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.

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.

Longitudinal estimation of Plasmodium falciparum prevalence in relation to malaria prevention measures in six sub-Saharan African countries.

BACKGROUND: Plasmodium falciparum prevalence (PfPR) is a widely used metric for assessing malaria transmission intensity. This study was carried out concurrently with the RTS,S/AS01 candidate malaria vaccine Phase III trial and estimated PfPR over ≤ 4 standardized cross-sectional surveys. METHODS: This epidemiology study (NCT01190202) was conducted in 8 sites from 6 countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, and Tanzania), between March 2011 and December 2013. Participants were enrolled in a 2:1:1 ratio according to age category: 6 months-4 years, 5-19 years, and ≥ 20 years, respectively, per year and per centre. All sites carried out surveys 1-3 while survey 4 was conducted only in 3 sites. Surveys were usually performed during the peak malaria parasite transmission season, in one home visit, when medical history and malaria risk factors/prevention measures were collected, and a blood sample taken for rapid diagnostic test, microscopy, and haemoglobin measurement. PfPR was estimated by site and age category. RESULTS: Overall, 6401 (survey 1), 6411 (survey 2), 6400 (survey 3), and 2399 (survey 4) individuals were included in the analyses. In the 6 months-4 years age group, the lowest prevalence (assessed using microscopy) was observed in 2 Tanzanian centres (4.6% for Korogwe and 9.95% for Bagamoyo) and Lambaréné, Gabon (6.0%), while the highest PfPR was recorded for Nanoro, Burkina Faso (52.5%). PfPR significantly decreased over the 3 years in Agogo (Ghana), Kombewa (Kenya), Lilongwe (Malawi), and Bagamoyo (Tanzania), and a trend for increased PfPR was observed over the 4 surveys for Kintampo, Ghana. Over the 4 surveys, for all sites, PfPR was predominantly higher in the 5-19 years group than in the other age categories. Occurrence of fever and anaemia was associated with high P. falciparum parasitaemia. Univariate analyses showed a significant association of anti-malarial treatment in 4 surveys (odds ratios [ORs]: 0.52, 0.52, 0.68, 0.41) and bed net use in 2 surveys (ORs: 0.63, 0.68, 1.03, 1.78) with lower risk of malaria infection. CONCLUSION: Local PfPR differed substantially between sites and age groups. In children 6 months-4 years old, a significant decrease in prevalence over the 3 years was observed in 4 out of the 8 study sites. Trial registration Clinical Trials.gov identifier: NCT01190202:NCT. GSK Study ID numbers: 114001.

Declining burden of malaria over two decades in a rural community of Muheza district, north-eastern Tanzania.

BACKGROUND: The recently reported declining burden of malaria in some African countries has been attributed to scaling-up of different interventions although in some areas, these changes started before implementation of major interventions. This study assessed the long-term trends of malaria burden for 20 years (1992-2012) in Magoda and for 15 years in Mpapayu village of Muheza district, north-eastern Tanzania, in relation to different interventions as well as changing national malaria control policies. METHODS: Repeated cross-sectional surveys recruited individuals aged 0 - 19 years from the two villages whereby blood smears were collected for detection of malaria parasites by microscopy. Prevalence of Plasmodium falciparum infections and other indices of malaria burden (prevalence of anaemia, splenomegaly and gametocytes) were compared across the years and between the study villages. Major interventions deployed including a mobile clinic, bed nets and other research activities, and changes in national malaria control policies were also marked. RESULTS: In Magoda, the prevalence of P. falciparum infections initially decreased between 1992 and 1996 (from 83.5 to 62.0%), stabilized between 1996 and 1997, and further declined to 34.4% in 2004. A temporary increase between 2004 and 2008 was followed by a progressive decline to 7.2% in 2012, which is more than 10-fold decrease since 1992. In Mpapayu (from 1998), the highest prevalence was 81.5% in 1999 and it decreased to 25% in 2004. After a slight increase in 2008, a steady decline followed, reaching <5% from 2011 onwards. Bed net usage was high in both villages from 1999 to 2004 (≥88%) but it decreased between 2008 and 2012 (range, 28% - 68%). After adjusting for the effects of bed nets, age, fever and year of study, the risk of P. falciparum infections decreased significantly by ≥97% in both villages between 1999 and 2012 (p < 0.001). The prevalence of splenomegaly (>40% to <1%) and gametocytes (23% to <1%) also decreased in both villages. DISCUSSION AND CONCLUSIONS: A remarkable decline in the burden of malaria occurred between 1992 and 2012 and the initial decline (1992 - 2004) was most likely due to deployment of interventions, such as bed nets, and better services through research activities. Apart from changes of drug policies, the steady decline observed from 2008 occurred when bed net coverage was low suggesting that other factors contributed to the most recent pattern. These results suggest that continued monitoring is required to determine causes of the changing malaria epidemiology and also to monitor the progress towards maintaining low malaria transmission and reaching related millennium development goals.

