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Article: BCL-2 in the crosshairs: tipping the balance of life and death.

Walensky, L D

2006 Volume 13, Issue 8, Page(s) 1339–1350

Abstract: The discovery of B-cell lymphoma-2 (BCL-2) over 20 years ago revealed a new paradigm in cancer biology: the development and persistence of cancer can be driven by molecular roadblocks along the natural pathway to cell death. The subsequent identification ...

Abstract	The discovery of B-cell lymphoma-2 (BCL-2) over 20 years ago revealed a new paradigm in cancer biology: the development and persistence of cancer can be driven by molecular roadblocks along the natural pathway to cell death. The subsequent identification of an expansive family of BCL-2 proteins provoked an intensive investigation of the interplay among these critical regulators of cell death. What emerged was a compelling tale of guardians and executioners, each participating in a molecular choreography that dictates cell fate. Ten years into the BCL-2 era, structural details defined how certain BCL-2 family proteins interact, and molecular targeting of the BCL-2 family has since become a pharmacological quest. Although many facets of BCL-2 family death signaling remain a mechanistic mystery, small molecules and peptides that effectively target BCL-2 are eliminating the roadblock to cell death, raising hopes for a medical breakthrough in cancer and other diseases of deregulated apoptosis.
MeSH term(s)	Animals ; Apoptosis ; Homeostasis ; Humans ; Protein Conformation ; Proto-Oncogene Proteins c-bcl-2/chemistry ; Proto-Oncogene Proteins c-bcl-2/classification ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Signal Transduction
Chemical Substances	Proto-Oncogene Proteins c-bcl-2
Language	English
Publishing date	2006-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1225672-9
ISSN	1350-9047
ISSN	1350-9047
DOI	10.1038/sj.cdd.4401992
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Zs.MG 80: Show issues

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Article ; Online: Inhibition of FOXP3 by stapled alpha-helical peptides dampens regulatory T cell function.

Hawley, Katrina M / Eclov, Rachel J / Schnorenberg, Mathew R / Tian, Yu / Shah, Rhea N / Thomas-Toth, Anika T / Fefferman, Marie / Bird, Gregory H / Walensky, Loren D / Tirrell, Matthew V / LaBelle, James L

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 42, Page(s) e2209044119

Abstract: Despite continuing advances in the development of novel cellular-, antibody-, and chemotherapeutic-based strategies to enhance immune reactivity, the presence of regulatory T cells (Treg cells) remains a complicating factor for their clinical efficacy. ... ...

Abstract	Despite continuing advances in the development of novel cellular-, antibody-, and chemotherapeutic-based strategies to enhance immune reactivity, the presence of regulatory T cells (Treg cells) remains a complicating factor for their clinical efficacy. To overcome dosing limitations and off-target effects from antibody-based Treg cell deletional strategies or small molecule drugging, we investigated the ability of hydrocarbon stapled alpha-helical (SAH) peptides to target FOXP3, the master transcription factor regulator of Treg cell development, maintenance, and suppressive function. Using the crystal structure of the FOXP3 homodimer as a guide, we developed SAHs in the likeness of a portion of the native FOXP3 antiparallel coiled-coil homodimerization domain (SAH-FOXP3) to block this key FOXP3 protein-protein interaction (PPI) through molecular mimicry. We describe the design, synthesis, and biochemical evaluation of single- and double-stapled SAHs covering the entire coiled-coil expanse. We show that lead SAH-FOXP3s bind FOXP3, are cell permeable and nontoxic to T cells, induce dose-dependent transcript and protein level alterations of FOXP3 target genes, impede Treg cell function, and lead to Treg cell gene expression changes in vivo consistent with FOXP3 dysfunction. These results demonstrate a proof of concept for rationally designed FOXP3-directed peptide therapeutics that could be used as approaches to amplify endogenous immune responsiveness.
MeSH term(s)	Forkhead Transcription Factors/metabolism ; Gene Expression Regulation ; Peptides/metabolism ; Protein Conformation, alpha-Helical ; T-Lymphocytes, Regulatory
Chemical Substances	Forkhead Transcription Factors ; Peptides
Language	English
Publishing date	2022-10-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2209044119
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Article ; Online: Mechanistic validation of a clinical lead stapled peptide that reactivates p53 by dual HDM2 and HDMX targeting.

