Characteristics of the Western Province, Zambia, trial site for evaluation of attractive targeted sugar baits for malaria vector control.

BACKGROUND: The attractive targeted sugar bait (ATSB) is a novel malaria vector control tool designed to attract and kill mosquitoes using a sugar-based bait, laced with oral toxicant. Western Province, Zambia, was one of three countries selected for a series of phase III cluster randomized controlled trials of the Westham ATSB Sarabi version 1.2. The trial sites in Kenya, Mali, and Zambia were selected to represent a range of different ecologies and malaria transmission settings across sub-Saharan Africa. This case study describes the key characteristics of the ATSB Zambia trial site to allow for interpretation of the results relative to the Kenya and Mali sites. METHODS: This study site characterization incorporates data from the trial baseline epidemiological and mosquito sugar feeding surveys conducted in 2021, as well as relevant literature on the study area. RESULTS: CHARACTERIZATION OF THE TRIAL SITE: The trial site in Zambia was comprised of 70 trial-designed clusters in Kaoma, Nkeyema, and Luampa districts. Population settlements in the trial site were dispersed across a large geographic area with sparsely populated villages. The overall population density in the 70 study clusters was 65.7 people per square kilometre with a total site population of 122,023 people living in a geographic area that covered 1858 square kilometres. However, the study clusters were distributed over a total area of approximately 11,728 square kilometres. The region was tropical with intense and seasonal malaria transmission. An abundance of trees and other plants in the trial site were potential sources of sugar meals for malaria vectors. Fourteen Anopheles species were endemic in the site and Anopheles funestus was the dominant vector, likely accounting for around 95% of all Plasmodium falciparum malaria infections. Despite high coverage of indoor residual spraying and insecticide-treated nets, the baseline malaria prevalence during the peak malaria transmission season was 50% among people ages six months and older. CONCLUSION: Malaria transmission remains high in Western Province, Zambia, despite coverage with vector control tools. New strategies are needed to address the drivers of malaria transmission in this region and other malaria-endemic areas in sub-Saharan Africa.

Evaluating the Impact of Programmatic Mass Drug Administration for Malaria in Zambia Using Routine Incidence Data.

BACKGROUND: In 2016, the Zambian National Malaria Elimination Centre started programmatic mass drug administration (pMDA) campaigns with dihydroartemisinin-piperaquine as a malaria elimination tool in Southern Province. Two rounds were administered, 2 months apart (coverage 70% and 57%, respectively). We evaluated the impact of 1 year of pMDA on malaria incidence using routine data. METHODS: We conducted an interrupted time series with comparison group analysis on monthly incidence data collected at the health facility catchment area (HFCA) level, with a negative binomial model using generalized estimating equations. Programmatic mass drug administration was conducted in HFCAs with greater than 50 cases/1000 people per year. Ten HFCAs with incidence rates marginally above this threshold (pMDA group) were compared with 20 HFCAs marginally below (comparison group). RESULTS: The pMDA HFCAs saw a 46% greater decrease in incidence at the time of intervention than the comparison areas (incidence rate ratio = 0.536; confidence interval = 0.337-0.852); however, incidence increased toward the end of the season. No HFCAs saw a transmission interruption. CONCLUSIONS: Programmatic mass drug administration, implemented during 1 year with imperfect coverage in low transmission areas with suboptimal vector control coverage, significantly reduced incidence. However, elimination will require additional tools. Routine data are important resources for programmatic impact evaluations and should be considered for future analyses.

Performance and utility of more highly sensitive malaria rapid diagnostic tests.

