Malaria epidemiology and key control interventions in the Democratic Republic of Congo

Malaria remains a major global public health problem causing over 400,000 deaths annually, mainly among children in sub Saharan Africa. The Democratic Republic of Congo (DRC), the second largest and the fourth most populated country in Africa, is one of the most malarious countries in the world. An estimated 97% of its 71 million inhabitants live in high transmission areas. Together with Nigeria, DRC accounts for about 40% of the total estimated malaria cases worldwide, and for more than 35% of the total estimated malaria deaths. The national malaria control programme (NMCP) is committed to reducing malaria and the associated morbidity and mortality in DRC through the implementation of specific proven interventions. The aim of this thesis was to contribute to the improvement of malaria control activities in the DRC, through the provision of new evidence on the epidemiology of malaria and key control interventions, to support evidence-based policy making. Kinshasa, the capital of DRC, has been expanding very rapidly in the past 20 years (going from an estimated 3 million inhabitants to a current estimate of 10 million) and available evidence has shown that urbanization had a significant impact on the ecosystems and disease patterns, including malaria. However, in the context of scaling up of interventions, data on malaria distribution in Kinshasa are scarce; the latest epidemiological study was conducted in 2000. We conducted two cross-sectional surveys to update malaria risk stratification in Kinshasa, identify factors contributing to the distribution patterns, and update information on malaria control activities. Geo-referenced data for key parameters were mapped at the level of the health area (HA) by means of a geographic information system (GIS). The overall standardized malaria prevalence was 11.7%, showing a decline compared to previous studies. The spatial distribution showed higher malaria risk in the peri-urban areas compared to the more urban central areas. Compared to the Demographic and Health Survey 2007 (DHS-DRC, 2007), coverage of malaria control measures showed considerable progresses in a pattern inversely proportional to the malaria risk distribution: low LLIN coverage in the peri-urban areas and higher coverage in the centre of the city. The analysis of drivers of malaria in both children less than five years and individuals aged older than five years highlighted the variation of the effect of age and reported history of fever by level of endemicity. In low endemicity strata, a shift in the peak of malaria prevalence towards the older age groups was observed, while the history of fever in the last two weeks increased the risk of malaria in all age groups and regardless of the level of endemicity. Individual use of LLIN was associated with reduced risk malaria infection among children less than five years. The risk of malaria was lower among children less than five years of the wealthiest socio economic group. This risk map constitutes a strong basis for the planning of malaria control interventions in Kinshasa. Following the publication of the results of two large open-label randomized controlled trials (SEAQUAMAT, AQUAMAT) that demonstrated the benefits of injectable artesunate over quinine in the treatment of severe malaria, and in line with the updated WHO guidelines, the NMCP changed the policy for treating severe malaria in children and adults from injectable quinine to injectable artesunate in 2012 A transition period of 3 years was set, including the need for operational research to support the national deployment. We conducted an operational comparative study of quinine and injectable artesunate for the treatment of severe malaria (MATIAS study) with the aims of assessing the operational feasibility of this introduction, providing national cost estimates, and assessing the acceptability of the new drug among both health care providers and patients. Our findings showed that all the operational parameters measured (time to discharge, interval between admission and the start of intravenous treatment, personnel time spent on patient management, and parasite clearance time) were equal or in favour of injectable artesunate. The mean total cost per patient treated for severe malaria in hospitals and health centres was also lower with injectable artesunate. There was a high acceptability by both health care providers and patients. These findings support the rapid scale up of injectable artesunate in the country. Mass distribution campaigns of LLIN are accepted as the best approach to rapidly increase coverage and use. To promote correct and consistent use of distributed LLIN, the WHO recommends the integration of door-to-door visits with “hang up” activities into mass distribution campaigns. Integrating hang-up activities requires obviously additional human and financial resources. Since published data on the effects and cost of door-to-door visits with hang up activities on LLIN use are scarce, more evidence is still required to optimize the efficiency of national LLIN programmes. We used a LLIN mass distribution campaign in the province of Kasai Occidental that used two different approaches, a fixed delivery strategy and a door-to-door strategy including hang-up activities, to evaluate comparatively household LLIN ownership, access and individual use, and examine factors associated with LLIN use. We also compared the two delivery strategies with regard to the LLIN coverage achieved and the cost of implementation. Results showed that the mass distribution campaign was effective at achieving high LLIN ownership and use. Having sufficient numbers of LLIN to cover all residents in the household was the strongest determinant of LLIN use. Compared with the door-to-door strategy, the fixed delivery strategy achieved a higher LLIN coverage at lower delivery cost, and seems to be a better LLIN delivery option in the context of DRC. Information on the number and distribution of malaria cases and deaths is fundamental for the design, implementation and evaluation of malaria control programmes. In many endemic areas, health facility-based data remain the only consistent and readily available source of information on malaria. Because of known inherent limitations, this source of date can underestimate the total burden of disease by a considerable fraction. In DRC, the use of rapid diagnostic tests has been expanded since 2010, leading to a marked increase in suspected malaria cases receiving a diagnostic test. Together with other management measures, this should improve the quality of the incidence rates obtained through the Health Monitoring Information System (HMIS). Based on household survey data, the Malaria Atlas Project (MAP) of the University of Oxford has produced estimates of clinical incidence of malaria for the years 2000-2015 for all African countries, providing something like a reference value on incidence rates. We compared the malaria incidence rates obtained from the HMIS data in the DRC from 2010 to 2014 to the MAP modelled incidence rates for the same time period, in order to assess the relative reporting of the HMIS system. Our preliminary results showed that due to the expansion of parasitological diagnosis, the number of confirmed malaria cases reported and hence the fraction of incident cases captured by the HMIS data had increased substantially over time. By contrast, the number of incident malaria cases predicted by the MAP model had progressively decreased. Because of inconsistencies in reporting, it has been difficult to establish trends in malaria morbidity, but the unchanged high values of test positivity rates suggest malaria transmission remains high and stable over time

