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Background: Chloroquine remains the mainstay of treatment for Plasmodium vivax malaria despite increasing reports of treatment failure. We did a systematic review and meta-analysis to investigate the effect of chloroquine dose and the addition of primaquine on the risk of recurrent vivax malaria across different settings., Methods: A systematic review done in MEDLINE, Web of Science, Embase, and Cochrane Database of Systematic Reviews identified P vivax clinical trials published between Jan 1, 2000, and March 22, 2017. Principal investigators were invited to share individual patient data, which were pooled using standardised methods. Cox regression analyses with random effects for study site were used to investigate the roles of chloroquine dose and primaquine use on rate of recurrence between day 7 and day 42 (primary outcome). The review protocol is registered in PROSPERO, number CRD42016053310., Findings: Of 134 identified chloroquine studies, 37 studies (from 17 countries) and 5240 patients were included. 2990 patients were treated with chloroquine alone, of whom 1041 (34·8%) received a dose below the target 25 mg/kg. The risk of recurrence was 32·4% (95% CI 29·8-35·1) by day 42. After controlling for confounders, a 5 mg/kg higher chloroquine dose reduced the rate of recurrence overall (adjusted hazard ratio [AHR] 0·82, 95% CI 0·69-0·97; p=0·021) and in children younger than 5 years (0·59, 0·41-0·86; p=0·0058). Adding primaquine reduced the risk of recurrence to 4·9% (95% CI 3·1-7·7) by day 42, which is lower than with chloroquine alone (AHR 0·10, 0·05-0·17; p<0·0001)., Interpretation: Chloroquine is commonly under-dosed in the treatment of vivax malaria. Increasing the recommended dose to 30 mg/kg in children younger than 5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine-resistant P vivax., Funding: Wellcome Trust, Australian National Health and Medical Research Council, and Bill & Melinda Gates Foundation., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Plasmodium vivax is the second most prevalent human malaria parasite in Bangladesh; however, there are no data of its genetic diversity. Several molecular markers are available where Pvcsp, Pvmsp 1 and Pvmsp 3α are most commonly used for P. vivax genotyping studies. The aim of the study was to investigate the population structure of P. vivax in Bangladesh., Methods: A total of 102 P. vivax-positive blood samples were collected from different malaria-endemic areas in Bangladesh and subsequently analysed for those three genotyping markers. Nested PCR was performed for diagnosis and genotyping analysis followed by PCR-RFLP to detect genetic diversity using Pvcsp, Pvmsp 1 and Pvmsp 3α markers., Results: Analysis of Pvcsp showed that the VK210 repeat type was highly prevalent (64.7%, 66/102) compared to VK247 (35.3%, 36/102), although the prevalence of VK247 was higher than other Southeast Asian countries. Analysis of these three genes revealed a diverse, circulating population of P. vivax where a total of ten, 56 and 35 distinct genotypes were detected for Pvcsp, Pvmsp 1 and Pvmsp 3α, respectively., Conclusion: This genotyping observation of P. vivax is the first report from Bangladesh and will provide valuable information for establishing the genotyping methods and circulating genetic variants of these three markers available in Bangladesh.

