The landscape of drug resistance in Plasmodium falciparum malaria in the Democratic Republic of Congo: a mapping systematic review.

CONTEXT: The Democratic Republic of Congo (DRC), one of the most malaria-affected countries worldwide, is a potential hub for global drug-resistant malaria. This study aimed at summarizing and mapping surveys of malaria parasites carrying molecular markers of drug-resistance across the country. METHODS: A systematic mapping review was carried out before July 2023 by searching for relevant articles through seven databases (PubMed, Embase, Scopus, African Journal Online, African Index Medicus, Bioline and Web of Science). RESULTS: We identified 1541 primary studies of which 29 fulfilled inclusion criteria and provided information related to 6385 Plasmodium falciparum clinical isolates (collected from 2000 to 2020). We noted the PfCRT K76T mutation encoding for chloroquine-resistance in median 32.1% [interquartile interval, IQR: 45.2] of analyzed malaria parasites. The proportion of parasites carrying this mutation decreased overtime, but wide geographic variations persisted. A single isolate had encoded the PfK13 R561H substitution that is invoked in artemisinin-resistance emergence in the Great Lakes region of Africa. Parasites carrying various mutations linked to resistance to the sulfadoxine-pyrimethamine combination were widespread and reflected a moderate resistance profile (PfDHPS A437G: 99.5% [IQR: 3.9]; PfDHPS K540E: 38.9% [IQR: 47.7]) with median 13.1% [IQR: 10.3] of them being quintuple IRN-GE mutants (i.e., parasites carrying the PfDHFR N51I-C59R-S108N and PfDHPS A437G-K540E mutations). These quintuple mutants tended to prevail in eastern regions of the country. Among circulating parasites, we did not record any parasites harboring mutations related to mefloquine-resistance, but we could suspect those with decreased susceptibility to quinine, amodiaquine, and lumefantrine based on corresponding molecular surrogates. CONCLUSIONS: Drug resistance poses a serious threat to existing malaria therapies and chemoprevention options in the DRC. This review provides a baseline for monitoring public health efforts as well as evidence for decision-making in support of national malaria policies and for implementing regionally tailored control measures across the country.

A roadmap for the digital management of long-lasting insecticide-treated mosquito nets (LLINs) distribution campaigns in the Democratic Republic of Congo.

The use of the long-lasting insecticide-treated mosquito net (LLIN) is one of the basic interventions recommended by the Global technical strategy for Malaria 2016-2030. Since the start of the LLIN distribution campaigns in 2006 in Democratic Republic of Congo (DRC), it was based on paper tools leading to poor quality data. The first digital campaigns date back to 2014 through "Interchurch medical assistance" (IMA), which used the ODK collect application for recording household count data and LLIN distribution data. In 2020 "Soins de santé primaire en milieu Rurale" (SANRU) developed both household registration and LLIN distribution data recording forms as well as additional modules for supervision, monitoring and training. This article briefly describes the status of the implementation process of this digital-based management of LIIN mass distribution. During the first half of 2020, a roadmap was developed between Sanru and the Global fund to fight Tuberculosis, AIDS and Malaria (GFTAM) on the objectives of digitization, the data to be digitized, and the timelines for implementing the changes. In the last quarter of 2021, an internal Sanru team composed of some members of its technical management, and staff in charge of the digitization of LLIN mass distribution campaign data participated in a document review of the deliverables in comparison with the roadmap and in group discussions. For recording household enumeration data and distribution data, forms configured on smartphones allow data recording and uploading without going through manual calculations and previously necessary transcriptions with management based on paper tools, thus removing sources of errors. Online data delivery and automated production of dashboards allow real-time sharing of information to all stakeholders and shorten data validation times. Feedback to actors in the field is possible thanks to access to information and maps generated on the basis of geolocation data from households. ODK forms for supervision and monitoring have been put in place to ensure that these activities are effectively deployed in the field in accordance with the standards set by geolocating the actors and using the data transmitted online for interactive feedback. The next step is to develop a material flow management module to improve the traceability of inputs.

Digitalized long-lasting insecticidal nets mass distribution campaign in the context of Covid-19 pandemic in Kongo Central, Democratic Republic of Congo: challenges and lessons learned.

