scholarly journals Optimizing G6PD testing for Plasmodium vivax case management and beyond: why sex, counseling, and community engagement matter

2020 ◽  
Vol 5 ◽  
pp. 21
Author(s):  
Cindy S Chu ◽  
Germana Bancone ◽  
Maureen Kelley ◽  
Nicole Advani ◽  
Gonzalo J Domingo ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
G6pd Deficiency ◽  
Point Of Care ◽  
Genetic Disorder ◽  
Treatment Options ◽  
Radical Cure ◽  
Sex Counseling ◽  
Point Of Care Diagnostics ◽  
Genetic Test Results ◽  
Human Genetic Disorder

Safe access to the most effective treatment options for Plasmodium vivax malaria are limited by the absence of accurate point-of-care testing to detect glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common human genetic disorder. G6PD-deficient patients are at risk of life-threatening hemolysis when exposed to 8-aminoquinolines, the only class of drugs efficacious against P. vivax hypnozoites. Until recently, only qualitative tests were available in most settings. These can identify patients with severe G6PD deficiency (mostly male) but not patients with intermediate G6PD deficiency (always female). This has led to and reinforced a gap in awareness in clinical practice of the risks and implications of G6PD deficiency in females—who, unlike males, can have a heterozygous genotype for G6PD. Increasing recognition of the need for radical cure of  P. vivax, first for patients’ health and then for malaria elimination, is driving the development of new point-of-care tests for G6PD deficiency and their accessibility to populations in low-resource settings. The availability of user-friendly, affordable, and accurate quantitative point-of-care diagnostics for the precise classification of the three G6PD phenotypes can reduce sex-linked disparities by ensuring safe and effective malaria treatment, providing opportunities to develop supportive counseling to enhance understanding of genetic test results, and improving the detection of all G6PD deficiency phenotypes in newborns and their family members.

scholarly journals Optimizing G6PD testing for Plasmodium vivax case management: why sex, counseling, and community engagement matter

2020 ◽  
Vol 5 ◽  
pp. 21
Author(s):  
Cindy S Chu ◽  
Germana Bancone ◽  
Maureen Kelley ◽  
Nicole Advani ◽  
Gonzalo J Domingo ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
G6pd Deficiency ◽  
Point Of Care ◽  
Genetic Disorder ◽  
Treatment Options ◽  
Radical Cure ◽  
Sex Counseling ◽  
Point Of Care Diagnostics ◽  
Genetic Test Results ◽  
Human Genetic Disorder

Safe access to the most effective treatment options for Plasmodium vivax malaria are limited by the absence of accurate point-of-care testing to detect glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common human genetic disorder. G6PD-deficient patients are at risk of life-threatening hemolysis when exposed to 8-aminoquinolines, the only class of drugs efficacious against P. vivax hypnozoites. Until recently, only qualitative tests were available in most settings. These accurately identify patients with severe G6PD deficiency (mostly male) but not patients with intermediate G6PD deficiency (always female). This has led to and reinforced a gap in awareness in clinical practice of the risks and implications of G6PD deficiency in females—who, unlike males, can have a heterozygous genotype for G6PD. Increasing recognition of the need for radical cure of P. vivax, first for patients’ health and then for malaria elimination, is driving the development of new point-of-care tests for G6PD deficiency and their accessibility to populations in low-resource settings. The availability of simple, affordable, and accurate point-of-care diagnostics for the precise classification of the three G6PD phenotypes can reduce sex-linked disparities by ensuring safe and effective malaria treatment, providing opportunities to develop supportive counseling to enhance understanding of genetic test results, and improving the detection of all G6PD deficiency phenotypes in newborns and their family members.

scholarly journals Protective effect of Mediterranean-type glucose-6-phosphate dehydrogenase deficiency against Plasmodium vivax malaria

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Ghulam R Awab ◽  
Fahima Aaram ◽  
Natsuda Jamornthanyawat ◽  
Kanokon Suwannasin ◽  
Watcharee Pagornrat ◽  
...  
Keyword(s):  
Protective Effect ◽  
Plasmodium Vivax ◽  
G6pd Deficiency ◽  
Vivax Malaria ◽  
Malaria Incidence ◽  
Large Population ◽  
Credible Interval ◽  
Radical Cure ◽  
Plasmodium Vivax Malaria ◽  
Glucose 6 Phosphate Dehydrogenase

