Jimee Hwang

The changing epidemiology of malaria elimination: new strategies for new challenges

Malaria-eliminating countries achieved remarkable success in reducing their malaria burdens between 2000 and 2010. As a result, the epidemiology of malaria in these settings has become more complex. Malaria is increasingly imported, caused by Plasmodium vivax in settings outside sub-Saharan Africa, and clustered in small geographical areas or clustered demographically into subpopulations, which are often predominantly adult men, with shared social, behavioural, and geographical risk characteristics. The shift in the populations most at risk of malaria raises important questions for malaria-eliminating countries, since traditional control interventions are likely to be less effective. Approaches to elimination need to be aligned with these changes through the development and adoption of novel strategies and methods. Knowledge of the changing epidemiological trends of malaria in the eliminating countries will ensure improved targeting of interventions to continue to shrink the malaria map.

Shrinking the malaria map: progress and prospects

Summary In the past 150 years, roughly half of the countries in the world eliminated malaria. Nowadays, there are 99 endemic countries—67 are controlling malaria and 32 are pursuing an elimination strategy. This four-part Series presents evidence about the technical, operational, and financial dimensions of malaria elimination. The first paper in this Series reviews definitions of elimination and the state that precedes it: controlled low-endemic malaria. Feasibility assessments are described as a crucial step for a country transitioning from controlled low-endemic malaria to elimination. Characteristics of the 32 malaria-eliminating countries are presented, and contrasted with countries that pursued elimination in the past. Challenges and risks of elimination are presented, including Plasmodium vivax, resistance in the parasite and mosquito populations, and potential resurgence if investment and vigilance decrease. The benefits of elimination are outlined, specifically elimination as a regional and global public good. Priorities for the next decade are described.

Malaria indicator survey 2007, Ethiopia: coverage and use of major malaria prevention and control interventions

BackgroundIn 2005, a nationwide survey estimated that 6.5% of households in Ethiopia owned an insecticide-treated net (ITN), 17% of households had been sprayed with insecticide, and 4% of children under five years of age with a fever were taking an anti-malarial drug. Similar to other sub-Saharan African countries scaling-up malaria interventions, the Government of Ethiopia set an ambitious national goal in 2005 to (i) provide 100% ITN coverage in malarious areas, with a mean of two ITNs per household; (ii) to scale-up indoor residual spraying of households with insecticide (IRS) to cover 30% of households targeted for IRS; and (iii) scale-up the provision of case management with rapid diagnostic tests (RDTs) and artemisinin-based combination therapy (ACT), particularly at the peripheral level.MethodsA nationally representative malaria indicator survey (MIS) was conducted in Ethiopia between September and December 2007 to determine parasite and anaemia prevalence in the population at risk and to assess coverage, use and access to scaled-up malaria prevention and control interventions. The survey used a two-stage random cluster sample of 7,621 households in 319 census enumeration areas. A total of 32,380 people participated in the survey. Data was collected using standardized Roll Back Malaria Monitoring and Evaluation Reference Group MIS household and womens questionnaires, which were adapted to the local context.ResultsData presented is for households in malarious areas, which according to the Ethiopian Federal Ministry of Health are defined as being located <2,000 m altitude. Of 5,083 surveyed households, 3,282 (65.6%) owned at least one ITN. In ITN-owning households, 53.2% of all persons had slept under an ITN the prior night, including 1,564/2,496 (60.1%) children <5 years of age, 1,891/3,009 (60.9%) of women 15 - 49 years of age, and 166/266 (65.7%) of pregnant women. Overall, 906 (20.0%) households reported to have had IRS in the past 12 months. Of 747 children with reported fever in the two weeks preceding the survey, 131 (16.3%) sought medical attention within 24 hours. Of those with fever, 86 (11.9%) took an anti-malarial drug and 41 (4.7%) took it within 24 hours of fever onset. Among 7,167 surveyed individuals of all ages, parasitaemia as estimated by microscopy was 1.0% (95% CI 0.5 - 1.5), with 0.7% and 0.3% due to Plasmodium falciparum and Plasmodium vivax, respectively. Moderate-severe anaemia (haemoglobin <8 g/dl) was observed in 239/3,366 (6.6%, 95% CI 4.9-8.3) children <5 years of age.ConclusionsSince mid-2005, the Ethiopian National Malaria Control Programme has considerably scaled-up its malaria prevention and control interventions, demonstrating the impact of strong political will and a committed partnership. The MIS showed, however, that besides sustaining and expanding malaria intervention coverage, efforts will have to be made to increase intervention access and use. With ongoing efforts to sustain and expand malaria intervention coverage, to increase intervention access and use, and with strong involvement of the community, Ethiopia expects to achieve its targets in terms of coverage and uptake of interventions in the coming years and move towards eliminating malaria.

