping ; Male ; Middle Aged ; Retrospective Studies
Chemical Substances	Anti-Retroviral Agents ; Autoantibodies ; Cytokines
Language	English
Publishing date	2014-01-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	639076-6
ISSN	1473-5571 ; 0269-9370 ; 1350-2840
ISSN (online)	1473-5571
ISSN	0269-9370 ; 1350-2840
DOI	10.1097/QAD.0000000000000006
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Article ; Online: Decreased interleukin 7 responsiveness of T lymphocytes in patients with idiopathic CD4 lymphopenia.

Puronen, Camille E / Thompson, William L / Imamichi, Hiromi / Beq, Stephanie / Hodge, Jessica N / Rehm, Catherine / Parker, Raphaelle / DerSimonian, Rebecca / Brenchley, Jason M / Sereti, Irini

The Journal of infectious diseases

2012 Volume 205, Issue 9, Page(s) 1382–1390

Abstract: Background: Elevated serum interleukin 7 (IL-7) levels are observed in lymphopenic conditions, including idiopathic CD4 lymphopenia (ICL), which is characterized by CD4 lymphopenia in the absence of human immunodeficiency virus infection or other known ... ...

Abstract	Background: Elevated serum interleukin 7 (IL-7) levels are observed in lymphopenic conditions, including idiopathic CD4 lymphopenia (ICL), which is characterized by CD4 lymphopenia in the absence of human immunodeficiency virus infection or other known immunodeficiency. Methods: To test whether defective IL-7 signaling could be an etiologic or contributing factor in ICL, peripheral blood mononuclear cells from patients with ICL (median CD4 T-cell count, 160 cells/μL) and healthy controls (median CD4 T-cell count, 582 cells/μL) were evaluated for expression of IL-7Rα chain (CD127) and intracellular phosphorylated STAT-5 (a marker of γc cytokine signaling) after cytokine stimulation. Gene expression was analyzed by real-time polymerase chain reaction following IL-7 stimulation. Results: The percentage of CD4+CD127+ T cells was lower in patients with ICL, compared with controls (P < .001). Lower levels of STAT-5 phosphorylation after IL-7 stimulation were observed in both CD4 and CD8 T cells from patients with ICL, compared with controls (P < .001 and P = .017, respectively), that inversely correlated in CD4 T cells with serum IL-7 levels (r = -0.734, P = .013). Destabilization of p27(kip1), a critical step for IL-7-induced T-cell cycling, was decreased in patients with ICL, compared with controls (P = .004), after IL-7 stimulation. Conclusions: These data suggest that diminished responsiveness to IL-7 in CD4 and CD8 T cells during ICL may be contributing to the dysregulation of T-cell homeostasis.
MeSH term(s)	Adult ; Female ; Humans ; Interleukin-7/blood ; Interleukin-7/genetics ; Interleukin-7/immunology ; Leukocytes, Mononuclear/metabolism ; Lymphocyte Count ; Male ; Middle Aged ; Phosphorylation ; Real-Time Polymerase Chain Reaction ; Receptors, Interleukin-7/blood ; Receptors, Interleukin-7/genetics ; Receptors, Interleukin-7/immunology ; STAT5 Transcription Factor/genetics ; STAT5 Transcription Factor/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytopenia, Idiopathic CD4-Positive/immunology ; T-Lymphocytopenia, Idiopathic CD4-Positive/metabolism ; Up-Regulation ; bcl-2-Associated X Protein/genetics ; bcl-2-Associated X Protein/metabolism
Chemical Substances	Interleukin-7 ; Receptors, Interleukin-7 ; STAT5 Transcription Factor ; bcl-2-Associated X Protein ; interleukin-7 receptor, alpha chain
Language	English
Publishing date	2012-03-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jis219
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Article ; Online: Administration of interleukin-7 increases CD4 T cells in idiopathic CD4 lymphocytopenia.

Sheikh, Virginia / Porter, Brian O / DerSimonian, Rebecca / Kovacs, Stephen B / Thompson, William L / Perez-Diez, Ainhoa / Freeman, Alexandra F / Roby, Gregg / Mican, JoAnn / Pau, Alice / Rupert, Adam / Adelsberger, Joseph / Higgins, Jeanette / Bourgeois, Jeffrey S / Jensen, Stig M R / Morcock, David R / Burbelo, Peter D / Osnos, Leah / Maric, Irina /

Natarajan, Ven / Croughs, Therese / Yao, Michael D / Estes, Jacob D / Sereti, Irini

Blood

2015 Volume 127, Issue 8, Page(s) 977–988

Abstract: Idiopathic CD4 lymphopenia (ICL) is a rare syndrome defined by low CD4 T-cell counts (<300/µL) without evidence of HIV infection or other known cause of immunodeficiency. ICL confers an increased risk of opportunistic infections and has no established ... ...