X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. The severe Mediterranean variant (G6PD Med) found across Europe and Asia is thought to confer protection against malaria, but its effect is unclear. We fitted a Bayesian statistical model to observed G6PD Med allele frequencies in 999 Pashtun patients presenting with acute Plasmodium vivax malaria and 1408 population controls. G6PD Med was associated with reductions in symptomatic P. vivax malaria incidence of 76% (95% credible interval [CI], 58–88) in hemizygous males and homozygous females combined and 55% (95% CI, 38–68) in heterozygous females. Unless there is very large population stratification within the Pashtun (confounding these results), the G6PD Med genotype confers a very large and gene-dose proportional protective effect against acute vivax malaria. The proportion of patients with vivax malaria at risk of haemolysis following 8-aminoquinoline radical cure is substantially overestimated by studies measuring G6PD deficiency prevalence in healthy subjects.

scholarly journals Assessment of Point-of-Care Diagnostics for G6PD Deficiency in Malaria Endemic Rural Eastern Indonesia

2016 ◽  
Vol 10 (2) ◽  
pp. e0004457 ◽  
Author(s):  
Ari W. Satyagraha ◽  
Arkasha Sadhewa ◽  
Rosalie Elvira ◽  
Iqbal Elyazar ◽  
Denny Feriandika ◽  
...  
Keyword(s):  
G6pd Deficiency ◽  
Point Of Care ◽  
Eastern Indonesia ◽  
Point Of Care Diagnostics

scholarly journals Point-of-Care Testing for G6PD Deficiency: Opportunities for Screening

2018 ◽  
Vol 4 (4) ◽  
pp. 34 ◽  
Author(s):  
Athena Anderle ◽  
Germana Bancone ◽  
Gonzalo Domingo ◽  
Emily Gerth-Guyette ◽  
Sampa Pal ◽  
...  
Keyword(s):  
Case Management ◽  
Malaria Case ◽  
G6pd Deficiency ◽  
High Throughput Screening ◽  
Point Of Care ◽  
Genetic Disorder ◽  
Gender Disparity ◽  
World Health ◽  
Malaria Case Management ◽  
Increased Risk

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked genetic disorder, is associated with increased risk of jaundice and kernicterus at birth. G6PD deficiency can manifest later in life as severe hemolysis, when the individual is exposed to oxidative agents that range from foods such as fava beans, to diseases such as typhoid, to medications such as dapsone, to the curative drugs for Plasmodium (P.) vivax malaria, primaquine and tafenoquine. While routine testing at birth for G6PD deficiency is recommended by the World Health Organization for populations with greater than 5% prevalence of G6PD deficiency and to inform P. vivax case management using primaquine, testing coverage is extremely low. Test coverage is low due to the need to prioritize newborn interventions and the complexity of currently available G6PD tests, especially those used to inform malaria case management. More affordable, accurate, point-of-care (POC) tests for G6PD deficiency are emerging that create an opportunity to extend testing to populations that do not have access to high throughput screening services. Some of these tests are quantitative, which provides an opportunity to address the gender disparity created by the currently available POC qualitative tests that misclassify females with intermediate G6PD activity as normal. In populations where the epidemiology for G6PD deficiency and P. vivax overlap, screening for G6PD deficiency at birth to inform care of the newborn can also be used to inform malaria case management over their lifetime.

scholarly journals In vivo efficacy of anti-malarial drugs against clinical Plasmodium vivax malaria in Ethiopia: a systematic review and meta-analysis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Tsige Ketema ◽  
Ketema Bacha ◽  
Kefelegn Getahun ◽  
Quique Bassat
Keyword(s):  
Plasmodium Vivax ◽  
Publication Bias ◽  
Vivax Malaria ◽  
Meta Analysis ◽  
Treatment Options ◽  
Significant Heterogeneity ◽  
Radical Cure ◽  
In Vivo Efficacy