BACKGROUND: The Democratic Republic of the Congo (DRC) organized a first mass distribution campaign of long-lasting insecticidal nets (LLINs) with digitalized data management with coordinated support from the Ministry of Health (MOH) and Santé Pour Tous En Milieu Rural-an 'Association sans but lucratif' (SANRU Asbl), in the context of the Covid-19 pandemic in Kongo Central province. This article describes the planning and implementation process of this campaign as well as the challenges and lessons learned. METHODS: The planning and implementation process was performed in line with the standard guidance issued by the National Malaria Control Programme (NMCP) following the start of Covid-19. The changes and adaptations put in place as well as the challenges encountered are described. RESULTS: A total of 5,629,211 people were registered (7.7% above projection) in 1,065,537 households (6.2% below projection) giving an average of 5.3 people per household. Of a total of 3,062,850 LLINs ordered, 2,886,096 were distributed to households (94%). Out of 11,070 villages and 3,947 teams planned, 91.7% of villages were reached and 93% of teams were established. CONCLUSION: The revision of standards of campaign implementation during Covid-19, as well as effective coordination supported by real-time decision-making through digital data management, have been factors in the success of this campaign. Maintaining this momentum is essential to ensure the continuity of malaria prevention services for the population.

Therapeutic Efficacy of Artemisinin-Based Combination Therapies in Democratic Republic of the Congo and Investigation of Molecular Markers of Antimalarial Resistance.

Routine assessment of the efficacy of artemisinin-based combination therapies (ACTs) is critical for the early detection of antimalarial resistance. We evaluated the efficacy of ACTs recommended for treatment of uncomplicated malaria in five sites in Democratic Republic of the Congo (DRC): artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ), and dihydroartemisinin-piperaquine (DP). Children aged 6-59 months with confirmed Plasmodium falciparum malaria were treated with one of the three ACTs and monitored. The primary endpoints were uncorrected and polymerase chain reaction (PCR)-corrected 28-day (AL and ASAQ) or 42-day (DP) cumulative efficacy. Molecular markers of resistance were investigated. Across the sites, uncorrected efficacy estimates ranged from 63% to 88% for AL, 73% to 100% for ASAQ, and 56% to 91% for DP. PCR-corrected efficacy estimates ranged from 86% to 98% for AL, 91% to 100% for ASAQ, and 84% to 100% for DP. No pfk13 mutations previously found to be associated with ACT resistance were observed. Statistically significant associations were found between certain pfmdr1 and pfcrt genotypes and treatment outcome. There is evidence of efficacy below the 90% cutoff recommended by WHO to consider a change in first-line treatment recommendations of two ACTs in one site not far from a monitoring site in Angola that has shown similar reduced efficacy for AL. Confirmation of these findings in future therapeutic efficacy monitoring in DRC is warranted.

The epidemiology of Plasmodium vivax among adults in the Democratic Republic of the Congo.

Reports of P. vivax infections among Duffy-negative hosts have accumulated throughout sub-Saharan Africa. Despite this growing body of evidence, no nationally representative epidemiological surveys of P. vivax in sub-Saharan Africa have been performed. To overcome this gap in knowledge, we screened over 17,000 adults in the Democratic Republic of the Congo (DRC) for P. vivax using samples from the 2013-2014 Demographic Health Survey. Overall, we found a 2.97% (95% CI: 2.28%, 3.65%) prevalence of P. vivax infections across the DRC. Infections were associated with few risk-factors and demonstrated a relatively flat distribution of prevalence across space with focal regions of relatively higher prevalence in the north and northeast. Mitochondrial genomes suggested that DRC P. vivax were distinct from circulating non-human ape strains and an ancestral European P. vivax strain, and instead may be part of a separate contemporary clade. Our findings suggest P. vivax is diffusely spread across the DRC at a low prevalence, which may be associated with long-term carriage of low parasitemia, frequent relapses, or a general pool of infections with limited forward propagation.

Care-seeking behaviour and socio-economic burden associated with uncomplicated malaria in the Democratic Republic of Congo.

BACKGROUND: This study aimed to estimate the socio-economic costs of uncomplicated malaria and to explore health care-seeking behaviours that are likely to influence these costs in the Democratic Republic of Congo (DRC), a country ranked worldwide as the second most affected by malaria. METHODS: In 2017, a cross-sectional survey included patients with uncomplicated malaria in 64 healthcare facilities from 10 sentinel sites of the National Malaria Control Programme (NMCP) in the DRC. A standard questionnaire was used to assess health care-seeking behaviours of patients. Health-related quality of life (HRQL) and disutility weights (DW) of illness were evaluated by using the EuroQol Group's descriptive system (EQ-5D-3L) and its visual analogue scale (EQ VAS). Malaria costs were estimated from a patient's perspective. Probabilistic sensitivity analyses (PSA) evaluated the uncertainty around the cost estimates. Generalized regression models were fitted to assess the effect of potential predictive factors on the time lost and the DW during illness. RESULTS: In total, 1080 patients (age: 13.1 ± 14 years; M/F ratio: 1.1) were included. The average total costs amounted to US$ 36.3 [95% CI 35.5-37.2] per malaria episode, including US$ 16.7 [95% CI 16.3-17.1] as direct costs and US$ 19.6 [95% CI 18.9-20.3] indirect costs. During care seeking, economically active patients and their relatives lost respectively 3.3 ± 1.8 and 3.4 ± 2.1 working days. This time loss occurred mostly at the pre-hospital stage and was the parameter associated the most with the uncertainty around malaria cost estimates. Patients self-rated an average 0.36 ± 0.2 DW and an average 0.62 ± 0.3 EQ-5D index score per episode. A lack of health insurance coverage (896 out of 1080; 82.9%) incurred substantially higher costs, lower quality of life, and heavier DW while leading to longer time lost during illness. Residing in rural areas incurred a disproportionally higher socioeconomic burden of uncomplicated malaria with longer time lost due to illness and limited access to health insurance mechanisms. CONCLUSION: Uncomplicated malaria is associated with high economic costs of care in the DRC. Efforts to reduce the cost-of-illness should target time lost at the pre-hospital stage and social disparities in the population, while reinforcing measures for malaria control in the country.

