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

BackgroundG6PD 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.MethodsThis 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.ResultsMutations 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.ConclusionsThe 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

Treatment of Vivax Malaria in Vietnam

Globally, relapse caused by Plasmodium vivax malaria is estimated to contribute approximately 50% to the overall number of vivax infections. In South-East Asia, relapse rates commonly exceed 50%, making relapse as the main source of vivax illness. Recurrent episodes of febrile illness and hemolysis inflict a significant public health burden particularly in vulnerable groups such as pregnant women and young children. Multiple relapses may contribute substantially to the delayed morbidity and unappreciated mortality relative to falciparum malaria. Therefore, the radical cure of P. vivax malaria requires a combination of both blood schizontocides to achieve acute clinical cure, and hypnozoiticides to prevent relapses in the future. The World Health Organization (WHO) recommends the standard 14-day primaquine regimen in curing and preventing relapse from vivax malaria. Another 8-aminoquinoline derivative with prolonged elimination half-life, tafenoquine, also propose an alternative choice in radical therapy. The main research question is: what is the most effective treatment to achieve radical cure of Plasmodium vivax in Vietnam? In order to answer this question a series of studies and clinical trials were conducted in Vietnam and our findings point to these conclusions: 1/ The short 7-day course of primaquine is an available, safe and highly efficacious antirelapse treatment that could improve the adherence of patients and hence the effectiveness of radical cure of vivax relapse. 2/ The single dose of 300 mg tafenoquine, an 8-aminoquinoline drug, has similar antirelapse activity compared to primaquine. When administered with chloroquine, this hypnozoiticidal agent is a potential candidate in the malaria elimination era. 3/ The prevalence and variants of G6PD deficiency determinants of hemolytic toxicity of 8-aminoquinolines in malaria endemic regions represent important factors to be considered when implementing radical cure of latent vivax malaria

Implementing parasite genotyping into national surveillance frameworks: Feedback from control programmes and researchers in the Asia-pacific region

The Asia-Pacific region faces formidable challenges in achieving malaria elimination by the proposed target in 2030. Molecular surveillance of Plasmodium parasites can provide important information on malaria transmission and adaptation, which can inform national malaria control programmes (NMCPs) in decision-making processes. In November 2019 a parasite genotyping workshop was held in Jakarta, Indonesia, to review molecular approaches for parasite surveillance and explore ways in which these tools can be integrated into public health systems and inform policy. The meeting was attended by 70 participants from 8 malaria-endemic countries and partners of the Asia Pacific Malaria Elimination Network. The participants acknowledged the utility of multiple use cases for parasite genotyping including: quantifying the prevalence of drug resistant parasites, predicting risks of treatment failure, identifying major routes and reservoirs of infection, monitoring imported malaria and its contribution to local transmission, characterizing the origins and dynamics of malaria outbreaks, and estimating the frequency of Plasmodium vivax relapses. However, the priority of each use case varies with different endemic settings. Although a one-size-fits-all approach to molecular surveillance is unlikely to be applicable across the Asia-Pacific region, consensus on the spectrum of added-value activities will help support data sharing across national boundaries. Knowledge exchange is needed to establish local expertise in different laboratory-based methodologies and bioinformatics processes. Collaborative research involving local and international teams will help maximize the impact of analytical outputs on the operational needs of NMCPs. Research is also needed to explore the cost-effectiveness of genetic epidemiology for different use cases to help to leverage funding for wide-scale implementation. Engagement between NMCPs and local researchers will be critical throughout this process

Human and Simian Malaria in the Greater Mekong Subregion and Challenges for Elimination

In recent years malaria initiatives have increasingly shifted from malaria control to a focus on achieving malaria elimination in the Southeast Asia region. However, this region experiences unique challenges in this transition due to its distinctive malaria ecosystem (mainly related to forests) and high volume of population movement (both within and between countries). These bioenvironmental factors increase the exposure of populations at higher risk due to their close association with forest, and contributes to outdoor and residual transmission. Given that this region has also historically been the source of resistance to anti-malarial drugs, the potential spread of artemisinin resistance via global transportation routes would pose a major threat to malaria control and elimination efforts worldwide. In addition, other factors also hinder the malaria elimination goal such as importation of parasite infection, uncontrolled monkey malaria (Plasmodium knowlesi), or the fact that many countries in this region experience mixed infections where P. vivax becomes a more predominant species as overall malaria transmission decreases. This chapter addresses these challenges in detail and provide recommendations and key priorities to overcome these obstacles to accelerate efforts for achieving malaria elimination

