Efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine and prevalence of molecular markers associated with resistance, Guinea: an open-label two-arm randomised controlled trial.

BACKGROUND: Anti-malarial resistance is a threat to recent gains in malaria control. This study aimed to assess the efficacy and safety of artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) in the management of uncomplicated malaria and to measure the prevalence of molecular markers of resistance of Plasmodium falciparum in sentinel sites in Maferinyah and Labé Health Districts in Guinea in 2016. METHODS: This was a two-arm randomised controlled trial of the efficacy of AL and ASAQ among children aged 6-59 months with uncomplicated Plasmodium falciparum malaria in two sites. Children were followed for 28 days to assess clinical and parasitological response. The primary outcome was the Kaplan-Meier estimate of Day 28 (D28) efficacy after correction by microsatellite-genotyping. Pre-treatment (D0) and day of failure samples were assayed for molecular markers of resistance in the pfk13 and pfmdr1 genes. RESULTS: A total of 421 participants were included with 211 participants in the Maferinyah site and 210 in Labé. No early treatment failure was observed in any study arms. However, 22 (5.3%) participants developed a late treatment failure (8 in the ASAQ arm and 14 in the AL arm), which were further classified as 2 recrudescences and 20 reinfections. The Kaplan-Meier estimate of the corrected efficacy at D28 was 100% for both AL and ASAQ in Maferinyah site and 99% (95% Confidence Interval: 97.2-100%) for ASAQ and 99% (97.1-100%) for AL in Labé. The majority of successfully analysed D0 (98%, 380/389) and all day of failure (100%, 22/22) samples were wild type for pfk13. All 9 observed pfk13 mutations were polymorphisms not associated with artemisinin resistance. The NFD haplotype was the predominant haplotype in both D0 (197/362, 54%) and day of failure samples (11/18, 61%) successfully analysed for pfmdr1. CONCLUSION: This study observed high efficacy and safety of both ASAQ and AL in Guinea, providing evidence for their continued use to treat uncomplicated malaria. Continued monitoring of ACT efficacy and safety and molecular makers of resistance in Guinea is important to detect emergence of parasite resistance and to inform evidence-based malaria treatment policies.

Prescriber practices and patient adherence to artemisinin-based combination therapy for the treatment of uncomplicated malaria in Guinea, 2016.

BACKGROUND: The World Health Organization recommends the use of artemisinin-based combination therapy (ACT) to treat uncomplicated malaria for the control of malaria across the world. There are several types of ACT used across malaria-endemic countries, yet there is little information about preferences and adherence practices regarding different types of ACT. The objective of this study was to evaluate levels of adherence to two types of ACT, artemether-lumefantrine (AL) and artesunate + amodiaquine (ASAQ), for the treatment of uncomplicated malaria among prescribers and patients in Guinea in 2016. METHODS: The study included a review of records of malaria patients and three health-facility, cross-sectional surveys. Patients diagnosed with uncomplicated malaria and prescribed ACT (n = 1830) were recruited and visited in their home after receiving the medication and administered a questionnaire regarding ACT adherence. Prescribers (n = 115) and drug dispensers (n = 43) were recruited at the same public health facilities and administered questionnaires regarding prescribing practices and opinions regarding the national treatment policies and protocols. RESULTS: According to the registry review, 35.8% of all-cause consultations were recorded as malaria. Of these, 26.6% were diagnosed clinically without documentation of laboratory confirmation. The diagnosis of uncomplicated malaria represented 64.1% of malaria cases among children under 5 years and 74.9% of those 5 years of age and older. An ACT was prescribed for 83.5% of cases of uncomplicated malaria. Among participants in the study, ACT adherence was 95.4% (95% CI 94.4, 96.3). Overall, about one in four patients (23.4%; 95% CI 21.5, 25.3) reported experiencing adverse events. While patients prescribed ASAQ were significantly more likely to report experiencing adverse effects than patients on AL (p < 0.001), given the overall high adherence, there was no evidence of a statistically significant difference in adherence between AL and ASAQ. Patients 5 years or older who reported experiencing adverse events were more likely to be non-adherent. CONCLUSION: Although there were more reported adverse events associated with ASAQ when compared with AL, both prescribers and patients were found to be mostly adherent to ACT for the treatment of malaria, regardless of ACT type.