Analysis of false-negative rapid diagnostic tests for symptomatic malaria in the Democratic Republic of the Congo.

The majority of Plasmodium falciparum malaria diagnoses in Africa are made using rapid diagnostic tests (RDTs) that detect histidine-rich protein 2. Increasing reports of false-negative RDT results due to parasites with deletions of the pfhrp2 and/or pfhrp3 genes (pfhrp2/3) raise concern about existing malaria diagnostic strategies. We previously identified pfhrp2-negative parasites among asymptomatic children in the Democratic Republic of the Congo (DRC), but their impact on diagnosis of symptomatic malaria is unknown. We performed a cross-sectional study of false-negative RDTs in symptomatic subjects in 2017. Parasites were characterized by microscopy; RDT; pfhrp2/3 genotyping and species-specific PCR assays; a bead-based immunoassay for Plasmodium antigens; and/or whole-genome sequencing. Among 3627 symptomatic subjects, 427 (11.8%) had RDT-/microscopy + results. Parasites from eight (0.2%) samples were initially classified as putative pfhrp2/3 deletions by PCR, but antigen testing and whole-genome sequencing confirmed the presence of intact genes. 56.8% of subjects had PCR-confirmed malaria. Non-falciparum co-infection with P. falciparum was common (13.2%). Agreement between PCR and HRP2-based RDTs was satisfactory (Cohen's kappa = 0.66) and superior to microscopy (0.33). Symptomatic malaria due to pfhrp2/3-deleted P. falciparum was not observed. Ongoing HRP2-based RDT use is appropriate for the detection of falciparum malaria in the DRC.

Efficacy and safety of malarial prophylaxis with mefloquine during pregnancy in Kisangani, Democratic Republic of Congo: A randomized clinical trial.

AIMS: Kisangani is an area with intense malaria transmission and sulfadoxine-pyrimethamine resistance. Alternative antimalaria prophylaxis medication and protocols are needed, particularly with pregnant individuals. In this study, we compare the tolerance and effectiveness of mefloquine regimen as a split dose with a meal vs. sulfadoxine-pyrimethamine for the intermittent preventive treatment in pregnant individuals in Kisangani. METHODS: This study was conducted from 15 May to 30 November 2019 as a single-blind, randomized clinical trial comparing 2 regimens of intermittent preventive treatment during pregnancy. The first regimen consisted of 4 doses of sulfadoxine-pyrimethamine, and the second of 2 doses of mefloquine taken as a split dose with meal. RESULTS: The occurrence of major or minor side-effects among patients treated with mefloquine and those treated with sulfadoxine-pyrimethamine were not statistically significant (major side effects: Fisher exact = 0.5014; minor side effects: P = .0961). Intermittent preventive treatment using mefloquine significantly reduced the risk of placental malaria (risk ratio [RR]: 0.4315, 95% confidence interval [CI]: 0.2201-0.8460), maternal peripheral parasitaemia (RR: 0.4397, 95% CI: 0.2377-0.8132) and low birth weight (RR: 0.4708, 95% CI: 0.2455-0.9029). CONCLUSION: Splitting dose and intake with a meal increased mefloquine tolerability while keeping its efficacy higher compared to sulfadoxine-pyrimethamine. Intermittent preventive treatment during pregnancy using mefloquine reduces the risk of placental malaria, maternal peripheral parasitaemia and low birth weight, compared to sulfadoxine-pyrimethamine. Thus, mefloquine is a good alternative to intermittent preventive treatment in pregnancy.

Performance evaluation of a prototype rapid diagnostic test for combined detection of gambiense human African trypanosomiasis and malaria.

