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      Strengthen Village Malaria Reporting to Better Target Reservoirs of Persistent Infections in Southeast Asia

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          To the Editor—The recent World Health Organization malaria surveillance, monitoring, and evaluation manual highlights the importance that strengthened community health worker (CHW) programs and their ability to report accurate and timely data hold for the elimination of malaria [1]. Mass Drug Administration (MDA) is proposed as a means of interrupting Plasmodium falciparum transmission in areas of emergent, multidrug-resistant parasites [2, 3]. The 2017 World Health Organization recommendations on MDA inform control programs how to implement this strategy, but there is no specific advice on how to target suitable populations in Southeast Asia [4, 5]. Since 2013, we have conducted population-based surveys to define the micro-epidemiology of asymptomatic malaria infections and have piloted MDA in Southeast Asia [6]. Asymptomatic P. falciparum infections persist, on average, for several months, with varying parasite densities that are periodically capable of transmission [7]. Our experience is that prevalence surveys are an expensive and time-consuming means of identifying foci of transmission in pre-elimination (low-transmission) settings, particularly where highly-sensitive molecular techniques are used to detect asymptomatic infections. Currently, CHWs are active in many more villages than could be practicably included in a baseline prevalence survey, but are well positioned—with strengthening of the reporting system where needed—to routinely collect travel and residency data to determine whether individual locations are sources where transmission occurs or sinks where cases are reported but not acquired. If of sufficient quality, CHW data could be used to identify locations for targeted MDA, such as village clusters where the P. falciparum incidence is above a locally-defined threshold. High-quality incidence data has been shown to be predictive of asymptomatic carriage rates in low-transmission settings, thus potentially obviating the need to screen populations using more expensive molecular methods to define targets for MDA [8]. Incidence data determined from reliable case reporting could also be the preferred metric to evaluate the impact of MDA. For example, a recent elimination program in Myanmar demonstrated a rapid decline in the incidence of malaria following the implementation of a strong village malaria worker network, demonstrating the effectiveness of conducting an MDA in a transmission hotspot [9]. In Southeast Asia, asymptomatic Plasmodium vivax infections are even more under-detected and undertreated than P. falciparum [10]. In our studies, a history of clinical malaria was a consistently strong risk factor for persistent asymptomatic infection. In a prior survey, we matched participants to treatment records and found that approximately a third of people with a history of clinical P. vivax were parasitaemic [11]. Therefore, local health services already have recorded the names and locations of thousands of people harboring P. vivax infections that contribute to ongoing transmission. These people could be screened for G6PD deficiencies and offered safe treatment with primaquine for radical cures of liver-stage parasites. Targeting persistent P. vivax from treatment records alone would neither catch all carriers nor interrupt transmission, but could treat an important fraction of extant P. vivax infections and represent a move from P. vivax control towards elimination. As countries progress towards elimination, investments in strengthening and expanding the coverage of CHW programs and case reporting are vital. Making better use of this data could identify persistent infections at both the community and individual levels, allowing for the targeting of elimination strategies that address the asymptomatic reservoir and for new screen-and-treat strategies, which may become viable with the deployment of highly-sensitive rapid diagnostics.

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          Optimising Strategies for Plasmodium falciparum Malaria Elimination in Cambodia: Primaquine, Mass Drug Administration and Artemisinin Resistance

          Background Malaria elimination requires a variety of approaches individually optimized for different transmission settings. A recent field study in an area of low seasonal transmission in South West Cambodia demonstrated dramatic reductions in malaria parasite prevalence following both mass drug administration (MDA) and high treatment coverage of symptomatic patients with artemisinin-piperaquine plus primaquine. This study employed multiple combined strategies and it was unclear what contribution each made to the reductions in malaria. Method and Findings A mathematical model fitted to the trial results was used to assess the effects of the various components of these interventions, design optimal elimination strategies, and explore their interactions with artemisinin resistance, which has recently been discovered in Western Cambodia. The modelling indicated that most of the initial reduction of P. falciparum malaria resulted from MDA with artemisinin-piperaquine. The subsequent continued decline and near elimination resulted mainly from high coverage with artemisinin-piperaquine treatment. Both these strategies were more effective with the addition of primaquine. MDA with artemisinin combination therapy (ACT) increased the proportion of artemisinin resistant infections, although much less than treatment of symptomatic cases with ACT, and this increase was slowed by adding primaquine. Artemisinin resistance reduced the effectiveness of interventions using ACT when the prevalence of resistance was very high. The main results were robust to assumptions about primaquine action, and immunity. Conclusions The key messages of these modelling results for policy makers were: high coverage with ACT treatment can produce a long-term reduction in malaria whereas the impact of MDA is generally only short-term; primaquine enhances the effect of ACT in eliminating malaria and reduces the increase in proportion of artemisinin resistant infections; parasite prevalence is a better surveillance measure for elimination programmes than numbers of symptomatic cases; combinations of interventions are most effective and sustained efforts are crucial for successful elimination.
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            Fighting fire with fire: mass antimalarial drug administrations in an era of antimalarial resistance.

