How long is the last mile? Evaluating successful malaria elimination trajectories.

BACKGROUND: Many national malaria programmes have set goals of eliminating malaria, but realistic timelines for achieving this goal remain unclear. In this investigation, historical data are collated on countries that successfully eliminated malaria to assess how long elimination has taken in the past, and thus to inform feasible timelines for achieving it in the future. METHODS: Annual malaria case series were sought for 56 successful elimination programmes through a non-systematic review. Up to 40 years of annual case counts were compiled leading up to the first year in which zero locally acquired or indigenous cases were reported. To separate the period over which effective elimination efforts occurred from prior background trends, annual case totals were log transformed, and their slopes evaluated for a breakpoint in linear trend using the segmented package in R. The number of years from the breakpoint to the first year with zero cases and the decline rate over that period were then calculated. Wilcox-Mann-Whitney tests were used to evaluate whether a set of territory characteristics were associated with the timelines and decline rates. RESULTS: Case series declining to the first year with zero cases were compiled for 45/56 of the candidate elimination programmes, and statistically significant breakpoints were identified for 42. The median timeline from the breakpoint to the first year with zero local cases was 12 years, over which cases declined at a median rate of 54% per year. Prior to the breakpoint, the median trend was slightly decreasing with median annual decline of < 3%. Timelines to elimination were fastest among territories that lacked land boundaries, had centroids in the Tropics, received low numbers of imported cases, and had elimination certified by the World Health Organization. CONCLUSION: The historical case series assembled here may help countries with aspirations of malaria elimination to set feasible milestones towards this goal. Setting goals for malaria elimination on short timescales may be most appropriate in isolated, low importation settings, such as islands, while other regions aiming to eliminate malaria must consider how to sustainably fund and maintain vital case management and vector control services until zero cases are reached.

An assessment of the supply, programmatic use, and regulatory issues of single low-dose primaquine as a Plasmodium falciparum gametocytocide for sub-Saharan Africa.

BACKGROUND: Global ambitions to eliminate malaria are intensifying, underscoring a critical need for transmission blocking tools. In 2012, the WHO recommended the use of 0.25 mg/kg of single low-dose (SLD) primaquine to stop Plasmodium falciparum transmission. To ensure the availability of SLD primaquine to countries in need of this tool, more information on the supply, programmatic, and regulatory barriers to the rollout of SLD primaquine is required. METHODS: Challenges to the rollout of SLD primaquine in sub-Saharan Africa were established through semi-structured qualitative interviews with three primaquine manufacturers, 43 key informants from Ethiopia, Senegal, Swaziland, Zambia, and Tanzania, and 16 malaria research experts. RESULTS: Sanofi and Remedica are the only two sources of SRA-approved primaquine suitable for procurement by international donors. Neither manufacturer produces primaquine tablet strengths suitable for the transmission blocking indication. In-country key informants revealed that the WHO weight-based recommendation to use SLD primaquine is challenging to implement in actual field settings. Malaria programmes expressed safety concerns of SLD primaquine use in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, as well as potential interactions between primaquine and co-morbidities, and drug-drug interactions with HIV and/or tuberculosis treatments. Regulatory processes are a major barrier to the rollout of SLD primaquine, requiring multiple steps at both the country and global level. Despite these barriers, demand for SLD primaquine is growing, and malaria researchers are interested in primaquine deployment through mass screen and treat and/or mass drug administration campaigns. CONCLUSION: Demand for primaquine as a transmission blocking agent is growing rapidly yet multiple barriers to SLD primaquine use exist. Research is needed to define the therapeutic dose range, which will guide dosing regimens in the field, inform the development of new, lower strength primaquine tablets and/or formulation(s), and allay programmatic safety concerns in individuals with G6PD deficiency. Potential interactions between primaquine and co-morbidities and treatments should be explored. To minimize regulatory delays, countries need to prepare for product registration at an early stage, WHO prequalification for suitable primaquine tablet strengths and/or new formulations should be sought, and in the meanwhile only Stringent Regulatory Authority (SRA)-approved primaquine should be used.

Strengthening malaria diagnosis and appropriate treatment in Namibia: a test of case management training interventions in Kavango Region.