Wachter, F / Morgan, A M / Godes, M / Mourtada, R / Bird, G H / Walensky, L D

Oncogene

2017 Volume 36, Issue 15, Page(s) 2184–2190

Abstract: Hydrocarbon-stapled peptides that display key residues of the p53 transactivation domain have emerged as bona fide clinical candidates for reactivating the tumor suppression function of p53 in cancer by dual targeting of the negative regulators HDM2 and ... ...

Abstract	Hydrocarbon-stapled peptides that display key residues of the p53 transactivation domain have emerged as bona fide clinical candidates for reactivating the tumor suppression function of p53 in cancer by dual targeting of the negative regulators HDM2 and HDMX. A recent study questioned the mechanistic specificity of such stapled peptides based on interrogating their capacity to disrupt p53/HDM2 and p53/HDMX complexes in living cells using a new recombinase enhanced bimolecular luciferase complementation platform (ReBiL). Here, we directly evaluate the cellular uptake, intracellular targeting selectivity and p53-dependent cytotoxicity of the clinical prototype ATSP-7041. We find that under standard serum-containing tissue culture conditions, ATSP-7041 achieves intracellular access without membrane disruption, dose-dependently dissociates both p53/HDM2 and p53/HDMX complexes but not an unrelated protein complex in long-term ReBiL experiments, and is selectively cytotoxic to cancer cells bearing wild-type p53 by inducing a surge in p53 protein level. These studies underscore the importance of a thorough stepwise approach, including consideration of the time-dependence of cellular uptake and intracellular distribution, in evaluating and advancing stapled peptides for clinical translation.
MeSH term(s)	Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Bone Neoplasms/drug therapy ; Bone Neoplasms/metabolism ; Cell Line, Tumor ; Humans ; Nuclear Proteins/metabolism ; Osteosarcoma/drug therapy ; Osteosarcoma/metabolism ; Peptides, Cyclic/pharmacokinetics ; Peptides, Cyclic/pharmacology ; Protein Binding/drug effects ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-mdm2/metabolism ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	ATSP-7041 ; Antineoplastic Agents ; MDM4 protein, human ; Nuclear Proteins ; Peptides, Cyclic ; Proto-Oncogene Proteins ; TP53 protein, human ; Tumor Suppressor Protein p53 ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2017-04
Publishing country	England
Document type	Journal Article
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/onc.2016.361
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Zs.A 2218: Show issues

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Article ; Online: Glucose metabolism and pyruvate carboxylase enhance glutathione synthesis and restrict oxidative stress in pancreatic islets.

Fu, Accalia / van Rooyen, Lara / Evans, Lindsay / Armstrong, Nina / Avizonis, Daina / Kin, Tatsuya / Bird, Gregory H / Reddy, Anita / Chouchani, Edward T / Liesa-Roig, Marc / Walensky, Loren D / Shapiro, A M James / Danial, Nika N

Cell reports

2021 Volume 37, Issue 8, Page(s) 110037

Abstract: Glucose metabolism modulates the islet β cell responses to diabetogenic stress, including inflammation. Here, we probed the metabolic mechanisms that underlie the protective effect of glucose in inflammation by interrogating the metabolite profiles of ... ...

