Reactive focal drug administration associated with decreased malaria transmission in an elimination setting: Serological evidence from the cluster-randomized CoRE study.

Efforts to eliminate malaria transmission need evidence-based strategies. However, accurately assessing end-game malaria elimination strategies is challenging due to the low level of transmission and the rarity of infections. We hypothesised that presumptively treating individuals during reactive case detection (RCD) would reduce transmission and that serology would more sensitively detect this change over standard approaches. We conducted a cluster randomised control trial (NCT02654912) of presumptive reactive focal drug administration (RFDA-intervention) compared to the standard of care, reactive focal test and treat (RFTAT-control) in Southern Province, Zambia-an area of low seasonal transmission (overall incidence of ~3 per 1,000). We measured routine malaria incidence from health facilities as well as PCR parasite prevalence / antimalarial seroprevalence in an endline cross-sectional population survey. No significant difference was identified from routine incidence data and endline prevalence by polymerase chain reaction (PCR) had insufficient numbers of malaria infections (i.e., 16 infections among 6,276 children) to assess the intervention. Comparing long-term serological markers, we found a 19% (95% CI = 4-32%) reduction in seropositivity for the RFDA intervention using a difference in differences approach incorporating serological positivity and age. We also found a 37% (95% CI = 2-59%) reduction in seropositivity to short-term serological markers in a post-only comparison. These serological analyses provide compelling evidence that RFDA both has an impact on malaria transmission and is an appropriate end-game malaria elimination strategy. Furthermore, serology provides a more sensitive approach to measure changes in transmission that other approaches miss, particularly in very low transmission settings. Trial Registration: Registered at www.clinicaltrials.gov (NCT02654912, 13/1/2016).

World Malaria Day 2021: Commemorating 15 Years of Contribution by the United States President's Malaria Initiative.

World Malaria Day 2021 coincides with the 15th anniversary of the United States President's Malaria Initiative (PMI) and follows the first anniversary of the declaration of the coronavirus disease (COVID-19) pandemic. From 2006 to the present, the PMI has led to considerable country-managed progress in malaria prevention, care, and treatment in 24 of the highest-burden countries in sub-Saharan Africa and three countries in the Southeast Asia Greater Mekong subregion. Furthermore, it has contributed to a 29% reduction in malaria cases and a 60% reduction in the death rates in sub-Saharan Africa. In this context of progress, substantial heterogeneity persists within and between countries, such that malaria control programs can seek subnational elimination in some populations but others still experience substantial malaria disease and death. During the COVID-19 pandemic, most malaria programs have shown resilience in delivering prevention campaigns, but many experienced important disruptions in their care and treatment of malaria illness. Confronting the COVID-19 pandemic and building on the progress against malaria will require fortitude, including strengthening the quality and ensuring the safety and resiliency of the existing programs, extending services to those currently not reached, and supporting the people and partners closest to those in need.

Correction to: Mass testing and treatment for malaria followed by weekly fever screening, testing and treatment in Northern Senegal: feasibility, cost and impact.

An amendment to this paper has been published and can be accessed via the original article.

Genetic evidence for imported malaria and local transmission in Richard Toll, Senegal.

BACKGROUND: Malaria elimination efforts can be undermined by imported malaria infections. Imported infections are classified based on travel history. METHODS: A genetic strategy was applied to better understand the contribution of imported infections and to test for local transmission in the very low prevalence region of Richard Toll, Senegal. RESULTS: Genetic relatedness analysis, based upon molecular barcode genotyping data derived from diagnostic material, provided evidence for both imported infections and ongoing local transmission in Richard Toll. Evidence for imported malaria included finding that a large proportion of Richard Toll parasites were genetically related to parasites from Thiès, Senegal, a region of moderate transmission with extensive available genotyping data. Evidence for ongoing local transmission included finding parasites of identical genotype that persisted across multiple transmission seasons as well as enrichment of highly related infections within the households of non-travellers compared to travellers. CONCLUSIONS: These data indicate that, while a large number of infections may have been imported, there remains ongoing local malaria transmission in Richard Toll. These proof-of-concept findings underscore the value of genetic data to identify parasite relatedness and patterns of transmission to inform optimal intervention selection and placement.

Mass testing and treatment for malaria followed by weekly fever screening, testing and treatment in Northern Senegal: feasibility, cost and impact.

