Efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine and prevalence of molecular markers of anti-malarial drug resistance in children in Togo in 2021.

BACKGROUND: Artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) are the currently recommended first- and second-line therapies for uncomplicated Plasmodium falciparum infections in Togo. This study assessed the efficacy of these combinations, the proportion of Day3-positive patients (D3 +), the proportion of molecular markers associated with P. falciparum resistance to anti-malarial drugs, and the variable performance of HRP2-based malaria rapid diagnostic tests (RDTs). METHODS: A single arm prospective study evaluating the efficacy of AL and DP was conducted at two sites (Kouvé and Anié) from September 2021 to January 2022. Eligible children were enrolled, randomly assigned to treatment at each site and followed up for 42 days after treatment initiation. The primary endpoint was polymerase chain reaction (PCR) adjusted adequate clinical and parasitological response (ACPR). At day 0, samples were analysed for mutations in the Pfkelch13, Pfcrt, Pfmdr-1, dhfr, dhps, and deletions in the hrp2/hrp3 genes. RESULTS: A total of 179 and 178 children were included in the AL and DP groups, respectively. After PCR correction, cure rates of patients treated with AL were 97.5% (91.4-99.7) at day 28 in Kouvé and 98.6% (92.4-100) in Anié, whereas 96.4% (CI 95%: 89.1-98.8) and 97.3% (CI 95%: 89.5-99.3) were observed at day 42 in Kouvé and Anié, respectively. The cure rates of patients treated with DP at day 42 were 98.9% (CI 95%: 92.1-99.8) in Kouvé and 100% in Anié. The proportion of patients with parasites on day 3 (D3 +) was 8.5% in AL and 2.6% in DP groups in Anié and 4.3% in AL and 2.1% DP groups in Kouvé. Of the 357 day 0 samples, 99.2% carried the Pfkelch13 wild-type allele. Two isolates carried nonsynonymous mutations not known to be associated with artemisinin partial resistance (ART-R) (A578S and A557S). Most samples carried the Pfcrt wild-type allele (97.2%). The most common Pfmdr-1 allele was the single mutant 184F (75.6%). Among dhfr/dhps mutations, the quintuple mutant haplotype N51I/C59R/S108N + 437G/540E, which is responsible for SP treatment failure in adults and children, was not detected. Single deletions in hrp2 and hrp3 genes were detected in 1/357 (0.3%) and 1/357 (0.3%), respectively. Dual hrp2/hrp3 deletions, which could affect the performances of HRP2-based RDTs, were not observed. CONCLUSION: The results of this study confirm that the AL and DP treatments are highly effective. The absence of the validated Pfkelch13 mutants in the study areas suggests the absence of ART -R, although a significant proportion of D3 + cases were found. The absence of dhfr/dhps quintuple or sextuple mutants (quintuple + 581G) supports the continued use of SP for IPTp during pregnancy and in combination with amodiaquine for seasonal malaria chemoprevention. TRIAL REGISTRATION: ACTRN12623000344695.

Effect of the COVID-19 pandemic on HIV, malaria and tuberculosis indicators in Togo: an interrupted time series analysis.

BACKGROUND: Limited data are available on the effects of the COVID-19 pandemic on health-related indicators in sub-Saharan Africa. This study aimed to estimate the effect of the COVID-19 pandemic on nine indicators of HIV, malaria and tuberculosis (TB) in Togo. METHODS: For this interrupted time series analysis, national health information system data from January 2019 to December 2021 and TB programmatic data from the first quarter of 2018 to the fourth quarter of 2022 were analysed. Nine indicators were included. We used Poisson segmented regression to estimate the immediate impact of the pandemic and per-pandemic period trends through incidence rate ratios (IRRs) with 95% CIs. RESULTS: Overall, there was a decrease in six of the nine indicators, ranging from 19.3% (IRR 0.807, 95% CI 0.682 to 0.955, p=0.024) for the hospitalisation of patients for malaria to 36.9% (IRR 0.631, 95% CI 0.457 to 0.871, p=0.013) for TB diagnosis by Mycobacterium tuberculosis Xpert immediately after the declaration of the COVID-19 pandemic. A comparison of the observed and predicted trends showed that the trend remained constant between the prepandemic and pandemic periods of COVID-19 for all malaria indicators. A significant downward monthly trend was observed in antiretroviral therapy initiation (IRR 0.909, 95% CI 0.892 to 0.926, p<0.001) and positive TB microscopy (IRR 0.919, 95% CI 0.880 to 0.960, p=0.002). CONCLUSION: HIV, malaria and TB services were generally maintained over time in Togo despite the COVID-19 pandemic. However, given the decline in levels immediately after the onset of the pandemic, there is an urgent need to improve the preparedness of the healthcare system.

