Study protocol for a cluster randomised controlled factorial design trial to assess the effectiveness and feasibility of reactive focal mass drug administration and vector control to reduce malaria transmission in the low endemic setting of Namibia.

INTRODUCTION: To interrupt malaria transmission, strategies must target the parasite reservoir in both humans and mosquitos. Testing of community members linked to an index case, termed reactive case detection (RACD), is commonly implemented in low transmission areas, though its impact may be limited by the sensitivity of current diagnostics. Indoor residual spraying (IRS) before malaria season is a cornerstone of vector control efforts. Despite their implementation in Namibia, a country approaching elimination, these methods have been met with recent plateaus in transmission reduction. This study evaluates the effectiveness and feasibility of two new targeted strategies, reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in Namibia. METHODS AND ANALYSIS: This is an open-label cluster randomised controlled trial with 2×2 factorial design. The interventions include: rfMDA (presumptive treatment with artemether-lumefantrine (AL)) versus RACD (rapid diagnostic testing and treatment using AL) and RAVC (IRS with Acellic 300CS) versus no RAVC. Factorial design also enables comparison of the combined rfMDA+RAVC intervention to RACD. Participants living in 56 enumeration areas will be randomised to one of four arms: rfMDA, rfMDA+RAVC, RACD or RACD+RAVC. These interventions, triggered by index cases detected at health facilities, will be targeted to individuals residing within 500 m of an index. The primary outcome is cumulative incidence of locally acquired malaria detected at health facilities over 1 year. Secondary outcomes include seroprevalence, infection prevalence, intervention coverage, safety, acceptability, adherence, cost and cost-effectiveness. ETHICS AND DISSEMINATION: Findings will be reported on clinicaltrials.gov, in peer-reviewed publications and through stakeholder meetings with MoHSS and community leaders in Namibia. TRIAL REGISTRATION NUMBER: NCT02610400; Pre-results

Multiple Origins and Regional Dispersal of Resistant dhps in African Plasmodium falciparum Malaria

Cally Roper and colleagues analyze the distribution of sulfadoxine resistance mutations and flanking microsatellite loci to trace the emergence and dispersal of drug-resistant Plasmodium falciparum malaria in Africa

Effectiveness of reactive focal mass drug administration and reactive focal vector control to reduce malaria transmission in the low malaria-endemic setting of Namibia: a cluster-randomised controlled, open-label, two-by-two factorial design trial.

BACKGROUND: In low malaria-endemic settings, screening and treatment of individuals in close proximity to index cases, also known as reactive case detection (RACD), is practised for surveillance and response. However, other approaches could be more effective for reducing transmission. We aimed to evaluate the effectiveness of reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in the low malaria-endemic setting of Zambezi (Namibia). METHODS: We did a cluster-randomised controlled, open-label trial using a two-by-two factorial design of 56 enumeration area clusters in the low malaria-endemic setting of Zambezi (Namibia). We randomly assigned these clusters using restricted randomisation to four groups: RACD only, rfMDA only, RAVC plus RACD, or rfMDA plus RAVC. RACD involved rapid diagnostic testing and treatment with artemether-lumefantrine and single-dose primaquine, rfMDA involved presumptive treatment with artemether-lumefantrine, and RAVC involved indoor residual spraying with pirimiphos-methyl. Interventions were administered within 500 m of index cases. To evaluate the effectiveness of interventions targeting the parasite reservoir in humans (rfMDA vs RACD), in mosquitoes (RAVC vs no RAVC), and in both humans and mosquitoes (rfMDA plus RAVC vs RACD only), an intention-to-treat analysis was done. For each of the three comparisons, the primary outcome was the cumulative incidence of locally acquired malaria cases. This trial is registered with ClinicalTrials.gov, number NCT02610400. FINDINGS: Between Jan 1, 2017, and Dec 31, 2017, 55 enumeration area clusters had 1118 eligible index cases that led to 342 interventions covering 8948 individuals. The cumulative incidence of locally acquired malaria was 30·8 per 1000 person-years (95% CI 12·8-48·7) in the clusters that received rfMDA versus 38·3 per 1000 person-years (23·0-53·6) in the clusters that received RACD; 30·2 per 1000 person-years (15·0-45·5) in the clusters that received RAVC versus 38·9 per 1000 person-years (20·7-57·1) in the clusters that did not receive RAVC; and 25·0 per 1000 person-years (5·2-44·7) in the clusters that received rfMDA plus RAVC versus 41·4 per 1000 person-years (21·5-61·2) in the clusters that received RACD only. After adjusting for imbalances in baseline and implementation factors, the incidence of malaria was lower in clusters receiving rfMDA than in those receiving RACD (adjusted incidence rate ratio 0·52 [95% CI 0·16-0·88], p=0·009), lower in clusters receiving RAVC than in those that did not (0·48 [0·16-0·80], p=0·002), and lower in clusters that received rfMDA plus RAVC than in those receiving RACD only (0·26 [0·10-0·68], p=0·006). No serious adverse events were reported. INTERPRETATION: In a low malaria-endemic setting, rfMDA and RAVC, implemented alone and in combination, reduced malaria transmission and should be considered as alternatives to RACD for elimination of malaria. FUNDING: Novartis Foundation, Bill & Melinda Gates Foundation, and Horchow Family Fund

