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Robert W Shafer - One of the best experts on this subject based on the ideXlab platform.
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hiv 1 Drug Resistance and Resistance testing
Infection Genetics and Evolution, 2016Co-Authors: Dana S Clutter, Michael R Jordan, Silvia Bertagnolio, Robert W ShaferAbstract:The global scale-up of antiretroviral (ARV) therapy (ART) has led to dramatic reductions in HIV-1 mortality and incidence. However, HIV Drug Resistance (HIVDR) poses a potential threat to the long-term success of ART and is emerging as a threat to the elimination of AIDS as a public health problem by 2030. In this review we describe the genetic mechanisms, epidemiology, and management of HIVDR at both individual and population levels across diverse economic and geographic settings. To describe the genetic mechanisms of HIVDR, we review the genetic barriers to Resistance for the most commonly used ARVs and describe the extent of cross-Resistance between them. To describe the epidemiology of HIVDR, we summarize the prevalence and patterns of transmitted Drug Resistance (TDR) and acquired Drug Resistance (ADR) in both high-income and low- and middle-income countries (LMICs). We also review to two categories of HIVDR with important public health relevance: (i) pre-treatment Drug Resistance (PDR), a World Health Organization-recommended HIVDR surveillance metric and (ii) and pre-exposure prophylaxis (PrEP)-related Drug Resistance, a type of ADR that can impact clinical outcomes if present at the time of treatment initiation. To summarize the implications of HIVDR for patient management, we review the role of genotypic Resistance testing and treatment practices in both high-income and LMIC settings. In high-income countries where Drug Resistance testing is part of routine care, such an understanding can help clinicians prevent virological failure and accumulation of further HIVDR on an individual level by selecting the most efficacious regimens for their patients. Although there is reduced access to diagnostic testing and to many ARVs in LMIC, understanding the scientific basis and clinical implications of HIVDR is useful in all regions in order to shape appropriate surveillance, inform treatment algorithms, and manage difficult cases.
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consensus Drug Resistance mutations for epidemiological surveillance basic principles and potential controversies
Antiviral Therapy, 2008Co-Authors: Robert W Shafer, Sooyon Rhee, Diane E. BennettAbstract:Programmes that monitor local, national and regional levels of transmitted HIV-1 Drug Resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programmes. The World Health Organization (WHO) has established a global programme for genotypic surveillance of HIV-1 Drug Resistance and has recommended the adoption of a consensus definition of genotypic Drug Resistance. Such a definition is necessary to accurately compare transmitted Drug Resistance rates across geographical regions and time periods. HIV-1 diversity and the large number of mutations associated with antiretroviral Drug Resistance complicate the development of a consensus definition for genotypic Drug Resistance. This paper reviews the data that must be considered to determine which of the many HIV-1 Drug Resistance mutations are likely to be both sensitive and specific indicators of transmitted Drug Resistance. The process used to create a previously published list of Drug Resistance mutations for HIV-1 surveillance is reviewed and alternative approaches to this process are discussed.
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rationale and uses of a public hiv Drug Resistance database
The Journal of Infectious Diseases, 2006Co-Authors: Robert W ShaferAbstract:Knowledge regarding the Drug Resistance of human immunodeficiency virus (HIV) is critical for surveillance of Drug Resistance, development of antiretroviral Drugs, and management of infections with Drug-resistant viruses. Such knowledge is derived from studies that correlate genetic variation in the targets of therapy with the antiretroviral treatments received by persons from whom the variant was obtained (genotype-treatment), with Drug-susceptibility data on genetic variants (genotype-phenotype), and with virological and clinical response to a new treatment regimen (genotype-outcome). An HIV Drug-Resistance database is required to represent, store, and analyze the diverse forms of data underlying our knowledge of Drug Resistance and to make these data available to the broad community of researchers studying Drug Resistance in HIV and clinicians using HIV Drug-Resistance tests. Such genotype-treatment, genotype-phenotype, and genotype-outcome correlations are contained in the Stanford HIV RT and Protease Sequence Database and have specific usefulness.
William S Dalton - One of the best experts on this subject based on the ideXlab platform.
