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      G6PD testing in support of treatment and elimination of malaria: recommendations for evaluation of G6PD tests

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          Abstract

          Malaria elimination will be possible only with serious attempts to address asymptomatic infection and chronic infection by both Plasmodium falciparum and Plasmodium vivax. Currently available drugs that can completely clear a human of P. vivax (known as “radical cure”), and that can reduce transmission of malaria parasites, are those in the 8-aminoquinoline drug family, such as primaquine. Unfortunately, people with glucose-6-phosphate dehydrogenase (G6PD) deficiency risk having severe adverse reactions if exposed to these drugs at certain doses. G6PD deficiency is the most common human enzyme defect, affecting approximately 400 million people worldwide.

          Scaling up radical cure regimens will require testing for G6PD deficiency, at two levels: 1) the individual level to ensure safe case management, and 2) the population level to understand the risk in the local population to guide Plasmodium vivax treatment policy. Several technical and operational knowledge gaps must be addressed to expand access to G6PD deficiency testing and to ensure that a patient’s G6PD status is known before deciding to administer an 8-aminoquinoline-based drug.

          In this report from a stakeholder meeting held in Thailand on October 4 and 5, 2012, G6PD testing in support of radical cure is discussed in detail. The focus is on challenges to the development and evaluation of G6PD diagnostic tests, and on challenges related to the operational aspects of implementing G6PD testing in support of radical cure. The report also describes recommendations for evaluation of diagnostic tests for G6PD deficiency in support of radical cure.

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          Most cited references35

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          G6PD deficiency: global distribution, genetic variants and primaquine therapy.

          Glucose-6-phosphate dehydrogenase (G6PD) is a potentially pathogenic inherited enzyme abnormality and, similar to other human red blood cell polymorphisms, is particularly prevalent in historically malaria endemic countries. The spatial extent of Plasmodium vivax malaria overlaps widely with that of G6PD deficiency; unfortunately the only drug licensed for the radical cure and relapse prevention of P. vivax, primaquine, can trigger severe haemolytic anaemia in G6PD deficient individuals. This chapter reviews the past and current data on this unique pharmacogenetic association, which is becoming increasingly important as several nations now consider strategies to eliminate malaria transmission rather than control its clinical burden. G6PD deficiency is a highly variable disorder, in terms of spatial heterogeneity in prevalence and molecular variants, as well as its interactions with P. vivax and primaquine. Consideration of factors including aspects of basic physiology, diagnosis, and clinical triggers of primaquine-induced haemolysis is required to assess the risks and benefits of applying primaquine in various geographic and demographic settings. Given that haemolytically toxic antirelapse drugs will likely be the only therapeutic options for the coming decade, it is clear that we need to understand in depth G6PD deficiency and primaquine-induced haemolysis to determine safe and effective therapeutic strategies to overcome this hurdle and achieve malaria elimination. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Diagnosis and management of G6PD deficiency.

            Glucose-6-phosphate dehydrogenase deficiency, the most common enzyme deficiency worldwide, causes a spectrum of disease including neonatal hyperbilirubinemia, acute hemolysis, and chronic hemolysis. Persons with this condition also may be asymptomatic. This X-linked inherited disorder most commonly affects persons of African, Asian, Mediterranean, or Middle-Eastern descent. Approximately 400 million people are affected worldwide. Homozygotes and heterozygotes can be symptomatic, although the disease typically is more severe in persons who are homozygous for the deficiency. The conversion of nicotinamide adenine dinucleotide phosphate to its reduced form in erythrocytes is the basis of diagnostic testing for the deficiency. This usually is done by fluorescent spot test. Different gene mutations cause different levels of enzyme deficiency, with classes assigned to various degrees of deficiency and disease manifestation. Because acute hemolysis is caused by exposure to an oxidative stressor in the form of an infection, oxidative drug, or fava beans, treatment is geared toward avoidance of these and other stressors. Acute hemolysis is self-limited, but in rare instances it can be severe enough to warrant a blood transfusion. Neonatal hyperbilirubinemia may require treatment with phototherapy or exchange transfusion to prevent kernicterus. The variant that causes chronic hemolysis is uncommon because it is related to sporadic gene mutation rather than the more common inherited gene mutation.
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              Review of key knowledge gaps in glucose-6-phosphate dehydrogenase deficiency detection with regard to the safe clinical deployment of 8-aminoquinoline treatment regimens: a workshop report