BACKGROUND: Population-wide interventions using malaria testing and treatment might decrease the reservoir of Plasmodium falciparum infection and accelerate towards elimination. Questions remain about their effectiveness and evidence from different transmission settings is needed. METHODS: A pilot quasi-experimental study to evaluate a package of population-wide test and treat interventions was conducted in six health facility catchment areas (HFCA) in the districts of Kanel, Linguère, and Ranérou (Senegal). Seven adjacent HFCAs were selected as comparison. Villages within the intervention HFCAs were stratified according to the 2013 incidences of passively detected malaria cases, and those with an incidence ≥ 15 cases/1000/year were targeted for a mass test and treat (MTAT) in September 2014. All households were visited, all consenting individuals were tested with a rapid diagnostic test (RDT), and, if positive, treated with dihydroartemisinin-piperaquine. This was followed by weekly screening, testing and treatment of fever cases (PECADOM++) until the end of the transmission season in January 2015. Villages with lower incidence received only PECADOM++ or case investigation. To evaluate the impact of the interventions over that transmission season, the incidence of passively detected, RDT-confirmed malaria cases was compared between the intervention and comparison groups with a difference-in-difference analysis using negative binomial regression with random effects on HFCA. RESULTS: During MTAT, 89% (2225/2503) of households were visited and 86% (18,992/22,170) of individuals were tested, for a combined 77% effective coverage. Among those tested, 291 (1.5%) were RDT positive (range 0-10.8 by village), of whom 82% were < 20 years old and 70% were afebrile. During the PECADOM++ 40,002 visits were conducted to find 2784 individuals reporting fever, with an RDT positivity of 6.5% (170/2612). The combination of interventions resulted in an estimated 38% larger decrease in malaria case incidence in the intervention compared to the comparison group (adjusted incidence risk ratio = 0.62, 95% CI 0.45-0.84, p = 0.002). The cost of the MTAT was $14.3 per person. CONCLUSIONS: It was operationally feasible to conduct MTAT and PECADOM++ with high coverage, although PECADOM++ was not an efficient strategy to complement MTAT. The modest impact of the intervention package suggests a need for alternative or complementary strategies.

Assessment of the Acceptability of Testing and Treatment during a Mass Drug Administration Trial for Malaria in Zambia Using Mixed Methods.

From 2014 to 2016, a community-randomized controlled trial in Southern Province, Zambia, compared mass drug administration (MDA) and focal MDA (fMDA) with the standard of care. Acceptability of the intervention was assessed quantitatively using closed-ended and Likert scale-based questions posed during three household surveys conducted from April to May in 2014, 2015, and 2016 in 40 health catchments that implemented MDA and fMDA and 20 catchments that served as trial controls. In 2014 and 2015, 47 households per catchment were selected, targeting 1,880 households in MDA and fMDA trial arms; in 2016, 55 households per catchment were selected for a target of 2,200 households in MDA and fMDA trial arms. Concurrently, 27 focus group discussions and 23 in-depth interviews with 248 participants were conducted on reasons for testing and treatment refusal, reasons for nonadherence, and community perception of the MDA campaign. Results demonstrated that the MDA campaign was highly accepted with more than 99% of respondents stating that they would take treatment if positive for malaria. High acceptability at baseline could be associated with test-and-treat campaigns recently conducted in the study area. There was a large increase in the acceptability of prophylactic treatment if negative for malaria from the baseline to follow-up survey for adults and children, from 62% to 96% for each. This likely resulted from an intensive community-wide sensitization program that occurred before the first treatment round at each household during community health worker visits.

Pyrethroid and Carbamate Resistance in Anopheles funestus Giles along Lake Kariba in Southern Zambia.

