#Evolution and #expansion of #MDR #malaria in southeast #Asia: a #genomic #epidemiology study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study

William L Hamilton, PhD †, Roberto Amato, PhD †, Rob W van der Pluijm, MD, Christopher G Jacob, PhD, Huynh Hong Quang, PhD, Nguyen Thanh Thuy-Nhien, PhD, et al.

Open Access / Published: July 22, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30392-5

 

Summary

Background

A multidrug-resistant co-lineage of Plasmodium falciparum malaria, named KEL1/PLA1, spread across Cambodia in 2008–13, causing high rates of treatment failure with the frontline combination therapy dihydroartemisinin-piperaquine. Here, we report on the evolution and spread of KEL1/PLA1 in subsequent years.

Methods

For this genomic epidemiology study, we analysed whole genome sequencing data from P falciparum clinical samples collected from patients with malaria between 2007 and 2018 from Cambodia, Laos, northeastern Thailand, and Vietnam, through the MalariaGEN P falciparum Community Project. Previously unpublished samples were provided by two large-scale multisite projects: the Tracking Artemisinin Resistance Collaboration II (TRAC2) and the Genetic Reconnaissance in the Greater Mekong Subregion (GenRe-Mekong) project. By investigating genome-wide relatedness between parasites, we inferred patterns of shared ancestry in the KEL1/PLA1 population.

Findings

We analysed 1673 whole genome sequences that passed quality filters, and determined KEL1/PLA1 status in 1615. Before 2009, KEL1/PLA1 was only found in western Cambodia; by 2016–17 its prevalence had risen to higher than 50% in all of the surveyed countries except for Laos. In northeastern Thailand and Vietnam, KEL1/PLA1 exceeded 80% of the most recent P falciparum parasites. KEL1/PLA1 parasites maintained high genetic relatedness and low diversity, reflecting a recent common origin. Several subgroups of highly related parasites have recently emerged within this co-lineage, with diverse geographical distributions. The three largest of these subgroups (n=84, n=79, and n=47) mostly emerged since 2016 and were all present in Cambodia, Laos, and Vietnam. These expanding subgroups carried new mutations in the crt gene, which arose on a specific genetic background comprising multiple genomic regions. Four newly emerging crt mutations were rare in the early period and became more prevalent by 2016–17 (Thr93Ser, rising to 19·8%; His97Tyr to 11·2%; Phe145Ile to 5·5%; and Ile218Phe to 11·1%).

Interpretation

After emerging and circulating for several years within Cambodia, the P falciparum KEL1/PLA1 co-lineage diversified into multiple subgroups and acquired new genetic features, including novel crt mutations. These subgroups have rapidly spread into neighbouring countries, suggesting enhanced fitness. These findings highlight the urgent need for elimination of this increasingly drug-resistant parasite co-lineage, and the importance of genetic surveillance in accelerating malaria elimination efforts.

Funding

Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and UK Department for International Development.

Keywords: Malaria; Plasmodium falciparum; Drugs resistance; Artemisin; Cambodia; Laos; Thailand; Vietnam.

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Decreased in vitro #artemisinin sensitivity of #Plasmodium falciparum across #India (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Decreased in vitro artemisinin sensitivity of Plasmodium falciparum across India

Rimi Chakrabarti, John White, Prasad H. Babar, Shiva Kumar, Devaraja Gouda Mudeppa, Anjali Mascarenhas, Ligia Pereira, Rashmi Dash, Jennifer N. Maki, Ambika Sharma, Kabita Gogoi,Devojit K. Sarma, Ipsita Pal Bhowmick, Suresh Kumar Manoharan, Edwin Gomes, Jagadish Mahanta, Pradyumna Kishore Mohapatra, Laura Chery, Pradipsinh K. Rathod

DOI: 10.1128/AAC.00101-19

 

ABSTRACT

Artemisinin Combination Therapy (ACT) has been used to treat uncomplicated Plasmodium falciparum infections in India since 2004. Since 2008 decreasing artemisinin effectiveness has been seen throughout the Greater Mekong Subregion. The geographic proximity and ecological similarities of northeastern India to southeast Asia may differentially affect the long-term management and sustainability of ACT in India. In order to collect baseline data on variations in ACT sensitivity in Indian parasites, 12 P. falciparum isolates from northeast India and 10 isolated from southwest India were studied in vitro. Ring Stage Survival Assay (RSA) showed reduced sensitivity to dihydroartemisinin in 50% of the 2014-2015 northeast Indian samples. Two of the 10 assayed samples from the southwest region of India, from as far back as 2012, also showed decreased sensitivity to artemisinin. In both these regions, kelch gene sequences were not predictive of reduced artemisinin sensitivity as measured by RSA. The present data justifies future investments in integrated approaches involving clinical follow-up studies, in vitrosurvival assays, and molecular markers, for tracking potential changes in artemisinin effectiveness against P. falciparum throughout India.

Copyright © 2019 Chakrabarti et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Malaria; Plasmodium falciparum; Drugs resistance; Artemisin; India.