BACKGROUND: Malaria is endemic in all regions where gambiense or rhodesiense human African trypanosomiasis (HAT) is reported, and both diseases have similarities in their symptomatology. A combined test could be useful for both diseases and would facilitate integration of the screening for gambiense HAT (gHAT) and malaria diagnosis. This study aimed to evaluate a combined prototype rapid diagnostic test (RDT) for gHAT and malaria. METHODS: Blood samples were collected in the Democratic Republic of the Congo and in Uganda to evaluate the performance of a prototype HAT/Malaria Combined RDT in comparison to an individual malaria RDT based on Plasmodium falciparum (P.f.) Histidine Rich Protein II (HRP-II or HRP2) antigen (SD BIOLINE Malaria Ag P.f. RDT) for malaria detection and an individual gHAT RDT based on recombinant antigens, the SD BIOLINE HAT 2.0 RDT for HAT screening. Due to the current low prevalence of gHAT in endemic regions, the set of blood samples that were collected was used to evaluate the specificity of the RDTs for gHAT, and additional archived plasma samples were used to complete the evaluation of the HAT/Malaria Combined RDT in comparison to the HAT 2.0 RDT. RESULTS: Frozen whole blood samples from a total of 486 malaria cases and 239 non-malaria controls, as well as archived plasma samples from 246 gHAT positive and 246 gHAT negative individuals were tested. For malaria, the sensitivity and specificity of the malaria band in the HAT/Malaria Combined RDT were 96.9% (95% CI: 95.0-98.3) and 97.1% (95% CI: 94.1-98.8) respectively. The sensitivity and specificity of the SD BIOLINE malaria Ag P.f. RDT were 97.3% (95% CI: 95.5-98.6) and 97.1% (95% CI: 94.1-98.8) respectively. For gHAT, using archived plasma samples, the sensitivity and specificity were respectively 89% (95% CI: 84.4-92.6) and 93.5% (95% CI: 89.7-96.2) with the HAT/Malaria Combined RDT, and 88.2% (95% CI: 83.5-92) and 94.7% (95% CI: 91.1-97.2) with the HAT 2.0 RDT. Using the whole blood samples that were collected during the study, the specificity of the HAT/Malaria Combined RDT for gHAT was 95.8% (95% CI: 94.3-97.0). CONCLUSION: The HAT/Malaria Combined prototype RDT was as accurate as the individual malaria or gHAT RDTs. The HAT/Malaria Combined prototype RDT is therefore suitable for both malaria diagnosis and gHAT screening. However, there is a need to assess its accuracy using fresh samples in prospective clinical trials.

Prevalence of Congenital Malaria in Kisangani, A Stable Malaria Transmission Area in Democratic Republic of the Congo.

Background: Gestational malaria is a major public health problem. It produces fetal complications such as low birth weight, perinatal mortality, and congenital malaria. The present study is aimed at determining the prevalence of congenital malaria and its neonatal complications in the city of Kisangani. Methods: We conducted a cross-sectional study in Kisangani from 1 January to 30 September 2018. Our study population was composed of 1248 newborns born in our study sites, during the period of our study. Just after their birth, we performed the thick drop smear in the placental print and in umbilical blood smear. Results: The prevalence of congenital malaria was 13.98%; 69.23% of newborns who contracted congenital malaria were from 18- to 34-year-old mothers, 53.85% from primiparous mothers, 92.31% from mothers who took intermittent preventive treatment in pregnancy with Sulfadoxine-Pyrimethamine, all (100%) from mothers using the insecticide-treated mosquito nets and 7.69% from HIV-positive mothers. Low birth weight and perinatal mortality were recorded in 76.92% and 7.69% of congenital malaria cases, respectively. Intermittent preventive treatment in pregnancy with Sulfadoxine-Pyrimethamine had no effect on congenital malaria (FE = 0.5218; OR: 0.8, 95% CI: 0.1651-3.8769) and on low birth weight (FE = 0.3675; OR: 1.2308, 95% CI: 0.0037-0.1464); however, it seemed to have protective effect against perinatal mortality (FE = 0.0001; OR: 0.0233, 95% CI: 0.0037-0.1464). Conclusion: Congenital malaria remains a major problem in stable malaria transmission area like Kisangani, and it is grafted by major perinatal complications, particularly low birth weight and perinatal mortality. We recommend an extended study to clarify the relationship between the outcome of pregnancy and the intermittent preventive treatment in pregnancy with Sulfadoxine-Pyrimethamine.

Molecular surveillance of anti-malarial drug resistance in Democratic Republic of Congo: high variability of chloroquinoresistance and lack of amodiaquinoresistance.

