Population pharmacokinetics of primaquine and its metabolites in African males.

BACKGROUND: Primaquine (PQ) is the prototype 8-aminoquinoline drug, a class which targets gametocytes and hypnozoites. The World Health Organization (WHO) recommends adding a single low dose of primaquine to the standard artemisinin-based combination therapy (ACT) in order to block malaria transmission in regions with low malaria transmission. However, the haemolytic toxicity is a major adverse outcome of primaquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient subjects. This study aimed to characterize the pharmacokinetic properties of primaquine and its major metabolites in G6PD-deficient subjects. METHODS: A single low-dose of primaquine (0.4-0.5 mg/kg) was administered in twenty-eight African males. Venous and capillary plasma were sampled up to 24 h after the drug administration. Haemoglobin levels were observed up to 28 days after drug administration. Only PQ, carboxy-primaquine (CPQ), and primaquine carbamoyl-glucuronide (PQCG) were present in plasma samples and measured using liquid chromatography mass spectrometry. Drug and metabolites' pharmacokinetic properties were investigated using nonlinear mixed-effects modelling. RESULTS: Population pharmacokinetic properties of PQ, CPQ, and PQCG can be described by one-compartment disposition kinetics with a transit-absorption model. Body weight was implemented as an allometric function on the clearance and volume parameters for all compounds. None of the covariates significantly affected the pharmacokinetic parameters. No significant correlations were detected between the exposures of the measured compounds and the change in haemoglobin or methaemoglobin levels. There was no significant haemoglobin drop in the G6PD-deficient patients after administration of a single low dose of PQ. CONCLUSIONS: A single low-dose of PQ was haematologically safe in this population of G6PD-normal and G6PD-deficient African males without malaria. Trial registration NCT02535767.

Applying the COM-B behaviour change model to a pilot study delivering volatile pyrethroid spatial repellents and insecticide-treated clothing to forest-exposed populations in Mondulkiri Province, Cambodia.

BACKGROUND: Southeast Asia is making tremendous progress towards their 2030 malaria elimination goal but needs new interventions to stop forest malaria. This study trials two new vector control tools, a volatile pyrethroid spatial repellent (VPSR) and insecticide-treated clothing (ITC), amongst forest-exposed populations in Mondulkiri Province Cambodia to inform their potential use for eliminating forest malaria. METHODS: 21 forest-exposed individuals were given a questionnaire on their perceptions of malaria and preventive practices used, after which they trialed two products sequentially. Clothes was treated with ITC by the study team. Mixed methods were used to understand their experience, attitudes, and preferences regarding the products trialed. Quantitative data was summarized and qualitative insights were analysed using thematic analysis, applying the Capability, Opportunity, and Motivation Behaviour Change (COM-B) model and Behaviour Change Wheel Framework to identify intervention functions to support tailored product rollout amongst these populations. RESULTS: Study participants reported a need for protection from mosquito bites in outdoor and forest-exposed settings and perceived both products trialed to be effective for this purpose. The VPSR product was preferred when travel was not required, whereas ITC was preferred for ease of use when going to the forest, especially in rainy conditions. COM-B analysis identified that key enablers for use of both products included their perceived efficacy and ease of use, which required no skill or preparation. For barriers to use, the odour of ITC was sometimes perceived as being toxic, as well as its inability to protect uncovered skin from mosquito bites, while the perceived usefulness of the VPSR product trialed was limited by its water sensitivity in rainy forest settings. Intervention components to encourage appropriate and sustained use of these products include education about how to use these products and what to expect, persuasion to use them from community leaders and targeted channels, and enablement to facilitate convenient and affordable access. CONCLUSION: The rollout of VPSRs and ITC amongst forest-exposed populations can be useful for eliminating malaria in Southeast Asia. Study findings can be applied to increase product uptake among forest exposed populations in Cambodia, while manufacturers can aim to develop products that are rainproof, easy to use in forest settings, and have favourable odour profiles to target users.

Testing and treatment for malaria elimination: a systematic review.

