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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.

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.

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.

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.

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.

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.

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.

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.