BACKGROUND: The loss of chloroquine (CQ) effectiveness has led to its withdrawal from national policies as a first-line treatment for uncomplicated malaria in several endemic countries, such as the Democratic Republic of Congo (DRC). The K76T mutation on the pfcrt gene has been identified as a marker of CQ resistance and the SVMNT haplotype in codons 72-76 on the same gene has been associated with resistance to amodiaquine (AQ). In the DRC, the prevalence of K76T has decreased from 100% in 2000 to 63.9% in 2014. The purpose of this study was to determine the prevalence of K76T mutations in circulating strains of Plasmodium falciparum, 16 years after CQ withdrawal in the DRC and to investigate the presence of the SVMNT haplotype. METHODS: In 2017, ten geographical sites across the DRC were selected. Dried blood samples were collected from patients attending health centres. Malaria was first detected by a rapid diagnostic test (RDT) available on site (SD Bioline Malaria Ag Pf or CareStart Malaria Pf) or thick blood smear and then confirmed by a P. falciparum species-specific real-time PCR assay. A pfcrt gene segment containing a fragment that encodes amino acids at positions 72-76 was amplified by conventional PCR before sequencing. RESULTS: A total of 1070 patients were enrolled. Of the 806 PCR-confirmed P. falciparum positive samples, 764 were successfully sequenced. The K76T mutation was detected in 218 samples (28.5%; 95% CI 25.4%-31.9%), mainly (96%) with the CVIET haplotype. Prevalence of CQ resistance marker was unequally distributed across the country, ranging from 1.5% in Fungurume to 89.5% in Katana. The SVMNT haplotype, related to AQ resistance, was not detected. CONCLUSION: Overall, the frequency of the P. falciparum CQ resistance marker has decreased significantly and no resistance marker to AQ was detected in the DRC in 2017. However, the between regions variability of CQ resistance remains high in the country. Further studies are needed for continuous monitoring of the CQ resistance level for its prospective re-use in malaria management. The absence of the AQ resistance marker is in line with the use of this drug in the current DRC malaria treatment policy.

Predictors of AIDS-related death among adult HIV-infected inpatients in Kisangani, the Democratic Republic of Congo.

INTRODUCTION: Human Immunodeficiency Virus (HIV) infection continues to be a major public health concern in sub-Saharan Africa. We aimed to evaluate potential factors associated with AIDS-related death among adult HIV-infected inpatients in Kisangani, the Democratic Republic of the Congo (DRC). METHODS: this is a hospital-based retrospective, observational analysis carried out between 1st January 2019 and 31st March 2020 among inpatients HIV, at 12 facilities integrating the HIV prevention and care packages in Kisangani. Factors associated with AIDS-related death were analyzed using the logistic regression models. RESULTS: a total of 347 HIV-infected inpatients were included. Among those, the rate of AIDS-related death was 25.1% (95% CI: 20.8-29.9). The rates of AIDS-related death were lower among patients with a university education (aOR: 0.03 [95% CI: 0.00-1.0]) and higher among patients in WHO clinical stage 4 (aOR: 15.4 [6.8-27.8]), patients with poor highly active antiretroviral therapy (HAART) observance (aOR: 14.5 [2.3-40.4), and patients suffering from opportunistic infections (aOR: 9.3 [95% CI: 3.4-25.1]), including cryptococcal meningitis (aOR: 27 [95% CI: 6.0-125.7]) and viral infections associated with zona and Kaposi sarcoma (aOR: 4.8 [95% CI: 2.2-10.4]). CONCLUSION: in our retrospective study on a large sample of inpatients hospitalized in Kisangani, classic causes of death were found. The association with the low level of education suggests that the economic level of the patients who die is a determining factor, difficult to correct. The identification of a limited number of other factors will allow a better medical management.

Trends in reported malaria cases and the effects of malaria control in the Democratic Republic of the Congo.

BACKGROUND: Considerable upscaling of malaria control efforts have taken place over the last 15 years in the Democratic Republic of Congo, the country with the second highest malaria case load after Nigeria. Malaria control interventions have been strengthened in line with the Millenium Development Goals. We analysed the effects of these interventions on malaria cases at health facility level, using a retrospective trend analysis of malaria cases between 2005 and 2014. Data were collected from outpatient and laboratory registers based on a sample of 175 health facilities that represents all eco-epidemiological malaria settings across the country. METHODS: We applied a time series analysis to assess trends of suspected and confirmed malaria cases, by health province and for different age groups. A linear panel regression model controlled for non-malaria outpatient cases, rain fall, nightlight intensity, health province and time fixed effects, was used to examine the relationship between the interventions and malaria case occurrences, as well as test positivity rates. RESULTS: Overall, recorded suspected and confirmed malaria cases in the DRC have increased. The sharp increase in confirmed cases from 2010 coincides with the introduction of the new treatment policy and the resulting scale-up of diagnostic testing. Controlling for confounding factors, the introduction of rapid diagnostic tests (RDTs) was significantly associated with the number of tested and confirmed cases. The test positivity rate fluctuated around 40% without showing any trend. CONCLUSION: The sharp increase in confirmed malaria cases from 2010 is unlikely to be due to a resurgence of malaria, but is clearly associated with improved diagnostic availability, mainly the introduction of RDTs. Before that, a great part of malaria cases were treated based on clinical suspicion. This finding points to a better detection of cases that potentially contributed to improved case management. Furthermore, the expansion of diagnostic testing along with the increase in confirmed cases implies that before 2010, cases were underreported, and that the accuracy of routine data to describe malaria incidence has improved.