Exploring malaria prediction models in Togo: a time series forecasting by health district and target group.

OBJECTIVES: Integrating malaria prediction models into malaria control strategies can help to anticipate the response to seasonal epidemics. This study aimed to explore the possibility of using routine malaria data and satellite-derived climate data to forecast malaria cases in Togo. METHODS: Generalised additive (mixed) models were developed to forecast the monthly number of malaria cases in 40 health districts and three target groups. Routinely collected malaria data from 2013 to 2016 and meteorological and vegetation data with a time lag of 1 or 2 months were used for model training, while the year 2017 was used for model testing. Two methods for selecting lagged meteorological and environmental variables were compared: a first method based on statistical approach ('SA') and a second method based on biological reasoning ('BR'). Both methods were applied to obtain a model per target group and health district and a mixed model per target group and health region with the health district as a random effect. The predictive skills of the four models were compared for each health district and target group. RESULTS: The most selected predictors in the models per district for the 'SA' method were the normalised difference vegetation index, minimum temperature and mean temperature. The 'SA' method provided the most accurate models for the training period, except for some health districts in children ≥5 years old and adults and in pregnant women. The most accurate models for the testing period varied by health district and target group, provided either by the 'SA' method or the 'BR' method. Despite the development of models with four different approaches, the number of malaria cases was inaccurately forecasted. CONCLUSIONS: These models cannot be used as such in malaria control activities in Togo. The use of finer spatial and temporal scales and non-environmental data could improve malaria prediction.

Prevalence and risk factors associated with malaria infection in children under two years of age in southern Togo prior to perennial malaria chemoprevention implementation.

BACKGROUND: Malaria remains the leading cause of mortality and morbidity in young children in sub-Saharan Africa. To prevent malaria in children living in moderate-to-high malaria transmission areas, the World Health Organization has recommended perennial malaria chemoprevention (PMC). Prior to piloting PMC implementation in southern Togo, a household survey was conducted to estimate malaria infection prevalence in children under 2 years of age (U2). METHODS: A cross-sectional community-based household survey was conducted in the Haho district in the Togo Plateaux region. A three-stage random sampling method was used to select study participants aged 10-23 months whose caretakers gave informed consent. The prevalence of Plasmodium infection, defined as a positive rapid diagnostic test (RDT), was estimated with 95% confidence interval (CI). Clinical malaria was defined as having a positive RDT plus fever (≥ 37.5 °C) or history of fever in the last 24 h. Mixed-effects logistic regression models were used to assess the child's, caretaker's, and household's factors associated with malaria infection. RESULTS: A total of 685 children were included in the survey conducted January-February in 2022 (dry season). Median age was 17 months (interquartile range: 13-21). About 80% of the children slept under a bed net the night before the interview. Malaria infection prevalence was 32.1% (95% CI 27.7-37.0) with significant area variation (cluster range: 0.0-73.3). Prevalence of clinical malaria was 15.4% (95% CI 12.2-19.2). Children whose caretakers were animist (aOR: 1.71, 95% CI 1.19-2.46) and those living in mother-headed households (aOR: 2.39, 95% CI 1.43-3.99) were more likely to have a positive RDT. Living more than 5 km away from the nearest health facility (aOR: 1.60, 95% CI 1.04-2.44) and presence of two or more under-5-years children in the household (aOR: 1.44, 95% CI 1.01-2.07) were also associated with increased risk of infection. CONCLUSION: One-third of the children U2 who participated in this survey had malaria infection, thus PMC could be a promising strategy to reduce malaria burden in young children in Plateaux region. Reinforcement of outreach services and targeting the poorest households should be prioritized to reduce the inequity in malaria prevention in children exposed to the infection.

Effectiveness of seasonal malaria chemoprevention in three regions of Togo: a population-based longitudinal study from 2013 to 2020.

BACKGROUND: In 2012, the World Health Organization (WHO) recommended seasonal malaria chemoprevention (SMC) in areas of high seasonal transmission. Though implemented since 2013, the effectiveness of SMC in Togo was never evaluated. METHODS: This study concerned routine data from 2013 to 2020 mass SMC campaigns for children under five in all health facilities of three Regions of Togo. Treatment coverage, reasons for non-treatment, and SMC-attributable adverse reactions were analysed per year and treatment round. Random effect logistic models estimated SMC effectiveness per health district, year, and treatment round. RESULTS: The overall coverage was 98% (7,971,877 doses for 8,129,668 children). Contraindication was the main reason for non-administration. Over the study period, confirmed malaria cases decreased from 11,269 (1st round of 2016) to 1395 (4th round of 2020). Only 2,398 adverse reactions were reported (prevalence: 3/10,000), but no severe Lyell syndrome or Stevens-Johnson-type skin reaction. Compared to 2016, malaria prevalence decrease was estimated at 22.6% in 2017 (p < 0.001) and 75% in 2020 (p < 0.001). SMC effectiveness ranged from 76.6% (2nd round) to 96.2% (4th round) comparison with the 1st round. CONCLUSIONS: SMC reduced significantly malaria cases among children under five. The results reassure all actors and call for effort intensification to reach the WHO goals for 2030.