Abstract	Idiopathic CD4 lymphopenia (ICL) is a rare syndrome defined by low CD4 T-cell counts (<300/µL) without evidence of HIV infection or other known cause of immunodeficiency. ICL confers an increased risk of opportunistic infections and has no established treatment. Interleukin-7 (IL-7) is fundamental for thymopoiesis, T-cell homeostasis, and survival of mature T cells, which provides a rationale for its potential use as an immunotherapeutic agent for ICL. We performed an open-label phase 1/2A dose-escalation trial of 3 subcutaneous doses of recombinant human IL-7 (rhIL-7) per week in patients with ICL who were at risk of disease progression. The primary objectives of the study were to assess safety and the immunomodulatory effects of rhIL-7 in ICL patients. Injection site reactions were the most frequently reported adverse events. One patient experienced a hypersensitivity reaction and developed non-neutralizing anti-IL-7 antibodies. Patients with autoimmune diseases that required systemic therapy at screening were excluded from the study; however, 1 participant developed systemic lupus erythematosus while on study and was excluded from further rhIL-7 dosing. Quantitatively, rhIL-7 led to an increase in the number of circulating CD4 and CD8 T cells and tissue-resident CD3 T cells in the gut mucosa and bone marrow. Functionally, these T cells were capable of producing cytokines after mitogenic stimulation. rhIL-7 was well tolerated at biologically active doses and may represent a promising therapeutic intervention in ICL. This trial was registered at www.clinicaltrials.gov as #NCT00839436.
MeSH term(s)	Adult ; Aged ; CD4-Positive T-Lymphocytes/drug effects ; Dose-Response Relationship, Drug ; Female ; Humans ; Immunologic Factors/administration & dosage ; Immunologic Factors/adverse effects ; Immunophenotyping ; Interleukin-7/administration & dosage ; Interleukin-7/adverse effects ; Male ; Middle Aged ; Recombinant Proteins/administration & dosage ; Recombinant Proteins/adverse effects ; T-Lymphocytopenia, Idiopathic CD4-Positive/drug therapy ; Young Adult
Chemical Substances	Immunologic Factors ; Interleukin-7 ; Recombinant Proteins
Language	English
Publishing date	2015-12-16
Publishing country	United States
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2015-05-645077
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Article ; Online: The effect of leflunomide on cycling and activation of T-cells in HIV-1-infected participants.

Read, Sarah W / DeGrezia, Mary / Ciccone, Emily J / DerSimonian, Rebecca / Higgins, Jeanette / Adelsberger, Joseph W / Starling, Judith M / Rehm, Catherine / Sereti, Irini

PloS one

2010 Volume 5, Issue 8, Page(s) e11937

Abstract: Background: The pathogenesis of immunodeficiency due to human immunodeficiency virus (HIV)-1 is incompletely understood, but immune activation is believed to play a central role. Immunomodulatory agents that decrease immune activation may be useful in ... ...

Abstract	Background: The pathogenesis of immunodeficiency due to human immunodeficiency virus (HIV)-1 is incompletely understood, but immune activation is believed to play a central role. Immunomodulatory agents that decrease immune activation may be useful in the treatment of HIV-1 infection. Methodology: A randomized, double blind, placebo-controlled pilot study of leflunomide for 28 days was performed in participants with HIV-1 infection who were not receiving antiretroviral therapy. Participants randomized to leflunomide were subsequently treated with cholestyramine until leflunomide levels were below detection limit. Findings: Treatment with leflunomide was well tolerated with mostly low-grade adverse events. Leflunomide administration reduced cycling of CD4 T cells (by ex vivo bromodeoxyuridine uptake and Ki67 expression) and decreased expression of activation markers (HLA-DR/CD38 co-expression) on CD8 T cells in peripheral blood. In addition, decreased expression of HIV-1 co-receptors was observed in both CD4 and CD8 T cells in the leflunomide group. There were no significant changes in naïve and memory T cell subsets, apoptosis of T cells or markers of microbial translocation. Conclusions: Leflunomide was effective in reducing immune activation in the setting of chronic HIV-1 infection suggesting that targeting immune activation with immunomodulatory agents may be a feasible strategy. Trial registration: ClinicalTrials.gov NCT00101374.
MeSH term(s)	Adult ; CD4-Positive T-Lymphocytes/cytology ; CD4-Positive T-Lymphocytes/drug effects ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/cytology ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; Drug-Related Side Effects and Adverse Reactions ; Female ; HIV Infections/immunology ; HIV-1/physiology ; Humans ; Immunologic Factors/adverse effects ; Immunologic Factors/metabolism ; Immunologic Factors/pharmacology ; Isoxazoles/adverse effects ; Isoxazoles/immunology ; Isoxazoles/metabolism ; Leflunomide ; Lymphocyte Count ; Male ; Phenotype ; RNA, Viral/blood ; T-Lymphocytes/cytology ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology
Chemical Substances	Immunologic Factors ; Isoxazoles ; RNA, Viral ; Leflunomide (G162GK9U4W)
Language	English
Publishing date	2010-08-03
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0011937
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Inter-library loan at ZB MED

Full text online

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In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Inter-library loan at ZB MED