Adherence to Ebola-specific malaria case management guidelines at health facilities in Guinea during the West African Ebola epidemic.

BACKGROUND: Malaria case management in the context of the 2014-2016 West African Ebola virus disease (EVD) epidemic was complicated by a similar initial clinical presentation of the two diseases. In September 2014, the World Health Organization (WHO) released recommendations titled, "Guidance on temporary malaria control measures in Ebola-affected countries", which aimed at reducing the risk of EVD transmission and improving malaria outcomes. This guidance recommended malaria diagnostic testing of fever cases only if adequate personal protective equipment (PPE) was available, defined as examination gloves, face shield, disposable gown, boots, and head cover; otherwise presumptive anti-malarial treatment was recommended. The extent to which health workers adhered to these guidelines in affected countries has not been assessed. METHODS: A cross-sectional survey was conducted in 118 health units in Guinea in November 2014 to produce a representative and probabilistic sample of health facilities and patients. Adherence to the EVD-specific malaria case management guidelines during the height of the EVD epidemic was assessed. Associations between case management practices and possible determinants were calculated using multivariate logistic regression, controlling for expected confounders and the complex sample design. RESULTS: Most (78%) facilities reported availability of examination gloves, but adequate PPE was available at only 27% of facilities. Only 28% of febrile patients received correct malaria case management per the WHO temporary malaria case management guidelines. The most common error was diagnostic testing in the absence of adequate PPE (45% of febrile patients), followed by no presumptive treatment in the absence of adequate PPE (14%). Having had a report of an EVD case at a health facility and health worker-reported participation in EVD-specific malaria trainings were associated with lower odds of diagnostic testing and higher odds of presumptive treatment. CONCLUSIONS: Adherence to guidance on malaria case management in EVD-affected countries was low at the height of the EVD epidemic in Guinea, and there was substantial malaria diagnostic testing in the absence of adequate PPE, which could have contributed to increased EVD transmission in the healthcare setting. Conversely, low presumptive treatment when diagnostic tests were not performed may have led to additional morbidity and mortality among malaria positive patients. National malaria control programs may consider preparing contingency plans for future implementation of temporary changes to malaria case management guidelines to facilitate uptake by health workers. Additional training on standard and transmission-based precautions should help health workers understand how to protect themselves in the face of emerging and unknown pathogens.

Evaluating the quality of routinely reported data on malaria commodity stocks in Guinea, 2014-2016.

BACKGROUND: Ensuring malaria commodity availability at health facilities is a cornerstone of malaria control. Since 2013, the Guinea National Malaria Control Programme has been routinely collecting data on stock levels of key malaria commodities through a monthly routine malaria information system (RMIS). In parallel, biannual end-user verification (EUV) surveys have also assessed malaria commodity availability at a subset of health facilities, potentially representing a duplication of efforts. METHODS: Data on 12 malaria commodity stock levels verified during four EUV surveys conducted between 2014 and 2016 was compared to data for the corresponding months submitted by the same health facilities through the RMIS. The sensitivity and specificity of the RMIS in detecting stock-outs was calculated, as was the percent difference between average stock levels reported through the two systems. RESULTS: Of the 171 health facilities visited during the four EUV surveys, 129 (75%) had data available in the RMIS. Of 351 commodity stock-outs observed during the EUV in the sampled reporting health facilities, 256 (73%) were also signaled through the corresponding RMIS reports. When the presence of malaria commodity stocks was confirmed during the EUV surveys, the RMIS also reported available stock 87% (677/775) of the time. For all commodities, the median percent difference in average stock levels between the EUV and RMIS was 4% (interquartile range - 7 to 27%). CONCLUSION: The concordance between stock levels reported through the RMIS and those verified during the EUV visits provides certain evidence that RMIS data can inform quantification and procurement decisions. However, lower than acceptable rates of reporting and incomplete detection of stock-outs from facilities that do report suggest that further systems strengthening is needed to improve RMIS reporting completeness and data quality.