Primaquine and tafenoquine are the only licensed drugs with activity against Plasmodium vivax hypnozoites but cause haemolysis in patients with glucose–6–phosphate dehydrogenase (G6PD) deficiency. Malaria also causes haemolysis, leading to the replacement of older erythrocytes with low G6PD activity by reticulocytes and young erythrocytes with higher activity. Aim of this study was to assess the impact of acute malaria on G6PD activity. Selected patients with uncomplicated malaria were recruited in Bangladesh (n = 87), Indonesia (n = 75), and Ethiopia (n = 173); G6PD activity was measured at the initial presentation with malaria and a median of 176 days later (range 140 to 998) in the absence of malaria. Among selected participants (deficient participants preferentially enrolled in Bangladesh but not at other sites) G6PD activity fell between malaria and follow up by 79.1% (95%CI: 40.4 to 117.8) in 6 participants classified as deficient (<30% activity), 43.7% (95%CI: 34.2 to 53.1) in 39 individuals with intermediate activity (30% to <70%), and by 4.5% (95%CI: 1.4 to 7.6) in 290 G6PD normal (≥70%) participants. In Bangladesh and Indonesia G6PD activity was significantly higher during acute malaria than when the same individuals were retested during follow up (40.9% (95%CI: 33.4–48.1) and 7.4% (95%CI: 0.2 to 14.6) respectively), whereas in Ethiopia G6PD activity was 3.6% (95%CI: -1.0 to -6.1) lower during acute malaria. The change in G6PD activity was apparent in patients presenting with either P. vivax or P. falciparum infection. Overall, 66.7% (4/6) severely deficient participants and 87.2% (34/39) with intermediate deficiency had normal activities when presenting with malaria. These findings suggest that G6PD activity rises significantly and at clinically relevant levels during acute malaria. Prospective case-control studies are warranted to confirm the degree to which the predicted population attributable risks of drug induced haemolysis is lower than would be predicted from cross sectional surveys. Author summary: Plasmodium vivax forms dormant liver stages in the human host that reactivate weeks to months after the first infection and cause significant morbidity and mortality in affected populations. The group of 8-aminoquinolines are the only class of licensed drugs that remove these liver stages from the human host but are contra-indicated in patients with low activities of the glucose-6-phosphate dehydrogenase enzyme (G6PD). The WHO therefore recommends testing G6PD activity prior to treatment to exclude individuals with low activities from standard treatment. We enrolled 335 patients with malaria in Bangladesh, Indonesia, and Ethiopia and measured G6PD activity in all participants. All participants were followed up and a second G6PD measurement was collected between 6 and 33 months after enrolment if participants were free of malaria. When comparing both measurements, G6PD activity was 10% higher during malaria. The increase in G6PD activity during malaria is probably triggered by the Plasmodium infection, the observed change in G6PD activity may alter the risk profile of standard malaria treatment with 8-aminoquinolines. [ABSTRACT FROM AUTHOR]

The proportion of Plasmodium vivax malaria among all malarias is increasing worldwide. Treatment with 8-aminoquinolines remain the only radical cure. However, 8-aminoquinolines can cause severe hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient patients. The population of the multi-ethnic Chittagong Hill Tracts (CHT) carry the highest malaria burden within Bangladesh. As in many countries the national treatment guidelines recommend 8-aminoquinoline based radical cure without routine G6PD deficiency (G6PDd) testing to guide treatment. Aim of this study was to determine the need for routine testing within a multi-ethnic population by assessing the prevalence of G6PDd among the local population. Participants from 11 ethnicities were randomly selected and malaria status was assessed by microscopy, rapid diagnostic test (RDT) and polymerase chain reaction (PCR). G6PD status was determined by spectrophotometry and G6PD genotyping. The adjusted male median (AMM) was defined as 100% G6PD activity, participants were categorized as G6PD deficient (<30% activity), G6PD intermediate (30% to 70% activity) or G6PD normal (>70% activity). Median G6PD activities between ethnicities were compared and the association between G6PD activity and malaria status was assessed. 