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Effect of Mass #Artesunate-Amodiaquine #Distribution on #Mortality of #Patients With #Ebola Virus Disease During West #African #Outbreak (Open Forum Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Open Forum Infect Dis. 2019 May 24;6(7):ofz250. doi: 10.1093/ofid/ofz250. eCollection 2019 Jul.

Effect of Mass Artesunate-Amodiaquine Distribution on Mortality of Patients With Ebola Virus Disease During West African Outbreak.

Garbern SC1, Yam D2, Aluisio AR1, Cho DK3, Kennedy SB4, Massaquoi M4, Sahr F5, Perera SM6, Levine AC1, Liu T2.

Author information: 1 Department of Emergency Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island. 2 Department of Biostatistics, Center for Statistical Sciences, Brown University School of Public Health, Providence, Rhode Island. 3 Brown University, Providence, Rhode Island. 4 Ministry of Health, Monrovia, Liberia. 5 Sierra Leone Ministry of Defense, Freetown, Sierra Leone. 6 International Medical Corps, Washington, DC.

 

Abstract

BACKGROUND:

Experiments in vitro have shown that the drug amodiaquine may inhibit Ebola virus activity. During the Ebola virus disease (EVD) epidemic in West Africa in 2014-2016, 2 mass drug administrations (MDAs) of artesunate-amodiaquine (ASAQ) were implemented to decrease the burden of malaria. The objective of this study was to assess the effect of the ASAQ MDAs on the mortality of patients with EVD.

METHODS:

A retrospective cohort design was used to analyze mortality data for patients with EVD admitted to 5 Ebola treatment units in Liberia and Sierra Leone. Patients admitted to the ETUs during the time period of ASAQ’s therapeutic effect from areas where the MDA was implemented were matched to controls not exposed to ASAQ, using a range of covariates, including malaria co-infection status, and a logistic regression analysis was performed. The primary outcome was Ebola treatment unit mortality.

RESULTS:

A total of 424 patients with EVD had sufficient data for analysis. Overall, the mortality of EVD patients was 57.5%. A total of 22 EVD patients were exposed to ASAQ during the MDAs and were found to have decreased risk of death compared with those not exposed in a matched analysis, but this did not reach statistical significance (relative risk, 0.63; 95% confidence interval, 0.37-1.07; P = .086).

CONCLUSIONS:

There was a non-statistically significantly decreased risk of mortality in EVD patients exposed to ASAQ during the 2 MDAs as compared with EVD patients not exposed to ASAQ. Further prospective trials are needed to determine the direct effect of ASAQ on EVD mortality.

KEYWORDS: Ebola virus disease; amodiaquine; epidemic; mass drug administration; mortality

PMID: 31281856 PMCID: PMC6602760 DOI: 10.1093/ofid/ofz250

Keywords: Ebola; Malaria; West Africa; Artesunate; Amodiquinine.

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Long-term #incidence of #severe #malaria following #RTS,S/AS01 #vaccination in #children and infants in #Africa: an open-label 3-year extension study of a phase 3 #RCT (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Long-term incidence of severe malaria following RTS,S/AS01 vaccination in children and infants in Africa: an open-label 3-year extension study of a phase 3 randomised controlled trial

Halidou Tinto, PhD †, Walter Otieno, PhD †, Samwel Gesase, MSc, Hermann Sorgho, PhD, Lucas Otieno, MSc, Edwin Liheluka, MPH, Innocent Valéa, MD, Valentine Sing’oei, MB, Anangisye Malabeja, MD, Daniel Valia, MD, Anne Wangwe, BScN, Emilia Gvozdenovic, PhD, Yolanda Guerra Mendoza, MD, Erik Jongert, PhD, Marc Lievens, MSc, François Roman, MD, Lode Schuerman, MD, John Lusingu, PhD

Published: July 09, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30300-7

 

Summary

Background

Results from a previous phase 3 study showed efficacy of the RTS,S/AS01 vaccine against severe and clinical malaria in children (in 11 sites in Africa) during a 3–4-year follow-up. We aimed to investigate malaria incidence up to 7 years postvaccination in three of the sites of the initial study.

Methods

In the initial phase 3 study, infants aged 6–12 weeks and children aged 5–17 months were randomly assigned (1:1:1) to receive four RTS,S/AS01 doses (four-dose group), three RTS,S/AS01 doses and a comparator dose (three-dose group), or four comparator doses (control group). In this open-label extension study in Korogwe (Tanzania), Kombewa (Kenya), and Nanoro (Burkina Faso), we assessed severe malaria incidences as the primary outcome for 3 additional years (January, 2014, to December, 2016), up to 6 years (younger children) or 7 years (older children) postprimary vaccination in the modified intention-to-treat population (ie, participants who received at least one dose of the study vaccine). As secondary outcomes, we evaluated clinical malaria incidences and serious adverse events. This trial is registered with ClinicalTrials.gov, number NCT02207816.