Whereas data on insecticide resistance and its underlying mechanisms exist for parts of Zambia, data remain limited in the southern part of the country. This study investigated the status of insecticide resistance, metabolic mechanisms, and parasite infection in Anopheles funestus along Lake Kariba in southern Zambia. Indoor-resting mosquitoes were collected from 20 randomly selected houses within clusters where a mass drug administration trial was conducted and raised to F1 progeny. Non-blood-fed 2- to 5-day-old female An. funestus were exposed to WHO insecticide-impregnated papers with 0.05% deltamethrin, 0.1% bendiocarb, 0.25% pirimiphos-methyl, or 4% dichloro-diphenyl-trichloroethane (DDT). In separate assays, An. funestus were pre-exposed to piperonyl butoxide (PBO) to determine the presence of monooxygenases. Wild-caught An. funestus that had laid eggs for susceptibility assays were screened for circumsporozoite protein of Plasmodium falciparum by ELISA, and sibling species were identified by polymerase chain reaction. Anopheles funestus showed resistance to deltamethrin and bendiocarb but remained susceptible to pirimiphos-methyl and DDT. The pre-exposure of An. funestus to PBO restored full susceptibility to deltamethrin but not to bendiocarb. The overall sporozoite infection rate in An. funestus populations was 5.8%. Detection of pyrethroid and carbamate resistance in An. funestus calls for increased insecticide resistance monitoring to guide planning and selection of effective insecticide resistance management strategies. To prevent the development of resistance and reduce the underlying vectorial capacity of mosquitoes in areas targeted for malaria elimination, an effective integrated vector management strategy is needed.

A Longitudinal Cohort to Monitor Malaria Infection Incidence during Mass Drug Administration in Southern Province, Zambia.

Rigorous evidence of effectiveness is needed to determine where and when to apply mass drug administration (MDA) or focal MDA (fMDA) as part of a malaria elimination strategy. The Zambia National Malaria Elimination Centre recently completed a community-randomized controlled trial in Southern Province to evaluate MDA and fMDA for transmission reduction. To assess the role of MDA and fMDA on infection incidence, we enrolled a longitudinal cohort for an 18-month period of data collection including monthly malaria parasite infection detection based on polymerase chain reaction and compared time to first infection and cumulative infection incidence outcomes across study arms using Cox proportional hazards and negative binomial models. A total of 2,026 individuals from 733 households were enrolled and completed sufficient follow-up for inclusion in analysis. Infection incidence declined dramatically across all study arms during the period of study, and MDA was associated with reduced risk of first infection (hazards ratio: 0.36; 95% CI: 0.16-0.80) and cumulative infection incidence during the first rainy season (first 5 months of follow-up) (incidence rate ratio: 0.34; 95% CI: 0.12-0.95). No significant effect was found for fMDA or for either arm over the full study period. Polymerase chain reaction infection status at baseline was strongly associated with follow-up infection. The short-term effects of MDA suggest it may be an impactful accelerator of transmission reduction in areas with high coverage of case management and vector control and should be considered as part of a malaria elimination strategy.

Cost-Effectiveness of Focal Mass Drug Administration and Mass Drug Administration with Dihydroartemisinin-Piperaquine for Malaria Prevention in Southern Province, Zambia: Results of a Community-Randomized Controlled Trial.

Community-wide administration of antimalarial drugs in therapeutic doses is a potential tool to prevent malaria infection and reduce the malaria parasite reservoir. To measure the effectiveness and cost of using the antimalarial drug combination dihydroartemisinin-piperaquine (DHAp) through different community-wide distribution strategies, Zambia's National Malaria Control Centre conducted a three-armed community-randomized controlled trial. The trial arms were as follows: 1) standard of care (SoC) malaria interventions, 2) SoC plus focal mass drug administration (fMDA), and 3) SoC plus MDA. Mass drug administration consisted of offering all eligible individuals DHAP, irrespective of a rapid diagnostic test (RDT) result. Focal mass drug administration consisted of offering DHAP to all eligible individuals who resided in a household where anyone tested positive by RDT. Results indicate that the costs of fMDA and MDA per person targeted and reached are similar (US$9.01 versus US$8.49 per person, respectively, P = 0.87), but that MDA was superior in all cost-effectiveness measures, including cost per infection averted, cost per case averted, cost per death averted, and cost per disability-adjusted life year averted. Subsequent costing of the MDA intervention in a non-trial, operational setting yielded significantly lower costs per person reached (US$2.90). Mass drug administration with DHAp also met the WHO thresholds for "cost-effective interventions" in the Zambian setting in 90% of simulations conducted using a probabilistic sensitivity analysis based on trial costs, whereas fMDA met these criteria in approximately 50% of simulations. A sensitivity analysis using costs from operational deployment and trial effectiveness yielded improved cost-effectiveness estimates. Mass drug administration may be a cost-effective intervention in the Zambian context and can help reduce the parasite reservoir substantially. Mass drug administration was more cost-effective in relatively higher transmission settings. In all scenarios examined, the cost-effectiveness of MDA was superior to that of fMDA.