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environmental mediated Drug Resistance a target for multiple myeloma therapy
Expert Review of Hematology, 2009Co-Authors: Kenneth H Shain, William S DaltonAbstract:Multiple myeloma is an incurable malignancy of mature clonal B cells. The refractory nature of this disease has long been attributed to the acquisition of Drug Resistance. Traditionally, mechanisms of Drug Resistance have been defined by genetic, acquired changes in the expression or function of specific genes products. However, over the past 10 years a large body of evidence has emerged demonstrating that in addition to mechanisms of Drug Resistance intrinsic to the cancer cell, there exist dynamic, de novo mechanisms coordinated by the tumor microenvironment resulting in a environmental-mediated Drug Resistance (EM-DR). Within this review we will provide an overview of some of these mechanisms of Drug Resistance and how they contribute to minimal residual disease and subsequent treatment failure. By understanding mechanisms of EM-DR, therapeutic targets can be identified and interventions designed to reduce minimal residual disease and improve clinical outcomes.
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environment mediated Drug Resistance a major contributor to minimal residual disease
Nature Reviews Cancer, 2009Co-Authors: Mark B Meads, Robert A Gatenby, William S DaltonAbstract:Environment-mediated Drug Resistance is a form of de novo Drug Resistance that protects tumour cells from the initial effects of diverse therapies. Surviving foci of residual disease can then develop complex and permanent acquired Resistance in response to the selective pressure of therapy. Recent evidence indicates that environment-mediated Drug Resistance arises from an adaptive, reciprocal signalling dialogue between tumour cells and the surrounding microenvironment. We propose that new therapeutic strategies targeting this interaction should be applied during initial treatment to prevent the emergence of acquired Resistance.
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the bone marrow microenvironment as a tumor sanctuary and contributor to Drug Resistance
Clinical Cancer Research, 2008Co-Authors: Mark B Meads, Lori A Hazlehurst, William S DaltonAbstract:The bone marrow microenvironment facilitates the survival, differentiation, and proliferation of hematopoietic cells. These cells are supported by fibroblast-like bone marrow stromal cells, osteoblasts, and osteoclasts which secrete soluble factors and extracellular matrix proteins that mediate these functions. This rich environment serves as a safe haven not only for normal and malignant hematopoietic cells, but also for epithelial tumor cells that metastasize to bone, offering protection from chemotherapeutic agents by common mechanisms. Soluble factors produced in the bone marrow, such as stromal cell–derived factor-1 and interleukin-6, mediate homing, survival, and proliferation of tumor cells, and integrin-mediated adhesion sequesters tumor cells to this protective niche. Environment-mediated Drug Resistance includes a combination of soluble factors and adhesion, and can be subdivided into soluble factor–mediated Drug Resistance and cell adhesion–mediated Drug Resistance. Because it is induced immediately by the microenvironment and is independent of epigenetic or genetic changes caused by the selective pressure of Drug exposure, environment-mediated Drug Resistance is a form of de novo Drug Resistance. In this form of Drug Resistance, tumor cells are transiently and reversibly protected from apoptosis induced by both chemotherapy and physiologic mediators of cell death. This protection allows tumor cells to survive the insult of chemotherapy, leading to minimal residual disease, and thereby increases the probability for the development of acquired Drug Resistance.
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integrin mediated Drug Resistance in multiple myeloma
Leukemia & Lymphoma, 2000Co-Authors: Jason Damiano, William S DaltonAbstract:Drug Resistance remains a major obstacle to the treatment of many hematopoietic malignancies such as multiple myeloma. Although much research has been focused on acquired Resistance phenotypes, we believe that de navo Drug Resistance mechanisms may be an important component in protecting cells from initial Drug exposure. It is now realized that many of the biological processes associated with this disease, including cell survival, may come as a result of the direct interactions of malignant plasma cells with the bone marrow microenvironment. This review examines the role of cell adhesion to one bone marrow component, fibronectin (FN), and the impact it may have on response to cytotoxic Drugs. We discuss the influence of the integrin VLA-4 (α44β1) on cell adhesion mediated Drug Resistance (CAM-DR) as well as the effects of chronic Drug exposure on integrin function. Data presented here demonstrates that Drug selection can make a non-adherent cell line adherent to FN through inside-out integrin activation a...
Diane E. Bennett - One of the best experts on this subject based on the ideXlab platform.