BACKGROUND: Despite its importance in control and elimination settings, malaria diagnosis rates tend to be low in many African countries. An operational research pilot was conducted in Namibia to identify the key barriers to appropriate diagnosis of malaria in public health facilities and to evaluate the effectiveness of various training approaches in improving the uptake and adherence to rapid diagnostic tests (RDTs). METHODS: After identifying case management weaknesses through focus group discussions, training interventions were designed to address these barriers over a six-month period. The study had three intervention districts and one control within the Kavango region of Namibia where poor case management practices were observed. The interventions included an enhanced training model, clinical mentorship, and SMS reminders. Monthly data on testing and treatment were collected for the period of April to September 2012 and, for comparison, the same months during the prior year from all 52 health facilities in Kavango. The same indicators were also obtained at district level for a follow-up period of 15 months from October 2012 to December 2013 to observe whether any improvements were sustained over time. RESULTS: All intervention arms produced significant improvements in case management practices compared to the control district (all p < 0.02). Overall, districts receiving any training improved testing rates from 25% to 66% at minimum compared to the control. The enhanced training plus mentorship arm resulted in a significantly greater proportion of fevers receiving RDTs compared to the district receiving enhanced training alone, increasing from 27% to over 90% at endline. No ACT was prescribed to untested patients after caregivers received mentorship or SMS reminders. These improvements were all sustained over the 15-month follow-up. CONCLUSIONS: These changes show a reversal of improper case management practices over the six-month study period and demonstrate that implementing simple training interventions can have a significant, sustainable impact on the uptake of and adherence to malaria RDTs. Findings from this work have already informed Namibia's roll out of a more robust case management training programme. The approaches used in Namibia may be applicable to other resource-constrained countries, providing practical guidance on sustainable approaches to febrile illness management.

Integrating rapid risk mapping and mobile phone call record data for strategic malaria elimination planning.

BACKGROUND: As successful malaria control programmes re-orientate towards elimination, the identification of transmission foci, targeting of attack measures to high-risk areas and management of importation risk become high priorities. When resources are limited and transmission is varying seasonally, approaches that can rapidly prioritize areas for surveillance and control can be valuable, and the most appropriate attack measure for a particular location is likely to differ depending on whether it exports or imports malaria infections. METHODS/RESULTS: Here, using the example of Namibia, a method for targeting of interventions using surveillance data, satellite imagery, and mobile phone call records to support elimination planning is described. One year of aggregated movement patterns for over a million people across Namibia are analyzed, and linked with case-based risk maps built on satellite imagery. By combining case-data and movement, the way human population movements connect transmission risk areas is demonstrated. Communities that were strongly connected by relatively higher levels of movement were then identified, and net export and import of travellers and infection risks by region were quantified. These maps can aid the design of targeted interventions to maximally reduce the number of cases exported to other regions while employing appropriate interventions to manage risk in places that import them. CONCLUSIONS: The approaches presented can be rapidly updated and used to identify where active surveillance for both local and imported cases should be increased, which regions would benefit from coordinating efforts, and how spatially progressive elimination plans can be designed. With improvements in surveillance systems linked to improved diagnosis of malaria, detailed satellite imagery being readily available and mobile phone usage data continually being collected by network providers, the potential exists to make operational use of such valuable, complimentary and contemporary datasets on an ongoing basis in infectious disease control and elimination.

Rapid case-based mapping of seasonal malaria transmission risk for strategic elimination planning in Swaziland.

BACKGROUND: As successful malaria control programmes move towards elimination, they must identify residual transmission foci, target vector control to high-risk areas, focus on both asymptomatic and symptomatic infections, and manage importation risk. High spatial and temporal resolution maps of malaria risk can support all of these activities, but commonly available malaria maps are based on parasite rate, a poor metric for measuring malaria at extremely low prevalence. New approaches are required to provide case-based risk maps to countries seeking to identify remaining hotspots of transmission while managing the risk of transmission from imported cases. METHODS: Household locations and travel histories of confirmed malaria patients during 2011 were recorded through routine surveillance by the Swaziland National Malaria Control Programme for the higher transmission months of January to April and the lower transmission months of May to December. Household locations for patients with no travel history to endemic areas were compared against a random set of background points sampled proportionate to population density with respect to a set of variables related to environment, population density, vector control, and distance to the locations of identified imported cases. Comparisons were made separately for the high and low transmission seasons. The Random Forests regression tree classification approach was used to generate maps predicting the probability of a locally acquired case at 100 m resolution across Swaziland for each season. RESULTS: Results indicated that case households during the high transmission season tended to be located in areas of lower elevation, closer to bodies of water, in more sparsely populated areas, with lower rainfall and warmer temperatures, and closer to imported cases than random background points (all p < 0.001). Similar differences were evident during the low transmission season. Maps from the fit models suggested better predictive ability during the high season. Both models proved useful at predicting the locations of local cases identified in 2012. CONCLUSIONS: The high-resolution mapping approaches described here can help elimination programmes understand the epidemiology of a disappearing disease. Generating case-based risk maps at high spatial and temporal resolution will allow control programmes to direct interventions proactively according to evidence-based measures of risk and ensure that the impact of limited resources is maximized to achieve and maintain malaria elimination.

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.

A national policy for malaria elimination in Swaziland: a first for sub-Saharan Africa.

Swaziland is working to be the first country in mainland sub-Saharan Africa to eliminate malaria. The highest level of Swaziland's government recently approved a national elimination policy, which endorses Swaziland's robust national elimination strategic plan. This commentary outlines Swaziland's progress towards elimination as well as the challenges that remain, primarily around securing long-term financial resources and managing imported cases from neighbouring countries.