Plasmodium vivax Infections in Duffy-Negative Individuals in the Democratic Republic of the Congo.

Although Plasmodium vivax has been assumed to be absent from sub-Saharan Africa because of the protective mutation conferring the Duffy-negative phenotype, recent evidence has suggested that P. vivax cases are prevalent in these regions. We selected 292 dried blood spots from children who participated in the 2013-2014 Demographic and Health Survey of the Democratic Republic of the Congo (DRC), to assess for P. vivax infection. Four P. vivax infections were identified by polymerase chain reaction, each in a geographically different survey cluster. Using these as index cases, we tested the remaining 73 samples from the four clusters. With this approach, 10 confirmed cases, three probable cases, and one possible case of P. vivax were identified. Among the 14 P. vivax cases, nine were coinfected with Plasmodium falciparum. All 14 individuals were confirmed to be Duffy-negative by sequencing for the single point mutation in the GATA motif that represses the expression of the Duffy antigen. This finding is consistent with a growing body of literature that suggests that P. vivax can infect Duffy-negative individuals in Africa. Future molecular and sequencing work is needed to understand the relationship of these isolates with other P. vivax samples from Asia and South America and discover variants linked to P. vivax virulence and erythrocyte invasion.

Prevalence of Plasmodium falciparum parasites resistant to sulfadoxine/pyrimethamine in the Democratic Republic of the Congo: emergence of highly resistant pfdhfr/pfdhps alleles.

Background: In 2005, the Democratic Republic of the Congo (DRC) switched to artesunate/amodiaquine as the first-line antimalarial in response to increasing sulfadoxine/pyrimethamine resistance and adopted intermittent preventive treatment using sulfadoxine/pyrimethamine in pregnancy. Objectives: To determine the prevalence of molecular markers of sulfadoxine/pyrimethamine resistance in southwestern DRC 10 years after the new policy was instituted. Methods: From March 2014 to December 2015, blood samples were collected from symptomatic patients presenting to outpatient centres in urban and rural areas. A total of 2030 confirmed Plasmodium falciparum isolates were genotyped at codons associated with sulfadoxine/pyrimethamine resistance. Results: The prevalence of pfdhfr-N51I, C59R and S108N and pfdhps-A437G mutations was consistently high; the prevalence of the pfdhps-K540E mutation was low but increased since its first report in 2008 in the same region, reaching 17.6% by 2015. The pfdhps-A581G mutation increased from ∼4.5% in 2014 to ∼14.0% in 2015 at urban sites while in rural areas it remained low (∼4.0%). The mutations pfdhfr-I164L and pfdhps-A613S were detected for the first time in DRC. Also, 11 (0.8%) isolates revealed the presence of the newly described pfdhps-I431V mutation. Combining pfdhfr and pfdhps alleles, quintuple and sextuple mutations were observed, with the emergence of septuple (IRNI/IAGEGA)- and octuple (IRNI/VAGKGS)-mutant genotypes. Conclusions: Intermittent preventive treatment using sulfadoxine/pyrimethamine during pregnancy remains warranted in southwestern DRC. However, the expansion of pfdhps-K540E mutation and emergence of mutants that cause higher levels of sulfadoxine/pyrimethamine resistance is concerning and may present a challenge for future preventive interventions in the country.

Drug use in the management of uncomplicated malaria in public health facilities in the Democratic Republic of the Congo.