The spatial epidemiology of the Duffy blood group and G6PD deficiency

Over a third of the world’s population lives at risk of potentially severe Plasmodium vivax malaria. Unique aspects of this parasite’s biology and interactions with its human host make it harder to control and eliminate than the better studied Plasmodium falciparum parasite. Spatial mapping of two human genetic polymorphisms were developed to support evidence-based targeting of control interventions and therapies. First, to enumerate and map the population at risk of P. vivax infection (PvPAR), the prevalence of this parasite’s human blood cell receptor – the Duffy antigen – was mapped globally. Duffy negative individuals are resistant to infection, and this map provided the means to objectively model the low endemicity of P. vivax across Africa. The Duffy maps helped resolve that only 3% of the global PvPAR was from Africa. The second major research focus was to map the spatial distribution of glucose-6-phosphate dehydrogenase enzyme deficiency (G6PDd), the genetic condition which predisposes individuals to potentially life-threatening haemolysis from primaquine therapy. Despite this drug’s vital role in being the only treatment of relapsing P. vivax parasites, risks of G6PDd-associated haemolysis result in significant under-use of primaquine. G6PDd was found to be widespread, with an estimated frequency of 8.0% (50% CI: 7.4-8.8%) across malarious regions. Third, it was important to represent more detailed descriptions of the genetic diversity underpinning this enzyme disorder, which ranges in phenotype from expressing mild to life-threatening primaquine-induced haemolysis. These variants’ spatial distributions were mapped globally and showed strikingly conspicuous distributions, with widespread A- dominance across Africa, predominance of the Mediterranean variant from the Middle East across to India, and east of India diversifying into a different and diverse array of variants, showing heterogeneity both at regional and community levels. Fourth, the G6PDd prevalence and severity maps were synthesised into a framework assessing the spatial variability of overall risk from G6PDd to primaquine therapy. This found that risks from G6PDd were too widespread and potentially severe to sanction primaquine treatment without prior G6PDd screening, particularly across Asia where the majority of the population are Duffy positive and G6PDd was common and severe. Finally, the conclusions from these studies were discussed and recommendations made for essential further research needed to support current efforts into P. vivax control

Longitudinal trends in malaria testing rates in the face of elimination in eastern Myanmar: a 7-year observational study

Background: Providing at-risk communities with uninterrupted access to early diagnosis and treatment is a key component in reducing malaria transmission and achieving elimination. As programmes approach malaria elimination targets it is critical that each case is tested and treated early, which may present a challenge when the burden of malaria is reduced. In this paper we investigate whether malaria testing rates decline over time and assess the impacts of integrating malaria and non-malaria services on testing rates in the malaria elimination task force (METF) programme in the Kayin state of Myanmar. Methods: A retrospective analysis was conducted using weekly collected data on testing rates from a network of more than 1200 malaria posts during the period from 2014 to 2020. To determine whether monthly testing rates changed over the years of programme operations, and whether integrating malaria and non-malaria services impacted these testing rates, we fitted negative binomial mixed-effects regression models to aggregate monthly data, accounting for malaria seasonal variation. Results: In the first year of malaria post operation, testing rates declined, correlating with a decline in attendance by people from outside the malaria post catchment area, but then remained fairly constant (the Rate Ratio (RR) for 2nd versus 1st year open ranged from 0.68 to 0.84 across the four townships included in the analysis, the RR for 3rd to 6th year versus 1st year open were similar, ranging from 0.59–0.78). The implementation of a training programme, which was intended to expand the role of the malaria post workers, had minimal impact on testing rates up to 24 months after training was delivered (RR for integrated versus malaria-only services ranged from 1.00 to 1.07 across METF townships). Conclusion: Despite the decline in malaria incidence from 2014 to 2020, there has been no decline in the malaria testing rate in the METF programme after the establishment of the complete malaria post network in 2016. While the integration of malaria posts with other health services provides benefits to the population, our evaluation questions the necessity of integrated services in maintaining malaria testing rates in areas approaching elimination of malaria

Artemisinin-Resistant Malaria: Research Challenges, Opportunities, and Public Health Implications

Artemisinin-based combination therapies are the most effective drugs to treat Plasmodium falciparum malaria. Reduced sensitivity to artemisinin monotherapy, coupled with the emergence of parasite resistance to all partner drugs, threaten to place millions of patients at risk of inadequate treatment of malaria. Recognizing the significance and immediacy of this possibility, the Fogarty International Center and the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health convened a conference in November 2010 to bring together the diverse array of stakeholders responding to the growing threat of artemisinin resistance, including scientists from malarious countries in peril. This conference encouraged and enabled experts to share their recent unpublished data from studies that may improve our understanding of artemisinin resistance. Conference sessions addressed research priorities to forestall artemisinin resistance and fostered collaborations between field- and laboratory-based researchers and international programs, with the aim of translating new scientific evidence into public health solutions. Inspired by this conference, this review summarizes novel findings and perspectives on artemisinin resistance, approaches for translating research data into relevant public health information, and opportunities for interdisciplinary collaboration to combat artemisinin resistance