BACKGROUND: Global interest in malaria elimination has prompted research on active test and treat (TaT) strategies. METHODS: A systematic review and meta-analysis were conducted to assess the effectiveness of TaT strategies to reduce malaria transmission. RESULTS: A total of 72 empirical research and 24 modelling studies were identified, mainly focused on proactive mass TaT (MTaT) and reactive case detection (RACD) in higher and lower transmission settings, respectively. Ten intervention studies compared MTaT to no MTaT and the evidence for impact on malaria incidence was weak. No intervention studies compared RACD to no RACD. Compared to passive case detection (PCD) alone, PCD + RACD using standard diagnostics increased infection detection 52.7% and 11.3% in low and very low transmission settings, respectively. Using molecular methods increased this detection of infections by 1.4- and 1.1-fold, respectively. CONCLUSION: Results suggest MTaT is not effective for reducing transmission. By increasing case detection, surveillance data provided by RACD may indirectly reduce transmission by informing coordinated responses of intervention targeting.

Efficacy of Single-Dose Primaquine With Artemisinin Combination Therapy on Plasmodium falciparum Gametocytes and Transmission: An Individual Patient Meta-Analysis.

BACKGROUND: Since the World Health Organization recommended single low-dose (0.25 mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant Plasmodium falciparum, several single-site studies have been conducted to assess efficacy. METHODS: An individual patient meta-analysis to assess gametocytocidal and transmission-blocking efficacy of PQ in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (1) gametocyte carriage in the first 2 weeks post treatment; and (2) the probability of infecting at least 1 mosquito or of a mosquito becoming infected. RESULTS: In 2574 participants from 14 studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytemia on day 0 (odds ratio [OR], 0.22; 95% confidence interval [CI], .17-.28 and OR, 0.12; 95% CI, .08-.16, respectively). Rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (P = .010 for day 7). Addition of 0.25 mg/kg PQ was associated with near complete prevention of transmission to mosquitoes. CONCLUSIONS: Transmission blocking is achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.

Safety of single-dose primaquine as a Plasmodium falciparum gametocytocide: a systematic review and meta-analysis of individual patient data.

BACKGROUND: In 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns. METHODS: A systematic review and individual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models. RESULTS: Data comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PD-normal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17-0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19-0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of becoming anaemic (Hb < 10 g/dL), with the nadir observed on ACT day 2 or 3, regardless of G6PD status and exposure to primaquine. Time to recovery from anaemia took longer in young children and those with baseline anaemia or hyperparasitaemia. Serious adverse haematological events after primaquine were few (9/3, 113, 0.3%) and transitory. One blood transfusion was reported in the primaquine arms, and there were no primaquine-related deaths. In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms. CONCLUSIONS: Our results support the WHO recommendation to use 0.25 mg/kg of primaquine as a P. falciparum gametocytocide, including in G6PD-deficient individuals. Although primaquine is associated with a transient reduction in haemoglobin levels in G6PD-deficient individuals, haemoglobin levels at clinical presentation are the major determinants of anaemia in these patients. TRIAL REGISTRATION: PROSPERO, CRD42019128185.

Effective management of district-level malaria control and elimination: implementing quality and participative process improvements.

Although it is widely recognized that strong program management is essential to achieving better health outcomes, this priority is not recognized in malaria programmatic practices. Increased management precision offers the opportunity to improve the effectiveness of malaria interventions, overcoming operational barriers to intervention coverage and accelerating the path to elimination. Here we propose a combined approach involving quality improvement, quality management, and participative process improvement, which we refer to as Combined Quality and Process Improvement (CQPI), to improve upon malaria program management. We draw on evidence from other areas of public health, as well as pilot implementation studies in Eswatini, Namibia and Zimbabwe to support the proposal. Summaries of the methodological approaches employed in the pilot studies, overview of activities and an outline of lessons learned from the implementation of CQPI are provided. Our findings suggest that a malaria management strategy that prioritizes quality and participative process improvements at the district-level can strengthen teamwork and communication while enabling the empowerment of subnational staff to solve service delivery challenges. Despite the promise of CQPI, however, policy makers and donors are not aware of its potential. Investments are therefore needed to allow CQPI to come to fruition.