BACKGROUND: Malaria the first causes of death from parasitic infection worldwide. Interventions to reduce the burden of malaria have produced a tremendous drop in malaria morbidity and mortality. However, progress is slower in DRC, which shares with Nigeria 39% of deaths related to malaria globally. Inappropriate use of drugs may be one of the factors of this below-average performance. The aim of this study was to describe the use of drugs in the management of uncomplicated malaria in public health facilities in DRC. METHODS: A drug use study was carried out in DRC from January to March 2014. In each of the former 11 provinces of DRC, one Rural Health Centre, one Urban Health Centre and one General Hospital were selected. In each of them, 100 patient's files containing prescription of anti-malarials from January to December 2013 were randomly selected. Among them, all of the files with diagnosis of uncomplicated malaria were included in this study. Prescribed anti-malarials, co-prescribed drugs and their indications were collected. Descriptive analyses were performed. RESULTS: A total of 2300 files out of 3300 (69.7%) concerned uncomplicated malaria and were included in analysis. Malaria treatment was initiated after a positive RDT or microscopy in 51.5% of cases, upon suspicion without requesting biological confirmation in 37% and despite negative results in 11%. Twenty-nine (29) different treatment regimens were used. The drugs recommended by the National Malaria Control Programme were used in 54.3% of cases (artesunate-amodiaquine 37.4% or artemether-lumefantrine 16.9%). The second most used anti-malarial was quinine (32.4%). Apart from anti-malarials, an average of 3.1 drugs per patient were prescribed, among which antibiotics (67.9%), analgesics and non-steroidal anti-inflammatory (NSAIDs) (all abbreviations to be explicated on first use) (70.6%), vitamins (29.1%), anaemia drugs, including blood transfusion (9.1%) and corticosteroids (5.7%), In 51.4% of cases there was no indication for the concomitant medication. CONCLUSION: Management of uncomplicated malaria in DRC is characterized by a low adherence to treatment policy, numerous treatment regimens, and abundant concomitant medication potentially harmful to the patient. This may contribute to the low performance of DRC in malaria control. Determinant of this irrational use of drugs need to be assessed in order to formulate and implement efficient corrective measures.

Nationwide insecticide resistance status and biting behaviour of malaria vector species in the Democratic Republic of Congo.

BACKGROUND: Globally, the Democratic Republic of Congo (DRC) accounted for 9% of malaria cases and 10% of malaria deaths in 2015. As part of control efforts, more than 40 million long-lasting insecticidal nets (LLINs) were distributed between 2008 and 2013, resulting in 70% of households owning one or more LLINs in 2014. To optimize vector control efforts, it is critical to monitor vector behaviour and insecticide resistance trends. Entomological data was collected from eight sentinel sites throughout DRC between 2013 and 2016 in Kingasani, Mikalayi, Lodja, Kabondo, Katana, Kapolowe, Tshikaji and Kalemie. Mosquito species present, relative densities and biting times were monitored using human landing catches (HLC) conducted in eight houses, three times per year. HLC was conducted monthly in Lodja and Kapolowe during 2016 to assess seasonal dynamics. Laboratory data included resistance mechanism frequency and sporozoite rates. Insecticide susceptibility testing was conducted with commonly used insecticides including deltamethrin and permethrin. Synergist bioassays were conducted with PBO to determine the role of oxidases in permethrin resistance. RESULTS: In Lodja, monthly Anopheles gambiae s.l. biting rates were consistently high at > 10 bites/person/night indoors and outdoors. In Kapolowe, An. gambiae s.l. dominated during the rainy season, and Anopheles funestus s.l. during the dry season. In all sites, An. gambiae and An. funestus biting occurred mostly late at night. In Kapolowe, significant biting of both species started around 19:00, typically before householders use nets. Sporozoite rates were high, with a mean of 4.3% (95% CI 3.4-5.2) for An. gambiae and 3.3% (95% CI 1.3-5.3) for An. funestus. Anopheles gambiae were resistant to permethrin in six out of seven sites in 2016. In three sites, susceptibility to deltamethrin was observed despite high frequency permethrin resistance, indicating the presence of pyrethroid-specific resistance mechanisms. Pre-exposure to PBO increased absolute permethrin-associated mortality by 24%, indicating that resistance was partly due to metabolic mechanisms. The kdr-1014F mutation in An. gambiae was present at high frequency (> 70%) in three sites (Kabondo, Kingasani and Tshikaji), and lower frequency (< 20%) in two sites (Lodja and Kapolowe). CONCLUSION: The finding of widespread resistance to permethrin in DRC is concerning and alternative insecticides should be evaluated.

The links between agriculture, Anopheles mosquitoes, and malaria risk in children younger than 5 years in the Democratic Republic of the Congo: a population-based, cross-sectional, spatial study.