BACKGROUND: A new more highly sensitive rapid diagnostic test (HS-RDT) for Plasmodium falciparum malaria (Alere™/Abbott Malaria Ag P.f RDT [05FK140], now called NxTek™ Eliminate Malaria Ag Pf) was launched in 2017. The test has already been used in many research studies in a wide range of geographies and use cases. METHODS: In this study, we collate all published and available unpublished studies that use the HS-RDT and assess its performance in (i) prevalence surveys, (ii) clinical diagnosis, (iii) screening pregnant women, and (iv) active case detection. Two individual-level data sets from asymptomatic populations are used to fit logistic regression models to estimate the probability of HS-RDT positivity based on histidine-rich protein 2 (HRP2) concentration and parasite density. The performance of the HS-RDT in prevalence surveys is estimated by calculating the sensitivity and positive proportion in comparison to polymerase chain reaction (PCR) and conventional malaria RDTs. RESULTS: We find that across 18 studies, in prevalence surveys, the mean sensitivity of the HS-RDT is estimated to be 56.1% (95% confidence interval [CI] 46.9-65.4%) compared to 44.3% (95% CI 32.6-56.0%) for a conventional RDT (co-RDT) when using nucleic acid amplification techniques as the reference standard. In studies where prevalence was estimated using both the HS-RDT and a co-RDT, we found that prevalence was on average 46% higher using a HS-RDT compared to a co-RDT. For use in clinical diagnosis and screening pregnant women, the HS-RDT was not significantly more sensitive than a co-RDT. CONCLUSIONS: Overall, the evidence presented here suggests that the HS-RDT is more sensitive in asymptomatic populations and could provide a marginal improvement in clinical diagnosis and screening pregnant women. Although the HS-RDT has limited temperature stability and shelf-life claims compared to co-RDTs, there is no evidence to suggest, given this test has the same cost as current RDTs, it would have any negative impacts in terms of malaria misdiagnosis if it were widely used in all four population groups explored here.

Molecular Detection and Characterization of Rickettsia asembonensis in Human Blood, Zambia.

Rickettsia asembonensis is a flea-related Rickettsia with unknown pathogenicity to humans. We detected R. asembonensis DNA in 2 of 1,153 human blood samples in Zambia. Our findings suggest the possibility of R. asembonensis infection in humans despite its unknown pathogenicity.

Outreach training and supportive supervision for malaria case management in Zambia: the effects of focused capacity building on indicators of diagnostic and clinical performance.

BACKGROUND: Accurate diagnosis of malaria and reduced reliance on presumptive treatment are crucial components of quality case management. From 2008 to 2012, the Improving Malaria Diagnostics project, in collaboration with the Zambia National Malaria Control Centre, implemented an external quality assurance scheme partially comprised of outreach training and supportive supervision (OTSS) in an effort to improve malaria case management across a spectrum of health facilities performing laboratory-based malaria diagnostics. OTSS assessments were conducted by project-trained laboratory and clinical supervisors on a regular basis and measured changes in health facility staff performance over time. Standardized supervision tools were used for data collection and guided OTSS teams to assess health facility infrastructure, record keeping practices, stores of supplies and consumables, good laboratory practices, and staff adherence to guidelines for the case management and diagnosis of suspected malaria cases via direct observations or record reviews. The structure of OTSS also allowed supervisors to provide ongoing support to clinicians and laboratory staff through regular mentoring and on-the-job training. RESULTS: This analysis included 88 laboratories and 64 clinics each with four repeated supervisory assessments. Over the course of the project there were significant declines in the number of laboratories experiencing stock-outs of microscopy reagents/consumables (p < 0.001) and significant increases in the number of laboratories instituting the use of microscopy positive controls (p < 0.01), conducting parasite counting (p < 0.05), and converting from a semi-quantitative to a quantitative parasite counting methodology (p < 0.001). Performance in malaria diagnostic and clinical practices [i.e. RDT use (mean(diff) = 14.3%, p < 0.001), blood slide preparation (mean(diff) = 14.7%, p < 0.001), blood slide staining and reading (mean(diff) = 14.0%, p < 0.001), fever case management (mean(diff) = 7.3%, p < 0.01)] and prescriber adherence to negative diagnostic test results (mean(diff) = 7.2%, p < 0.05) showed modest, but significant gains from assessment 1 to assessment 4. CONCLUSION: The external quality assurance scheme provided periodic representations of clinical and laboratory staff performance. OTSS-enrolled health facilities demonstrated improvements to malaria diagnostic skills, adoption of laboratory best practices, strengthened fever case management practices, and improved prescriber adherence to negative malaria test results.

Capacity Development through the US President's Malaria Initiative-Supported Antimalarial Resistance Monitoring in Africa Network.

Antimalarial drug resistance is an evolving global health security threat to malaria control. Early detection of Plasmodium falciparum resistance through therapeutic efficacy studies and associated genetic analyses may facilitate timely implementation of intervention strategies. The US President's Malaria Initiative-supported Antimalarial Resistance Monitoring in Africa Network has assisted numerous laboratories in partner countries in acquiring the knowledge and capability to independently monitor for molecular markers of antimalarial drug resistance.