1002 participants were enrolled and tested for malaria. G6PD activity was measured by spectrophotometry in 999 participants and host G6PD genotyping undertaken in 323 participants. Seven participants (0.7%) had peripheral parasitaemia detected by microscopy or RDT and 42 by PCR (4.2%). Among 106 participants (32.8%) with confirmed genotype, 99 (93.4%) had the Mahidol variant. The AMM was 7.03U/gHb with 90 (9.0%) G6PD deficient participants and 133 (13.3%) with intermediate G6PD activity. Median G6PD activity differed significantly between ethnicities (p<0.001), proportions of G6PD deficient individuals ranged from 2% to 26% but did not differ between participants with and without malaria. The high G6PDd prevalence and significant variation between ethnicities suggest routine G6PDd testing to guide 8-aminoquinoline based radical in the CHT and comparable settings. Author summary: The Plasmodium vivax malaria parasite is a major public health burden in many parts of the Asia-Pacific and Americas. Primaquine-based radical cure is the only available treatment that effectively removes P. vivax from the human host but can cause severe side effects in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The WHO recommends testing for G6PD deficiency to guide treatment, but this is not done on a routine basis in many countries. The aim of this study was to determine the importance of routine testing in multi-ethnic populations. The study was conducted in a multi-ethnic population in the Chittagong Hill Tracts (Bangladesh), which carries the highest burden of malaria within the country. We enrolled 1002 participants from 11 major ethnicities within the area and assessed the prevalence of G6PD deficiency by phenotype and genotype. Based on phenotype 9.0% of the population were not eligible for standard primaquine based radical cure, however numbers varied significantly between ethnicities, ranging from 2% to 26%. In 93% of cases where a genotype was identified, the severe Mahidol G6PD variant was found. Our findings highlight the importance of routine G6PD testing prior to primaquine based radical cure in multi-ethnic populations. [ABSTRACT FROM AUTHOR]

Background: The radical cure of Plasmodium vivax and P. ovale requires treatment with primaquine or tafenoquine to clear dormant liver stages. Either drug can induce haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, necessitating screening. The reference diagnostic method for G6PD activity is ultraviolet (UV) spectrophotometry; however, a universal G6PD activity threshold above which these drugs can be safely administered is not yet defined. Our study aimed to quantify assay-based variation in G6PD spectrophotometry and to explore the diagnostic implications of applying a universal threshold. Methods and findings: Individual-level data were pooled from studies that used G6PD spectrophotometry. Studies were identified via PubMed search (25 April 2018) and unpublished contributions from contacted authors (PROSPERO: CRD42019121414). Studies were excluded if they assessed only individuals with known haematological conditions, were family studies, or had insufficient details. Studies of malaria patients were included but analysed separately. Included studies were assessed for risk of bias using an adapted form of the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Repeatability and intra- and interlaboratory variability in G6PD activity measurements were compared between studies and pooled across the dataset. A universal threshold for G6PD deficiency was derived, and its diagnostic performance was compared to site-specific thresholds. Study participants (n = 15,811) were aged between 0 and 86 years, and 44.4% (7,083) were women. Median (range) activity of G6PD normal (G6PDn) control samples was 10.0 U/g Hb (6.3–14.0) for the Trinity assay and 8.3 U/g Hb (6.8–15.6) for the Randox assay. G6PD activity distributions varied significantly between studies. For the 13 studies that used the Trinity assay, the adjusted male median (AMM; a standardised metric of 100% G6PD activity) varied from 5.7 to 12.6 U/g Hb (p < 0.001). Assay precision varied between laboratories, as assessed by variance in control measurements (from 0.1 to 1.5 U/g Hb; p < 0.001) and study-wise mean coefficient of variation (CV) of replicate measures (from 1.6% to 14.9%; p < 0.001). A universal threshold of 100% G6PD activity was defined as 9.4 U/g Hb, yielding diagnostic thresholds of 6.6 U/g Hb (70% activity) and 2.8 U/g Hb (30% activity). These thresholds diagnosed individuals with less than 30% G6PD activity with study-wise sensitivity from 89% (95% CI: 81%–94%) to 100% (95% CI: 96%–100%) and specificity from 96% (95% CI: 89%–99%) to 100% (100%–100%). However, when considering intermediate deficiency (<70% G6PD activity), sensitivity