Mapping of schistosomiasis and soil-transmitted helminths in Namibia: The first large-scale protocol to formally include rapid diagnostic tests

Background: Namibia is now ready to begin mass drug administration of praziquantel and albendazole against schistosomiasis and soil-transmitted helminths, respectively. Although historical data identifies areas of transmission of these neglected tropical diseases (NTDs), there is a need to update epidemiological data. For this reason, Namibia adopted a new protocol for mapping of schistosomiasis and geohelminths, formally integrating rapid diagnostic tests (RDTs) for infections and morbidity. In this article, we explain the protocol in detail, and introduce the concept of 'mapping resolution', as well as present results and treatment recommendations for northern Namibia.Methods/Findings/Interpretation: This new protocol allowed a large sample to be surveyed (N = 17 896 children from 299 schools) at relatively low cost (7 USD per person mapped) and very quickly (28 working days). All children were analysed by RDTs, but only a sub-sample was also diagnosed by light microscopy. Overall prevalence of schistosomiasis in the surveyed areas was 9.0%, highly associated with poorer access to potable water (OR = 1.5, P<0.001) and defective (OR = 1.2, P<0.001) or absent sanitation infrastructure (OR = 2.0, P<0.001). Overall prevalence of geohelminths, more particularly hookworm infection, was 12.2%, highly associated with presence of faecal occult blood (OR = 1.9, P<0.001). Prevalence maps were produced and hot spots identified to better guide the national programme in drug administration, as well as targeted improvements in water, sanitation and hygiene. The RDTs employed (circulating cathodic antigen and microhaematuria for Schistosoma mansoni and S. haematobium, respectively) performed well, with sensitivities above 80% and specificities above 95%.Conclusion/Significance: This protocol is cost-effective and sensitive to budget limitations and the potential economic and logistical strains placed on the national Ministries of Health. Here we present a high resolution map of disease prevalence levels, and treatment regimens are recommended.Peer reviewedEntomology and Plant Patholog

Spatial clustering of patent and sub-patent malaria infections in northern Namibia: Implications for surveillance and response strategies for elimination.

BACKGROUND:Reactive case detection (RACD) around passively detected malaria cases is a strategy to identify and treat hotspots of malaria transmission. This study investigated the unproven assumption on which this approach is based, that in low transmission settings, infections cluster over small scales. METHODS:A prospective case-control study was conducted between January 2013 and August 2014 in Ohangwena and Omusati regions in north central Namibia. Patients attending health facilities who tested positive by malaria rapid diagnostic test (RDT) (index cases) were traced back to their home. All occupants of index case households (n = 116 households) and surrounding households (n = 225) were screened for Plasmodium infection with a rapid diagnostic test (RDT) and loop mediated isothermal amplification (LAMP) and interviewed to identify risk factors. A comparison group of 286 randomly-selected control households was also screened, to compare infection levels of RACD and non-RACD households and their neighbours. Logistic regression was used to investigate spatial clustering of patent and sub-patent infections around index cases and to identify potential risk factors that would inform screening approaches and identify risk groups. Estimates of the impact of RACD on onward transmission to mosquitoes was made using previously published figures of infection rates. RESULTS:Prevalence of Plasmodium falciparum infection by LAMP was 3.4%, 1.4% and 0.4% in index-case households, neighbors of index case households and control households respectively; adjusted odds ratio 6.1 [95%CI 1.9-19.5] comparing case households versus control households. Using data from Engela, neighbors of cases had higher odds of infection [adjusted OR 5.0 95%CI 1.3-18.9] compared to control households. All infections identified by RDTs were afebrile and RDTs identified only a small proportion of infections in case (n = 7; 17%) and control (0%) neighborhoods. Based on published estimates of patent and sub-patent infectiousness, these results suggest that infections missed by RDTs during RACD would allow 50-71% of infections to mosquitoes to occur in this setting. CONCLUSION:Malaria infections cluster around passively detected cases. The majority of infections are asymptomatic and of densities below the limit of detection of current RDTs. RACD using standard RDTs are unlikely to detect enough malaria infections to dramatically reduce transmission. In low transmission settings such as Namibia more sensitive field diagnostics or forms of focal presumptive treatment should be tested as strategies to reduce malaria transmission

Map of contemporary first level administrative units of Namibia showing the spatial limits of P.falciparum transmission (dark pink) and location of PfPR survey data from the year 1967 to 1992.

