Reducing malaria transmission with reactive focal interventions
Authors: Manuel W Hetzel, Nakul Chitnis
Journal: The Lancet (2020)

A massive scale-up of investments in malaria control resulted in an estimated 663 million clinical cases averted in sub-Saharan Africa between 2000 and 2015,1Bhatt S Weiss DJ Cameron E et al.The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015.Nature. 2015; 526: 207-211Crossref PubMed Scopus (1243) Google Scholar and 11 countries have been certified malaria-free in the current millennium.2WHOCountries and territories certified malaria-free by WHO.https://www.who.int/malaria/areas/elimination/malaria-free-countries/en/Date: 2019Date accessed: March 10, 2020Google Scholar Unfortunately, progress has stalled recently, and increases in malaria incidence were observed in several endemic countries.3WHOWorld malaria report 2018. World Health Organization, Geneva, Switzerland2018Google Scholar Continuing with business as usual is likely to jeopardise gains made in the past 20 years, and slow the progress towards elimination goals. Innovative and targeted measures are required to complement universal coverage with basic vector control and case management interventions, especially as heterogeneity in case incidence increases with declining transmission. In the last mile to achieving elimination, malaria transmission and the appearance of asymptomatic and clinical infections become increasingly focal. Targeted reactive approaches, such as reactive case detection (RACD), are likely to form efficient interventions to eliminate infections and prevent onward transmission.4WHOA framework for malaria elimination. World Health Organization, Geneva, Switzerland2017Google Scholar Supporting research on the effectiveness and operational feasibility of various forms of reactive focal strategies is required.5Rabinovich RN Drakeley C Djimde AA et al.malERA: an updated research agenda for malaria elimination and eradication.PLoS Med. 2017; 14e1002456Crossref PubMed Scopus (101) Google Scholar In the low Plasmodium falciparum-endemic area of northeastern Namibia, Michelle Hsiang and colleagues6Hsiang M Ntuku H Roberts K et al.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.Lancet. 2020; 395: 1361-1373Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar report in The Lancet an innovative approach to test two such interventions: reactive focal mass drug administration (rfMDA), implemented as presumptive treatment with artemether-lumefantrine, and reactive focal vector control (RAVC) by indoor residual spraying of the insecticide pirimiphos-methyl. The cluster-randomised trial was done in 56 census enumeration area clusters. The study applied a two-by-two factorial design that allowed rfMDA to be compared with RACD (rapid diagnostic testing and treatment with artemether-lumefantrine), RAVC to be compared with no RAVC, and rfMDA plus RAVC to be compared with RACD only. An intention-to-treat analysis was done, and the primary outcome was the cluster-level cumulative incidence of autochthonous malaria cases. Testing an intervention in a low-transmission setting means that finding a sufficient number of cases to demonstrate effectiveness is difficult. Nevertheless, the study6Hsiang M Ntuku H Roberts K et al.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.Lancet. 2020; 395: 1361-1373Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar provided evidence that rfMDA and RAVC are both effective in reducing the incidence of malaria (rfMDA vs RACD, adjusted incidence rate ratio 0·52 [95% CI 0·16–0·88], p=0·009; and RAVC vs no RAVC, 0·48 [0·16–0·80], p=0·002), and that combining both interventions could be beneficial (rfMDA plus RAVC vs RACD only, 0·26 [0·10–0·68], p=0·006). Simultaneously, this study6Hsiang M Ntuku H Roberts K et al.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.Lancet. 2020; 395: 1361-1373Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar also highlights the difficulty inherent in demonstrating the effectiveness of interventions in a real-world setting.7malERA Refresh Consultative Panel on Health Systems and Policy ResearchmalERA: an updated research agenda for health systems and policy research in malaria elimination and eradication.PLoS Med. 2017; 14e1002454Crossref PubMed Scopus (11) Google Scholar The study period,6Hsiang M Ntuku H Roberts K et al.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.Lancet. 