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Drug Resistance mutations for surveillance of transmitted hiv 1 Drug Resistance 2009 update
PLOS ONE, 2009Co-Authors: Diane E. Bennett, Ricardo Jorge Camacho, Dan Otelea, Daniel R Kuritzkes, Herve Fleury, Mark Kiuchi, Walid Heneine, Rami Kantor, Michael R Jordan, Jonathan M SchapiroAbstract:Programs that monitor local, national, and regional levels of transmitted HIV-1 Drug Resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programs. To accurately compare transmitted Drug Resistance rates across geographic regions and times, the World Health Organization has recommended the adoption of a consensus genotypic definition of transmitted HIV-1 Drug Resistance. In January 2007, we outlined criteria for developing a list of mutations for Drug-Resistance surveillance and compiled a list of 80 RT and protease mutations meeting these criteria (surveillance Drug Resistance mutations; SDRMs). Since January 2007, several new Drugs have been approved and several new Drug-Resistance mutations have been identified. In this paper, we follow the same procedures described previously to develop an updated list of SDRMs that are likely to be useful for ongoing and future studies of transmitted Drug Resistance. The updated SDRM list has 93 mutations including 34 NRTI-Resistance mutations at 15 RT positions, 19 NNRTI-Resistance mutations at 10 RT positions, and 40 PI-Resistance mutations at 18 protease positions.
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consensus Drug Resistance mutations for epidemiological surveillance basic principles and potential controversies
Antiviral Therapy, 2008Co-Authors: Robert W Shafer, Sooyon Rhee, Diane E. BennettAbstract:Programmes that monitor local, national and regional levels of transmitted HIV-1 Drug Resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programmes. The World Health Organization (WHO) has established a global programme for genotypic surveillance of HIV-1 Drug Resistance and has recommended the adoption of a consensus definition of genotypic Drug Resistance. Such a definition is necessary to accurately compare transmitted Drug Resistance rates across geographical regions and time periods. HIV-1 diversity and the large number of mutations associated with antiretroviral Drug Resistance complicate the development of a consensus definition for genotypic Drug Resistance. This paper reviews the data that must be considered to determine which of the many HIV-1 Drug Resistance mutations are likely to be both sensitive and specific indicators of transmitted Drug Resistance. The process used to create a previously published list of Drug Resistance mutations for HIV-1 surveillance is reviewed and alternative approaches to this process are discussed.
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The requirement for surveillance of HIV Drug Resistance within antiretroviral rollout in the developing world.
Current Opinion in Infectious Diseases, 2006Co-Authors: Diane E. BennettAbstract:The purpose was to describe surveillance measures to inform HIV Drug-Resistance prevention as part of the public health approach to antiretroviral therapy in developing countries. Neither HIV Drug-Resistance transmission nor its emergence in treatment is routinely assessed in the developing world but routine methods should be part of antiretroviral therapy scale-up. Mathematical modelling and experience in resource-rich countries suggest HIV Drug-Resistance transmission will increase as antiretroviral therapy coverage increases but its rise will be limited initially. Transmission surveys should begin in geographic areas in each country where antiretroviral therapy coverage is widespread. Reports from resource-limited countries suggest that antiretroviral therapy programs are as effective as in resource-rich countries which should limit HIV Drug Resistance if effectiveness is maintained with antiretroviral therapy expansion. Surveillance of HIV Drug Resistance emerging in treatment and other factors will support implementation of prevention measures on a population level. Standardized surveillance of transmitted and treatment-associated HIV Drug Resistance is critical to the success of antiretroviral therapy expansion in developing countries. Routine assessment of prescribing practices availability of and access to appropriate regimens for adults and children antiretroviral Drug supply continuity and measures to prevent HIV transmission will supply critical information for HIV Drug-Resistance prevention. (authors)
Wing Wai Yew - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of Drug Resistance in mycobacterium tuberculosis
International Journal of Tuberculosis and Lung Disease, 2009Co-Authors: Ying Zhang, Wing Wai YewAbstract:Drug Resistance in tuberculosis (TB) is a particular problem because the lengthy therapy of at least 6 months makes patient compliance very difficult, which frequently creates Drug-resistant strains of Mycobacterium tuberculosis. This chapter provides an update on genes associated with Drug Resistance and the current understanding of mechanisms of Drug Resistance and Drug action in M. tuberculosis. The emergence of Drug Resistance in bacteria is one of the easiest demonstrations of the "survival of the fittest" concept of Darwin's theory of evolution. Resistance is thus due to a change in the genotype resulting in a Drug-resistant phenotype of a bacterium, which can be passed on to subsequent generations. This is in contrast to tolerance, or phenotypic Resistance, another phenomenon that is common to M. tuberculosis and other bacterial species, in which changes in the metabolic or physiological status of the cell induce temporary Drug Resistance as seen in stationary-phase, starved, or dormant bacteria. Knowledge about the mutations conferring Drug Resistance not only leads to understanding of the mechanisms of Drug Resistance and Drug action but also facilitates rapid detection of Drug Resistance by molecular means. Phenotypic Resistance is a major problem for antibiotic therapy, especially for TB. Nongrowing bacteria can be divided roughly into two different types depending on whether they grow immediately on subculture into a defined fresh medium.