Persistence of mRNA indicative of Plasmodium falciparum ring-stage parasites 42 days after artemisinin and non-artemisinin combination therapy in naturally infected Malians.

BACKGROUND: Malaria control in sub-Saharan Africa relies upon prompt case management with artemisinin-based combination therapy (ACT). Ring-stage parasite mRNA, measured by sbp1 quantitative reverse-transcriptase PCR (qRT-PCR), was previously reported to persist after ACT treatment and hypothesized to reflect temporary arrest of the growth of ring-stage parasites (dormancy) following exposure to artemisinins. Here, the persistence of ring-stage parasitaemia following ACT and non-ACT treatment was examined. METHODS: Samples were used from naturally infected Malian gametocyte carriers who received dihydroartemisinin-piperaquine (DP) or sulfadoxine-pyrimethamine (SP-AQ) with or without gametocytocidal drugs. Gametocytes and ring-stage parasites were quantified by qRT-PCR during 42 days of follow-up. RESULTS: At baseline, 89% (64/73) of participants had measurable ring-stage parasite mRNA. Following treatment, the proportion of ring-stage parasite-positive individuals and estimated densities declined for all four treatment groups. Ring-stage parasite prevalence and density was generally lower in arms that received DP compared to SP-AQ. This finding was most apparent days 1, 2, and 42 of follow-up (p < 0.01). Gametocytocidal drugs did not influence ring-stage parasite persistence. Ring-stage parasite density estimates on days 14 and 28 after initiation of treatment were higher among individuals who subsequently experienced recurrent parasitaemia compared to those who remained free of parasites until day 42 after initiation of treatment (pday 14 = 0.011 and pday 28 = 0.068). No association of ring-stage persistence with gametocyte carriage was observed. CONCLUSIONS: The current findings of lower ring-stage persistence after ACT without an effect of gametocytocidal partner drugs affirms the use of sbp1 as ring-stage marker. Lower persistence of ring-stage mRNA after ACT treatment suggests the marker may not reflect dormant parasites whilst it was predictive of re-appearance of parasitaemia.

Trends in Ethnicity, Race, and Sex Among Psychiatry and Non-psychiatry Residency Applicants, 2008-2019.

OBJECTIVE: The objective of this study was to examine trends in racial/ethnic and gender representation among US psychiatry residency applicants compared with non-psychiatry applicants. METHODS: Using publicly available applicant data, racial/ethnic and gender distributions of psychiatry residency applicants from 2008 to 2019 were examined and compared with non-psychiatry residency applicants. Both longitudinal trends within both cohorts and cross-sectional, between-group differences were examined. RESULTS: From 2008 to 2019, the percentage of female, American Indian/Alaskan Native (AIAN), Black, Hispanic, and Native Hawaiian/Other Pacific Islander (NHPI) psychiatry and non-psychiatry residency applicants increased (p<.001). Within each year, Black and Asian applicants comprised a larger percentage of psychiatry applicants compared with non-psychiatry applicants (p<.001). Between 2008 and 2019, Black psychiatry and non-psychiatry applicants increased from 9.1% to 11.6% and 6.6% to 7.6%, respectively; Asian psychiatry and non-psychiatry applicants decreased from 39.5% to 30.5% and 27.5% to 26.6%, respectively; White psychiatry and non-psychiatry applicants increased from 26.7% to 38.2% and 42.7% to 49.2%, respectively. CONCLUSIONS: Racial/ethnic and gender characteristics of US psychiatry residency applicants represent the future of the US psychiatric workforce. The US psychiatry residency applicant pool has become increasingly diverse from 2008 to 2019. Initiatives should work to enhance representation of psychiatry applicants from historically marginalized backgrounds, and simultaneously to recruit and retain a diverse psychiatric workforce following residency training.