Review of Mass Drug Administration for Malaria and Its Operational Challenges

Mass drug administration (MDA) was a component of many malaria programs during the eradication era, but later was seldomly deployed due to concerns regarding efficacy and feasibility and fear of accelerating drug resistance. Recently, however, there has been renewed interest in the role of MDA as an elimination tool. Following a 2013 Cochrane Review that focused on the quantitative effects of malaria MDA, we have conducted a systematic, qualitative review of published, unpublished, and gray literature documenting past MDA experiences. We have also consulted with field experts, using their historical experience to provide an informed, contextual perspective on the role of MDA in malaria elimination. Substantial knowledge gaps remain and more research is necessary, particularly on optimal target population size, methods to improve coverage, and primaquine safety. Despite these gaps, MDA has been used successfully to control and eliminate Plasmodium falciparum and P. vivax malaria in the past, and should be considered as part of a comprehensive malaria elimination strategy in specific settings.

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

Malaria elimination will be possible only with serious attempts to address asymptomatic infection and chronic infection by both Plasmodium falciparum and Plasmodium vivax. Currently available drugs that can completely clear a human of P. vivax (known as “radical cure”), and that can reduce transmission of malaria parasites, are those in the 8-aminoquinoline drug family, such as primaquine. Unfortunately, people with glucose-6-phosphate dehydrogenase (G6PD) deficiency risk having severe adverse reactions if exposed to these drugs at certain doses. G6PD deficiency is the most common human enzyme defect, affecting approximately 400 million people worldwide.Scaling up radical cure regimens will require testing for G6PD deficiency, at two levels: 1) the individual level to ensure safe case management, and 2) the population level to understand the risk in the local population to guide Plasmodium vivax treatment policy. Several technical and operational knowledge gaps must be addressed to expand access to G6PD deficiency testing and to ensure that a patient’s G6PD status is known before deciding to administer an 8-aminoquinoline-based drug.In this report from a stakeholder meeting held in Thailand on October 4 and 5, 2012, G6PD testing in support of radical cure is discussed in detail. The focus is on challenges to the development and evaluation of G6PD diagnostic tests, and on challenges related to the operational aspects of implementing G6PD testing in support of radical cure. The report also describes recommendations for evaluation of diagnostic tests for G6PD deficiency in support of radical cure.

Surveillance for Malaria Elimination in Swaziland: A National Cross-Sectional Study Using Pooled PCR and Serology

Background To guide malaria elimination efforts in Swaziland and other countries, accurate assessments of transmission are critical. Pooled-PCR has potential to efficiently improve sensitivity to detect infections; serology may clarify temporal and spatial trends in exposure. Methodology/Principal Findings Using a stratified two-stage cluster, cross-sectional design, subjects were recruited from the malaria endemic region of Swaziland. Blood was collected for rapid diagnostic testing (RDT), pooled PCR, and ELISA detecting antibodies to Plasmodium falciparum surface antigens. Of 4330 participants tested, three were RDT-positive yet false positives by PCR. Pooled PCR led to the identification of one P. falciparum and one P. malariae infection among RDT-negative participants. The P. falciparum-infected participant reported recent travel to Mozambique. Compared to performing individual testing on thousands of samples, PCR pooling reduced labor and consumable costs by 95.5%. Seropositivity was associated with age ≥20 years (11·7% vs 1·9%, P<0.001), recent travel to Mozambique (OR 4.4 [95% CI 1.0–19.0]) and residence in southeast Swaziland (RR 3.78, P<0.001). Conclusions The prevalence of malaria infection and recent exposure in Swaziland are extremely low, suggesting elimination is feasible. Future efforts should address imported malaria and target remaining foci of transmission. Pooled PCR and ELISA are valuable surveillance tools for guiding elimination efforts.

