Effectiveness of reactive focal mass drug administration and reactive focal vector control to reduce malaria transmission in the low malaria-endemic setting of Namibia: a cluster-randomised controlled, open-label, two-by-two factorial design trial.

BACKGROUND: In low malaria-endemic settings, screening and treatment of individuals in close proximity to index cases, also known as reactive case detection (RACD), is practised for surveillance and response. However, other approaches could be more effective for reducing transmission. We aimed to evaluate the effectiveness of reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in the low malaria-endemic setting of Zambezi (Namibia). METHODS: We did a cluster-randomised controlled, open-label trial using a two-by-two factorial design of 56 enumeration area clusters in the low malaria-endemic setting of Zambezi (Namibia). We randomly assigned these clusters using restricted randomisation to four groups: RACD only, rfMDA only, RAVC plus RACD, or rfMDA plus RAVC. RACD involved rapid diagnostic testing and treatment with artemether-lumefantrine and single-dose primaquine, rfMDA involved presumptive treatment with artemether-lumefantrine, and RAVC involved indoor residual spraying with pirimiphos-methyl. Interventions were administered within 500 m of index cases. To evaluate the effectiveness of interventions targeting the parasite reservoir in humans (rfMDA vs RACD), in mosquitoes (RAVC vs no RAVC), and in both humans and mosquitoes (rfMDA plus RAVC vs RACD only), an intention-to-treat analysis was done. For each of the three comparisons, the primary outcome was the cumulative incidence of locally acquired malaria cases. This trial is registered with ClinicalTrials.gov, number NCT02610400. FINDINGS: Between Jan 1, 2017, and Dec 31, 2017, 55 enumeration area clusters had 1118 eligible index cases that led to 342 interventions covering 8948 individuals. The cumulative incidence of locally acquired malaria was 30·8 per 1000 person-years (95% CI 12·8-48·7) in the clusters that received rfMDA versus 38·3 per 1000 person-years (23·0-53·6) in the clusters that received RACD; 30·2 per 1000 person-years (15·0-45·5) in the clusters that received RAVC versus 38·9 per 1000 person-years (20·7-57·1) in the clusters that did not receive RAVC; and 25·0 per 1000 person-years (5·2-44·7) in the clusters that received rfMDA plus RAVC versus 41·4 per 1000 person-years (21·5-61·2) in the clusters that received RACD only. After adjusting for imbalances in baseline and implementation factors, the incidence of malaria was lower in clusters receiving rfMDA than in those receiving RACD (adjusted incidence rate ratio 0·52 [95% CI 0·16-0·88], p=0·009), lower in clusters receiving RAVC than in those that did not (0·48 [0·16-0·80], p=0·002), and lower in clusters that received rfMDA plus RAVC than in those receiving RACD only (0·26 [0·10-0·68], p=0·006). No serious adverse events were reported. INTERPRETATION: In a low malaria-endemic setting, rfMDA and RAVC, implemented alone and in combination, reduced malaria transmission and should be considered as alternatives to RACD for elimination of malaria. FUNDING: Novartis Foundation, Bill & Melinda Gates Foundation, and Horchow Family Fund.

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.

"We were afraid of the lion that has roared next to us"; community response to reactive focal mass drug administration for malaria in Eswatini (formerly Swaziland).