Impact of Four Rounds of Mass Drug Administration with Dihydroartemisinin-Piperaquine Implemented in Southern Province, Zambia.

Over the past decade, Zambia has made substantial progress against malaria and has recently set the ambitious goal of eliminating by 2021. In the context of very high vector control and improved access to malaria diagnosis and treatment in Southern Province, we implemented a community-randomized controlled trial to assess the impact of four rounds of community-wide mass drug administration (MDA) and household-level MDA (focal MDA) with dihydroartemisinin-piperaquine (DHAP) implemented between December 2014 and February 2016. The mass treatment campaigns achieved relatively good household coverage (63-79%), were widely accepted by the community (ranging from 87% to 94%), and achieved very high adherence to the DHAP regimen (81-96%). Significant declines in all malaria study end points were observed, irrespective of the exposure group, with the overall parasite prevalence during the peak transmission season declining by 87.2% from 31.3% at baseline to 4.0% in 2016 at the end of the trial. Children in areas of lower transmission (< 10% prevalence at baseline) that received four MDA rounds had a 72% (95% CI = 12-91%) reduction in malaria parasite prevalence as compared with those with the standard of care without any mass treatment. Mass drug administration consistently had the largest short-term effect size across study end points in areas of lower transmission following the first two MDA rounds. In the context of achieving very high vector control coverage and improved access to diagnosis and treatment for malaria, our results suggest that MDA should be considered for implementation in African settings for rapidly reducing malaria outcomes in lower transmission settings.

Recent Travel History and Plasmodium falciparum Malaria Infection in a Region of Heterogenous Transmission in Southern Province, Zambia.

As Zambia continues to reduce its malaria incidence and target elimination in Southern Province, there is a need to identify factors that can reintroduce parasites and sustain malaria transmission. To examine the relative contributions of types of human mobility on malaria prevalence, this analysis quantifies the proportion of the population having recently traveled during both peak and nonpeak transmission seasons over the course of 2 years and assesses the relationship between short-term travel and malaria infection status. Among all residents targeted by mass drug administration in the Lake Kariba region of Southern Province, 602,620 rapid diagnostic tests and recent travel histories were collected during four campaign rounds occurring between December 2014 and February 2016. Rates of short-term travel in the previous 2 weeks fluctuated seasonally from 0.3% to 1.2%. Travel was significantly associated with prevalent malaria infection both seasonally and overall (adjusted odds ratio [AOR]: 2.55; 95% CI: 2.28-2.85). The strength of association between travel and malaria infection varied by travelers' origin and destination, with those recently traveling to high-prevalence areas from low-prevalence areas experiencing the highest odds of malaria infection (AOR: 7.38). Long-lasting insecticidal net usage while traveling was associated with a relative reduction in infections (AOR: 0.74) compared with travelers not using a net. Although travel was directly associated with only a small fraction of infections, importation of malaria via human movement may play an increasingly important role in this elimination setting as transmission rates continue to decline.

Treatment Coverage Estimation for Mass Drug Administration for Malaria with Dihydroartemisinin-Piperaquine in Southern Province, Zambia.

Mass drug administration (MDA) is currently being considered as an intervention in low-transmission areas to complement existing malaria control and elimination efforts. The effectiveness of any MDA strategy is dependent on achieving high epidemiologic coverage and participant adherence rates. A community-randomized controlled trial was conducted from November 2014 to March 2016 to evaluate the impact of four rounds of MDA or focal MDA (fMDA)-where treatment was given to all eligible household members if anyone in the household had a positive malaria rapid diagnostic test-on malaria outcomes in Southern Province, Zambia (population approximately 300,000). This study examined epidemiologic coverage and program reach using capture-recapture and satellite enumeration methods to estimate the degree to which the trial reached targeted individuals. Overall, it was found that the percentage of households visited by campaign teams ranged from 62.9% (95% CI: 60.0-65.8) to a high of 77.4% (95% CI: 73.8-81.0) across four rounds of treatment. When the maximum number of visited households across all campaign rounds was used as the numerator, program reach for at least one visit would have been 86.4% (95% CI: 80.8-92.0) in MDA and 83.5% (95% CI: 78.0-89.1) in fMDA trial arms. As per the protocol, the trial provided dihydroartemisinin-piperaquine treatment to an average of 58.8% and 13.3% of the estimated population based on capture-recapture in MDA and fMDA, respectively, across the four rounds.

