Risk factors associated with malaria infection identified through reactive case detection in Zanzibar, 2012-2019.

BACKGROUND: Over the past two decades, Zanzibar substantially reduced malaria burden. As malaria decreases, sustainable improvements in control interventions may increasingly depend on accurate knowledge of malaria risk factors to further target interventions. This study aimed to investigate the risk factors associated with malaria infection in Zanzibar. METHODS: Surveillance data from Zanzibar's Malaria Case Notification system from August 2012 and December 2019 were analyzed. This system collects data on malaria cases passively detected and reported by all health facilities (index cases), and household-based reactive case detection (RCD) activities linked to those primary cases. All members of households of the index cases were screened for malaria using a malaria rapid diagnostic test (RDT). Individuals with a positive RDT were treated with artemisinin-based combination therapy. Univariate and multivariate logistic regression analyses were done to investigate the association between RDT positivity among the household members and explanatory factors with adjustment for seasonality and clustering at Shehia level. RESULTS: A total of 30,647 cases were reported of whom household RCD was completed for 21,443 (63%) index case households and 85,318 household members tested for malaria. The findings show that younger age (p-value for trend [Ptrend] < 0.001), history of fever in the last 2 weeks (odds ratio [OR] = 35.7; 95% CI 32.3-39.5), travel outside Zanzibar in the last 30 days (OR = 2.5; 95% CI 2.3-2.8) and living in Unguja (OR = 1.2; 95% CI 1.0-1.5) were independently associated with increased odds of RDT positivity. In contrast, male gender (OR=0.8; 95% CI 0.7-0.9), sleeping under an LLIN the previous night (OR = 0.9; 95% CI 0.7-0.9), having higher household net access (Ptrend < 0.001), and living in a household that received IRS in the last 12 months (OR = 0.8; 95% CI 0.7-0.9) were independently associated with reduced odds of RDT positivity. A significant effect modification of combining IRS and LLIN was also noted (OR = 0.7; 95% CI 0.6-0.8). CONCLUSIONS: The findings suggest that vector control remains an important malaria prevention intervention: they underscore the need to maintain universal access to LLINs, the persistent promotion of LLIN use, and application of IRS. Additionally, enhanced behavioural change and preventive strategies targeting children aged 5-14 years and travellers are needed.

Increased Sensitivity of Plasmodium falciparum to Artesunate/Amodiaquine Despite 14 Years as First-Line Malaria Treatment, Zanzibar.

Artemisinin-based combination therapies (ACTs) are first-line treatments for uncomplicated Plasmodium falciparum malaria. ACT resistance is spreading in Asia but not yet in Africa. Reduced effects of ACT partner drugs have been reported but with little information regarding widely used artesunate/amodiaquine (ASAQ). We studied its efficacy in Zanzibar after 14 years as first-line treatment directly by an in vivo, single-armed trial and indirectly by prevalences of different genotypes in the P. falciparum chloroquine-resistance transporter, multidrug-resistance 1, and Kelch 13 propeller domain genes. In vivo efficacy was higher during 2017 (100%; 95% CI 97.4%-100%) than during 2002-2005 (94.7%; 95% CI 91.9%-96.7%) (p = 0.003). Molecular findings showed no artemisinin resistance-associated genotypes and major increases in genotypes associated with high sensitivity/efficacy for amodiaquine than before ASAQ was introduced. Thus, the efficacy of ASAQ is maintained and appears to be increased after long-term use in contrast to what is observed for other ACTs used in Africa.

Adaptation of the in vitro micronucleus assay for genotoxicity testing using 3D liver models supporting longer-term exposure durations.