Identifying risk factors for Plasmodium infection and anaemia in Kinshasa, Democratic Republic of Congo

There is little data on the risk factors for malaria infection in large cities in central Africa and in all age groups. There may be different associations with the risk factors for areas with different malaria transmission intensities such as the effect of fever or age. This study aimed at identifying risk factors associated with Plasmodium infection and anaemia among children 6-59 months and individuals aged older than 5 years in Kinshasa, a large city with heterogeneity in malaria prevalence.; This study analysed data from 3342 children aged 6-59 months from 25 non-rural health zones (HZs) and for 816 individuals aged older than 5 years from two HZs in Kinshasa (non-rural), collected during a cross sectional malaria survey in 2011. Logistic regression with random effects was used to investigate predictors for malaria and anaemia. Differences in risk factors in areas with a prevalence of less than 10 and 10 % or greater were investigated.; There was evidence of a different age-pattern in the two transmission settings. For children under 5 years, the highest prevalence of malaria was observed in the 48-59 months group in both transmission settings, but it increased more gently for the lower transmission HZs (p = 0.009). In a separate analysis in children over 5 years in two selected HZs, the peak prevalence was in 5-9 years old in the higher transmission setting and in 15-19 years old in the lower transmission setting. Reported fever was associated with malaria in both transmission strata, with no evidence of a difference in these associations (p = 0.71); however in children older than 5 years there was a significant interaction with a stronger association in the low transmission HZ. Insecticide-treated net (ITN) use was associated with a lower risk of malaria infection in children 6-59 months in the high transmission HZs. Similar estimates were found in children over 5 years and the lower transmission HZ but the associations there were not significant. There was no evidence of a difference in these associations by strata. The risk of anaemia decreased with increasing age in all strata, whereas it increased with malaria infection and reported fever. ITN use did not show evidence of protection against anaemia. Low socio-economic status was associated with malaria in high transmission setting in children 6-59 months and anaemia in low transmission setting.; This study shows that in areas of low transmission in Kinshasa, the peak prevalence occurs in older age groups however ITN use was highest in children under 5 years. Targeted distribution of ITN to all age groups should be continued. For most risk factors, there was no evidence of an interaction with transmission intensity however the associations with age and with fever in the last 2 weeks did vary significantly

Long-lasting insecticidal net (LLIN) ownership, use and cost of implementation after a mass distribution campaign in Kasaï Occidental Province, Democratic Republic of Congo