            The emergence and spread of antimalarial resistance has been a major liability for malaria control. The spread of chloroquine-resistant Plasmodium falciparum strains had catastrophic consequences for people in malaria-endemic regions, particularly in sub-Saharan Africa. The recent emergence of artemisinin-resistant P. falciparum strains is of highest concern. Current efforts to contain artemisinin resistance have yet to show success. In the absence of more promising plans, it has been suggested to eliminate falciparum malaria from foci of artemisinin resistance using a multipronged approach, including mass drug administrations. The use of mass drug administrations is controversial as it increases drug pressure. Based on current knowledge it is difficult to conceptualize how targeted malaria elimination could contribute to artemisinin resistance, provided a full treatment course is ensured.
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              Effect of generalised access to early diagnosis and treatment and targeted mass drug administration on Plasmodium falciparum malaria in Eastern Myanmar: an observational study of a regional elimination programme

              Summary Background Potentially untreatable Plasmodium falciparum malaria threatens the Greater Mekong subregion. A previous series of pilot projects in Myanmar, Laos, Cambodia, and Vietnam suggested that mass drug administration was safe, and when added to provision of early diagnosis and treatment, could reduce the reservoir of P falciparum and interrupts transmission. We examined the effects of a scaled-up programme of this strategy in four townships of eastern Myanmar on the incidence of P falciparum malaria. Methods The programme was implemented in the four townships of Myawaddy, Kawkareik, Hlaingbwe, and Hpapun in Kayin state, Myanmar. Increased access to early diagnosis and treatment of malaria was provided to all villages through community-based malaria posts equipped with rapid diagnostic tests, and treatment with artemether–lumefantrine plus single low-dose primaquine. Villages were identified as malarial hotspots (operationally defined as >40% malaria, of which 20% was P falciparum) with surveys using ultrasensitive quantitative PCR either randomly or targeted at villages where the incidence of clinical cases of P falciparum malaria remained high (ie, >100 cases per 1000 individuals per year) despite a functioning malaria post. During each survey, a 2 mL sample of venous blood was obtained from randomly selected adults. Hotspots received targeted mass drug administration with dihydroartemisinin–piperaquine plus single-dose primaquine once per month for 3 consecutive months in addition to the malaria posts. The main outcome was the change in village incidence of clinical P falciparum malaria, quantified using a multivariate, generalised, additive multilevel model. Malaria prevalence was measured in the hotspots 12 months after mass drug administration. Findings Between May 1, 2014, and April 30, 2017, 1222 malarial posts were opened, providing early diagnosis and treatment to an estimated 365 000 individuals. Incidence of P falciparum malaria decreased by 60 to 98% in the four townships. 272 prevalence surveys were undertaken and 69 hotspot villages were identified. By April 2017, 50 hotspots were treated with mass drug administration. Hotspot villages had a three times higher incidence of P falciparum at malarial posts than neighbouring villages (adjusted incidence rate ratio [IRR] 2·7, 95% CI 1·8–4·4). Early diagnosis and treatment was associated with a significant decrease in P falciparum incidence in hotspots (IRR 0·82, 95% CI 0·76–0·88 per quarter) and in other villages (0·75, 0·73–0·78 per quarter). Mass drug administration was associated with a five-times decrease in P falciparum incidence within hotspot villages (IRR 0·19, 95% CI 0·13–0·26). By April, 2017, 965 villages (79%) of 1222 corresponding to 104 village tracts were free from P falciparum malaria for at least 6 months. The prevalence of wild-type genotype for K13 molecular markers of artemisinin resistance was stable over the three years (39%; 249/631). Interpretation Providing early diagnosis and effective treatment substantially decreased village-level incidence of artemisinin-resistant P falciparum malaria in hard-to-reach, politically sensitive regions of eastern Myanmar. Targeted mass drug administration significantly reduced malaria incidence in hotspots. If these activities could proceed in all contiguous endemic areas in addition to standard control programmes already implemented, there is a possibility of subnational elimination of P falciparum. Funding The Bill & Melinda Gates Foundation, the Regional Artemisinin Initiative (Global Fund against AIDS, Tuberculosis and Malaria), and the Wellcome Trust.

                Author and article information

                Clin Infect Dis
                Clin. Infect. Dis
                Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
                Oxford University Press (US )
                15 March 2019
                22 October 2018
                22 October 2018
                : 68
                : 6
                : 1066-1067
                [1 ]Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
                [2 ]Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom
                [3 ]Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts
                Author notes
                Correspondence: T. J. Peto, Mahidol University-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd, Rajthevee, Bangkok 10400, Thailand ( tom@ ).
                © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Pages: 2


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