Acquisition of antibodies to merozoite surface protein 3 among residents of Korogwe, north eastern Tanzania.

BACKGROUND: A polymorphic malaria parasite antigen, merozoite surface protein 3 (MSP3), is among the blood stage malaria vaccine candidates. It is believed to induce immunity through cytophilic antibodies that disrupt the process of erythrocytes invasion by merozoites. This study aimed at assessing natural acquisition of antibodies to MSP3 in individuals living in an area with different malaria transmission intensity in preparation for malaria vaccine trials. METHODS: The study was conducted in individuals aged 0-19 years from villages located in lowland, intermediate and highland strata in Korogwe district, northeastern Tanzania. Blood samples from 492 study participants were collected between May and June 2006 for malaria diagnosis and immunological investigations. Reactivity of MSP3 to different types of antibodies (immunoglobulin M, G and IgG subclass 1 and 3) were analysed by Enzyme Linked ImmunoSorbent Assay (ELISA). RESULTS: Malaria parasite prevalence was higher in the lowland (50%) compared to the intermediate (23.1%) and highland (9.8%) strata. Immunogloblin G subclasses 1 and 3 (IgG1 & IgG3), total IgG and IgM were found to increase with increasing age. IgG3 levels were significantly higher than IgG1 (p < 0.001). Furthermore, Plasmodium falciparum infection was associated with higher IgG3 levels (p = 0.008). Adjusting by strata and age in individuals who had positive blood smears, both IgG and IgM were associated with parasite density, whereby IgG levels decreased by 0.227 (95%CI: 0.064 - 0.391; p = 0.007) while IgM levels decreased by 0.165 (95%CI: 0.044 - 0.286; p = 0.008). CONCLUSION: Individuals with higher levels of IgG3 might be partially protected from malaria infection. Higher levels of total IgG and IgM in highlands might be due to low exposure to malaria infection, recent infection or presence of cross-reactive antigens. Further studies of longitudinal nature are recommended. Data obtained from this study were used in selection of one village (Kwashemshi) for conducting MSP3 phase 1b malaria vaccine trial in Korogwe.

Epidemiology of malaria in an area prepared for clinical trials in Korogwe, north-eastern Tanzania.

BACKGROUND: Site preparation is a pre-requesite in conducting malaria vaccines trials. This study was conducted in 12 villages to determine malariometric indices and associated risk factors, during long and short rainy seasons, in an area with varying malaria transmission intensities in Korogwe district, Tanzania. Four villages had passive case detection (PCD) of fever system using village health workers. METHODS: Four malariometric cross-sectional surveys were conducted between November 2005 and May 2007 among individuals aged 0-19 years, living in lowland urban, lowland rural and highland strata. A total of 10,766 blood samples were collected for malaria parasite diagnosis and anaemia estimation. Blood smears were stained with Giemsa while haemoglobin level was measured by HaemoCue. Socio-economic data were collected between Jan-Apr 2006. RESULTS: Adjusting for the effect of age, the risk of Plasmodium falciparum parasitaemia was significantly lower in both lowland urban, (OR = 0.26; 95%CI: 0.23-0.29, p < 0.001) and highlands, (OR = 0.21; 95%CI: 0.17-0.25, p < 0.001) compared to lowland rural. Individuals aged 6-9 years in the lowland rural and 4-19 years in both lowland urban and highlands had the highest parasite prevalence, whilst children below five years in all strata had the highest parasite density. Prevalence of splenomegaly and gametocyte were also lower in both lowland urban and highlands than in lowland rural. Anaemia (Hb <11 g/dl) prevalence was lowest in the lowland urban. Availability of PCD and higher socio-economic status (SES) were associated with reduced malaria and anaemia prevalence. CONCLUSION: Higher SES and use of bed nets in the lowland urban could be the important factors for low malaria infections in this stratum. Results obtained here were used together with those from PCD and DSS in selecting a village for Phase 1b MSP3 vaccine trial, which was conducted in the study area in year 2008.