Abstract	Glucose metabolism modulates the islet β cell responses to diabetogenic stress, including inflammation. Here, we probed the metabolic mechanisms that underlie the protective effect of glucose in inflammation by interrogating the metabolite profiles of primary islets from human donors and identified de novo glutathione synthesis as a prominent glucose-driven pro-survival pathway. We find that pyruvate carboxylase is required for glutathione synthesis in islets and promotes their antioxidant capacity to counter inflammation and nitrosative stress. Loss- and gain-of-function studies indicate that pyruvate carboxylase is necessary and sufficient to mediate the metabolic input from glucose into glutathione synthesis and the oxidative stress response. Altered redox metabolism and cellular capacity to replenish glutathione pools are relevant in multiple pathologies beyond obesity and diabetes. Our findings reveal a direct interplay between glucose metabolism and glutathione biosynthesis via pyruvate carboxylase. This metabolic axis may also have implications in other settings where sustaining glutathione is essential.
MeSH term(s)	Adult ; Animals ; Antioxidants/physiology ; Female ; Glucose/metabolism ; Glutathione/biosynthesis ; Glutathione/metabolism ; Humans ; Insulin/metabolism ; Islets of Langerhans/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Oxidation-Reduction ; Oxidative Stress/physiology ; Primary Cell Culture ; Pyruvate Carboxylase/metabolism
Chemical Substances	Antioxidants ; Insulin ; Pyruvate Carboxylase (EC 6.4.1.1) ; Glutathione (GAN16C9B8O) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2021-11-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2021.110037
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Article ; Online: Regulation of mitochondrial ceramide distribution by members of the BCL-2 family.

Zhang, Tejia / Barclay, Lauren / Walensky, Loren D / Saghatelian, Alan

Journal of lipid research

2015 Volume 56, Issue 8, Page(s) 1501–1510

Abstract: Apoptosis is an intricately regulated cellular process that proceeds through different cell type- and signal-dependent pathways. In the mitochondrial apoptotic program, mitochondrial outer membrane permeabilization by BCL-2 proteins leads to the release ... ...

Abstract	Apoptosis is an intricately regulated cellular process that proceeds through different cell type- and signal-dependent pathways. In the mitochondrial apoptotic program, mitochondrial outer membrane permeabilization by BCL-2 proteins leads to the release of apoptogenic factors, caspase activation, and cell death. In addition to protein components of the mitochondrial apoptotic machinery, an interesting role for lipids and lipid metabolism in BCL-2 family-regulated apoptosis is also emerging. We used a comparative lipidomics approach to uncover alterations in lipid profile in the absence of the proapoptotic proteins BAX and BAK in mouse embryonic fibroblasts (MEFs). We detected over 1,000 ions in these experiments and found changes in an ion with an m/z of 534.49. Structural elucidation of this ion through tandem mass spectrometry revealed that this molecule is a ceramide with a 16-carbon N-acyl chain and sphingadiene backbone (d18:2/16:0 ceramide). Targeted LC/MS analysis revealed elevated levels of additional sphingadiene-containing ceramides (d18:2-Cers) in BAX, BAK-double knockout MEFs. Elevated d18:2-Cers are also found in immortalized baby mouse kidney epithelial cells lacking BAX and BAK. These results support the existence of a distinct biochemical pathway for regulating ceramides with different backbone structures and suggest that sphingadiene-containing ceramides may have functions that are distinct from the more common sphingosine-containing species.
MeSH term(s)	Animals ; Cell Line ; Ceramides/chemistry ; Ceramides/metabolism ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Gene Knockout Techniques ; Mice ; Mitochondria/metabolism ; Up-Regulation ; bcl-2 Homologous Antagonist-Killer Protein/deficiency ; bcl-2 Homologous Antagonist-Killer Protein/genetics ; bcl-2 Homologous Antagonist-Killer Protein/metabolism ; bcl-2-Associated X Protein/deficiency ; bcl-2-Associated X Protein/genetics ; bcl-2-Associated X Protein/metabolism
Chemical Substances	Ceramides ; bcl-2 Homologous Antagonist-Killer Protein ; bcl-2-Associated X Protein
Language	English
Publishing date	2015-06-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1194/jlr.M058750
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Article: The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members.