Abstract Background Ethiopia is one of the few countries in Africa where Plasmodium vivax commonly co-exists with Plasmodium falciparum, and which accounts for ~ 40% of the total number of malaria infections in the country. Regardless of the growing evidence over many decades of decreasing sensitivity of this parasite to different anti-malarial drugs, there has been no comprehensive attempt made to systematically review and meta-analyse the efficacy of different anti-malarial drugs against P. vivax in the country. However, outlining the efficacy of available anti-malarial drugs against this parasite is essential to guide recommendations for the optimal therapeutic strategy to use in clinical practice. The aim of this study was to synthesize evidence on the efficacy of anti-malarial drugs against clinical P. vivax malaria in Ethiopia. Methods All potentially relevant, peer-reviewed articles accessible in PubMed, Scopus, Web of Science, and Clinical Trial.gov electronic databases were retrieved using a search strategy combining keywords and related database-specific subject terms. Randomized controlled trials (RCTs) and non-randomized trials aiming to investigate the efficacy of anti-malarial drugs against P. vivax were included in the review. Data were analysed using Review Manager Software. Cochrane Q (χ2) and the I2 tests were used to assess heterogeneity. The funnel plot and Egger’s test were used to examine risk of publication bias. Results Out of 1294 identified citations, 14 articles that presented data on 29 treatment options were included in the analysis. These studies enrolled 2144 clinical vivax malaria patients. The pooled estimate of in vivo efficacy of anti-malarial drugs against vivax malaria in Ethiopia was 97.91% (95% CI: 97.29–98.52%), with significant heterogeneity (I2 = 86%, p < 0.0001) and publication bias (Egger’s test = -12.86, p < 0.001). Different anti-malarial drugs showed varied efficacies against vivax malaria. The duration of follow-up significantly affected the calculated efficacy of any given anti-malarial drug, with longer duration of the follow-up (42 days) associated with significantly lower efficacy than efficacy reported on day 28. Also, pooled PCR-corrected efficacy and efficacy estimated from altitudinally lower transmission settings were significantly higher than PCR-uncorrected efficacy that estimated for moderate transmission settings, respectively. Conclusion The overall efficacy of anti-malarial drugs evaluated for the treatment of vivax malaria in Ethiopia was generally high, although there was wide-ranging degree of efficacy, which was affected by the treatment options, duration of follow-up, transmission intensity, and the confirmation procedures for recurrent parasitaemia. Regardless of evidence of sporadic efficacy reduction reported in the country, chloroquine (CQ), the first-line regimen in Ethiopia, remained highly efficacious, supporting its continuous utilization for confirmed P. vivax mono-infections. The addition of primaquine (PQ) to CQ is recommended, as this is the only approved way to provide radical cure, and thus ensure sustained efficacy and longer protection against P. vivax. Continuous surveillance of the efficacy of anti-malarial drugs and clinical trials to allow robust conclusions remains necessary to proactively act against possible emergence and spread of drug-resistant P. vivax in Ethiopia.

scholarly journals Prevalence and distribution of G6PD deficiency: implication for the use of primaquine in malaria treatment in Ethiopia

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Eugenia Lo ◽  
Daibin Zhong ◽  
Beka Raya ◽  
Kareen Pestana ◽  
Cristian Koepfli ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
G6pd Deficiency ◽  
Enzyme Level ◽  
Gene Mutations ◽  
Malaria Treatment ◽  
Fisher Exact Test ◽  
Radical Cure ◽  
Febrile Patient ◽  
South Ethiopia ◽  
G6pd Gene

Abstract Background G6PD enzyme deficiency is a common enzymatic X-linked disorder. Deficiency of the G6PD enzyme can cause free radical-mediated oxidative damage to red blood cells, leading to premature haemolysis. Treatment of Plasmodium vivax malaria with primaquine poses a potential risk of mild to severe acute haemolytic anaemia in G6PD deficient people. In this study, the prevalence and distribution of G6PD mutations were investigated across broad areas of Ethiopia, and tested the association between G6PD genotype and phenotype with the goal to provide additional information relevant to the use of primaquine in malaria treatment. Methods This study examined G6PD mutations in exons 3–11 for 344 febrile patient samples collected from seven sites across Ethiopia. In addition, the G6PD enzyme level of 400 febrile patient samples from Southwestern Ethiopia was determined by the CareStart™ biosensor. The association between G6PD phenotype and genotype was examined by Fisher exact test on a subset of 184 samples. Results Mutations were observed at three positions of the G6PD gene. The most common G6PD mutation across all sites was A376G, which was detected in 21 of 344 (6.1%) febrile patients. Thirteen of them were homozygous and eight were heterozygous for this mutation. The G267+119C/T mutation was found in 4 (1.2%) individuals in South Ethiopia, but absent in other sites. The G1116A mutation was also found in 4 (1.2%) individuals from East and South Ethiopia. For the 400 samples in the south, 17 (4.25%) were shown to be G6PD-deficient. G6PD enzyme level was not significantly different by age or gender. Among a subset of 202 febrile patients who were diagnosed with malaria, 11 (5.45%) were G6PD-deficient. These 11 infected samples were diagnosed with Plasmodium vivax by microscopy. Parasitaemia was not significantly different between the G6PD-deficient and G6PD-normal infections. Conclusions The prevalence of G6PD deficiency is modest among febrile patients in Ethiopia. G6PD deficiency testing is thus recommended before administrating primaquine for radical cure of P. vivax infected patients. The present study did not indicate a significant association between G6PD gene mutations and enzyme levels.