BACKGROUND: The relationship between agriculture, Anopheles mosquitoes, and malaria in Africa is not fully understood, but it is important for malaria control as countries consider expanding agricultural projects to address population growth and food demand. Therefore, we aimed to assess the effect of agriculture on Anopheles biting behaviour and malaria risk in children in rural areas of the Democratic Republic of the Congo (DR Congo). METHODS: We did a population-based, cross-sectional, spatial study of rural children (<5 years) in the DR Congo. We used information about the presence of malaria parasites in each child, as determined by PCR analysis of dried-blood spots from the 2013-14 DR Congo Demographic and Health Survey (DHS). We also used data from the DHS, a longitudinal entomological study, and available land cover and climate data to evaluate the relationships between agriculture, Anopheles biting behaviour, and malaria prevalence. Satellite imagery was used to measure the percentage of agricultural land cover around DHS villages and Anopheles sites. Anopheles biting behaviour was assessed by Human Landing Catch. We used probit regression to assess the relationship between agriculture and the probability of malaria infection, as well as the relationship between agriculture and the probability that a mosquito was caught biting indoors. FINDINGS: Between Aug 13, 2013, and Feb 13, 2014, a total of 9790 dried-blood spots were obtained from the DHS, of which 4612 participants were included in this study. Falciparum malaria infection prevalence in rural children was 38·7% (95% uncertainty interval [UI] 37·3-40·0). Increasing exposure to agriculture was associated with increasing malaria risk with a high posterior probability (estimate 0·07, 95% UI -0·04 to 0·17; posterior probability [estimate >0]=0·89), with the probability of malaria infection increased between 0·2% (95% UI -0·1 to 3·4) and 2·6% (-1·5 to 6·6) given a 15% increase in agricultural cover, depending on other risk factors. The models predicted that large increases in agricultural cover (from 0% to 75%) increase the probability of infection by as much as 13·1% (95% UI -7·3 to 28·9). Increased risk might be due to Anopheles gambiae sensu lato, whose probability of biting indoors increased between 11·3% (95% UI -15·3 to 25·6) and 19·7% (-12·1 to 35·9) with a 15% increase in agriculture. INTERPRETATION: Malaria control programmes must consider the possibility of increased risk due to expanding agriculture. Governments considering initiating large-scale agricultural projects should therefore also consider accompanying additional malaria control measures. FUNDING: National Institutes of Health, National Science Foundation, Bill & Melinda Gates Foundation, President's Malaria Initiative, and Royster Society of Fellows at the University of North Carolina at Chapel Hill.

Effect of individual and community-level bed net usage on malaria prevalence among under-fives in the Democratic Republic of Congo.

BACKGROUND: Understanding the contribution of community-level long-lasting, insecticidal net (LLIN) coverage to malaria control is critical to planning and assessing intervention campaigns. The Democratic Republic of Congo (DRC), which has one of the highest burdens of malaria cases and deaths and has dramatically scaled up LLIN ownership in recent years thus it is an ideal setting to evaluate the effect of individual versus community-level use to prevent malaria among children under the age of 5. RESULTS: Data were derived from the 2013-2014 DRC Demographic and Health Survey. Community-level LLIN usage was significantly associated with protection against malaria, even when individual-level LLIN usage was included in the model. In stratified analysis, higher levels of community LLIN coverage enhanced the protective effect of individual LLIN usage, resulting in lower malaria prevalence among individuals who used a LLIN. A sub-analysis of individual LLIN usage by insecticide type revealed deltamethrin-treated nets were more protective than permethrin-treated nets, suggesting that mosquitoes in the DRC are more susceptible to deltamethrin. CONCLUSIONS: This study examines the effects of individual and community-level LLIN usage in young children in an area of high ITN usage. Individual and community LLIN usage were significantly associated with protection against malaria in children under 5 in the DRC. Importantly, the protective effect of individual LLIN usage against malaria is enhanced when community LLIN coverage is higher, demonstrating the importance of increasing community-level LLIN usage. LLINs treated with deltamethrin were shown to be more protective against malaria than LLINs treated with permethrin. Demographic and Health Surveys are thus a novel and important means of surveillance for insecticide resistance.

[Effectiveness of vaccine management and quality of immunization services in the Expanded Programme on Immunization (EPI) antenna in the Kisangani region, Democratic Republic of Congo]. / Efficacité de la gestion de vaccins et qualité de vaccination à l'antenne PEV Kisangani en République Démocratique du Congo.

INTRODUCTION: The quality of vaccines is critical for good immunization outcomes. It is dependent on the effectiveness of technical and logistics management system put in place. This study aimed to assess the effectiveness of vaccine management and to learn something from this. METHODS: We conducted a retrospective study of logistic management of vaccines in the Expanded Programme on Immunization (EPI) antenna in the Kisangani region over the period 2010-2014. A literature review completed by semi-structured interviews of immunization services managers and providers helped to evaluate vaccine management using the WHO GEV model in order to identify the gaps. RESULTS: Provider's demonstrated low level of knowledge of the vaccines that cannot be frozen, of freezing tests and of other vaccine damages. Computerized data management was properly ensured in the antenna. No evaluation criteria reached the goal of 80%. Compliance with the storage temperature was 70% in the antenna; the criterion for vaccine management was 65% and 67% in the health area central office and in the health centre respectively. The maintenance criterion was zero at all levels. CONCLUSION: Malfunctioning of the logistic system is remarkable at all levels of the health pyramid; this could interfere with the quality and the expected impact of vaccination. Particular attention should be paid to the maintenance of the equipment.