Verdine, Gregory L / Walensky, Loren D

Clinical cancer research : an official journal of the American Association for Cancer Research

2007 Volume 13, Issue 24, Page(s) 7264–7270

Abstract: The genomic and proteomic revolutions have provided us with an ever-increasing number of mechanistic insights into cancer pathogenesis. Mutated genes and pathologic protein products have emerged as the basis for modern anticancer drug development. With ... ...

Abstract	The genomic and proteomic revolutions have provided us with an ever-increasing number of mechanistic insights into cancer pathogenesis. Mutated genes and pathologic protein products have emerged as the basis for modern anticancer drug development. With the increasing realization of the importance of disrupting oncogenic protein-protein interaction, new challenges have emerged for classical small molecule and protein-based drug modalities, i.e., the critical need to target flat and extended protein surfaces. Here, we highlight two distinct technologies that are being used to bridge the pharmacologic gap between small molecules and protein therapeutics. With the BCL-2 family of survival proteins as their substrate for intracellular targeting, we conclude that peptide stapling and fragment-based drug discovery show promise to traverse the critical surface features of proteins that drive human cancer.
MeSH term(s)	Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/metabolism ; Drug Delivery Systems/methods ; Drug Design ; Humans ; Neoplasms/drug therapy ; Protein Binding ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-bcl-2/chemistry ; Proto-Oncogene Proteins c-bcl-2/metabolism
Chemical Substances	Antineoplastic Agents ; Proto-Oncogene Proteins c-bcl-2
Language	English
Publishing date	2007-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-07-2184
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Zs.A 4223: Show issues

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Article ; Online: Bim

Cerqueira, Débora M / Bodnar, Andrew J / Phua, Yu Leng / Freer, Rachel / Hemker, Shelby L / Walensky, Loren D / Hukriede, Neil A / Ho, Jacqueline

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2017 Volume 31, Issue 8, Page(s) 3540–3554

Abstract: Low nephron endowment at birth has been associated with an increased risk for developing hypertension and chronic kidney disease. We demonstrated in an earlier study that conditional deletion of the microRNA (miRNA)-processing enzyme Dicer from nephron ... ...

Abstract	Low nephron endowment at birth has been associated with an increased risk for developing hypertension and chronic kidney disease. We demonstrated in an earlier study that conditional deletion of the microRNA (miRNA)-processing enzyme Dicer from nephron progenitors results in premature depletion of the progenitors and increased expression of the proapoptotic protein Bim (also known as Bcl-2L11). In this study, we generated a compound mouse model with conditional deletion of both
MeSH term(s)	Animals ; Apoptosis/physiology ; Bcl-2-Like Protein 11/genetics ; Bcl-2-Like Protein 11/metabolism ; DEAD-box RNA Helicases/genetics ; DEAD-box RNA Helicases/metabolism ; Embryo, Nonmammalian ; Gene Deletion ; Gene Dosage/physiology ; Gene Expression Regulation, Developmental/physiology ; HEK293 Cells ; Humans ; Kidney/embryology ; Mice ; Mice, Transgenic ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Nephrons/cytology ; Ribonuclease III/genetics ; Ribonuclease III/metabolism ; Stem Cells/cytology ; Xenopus laevis/embryology
Chemical Substances	Bcl-2-Like Protein 11 ; Bcl2l11 protein, mouse ; MicroRNAs ; Dicer1 protein, mouse (EC 3.1.26.3) ; Ribonuclease III (EC 3.1.26.3) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.201700010R
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Article ; Online: Cost-effectiveness and budget impact of immediate antiretroviral therapy initiation for treatment of HIV infection in Côte d'Ivoire: A model-based analysis.

Ouattara, Eric N / MacLean, Rachel L / Danel, Christine / Borre, Ethan D / Gabillard, Delphine / Huang, Mingshu / Moh, Raoul / Paltiel, A David / Eholié, Serge P / Walensky, Rochelle P / Anglaret, Xavier / Freedberg, Kenneth A

PloS one

2019 Volume 14, Issue 6, Page(s) e0219068

Abstract: Introduction: The Temprano and START trials provided evidence to support early ART initiation recommendations. We projected long-term clinical and economic outcomes of immediate ART initiation in Côte d'Ivoire.: Methods: We used a mathematical model ... ...