Satisfactory safety and immunogenicity of MSP3 malaria vaccine candidate in Tanzanian children aged 12-24 months.

BACKGROUND: Development and deployment of an effective malaria vaccine would complement existing malaria control measures. A blood stage malaria vaccine candidate, Merozoite Surface Protein-3 (MSP3), produced as a long synthetic peptide, has been shown to be safe in non-immune and semi-immune adults. A phase Ib dose-escalating study was conducted to assess the vaccine's safety and immunogenicity in children aged 12 to 24 months in Korogwe, Tanzania (ClinicalTrials.gov number: NCT00469651). METHODS: This was a double-blind, randomized, controlled, dose escalation phase Ib trial, in which children were given one of two different doses of the MSP3 antigen (15 microg or 30 microg) or a control vaccine (Engerix B). Children were randomly allocated either to the MSP3 candidate malaria vaccine or the control vaccine administered at a schedule of 0, 1, and 2 months. Immunization with lower and higher doses was staggered for safety reasons starting with the lower dose. The primary endpoint was safety and reactogenicity within 28 days post-vaccination. Blood samples were obtained at different time points to measure immunological responses. Results are presented up to 84 days post-vaccination. RESULTS: A total of 45 children were enrolled, 15 in each of the two MSP3 dose groups and 15 in the Engerix B group. There were no important differences in reactogenicity between the two MSP3 groups and Engerix B. Grade 3 adverse events were infrequent; only five were detected throughout the study, all of which were transient and resolved without sequelae. No serious adverse event reported was considered to be related to MSP3 vaccine. Both MSP3 dose regimens elicited strong cytophilic IgG responses (subclasses IgG1 and IgG3), the isotypes involved in the monocyte-dependant mechanism of Plasmodium falciparum parasite-killing. The titers reached are similar to those from African adults having reached a state of premunition. Furthermore, vaccination induced seroconversion in all vaccinees. CONCLUSION: The MSP3 malaria vaccine candidate was safe, well tolerated and immunogenic in children aged 12-24 months living in a malaria endemic community. Given the vaccine's safety and its induction of cytophilic IgG responses, its efficacy against P. falciparum infection and disease needs to be evaluated in Phase 2 studies.

High reinfection rate and treatment failures in children treated with amodiaquine for falciparum malaria in Muheza villages, Northeastern Tanzania.

In May 2003, we studied amodiaquine (AQ) efficacy in children < 5 years of age with uncomplicated falciparum malaria in Magoda and Mpapayu (with insecticide treated nets [ITNs]) and Mgome (without ITNs) in Muheza, Tanzania. The trial involved 28 days of follow-up, and data were adjusted by polymerase chain reaction (PCR) genotyping of msp1 and msp2 genes. Additionally, Pfcrt codon 72-76 polymorphisms were studied by PCR and sequence-specific oligonucleotide probe (SSOP) ELISA. In 54 cases with complete follow-up, a significant difference in late treatment failure (LTF) rates was seen (60.7% in ITN versus 88.5% in non-ITN villages, P = 0.02) before PCR correction. However, after PCR correction, 23 cases (60.5%) were confirmed as reinfections, giving a true LTF rate of 21.4% (6/28) and 34.6% (9/26) in the above settings, respectively. Frequency of Pfcrt CVIET haplotype mutation pretreatment was high (97.0%); the remaining samples were CVMNK. We conclude that AQ alone is no longer effective in the study area.