Following advancements in the field of genotoxicology, it has become widely accepted that 3D models are not only more physiologically relevant but also have the capacity to elucidate more complex biological processes that standard 2D monocultures are unable to. Whilst 3D liver models have been developed to evaluate the short-term genotoxicity of chemicals, the aim of this study was to develop a 3D model that could be used with the regulatory accepted in vitro micronucleus (MN) following low-dose, longer-term (5 days) exposure to engineered nanomaterials (ENMs). A comparison study was carried out between advanced models generated from two commonly used liver cell lines, namely HepaRG and HepG2, in spheroid format. While both spheroid systems displayed good liver functionality and viability over 14 days, the HepaRG spheroids lacked the capacity to actively proliferate and, therefore, were considered unsuitable for use with the MN assay. This study further demonstrated the efficacy of the in vitro 3D HepG2 model to be used for short-term (24 h) exposures to genotoxic chemicals, aflatoxin B1 (AFB1) and methyl-methanesulfonate (MMS). The 3D HepG2 liver spheroids were shown to be more sensitive to DNA damage induced by AFB1 and MMS when compared to the HepG2 2D monoculture. This 3D model was further developed to allow for longer-term (5 day) ENM exposure. Four days after seeding, HepG2 spheroids were exposed to Zinc Oxide ENM (0-2 µg/ml) for 5 days and assessed using both the cytokinesis-block MN (CBMN) version of the MN assay and the mononuclear MN assay. Following a 5-day exposure, differences in MN frequency were observed between the CBMN and mononuclear MN assay, demonstrating that DNA damage induced within the first few cell cycles is distributed across the mononucleated cell population. Together, this study demonstrates the necessity to adapt the MN assay accordingly, to allow for the accurate assessment of genotoxicity following longer-term, low-dose ENM exposure.

A cluster randomised controlled trial of two rounds of mass drug administration in Zanzibar, a malaria pre-elimination setting-high coverage and safety, but no significant impact on transmission.

BACKGROUND: Mass drug administration (MDA) has the potential to interrupt malaria transmission and has been suggested as a tool for malaria elimination in low-endemic settings. This study aimed to determine the effectiveness and safety of two rounds of MDA in Zanzibar, a pre-elimination setting. METHODS: A cluster randomised controlled trial was conducted in 16 areas considered as malaria hotspots, with an annual parasite index of > 0.8%. The areas were randomised to eight intervention and eight control clusters. The intervention included two rounds of MDA with dihydroartemisinin-piperaquine and single low-dose primaquine 4 weeks apart in May-June 2016. Primary and secondary outcomes were cumulative confirmed malaria case incidences 6 months post-MDA and parasite prevalences determined by PCR 3 months post-MDA. Additional outcomes included intervention coverage, treatment adherence, occurrence of adverse events, and cumulative incidences 3, 12, and 16 months post-MDA. RESULTS: Intervention coverage was 91.0% (9959/10944) and 87.7% (9355/10666) in the first and second rounds, respectively; self-reported adherence was 82.0% (881/1136) and 93.7% (985/1196). Adverse events were reported in 11.6% (147/1268) and 3.2% (37/1143) of post-MDA survey respondents after both rounds respectively. No serious adverse event was reported. No difference in cumulative malaria case incidence was observed between the control and intervention arms 6 months post-MDA (4.2 and 3.9 per 1000 population; p = 0.94). Neither was there a difference in PCR-determined parasite prevalences 3 months post-MDA (1.4% and 1.7%; OR = 1.0, p = 0.94), although having received at least the first MDA was associated with reduced odds of malaria infection (aOR = 0.35; p = 0.02). Among confirmed malaria cases at health facilities, 26.0% and 26.3% reported recent travel outside Zanzibar in the intervention and control shehias (aOR ≥ 85; p ≤ 0.001). CONCLUSIONS: MDA was implemented with high coverage, adherence, and tolerability. Despite this, no significant impact on transmission was observed. The findings suggest that two rounds of MDA in a single year may not be sufficient for a sustained impact on transmission in a pre-elimination setting, especially when the MDA impact is restricted by imported malaria. Importantly, this study adds to the limited evidence for the use of MDA in low transmission settings in sub-Saharan Africa. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02721186 (registration date: March 29, 2016).

Artemisinin combination therapy mass drug administration in a setting of low malaria endemicity: programmatic coverage and adherence during an observational study in Zanzibar.

BACKGROUND: Mass drug administration (MDA) appears to be effective in reducing the risk of malaria parasitaemia. This study reports on programmatic coverage and compliance of MDA using artemisinin-based combination therapy (ACT) in four shehias (smallest administration unit) that had been identified as hotspots through Zanzibar's malaria case notification surveillance system. METHODS: Mass drug administration was done in four shehias selected on the basis of: being an established malaria hot spot; having had mass screening and treatment (MSaT) 2-6 weeks previously; and exceeding the epidemic alert threshold of 5 cases within a week even after MSaT. Communities were sensitized and MDA was conducted using a house-to-house approach. All household members, except pregnant women and children aged less than 2 months, were provided with ACT medicine. Two weeks after the MDA campaign, a survey was undertaken to investigate completion of ACT doses. RESULTS: A total of 8816 [97.1% of eligible; 95% confidence interval (CI) 96.8-97.5] people received ACT. During post MDA surveys, 2009 people were interviewed: 90.2% reported having completed MDA doses; 1.9% started treatment but did not complete dosage; 4.7% did not take treatment; 2.0% were absent during MDA and 1.2% were ineligible (i.e. infants <2 months and pregnant women). Main reasons for failure to complete treatment were experience of side-effects and forgetting to take subsequent doses. Failure to take treatment was mainly due to fear of side-effects, reluctance due to lack of malaria symptoms and caregivers forgetting to give medication to children. CONCLUSION: Mass drug administration for malaria was well accepted by communities at high risk of malaria in Zanzibar, with high participation and completion rates. Further work to investigate the potential of MDA in accelerating Zanzibar's efforts towards malaria elimination should be pursued.

Field deployment of loop-mediated isothermal amplification for centralized mass-screening of asymptomatic malaria in Zanzibar: a pre-elimination setting.

BACKGROUND: Molecular tools for detection of low-density asymptomatic Plasmodium infections are needed in malaria elimination efforts. This study reports results from the hitherto largest implementation of loop-mediated isothermal amplification (LAMP) for centralized mass screening of asymptomatic malaria in Zanzibar. METHODS: Healthy individuals present and willing to participate in randomly selected households in 60 villages throughout Zanzibar were screened for malaria by rapid diagnostic tests (RDT). In 50% of the study households, participants were asked to provide 60 µL of finger-prick blood for additional LAMP screening. LAMP was conducted in two centralized laboratories in Zanzibar, by trained technicians with limited or no previous experience of molecular methods. The LAMP assay was performed with Loopamp(TM) MALARIA Pan/Pf Detection Kit (Eiken Chemical Company, Japan). Samples positive for Plasmodium genus (Pan)-LAMP were re-tested using Plasmodium falciparum-specific LAMP kits. RESULTS: Paired RDT and LAMP samples were available from 3983 individuals. The prevalence of asymptomatic malaria was 0.5% (CI 95% 0.1-0.8) and 1.6% (CI 95% 1.1-2.2) by RDT and Pan-LAMP, respectively. LAMP detected 3.4 (CI 95% 2.2-5.2) times more Plasmodium positive samples than RDT. DNA contamination was experienced, but solved by repetitive decontamination of all equipment and reagents. CONCLUSIONS: LAMP is a simple and sensitive molecular tool, and has potential in active surveillance and mass-screening programmes for detection of low-density asymptomatic malaria in pre-elimination settings. However, in order to deploy LAMP more effectively in field settings, protocols may need to be adapted for processing larger numbers of samples. A higher throughput, affordable closed system would be ideal to avoid contamination.

A good night's sleep and the habit of net use: perceptions of risk and reasons for bed net use in Bukoba and Zanzibar.

BACKGROUND: Intensive malaria control interventions in the United Republic of Tanzania have contributed to reductions in malaria prevalence. Given that malaria control remains reliant upon continued use of long-lasting insecticidal bed nets (LLINs) even when the threat of malaria has been reduced, this qualitative study sought to understand how changes in perceived risk influence LLIN usage, and to explore in more detail the benefits of net use that are unrelated to malaria. METHODS: Eleven focus group discussions were conducted in Bukoba Rural district and in Zanzibar Urban West district in late 2011. Participants were males aged 18 and over, females between the ages of 18 and 49, and females at least 50 years old. RESULTS: The perceived risk of malaria had decreased among the respondents, and malaria control interventions were credited for the decline. Participants cited reductions in both the severity of malaria and in their perceived susceptibility to malaria. However, malaria was still considered a significant threat. Participants' conceptualization of risk appeared to be an important consideration for net use. At the same time, comfort and aspects of comfort (getting a good night's sleep, avoiding biting pests) appeared to play a large role in personal decisions to use nets consistently or not. Barriers to comfort (feeling uncomfortable or trapped; perceived difficulty breathing, or itching/rashes) were frequently cited as reasons not to use a net consistently. While it was apparent that participants acknowledged the malaria-prevention benefits of net use, the exploration of the risk and comfort determinants of net use provides a richer understanding of net use behaviours, particularly in a setting where transmission has fallen and yet consistent net use is still crucial to maintaining those gains. CONCLUSION: Future behaviour change communication campaigns should capitalize on the non-malaria benefits of net use that provide a long-term rationale for consistent use even when the immediate threat of malaria transmission has been reduced.

Febrile illness management in children under five years of age: a qualitative pilot study on primary health care workers' practices in Zanzibar.

BACKGROUND: In Zanzibar, malaria prevalence dropped substantially in the last decade and presently most febrile patients seen in primary health care facilities (PHCF) test negative for malaria. The availability of rapid diagnostic tests (RDTs) allows rural health workers to reliably rule out malaria in fever patients. However, additional diagnostic tools to identify alternative fever causes are scarce, often leaving RDT-negative patients without a clear diagnosis and management plan. This pilot study aimed to explore health workers' practices with febrile children and identify factors influencing their diagnostic and management decisions in non-malarial fever patients. METHODS: Semi-structured key informant interviews were conducted with 12 health workers in six PHCFs in North A district, Zanzibar, April to June 2011. Interviews were coded using Atlas.ti to identify emerging themes that play a role in the diagnosis and management of febrile children. RESULTS: The following themes were identified: 1) health workers use caregivers' history of illness and RDT results for initial diagnostic and management decisions, but suggest caregivers need more education to prevent late presentation and poor health outcomes; 2) there is uncertainty regarding viral versus bacterial illness and health workers feel additional point-of-care diagnostic tests would help with differential diagnoses; 3) stock-outs of medications and limited caregivers' resources are barriers to delivering good care; 4) training, short courses and participation in research as well as; 5) weather also influences diagnostic decision-making. CONCLUSIONS: This pilot study found that health workers in Zanzibar use caregiver history of fever and results of malaria RDTs to guide management of febrile children. However, since most febrile children test negative for malaria, health workers believe additional training and point-of-care tests would improve their ability to diagnose and manage non-malarial fevers. Educating caregivers on signs and symptoms of febrile illness, as well as the introduction of additional tests to differentiate between viral and bacterial illness, would be important steps to get children to PHCFs earlier and decrease unnecessary antibiotic prescribing without compromising patient safety. More research is needed to expand an understanding of what would improve fever management in other resource-limited settings with decreasing malaria.

Perception of malaria risk in a setting of reduced malaria transmission: a qualitative study in Zanzibar.

BACKGROUND: Malaria transmission has declined dramatically in Zanzibar in recent years. Continuing use of preventive measures such as long-lasting insecticidal-treated nets (LLINs), and use of malaria rapid diagnostic tests (RDTs) are essential to prevent malaria resurgence. This study employed qualitative methods to explore community perceptions of malaria risk and adherence to prevention measures in two districts in Zanzibar. METHODS: Key informant interviews with 24 primary health care providers and 24 focus group discussions with local residents in Zanzibar districts Wete and Central were conducted during April and May 2012 focusing on perception of malaria risk, current preventive practices used, reasons for using preventive practices and effective strategies for malaria control. RESULTS: Health care providers and residents appear to be aware of the decreasing incidence of malaria. Both groups continue the use of malaria preventive practices in this low and seasonal transmission setting. The most important preventive measures identified were LLINs, indoor residual spraying (IRS), and education. Barriers to malaria prevention include: lack of staff at clinics, insufficient number of LLINs distributed, and inadequate malaria education. Reasons for continued use of preventive practices include: fear of malaria returning to high levels, presence of mosquitoes during rainy seasons, and concern about local cases from other villages or imported cases from mainland Tanzania. Mosques, clinics, schools and community meetings were listed as most important sources of education. However, residents express the desire for more education. CONCLUSION: Health care providers and residents generally reported consistent use of malaria preventive measures. However, maintaining and continuing to reduce malaria transmission will require ongoing education for both health care providers and residents to reinforce the importance of using preventive measures. Successful efforts to reduce malaria in Zanzibar will be jeopardized if residents believe that they are no longer at risk for malaria. In future studies, a year-round evaluation of the perception of malaria risk and use of preventive measures will inform the timing of education and prevention strategies for sustained malaria control.

High effective coverage of vector control interventions in children after achieving low malaria transmission in Zanzibar, Tanzania.

BACKGROUND: Formerly a high malaria transmission area, Zanzibar is now targeting malaria elimination. A major challenge is to avoid resurgence of malaria, the success of which includes maintaining high effective coverage of vector control interventions such as bed nets and indoor residual spraying (IRS). In this study, caretakers' continued use of preventive measures for their children is evaluated, following a sharp reduction in malaria transmission. METHODS: A cross-sectional community-based survey was conducted in June 2009 in North A and Micheweni districts in Zanzibar. Households were randomly selected using two-stage cluster sampling. Interviews were conducted with 560 caretakers of under-five-year old children, who were asked about perceptions on the malaria situation, vector control, household assets, and intention for continued use of vector control as malaria burden further decreases. RESULTS: Effective coverage of vector control interventions for under-five children remains high, although most caretakers (65%; 363/560) did not perceive malaria as presently being a major health issue. Seventy percent (447/643) of the under-five children slept under a long-lasting insecticidal net (LLIN) and 94% (607/643) were living in houses targeted with IRS. In total, 98% (628/643) of the children were covered by at least one of the vector control interventions. Seasonal bed-net use for children was reported by 25% (125/508) of caretakers of children who used bed nets. A high proportion of caretakers (95%; 500/524) stated that they intended to continue using preventive measures for their under-five children as malaria burden further reduces. Malaria risk perceptions and different perceptions of vector control were not found to be significantly associated with LLIN effective coverage. CONCLUSIONS: While the majority of caretakers felt that malaria had been reduced in Zanzibar, effective coverage of vector control interventions remained high. Caretakers appreciated the interventions and recognized the value of sustaining their use. Thus, sustaining high effective coverage of vector control interventions, which is crucial for reaching malaria elimination in Zanzibar, can be achieved by maintaining effective delivery of these interventions.

Rapid diagnostic tests for molecular surveillance of Plasmodium falciparum malaria -assessment of DNA extraction methods and field applicability.

BACKGROUND: The need for new malaria surveillance tools and strategies is critical, given improved global malaria control and regional elimination efforts. High quality Plasmodium falciparum DNA can reliably be extracted from malaria rapid diagnostic tests (RDTs). Together with highly sensitive molecular assays, wide scale collection of used RDTs may serve as a modern tool for improved malaria case detection and drug resistance surveillance. However, comparative studies of DNA extraction efficiency from RDTs and the field applicability are lacking. The aim of this study was to compare and evaluate different methods of DNA extraction from RDTs and to test the field applicability for the purpose of molecular epidemiological investigations. METHODS: DNA was extracted from two RDT devices (Paracheck-Pf® and SD Bioline Malaria Pf/Pan®), seeded in vitro with 10-fold dilutions of cultured 3D7 P. falciparum parasites diluted in malaria negative whole blood. The level of P. falciparum detection was determined for each extraction method and RDT device with multiple nested-PCR and real-time PCR assays. The field applicability was tested on 855 paired RDT (Paracheck-Pf) and filter paper (Whatman® 3MM) blood samples (734 RDT negative and 121 RDT positive samples) collected from febrile patients in Zanzibar 2010. RDT positive samples were genotyped at four key single nucleotide polymorphisms (SNPs) in pfmdr1 and pfcrt as well as for pfmdr1 copy number, all associated with anti-malarial drug resistance. RESULTS: The P. falciparum DNA detection limit varied with RDT device and extraction method. Chelex-100 extraction performed best for all extraction matrixes. There was no statistically significant difference in PCR detection rates in DNA extracted from RDTs and filter paper field samples. Similarly there were no significant differences in the PCR success rates and genotyping outcomes for the respective SNPs in the 121 RDT positive samples. CONCLUSIONS: The results support RDTs as a valuable source of parasite DNA and provide evidence for RDT-DNA extraction for improved malaria case detection, molecular drug resistance surveillance, and RDT quality control.

How Real-Time Case-Based Malaria Surveillance Helps Zanzibar Get a Step Closer to Malaria Elimination: Description of Operational Platform and Resources.

Testing and treating asymptomatic populations have the potential to reduce the population's parasite reservoir and reduce malaria transmission. Zanzibar's malaria case notification (MCN) platform collects detailed sociodemographic and epidemiological data from all confirmed malaria cases to inform programmatic decision-making. We describe the design and operationalization process of the platform and other malaria surveillance resources that are enabling Zanzibar's progress toward malaria elimination.The MCN platform consists of an interactive short message service (SMS) system for case notification, a software application for Android mobile devices, a visual question set and workflow manager, a back-end database server, and a web browser-based application for data analytics, configuration, and management. Malaria case data were collected from August 2012 to December 2021 and reported via SMS from all public and private health facilities to a central database and then to district malaria surveillance officers' mobile devices. Data included patient names, shehia (administrative area), and date of diagnosis, enabling officers to track patients, ideally within 24 hours of reporting. Patients' household members were tested for malaria using conventional rapid diagnostic tests (RDTs). Treatment using artemisinin-based combination therapy was provided for persons testing positive.Between 2012 and 2021, a total of 48,899 index malaria cases were confirmed at health facilities, 22,152 (45.3%) within 24 hours of reporting; 41,886 (85.7%) cases were fully investigated and followed up to the household level. A total of 111,811 additional household members were tested with RDTs, of whom 10,602 (9.5%) were malaria positive.The MCN platform reports malaria case data in near real time, enabling prompt follow-up of index cases and prompt testing and treatment of members in index case households. Along with routine testing and treatment and other preventive interventions, the MCN platform is foundational to the programmatic efforts in further reducing malaria and ultimately eliminating autochthonous malaria transmission in Zanzibar.

A qualitative study on caretakers' perceived need of bed-nets after reduced malaria transmission in Zanzibar, Tanzania.

BACKGROUND: The elimination of malaria in Zanzibar is highly dependent on sustained effective coverage of bed-nets to avoid malaria resurgence. The Health Belief Model (HBM) framework was used to explore the perceptions of malaria and bed-net use after a noticeable reduction in malaria incidence. METHODS: Nineteen in-depth interviews were conducted with female and male caretakers of children under five in North A district, Zanzibar. Deductive content analysis was used to identify meaning units that were condensed, coded and assigned to pre-determined elements of the HBM. RESULTS: Awareness of malaria among caretakers was high but the illness was now seen as easily curable and uncommon. In addition to the perceived advantage of providing protection against malaria, bed-nets were also thought to be useful for avoiding mosquito nuisance, especially during the rainy season when the malaria and mosquito burden is high. The discomfort of sleeping under a net during the hot season was the main barrier that interrupted consistent bed-net usage. The main cue to using a bed-net was high mosquito density, and children were prioritized when it came to bed-net usage. Caretakers had high perceived self-efficacy and did not find it difficult to use bed-nets. Indoor Residual Spraying (IRS), which was recognized as an additional means of mosquito prevention, was not identified as an alternative for bed-nets. A barrier to net ownership was the increasingly high cost of bed-nets. CONCLUSIONS: Despite the reduction in malaria incidence and the resulting low malaria risk perceptions among caretakers, the benefit of bed-nets as the most proficient protection against mosquito bites upholds their use. This, in combination with the perceived high self-efficacy of caretakers, supports bed-net usage, while seasonality interrupts consistent use. High effective coverage of bed-nets could be further improved by reinforcing the benefits of bed-nets, addressing the seasonal heat barrier by using nets with larger mesh sizes and ensuring high bed-net ownership rates through sustainable and affordable delivery mechanisms.

Modelling Insecticide Resistance of Malaria Vector Populations in Tanzania.

Anopheline mosquito insecticide resistance is a major threat to malaria control efforts and ultimately countries' ability to eliminate malaria. Using publicly available and published data we conducted spatial analyses to document and model the geo-spatial distribution of Anopheles gambiae s.l. insecticide resistance in Tanzania at national, regional, district and sub-district levels for the 2011 - 2017 period. We document anopheline mosquito resistance to all four major insecticide classes, with overall mosquito mortality declining from 2011 to 2016, and mean reductions of 1.6%, 0.5%, 0.4%, and 9.9% observed for organophosphates, carbamates, organochlorines and pyrethroids, respectively. An insecticide resistance map modeled for 2017 predicted that anopheline vector mortality was still above the 90% susceptibility threshold for all insecticide classes, except for pyrethroids. Using the model's output we calculated that resistance to organophosphates, carbamates, organochlorines, and pyrethroids is expected to exist in 11.6%, 15.6%, 8.1%, and 19.5% of Tanzania's territory, respectively, with areas in the Lake Zone and eastern Tanzania particularly affected. The methodology to predictively model available insecticide resistance data can readily be updated annually, allowing policy makers and malaria program management staff to continuously adjust their vector control approaches and plans, and determine where specific insecticides from various classes should be used to maximize intervention effectiveness.

Reductions in malaria and anaemia case and death burden at hospitals following scale-up of malaria control in Zanzibar, 1999-2008.

BACKGROUND: In Zanzibar, the Ministry of Health and partners accelerated malaria control from September 2003 onwards. The impact of the scale-up of insecticide-treated nets (ITN), indoor-residual spraying (IRS) and artemisinin-combination therapy (ACT) combined on malaria burden was assessed at six out of seven in-patient health facilities. METHODS: Numbers of outpatient and inpatient cases and deaths were compared between 2008 and the pre-intervention period 1999-2003. Reductions were estimated by segmented log-linear regression, adjusting the effect size for time trends during the pre-intervention period. RESULTS: In 2008, for all age groups combined, malaria deaths had fallen by an estimated 90% (95% confidence interval 55-98%)(p < 0.025), malaria in-patient cases by 78% (48-90%), and parasitologically-confirmed malaria out-patient cases by 99.5% (92-99.9%). Anaemia in-patient cases decreased by 87% (57-96%); anaemia deaths and out-patient cases declined without reaching statistical significance due to small numbers. Reductions were similar for children under-five and older ages. Among under-fives, the proportion of all-cause deaths due to malaria fell from 46% in 1999-2003 to 12% in 2008 (p < 0.01) and that for anaemia from 26% to 4% (p < 0.01). Cases and deaths due to other causes fluctuated or increased over 1999-2008, without consistent difference in the trend before and after 2003. CONCLUSIONS: Scaling-up effective malaria interventions reduced malaria-related burden at health facilities by over 75% within 5 years. In high-malaria settings, intensified malaria control can substantially contribute to reaching the Millennium Development Goal 4 target of reducing under-five mortality by two-thirds between 1990 and 2015.

System effectiveness of a targeted free mass distribution of long lasting insecticidal nets in Zanzibar, Tanzania.

BACKGROUND: Insecticide-treated nets (ITN) and long-lasting insecticidal treated nets (LLIN) are important means of malaria prevention. Although there is consensus regarding their importance, there is uncertainty as to which delivery strategies are optimal for dispensing these life saving interventions. A targeted mass distribution of free LLINs to children under five and pregnant women was implemented in Zanzibar between August 2005 and January 2006. The outcomes of this distribution among children under five were evaluated, four to nine months after implementation. METHODS: Two cross-sectional surveys were conducted in May 2006 in two districts of Zanzibar: Micheweni (MI) on Pemba Island and North A (NA) on Unguja Island. Household interviews were conducted with 509 caretakers of under-five children, who were surveyed for socio-economic status, the net distribution process, perceptions and use of bed nets. Each step in the distribution process was assessed in all children one to five years of age for unconditional and conditional proportion of success. System effectiveness (the accumulated proportion of success) and equity effectiveness were calculated, and predictors for LLIN use were identified. RESULTS: The overall proportion of children under five sleeping under any type of treated net was 83.7% (318/380) in MI and 91.8% (357/389) in NA. The LLIN usage was 56.8% (216/380) in MI and 86.9% (338/389) in NA. Overall system effectiveness was 49% in MI and 87% in NA, and equity was found in the distribution scale-up in NA. In both districts, the predicting factor of a child sleeping under an LLIN was caretakers thinking that LLINs are better than conventional nets (OR = 2.8, p = 0.005 in MI and 2.5, p = 0.041 in NA), in addition to receiving an LLIN (OR = 4.9, p < 0.001 in MI and in OR = 30.1, p = 0.001 in NA). CONCLUSIONS: Targeted free mass distribution of LLINs can result in high and equitable bed net coverage among children under five. However, in order to sustain high effective coverage, there is need for complimentary distribution strategies between mass distribution campaigns. Considering the community's preferences prior to a mass distribution and addressing the communities concerns through information, education and communication, may improve the LLIN usage.

Adherence to artesunate-amodiaquine combination therapy for uncomplicated malaria in children in Zanzibar, Tanzania.

OBJECTIVES: To estimate caretaker adherence to co-blistered, but not co-formulated, artesunate-amodiaquine (AsAq) for uncomplicated malaria and identify factors associated with caretaker adherence. METHODS: Cross sectional household survey of caretakers of 210 children under 5 years of age who had been prescribed and dispensed AsAq at 21 public health facilities (HFs). The caretakers were interviewed in their homes on the 4th day of receiving the 3 day treatment. Adherence of caretakers was assessed by self report and pill count. RESULTS: Caretaker adherence to AsAq was 77% (95% CI: 67%-87%). Non-adherence resulted in under-dosing (3/4) of the time and was most often in the form of wrong daily doses due to misunderstanding or forgetting the correct dose regimens. Predictors of adherence were education exceeding 7 years (OR = 5.08, P = 0.008) and receiving the exact number of pills to complete the treatment regimen (OR = 4.09, P = 0.006). All caretakers of children who were administered the first dose at the HF had adhered to the treatment. CONCLUSION: We found moderate levels of caretaker adherence to AsAq. Further improvement could be achieved by producing dose-specific packaging for infants, providing clear instructions and giving the first dose under observation at the HF.

The use of mobile phone data for the estimation of the travel patterns and imported Plasmodium falciparum rates among Zanzibar residents.

BACKGROUND: Malaria endemicity in Zanzibar has reached historically low levels, and the epidemiology of malaria transmission is in transition. To capitalize on these gains, Zanzibar has commissioned a feasibility assessment to help inform on whether to move to an elimination campaign. Declining local transmission has refocused attention on imported malaria. Recent studies have shown that anonimized mobile phone records provide a valuable data source for characterizing human movements without compromising the privacy of phone users. Such movement data in combination with spatial data on P. falciparum endemicity provide a way of characterizing the patterns of parasite carrier movements and the rates of malaria importation, which have been used as part of the malaria elimination feasibility assessment for the islands of Zanzibar. DATA AND METHODS: Records encompassing three months of complete mobile phone usage for the period October-December 2008 were obtained from the Zanzibar Telecom (Zantel) mobile phone network company, the principal provider on the islands of Zanzibar. The data included the dates of all phone usage by 770,369 individual anonymous users. Each individual call and message was spatially referenced to one of six areas: Zanzibar and five mainland Tanzania regions. Information on the numbers of Zanzibar residents travelling to the mainland, locations visited and lengths of stay were extracted. Spatial and temporal data on P. falciparum transmission intensity and seasonality enabled linkage of this information to endemicity exposure and, motivated by malaria transmission models, estimates of the expected patterns of parasite importation to be made. RESULTS: Over the three month period studied, 88% of users made calls that were routed only through masts on Zanzibar, suggesting that no long distance travel was undertaken by this group. Of those who made calls routed through mainland masts the vast majority of trips were estimated to be of less than five days in length, and to the Dar Es Salaam Zantel-defined region. Though this region covered a wide range of transmission intensities, data on total infection numbers in Zanzibar combined with mathematical models enabled informed estimation of transmission exposure and imported infection numbers. These showed that the majority of trips made posed a relatively low risk for parasite importation, but risk groups visiting higher transmission regions for extended periods of time could be identified. CONCLUSION: Anonymous mobile phone records provide valuable information on human movement patterns in areas that are typically data-sparse. Estimates of human movement patterns from Zanzibar to mainland Tanzania suggest that imported malaria risk from this group is heterogeneously distributed; a few people account for most of the risk for imported malaria. In combination with spatial data on malaria endemicity and transmission models, movement patterns derived from phone records can inform on the likely sources and rates of malaria importation. Such information is important for assessing the feasibility of malaria elimination and planning an elimination campaign.

Use of Routine Health Information System Data to Evaluate Impact of Malaria Control Interventions in Zanzibar, Tanzania from 2000 to 2015.

BACKGROUND: Impact evaluations allow countries to assess public health gains achieved through malaria investments. This study uses routine health management information system (HMIS) data from Zanzibar to describe changes in confirmed malaria incidence and impact of case management and vector control interventions during 2000-2015. METHODS: HMIS data from 129 (82%) public outpatient facilities were analyzed using interrupted time series models to estimate the impact of artemisinin-based combination therapy (ACT), indoor residual spray, and long-lasting insecticidal nets. Evaluation periods were defined as pre-intervention (January 2000 to August 2003), ACT-only (September 2003 to December 2005) and ACT plus vector control (2006-2015). FINDINGS: After accounting for climate, seasonality, diagnostic testing rates, and outpatient attendance, average monthly incidence of confirmed malaria showed no trend over the pre-intervention period 2000-2003 (incidence rate ratio (IRR) 0.998, 95% CI 0.995-1.000). During the ACT-only period (2003-2005), the average monthly malaria incidence rate declined compared to the pre-intervention period, showing an overall declining trend during the ACT-only period (IRR 0.984, 95% CI 0.978-0.990). There was no intercept change at the start of the ACT-only period (IRR 1.081, 95% CI 0.968-1.208), but a drop in intercept was identified at the start of the ACT plus vector control period (IRR 0.683, 95% CI 0.597-0.780). During the ACT plus vector control period (2006-2015), the rate of decline in average monthly malaria incidence slowed compared to the ACT-only period, but the incidence rate continued to show an overall slight declining trend during 2006-2015 (IRR 0.993, 95% CI 0.992-0.994). INTERPRETATION: This study presents a rigorous approach to the use of HMIS data in evaluating the impact of malaria control interventions. Evidence is presented for a rapid decline in malaria incidence during the period of ACT roll out compared to pre-intervention, with a rapid drop in malaria incidence following introduction of vector control and a slower declining incidence trend thereafter.