fell to a minimum of 64% (95% CI: 52%–75%) and specificity to 35% (95% CI: 24%–46%). Our ability to identify underlying factors associated with study-level heterogeneity was limited by the lack of availability of covariate data and diverse study contexts and methodologies. Conclusions: Our findings indicate that there is substantial variation in G6PD measurements by spectrophotometry between sites. This is likely due to variability in laboratory methods, with possible contribution of unmeasured population factors. While an assay-specific, universal quantitative threshold offers robust diagnosis at the 30% level, inter-study variability impedes performance of universal thresholds at the 70% level. Caution is advised in comparing findings based on absolute G6PD activity measurements across studies. Novel handheld quantitative G6PD diagnostics may allow greater standardisation in the future. Daniel Pfeffer and coauthors report on the assessment of glucose-6-phosphate dehydrogenase activity, which is required for safe use of some malaria treatments. Author summary: Why was this study done?: Complete cure of vivax malaria, the most geographically widespread malaria species, requires the use of 8-aminoquinoline drugs to clear dormant liver stages of the parasite ('radical cure'); however, these drugs can cause severe haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Ultraviolet (UV) spectrophotometry is used as the reference test to measure G6PD activity, for validating new point-of-care diagnostics, and to determine population-specific definitions of G6PD deficiency. Currently, there is no universal threshold to define G6PD deficiency, and each laboratory must invest time and resources to derive site- and laboratory-specific definitions of G6PD deficiency. What did the researchers do and find?: We pooled measurements of G6PD activity from studies conducted across different countries and laboratories worldwide. We assessed the comparability of spectrophotometry results between these laboratories to see whether a universal definition and diagnostic cutoff for G6PD deficiency could be determined. There was substantial variation in the performance and absolute measurements of spectrophotometry conducted in different laboratories, hindering the definition of a universal cutoff for G6PD deficiency. What do these findings mean?: These findings highlight the importance of quality-control measures to minimise the influence of laboratory procedures on observed measurements. The data suggest that while a robust universal, assay-specific G6PD activity cutoff value can be established for diagnosis of severe G6PD deficiency (<30% normal enzyme activity), this approach is less robust for diagnosing intermediate G6PD deficiency. Newly developed diagnostic assays that are less sensitive to laboratory conditions and require less sample preparation are required and may help provide more standardised quantitative G6PD activity measurements across different contexts. [ABSTRACT FROM AUTHOR]

Background: Malaria is endemic in 13 districts of Bangladesh. A baseline malaria prevalence survey across the endemic districts of Bangladesh was conducted in 2007, when the prevalence was reported around 39.7 per 1000 population. After two rounds of Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM)-funded intervention by the National Malaria Control Programme (NMCP) and a BRAC-led NGO consortium, a follow-up survey was conducted across the malaria-endemic districts of Bangladesh to measure the change in prevalence rate and in people's knowledge of malaria. Methods: The survey was carried out from August to November 2013 in 70 upazilas (sub-districts) of 13 malariaendemic districts of Bangladesh, following the same multi-stage cluster sampling design and the same number of households enrolled during the baseline prevalence survey in 2007, to collect 9750 randomly selected blood samples. For on-the-spot diagnosis of malaria, a rapid diagnostic test was used. The household head or eldest person available was interviewed using a pre-coded structured questionnaire to collect data on the knowledge and awareness of malaria in the household. Results: Based on a weighted calculation, the overall malaria prevalence was found to be 1.41 per 1000 population. The proportion of Plasmodium falciparum mono-infection was 77.78% while both Plasmodium vivax mono-infection and mixed infection of the two species were found to be 11.11%. Bandarban had the highest prevalence (6.67 per 1000 population). Knowledge of malaria signs, symptoms and mode of transmission were higher in the follow-up survey (97.26%) than the baseline survey. Use of bed nets for prevention of malaria was found to be high (90.15%) at respondent level. People's knowledge of selected parameters increased significantly during the follow-up survey compared to the baseline survey conducted in 2007. Conclusions: A reduced prevalence rate of malaria and increased level of knowledge were observed in the present malaria prevalence survey in Bangladesh. [ABSTRACT FROM AUTHOR]