Long-lasting insecticidal nets (LLIN) are a highly effective means for preventing malaria infection and reducing associated morbidity and mortality. Mass free distribution campaigns have been shown to rapidly increase LLIN ownership and use. Around 3.5 million LLINs were distributed free of charge in the Kasaï Occidental Province in the Democratic Republic of Congo (DRC) in September-October 2014, using two different approaches, a fixed delivery strategy and a door-to-door strategy including hang-up activities.; Repeated community-based cross-sectional surveys were conducted 2 months before and six months after the mass distribution. Descriptive statistics were used to measure changes in key malaria household indicators. LLIN ownership and use were compared between delivery strategies. Univariate and multivariate logistic regression analyses were used to identify factors associated with LLIN use before and after the mass distribution. A comparative financial cost analysis between the fixed delivery and door-to-door distribution strategies was carried out from the provider's perspective.; Household ownership of at least one LLIN increased from 39.4% pre-campaign to 91.4% post-campaign and LLIN universal coverage, measured as the proportion of households with at least one LLIN for every two people increased from 4.1 to 41.1%. Population access to LLIN within the household increased from 22.2 to 80.7%, while overall LLIN use increased from 18.0 to 68.3%. Higher LLIN ownership was achieved with the fixed delivery strategy compared with the door-to-door (92.5% [95% CI 90.2-94.4%] versus 85.2% [95% CI 78.5-90.0%]), while distribution strategy did not have a significant impact on LLIN use (69.6% [95% CI 63.1-75.5%] versus 65.7% [95% CI 52.7-76.7%]). Malaria prevalence among children aged 6-59 months was 44.8% post-campaign. Living in a household with sufficient numbers of LLIN to cover all members was the strongest determinant of LLIN use. The total financial cost per LLIN distributed was 6.58 USD for the fixed distribution strategy and 6.61 USD for the door-to-door strategy.; The mass distribution campaign was effective for rapidly increasing LLIN ownership and use. These gains need to be sustained for long-term reduction in malaria burden. The fixed delivery strategy achieved a higher LLIN coverage at lower delivery cost compared with the door-to-door strategy and seems to be a better distribution strategy in the context of the present study setting

District-level approach for tailoring and targeting interventions: a new path for malaria control and elimination.

Despite huge investments and implementation of effective interventions for malaria, progress has stalled, with transmission being increasingly localized among difficult-to-reach populations and outdoor-biting vectors. Targeting difficult pockets of transmission will require the development of tailored and targeted approaches suited to local context, drawing from insights close to the frontlines. Districts are best placed to develop tailored, locally appropriate approaches. We propose a reorganization of how malaria services are delivered. Firstly, enabling district health officers to serve as conduits between technical experts in national malaria control programmes and local community leaders with knowledge specific to local, at-risk populations; secondly, empowering district health teams to make malaria control decisions. This is a radical shift that requires the national programme to cede some control. Shifting towards a district or provincial level approach will necessitate deliberate planning, and repeated, careful assessment, starting with piloting and learning through experience. Donors will need to alter current practice, allowing for flexible funding to be controlled at sub-national levels, and to mix finances between case management, vector control and surveillance, monitoring and evaluation. System-wide changes proposed are challenging but may be necessary to overcome stalled progress in malaria control and elimination and introduce targeted interventions tailored to the needs of diverse malaria affected populations

Community acceptance of reactive focal mass drug administration and reactive focal vector control using indoor residual spraying, a mixed-methods study in Zambezi region, Namibia.

BACKGROUND: In Namibia, as in many malaria elimination settings, reactive case detection (RACD), or malaria testing and treatment around index cases, is a standard intervention. Reactive focal mass drug administration (rfMDA), or treatment without testing, and reactive focal vector control (RAVC) in the form of indoor residual spraying, are alternative or adjunctive interventions, but there are limited data regarding their community acceptability. METHODS: A parent trial aimed to compare the effectiveness of rfMDA versus RACD, RAVC versus no RAVC, and rfMDA + RAVC versus RACD only. To assess acceptability of these interventions, a mixed-methods study was conducted using key informant interviews (KIIs) and focus group discussions (FGDs) in three rounds (pre-trial and in years 1 and 2 of the trial), and an endline survey. RESULTS: In total, 17 KIIs, 49 FGDs were conducted with 449 people over three annual rounds of qualitative data collection. Pre-trial, community members more accurately predicted the level of community acceptability than key stakeholders. Throughout the trial, key participant motivators included: malaria risk perception, access to free community-based healthcare and IRS, and community education by respectful study teams. RACD or rfMDA were offered to 1372 and 8948 individuals in years 1 and 2, respectively, and refusal rates were low (< 2%). RAVC was offered to few households (n = 72) in year 1. In year 2, RAVC was offered to more households (n = 944) and refusals were < 1%. In the endline survey, 94.3% of 2147 respondents said they would participate in the same intervention again. CONCLUSIONS: Communities found both reactive focal interventions and their combination highly acceptable. Engaging communities and centering and incorporating their perspectives and experiences during design, implementation, and evaluation of this community-based intervention was critical for optimizing study engagement

Subpatent malaria in a low transmission African setting: a cross-sectional study using rapid diagnostic testing (RDT) and loop-mediated isothermal amplification (LAMP) from Zambezi region, Namibia.