Encouraging impact following 2.5 years of reinforced malaria control interventions in a hyperendemic region of the Republic of Guinea.

BACKGROUND: Malaria is one of the principal causes of morbidity and mortality in the Republic of Guinea, particularly in the highly endemic regions. To assist in malaria control efforts, a multi-component malaria control intervention was implemented in the hyperendemic region of Guéckédou Prefecture. The coverage of the intervention and its impact on malaria parasite prevalence were assessed. METHODS: Five cross-sectional surveys using cluster-based sampling and stratified by area were conducted from 2011 to 2013 in three sous-préfectures of Guéckédou Préfecture that received the intervention: Guéckédou City, Tékoulo and Guendembou in addition to one comparison sous-préfecture that did not receive the intervention, Koundou. Surveys were repeated every 6 months, corresponding with the dry and rainy seasons. Rapid diagnostic tests (RDT) were used to diagnose malaria infection. In each selected household, bed net use and ownership were assessed. RESULTS: A total of 35,123 individuals participated in the surveys. Malaria parasite prevalence declined in all intervention sous-préfectures from 2011 to 2013 (56.4-45.9 % in Guéckédou City, 64.9-54.1 % in Tékoulo and 69.4-56.9 % in Guendembou) while increasing in the comparison sous-préfecture (64.5-69 %). It was consistently higher in children 5-14 years of age followed by those 1-59 months and ≥15 years. Indicators of intervention coverage, the proportion of households reporting ownership of at least one bed net and the proportion of survey participants with fever who received treatment from a health facility or community health worker also increased significantly in the intervention areas. CONCLUSIONS: Implementation of the multi-component malaria control intervention significantly reduced the prevalence of malaria in the sous-préfectures of intervention while also increasing the coverage of bed nets. However, malaria prevalence remains unacceptably high and disproportionately affects children <15 years of age. In such situations additional vector control interventions and age specific interventions should be considered.

Malaria trends in districts that were targeted and not-targeted for seasonal malaria chemoprevention in children under 5 years of age in Guinea, 2014-2021.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a main intervention to prevent and reduce childhood malaria. Since 2015, Guinea has implemented SMC targeting children aged 3-59 months (CU5) in districts with high and seasonal malaria transmission. OBJECTIVE: We assessed the programmatic impact of SMC in Guinea's context of scaled up malaria intervention programming by comparing malaria-related outcomes in 14 districts that had or had not been targeted for SMC. METHODS: Using routine health management information system data, we compared the district-level monthly test positivity rate (TPR) and monthly uncomplicated and severe malaria incidence for the whole population and disaggregated age groups (<5 years and ≥5 years of age). Changes in malaria indicators through time were analysed by calculating the district-level compound annual growth rate (CAGR) from 2014 to 2021; we used statistical analyses to describe trends in tested clinical cases, TPR, uncomplicated malaria incidence and severe malaria incidence. RESULTS: The CAGR of TPR of all age groups was statistically lower in SMC (median=-7.8%) compared with non-SMC (median=-3.0%) districts. Similarly, the CAGR in uncomplicated malaria incidence was significantly lower in SMC (median=1.8%) compared with non-SMC (median=11.5%) districts. For both TPR and uncomplicated malaria incidence, the observed difference was also significant when age disaggregated. The CAGR of severe malaria incidence showed that all age groups experienced a decline in severe malaria in both SMC and non-SMC districts. However, this decline was significantly higher in SMC (median=-22.3%) than in non-SMC (median=-5.1%) districts for the entire population, as well as both CU5 and people over 5 years of age. CONCLUSION: Even in an operational programming context, adding SMC to the malaria intervention package yields a positive epidemiological impact and results in a greater reduction in TPR, as well as the incidence of uncomplicated and severe malaria in CU5.