District-level approach for tailoring and targeting interventions: a new path for malaria control and elimination.

Despite huge investments and implementation of effective interventions for malaria, progress has stalled, with transmission being increasingly localized among difficult-to-reach populations and outdoor-biting vectors. Targeting difficult pockets of transmission will require the development of tailored and targeted approaches suited to local context, drawing from insights close to the frontlines. Districts are best placed to develop tailored, locally appropriate approaches. We propose a reorganization of how malaria services are delivered. Firstly, enabling district health officers to serve as conduits between technical experts in national malaria control programmes and local community leaders with knowledge specific to local, at-risk populations; secondly, empowering district health teams to make malaria control decisions. This is a radical shift that requires the national programme to cede some control. Shifting towards a district or provincial level approach will necessitate deliberate planning, and repeated, careful assessment, starting with piloting and learning through experience. Donors will need to alter current practice, allowing for flexible funding to be controlled at sub-national levels, and to mix finances between case management, vector control and surveillance, monitoring and evaluation. System-wide changes proposed are challenging but may be necessary to overcome stalled progress in malaria control and elimination and introduce targeted interventions tailored to the needs of diverse malaria affected populations.

CYP2D6 Polymorphisms and the Safety and Gametocytocidal Activity of Single-Dose Primaquine for Plasmodium falciparum.

Single-dose primaquine (PQ) clears mature gametocytes and reduces the transmission of Plasmodium falciparum after artemisinin combination therapy. Genetic variation in CYP2D6, the gene producing the drug-metabolizing enzyme cytochrome P450 2D6 (CYP2D6), influences plasma concentrations of PQ and its metabolites and is associated with PQ treatment failure in Plasmodium vivax malaria. Using blood and saliva samples of varying quantity and quality from 8 clinical trials across Africa (n = 1,076), we were able to genotype CYP2D6 for 774 samples (72%). We determined whether genetic variation in CYP2D6 has implications for PQ efficacy in individuals with gametocytes at the time of PQ administration (n = 554) and for safety in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals treated with PQ (n = 110). Individuals with a genetically inferred CYP2D6 poor/intermediate metabolizer status had a higher gametocyte prevalence on day 7 or 10 after PQ than those with an extensive/ultrarapid CYP2D6 metabolizer status (odds ratio [OR] = 1.79 [95% confidence interval {CI}, 1.10, 2.90]; P = 0.018). The mean minimum hemoglobin concentrations during follow-up for G6PD-deficient individuals were 11.8 g/dl for CYP2D6 extensive/ultrarapid metabolizers and 12.1 g/dl for CYP2D6 poor/intermediate metabolizers (P = 0. 803). CYP2D6 genetically inferred metabolizer status was also not associated with anemia following PQ treatment (P = 0.331). We conclude that CYP2D6 poor/intermediate metabolizer status may be associated with prolonged gametocyte carriage after treatment with single-low-dose PQ but not with treatment safety.

What is community engagement and how can it drive malaria elimination? Case studies and stakeholder interviews.

BACKGROUND: In light of increasing complexity of identifying and treating malaria cases in low transmission settings, operational solutions are needed to increase effective delivery of interventions. Community engagement (CE) is at the forefront of this conversation given the shift toward creating local and site-specific solutions. Malaria programmes often confuse CE with providing information to the community or implementing community-based interventions. This study seeks to expand on CE approaches for malaria by looking to a variety of health and development programmes for lessons that can be applied to malaria elimination. METHODS: Qualitative data was collected from key informant interviews and community-based focus group discussions. Manual analysis was conducted with a focus on key principles, programme successes and challenges, the operational framework, and any applicable results. RESULTS: Ten programmes were included in the analysis: Ebola, HIV/Hepatitis C, Guinea worm, malaria, nutrition, and water, sanitation and hygiene. Seven focus group discussions (FGDs) with 69 participants, 49 key informant (KI) interviews with programme staff, and 7 KI interviews with thought leaders were conducted between October-April 2018. Participants discussed the critical role that village leaders and community health workers play in CE. Many programmes stated understanding community priorities is key for CE and that CE should be proactive and iterative. A major theme was prioritizing bi-directional interpersonal communication led by local community health workers. Programmes reported that measuring CE is difficult, particularly since CE is ongoing and fluid. CONCLUSIONS: Results overwhelmingly suggest that CE must be an iterative process that relies on early involvement, frequent feedback and active community participation to be successful. Empowering districts and communities in planning and executing community-based interventions is necessary. Communities affected by the disease will ultimately achieve malaria elimination. For this to happen, the community itself must define, believe in, and commit to strategies to interrupt transmission.