<p>Where survey data are available for a location in more than one year, the highest <u>Pf</u>PR value is displayed top. Light pink areas support unstable transmission and grey areas are malaria free. <b>Footnote:</b> A temperature suitability index (TSI) for malaria transmission at 1×1 km spatial resolution <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063350#pone.0063350-Gosoniu1" target="_blank">[10]</a> was used to delineate areas in Namibia where malaria is unlikely to occur, defined as areas where TSI was equal to zero. TSI was constructed using monthly temperature time series within a biological modelling framework to quantify the effect of ambient temperature on sporogony and vector survivorship and determine the suitability of an area to support transmission globally separately for both P. falciparum and P. vivax. Extreme aridity was defined using synoptic mean monthly enhanced vegetation index (EVI) data <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063350#pone.0063350-Hay1" target="_blank">[11]</a> to classify into areas unlikely to support transmission, defined as areas where EVI was <0.1 in any two consecutive months of the year <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063350#pone.0063350-Kazembe1" target="_blank">[7]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063350#pone.0063350-Gething1" target="_blank">[12]</a>. In Namibia TSI and aridity identified the Namib Desert on the Atlantic Coast, parts of the Kalahari Desert in the South and the Etosha and other smaller saltpans as areas that were too hot or dry to support malaria transmission. Finally areas defined as operationally risk free based on reported incidences <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063350#pone.0063350-Ministry1" target="_blank">[2]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063350#pone.0063350-Diggle1" target="_blank">[6]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063350#pone.0063350-Kazembe1" target="_blank">[7]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063350#pone.0063350-Miller1" target="_blank">[24]</a> were identified (southern parts of the regions of Kunene and Omaheke and all of Erongo, Hardap, Khomas and Karas). It is hard to eliminate the possibility of any risks and therefore the parts of Erongo, the whole of Khomas and the southern parts of Omaheke were classified to be of unstable transmission where aridity and temperature do not exclude transmission.</p

Human resilience in the face of biodiversity tipping points at local and regional scales

<div><p>Background</p><p>Historical evidence of the levels of intervention scale up and its relationships to changing malaria risks provides important contextual information for current ambitions to eliminate malaria in various regions of Africa today.</p><p>Methods</p><p>Community-based <i>Plasmodium falciparum</i> prevalence data from 3,260 geo-coded time-space locations between 1969 and 1992 were assembled from archives covering an examination of 230,174 individuals located in northern Namibia. These data were standardized the age-range 2 to less than 10 years and used within a Bayesian model-based geo-statistical framework to examine the changes of malaria risk in the years 1969, 1974, 1979, 1984 and 1989 at 5×5 km spatial resolution. This changing risk was described against rainfall seasons and the wide-scale use of indoor-residual house-spraying and mass drug administration.</p><p>Results</p><p>Most areas of Northern Namibia experienced low intensity transmission during a ten-year period of wide-scale control activities between 1969 and 1979. As control efforts waned, flooding occurred, drug resistance emerged and the war for independence intensified the spatial extent of moderate-to-high malaria transmission expanded reaching a peak in the late 1980s.</p><p>Conclusions</p><p>Targeting vectors and parasite in northern Namibia was likely to have successfully sustained a situation of low intensity transmission, but unraveled quickly to a peak of transmission intensity following a sequence of events by the early 1990s.</p></div

Graphs A–C show scatter plots with lowess regression fit of PfPR_2–10 by year of survey and the main intervention and political events that may have determined the observed transmission patterns in Caprivi, Kavango and Ovambo respectively.

<p>D) is a summary of the droughts (orange) and above average rainfall (green) as measured using rainfall in the October – April rainfall in Caprivi, Kavango and Ovambo. Seasons not designated as one of drought or above average rainfall are considered to have received average rainfall.</p

Summary intervention distribution and coverage data assembled from monthly and annual reports archived at Tzaneen for Caprivi, Kavango and Ovambo (present-day Omusati, Oshana, Ohangwena and Oshikoto regions) of: A) the amount of DDT (kilograms) used for IRS; B) the number of house structures sprayed; and C) the number of Darachlor tablets dispensed during the period 1965 to 1989 in A) Kavango and B) Ovambo.

<p>Data were unavailable for DDT, housing structures sprayed and Darachor tablets dispensed for the years where data is not shown. Darachlor use was terminated after 1989.</p