Short-term Impact of Mass Drug Administration With Dihydroartemisinin Plus Piperaquine on Malaria in Southern Province Zambia: A Cluster-Randomized Controlled Trial.

BACKGROUND: Mass drug administration (MDA) using dihydroartemisinin plus piperaquine (DHAp) represents a potential strategy to clear Plasmodium falciparum infections and reduce the human parasite reservoir. METHODS: A cluster-randomized controlled trial in Southern Province, Zambia, was used to assess the short-term impact of 2 rounds of community-wide MDA and household-level (focal) MDA with DHAp compared with no mass treatment. Study end points included parasite prevalence in children, infection incidence, and confirmed malaria case incidence. RESULTS: All end points significantly decreased after intervention, irrespective of treatment group. Parasite prevalence from 7.71% at baseline to 0.54% after MDA in lower-transmission areas, resulting in an 87% reduction compared with control (adjusted odds ratio, 0.13; 95% confidence interval, .02-.92; P = .04). No difference between treatment groups was observed in areas of high transmission. The 5-month cumulative infection incidence was 70% lower (crude incidence rate ratio, 0.30; 95% confidence interval, .06-1.49; P = .14) and 58% lower (0.42; .18-.98; P = .046) after MDA compared with control in lower- and higher-transmission areas, respectively. No significant impact of focal MDA was observed for any end point. CONCLUSIONS: Two rounds of MDA with DHAp rapidly reduced infection prevalence, infection incidence, and confirmed case incidence rates, especially in low-transmission areas. CLINICAL TRIALS REGISTRATION: NCT02329301.

Incremental impact upon malaria transmission of supplementing pyrethroid-impregnated long-lasting insecticidal nets with indoor residual spraying using pyrethroids or the organophosphate, pirimiphos methyl.

BACKGROUND: Long-lasting, insecticidal nets (LLINs) and indoor residual spraying (IRS) are the most widely accepted and applied malaria vector control methods. However, evidence that incremental impact is achieved when they are combined remains limited and inconsistent. METHODS: Fourteen population clusters of approximately 1000 residents each in Zambia's Luangwa and Nyimba districts, which had high pre-existing usage rates (81.7 %) of pyrethroid-impregnated LLINs were quasi-randomly assigned to receive IRS with either of two pyrethroids, namely deltamethrin [Wetable granules (WG)] and lambdacyhalothrin [capsule suspension (CS)], with an emulsifiable concentrate (EC) or CS formulation of the organophosphate pirimiphos methyl (PM), or with no supplementary vector control measure. Diagnostic positivity of patients tested for malaria by community health workers in these clusters was surveyed longitudinally over pre- and post-treatment periods spanning 29 months, over which the treatments were allocated and re-allocated in advance of three sequential rainy seasons. RESULTS: Supplementation of LLINs with PM CS offered the greatest initial level of protection against malaria in the first 3 months of application (incremental protective efficacy (IPE) [95 % confidence interval (CI)] = 0.63 [CI 0.57, 0.69], P < 0.001), followed by lambdacyhalothrin (IPE [95 % CI] = 0.31 [0.10, 0.47], P = 0.006) and PM EC (IPE, 0.23 [CI 0.15, 0.31], P < 0.001) and then by deltamethrin (IPE [95 % CI] = 0.19 [-0.01, 0.35], P = 0.064). Neither pyrethroid formulation provided protection beyond 3 months after spraying, but the protection provided by both PM formulations persisted undiminished for longer periods: 6 months for CS and 12 months for EC. The CS formulation of PM provided greater protection than the combined pyrethroid IRS formulations throughout its effective life IPE [95 % CI] = 0.79 [0.75, 0.83] over 6 months. The EC formulation of PM provided incremental protection for the first 3 months (IPE [95 % CI] = 0.23 [0.15, 0.31]) that was approximately equivalent to the two pyrethroid formulations (lambdacyhalothrin, IPE [95 % CI] = 0.31 [0.10, 0.47] and deltamethrin, IPE [95 % CI] = 0.19 [-0.01, 0.35]) but the additional protection provided by the former, apparently lasted an entire year. CONCLUSION: Where universal coverage targets for LLIN utilization has been achieved, supplementing LLINs with IRS using pyrethroids may reduce malaria transmission below levels achieved by LLIN use alone, even in settings where pyrethroid resistance occurs in the vector population. However, far greater reduction of transmission can be achieved under such conditions by supplementing LLINs with IRS using non-pyrethroid insecticide classes, such as organophosphates, so this is a viable approach to mitigating and managing pyrethroid resistance.