Using Short Message Service Alerts to Increase Antenatal Care and Malaria Prevention: Findings from Implementation Research Pilot in Guinea.

Intermittent preventive treatment with sulfadoxine-pyrimethamine (SP) is recommended to prevent malaria in pregnancy. Treatment coverage, particularly for three or more doses, is dependent on pregnant women attending antenatal care (ANC) services as scheduled. The StopPalu project pilot tested short message services (SMSs) to remind women of upcoming ANC visits in the Conakry and Kindia regions of Guinea. Health facilities were selected as pilot and comparison facilities. All women who attended an initial ANC visit at a selected facility during the pilot period and had access to a mobile telephone were enrolled. The pilot group was sent an SMS before each appointment. Percentage of attendance and SP distribution were calculated. A log-binomial regression model determined odds ratios. Pregnant women receiving SMS were 48 times more likely to attend all visits and were 12 times more likely to receive all SP doses during pregnancy.

Quality of Malaria Case Management and Reporting at Public Health Facilities in Six Health Districts in Guinea, 2018.

Data on fever and malaria cases reported by health facilities are used for tracking incidence and quantification of malaria commodity needs in Guinea. Periodic assessments of the quality of malaria case management and routine data are a critical activity for the malaria program. In May-June 2018, survey teams visited 126 health facilities in six health districts purposefully selected to represent a spectrum (Stratum 1-high, Stratum 2-intermediate, and Stratum 3-low) of perceived quality of case management and reporting, as assessed from an a priori analysis of routine data. Surveyors performed exit interviews with 939 outpatients and compared results with registry data for interviewed patients. Availability of rapid diagnostic tests (RDTs) and artemisinin-based combination therapies (ACTs) was 100% in Strata 1 and 2, compared with 82% (95% CI: 63-92%) for RDTs and 86% (68-95%) for any formulation of ACT in Stratum 3. Correct case management for suspect malaria cases was 85% in both Stratum 1 (95% CI: 78-90%) and Stratum 2 (79-89%), but only 52% (37-67%) in Stratum 3. Concordance between exit interviews and registry entries for key malaria indicators was significantly higher in Strata 1 and 2 than in Stratum 3. Both adherence to national guidelines for testing and treatment and data quality were high in Strata 1 and 2, but substandard in Stratum 3. The survey results reflected the trends seen in the routine data, suggesting that analysis of routine data can identify areas requiring more attention to improve malaria case management and reporting.

How Far Are We from Reaching Universal Malaria Testing of All Fever Cases?

Universal malaria diagnostic testing of all fever cases is the first step in correct malaria case management. However, monitoring adherence to universal testing is complicated by unreliable recording and reporting of the true number of fever cases. We searched the literature to obtain gold-standard estimates for the proportion of patients attending outpatient clinics in sub-Saharan Africa with malarial and non-malarial febrile illness. To correct for differences in malaria transmission, we calculated the proportion of patients with fever after excluding confirmed malaria cases. Next, we analyzed routine data from Guinea and Senegal to calculate the proportion of outpatients tested after exclusion of confirmed malaria cases from the numerator and denominator. From 12 health facility surveys in sub-Saharan Africa with gold-standard fever screening, the median proportion of febrile illness among outpatients after exclusion of confirmed malaria fevers was 57% (range: 46-80%). Analysis of routine data after exclusion of confirmed malaria cases demonstrated much lower testing proportions of 23% (Guinea) and 13% (Senegal). There was substantial spatial and temporal heterogeneity in this testing proportion, and testing in Senegal was correlated with malaria season. Given the evidence from gold-standard surveys that at least 50% of non-malaria consultations in sub-Saharan Africa are for febrile illness, it appears that a substantial proportion of patients with fever are not tested for malaria in health facilities when considering routine data. Tracking the proportion of patients tested for malaria after exclusion of the confirmed malaria cases could allow programs to make inferences about malaria testing practices using routine data.