Prevalence of Plasmodium falciparum and Non-falciparum Infections by Photo-Induced Electron Transfer-PCR in a Longitudinal Cohort of Individuals Enrolled in a Mass Drug Administration Trial in Southern Province, Zambia.

Malaria burden in Zambia has significantly declined over the last decade because of improved coverage of several key malaria interventions (e.g., vector control, case management, bed net distributions, and enhanced surveillance/responses). Campaign-based mass drug administration (MDA) and focal MDA (fMDA) were assessed in a trial in Southern Province, Zambia, to identify its utility in elimination efforts. As part of the study, a longitudinal cohort was visited and tested (by PCR targeting the 18s rRNA and a Plasmodium falciparum-specific rapid diagnostic test [RDT] from SD Bioline) every month for the trial duration (18 months). Overall, there was high concordance (> 97%) between the PCR and RDT results, using the PCR as the gold standard. The RDTs had high specificity and negative predictive values (98.5% and 98.6%, respectively) but low sensitivity (53.0%) and a low positive predictive value (53.8%). There was evidence for persistent antigenemia affecting the low specificity of the RDT, while false-negative RDTs were associated with a lower parasite density than true positive RDTs. Plasmodium falciparum was the dominant species identified, with 98.3% of all positive samples containing P. falciparum. Of these, 97.5% were mono-infections and 0.8% coinfections with one other species. Plasmodium malariae was found in 1.4% of all positive samples (50% mono-infections and 50% coinfections with P. falciparum), whereas Plasmodium ovale was found in 1.1% of all positive samples (90% mono-infections and 10% coinfections with P. falciparum). Although MDA/fMDA appeared to reduce P. malariae prevalence, P. ovale prevalence appeared unchanged.

Evidence for Reduced Malaria Parasite Population after Application of Population-Level Antimalarial Drug Strategies in Southern Province, Zambia.

A mass drug administration trial was carried out in Southern Province, Zambia, between 2014 and 2016, in conjunction with a standard of care package that included improved surveillance, increased access to malaria case management, and sustained high levels of vector control coverage. This was preceded by mass test and treatment in the same area from 2011 to 2013. Concordant decreases in malaria prevalence in Southern Province and deaths attributed to malaria in Zambia over this time suggest that these strategies successfully reduced the malaria burden. Genetic epidemiological studies were used to assess the consequences of these interventions on parasite population structure. Analysis of parasite material derived from 1,620 rapid diagnostic test (RDT)-positive individuals obtained from studies to evaluate trial outcomes revealed a reduction in the average complexity of infection and consequential increase in the proportion of infections that harbored a single parasite genome (monogenomic infections). Highly related parasites, consistent with inbreeding, were detected after interventions were deployed. Geographical analysis indicated that the highly related infections were both clustered focally and dispersed across the study area. These findings provide genetic evidence for a reduced parasite population, with indications of inbreeding following the application of comprehensive interventions, including drug-based campaigns, that reduced the malaria burden in Southern Province. Genetic data additionally revealed the relationship between individual infections in the context of these population-level patterns, which has the potential to provide useful data for stratification and targeting of interventions to reduce the malaria burden.

Adherence to Mass Drug Administration with Dihydroartemisinin-Piperaquine and Plasmodium falciparum Clearance in Southern Province, Zambia.