BACKGROUND: Subpatent malaria infections, or low-density infections below the detection threshold of microscopy or standard rapid diagnostic testing (RDT), can perpetuate persistent transmission and, therefore, may be a barrier for countries like Namibia that are pursuing malaria elimination. This potential burden in Namibia has not been well characterized. METHODS: Using a two-stage cluster sampling, cross-sectional design, subjects of all age were enrolled during the end of the 2015 malaria transmission season in Zambezi region, located in northeast Namibia. Malaria RDTs were performed with subsequent gold standard testing by loop-mediated isothermal amplification (LAMP) using dried blood spots. Infection prevalence was measured and the diagnostic accuracy of RDT calculated. Relationships between recent fever, demographics, epidemiological factors, and infection were assessed. RESULTS: Prevalence of Plasmodium falciparum malaria infection was low: 0.8% (16/1919) by RDT and 2.2% (43/1919) by LAMP. All but one LAMP-positive infection was RDT-negative. Using LAMP as gold standard, the sensitivity and specificity of RDT were 2.3% and 99.2%, respectively. Compared to LAMP-negative infections, a higher portion LAMP-positive infections were associated with fever (45.2% vs. 30.4%, p = 0.04), though 55% of infections were not associated with fever. Agricultural occupations and cattle herding were significantly associated with LAMP-detectable infection (Adjusted ORs 5.02, 95% CI 1.77-14.23, and 11.82, 95% CI 1.06-131.81, respectively), while gender, travel, bed net use, and indoor residual spray coverage were not. CONCLUSIONS: This study presents results from the first large-scale malaria cross-sectional survey from Namibia using molecular testing to characterize subpatent infections. Findings suggest that fever history and standard RDTs are not useful to address this burden. Achievement of malaria elimination may require active case detection using more sensitive point-of-care diagnostics or presumptive treatment and targeted to high-risk groups

Study protocol for a cluster randomised controlled factorial design trial to assess the effectiveness and feasibility of reactive focal mass drug administration and vector control to reduce malaria transmission in the low endemic setting of Namibia.

INTRODUCTION: To interrupt malaria transmission, strategies must target the parasite reservoir in both humans and mosquitos. Testing of community members linked to an index case, termed reactive case detection (RACD), is commonly implemented in low transmission areas, though its impact may be limited by the sensitivity of current diagnostics. Indoor residual spraying (IRS) before malaria season is a cornerstone of vector control efforts. Despite their implementation in Namibia, a country approaching elimination, these methods have been met with recent plateaus in transmission reduction. This study evaluates the effectiveness and feasibility of two new targeted strategies, reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in Namibia. METHODS AND ANALYSIS: This is an open-label cluster randomised controlled trial with 2×2 factorial design. The interventions include: rfMDA (presumptive treatment with artemether-lumefantrine (AL)) versus RACD (rapid diagnostic testing and treatment using AL) and RAVC (IRS with Acellic 300CS) versus no RAVC. Factorial design also enables comparison of the combined rfMDA+RAVC intervention to RACD. Participants living in 56 enumeration areas will be randomised to one of four arms: rfMDA, rfMDA+RAVC, RACD or RACD+RAVC. These interventions, triggered by index cases detected at health facilities, will be targeted to individuals residing within 500 m of an index. The primary outcome is cumulative incidence of locally acquired malaria detected at health facilities over 1 year. Secondary outcomes include seroprevalence, infection prevalence, intervention coverage, safety, acceptability, adherence, cost and cost-effectiveness. ETHICS AND DISSEMINATION: Findings will be reported on clinicaltrials.gov, in peer-reviewed publications and through stakeholder meetings with MoHSS and community leaders in Namibia. TRIAL REGISTRATION NUMBER: NCT02610400; Pre-results