The use of video job-aids to improve the quality of seasonal malaria chemoprevention delivery.

Mobile phones are increasingly used in community health programmes, but the use of video job-aids that can be displayed on smart phones has not been widely exploited. We investigated the use of video job-aids to support the delivery of seasonal malaria chemoprevention (SMC) in countries in West and Central Africa. The study was prompted by the need for training tools that could be used in a socially distanced manner during the COVID-19 pandemic. Animated videos were developed in English, French, Portuguese, Fula and Hausa, illustrating key steps for administering SMC safely, including wearing masks, washing hands, and social distancing. Through a consultative process with the national malaria programmes of countries using SMC, successive versions of the script and videos were reviewed to ensure accurate and relevant content. Online workshops were held with programme managers to plan how to use the videos in SMC staff training and supervision, and the use of the videos was evaluated in Guinea through focus groups and in-depth interviews with drug distributors and other staff involved in SMC delivery and through direct observations of SMC administration. Programme managers found the videos useful as they reinforce messages, can be viewed at any time and repeatedly, and when used during training sessions, provide a focus of discussion and support for trainers and help retain messages. Managers requested that local specificities of SMC delivery in their setting be included in tailored versions of the video for their country, and videos were required to be narrated in a variety of local languages. In Guinea, SMC drug distributors found the video covered the all the essential steps and found the video easy to understand. However, not all key messages were followed as some of the safety measures, social distancing and wearing masks, were perceived by some as creating mistrust amongst communities. Video job-aids can potentially provide an efficient means of reaching large numbers of drug distributors with guidance for safe and effective distribution of SMC. Not all distributors use android phones, but SMC programmes are increasingly providing drug distributors with android devices to track delivery, and personal ownership of smartphones in sub-Saharan Africa is growing. The use of video job-aids for community health workers to improve the quality delivery of SMC, or of other primary health care interventions, should be more widely evaluated.

Potential Emergence of Plasmodium Resistance to Artemisinin Induced by the Use of Artemisia annua for Malaria and COVID-19 Prevention in Sub-African Region.

Plasmodium resistance to antimalarial drugs is an obstacle to the elimination of malaria in endemic areas. This situation is particularly dramatic for Africa, which accounts for nearly 92% of malaria cases worldwide. Drug pressure has been identified as a key factor in the emergence of antimalarial drug resistance. Indeed, this pressure is favoured by several factors, including the use of counterfeit forms of antimalarials, inadequate prescription controls, poor adherence to treatment regimens, dosing errors, and the increasing use of other forms of unapproved antimalarials. This resistance has led to the replacement of chloroquine (CQ) by artemisinin-based combination therapies (ACTs) which are likely to become ineffective in the coming years due to the uncontrolled use of Artemisia annua in the sub-Saharan African region for malaria prevention and COVID-19. The use of Artemisia annua for the prevention of malaria and COVID-19 could be an important factor in the emergence of resistance to Artemisinin-based combination therapies.

Seasonality of confirmed malaria cases from 2008 to 2017 in Togo: a time series analysis by health district and target group.

BACKGROUND: This study aimed to assess the seasonality of confirmed malaria cases in Togo and to provide new indicators of malaria seasonality to the National Malaria Control Programme (NMCP). METHODS: Aggregated data of confirmed malaria cases were collected monthly from 2008 to 2017 by the Togo's NMCP and stratified by health district and according to three target groups: children < 5 years old, children ≥ 5 years old and adults, and pregnant women. Time series analysis was carried out for each target group and health district. Seasonal decomposition was used to assess the seasonality of confirmed malaria cases. Maximum and minimum seasonal indices, their corresponding months, and the ratio of maximum/minimum seasonal indices reflecting the importance of malaria transmission, were provided by health district and target group. RESULTS: From 2008 to 2017, 7,951,757 malaria cases were reported in Togo. Children < 5 years old, children ≥ 5 years old and adults, and pregnant women represented 37.1%, 57.7% and 5.2% of the confirmed malaria cases, respectively. The maximum seasonal indices were observed during or shortly after a rainy season and the minimum seasonal indices during the dry season between January and April in particular. In children < 5 years old, the ratio of maximum/minimum seasonal indices was higher in the north, suggesting a higher seasonal malaria transmission, than in the south of Togo. This is also observed in the other two groups but to a lesser extent. CONCLUSIONS: This study contributes to a better understanding of malaria seasonality in Togo. The indicators of malaria seasonality could allow for more accurate forecasting in malaria interventions and supply planning throughout the year.