              The diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency is a crucial aspect in the current phases of malaria control and elimination, which will require the wider use of 8-aminoquinolines for both reducing Plasmodium falciparum transmission and achieving the radical cure of Plasmodium vivax. 8-aminoquinolines, such as primaquine, can induce severe haemolysis in G6PD-deficient individuals, potentially creating significant morbidity and undermining confidence in 8-aminoquinoline prescription. On the other hand, erring on the side of safety and excluding large numbers of people with unconfirmed G6PD deficiency from treatment with 8-aminoquinolines will diminish the impact of these drugs. Estimating the remaining G6PD enzyme activity is the most direct, accessible, and reliable assessment of the phenotype and remains the gold standard for the diagnosis of patients who could be harmed by the administration of primaquine. Genotyping seems an unambiguous technique, but its use is limited by cost and the large range of recognized G6PD genotypes. A number of enzyme activity assays diagnose G6PD deficiency, but they require a cold chain, specialized equipment, and laboratory skills. These assays are impractical for care delivery where most patients with malaria live. Improvements to the diagnosis of G6PD deficiency are required for the broader and safer use of 8-aminoquinolines to kill hypnozoites, while lower doses of primaquine may be safely used to kill gametocytes without testing. The discussions and conclusions of a workshop conducted in Incheon, Korea in May 2012 to review key knowledge gaps in G6PD deficiency are reported here.
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                Author and article information

                Contributors
                Journal
                Malar J
                Malar. J
                Malaria Journal
                BioMed Central
                1475-2875
                2013
                4 November 2013
                : 12
                : 391
                Affiliations
                [1 ]PATH, 2201 Westlake Avenue, Suite 200, Seattle, WA 98121, USA
                [2 ]Eijkman Institute for Molecular Biology, Jakarta, Indonesia
                [3 ]National Institute of Malaria Research, New Delhi, India
                [4 ]Eijkman- Oxford Clinical Research Unit, Jakarta, Indonesia
                [5 ]Shoklo Malaria Research Unit, Mae Sot, Thailand
                [6 ]GlaxoSmithKline, Stockley Park, Uxbridge, UK
                [7 ]Australian Army Malaria Institute, Enoggera, Australia
                [8 ]Bill & Melinda Gates Foundation, Seattle, USA
                [9 ]London School of Hygiene and Tropical Medicine, London, UK
                [10 ]President's Malaria Initiative, Greater Mekong Subregion, Bangkok, Thailand
                [11 ]Centers for Disease Control and Prevention; Global Health Group, University of California, San Francisco, USA
                [12 ]University of the State of Amazonas, Manaus, Brazil
                [13 ]Institut Pasteur du Cambodge, Phnom Penh, Cambodia
                [14 ]Mahidol Oxford Research Unit, Bangkok, Thailand
                [15 ]Chulalongkorn University, Bangkok, Thailand
                [16 ]Department of Medical Research, Lower Myanmar, Yangon, Myanmar
                [17 ]Bureau of Vector Borne Diseases, Bangkok, Thailand
                [18 ]PATH, Bangkok, Thailand
                [19 ]Malaria Consortium, Phnom Penh, Cambodia
                [20 ]Thailand Ministry of Public Health, Bangkok, Thailand
                [21 ]National Malaria Control Programme, Phnom Penh, Cambodia
                [22 ]WHO/WPRO, Manila, Philippines
                [23 ]Menzies School of Health Research, Darwin, Australia
                Article
                1475-2875-12-391
                10.1186/1475-2875-12-391
                3830439
                24188096
                17cbe51e-de89-4148-be6e-01ab82969d7d
                Copyright © 2013 Domingo et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 11 September 2013
                : 30 October 2013
                Categories
                Meeting Report

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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