Abstract	Introduction: The Temprano and START trials provided evidence to support early ART initiation recommendations. We projected long-term clinical and economic outcomes of immediate ART initiation in Côte d'Ivoire. Methods: We used a mathematical model to compare three potential ART initiation criteria: 1) CD4 <350/μL (ART<350/μL); 2) CD4 <500/μL (ART<500/μL); and 3) ART at presentation (Immediate ART). Outcomes from the model included life expectancy, 10-year medical resource use, incremental cost-effectiveness ratios (ICERs) in $/year of life saved (YLS), and 5-year budget impact. We simulated people with HIV (PWH) in care (mean CD4: 259/μL, SD 198/μL) and transmitted cases. Key input parameters to the analysis included first-line ART efficacy (80% suppression at 6 months) and ART cost ($90/person-year). We assessed cost-effectiveness relative to Côte d'Ivoire's 2017 per capita annual gross domestic product ($1,600). Results: Immediate ART increased life expectancy by 0.34 years compared to ART<350/μL and 0.17 years compared to ART<500/μL. Immediate ART resulted in 4,500 fewer 10-year transmissions per 170,000 PWH compared to ART<350/μL. In cost-effectiveness analysis, Immediate ART had a 10-year ICER of $680/YLS compared to ART<350/μL, ranging from cost-saving to an ICER of $1,440/YLS as transmission rates varied. ART<500/μL was "dominated" (an inefficient use of resources), compared with Immediate ART. Immediate ART increased the 5-year HIV care budget from $801.9M to $812.6M compared to ART<350/μL. Conclusions: In Côte d'Ivoire, immediate compared to later ART initiation will increase life expectancy, decrease HIV transmission, and be cost-effective over the long-term, with modest budget impact. Immediate ART initiation is an appropriate, high-value standard of care in Côte d'Ivoire and similar settings.
MeSH term(s)	Adolescent ; Adult ; Anti-HIV Agents/administration & dosage ; Anti-HIV Agents/economics ; Budgets ; CD4 Lymphocyte Count ; Cohort Studies ; Computer Simulation ; Cost-Benefit Analysis ; Cote d'Ivoire ; Drug Costs ; Female ; HIV Infections/drug therapy ; HIV Infections/economics ; HIV Infections/immunology ; Health Resources/economics ; Humans ; Life Expectancy ; Male ; Middle Aged ; Models, Biological ; Models, Economic ; Treatment Outcome ; Young Adult
Chemical Substances	Anti-HIV Agents
Language	English
Publishing date	2019-06-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0219068
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Article ; Online: Distinct BimBH3 (BimSAHB) stapled peptides for structural and cellular studies.

Bird, Greg H / Gavathiotis, Evripidis / LaBelle, James L / Katz, Samuel G / Walensky, Loren D

ACS chemical biology

2014 Volume 9, Issue 3, Page(s) 831–837

Abstract: Hydrocarbon stapling is a chemical approach to restoring and fortifying the natural α-helical structure of peptides that otherwise unfold when taken out of context from the host protein. By iterating the peptide sequence, staple type, and sites of ... ...

Abstract	Hydrocarbon stapling is a chemical approach to restoring and fortifying the natural α-helical structure of peptides that otherwise unfold when taken out of context from the host protein. By iterating the peptide sequence, staple type, and sites of insertion, discrete compositions can be generated to suit a diversity of biochemical, structural, proteomic, cellular, and drug development applications. Here, we reinforce key design considerations to avoid pitfalls and maximize progress when applying stapled peptides in chemistry and biology research.
MeSH term(s)	Animals ; Apoptosis ; Humans ; Peptide Fragments/chemistry ; Peptide Fragments/metabolism ; Proto-Oncogene Proteins/chemistry ; Proto-Oncogene Proteins/metabolism
Chemical Substances	Peptide Fragments ; Proto-Oncogene Proteins
Language	English
Publishing date	2014-01-03
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural ; Comment
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/cb4003305
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Article ; Online: Cost-effectiveness of a Novel Lipoarabinomannan Test for Tuberculosis in Patients With Human Immunodeficiency Virus.