Changes in registered malaria cases and deaths in Togo from 2008 to 2017.

OBJECTIVE: The WHO Malaria Report 2019 stated that "globally, the burden of malaria was lower than ten years ago, but, in the last few years, there has been an increase in the number of malaria cases around the world". This study reported changes in malaria cases and deaths at the Togo national level (2008-2017) and presented anti-malaria fight results and eradication chances by 2030 in Togo. METHODS: Cases and deaths were collected from medical records, monthly reports, and notes of 6000 health workers; then summarized by Region, District, year, and specific subpopulations. Estimates of annual trends of numbers of cases and deaths were obtained through generalized linear models. RESULTS: The number of cases increased by four times, whereas the population increased by 1.3 times (2008-2017). Increases affected all regions and subpopulations; the mean annual relative increases in children <5, pregnant women, and other persons ≥5 were 13%, 10%, and 14%, respectively. Death rates decreased in all Regions; the mean annual relative decreases in the subpopulations were 7%, 16%, and 6%, respectively. CONCLUSION: Case increases were associated with higher investments and better monitoring and death decreases to better prevention, diagnosis, and treatment. These trends should incite government and partners to maintain or intensify current efforts to meet the elimination goals by 2030.

Implementation of a malaria sentinel surveillance system in Togo: a pilot study.

BACKGROUND: In Togo, the National Malaria Control Programme, in collaboration with the Global Fund to Fight AIDS, Tuberculosis and Malaria, has implemented a pilot study for malaria sentinel surveillance since 2017, which consists of collecting information in real time and analysing this information for decision-making. The first 20 months of malaria morbidity and mortality trends, and malaria case management in health facilities included in the surveillance were assessed. METHODS: Since July 2017, 16 health facilities called sentinel sites, 4 hospitals and 12 peripheral care units located in 2 epidemiologically different health regions, have provided weekly data on malaria morbidity and mortality for the following 3 target groups: < 5-years-old children, ≥ 5-years-old children and adults, and pregnant women. Data from week 29 in 2017 to week 13 in 2019 were analysed. RESULTS: Each sentinel site provided complete data and the median time to data entry was 4 days. The number of confirmed malaria cases increased during the rainy seasons both in children under 5 years old and in children over 5 years old and adults. Malaria-related deaths occurred mainly in children under 5 years old and increased during the rainy seasons. The mean percentage of tested cases for malaria among suspected malaria cases was 99.0%. The mean percentage of uncomplicated malaria cases handled in accordance with national guidelines was 99.4%. The mean percentage of severe malaria cases detected in peripheral care units that were referred to a hospital was 100.0%. Rapid diagnostic tests and artemisinin-based combination therapies were out of stock several times, mainly at the beginning and end of the year. No hospital was out of stock of injectable artesunate or injectable artemether. CONCLUSIONS: These indicators showed good management of malaria cases in the sentinel sites. Real-time availability of data requires a good follow-up of data entry on the online platform. The management of input stocks and the promptness of data need to be improved to meet the objectives of this malaria sentinel surveillance system.

Potential Roles of Environmental and Socio-Economic Factors in the Distribution of Insecticide Resistance in Anopheles gambiae sensu lato (Culicidae: Diptera) Across Togo, West Africa.

Vector control strategies recommended by the World Health Organization are threatened by resistance of Anopheles mosquitoes to insecticides. Information on the distribution of resistant genotypes of malaria vectors is increasingly needed to address the problem. Ten years of published and unpublished data on malaria vector susceptibility/resistance and resistance genes have been collected across Togo. Relationships between the spatial distribution of resistance status and environmental, socio-economic, and landscape features were tested using randomization tests, and calculating Spearman rank and Pearson correlation coefficients between mosquito mortality and different gridded values. Anopheles gambiae sensu lato was resistant to DDT, pyrethroids, and the majority of carbamates and organophosphates. Three sibling species were found (i.e., An. gambiae, Anopheles coluzzii, and Anopheles arabiensis) with four resistance genes, including kdr (L1014F, L1014S, and N1575Y) and ace1 (G119S). The most frequent resistance gene was L1014F. Overall, no association was found between the susceptibility/resistance status and environmental features, suggesting that evolution of resistance may be most closely related to extreme selection from local insecticide use. Nevertheless, further research is necessary for firm conclusions about this lack of association, and the potential role of landscape characteristics such as presence of crops and percentage of tree cover.