scholarly journals Real-life implementation of a G6PD deficiency screening qualitative test into routine vivax malaria diagnostic units in the Brazilian Amazon (SAFEPRIM study)

2021 ◽  
Vol 15 (5) ◽  
pp. e0009415
Author(s):  
Jose Diego Brito-Sousa ◽  
Felipe Murta ◽  
Sheila Vitor-Silva ◽  
Vanderson S. Sampaio ◽  
Maxwell O. Mendes ◽  
...  
Keyword(s):  
Health Care Professionals ◽  
G6pd Deficiency ◽  
Endemic Area ◽  
Point Of Care ◽  
Training Session ◽  
Real Life ◽  
High Sensitivity ◽  
Brazilian Amazon ◽  
Radical Cure ◽  
Effectiveness Of Training

Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency greatly hinders Plasmodium vivax malaria radical cure and further elimination due to 8-aminoquinolines-associated hemolysis. Although the deleterious health effects of primaquine in G6PD deficient individuals have been known for over 50 years, G6PD testing is not routinely performed before primaquine treatment in most P. vivax endemic areas. Method/Principal findings The qualitative CareStart G6PD screening test was implemented in 12 malaria treatment units (MTUs) in the municipality of Rio Preto da Eva, Western Brazilian Amazon, a malaria endemic area, between February 2019 and early January 2020. Training materials were developed and validated; evaluations were conducted on the effectiveness of training health care professionals (HCPs) to perform the test, the interpretation and reliability of routine testing performed by HCPs, and perceptions of HCPs and patients. Most HCPs were unaware of G6PD deficiency and primaquine-related adverse effects. Most of 110 HCPs trained (86/110, 78%) were able to correctly perform the G6PD test after a single 4-hour training session. The test performed by HCPs during implementation showed 100.0% (4/4) sensitivity and 68.1% (62/91) specificity in identifying G6PD deficient patients as compared to a point-of-care quantitative test (Standard G6PD). Conclusions/Significance G6PD screening using the qualitative CareStart G6PD test performed by HCPs in MTUs of an endemic area showed high sensitivity and concerning low specificity. The amount of false G6PD deficiency detected led to substantial loss of opportunities for radical cure.

scholarly journals Genotypes and phenotypes of G6PD deficiency among Indonesian females across diagnostic thresholds of G6PD activity guiding safe primaquine therapy of latent malaria

2021 ◽  
Vol 15 (7) ◽  
pp. e0009610
Author(s):  
Ari Winasti Satyagraha ◽  
Arkasha Sadhewa ◽  
Lydia Visita Panggalo ◽  
Decy Subekti ◽  
Iqbal Elyazar ◽  
...  
Keyword(s):  
At Risk ◽  
G6pd Deficiency ◽  
Point Of Care ◽  
Normal Activity ◽  
G6pd Activity ◽  
Radical Cure ◽  
Diagnostic Thresholds ◽  
Hemolytic Crisis ◽  
Compound Heterozygotes ◽  
Patent Infection

Background Plasmodium vivax occurs as a latent infection of liver and a patent infection of red blood cells. Radical cure requires both blood schizontocidal and hypnozoitocidal chemotherapies. The hypnozoitocidal therapies available are primaquine and tafenoquine, 8-aminoquinoline drugs that can provoke threatening acute hemolytic anemia in patients having an X-linked G6PD-deficiency. Heterozygous females may screen as G6PD-normal prior to radical cure and go on to experience hemolytic crisis. Methods & findings This study examined G6PD phenotypes in 1928 female subjects living in malarious Sumba Island in eastern Indonesia to ascertain the prevalence of females vulnerable to diagnostic misclassification as G6PD-normal. All 367 (19%) females having <80% G6PD normal activity were genotyped. Among those, 103 (28%) were G6PD wild type, 251 (68·4%) were heterozygous, three (0·8%) were compound heterozygotes, and ten (2·7%) were homozygous deficient. The variants Vanua Lava, Viangchan, Coimbra, Chatham, and Kaiping occurred among them. Below the 70% of normal G6PD activity threshold, just 18 (8%) were G6PD-normal and 214 (92%) were G6PD-deficient. Among the 31 females with <30% G6PD normal activity were all ten homozygotes, all three compound heterozygotes, and just 18 were heterozygotes (7% of those). Conclusions In this population, most G6PD heterozygosity in females occurred between 30% and 70% of normal (69·3%; 183/264). The prevalence of females at risk of G6PD misclassification as normal by qualitative screening was 9·5% (183/1928). Qualitative G6PD screening prior to 8-aminoquinoline therapies against P. vivax may leave one in ten females at risk of hemolytic crisis, which may be remedied by point-of-care quantitative tests.