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mechanisms of Drug Resistance in mycobacterium tuberculosis
International Journal of Tuberculosis and Lung Disease, 2009Co-Authors: Ying Zhang, Wing Wai YewAbstract:The increasing emergence of multiDrug-resistant (MDR) and extensively Drug-resistant (XDR) tuberculosis (TB) in the era of human immunodeficiency virus (HIV) infection presents a major threat to effective control of TB. Drug Resistance in Mycobacterium tuberculosis arises from spontaneous chromosomal mutations at low frequency. Clinical Drug-resistant TB largely occurs as a result of man-made selection during disease treatment of these genetic alterations through erratic Drug supply, suboptimal physician prescription and poor patient adherence. Molecular mechanisms of Drug Resistance have been elucidated for the major first- and second-line Drugs rifampicin, isoniazid, pyrazinamide, ethambutol, the aminoglycosides and the fluoroquinolones. The relationship between Drug Resistance in M. tuberculosis strains and their virulence/transmissibility needs to be further investigated. Understanding the mechanisms of Drug Resistance in M. tuberculosis would enable the development of rapid molecular diagnostic tools and furnish possible insights into new Drug development for the treatment of TB.
Leah E Cowen - One of the best experts on this subject based on the ideXlab platform.
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molecular evolution of antifungal Drug Resistance
Annual Review of Microbiology, 2017Co-Authors: Nicole Robbins, Tavia Caplan, Leah E CowenAbstract:The fungal pathogens Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus have transitioned from a rare curiosity to a leading cause of human mortality. The management of infections caused by these organisms is intimately dependent on the efficacy of antifungal agents; however, fungi that are resistant to these treatments are regularly isolated in the clinic, impeding our ability to control infections. Given the significant impact fungal pathogens have on human health, it is imperative to understand the molecular mechanisms that govern antifungal Drug Resistance. This review describes our current knowledge of the mechanisms by which antifungal Drug Resistance evolves in experimental populations and clinical settings. We explore current antifungal treatment options and discuss promising strategies to impede the evolution of Drug Resistance. By tackling antifungal Drug Resistance as an evolutionary problem, there is potential to improve the utility of current treatments and accelerate the development of novel therapeutic strategies.
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mechanisms of antifungal Drug Resistance
Cold Spring Harbor Perspectives in Medicine, 2015Co-Authors: Leah E Cowen, Dominique Sanglard, Susan J Howard, David P Rogers, David S PerlinAbstract:Antifungal therapy is a central component of patient management for acute and chronic mycoses. Yet, treatment choices are restricted because of the sparse number of antifungal Drug classes. Clinical management of fungal diseases is further compromised by the emergence of antifungal Drug Resistance, which eliminates available Drug classes as treatment options. Once considered a rare occurrence, antifungal Drug Resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multiDrug- resistant organisms refractory to several different classes of antifungal agents, especially among common Candida species. The mechanisms responsible are mostly shared by both resistant strains displaying inherently reduced susceptibility and those acquiring Resistance during therapy. The molecular mechanisms include altered Drug affinity and target abundance, reduced intracellular Drug levels caused by efflux pumps, and formation of biofilms. New insights into genetic factors regulating these mechanisms, as well as cellular factors important for stress adaptation, provide a foundation to better understand the emergence of antifungal Drug Resistance.
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hsp90 governs dispersion and Drug Resistance of fungal biofilms
PLOS Pathogens, 2011Co-Authors: Nicole Robbins, Priya Uppuluri, Jeniel E Nett, Ranjith Rajendran, Gordon Ramage, Jose L Lopezribot, David R Andes, Leah E CowenAbstract:Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic Drug Resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and Drug Resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of Drug Resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated Resistance of C. albicans biofilms to the most widely deployed class of antifungal Drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates Drug Resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole Resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced Resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm Drug Resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving clinical outcome in the treatment of biofilm infections.