Rapid Epidemiological and Entomological Survey for Validation of Reported Indicators and Characterization of Local Malaria Transmission in Guinea, 2017.

To confirm and investigate possible explanations for unusual trends in malaria indicators, a protocol for rapid, focal assessment of malaria transmission and control interventions was piloted in N'Zérékoré and Macenta Prefectures, which each reported surprisingly low incidence of malaria during the peak transmission months during 2017 in holoendemic Forested Guinea. In each prefecture, epidemiological and entomological cross-sectional surveys were conducted in two sub-prefectures reporting high incidence and one sub-prefecture reporting low incidence. Investigators visited six health facilities and 356 households, tested 476 children, performed 14 larval breeding site transects, and conducted 12 nights of human landing catches during the 2-week investigation. Rapid diagnostic test positivity in the community sample of children under five ranged from 23% to 68% by subprefecture. Only 38% of persons with fever reported seeking care in the public health sector; underutilization was confirmed by verification of health facility and community healthcare worker (CHW) registries. High numbers of Anopheles mosquitoes were collected in human landing collections in N'Zérékoré (38 per night in combined indoor and outdoor collections) and Macenta (87). Most of the detected breeding sites positive for Anopheles larvae (83%) were shallow roadside puddles. In the investigated prefectures, malaria rates remain high and the low reported incidence likely reflects low utilization of the public health-care sector. Strengthening the CHW program to rapidly identify and treat malaria cases and elimination of roadside puddles as part of routine cleanup campaigns should be considered. Systematic joint epidemiological/entomological investigations in areas reporting anomalous signals in routine data can allow control programs to respond with tailored local interventions.

Effect of the Ebola-virus-disease epidemic on malaria case management in Guinea, 2014: a cross-sectional survey of health facilities.

BACKGROUND: The ongoing west Africa Ebola-virus-disease epidemic has disrupted the entire health-care system in affected countries. Because of the overlap of symptoms of Ebola virus disease and malaria, the care delivery of malaria is particularly sensitive to the indirect effects of the current Ebola-virus-disease epidemic. We therefore characterise malaria case management in the context of the Ebola-virus-disease epidemic and document the effect of the Ebola-virus-disease epidemic on malaria case management. METHODS: We did a cross-sectional survey of public health facilities in Guinea in December, 2014. We selected the four prefectures most affected by Ebola virus disease and selected four randomly from prefectures without any reported cases of the disease. 60 health facilities were sampled in Ebola-affected and 60 in Ebola-unaffected prefectures. Study teams abstracted malaria case management indicators from registers for January to November for 2013 and 2014 and interviewed health-care workers. Nationwide weekly surveillance data for suspect malaria cases reported between 2011 and 2014 were analysed independently. Data for malaria indicators in 2014 were compared with previous years. FINDINGS: We noted substantial reductions in all-cause outpatient visits (by 23 103 [11%] of 214 899), cases of fever (by 20249 [15%] of 131 330), and patients treated with oral (by 22 655 [24%] of 94 785) and injectable (by 5219 [30%] of 17 684) antimalarial drugs in surveyed health facilities. In Ebola-affected prefectures, 73 of 98 interviewed community health workers were operational (74%, 95% CI 65-83) and 35 of 73 were actively treating malaria cases (48%, 36-60) compared with 106 of 112 (95%, 89-98) and 102 of 106 (96%, 91-99), respectively, in Ebola-unaffected prefectures. Nationwide, the Ebola-virus-disease epidemic was estimated to have resulted in 74 000 (71 000-77 000) fewer malaria cases seen at health facilities in 2014. INTERPRETATION: The reduction in the delivery of malaria care because of the Ebola-virus-disease epidemic threatens malaria control in Guinea. Untreated and inappropriately treated malaria cases lead to excess malaria mortality and more fever cases in the community, impeding the Ebola-virus-disease response. FUNDING: Global Fund to Fight AIDS, Tuberculosis and Malaria, and President's Malaria Initiative.