Increasing prevalence of wildtypes in the dihydrofolate reductase gene of Plasmodium falciparum in an area with high levels of sulfadoxine/pyrimethamine resistance after introduction of treated bed nets.

In Magoda and Mpapayu villages in Tanzania, we have previously found comparable high prevalence of Plasmodium falciparum resistance to sulfadoxine/pyrimethamine (S/P) in vivo and of mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes of P. falciparum responsible for resistance to S/P. In December 1998, Magoda received insecticide-treated nets (ITNs), whereas ITNs were introduced in Mpapayu in March 2001. We have studied the effect of ITNs on P. falciparum resistance genes by monitoring the prevalence of dhfr and dhps genotypes in children less than five years old living in the villages from 1998 to 2000. In 2000, after two years of bed net use, the prevalence of wild types in codon 51, 59, and 108 of dhfr increased significantly in Magoda compared with previous years. Furthermore, the prevalence of dhfr wild types was significantly higher in Magoda than in Mpapayu in 2000. The impact of ITNs on the transmission intensity seems not only to affect the overall malaria morbidity, but may even facilitate restoration of susceptibility to antimalarial drugs.

Impact of insecticide treated mosquito nets and low dose monthly diethylcarbamazine on lymphatic filariasis infection between 1999 and 2004 in two endemic communities of north-eastern Tanzania.

Lymphatic filariasis (LF) is among the poverty related neglected tropical diseases earmarked for elimination using mass drug administration (MDA) strategy. Additional use of insecticide treated mosquito nets (ITNs) might enhance elimination of LF infection. Between August 1998 and July 1999, all individuals aged 8 months from Magoda and Mpapayu villages in north-eastern Tanzania, were administered with monthly low dose diethylcarbamazine (DEC) at a dosage of 50mg in children aged < 15 years and 100mg in adults aged ≥ 15 years. ITNs were also distributed to Magoda in December 1998 and to Mpapayu in March 2001. The main objective of our study was to assess the impact of ITNs and low dose DEC on microfilaria (mf) prevalence and intensity and incidence of new mf infections. Four annual cross-sectional surveys were conducted between 1999 and 2004 in the two villages to screen for Wuchereria bancrofti microfilariae in individuals aged ≥ 1 year. Overall, 80% of the population in Magoda and 66% in Mpapayu were covered during these surveys. Results revealed a significant decrease in both mf prevalence and intensity in both villages. Furthermore, there was a steady decrease in mf incidence in Magoda; with 36.7 cases per 1000 person years in 2000 and 7.4 in 2004. In Mpapayu, the incidence initially increased from 20.8 cases in 2000 to 24.3 in 2001 and then decreased to 7.2 cases in 2004. Individuals using ITNs in Magoda had significantly lower risk of mf (OR=0.681; 95%CI: 0.496-0.934); and the risk of new infections was reduced by 58.8% (95%CI: 30.3-75.4). These results suggest that when MDA is complemented with ITNs there is high likelihood to half filariasis transmission within a shorter period than using chemotherapy alone.

Community views on health sector reform and their participation in health priority setting: case of Lushoto and Muheza districts, Tanzania.

BACKGROUND: Community participation (CP) is a key concept under 'primary health care' programmes and 'Health Sector Reform' (HSR) in many countries. However, international literature with current empirical evidence on CP in health priority setting and HSR in Tanzania is scanty. OBJECTIVES: To explore and describe community views on HSR and their participation in setting health priorities. METHODS: A multistage sampling of wards and villages was done, involving group discussions with members of households, Village Development Committees (VDCs) and Ward Development Committees (WDCs). RESULTS: Respondents at village and ward levels in both districts related HSR with a cost sharing system at public health facilities. Views on the advantages or disadvantages of HSR were mixed, most of the residents pointing out that user charges burden the poor, there is a shortage of drugs at peripheral health facilities, the performance of government health service staff and village health workers does not satisfy community needs, health insurance is promoted more than people actually benefit, VDC and WDC poorly function as compared to local community-participatory priority-setting structures. CONCLUSION: HSR may not meet the desired health needs unless more efforts are made to enhance the performance of the existing HSR structures and community knowledge and enhance trust and participation in the health sector programmes at all levels.