Factors associated with mosquito net use by individuals in households owning nets in Ethiopia

BackgroundOwnership of insecticidal mosquito nets has dramatically increased in Ethiopia since 2006, but the proportion of persons with access to such nets who use them has declined. It is important to understand individual level net use factors in the context of the home to modify programmes so as to maximize net use.MethodsGeneralized linear latent and mixed models (GLLAMM) were used to investigate net use using individual level data from people living in net-owning households from two surveys in Ethiopia: baseline 2006 included 12,678 individuals from 2,468 households and a sub-sample of the Malaria Indicator Survey (MIS) in 2007 included 14,663 individuals from 3,353 households. Individual factors (age, sex, pregnancy); net factors (condition, age, net density); household factors (number of rooms [2006] or sleeping spaces [2007], IRS, womens knowledge and school attendance [2007 only], wealth, altitude); and cluster level factors (rural or urban) were investigated in univariate and multi-variable models for each survey.ResultsIn 2006, increased net use was associated with: age 25-49 years (adjusted (a) OR = 1.4, 95% confidence interval (CI) 1.2-1.7) compared to children U5; female gender (aOR = 1.4; 95% CI 1.2-1.5); fewer nets with holes (Ptrend = 0.002); and increasing net density (Ptrend < 0.001). Reduced net use was associated with: age 5-24 years (aOR = 0.2; 95% CI 0.2-0.3). In 2007, increased net use was associated with: female gender (aOR = 1.3; 95% CI 1.1-1.6); fewer nets with holes (aOR [all nets in HH good] = 1.6; 95% CI 1.2-2.1); increasing net density (Ptrend < 0.001); increased womens malaria knowledge (Ptrend < 0.001); and urban clusters (aOR = 2.5; 95% CI 1.5-4.1). Reduced net use was associated with: age 5-24 years (aOR = 0.3; 95% CI 0.2-0.4); number of sleeping spaces (aOR [per additional space] = 0.6, 95% CI 0.5-0.7); more old nets (aOR [all nets in HH older than 12 months] = 0.5; 95% CI 0.3-0.7); and increasing household altitude (Ptrend < 0.001).ConclusionIn both surveys, net use was more likely by women, if nets had fewer holes and were at higher net per person density within households. School-age children and young adults were much less likely to use a net. Increasing availability of nets within households (i.e. increasing net density), and improving net condition while focusing on education and promotion of net use, especially in school-age children and young adults in rural areas, are crucial areas for intervention to ensure maximum net use and consequent reduction of malaria transmission.

Primaquine to reduce transmission of Plasmodium falciparum malaria in Mali: a single-blind, dose-ranging, adaptive randomised phase 2 trial

BACKGROUND Single low doses of primaquine, when added to artemisinin-based combination therapy, might prevent transmission of Plasmodium falciparum malaria to mosquitoes. We aimed to establish the activity and safety of four low doses of primaquine combined with dihydroartemisinin-piperaquine in male patients in Mali. METHODS In this phase 2, single-blind, dose-ranging, adaptive randomised trial, we enrolled boys and men with uncomplicated P falciparum malaria at the Malaria Research and Training Centre (MRTC) field site in Ouelessebougou, Mali. All participants were confirmed positive carriers of gametocytes through microscopy and had normal function of glucose-6-phosphate dehydrogenase (G6PD) on colorimetric quantification. In the first phase, participants were randomly assigned (1:1:1) to one of three primaquine doses: 0 mg/kg (control), 0·125 mg/kg, and 0·5 mg/kg. Randomisation was done with a computer-generated randomisation list (in block sizes of six) and concealed with sealed, opaque envelopes. In the second phase, different participants were sequentially assigned (1:1) to 0·25 mg/kg primaquine or 0·0625 mg/kg primaquine. Primaquine tablets were dissolved into a solution and administered orally in a single dose. Participants were also given a 3 day course of dihydroartemisinin-piperaquine, administered by weight (320 mg dihydroartemisinin and 40 mg piperaquine per tablet). Outcome assessors were masked to treatment allocation, but participants were permitted to find out group assignment. Infectivity was assessed through membrane-feeding assays, which were optimised through the beginning part of phase one. The primary efficacy endpoint was the mean within-person percentage change in mosquito infectivity 2 days after primaquine treatment in participants who completed the study after optimisation of the infectivity assay, had both a pre-treatment infectivity measurement and at least one follow-up infectivity measurement, and who were given the correct primaquine dose. The safety endpoint was the mean within-person change in haemoglobin concentration during 28 days of study follow-up in participants with at least one follow-up visit. This study is registered with ClinicalTrials.gov, number NCT01743820. FINDINGS Between Jan 2, 2013, and Nov 27, 2014, we enrolled 81 participants. In the primary analysis sample (n=71), participants in the 0·25 mg/kg primaquine dose group (n=15) and 0·5 mg/kg primaquine dose group (n=14) had significantly lower mean within-person reductions in infectivity at day 2-92·6% (95% CI 78·3-100; p=0·0014) for the 0·25 mg/kg group; and 75·0% (45·7-100; p=0·014) for the 0·5 mg/kg primaquine group-compared with those in the control group (n=14; 11·3% [-27·4 to 50·0]). Reductions were not significantly different from control for participants assigned to the 0·0625 mg/kg dose group (n=16; 41·9% [1·4-82·5]; p=0·16) and the 0·125 mg/kg dose group (n=12; 54·9% [13·4-96·3]; p=0·096). No clinically meaningful or statistically significant drops in haemoglobin were recorded in any individual in the haemoglobin analysis (n=70) during follow-up. No serious adverse events were reported and adverse events did not differ between treatment groups. INTERPRETATION A single dose of 0·25 mg/kg primaquine, given alongside dihydroartemisinin-piperaquine, was safe and efficacious for the prevention of P falciparum malaria transmission in boys and men who are not deficient in G6PD. Future studies should assess the safety of single-dose primaquine in G6PD-deficient individuals to define the therapeutic range of primaquine to enable the safe roll-out of community interventions with primaquine. FUNDING Bill & Melinda Gates Foundation.