Patterns of mixed Plasmodium species infections among children six years and under in selected malaria hyper-endemic communities of Zambia: population-based survey observations.

BACKGROUND: Although malaria is preventable and treatable, it still claims 660,000 lives every year globally with children under five years of age having the highest burden. In Zambia, malaria rapid diagnostic tests (RDTs) that only detect Plasmodium falciparum are the main confirmatory means for malaria diagnosis in most health facilities without microscopy services. As a consequence of this P. falciparum species diagnostic approach, non-falciparum malaria is not only under-diagnosed but entirely missed, thereby making the exact disease burden unknown. We thus investigated the prevalence of various Plasmodium spp. and associated burden of infection in selected communities in Zambia. METHODS: Data from two malaria hyper-endemic provinces (Eastern and Luapula) of the 2012 National Malaria Indicator Survey (MIS), conducted between April and May 2012, were used. The MIS is a nationally representative, two-stage cluster survey conducted to coincide with the end of the malaria transmission season. Social, behavioural and background information were collected from households as part of the survey. Thick blood smears, RDTs and dried blood spots (DBS) were collected from children below six years of age. Slides were stained using Giemsa and examined by microscopy while polymerase chain reaction (PCR) was used to analyse the DBS for malaria Plasmodium spp. Multivariate logistic regression was employed to examine the association between background factors and malaria. RESULTS: Overall, 873 children younger than six years of age were surveyed. The overall prevalence of Plasmodium spp. by PCR was 54.3% (95% CI 51-57.6%). Of the total Plasmodium isolates, 88% were P. falciparum, 10.6% were mixed infections and 1.4% were non-falciparum mono infections. Among the mixed infections, the majority were a combination of P. falciparum and P. malariae (6.5% of all mixed infections). Children two years and older (2-5 years) had three-fold higher risk of mixed malaria infections (aOR 2.8 CI 1.31-5.69) than children younger than two years of age. CONCLUSION: The high prevalence of mixed Plasmodium spp. infections in this population stresses review of the current malaria RDT diagnostic approaches. The observed less incidence of mixed infections in children under two years of age compared to their older two-to-five-year-old counterparts is probably due to the protective maternal passive immunity, among other factors, in that age group.

Therapeutic efficacy of artemether-lumefantrine on treatment of uncomplicated Plasmodium falciparum mono-infection in an area of high malaria transmission in Zambia.

BACKGROUND: Anti-malarial drug resistance continues to be a leading threat to ongoing malaria control efforts and calls for continued monitoring of the efficacy of these drugs in order to inform national anti-malarial drug policy decision-making. This study assessed the therapeutic efficacy and safety of artemether-lumefantrine (AL)(Coartem®) for the treatment of uncomplicated Plasmodium falciparum malaria in two sentinel high malaria transmission districts in the Eastern Province of Zambia in persons aged six months and above, excluding women aged 12 to 18 years. METHODS: This was an observational cohort of 176 symptomatic patients diagnosed with uncomplicated Plasmodium falciparum mono-infection. A World Health Organization (WHO)-standardized 28-day assessment protocol was used to assess clinical and parasitological responses to directly observed AL treatment of uncomplicated malaria. DNA polymerase chain reaction (PCR) analysis for molecular markers of AL resistance was conducted on positive blood samples and differentiated recrudescence from re-infections of the malaria parasites. RESULTS: All patients (CI 97.6-100) had adequate clinical and parasitological responses to treatment with AL. At the time of enrolment, mean slide positivity among study participants was 71.8% and 55.2% in Katete and Chipata, respectively. From a mean parasite density of 55,087, 98% of the study participants presented with zero parasitaemia by day 3 of the study. Fever clearance occurred within 24 hours of treatment with AL. However mean parasite density declines were most dramatic in participants in the older age. No adverse reactions to AL treatment were observed during the study. CONCLUSION: AL remains a safe and efficacious drug for the treatment of uncomplicated Plasmodium falciparum malaria in Zambia, endemic for malaria, with some provinces experiencing high transmission intensity. However, the delayed parasite clearance in younger patients calls for further sentinel and periodical monitoring of AL efficacy in different areas of the country.