Assessing the role of the private sector in surveillance for malaria elimination in Haiti and the Dominican Republic: a qualitative study.

BACKGROUND: Haiti and the Dominican Republic (DR) are targeting malaria elimination by 2022. The private health sector has been relatively unengaged in these efforts, even though most primary health care in Haiti is provided by non-state actors, and many people use traditional medicine. Data on private health sector participation in malaria elimination efforts are lacking, as are data on care-seeking behaviour of patients in the private health sector. This study sought to describe the role of private health sector providers, care-seeking behaviour of individuals at high risk of malaria, and possible means of engaging the private health sector in Hispaniola's malaria elimination efforts. METHODS: In-depth interviews with 26 key informants (e.g. government officials), 62 private providers, and 63 patients of private providers, as well as 12 focus group discussions (FGDs) with community members, were conducted within seven study sites in Haiti and the DR. FGDs focused on local definitions of the private health sector and identified private providers for interview recruitment, while interviews focused on private health sector participation in malaria elimination activities and treatment-seeking behaviour of febrile individuals. RESULTS: Interviews revealed that self-medication is the most common first step in the trajectory of care for fevers in both Haiti and the DR. Traditional medicine is more commonly used in Haiti than in the DR, with many patients seeking care from traditional healers before, during, and/or after care in the formal health sector. Private providers were interested in participating in malaria elimination efforts but emphasized the need for ongoing support and training. Key informants agreed that the private health sector needs to be engaged, especially traditional healers in Haiti. The Haitian migrant population was reported to be one of the most at-risk groups by participants from both countries. CONCLUSION: Malaria elimination efforts across Hispaniola could be enhanced by engaging traditional healers in Haiti and other private providers with ongoing support and trainings; directing educational messaging to encourage proper treatment-seeking behaviour; and refining cross-border strategies for surveillance of the high-risk migrant population. Increasing distribution of rapid diagnostic tests (RDTs) and bi-therapy to select private health sector facilities, accompanied by adopting regulatory policies, could help increase numbers of reported and correctly treated malaria cases.

Safety of Single-Dose Primaquine in G6PD-Deficient and G6PD-Normal Males in Mali Without Malaria: An Open-Label, Phase 1, Dose-Adjustment Trial.

Background: The World Health Organization recommendation on the use of a single low dose of primaquine (SLD-PQ) to reduce Plasmodium falciparum malaria transmission requires more safety data. Methods: We conducted an open-label, nonrandomized, dose-adjustment trial of the safety of 3 single doses of primaquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient adult males in Mali, followed by an assessment of safety in G6PD-deficient boys aged 11-17 years and those aged 5-10 years, including G6PD-normal control groups. The primary outcome was the greatest within-person percentage drop in hemoglobin concentration within 10 days after treatment. Results: Fifty-one participants were included in analysis. G6PD-deficient adult males received 0.40, 0.45, or 0.50 mg/kg of SLD-PQ. G6PD-deficient boys received 0.40 mg/kg of SLD-PQ. There was no evidence of symptomatic hemolysis, and adverse events considered related to study drug (n = 4) were mild. The mean largest within-person percentage change in hemoglobin level between days 0 and 10 was -9.7% (95% confidence interval [CI], -13.5% to -5.90%) in G6PD-deficient adults receiving 0.50 mg/kg of SLD-PQ, -11.5% (95% CI, -16.1% to -6.96%) in G6PD-deficient boys aged 11-17 years, and -9.61% (95% CI, -7.59% to -13.9%) in G6PD-deficient boys aged 5-10 years. The lowest hemoglobin concentration at any point during the study was 92 g/L. Conclusion: SLD-PQ doses between 0.40 and 0.50 mg/kg were well tolerated in G6PD-deficient males in Mali. Clinical Trials Registration: NCT02535767.