Reddy, Krishna P / Denkinger, Claudia M / Broger, Tobias / McCann, Nicole C / Gupta-Wright, Ankur / Kerkhoff, Andrew D / Pei, Pamela P / Shebl, Fatma M / Fielding, Katherine L / Nicol, Mark P / Horsburgh, C Robert / Meintjes, Graeme / Freedberg, Kenneth A / Wood, Robin / Walensky, Rochelle P

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

2020 Volume 73, Issue 7, Page(s) e2077–e2085

Abstract: Background: A novel urine lipoarabinomannan assay (FujiLAM) has higher sensitivity and higher cost than the first-generation AlereLAM assay. We evaluated the cost-effectiveness of FujiLAM for tuberculosis testing among hospitalized people with human ... ...

Abstract	Background: A novel urine lipoarabinomannan assay (FujiLAM) has higher sensitivity and higher cost than the first-generation AlereLAM assay. We evaluated the cost-effectiveness of FujiLAM for tuberculosis testing among hospitalized people with human immunodeficiency virus (HIV), irrespective of symptoms. Methods: We used a microsimulation model to project clinical and economic outcomes of 3 testing strategies: (1) sputum Xpert MTB/RIF (Xpert), (2) sputum Xpert plus urine AlereLAM (Xpert+AlereLAM), (3) sputum Xpert plus urine FujiLAM (Xpert+FujiLAM). The modeled cohort matched that of a 2-country clinical trial. We applied diagnostic yields from a retrospective study (yields for Xpert/Xpert+AlereLAM/Xpert+FujiLAM among those with CD4 <200 cells/µL: 33%/62%/70%; among those with CD4 ≥200 cells/µL: 33%/35%/47%). Costs of Xpert/AlereLAM/FujiLAM were US$15/3/6 (South Africa) and $25/3/6 (Malawi). Xpert+FujiLAM was considered cost-effective if its incremental cost-effectiveness ratio (US$/year-of-life saved) was <$940 (South Africa) and <$750 (Malawi). We varied key parameters in sensitivity analysis and performed a budget impact analysis of implementing FujiLAM countrywide. Results: Compared with Xpert+AlereLAM, Xpert+FujiLAM increased life expectancy by 0.2 years for those tested in South Africa and Malawi. Xpert+FujiLAM was cost-effective in both countries. Xpert+FujiLAM for all patients remained cost-effective compared with sequential testing and CD4-stratified testing strategies. FujiLAM use added 3.5% (South Africa) and 4.7% (Malawi) to 5-year healthcare costs of tested patients, primarily reflecting ongoing HIV treatment costs among survivors. Conclusions: FujiLAM with Xpert for tuberculosis testing in hospitalized people with HIV is likely to increase life expectancy and be cost-effective at the currently anticipated price in South Africa and Malawi. Additional studies should evaluate FujiLAM in clinical practice settings.
MeSH term(s)	Cost-Benefit Analysis ; HIV ; HIV Infections/complications ; Humans ; Lipopolysaccharides ; Retrospective Studies ; Sensitivity and Specificity ; Sputum ; Tuberculosis/diagnosis
Chemical Substances	Lipopolysaccharides ; lipoarabinomannan
Language	English
Publishing date	2020-11-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1099781-7
ISSN	1537-6591 ; 1058-4838
ISSN (online)	1537-6591
ISSN	1058-4838
DOI	10.1093/cid/ciaa1698
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Zs.MO 480: Show issues

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Inter-library loan at ZB MED

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Kategorien

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito