Gentamicin concentration and acute kidney injury in term neonates treated for neonatal sepsis with gentamicin and ampicillin-cloxacillin combination.

Gentamicin is widely used to treat neonatal infections caused by both Gram-negative and Gram-positive bacteria, and the WHO recommends its use while monitoring serum creatinine and gentamicin concentrations to avoid drug-induced nephrotoxicity and ototoxicity. Yet in some resource-limited settings, the drug is used without monitoring. A population pharmacokinetics study involving term neonates with neonatal infection admitted to a neonatal unit. Participants were started on intravenous gentamicin 5 mg/kg once a day in combination with ampicilin-cloxacillin. Blood samples for serum gentamicin concentration were taken at 0.25, 0.5, 1, 2, 3, 5, 6, 8, 10, 12, 14, 16, 18, 20, 23, and 24 hours after the initial dose, each participant contributing two samples to the 24 hour sampling schedule. An additional sample for trough concentration was taken from each participant just before the third gentamicin dose while serum creatinine concentration was measured before and after treatment. Twenty-four participants were enrolled into the study and included in the final analysis. Mean (SD) peak and trough serum gentamicin concentrations were 16.66 (0.64) µg/mL and 3.28 (0.70) µg/mL, respectively. Gentamicin clearance (CL) was 0.40 mL min-1 kg-1 and volume of distribution (VD) was 0.31 L kg-1. Mean (SD) serum creatinine level after treatment was 209.7 (70.4) µmol/L compared to 103.3 (23.6) µmol/L before treatment [mean difference (106.4 ± 67.1; 95% confidence interval (CI): 78.1; 134.7 µmol/L; t (23) = 7.77; P < 0.001]. All participants fulfilled the Kidney Disease Improving Global Outcomes (KDIGO) criteria for acute kidney injury after treatment. Treatment of neonatal infection with antimicrobial regimen containing gentamicin, without renal function and gentamicin concentration monitoring, carries a significant risk for drug-induced acute kidney injury.

Efficacy of artesunate-amodiaquine for treatment of uncomplicated Plasmodium falciparum malaria in mainland Tanzania.

BACKGROUND: Diversification of artemisinin-based combination therapy (ACT) is suggested as one of the strategies that can be used to contain artemisinin resistance. Artesunate-amodiaquine (ASAQ) is one of the artemisinin-based combinations that can be used in the diversification strategy as an alternative first-line treatment for uncomplicated malaria in mainland Tanzania. There is however limited data on the efficacy of ASAQ in mainland Tanzania. This study assessed the efficacy of ASAQ for treatment of uncomplicated Plasmodium falciparum malaria in selected sentinel sites for therapeutic efficacy studies in mainland Tanzania. METHODS: Between December 2018 and March 2020, children aged between 6 months and 10 years, attending at Nagaga, Mkuzi, and Mlimba primary health facilities, and with suspected uncomplicated malaria infection were screened for eligibility to participate in the study. Malaria infection was screened using microscopy. Children with uncomplicated P. falciparum monoinfection and who fulfilled all other inclusion criteria, and had none of the exclusion criteria, according to the World Health Organization (WHO) guidelines, were treated with ASAQ. Follow-up visits were scheduled on days 0, 1, 2, 3, 7, 14, 21, and 28 or on any day of recurrent infection for clinical and laboratory assessment. Polymerase chain reaction (PCR)-corrected cure rate on day 28 was the primary outcome. RESULTS: A total of 264 children, 88 in each of the three study sites (Mlimba, Mkuzi and Nagaga health facilities) were enrolled and treated with ASAQ. The ASAQ PCR-corrected cure rate was 100% at all the three study sites. None of the participants had early treatment failure or late clinical failure. Furthermore, none of the participants had a serious adverse event. CONCLUSION: ASAQ was highly efficacious for the treatment of uncomplicated P. falciparum malaria in mainland Tanzania, therefore, it can be deployed as an alternative first-line treatment for uncomplicated malaria as part of diversification strategy to contain the spread of partial artemisinin resistance in the country.

Microsatellites reveal high polymorphism and high potential for use in anti-malarial efficacy studies in areas with different transmission intensities in mainland Tanzania.

BACKGROUND: Tanzania is currently implementing therapeutic efficacy studies (TES) in areas of varying malaria transmission intensities as per the World Health Organization (WHO) recommendations. In TES, distinguishing reinfection from recrudescence is critical for the determination of anti-malarial efficacy. Recently, the WHO recommended genotyping polymorphic coding genes, merozoite surface proteins 1 and 2 (msp1 and msp2), and replacing the glutamate-rich protein (glurp) gene with one of the highly polymorphic microsatellites in Plasmodium falciparum to adjust the efficacy of antimalarials in TES. This study assessed the polymorphisms of six neutral microsatellite markers and their potential use in TES, which is routinely performed in Tanzania. METHODS: Plasmodium falciparum samples were obtained from four TES sentinel sites, Kibaha (Pwani), Mkuzi (Tanga), Mlimba (Morogoro) and Ujiji (Kigoma), between April and September 2016. Parasite genomic DNA was extracted from dried blood spots on filter papers using commercial kits. Genotyping was done using six microsatellites (Poly-α, PfPK2, TA1, C3M69, C2M34 and M2490) by capillary method, and the data were analysed to determine the extent of their polymorphisms and genetic diversity at the four sites. RESULTS: Overall, 83 (88.3%) of the 94 samples were successfully genotyped (with positive results for ≥ 50.0% of the markers), and > 50.0% of the samples (range = 47.6-59.1%) were polyclonal, with a mean multiplicity of infection (MOI) ranging from 1.68 to 1.88 among the four sites. There was high genetic diversity but limited variability among the four sites based on mean allelic richness (RS = 7.48, range = 7.27-8.03, for an adjusted minimum sample size of 18 per site) and mean expected heterozygosity (He = 0.83, range = 0.80-0.85). Cluster analysis of haplotypes using STRUCTURE, principal component analysis, and pairwise genetic differentiation (FST) did not reveal population structure or clustering of parasites according to geographic origin. Of the six markers, Poly-α was the most polymorphic, followed by C2M34, TA1 and C3M69, while M2490 was the least polymorphic. CONCLUSION: Microsatellite genotyping revealed high polyclonality and genetic diversity but no significant population structure. Poly-α, C2M34, TA1 and C3M69 were the most polymorphic markers, and Poly-α alone or with any of the other three markers could be adopted for use in TES in Tanzania.

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2019.

BACKGROUND: Artemisinin-based combination therapy (ACT) has been a major contributor to the substantial reductions in global malaria morbidity and mortality over the last decade. In Tanzania, artemether-lumefantrine (AL) was introduced as the first-line treatment for uncomplicated Plasmodium falciparum malaria in 2006. The World Health Organization (WHO) recommends regular assessment and monitoring of the efficacy of the first-line treatment, specifically considering that artemisinin resistance has been confirmed in the Greater Mekong sub-region. This study's main aim was to assess the efficacy and safety of AL for treating uncomplicated P. falciparum malaria in Tanzania. METHODS: This was a single-arm prospective antimalarial drug efficacy trial conducted in four of the eight National Malaria Control Programme (NMCP) sentinel sites in 2019. The trial was carried out in outpatient health facilities in Karume-Mwanza region, Ipinda-Mbeya region, Simbo-Tabora region, and Nagaga-Mtwara region. Children aged six months to 10 years with microscopy confirmed uncomplicated P. falciparum malaria who met the inclusion criteria were recruited based on the WHO protocol. The children received AL (a 6-dose regimen of AL twice daily for three days). Clinical and parasitological parameters were monitored during follow-up over 28 days to evaluate drug efficacy. RESULTS: A total of 628 children were screened for uncomplicated malaria, and 349 (55.6%) were enrolled between May and September 2019. Of the enrolled children, 343 (98.3%) completed the 28-day follow-up or attained the treatment outcomes. There were no early treatment failures; recurrent infections during follow-up were common at two sites (Karume 29.5%; Simbo 18.2%). PCR-corrected adequate clinical and parasitological response (ACPR) by survival analysis to AL on day 28 of follow-up varied from 97.7% at Karume to 100% at Ipinda and Nagaga sites. The commonly reported adverse events were cough, skin pallor, and abdominal pain. The drug was well tolerated, and no serious adverse event was reported. CONCLUSION: This study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria in Tanzania in 2019. The high recurrent infections were mainly due to new infections, highlighting the potential role of introducing alternative artemisinin-based combinations that offer improved post-treatment prophylaxis, such as artesunate-amodiaquine (ASAQ).

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2018.

BACKGROUND: The use of artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated falciparum malaria. Artemether-lumefantrine (AL) is the most widely adopted first-line ACT for uncomplicated malaria in sub-Saharan Africa (SSA), including mainland Tanzania, where it was introduced in December 2006. The WHO recommends regular assessment to monitor the efficacy of the first-line treatment specifically considering that artemisinin partial resistance was reported in Greater Mekong sub-region and has been confirmed in East Africa (Rwanda and Uganda). The main aim of this study was to assess the efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in mainland Tanzania. METHODS: A single-arm prospective anti-malarial drug efficacy trial was conducted in Kibaha, Mlimba, Mkuzi, and Ujiji (in Pwani, Morogoro, Tanga, and Kigoma regions, respectively) in 2018. The sample size of 88 patients per site was determined based on WHO 2009 standard protocol. Participants were febrile patients (documented axillary temperature ≥ 37.5 °C and/or history of fever during the past 24 h) aged 6 months to 10 years. Patients received a 6-dose AL regimen by weight twice a day for 3 days. Clinical and parasitological parameters were monitored during 28 days of follow-up to evaluate the drug efficacy and safety. RESULTS: A total of 653 children were screened for uncomplicated malaria and 349 (53.7%) were enrolled between April and August 2018. Of the enrolled children, 345 (98.9%) completed the 28 days of follow-up or attained the treatment outcomes. There were no early treatment failures, but recurrent infections were higher in Mkuzi (35.2%) and Ujiji (23%). By Kaplan-Meier analysis of polymerase chain reaction (PCR) uncorrected adequate clinical and parasitological response (ACPR) ranged from 63.4% in Mkuzi to 85.9% in Mlimba, while PCR-corrected ACPR on day 28 varied from 97.6% in Ujiji to 100% in Mlimba. The drug was well tolerated; the commonly reported adverse events were cough, runny nose, and abdominal pain. No serious adverse event was reported. CONCLUSION: This study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria. The high number of recurrent infections were mainly due to new infections, indicating the necessity of utilizing alternative artemisinin-based combinations, such as artesunate amodiaquine, which provide a significantly longer post-treatment prophylactic effect.

Trends of Plasmodium falciparum molecular markers associated with resistance to artemisinins and reduced susceptibility to lumefantrine in Mainland Tanzania from 2016 to 2021.

BACKGROUND: Therapeutic efficacy studies (TESs) and detection of molecular markers of drug resistance are recommended by the World Health Organization (WHO) to monitor the efficacy of artemisinin-based combination therapy (ACT). This study assessed the trends of molecular markers of artemisinin resistance and/or reduced susceptibility to lumefantrine using samples collected in TES conducted in Mainland Tanzania from 2016 to 2021. METHODS: A total of 2,015 samples were collected during TES of artemether-lumefantrine at eight sentinel sites (in Kigoma, Mbeya, Morogoro, Mtwara, Mwanza, Pwani, Tabora, and Tanga regions) between 2016 and 2021. Photo-induced electron transfer polymerase chain reaction (PET-PCR) was used to confirm presence of malaria parasites before capillary sequencing, which targeted two genes: Plasmodium falciparum kelch 13 propeller domain (k13) and P. falciparum multidrug resistance 1 (pfmdr1). RESULTS: Sequencing success was ≥ 87.8%, and 1,724/1,769 (97.5%) k13 wild-type samples were detected. Thirty-seven (2.1%) samples had synonymous mutations and only eight (0.4%) had non-synonymous mutations in the k13 gene; seven of these were not validated by the WHO as molecular markers of resistance. One sample from Morogoro in 2020 had a k13 R622I mutation, which is a validated marker of artemisinin partial resistance. For pfmdr1, all except two samples carried N86 (wild-type), while mutations at Y184F increased from 33.9% in 2016 to about 60.5% in 2021, and only four samples (0.2%) had D1246Y mutations. pfmdr1 haplotypes were reported in 1,711 samples, with 985 (57.6%) NYD, 720 (42.1%) NFD, and six (0.4%) carrying minor haplotypes (three with NYY, 0.2%; YFD in two, 0.1%; and NFY in one sample, 0.1%). Between 2016 and 2021, NYD decreased from 66.1% to 45.2%, while NFD increased from 38.5% to 54.7%. CONCLUSION: This is the first report of the R622I (k13 validated mutation) in Tanzania. N86 and D1246 were nearly fixed, while increases in Y184F mutations and NFD haplotype were observed between 2016 and 2021. Despite the reports of artemisinin partial resistance in Rwanda and Uganda, this study did not report any other validated mutations in these study sites in Tanzania apart from R622I suggesting that intensified surveillance is urgently needed to monitor trends of drug resistance markers and their impact on the performance of ACT.

Similar Prevalence of Plasmodium falciparum and Non-P. falciparum Malaria Infections among Schoolchildren, Tanzania1.

Achieving malaria elimination requires considering both Plasmodium falciparum and non-P. falciparum infections. We determined prevalence and geographic distribution of 4 Plasmodium spp. by performing PCR on dried blood spots collected within 8 regions of Tanzania during 2017. Among 3,456 schoolchildren, 22% had P. falciparum, 24% had P. ovale spp., 4% had P. malariae, and 0.3% had P. vivax infections. Most (91%) schoolchildren with P. ovale infections had low parasite densities; 64% of P. ovale infections were single-species infections, and 35% of those were detected in low malaria endemic regions. P. malariae infections were predominantly (73%) co-infections with P. falciparum. P. vivax was detected mostly in northern and eastern regions. Co-infections with >1 non-P. falciparum species occurred in 43% of P. falciparum infections. A high prevalence of P. ovale infections exists among schoolchildren in Tanzania, underscoring the need for detection and treatment strategies that target non-P. falciparum species.

Community knowledge, attitude, practices and beliefs associated with persistence of malaria transmission in North-western and Southern regions of Tanzania.

BACKGROUND: Despite significant decline in the past two decades, malaria is still a major public health concern in Tanzania; with over 93% of the population still at risk. Community knowledge, attitudes and practices (KAP), and beliefs are key in enhancing uptake and utilization of malaria control interventions, but there is a lack of information on their contribution to effective control of the disease. This study was undertaken to determine KAP and beliefs of community members and service providers on malaria, and how they might be associated with increased risk and persistence of the disease burden in North-western and Southern regions of Tanzania. METHODS: This was an exploratory study that used qualitative methods including 16 in-depth interviews (IDI) and 32 focus group discussions (FGDs) to collect data from health service providers and community members, respectively. The study was conducted from September to October 2017 and covered 16 villages within eight districts from four regions of mainland Tanzania (Geita, Kigoma, Mtwara and Ruvuma) with persistently high malaria transmission for more than two decades. RESULTS: Most of the participants had good knowledge of malaria and how it is transmitted but some FGD participants did not know the actual cause of malaria, and thought that it is caused by bathing and drinking un-boiled water, or consuming contaminated food that has malaria parasites without warming it. Reported barriers to malaria prevention and control (by FGD and IDI participants) included shortage of qualified health workers, inefficient health financing, low care-seeking behaviour, consulting traditional healers, use of local herbs to treat malaria, poverty, increased breeding sites by socio-economic activities and misconceptions related to the use of bed nets and indoor residual spraying (IRS). Among the misconceptions, some participants believed that bed nets provided for free by the government came with bedbugs while others reported that free bed nets caused impotence among men. CONCLUSION: Despite good knowledge of malaria, several risk factors, such as socio-economic and behavioural issues, and misconceptions related to the use of bed nets and IRS were reported. Other key factors included unavailability or limited access to health services, poor health financing and economic activities that potentially contributed to persistence of malaria burden in these regions. Relevant policies and targeted malaria interventions, focusing on understanding socio-cultural factors, should be implemented to reduce and finally eliminate the disease in the study regions and others with persistent transmission.

Implementation research of a cluster randomized trial evaluating the implementation and effectiveness of intermittent preventive treatment for malaria using dihydroartemisinin-piperaquine on reducing malaria burden in school-aged children in Tanzania: methodology, challenges, and mitigation.

BACKGROUND: It has been more than 20 years since the malaria epidemiologic shift to school-aged children was noted. In the meantime, school-aged children (5-15 years) have become increasingly more vulnerable with asymptomatic malaria prevalence reaching up to 70%, making them reservoirs for subsequent transmission of malaria in the endemic communities. Intermittent Preventive Treatment of malaria in schoolchildren (IPTsc) has proven to be an effective tool to shrink this reservoir. As of 3rd June 2022, the World Health Organization recommends IPTsc in moderate and high endemic areas. Even so, for decision-makers, the adoption of scientific research recommendations has been stifled by real-world implementation challenges. This study presents methodology, challenges faced, and mitigations used in the evaluation of the implementation of IPTsc using dihydroartemisinin-piperaquine (DP) in three councils (Handeni District Council (DC), Handeni Town Council (TC) and Kilindi DC) of Tanga Region, Tanzania so as to understand the operational feasibility and effectiveness of IPTsc on malaria parasitaemia and clinical malaria incidence. METHODS: The study deployed an effectiveness-implementation hybrid design to assess feasibility and effectiveness of IPTsc using DP, the interventional drug, against standard of care (control). Wards in the three study councils were the randomization unit (clusters). Each ward was randomized to implement IPTsc or not (control). In all wards in the IPTsc arm, DP was given to schoolchildren three times a year in four-month intervals. In each council, 24 randomly selected wards (12 per study arm, one school per ward) were chosen as representatives for intervention impact evaluation. Mixed design methods were used to assess the feasibility and acceptability of implementing IPTsc as part of a more comprehensive health package for schoolchildren. The study reimagined an existing school health programme for Neglected Tropical Diseases (NTD) control include IPTsc implementation. RESULTS: The study shows IPTsc can feasibly be implemented by integrating it into existing school health and education systems, paving the way for sustainable programme adoption in a cost-effective manner. CONCLUSIONS: Through this article other interested countries may realise a feasible plan for IPTsc implementation. Mitigation to any challenge can be customized based on local circumstances without jeopardising the gains expected from an IPTsc programme. Trial registration clinicaltrials.gov, NCT04245033. Registered 28 January 2020, https://clinicaltrials.gov/ct2/show/NCT04245033.

Sub-national tailoring of malaria interventions in Mainland Tanzania: simulation of the impact of strata-specific intervention combinations using modelling.

BACKGROUND: To accelerate progress against malaria in high burden countries, a strategic reorientation of resources at the sub-national level is needed. This paper describes how mathematical modelling was used in mainland Tanzania to support the strategic revision that followed the mid-term review of the 2015-2020 national malaria strategic plan (NMSP) and the epidemiological risk stratification at the council level in 2018. METHODS: Intervention mixes, selected by the National Malaria Control Programme, were simulated for each malaria risk strata per council. Intervention mixes included combinations of insecticide-treated bed nets (ITN), indoor residual spraying, larval source management, and intermittent preventive therapies for school children (IPTsc). Effective case management was either based on estimates from the malaria indicator survey in 2016 or set to a hypothetical target of 85%. A previously calibrated mathematical model in OpenMalaria was used to compare intervention impact predictions for prevalence and incidence between 2016 and 2020, or 2022. RESULTS: For each malaria risk stratum four to ten intervention mixes were explored. In the low-risk and urban strata, the scenario without a ITN mass campaign in 2019, predicted high increase in prevalence by 2020 and 2022, while in the very-low strata the target prevalence of less than 1% was maintained at low pre-intervention transmission intensity and high case management. In the moderate and high strata, IPTsc in addition to existing vector control was predicted to reduce the incidence by an additional 15% and prevalence by 22%. In the high-risk strata, all interventions together reached a maximum reduction of 76%, with around 70% of that reduction attributable to high case management and ITNs. Overall, the simulated revised NMSP was predicted to achieve a slightly lower prevalence in 2020 compared to the 2015-2020 NMSP (5.3% vs 6.3%). CONCLUSION: Modelling supported the choice of intervention per malaria risk strata by providing impact comparisons of various alternative intervention mixes to address specific questions relevant to the country. The use of a council-calibrated model, that reproduces local malaria trends, represents a useful tool for compiling available evidence into a single analytical platform, that complement other evidence, to aid national programmes with decision-making processes.

The use of routine health facility data for micro-stratification of malaria risk in mainland Tanzania.

BACKGROUND: Current efforts to estimate the spatially diverse malaria burden in malaria-endemic countries largely involve the use of epidemiological modelling methods for describing temporal and spatial heterogeneity using sparse interpolated prevalence data from periodic cross-sectional surveys. However, more malaria-endemic countries are beginning to consider local routine data for this purpose. Nevertheless, routine information from health facilities (HFs) remains widely under-utilized despite improved data quality, including increased access to diagnostic testing and the adoption of the electronic District Health Information System (DHIS2). This paper describes the process undertaken in mainland Tanzania using routine data to develop a high-resolution, micro-stratification risk map to guide future malaria control efforts. METHODS: Combinations of various routine malariometric indicators collected from 7098 HFs were assembled across 3065 wards of mainland Tanzania for the period 2017-2019. The reported council-level prevalence classification in school children aged 5-16 years (PfPR5-16) was used as a benchmark to define four malaria risk groups. These groups were subsequently used to derive cut-offs for the routine indicators by minimizing misclassifications and maximizing overall agreement. The derived-cutoffs were converted into numbered scores and summed across the three indicators to allocate wards into their overall risk stratum. RESULTS: Of 3065 wards, 353 were assigned to the very low strata (10.5% of the total ward population), 717 to the low strata (28.6% of the population), 525 to the moderate strata (16.2% of the population), and 1470 to the high strata (39.8% of the population). The resulting micro-stratification revealed malaria risk heterogeneity within 80 councils and identified wards that would benefit from community-level focal interventions, such as community-case management, indoor residual spraying and larviciding. CONCLUSION: The micro-stratification approach employed is simple and pragmatic, with potential to be easily adopted by the malaria programme in Tanzania. It makes use of available routine data that are rich in spatial resolution and that can be readily accessed allowing for a stratification of malaria risk below the council level. Such a framework is optimal for supporting evidence-based, decentralized malaria control planning, thereby improving the effectiveness and allocation efficiency of malaria control interventions.

Performance of antigen detection for HRP2-based malaria rapid diagnostic tests in community surveys: Tanzania, July-November 2017.

BACKGROUND: Malaria rapid diagnostic tests (RDTs) based on the detection of the Plasmodium falciparum histidine-rich protein 2 (HRP2) antigen are widely used for detection of active infection with this parasite and are the only practical malaria diagnostic test in some endemic settings. External validation of RDT results from field surveys can confirm appropriate RDT performance. METHODS: A community-based cross-sectional survey was conducted between July and November 2017 enrolling participants of all ages in households from 15 villages in four border regions of Tanzania: Geita, Kigoma, Mtwara and Ruvuma. All participants had an RDT performed in the field and provided a blood sample for later laboratory multiplex antigen detection of HRP2. In assessing the continuous HRP2 levels in participant blood versus RDT result, dose-response logistic regression provided quantitative estimates for HRP2 limit of detection (LOD). RESULTS: From the 15 study villages, 6941 persons were enrolled that had a RDT at time of enrollment and provided a DBS for later laboratory antigen detection. RDT positive prevalence for the HRP2 band by village ranged from 20.0 to 43.6%, but the magnitude of this prevalence did not have an effect on the estimated LOD of RDTs utilized in different villages. Overall, HRP2 single-target tests had a lower LOD at the 95% probability of positive RDT (4.3 ng/mL; 95% CI 3.4-5.4) when compared to pLDH/HRP2 dual target tests (5.4 ng/mL; 4.5-6.3), though this difference was not significant. With the exception of one village, all other 14 villages (93.3%) showed RDT LOD estimates at 90% probability of positive RDT between 0.5 and 12.0 ng/mL. CONCLUSIONS: Both HRP2-only and pLDH/HRP2 combo RDTs utilized in a 2017 Tanzania cross-sectional survey of border regions generally performed well, and reliably detected HRP2 antigen in the low ng/mL range. Though single target tests had lower levels of HRP2 detection, both tests were within similar ranges among the 15 villages. Comparison of quantitative HRP2 detection limits among study sites can help interpret RDT testing results when generating population prevalence estimates for malaria infection.

Evaluating malaria prevalence and land cover across varying transmission intensity in Tanzania using a cross-sectional survey of school-aged children.

BACKGROUND: Transmission of malaria in sub-Saharan Africa has become increasingly stratified following decades of malaria control interventions. The extent to which environmental and land cover risk factors for malaria may differ across distinct strata of transmission intensity is not well known and could provide actionable targets to maximize the success of malaria control efforts. METHODS: This study used cross-sectional malaria survey data from a nationally representative cohort of school-aged children in Tanzania, and satellite-derived measures for environmental features and land cover. Hierarchical logistic regression models were applied to evaluate associations between land cover and malaria prevalence within three distinct strata of transmission intensity: low and unstable, moderate and seasonal, and high and perennial. RESULTS: In areas with low malaria transmission, each 10-percentage point increase in cropland cover was associated with an increase in malaria prevalence odds of 2.44 (95% UI: 1.27, 5.11). However, at moderate and higher levels of transmission intensity, no association between cropland cover and malaria prevalence was detected. Small associations were observed between greater grassland cover and greater malaria prevalence in high intensity settings (prevalence odds ratio (POR): 1.10, 95% UI: 1.00, 1.21), and between greater forest cover and reduced malaria prevalence in low transmission areas (POR: 0.74, 95% UI: 0.51, 1.03), however the uncertainty intervals of both estimates included the null. CONCLUSIONS: The intensity of malaria transmission appears to modify relationships between land cover and malaria prevalence among school-aged children in Tanzania. In particular, greater cropland cover was positively associated with increased malaria prevalence in areas with low transmission intensity and presents an actionable target for environmental vector control interventions to complement current malaria control activities. As areas are nearing malaria elimination, it is important to re-evaluate environmental risk factors and employ appropriate interventions to effectively address low-level malaria transmission.

Improvements in malaria surveillance through the electronic Integrated Disease Surveillance and Response (eIDSR) system in mainland Tanzania, 2013-2021.

BACKGROUND: Tanzania has made remarkable progress in reducing malaria burden and aims to transition from malaria control to sub-national elimination. In 2013, electronic weekly and monthly reporting platforms using the District Health Information System 2 (DHIS2) were introduced. Weekly reporting was implemented through the mobile phone-based Integrated Disease Surveillance and Response (eIDSR) platform and progressively scaled-up from 67 to 7471 (100%) public and private health facilities between 2013 and 2020. This study describes the roll-out and large-scale implementation of eIDSR and compares the consistency between weekly eIDSR and monthly DHIS2 malaria indicator data reporting, including an assessment of its usefulness for malaria outbreak detection and case-based surveillance (CBS) in low transmission areas. METHODS: The indicators included in the analysis were number of patients tested for malaria, number of confirmed malaria cases, and clinical cases (treated presumptively for malaria). The analysis described the time trends of reporting, testing, test positivity, and malaria cases between 2013 and 2021. For both weekly eIDSR and monthly DHIS2 data, comparisons of annual reporting completeness, malaria cases and annualized incidence were performed for 2020 and 2021; additionally, comparisons were stratified by malaria epidemiological strata (parasite prevalence: very low < 1%, low 1 ≤ 5%, moderate 5 ≤ 30%, and high > 30%). RESULTS: Weekly eIDSR reporting completeness steadily improved over time, with completeness being 90.2% in 2020 and 93.9% in 2021; conversely, monthly DHIS2 reporting completeness was 98.9% and 98.7% in 2020 and 2021, respectively. Weekly eIDSR reporting completeness and timeliness were highest in the very low epidemiological stratum. Annualized malaria incidence as reported by weekly eIDSR was 17.5% and 12.4% lower than reported by monthly DHIS2 in 2020 and 2021; for both 2020 and 2021, annualized incidence was similar across weekly and monthly data in the very low stratum. CONCLUSION: The concurrence of annualized weekly eIDSR and monthly DHIS2 reporting completeness, malaria cases and incidence in very low strata suggests that eIDSR could be useful tool for early outbreak detection, and the eIDSR platform could reliably be expanded by adding more indicators and modules for CBS in the very low epidemiological stratum.

Describing the current status of Plasmodium falciparum population structure and drug resistance within mainland Tanzania using molecular inversion probes.

High-throughput Plasmodium genomic data is increasingly useful in assessing prevalence of clinically important mutations and malaria transmission patterns. Understanding parasite diversity is important for identification of specific human or parasite populations that can be targeted by control programmes, and to monitor the spread of mutations associated with drug resistance. An up-to-date understanding of regional parasite population dynamics is also critical to monitor the impact of control efforts. However, this data is largely absent from high-burden nations in Africa, and to date, no such analysis has been conducted for malaria parasites in Tanzania countrywide. To this end, over 1,000 P. falciparum clinical isolates were collected in 2017 from 13 sites in seven administrative regions across Tanzania, and parasites were genotyped at 1,800 variable positions genome-wide using molecular inversion probes. Population structure was detectable among Tanzanian P. falciparum parasites, approximately separating parasites from the northern and southern districts and identifying genetically admixed populations in the north. Isolates from nearby districts were more likely to be genetically related compared to parasites sampled from more distant districts. Known drug resistance mutations were seen at increased frequency in northern districts (including two infections carrying pfk13-R561H), and additional variants with undetermined significance for antimalarial resistance also varied by geography. Malaria Indicator Survey (2017) data corresponded with genetic findings, including average region-level complexity-of-infection and malaria prevalence estimates. The parasite populations identified here provide important information on extant spatial patterns of genetic diversity of Tanzanian parasites, to which future surveys of genetic relatedness can be compared.

Acceptability of single screening and treatment policy for the control of malaria in pregnancy: perceptions of providers and pregnant women from selected health facilities in Lindi region, Tanzania.

BACKGROUND: Tanzania started implementing single screening and treatment (SST) for all pregnant women attending their first antenatal care (ANC) visits in 2014, using malaria rapid diagnostic tests (RDTs) and treating those who test positive according to the national guidelines. However, there is a paucity of data to show the acceptability of SST to both pregnant women and health care workers (HCWs), taking into consideration the shortage of workers and the added burden of this policy to the health system. This study assessed the perceptions and opinions of health service users and providers to determine the acceptability of SST policy. METHODS: Pregnant women and HCWs in eight health facilities in two districts of Lindi region (Kilwa and Lindi) were interviewed using semi-structured questionnaires with open and close-ended questions. Both qualitative and quantitative data were collected, including demographic characteristics, women's experience, their perception on SST and challenges they face when receiving services for malaria offered at ANC. Experience of HCWs regarding the implementation of SST as part of routine services and the challenges encountered when providing ANC services for malaria in pregnancy (MIP) were also assessed. RESULTS: Of the 143 pregnant women interviewed, 97% viewed testing favourably and would wish to be tested for malaria again, while 95% were satisfied with services and reasons for testing during the first ANC visit. Nearly all (99%) would recommend their fellow pregnant women to be tested for malaria and all women recommended that the Ministry of Health should continue the SST strategy. This was despite the fact that 76% of the women experienced pain and 16% had anxiety as a result of finger prick. Sixteen HCWs (mostly nurses) were interviewed; they also viewed SST implementation favourably and reported feeling empowered to use RDTs for malaria screening. The main challenge identified by HCWs was that nurses are not allowed to prescribe anti-malarials to women who test positive and need to refer them to the outpatient department for treatment. CONCLUSION: SST was considered an acceptable approach to control MIP by HCWs and pregnant women, and they recommended the continuation of the policy. In addition, consideration should be given to implementing a task-shifting policy to allow nurses to dispense anti-malarials to pregnant women.

Applied mathematical modelling to inform national malaria policies, strategies and operations in Tanzania.

BACKGROUND: More than ever, it is crucial to make the best use of existing country data, and analytical tools for developing malaria control strategies as the heterogeneity in malaria risk within countries is increasing, and the available malaria control tools are expanding while large funding gaps exist. Global and local policymakers, as well as funders, increasingly recognize the value of mathematical modelling as a strategic tool to support decision making. This case study article describes the long-term use of modelling in close collaboration with the National Malaria Control Programme (NMCP) in Tanzania, the challenges encountered and lessons learned. CASE DESCRIPTION: In Tanzania, a recent rebound in prevalence led to the revision of the national malaria strategic plan with interventions targeted to the malaria risk at the sub-regional level. As part of the revision, a mathematical malaria modelling framework for setting specific predictions was developed and used between 2016 and 2019 to (1) reproduce setting specific historical malaria trends, and (2) to simulate in silico the impact of future interventions. Throughout the project, multiple stakeholder workshops were attended and the use of mathematical modelling interactively discussed. EVALUATION: In Tanzania, the model application created an interdisciplinary and multisectoral dialogue platform between modellers, NMCP and partners and contributed to the revision of the national malaria strategic plan by simulating strategies suggested by the NMCP. The uptake of the modelling outputs and sustained interest by the NMCP were critically associated with following factors: (1) effective sensitization to the NMCP, (2) regular and intense communication, (3) invitation for the modellers to participate in the strategic plan process, and (4) model application tailored to the local context. CONCLUSION: Empirical data analysis and its use for strategic thinking remain the cornerstone for evidence-based decision-making. Mathematical impact modelling can support the process both by unifying all stakeholders in one strategic process and by adding new key evidence required for optimized decision-making. However, without a long-standing partnership, it will be much more challenging to sensibilize programmes to the usefulness and sustained use of modelling and local resources within the programme or collaborating research institutions need to be mobilized.

Evaluation of a single screen and treat strategy to detect asymptomatic malaria among pregnant women from selected health facilities in Lindi region, Tanzania.

BACKGROUND: In areas of high transmission, malaria in pregnancy (MiP) primarily causes asymptomatic infections; these infections nonetheless increase the risk of adverse maternal and fetal outcomes. In 2014, Tanzania initiated a single screening and treatment (SST) strategy for all pregnant women at their first antenatal care (ANC) visit using malaria rapid diagnostic tests (RDT) for surveillance purposes. However, there is paucity of data on the effectiveness of SST in the prevention of MiP. The objective of this study was to estimate the number of asymptomatic infections among pregnant women detected by SST, which would have been missed in the absence of the policy. METHODS: Data from pregnant women attending their first ANC visits between October 2017 and June 2018, including gestational age, history of fever, and RDT results, were abstracted from ANC registers in eight health centres in two randomly selected districts, Kilwa and Lindi, in Lindi Region. The proportion of symptomatic (with history of fever in the past 48 h) and asymptomatic pregnant women with positive RDTs were calculated and stratified by trimester (first, second and third). The study areas were categorized as low transmission with prevalence < 10% or moderate/high with ≥ 10%. RESULTS: Over the study period, 1,845 women attended their first ANC visits; 22.1% were in the first trimester (< 12 weeks gestation age). Overall 15.0% of the women had positive RDTs, and there was a trend towards higher malaria prevalence in the first (15.9%) and second (15.2%) trimesters, compared to the third (7.1%), although the differences were not statistically significant (p = 0.07). In total, 6.9% of women reported fever within the past 48 h and, of these, 96.1% were RDT positive. For every 100 pregnant women in the moderate/high and low transmission areas, SST identified 60 and 26 pregnant women, respectively, with asymptomatic infections that would have otherwise been missed. Among the 15.9% of women detected in the first trimester, 50.7% were asymptomatic. CONCLUSION: In areas of moderate/high transmission, many infected women were asymptomatic, and would have been missed in the absence of SST. The benefits on maternal and fetal birth outcomes of identifying these infections depend heavily on the protection afforded by treatment, which is likely to be greatest for women presenting in the first trimester when intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP) is contraindicated, and in areas with high SP resistance, such as most parts of Tanzania. An evaluation of the impact and cost-effectiveness of SST across different transmission strata is warranted.

Sub-national stratification of malaria risk in mainland Tanzania: a simplified assembly of survey and routine data.

BACKGROUND: Recent malaria control efforts in mainland Tanzania have led to progressive changes in the prevalence of malaria infection in children, from 18.1% (2008) to 7.3% (2017). As the landscape of malaria transmission changes, a sub-national stratification becomes crucial for optimized cost-effective implementation of interventions. This paper describes the processes, data and outputs of the approach used to produce a simplified, pragmatic malaria risk stratification of 184 councils in mainland Tanzania. METHODS: Assemblies of annual parasite incidence and fever test positivity rate for the period 2016-2017 as well as confirmed malaria incidence and malaria positivity in pregnant women for the period 2015-2017 were obtained from routine district health information software. In addition, parasite prevalence in school children (PfPR5to16) were obtained from the two latest biennial council representative school malaria parasitaemia surveys, 2014-2015 and 2017. The PfPR5to16 served as a guide to set appropriate cut-offs for the other indicators. For each indicator, the maximum value from the past 3 years was used to allocate councils to one of four risk groups: very low (< 1%PfPR5to16), low (1- < 5%PfPR5to16), moderate (5- < 30%PfPR5to16) and high (≥ 30%PfPR5to16). Scores were assigned to each risk group per indicator per council and the total score was used to determine the overall risk strata of all councils. RESULTS: Out of 184 councils, 28 were in the very low stratum (12% of the population), 34 in the low stratum (28% of population), 49 in the moderate stratum (23% of population) and 73 in the high stratum (37% of population). Geographically, most of the councils in the low and very low strata were situated in the central corridor running from the north-east to south-west parts of the country, whilst the areas in the moderate to high strata were situated in the north-west and south-east regions. CONCLUSION: A stratification approach based on multiple routine and survey malaria information was developed. This pragmatic approach can be rapidly reproduced without the use of sophisticated statistical methods, hence, lies within the scope of national malaria programmes across Africa.

Community-based surveys for Plasmodium falciparum pfhrp2 and pfhrp3 gene deletions in selected regions of mainland Tanzania.

BACKGROUND: Histidine-rich protein 2 (HRP2)-based malaria rapid diagnostic tests (RDTs) are effective and widely used for the detection of wild-type Plasmodium falciparum infections. Although recent studies have reported false negative HRP2 RDT results due to pfhrp2 and pfhrp3 gene deletions in different countries, there is a paucity of data on the deletions of these genes in Tanzania. METHODS: A community-based cross-sectional survey was conducted between July and November 2017 in four regions: Geita, Kigoma, Mtwara and Ruvuma. All participants had microscopy and RDT performed in the field and provided a blood sample for laboratory multiplex antigen detection (for Plasmodium lactate dehydrogenase, aldolase, and P. falciparum HRP2). Samples showing RDT false negativity or aberrant relationship of HRP2 to pan-Plasmodium antigens were genotyped to detect the presence/absence of pfhrp2/3 genes. RESULTS: Of all samples screened by the multiplex antigen assay (n = 7543), 2417 (32.0%) were positive for any Plasmodium antigens while 5126 (68.0%) were negative for all antigens. The vast majority of the antigen positive samples contained HRP2 (2411, 99.8%), but 6 (0.2%) had only pLDH and/or aldolase without HRP2. Overall, 13 samples had an atypical relationship between a pan-Plasmodium antigen and HRP2, but were positive by PCR. An additional 16 samples with negative HRP2 RDT results but P. falciparum positive by microscopy were also chosen for pfhrp2/3 genotyping. The summation of false negative RDT results and laboratory antigen results provided 35 total samples with confirmed P. falciparum DNA for pfhrp2/3 genotyping. Of the 35 samples, 4 (11.4%) failed to consistently amplify positive control genes; pfmsp1 and pfmsp2 and were excluded from the analysis. The pfhrp2 and pfhrp3 genes were successfully amplified in the remaining 31 (88.6%) samples, confirming an absence of deletions in these genes. CONCLUSIONS: This study provides evidence that P. falciparum parasites in the study area have no deletions of both pfhrp2 and pfhrp3 genes. Although single gene deletions could have been missed by the multiplex antigen assay, the findings support the continued use of HRP2-based RDTs in Tanzania for routine malaria diagnosis. There is a need for the surveillance to monitor the status of pfhrp2 and/or pfhrp3 deletions in the future.