2020; 395: 1361-1373Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar which was originally planned for 2 years, had to be limited to 1 year because of unforeseen operational challenges resulting from an increase in malaria cases in the first year. The observed outcomes are thus short-term results, and the sustainability of the achieved coverage and resulting effects are yet to be determined. Longer-term evaluations are essential, as effectiveness might reduce over time because of epidemiological fluctuations and health system constraints;7malERA Refresh Consultative Panel on Health Systems and Policy ResearchmalERA: an updated research agenda for health systems and policy research in malaria elimination and eradication.PLoS Med. 2017; 14e1002454Crossref PubMed Scopus (11) Google Scholar, 8Vlassoff C Tanner M The relevance of rapid assessment to health research and interventions.Health Policy Plan. 1992; 7: 1-9Crossref Scopus (47) Google Scholar and studies9Bousema T Stresman G Baidjoe AY et al.The impact of hotspot-targeted interventions on malaria transmission in Rachuonyo South District in the western Kenyan highlands: a cluster-randomized controlled trial.PLoS Med. 2016; 13e1001993Crossref PubMed Scopus (65) Google Scholar in other settings have found the effect of targeting hotspots to be transient. This requires long-term commitment from funding agencies, stamina from researchers and implementers, and acceptance from the scientific community that generating comprehensive results requires time. An imbalance in the baseline characteristics across the study arms6Hsiang M Ntuku H Roberts K et al.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.Lancet. 2020; 395: 1361-1373Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar could be adjusted for, thanks to a robust study design that measured the relevant indicators. However, the absence of buffer zones between implementation clusters could have led to a contamination effect that reduced the observed effectiveness of RAVC in this study. Furthermore, RAVC by indoor residual spraying of an insecticide has a residual effect that lasts for months (unlike RACD and rfMDA) and might therefore prevent onward transmission from future importations. The effectiveness of RAVC requires further investigation in longer running trials, as it could become a cornerstone of malaria elimination strategies. The study6Hsiang M Ntuku H Roberts K et al.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.Lancet. 2020; 395: 1361-1373Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar in Namibia was implemented as a trial, and hence with substantial external support. A high coverage (>80%) was achieved for all interventions. Case management, though not discussed in detail in the manuscript, could well have been better (in terms of coverage and quality) than in a non-study context. Most importantly, the study team invested substantial time and effort in working with local authorities to improve the completeness and timeliness of the passive surveillance system. As modelling suggests that the effectiveness of RACD (and probably also rfMDA) depends strongly on the quality of the passive surveillance system,10Reiker T Chitnis N Smith T Modelling reactive case detection strategies for interrupting transmission of Plasmodium falciparum malaria.Malar J. 2019; 18: 259Crossref PubMed Scopus (6) Google Scholar these interventions might not work equally as well outside of a trial setting. Additionally, the frequency of malaria importation from higher endemic areas, mosquito ecology and behaviour, and the presence of other malaria species (most notably Plasmodium vivax) could influence the effectiveness of the interventions tested in Namibia. The limitations and challenges in the study by Hsiang and colleagues6Hsiang M Ntuku H Roberts K et al.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.Lancet. 2020; 395: 1361-1373Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar do not diminish the relevance of their findings. Challenges with RACD due to high levels of subpatent infections not detected by conventional diagnostic tools have been found elsewhere.11Grossenbacher B Holzschuh A Hofmann NE et al.Molecular methods for tracking residual Plasmodium falciparum transmission in a close-to-elimination setting in Zanzibar.Malar J. 2020; 19: 50Crossref PubMed Scopus (6) Google Scholar Bold but evidence-supported actions are required to accelerate progress towards malaria elimination wherever possible. The presented evidence on rfMDA and RAVC, alone or in combination, should encourage larger scale implementation of these strategies in other settings, accompanied by well designed, long-term evaluations. This online publication has been corrected. The corrected version first appeared at thelancet.com on May 7, 2020 This online publication has been corrected. The corrected version first appeared at thelancet.com on May 7, 2020 NC reports grants from the Bill & Melinda Gates Foundation. MWH declares no competing interests. 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 trialIn 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. Full-Text PDF Open AccessDepartment of ErrorHetzel MW, Chitnis N. Reducing malaria transmission with reactive focal interventions. Lancet 2020; 395: 1317–19—In this Comment, the first sentence should read “A massive scale-up of investments in malaria control resulted in an estimated 663 million clinical cases averted in sub-Saharan Africa between 2000 and 2015,1 and 11 countries have been certified malaria-free in the current millennium.2” This correction has been made to the online version as of May 7, 2020. Full-Text PDF Open Access