Mass drug administration (MDA) with artemisinin combination therapy is a potentially useful tool for malaria elimination programs, but its success depends partly on drug effectiveness and treatment coverage in the targeted population. As part of a cluster-randomized controlled trial in Southern Province, Zambia evaluating the impact of MDA and household focal MDA (fMDA) with dihydroartemisinin-piperaquine (DHAp), sub-studies were conducted investigating population drug adherence rates and effectiveness of DHAp as administered in clearing Plasmodium falciparum infections following household mass administration. Adherence information was reported for 181,534 of 336,821 DHAp (53.9%) treatments administered during four rounds of MDA/fMDA, of which 153,197 (84.4%) reported completing the full course of DHAp. The proportion of participants fully adhering to the treatment regimen differed by MDA modality (MDA versus fMDA), RDT status, and whether the first dose was observed by those administering treatments. Among a subset of participants receiving DHAp and selected for longitudinal follow-up, 58 were positive for asexual-stage P. falciparum infection by microscopy at baseline. None of the 45 participants followed up at days 3 and/or 7 were slide positive for asexual-stage parasitemia. For those with longer term follow-up, one participant was positive 47 days after treatment, and two additional participants were positive after 69 days, although these two were determined to be new infections by genotyping. High completion of a 3-day course of DHAp and parasite clearance in the context of household MDA are promising as Zambia's National Malaria Programme continues to weigh appropriate interventions for malaria elimination.

Factors Associated with the Rapid and Durable Decline in Malaria Incidence in El Salvador, 1980-2017.

A decade after the Global Malaria Eradication Program, El Salvador had the highest burden of malaria in Mesoamerica, with approximately 20% due to Plasmodium falciparum. A resurgence of malaria in the 1970s led El Salvador to alter its national malaria control strategy. By 1995, El Salvador recorded its last autochthonous P. falciparum case with fewer than 20 Plasmodium vivax cases annually since 2011. By contrast, its immediate neighbors continue to have the highest incidences of malaria in the region. We reviewed and evaluated the policies and interventions implemented by the Salvadoran National Malaria Program that likely contributed to this progress toward malaria elimination. Decentralization of the malaria program, early regional stratification by risk, and data-driven stratum-specific actions resulted in the timely and targeted allocation of resources for vector control, surveillance, case detection, and treatment. Weekly reporting by health workers and volunteer collaborators-distributed throughout the country by strata and informed via the national surveillance system-enabled local malaria teams to provide rapid, adaptive, and focalized program actions. Sustained investments in surveillance and response have led to a dramatic reduction in local transmission, with most current malaria cases in El Salvador due to importation from neighboring countries. Additional support for systematic elimination efforts in neighboring countries would benefit the region and may be needed for El Salvador to achieve and maintain malaria elimination. El Salvador's experience provides a relevant case study that can guide the application of similar strategies in other countries committed to malaria elimination.

Estimation of malaria parasite reservoir coverage using reactive case detection and active community fever screening from census data with rapid diagnostic tests in southern Zambia: a re-sampling approach.

BACKGROUND AND METHODS: In areas where malaria transmission has been suppressed by vector control interventions many malaria control and elimination programmes are actively seeking new interventions to further reduce malaria prevalence, incidence and transmission. Malaria infection prevalence and incidence has been shown to cluster geographically, especially at lower transmission levels, and as such a reactive strategy is frequently used, by which index cases presenting to a passive surveillance system are used to target small areas for testing and treatment, reactive case detection (RCD), or focal drug administration (fDA). This study utilizes geo-located data from a census with parasitological testing with rapid diagnostic tests (RDTs) and treatment-seeking data collection conducted in southern Zambia to estimate the coverage of RCD or fDA in terms of the population and parasite reservoir as well as the operational requirements of such strategies, using a re-sampling algorithm developed exclusively for this purpose. This re-sampling algorithm allows for the specification of several parameters, such that different operational variants of these reactive strategies can be examined, including varying the search radius, screening for fever, or presumptive treatment (fDA). RESULTS: Results indicate that RCD, fDA and active fever screening followed by RCD, even with search radii over several hundered meters will only yield limited coverage of the RDT positive parasite reservoir during a short period. Long-term use of these strategies may increase this proportion. Reactive strategies detect a higher proportion of the reservoir of infections than random searches, but this effect appears to be greater in areas of low, but not moderate malaria prevalence in southern Zambia. DISCUSSION: Increases in the sensitivity of RDTs could also affect these results. The number of individuals and households that need to be searched increase rapidly, but approximately linearly with search radius. CONCLUSIONS: Reactive strategies in southern Zambia yield improved identification of the parasite reservoir when targeted to areas with prevalence less than 10%. The operational requirements of delivering reactive strategies routinely are likely to prevent their uptake until prevalence falls far below this level.