Low risk of recurrence following artesunate-Sulphadoxine-pyrimethamine plus primaquine for uncomplicated Plasmodium falciparum and Plasmodium vivax infections in the Republic of the Sudan.

BACKGROUND: First-line schizontocidal treatment for uncomplicated malaria in the Republic of the Sudan is artesunate (total dose 12 mg/kg) plus Sulphadoxine/pyrimethamine (25/1.25 mg/kg) (AS/SP). Patients with Plasmodium vivax are also treated with 14 days primaquine (total dose 3.5 mg/kg) (PQ). The aim of this study was to assess the efficacy of the national policy. METHODS: Patients above 1 year, with microscopy-confirmed, Plasmodium falciparum and/or P. vivax malaria were treated with AS/SP. Patients with P. falciparum were randomized to no primaquine (Pf-noPQ) or a single 0.25 mg/kg dose of PQ (Pf-PQ1). Patients with P. vivax received 14 days unsupervised 3.5 mg/kg PQ (Pv-PQ14) on day 2 or at the end of follow up (Pv-noPQ). Primary endpoint was the risk of recurrent parasitaemia at day 42. G6PD activity was measured by spectrophotometry and the Accessbio Biosensor™. RESULTS: 231 patients with P. falciparum (74.8%), 77 (24.9%) with P. vivax and 1 (0.3%) patient with mixed infection were enrolled. The PCR corrected cumulative risk of recurrent parasitaemia on day 42 was 3.8% (95% CI 1.2-11.2%) in the Pf-noPQ arm compared to 0.9% (95% CI 0.1-6.0%) in the Pf-PQ1 arm; (HR = 0.25 [95% CI 0.03-2.38], p = 0.189). The corresponding risks of recurrence were 13.4% (95% CI 5.2-31.9%) in the Pv-noPQ arm and 5.3% (95% CI 1.3-19.4%) in the Pv-PQ14 arm (HR 0.36 [95% CI 0.1-2.0], p = 0.212). Two (0.9%) patients had G6PD enzyme activity below 10%, 19 (8.9%) patients below 60% of the adjusted male median. Correlation between spectrophotometry and Biosensor™ was low (rs = 0.330, p < 0.001). CONCLUSION: AS/SP remains effective for the treatment of P. falciparum and P. vivax. The addition of PQ reduced the risk of recurrent P. falciparum and P. vivax by day 42, although this did not reach statistical significance. The version of the Biosensor™ assessed is not suitable for routine use. Trial registration https://clinicaltrials.gov/ct2/show/NCT02592408.

A Molecular Assay to Quantify Male and Female Plasmodium falciparum Gametocytes: Results From 2 Randomized Controlled Trials Using Primaquine for Gametocyte Clearance.

Background: Single low-dose primaquine (PQ) reduces Plasmodium falciparum infectivity before it impacts gametocyte density. Here, we examined the effect of PQ on gametocyte sex ratio as a possible explanation for this early sterilizing effect. Methods: Quantitative reverse-transcription polymerase chain reaction assays were developed to quantify female gametocytes (targeting Pfs25 messenger RNA [mRNA]) and male gametocytes (targeting Pf3D7_1469900 mRNA) in 2 randomized trials in Kenya and Mali, comparing dihydroartemisinin-piperaquine (DP) alone to DP with PQ. Gametocyte sex ratio was examined in relation to time since treatment and infectivity to mosquitoes. Results: In Kenya, the median proportion of male gametocytes was 0.33 at baseline. Seven days after treatment, gametocyte density was significantly reduced in the DP-PQ arm relative to the DP arm (females: 0.05% [interquartile range {IQR}, 0.0-0.7%] of baseline; males: 3.4% [IQR, 0.4%-32.9%] of baseline; P < .001). Twenty-four hours after treatment, gametocyte sex ratio became male-biased and was not significantly different between the DP and DP-PQ groups. In Mali, there was no significant difference in sex ratio between the DP and DP-PQ groups (>0.125 mg/kg) 48 hours after treatment, and gametocyte sex ratio was not associated with mosquito infection rates. Conclusions: The early sterilizing effects of PQ may not be explained by the preferential clearance of male gametocytes and may be due to an effect on gametocyte fitness.