BACKGROUND: Reactive focal mass drug administration (rfMDA), or presumptive treatment without malaria testing of household members and neighbours of a passively identified malaria case, is currently being explored as a possible malaria elimination strategy in low transmission settings. One of the primary factors determining the effectiveness of rfMDA on reducing or interrupting transmission is achieving high coverage of the target population with drug administration. This study aims to explore the acceptability of rfMDA and identify facilitators and barriers to its potential implementation, as well as the community's general knowledge, attitudes and beliefs with regard to malaria elimination. METHODS: A qualitative study was performed using focus group discussions (FGDs) among villagers that received rfMDA through the National Malaria Control Programme in the low transmission setting of Eswatini as part of a 2-year clinical trial. FGDs were audio-recorded, transcribed and translated into English. All transcripts were managed in Dedoose and underwent qualitative content analysis. RESULTS: The majority of participants perceived their community to be at high risk of malaria. Witnessing others in their community suffer from malaria, proximity to Mozambique, various ecological factors, and the presence of mosquitoes contributed to this perception. The greatest motivator of participation in rfMDA was witnessing someone else suffer from malaria, since most participants had not personally experienced malaria themselves. Participants valued the education on rfMDA and on malaria in general, particularly when communicated by nurses and other health workers from the Ministry of Health. Participants were overwhelmingly motivated to participate in rfMDA in order to obtain protection from malaria. Most participants did not understand the concept of sub-clinical infection and, therefore, did not perceive the anti-malarial medication given in rfMDA to be a treatment medication. CONCLUSIONS: Perceived risk for malaria was a major driver of acceptability; therefore, future intervention campaigns could aim to better quantify risk to inform interventions and encourage uptake. There were misunderstandings about the asymptomatic reservoir of parasites in humans. Given that this phenomenon is the rationale for rfMDA, this misunderstanding could threaten the uptake of the intervention if it persists in the community. Using local authorities to deliver messaging, additional education on this concept with re-inforcement that risk of malaria is ongoing, even in the absence of frequent cases, may help to maximize and maintain acceptability.

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.

Cost and cost effectiveness of reactive case detection (RACD), reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) to reduce malaria in the low endemic setting of Namibia: an analysis alongside a 2×2 factorial design cluster randomised controlled trial.

OBJECTIVES: To estimate the cost and cost effectiveness of reactive case detection (RACD), reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) to reduce malaria in a low endemic setting. SETTING: The study was part of a 2×2 factorial design cluster randomised controlled trial within the catchment area of 11 primary health facilities in Zambezi, Namibia. PARTICIPANTS: Cost and outcome data were collected from the trial, which included 8948 community members that received interventions due to their residence within 500 m of malaria index cases. OUTCOME MEASURES: The primary outcome was incremental cost effectiveness ratio (ICER) per in incident case averted. ICER per prevalent case and per disability-adjusted life years (DALY) averted were secondary outcomes, as were per unit interventions costs and personnel time. Outcomes were compared as: (1) rfMDA versus RACD, (2) RAVC versus no RAVC and (3) rfMDA+RAVC versus RACD only. RESULTS: rfMDA cost 1.1× more than RACD, and RAVC cost 1.7× more than no RAVC. Relative to RACD only, the cost of rfMDA+RAVC was double ($3082 vs $1553 per event). The ICERs for rfMDA versus RACD, RAVC versus no RAVC and rfMDA+RAVC versus RACD only were $114, $1472 and $842, per incident case averted, respectively. Using prevalent infections and DALYs as outcomes, trends were similar. The median personnel time to implement rfMDA was 20% lower than for RACD (30 vs 38 min per person). The median personnel time for RAVC was 34 min per structure sprayed. CONCLUSION: Implemented alone or in combination, rfMDA and RAVC were cost effective in reducing malaria incidence and prevalence despite higher implementation costs in the intervention compared with control arms. Compared with RACD, rfMDA was time saving. Cost and time requirements for the combined intervention could be decreased by implementing rfMDA and RAVC simultaneously by a single team. TRIAL REGISTRATION NUMBER: NCT02610400; Post-results.

Serological evaluation of the effectiveness of reactive focal mass drug administration and reactive vector control to reduce malaria transmission in Zambezi Region, Namibia: Results from a secondary analysis of a cluster randomised trial.