Monitoring, characterization and control of chronic, symptomatic malaria infections in rural Zambia through monthly household visits by paid community health workers.

BACKGROUND: Active, population-wide mass screening and treatment (MSAT) for chronic Plasmodium falciparum carriage to eliminate infectious reservoirs of malaria transmission have proven difficult to apply on large national scales through trained clinicians from central health authorities. METHODOLOGY: Fourteen population clusters of approximately 1,000 residents centred around health facilities (HF) in two rural Zambian districts were each provided with three modestly remunerated community health workers (CHWs) conducting active monthly household visits to screen and treat all consenting residents for malaria infection with rapid diagnostic tests (RDT). Both CHWs and HFs also conducted passive case detection among residents who self-reported for screening and treatment. RESULTS: Diagnostic positivity was higher among symptomatic patients self-reporting to CHWs (42.5%) and HFs (24%) than actively screened residents (20.3%), but spatial and temporal variations of diagnostic positivity were highly consistent across all three systems. However, most malaria infections (55.6%) were identified through active home visits by CHWs rather than self-reporting to CHWs or HFs. Most (62%) malaria infections detected actively by CHWs reported one or more symptoms of illness. Most reports of fever and vomiting, plus more than a quarter of history of fever, headache and diarrhoea, were attributable to malaria infection. The minority of residents who participated >12 times had lower rates of malaria infection and associated symptoms in later contacts but most residents were tested <4 times and high malaria diagnostic positivity (32%) in active surveys, as well as incidence (1.7 detected infections per person per year) persisted in the population. Per capita cost for active service delivery by CHWs was US$5.14 but this would rise to US$10.68 with full community compliance with monthly testing at current levels of transmission, and US$6.25 if pre-elimination transmission levels and negligible treatment costs were achieved. CONCLUSION: Monthly active home visits by CHWs equipped with RDTs were insufficient to eliminate the human infection reservoir in this typical African setting, despite reasonably high LLIN/IRS coverage. However, dramatic impact upon infection and morbidity burden might be attainable and cost-effective if community participation in regular testing could be improved and the substantial, but not necessarily prohibitive, costs are affordable to national programmes.

A methodological framework for the improved use of routine health system data to evaluate national malaria control programs: evidence from Zambia.

BACKGROUND: Due to challenges in laboratory confirmation, reporting completeness, timeliness, and health access, routine incidence data from health management information systems (HMIS) have rarely been used for the rigorous evaluation of malaria control program scale-up in Africa. METHODS: We used data from the Zambia HMIS for 2009-2011, a period of rapid diagnostic and reporting scale-up, to evaluate the association between insecticide-treated net (ITN) program intensity and district-level monthly confirmed outpatient malaria incidence using a dose-response national platform approach with district-time units as the unit of analysis. A Bayesian geostatistical model was employed to estimate longitudinal district-level ITN coverage from household survey and programmatic data, and a conditional autoregressive model (CAR) was used to impute missing HMIS data. The association between confirmed malaria case incidence and ITN program intensity was modeled while controlling for known confounding factors, including climate variability, reporting, testing, treatment-seeking, and access to health care, and additionally accounting for spatial and temporal autocorrelation. RESULTS: An increase in district level ITN coverage of one ITN per household was associated with an estimated 27% reduction in confirmed case incidence overall (incidence rate ratio (IRR): 0 · 73, 95% Bayesian Credible Interval (BCI): 0 · 65-0 · 81), and a 41% reduction in areas of lower malaria burden. CONCLUSIONS: When improved through comprehensive parasitologically confirmed case reporting, HMIS data can become a valuable tool for evaluating malaria program scale-up. Using this approach we provide further evidence that increased ITN coverage is associated with decreased malaria morbidity and use of health services for malaria illness in Zambia. These methods and results are broadly relevant for malaria program evaluations currently ongoing in sub-Saharan Africa, especially as routine confirmed case data improve.

Finding parasites and finding challenges: improved diagnostic access and trends in reported malaria and anti-malarial drug use in Livingstone district, Zambia.