Background WHO has reported that RDT and microscopy-confirmed malaria cases have declined in recent years. However, it is still unclear if this reflects a real decrease in incidence in Bangladesh, as particularly the hilly and forested areas of the Chittagong Hill Tract (CHT) Districts report more than 80% of all cases and deaths. PCR-confirmed surveillance and epidemiological data on malaria from the CHT are limited; existing data report Plasmodium falciparum and Plasmodium vivax as the dominant species. Methods A cross-sectional survey was conducted in the District of Bandarban, the southernmost of the three Hill Tracts Districts, to collect district-wide malaria prevalence data from one of the regions with the highest malaria endemicity in Bangladesh. A multistage cluster sampling technique was used to collect blood samples from febrile and afebrile participants and malaria microscopy and standardized nested PCR for diagnosis were performed. Demographic data, vital signs and splenomegaly were recorded. Results Malaria prevalence across all subdistricts in the monsoon season was 30.7% (95% CI: 28.3- 33.2) and 14.2% (95% CI: 12.5-16.2) by PCR and microscopy, respectively. Plasmodium falciparum mono-infections accounted for 58.9%, P. vivax mono-infections for 13.6%, Plasmodium malariae for 1.8%, and Plasmodium ovale for 1.4% of all positive cases. In 24.4% of all cases mixed infections were identified by PCR. The proportion of asymptomatic infections among PCR-confirmed cases was 77.0%, oligosymptomatic and symptomatic cases accounted for only 19.8 and 3.2%, respectively. Significantly (p < 0.01) more asymptomatic cases were recorded among participants older than 15 years as compared to younger participants, whereas prevalence and parasite density were significantly (p < 0.01) higher in patients younger than 15 years. Spleen rate and malaria prevalence in two to nine year olds were 18.6 and 34.6%, respectively. No significant difference in malaria prevalence and parasite density was observed between dry and rainy season. Conclusions A large proportion of asymptomatic plasmodial infections was found which likely act as a reservoir of transmission. This has major implications for ongoing malaria control programmes that are based on the treatment of symptomatic patients. These findings highlight the need for new intervention strategies targeting asymptomatic carriers. [ABSTRACT FROM AUTHOR]

Bangladesh has dramatically reduced malaria by 93% from 2008 to 2020. The strategy has been district-wise, phased elimination; however, the last districts targeted for elimination include remote, forested regions which present several challenges for prevention, detection, and treatment of malaria. These districts border Myanmar which harbors Plasmodium falciparum malaria parasites resistant to artemisinins, key drugs used in artemisinin-based combination therapies (ACTs) that have been vital for control programs. Challenges in monitoring emergence of artemisinin resistance (AR), tracking parasite reservoirs, changes in vector behavior and responses to insecticides, as well as other environmental and host factors (including the migration of Forcibly Displaced Myanmar Nationals; FDMNs) may pose added hazards in the final phase of eliminating malaria in Bangladesh. Multiple approaches are needed to assess whether Plasmodium falciparum malaria in the Chittagong Hill Tracts (CHTs) of Bangladesh has gained resistance to artemisinins, frontline antimalarials needed for control. Artemisinin resistance (AR) may emerge indigenously or be imported across district and country borders. Symptomatic and asymptomatic infections undetected by rapid diagnostic tests must be uncovered to expose transmission reservoirs. Infections may be influenced by host factors, climate change, and human migration, all relevant for malaria in the CHTs. Malaria-transmitting Anopheles mosquitoes need to be studied for speciation, population genetics, temporal resting, and feeding behaviors. Changes in these parameters may boost insecticide resistance as well as outdoor transmission to agricultural workers in forests or tea gardens, to bypass protection afforded by insecticide-impregnated bed-nets. [ABSTRACT FROM AUTHOR]