BACKGROUND: Due to challenges in measuring changes in malaria at low transmission, serology is increasingly being used to complement clinical and parasitological surveillance. Longitudinal studies have shown that serological markers, such as Etramp5.Ag1, can reflect spatio-temporal differences in malaria transmission. However, these markers have yet to be used as endpoints in intervention trials. METHODS: Based on data from a 2017 cluster randomised trial conducted in Zambezi Region, Namibia, evaluating the effectiveness of reactive focal mass drug administration (rfMDA) and reactive vector control (RAVC), this study conducted a secondary analysis comparing antibody responses between intervention arms as trial endpoints. Antibody responses were measured on a multiplex immunoassay, using a panel of eight serological markers of Plasmodium falciparum infection - Etramp5.Ag1, GEXP18, HSP40.Ag1, Rh2.2030, EBA175, PfMSP119, PfAMA1, and PfGLURP.R2. FINDINGS: Reductions in sero-prevalence to antigens Etramp.Ag1, PfMSP119, Rh2.2030, and PfAMA1 were observed in study arms combining rfMDA and RAVC, but only effects for Etramp5.Ag1 were statistically significant. Etramp5.Ag1 sero-prevalence was significantly lower in all intervention arms. Compared to the reference arms, adjusted prevalence ratio (aPR) for Etramp5.Ag1 was 0.78 (95%CI 0.65 - 0.91, p = 0.0007) in the rfMDA arms and 0.79 (95%CI 0.67 - 0.92, p = 0.001) in the RAVC arms. For the combined rfMDA plus RAVC intervention, aPR was 0.59 (95%CI 0.46 - 0.76, p < 0.0001). Significant reductions were also observed based on continuous antibody responses. Sero-prevalence as an endpoint was found to achieve higher study power (99.9% power to detect a 50% reduction in prevalence) compared to quantitative polymerase chain reaction (qPCR) prevalence (72.9% power to detect a 50% reduction in prevalence). INTERPRETATION: While the observed relative reduction in qPCR prevalence in the study was greater than serology, the use of serological endpoints to evaluate trial outcomes measured effect size with improved precision and study power. Serology has clear application in cluster randomised trials, particularly in settings where measuring clinical incidence or infection is less reliable due to seasonal fluctuations, limitations in health care seeking, or incomplete testing and reporting. FUNDING: This study was supported by Novartis Foundation (A122666), the Bill & Melinda Gates Foundation (OPP1160129), and the Horchow Family Fund (5,300,375,400).

Effectiveness and safety of reactive focal mass drug administration (rfMDA) using dihydroartemisinin-piperaquine to reduce malaria transmission in the very low-endemic setting of Eswatini: a pragmatic cluster randomised controlled trial.

INTRODUCTION: To reduce malaria transmission in very low-endemic settings, screening and treatment near index cases (reactive case detection (RACD)), is widely practised, but the rapid diagnostic tests (RDTs) used miss low-density infections. Reactive focal mass drug administration (rfMDA) may be safe and more effective. METHODS: We conducted a pragmatic cluster randomised controlled trial in Eswatini, a very low-endemic setting. 77 clusters were randomised to rfMDA using dihydroartemisin-piperaquine (DP) or RACD involving RDTs and artemether-lumefantrine. Interventions were delivered by the local programme. An intention-to-treat analysis was used to compare cluster-level cumulative confirmed malaria incidence among clusters with cases. Secondary outcomes included safety and adherence. RESULTS: From September 2015 to August 2017, 222 index cases from 47 clusters triggered 46 RACD events and 64 rfMDA events. RACD and rfMDA were delivered to 1455 and 1776 individuals, respectively. Index case coverage was 69.5% and 62.4% for RACD and rfMDA, respectively. Adherence to DP was 98.7%. No serious adverse events occurred. For rfMDA versus RACD, cumulative incidences (per 1000 person-years) of all malaria were 2.11 (95% CI 1.73 to 2.59) and 1.97 (95% CI 1.57 to 2.47), respectively; and of locally acquired malaria, they were 1.29 (95% CI 1.00 to 1.67) and 0.97 (95% CI 0.71 to 1.34), respectively. Adjusting for imbalance in baseline incidence, incidence rate ratio for rfMDA versus RACD was 0.95 (95% CI 0.55 to 1.65) for all malaria and 0.82 (95% CI 0.40 to 1.71) for locally acquired malaria. Similar results were obtained in a per-protocol analysis that excluded clusters with <80% index case coverage. CONCLUSION: In a very low-endemic, real-world setting, rfMDA using DP was safe, but did not lower incidence compared with RACD, potentially due to insufficient coverage and/or power. To assess impact of interventions in very low-endemic settings, improved coverage, complementary interventions and adaptive ring trial designs may be needed. TRIAL REGISTRATION NUMBER: NCT02315690.