BACKGROUND: Understanding the impact of malaria rapid diagnostic test (RDT) use on management of acute febrile disease at a community level, and on the consumption of anti-malarial medicines, is critical to the planning and success of scale-up to universal parasite-based diagnosis by health systems in malaria-endemic countries. METHODS: A retrospective study of district-wide community-level RDT introduction was conducted in Livingstone District, Zambia, to assess the impact of this programmed on malaria reporting, incidence of mortality and on district anti-malarial consumption. RESULTS: Reported malaria declined from 12,186 cases in the quarter prior to RDT introduction in 2007 to an average of 12.25 confirmed and 294 unconfirmed malaria cases per quarter over the year to September 2009. Reported malaria-like fever also declined, with only 4,381 RDTs being consumed per quarter over the same year. Reported malaria mortality declined to zero in the year to September 2009, and all-cause mortality declined. Consumption of artemisinin-based combination therapy (ACT) dropped dramatically, but remained above reported malaria, declining from 12,550 courses dispensed by the district office in the quarter prior to RDT implementation to an average of 822 per quarter over the last year. Quinine consumption in health centres also declined, with the district office ceasing to supply due to low usage, but requests for sulphadoxine-pyrimethamine (SP) rose to well above previous levels, suggesting substitution of ACT with this drug in RDT-negative cases. CONCLUSIONS: RDT introduction led to a large decline in reported malaria cases and in ACT consumption in Livingstone district. Reported malaria mortality declined to zero, indicating safety of the new diagnostic regime, although adherence and/or use of RDTs was still incomplete. However, a deficiency is apparent in management of non-malarial fever, with inappropriate use of a low-cost single dose drug, SP, replacing ACT. While large gains have been achieved, the full potential of RDTs will only be realized when strategies can be put in place to better manage RDT-negative cases.

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).

Community case management of malaria using ACT and RDT in two districts in Zambia: achieving high adherence to test results using community health workers.

BACKGROUND: Access to prompt and effective treatment is a cornerstone of the current malaria control strategy. Delays in starting appropriate treatment is a major contributor to malaria mortality. WHO recommends home management of malaria using artemisininbased combination therapy (ACT) and Rapid Diagnostic tests (RDTs) as one of the strategies for improving access to prompt and efective malaria case management. METHODS: A prospective evaluation of the effectiveness of using community health workers (CHWs) as delivery points for ACT and RDTs in the home management of malaria in two districts in Zambia. RESULTS: CHWs were able to manage malaria fevers by correctly interpreting RDT results and appropriately prescribing antimalarials. All severe malaria cases and febrile non-malaria fevers were referred to a health facility for further management. There were variations in malaria prevalence between the two districts and among the villages in each district. 100% and 99.4% of the patients with a negative RDT result were not prescribed an antimalarial in the two districts respectively. No cases progressed to severe malaria and no deaths were recorded during the study period. Community perceptions were positive. CONCLUSION: CHWs are effective delivery points for prompt and effective malaria case management at community level. Adherence to test results is the best ever reported in Zambia. Further areas of implementation research are discussed.

Relative costs and effectiveness of treating uncomplicated malaria in two rural districts in Zambia: implications for nationwide scale-up of home-based management.

BACKGROUND: Malaria case management is one of the key strategies to control malaria. Various studies have demonstrated the feasibility of home management of malaria (HMM). However, data on the costs and effectiveness of artemisinin-based combination therapy (ACT) and rapid diagnostic tests via HMM is limited. METHOD: Cost-effectiveness of home management versus health facility-based management of uncomplicated malaria in two rural districts in Zambia was analysed from a providers' perspective. The sample included 16 community health workers (CHWs) and 15 health facilities. The outcome measure was the cost per case appropriately diagnosed and treated. Costs of scaling-up HMM nationwide were estimated based on the CHW utilisation rates observed in the study. RESULTS: HMM was more cost effective than facility-based management of uncomplicated malaria. The cost per case correctly diagnosed and treated was USD 4.22 for HMM and USD 6.12 for facility level. Utilization and adherence to diagnostic and treatment guidelines was higher in HMM than at a health facility. CONCLUSION: HMM using ACT and RDTs was more efficient at appropriately diagnosing and treating malaria than the health facility level. Scaling up this intervention requires significant investments.

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.

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.

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.

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.