scholarly journals Recombinant human G6PD for quality control and quality assurance of novel point-of-care diagnostics for G6PD deficiency

PLoS ONE ◽  
2017 ◽  
Vol 12 (5) ◽  
pp. e0177885 ◽  
Author(s):  
Maria Kahn ◽  
Nicole LaRue ◽  
Changcheng Zhu ◽  
Sampa Pal ◽  
Jack S. Mo ◽  
...  
Keyword(s):  
Quality Control ◽  
Quality Assurance ◽  
G6pd Deficiency ◽  
Point Of Care ◽  
Point Of Care Diagnostics

scholarly journals Global economic costs due to vivax malaria and the potential impact of its radical cure: A modelling study

PLoS Medicine ◽  
2021 ◽  
Vol 18 (6) ◽  
pp. e1003614
Author(s):  
Angela Devine ◽  
Katherine E. Battle ◽  
Niamh Meagher ◽  
Rosalind E. Howes ◽  
Saber Dini ◽  
...  
Keyword(s):  
Healthcare Provider ◽  
G6pd Deficiency ◽  
Vivax Malaria ◽  
Patient Adherence ◽  
Treatment Options ◽  
Radical Cure ◽  
Potential Cost ◽  
Global Cost ◽  
Household Costs ◽  
Modelling Study

Background In 2017, an estimated 14 million cases of Plasmodium vivax malaria were reported from Asia, Central and South America, and the Horn of Africa. The clinical burden of vivax malaria is largely driven by its ability to form dormant liver stages (hypnozoites) that can reactivate to cause recurrent episodes of malaria. Elimination of both the blood and liver stages of the parasites (“radical cure”) is required to achieve a sustained clinical response and prevent ongoing transmission of the parasite. Novel treatment options and point-of-care diagnostics are now available to ensure that radical cure can be administered safely and effectively. We quantified the global economic cost of vivax malaria and estimated the potential cost benefit of a policy of radical cure after testing patients for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Methods and findings Estimates of the healthcare provider and household costs due to vivax malaria were collated and combined with national case estimates for 44 endemic countries in 2017. These provider and household costs were compared with those that would be incurred under 2 scenarios for radical cure following G6PD screening: (1) complete adherence following daily supervised primaquine therapy and (2) unsupervised treatment with an assumed 40% effectiveness. A probabilistic sensitivity analysis generated credible intervals (CrIs) for the estimates. Globally, the annual cost of vivax malaria was US$359 million (95% CrI: US$222 to 563 million), attributable to 14.2 million cases of vivax malaria in 2017. From a societal perspective, adopting a policy of G6PD deficiency screening and supervision of primaquine to all eligible patients would prevent 6.1 million cases and reduce the global cost of vivax malaria to US$266 million (95% CrI: US$161 to 415 million), although healthcare provider costs would increase by US$39 million. If perfect adherence could be achieved with a single visit, then the global cost would fall further to US$225 million, equivalent to $135 million in cost savings from the baseline global costs. A policy of unsupervised primaquine reduced the cost to US$342 million (95% CrI: US$209 to 532 million) while preventing 2.1 million cases. Limitations of the study include partial availability of country-level cost data and parameter uncertainty for the proportion of patients prescribed primaquine, patient adherence to a full course of primaquine, and effectiveness of primaquine when unsupervised. Conclusions Our modelling study highlights a substantial global economic burden of vivax malaria that could be reduced through investment in safe and effective radical cure achieved by routine screening for G6PD deficiency and supervision of treatment. Novel, low-cost interventions for improving adherence to primaquine to ensure effective radical cure and widespread access to screening for G6PD deficiency will be critical to achieving the timely global elimination of P. vivax.

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