Malaria risk factors and care-seeking behaviour within the private sector among high-risk populations in Vietnam: a qualitative study.

BACKGROUND: Vietnam has successfully reduced malaria incidence by more than 90% over the past 10 years, and is now preparing for malaria elimination. However, the remaining malaria burden resides in individuals that are hardest to reach, in highly remote areas, where many malaria cases are treated through the informal private sector and are not reported to public health systems. This qualitative study aimed to contextualize and characterize the role of private providers, care-seeking behaviour of individuals at high risk of malaria, as well as risk factors that should be addressed through malaria elimination programmes in Vietnam. METHODS: Semi-structured qualitative interviews were conducted with 11 key informants in Hanoi, 30 providers, 9 potential patients, and 11 individuals at risk of malaria in Binh Phuoc and Kon Tum provinces. Audio recorded interviews were transcribed and uploaded to Atlas TI™, themes were identified, from which programmatic implications and recommendations were synthesized. RESULTS: Qualitative interviews revealed that efforts for malaria elimination in Vietnam should concentrate on reaching highest-risk populations in remote areas as well their care providers, in particular private pharmacies, private clinics, and grocery stores. Among these private providers, diagnosis is currently based on symptoms, leaving unconfirmed cases that are not reported to public health surveillance systems. Among at-risk individuals, knowledge of malaria was limited, and individuals reported not taking full courses of treatment, a practice that threatens selection for drug resistance. Access to insecticide-treated hammock nets, a potentially important preventive measure for settings with outdoor biting Anopheles vectors, was also limited. CONCLUSIONS: Malaria elimination efforts in Vietnam can be accelerated by targeting improved treatment, diagnosis, and reporting practices to private pharmacies, private clinics, and grocery stores. Programmes should also seek to increase awareness and understanding of malaria among at-risk populations, in particular the importance of using preventive measures and adhering to complete courses of anti-malarial medicines.

Barriers to routine G6PD testing prior to treatment with primaquine.

BACKGROUND: Primaquine is essential for the radical cure of vivax malaria, however its broad application is hindered by the risk of drug-induced haemolysis in individuals with glucose-6-phosphate-dehydrogenase (G6PD) deficiency. Rapid diagnostic tests capable of diagnosing G6PD deficiency are now available, but these are not used widely. METHODS: A series of qualitative interviews were conducted with policy makers and healthcare providers in four vivax-endemic countries. Routine G6PD testing is not part of current policy in Bangladesh, Cambodia or China, but it is in Malaysia. The interviews were analysed with regard to respondents perceptions of vivax malaria, -primaquine based treatment for malaria and the complexities of G6PD deficiency. RESULTS: Three barriers to the roll-out of routine G6PD testing were identified in all sites: (a) a perceived low risk of drug-induced haemolysis; (b) the perception that vivax malaria was benign and accordingly treatment with primaquine was not regarded as a priority; and, (c) the additional costs of introducing routine testing. In Malaysia, respondents considered the current test and treat algorithm suitable and the need for an alternative approach was only considered relevant in highly mobile and hard to reach populations. CONCLUSIONS: Greater efforts are needed to increase awareness of the benefits of the radical cure of Plasmodium vivax and this should be supported by economic analyses exploring the cost effectiveness of routine G6PD testing.