Mass drug administration for the control and elimination of Plasmodium vivax malaria: An ecological study from Jiangsu province, China

BackgroundRecent progress in malaria control has caused renewed interest in mass drug administration (MDA) as a potential elimination strategy but the evidence base is limited. China has extensive experience with MDA, but it is not well documented.MethodsAn ecological study was conducted to describe the use of MDA for the control and elimination of Plasmodium vivax in Jiangsu Province and explore the association between MDA and malaria incidence. Two periods were focused on: 1973 to 1983 when malaria burden was high and MDA administered to highly endemic counties province-wide, and 2000 to 2009, when malaria burden was low and a focal approach was used in two counties. All available data about the strategies implemented, MDA coverage, co-interventions, incidence, and adverse events were collected and described. Joinpoint analysis was used to describe trends in incidence and the relationship between MDA coverage and incidence was explored in negative binomial regression models.ResultsFrom 1973 to 1983, MDA with pyrimethamine and primaquine was used on a large scale, with up to 30 million people in target counties covered in a peak year (50% of the total population). Joinpoint analyses identified declines in annual incidence, -56.7% (95% CI -75.5 to -23.7%) from 1973–1976 and -12.4% (95% CI -24.7 to 2.0%) from 1976–1983. Population average negative binomial models identified a relationship between higher total population MDA coverage and lower monthly incidence from 1973–1976, IRR 0.98 (95% CI 0.97 to 1.00), while co-interventions, rainfall and GDP were not associated. From 2000–2009, incidence in two counties declined (annual change -43.7 to -14.0%) during a time when focal MDA using chloroquine and primaquine was targeted to villages and/or individuals residing near passively detected index cases (median 0.04% of total population). Although safety data were not collected systematically, there were rare reports of serious but non-fatal events.ConclusionsIn Jiangsu Province, China, large-scale MDA was implemented and associated with declines in high P. vivax malaria transmission; a more recent focal approach may have contributed to interruption of transmission. MDA should be considered a potential key strategy for malaria control and elimination.

Rationale for short course primaquine in Africa to interrupt malaria transmission

Following the recent successes of malaria control in sub-Saharan Africa, the gametocytocidal drug primaquine needs evaluation as a tool to further reduce the transmission of Plasmodium falciparum malaria. The drug has scarcely been used in Africa because of concerns about its safety in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The evidence base for the use of primaquine as a transmission blocker is limited by a lack of comparable clinical and parasitological endpoints between trials. In March 2012, a group of experts met in London to discuss the existing evidence on the ability of primaquine to block malaria transmission, to define the roadblocks to the use of primaquine in Africa and to develop a roadmap to enable its rapid, safe and effective deployment. The output of this meeting is a strategic plan to optimize trial design to reach desired goals efficiently. The roadmap includes suggestions for a series of phase 1, 2, 3 and 4 studies to address specific hurdles to primaquine’s deployment. These include ex-vivo studies on efficacy, primaquine pharmacokinetics and pharmacodynamics and dose escalation studies for safety in high-risk groups. Phase 3 community trials are proposed, along with Phase 4 studies to evaluate safety, particularly in pregnancy, through pharmacovigilance in areas where primaquine is already deployed. In parallel, efforts need to be made to address issues in drug supply and regulation, to map G6PD deficiency and to support the evaluation of alternative gametocytocidal compounds.