Findings

We enrolled 1739 older children (aged 5–7 years) and 1345 younger children (aged 3–5 years). During the 3-year extension, 66 severe malaria cases were reported, resulting in severe malaria incidence of 0·004 cases per person-years at risk (PPY; 95% CI 0–0·033) in the four-dose group, 0·007 PPY (0·001–0·052) in the three-dose group, and 0·009 PPY (0·001–0·066) in the control group in the older children category and a vaccine efficacy against severe malaria that did not contribute significantly to the overall efficacy (four-dose group 53·7% [95% CI −13·7 to 81·1], p=0·093; three-dose group 23·3% [–67·1 to 64·8], p=0·50). In younger children, severe malaria incidences were 0·007 PPY (0·001–0·058) in the four-dose group, 0·007 PPY (0·001–0·054) in the three-dose group, and 0·011 PPY (0·001–0·083) in the control group. Vaccine efficacy against severe malaria also did not contribute significantly to the overall efficacy (four-dose group 32·1% [–53·1 to 69·9], p=0·35; three-dose group 37·6% [–44·4 to 73·0], p=0·27). Malaria transmission was still occurring as evidenced by an incidence of clinical malaria ranging from 0·165 PPY to 3·124 PPY across all study groups and sites. In older children, clinical malaria incidence was 1·079 PPY (95% CI 0·152–7·662) in the four-dose group, 1·108 PPY (0·156–7·868) in the three-dose group, and 1·016 PPY (0·14–7·213) in the control group. In younger children, malaria incidence was 1·632 PPY (0·23–11·59), 1·563 PPY (0·22–11·104), and 1·686 PPY (0·237–11·974), respectively. In the older age category in Nanoro, clinical malaria incidence was higher in the four-dose (2·444 PPY; p=0·011) and three-dose (2·411 PPY; p=0·034) groups compared with the control group (1·998 PPY). Three cerebral malaria episodes and five meningitis cases, but no vaccine-related severe adverse events, were reported.

Interpretation

Overall, severe malaria incidence was low in all groups, with no evidence of rebound in RTS,S/AS01 recipients, despite an increased incidence of clinical malaria in older children who received RTS,S/AS01 compared with the comparator group in Nanoro. No safety signal was identified.

Funding

GlaxoSmithKline Biologicals SA.

Keywords: Malaria; Vaccines.

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#RTS,S #malaria #vaccine pilot studies: addressing the #human #realities in large-scale clinical trials (Trials, abstract)

[Source: Trials, full page: (LINK). Abstract, edited.]

Commentary / Open Access / Open Peer Review

RTS,S malaria vaccine pilot studies: addressing the human realities in large-scale clinical trials

Machteld van den Berg, Bernhards Ogutu, Nelson K. Sewankambo, Nikola Biller-Andorno and Marcel Tanner

Trials, 201920:316 / DOI: https://doi.org/10.1186/s13063-019-3391-7

©  The Author(s). 2019

Received: 18 December 2018 – Accepted: 2 May 2019 – Published: 31 May 2019 – Open Peer Review reports

 

Abstract

A malaria vaccine as part of the integrated malaria control and elimination efforts will have a major impact on public health in sub-Sahara Africa. The first malaria vaccine, RTS,S, now enters pilot implementation in three African countries. These pilot implementation studies are being initiated in Kenya, Malawi, and Ghana to inform the broader roll-out recommendation. Based on the malaria vaccine clinical trial experiences, key ethical practices for effective clinical trial research in low-resource settings are described. For successful vaccine integration into malaria intervention programs, the relational dynamics between researchers and trial communities must be made explicit. Incorporating community values and returning to research practices that serve the intended benefactors are key strategies that address the human realities in large-scale clinical trials and pilot implementation, leading to positive public health outcomes.

Keywords: Malaria vaccine – Pilot studies – Low-resource settings – Community engagement – Ethics – Transnational clinical trials

Keywords: Malaria; Vaccines; Bioethics.

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#Arboviral #diseases and #malaria in #Australia, 2014–15: Annual report of the National Arbovirus and Malaria Advisory Committee (Commun Dis Intell (2018), abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Commun Dis Intell (2018). 2019 Apr 15;43. doi: 10.33321/cdi.2019.43.14.

Arboviral diseases and malaria in Australia, 2014–15: Annual report of the National Arbovirus and Malaria Advisory Committee

Knope K1, Doggett SL2, Jansen CC3, Johansen CA4,5, Kurucz N6, Feldman R7, Lynch SE8, Hobby MP9, Sly A10, Jardine A11, Bennett S3, Currie BJ12, the National Arbovirus and Malaria Advisory Committee.

Author information: 1 Zoonoses, Foodborne and Emerging Infectious Diseases Section, Health Protection Policy Branch, Office of Health Protection, Department of Health, Canberra, Australian Capital Territory; 2 Department of Medical Entomology, Pathology West, Institute for Clinical Pathology and Medical Research, Westmead Hospital, Westmead, New South Wales; 3 Communicable Diseases Branch, Department of Health, Queensland Government, Herston, Qld 4006; 4 Arbovirus Surveillance and Research Laboratory, School of Pathology and Laboratory Medicine, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Nedlands, Western Australia. 5
As of July 2015: Division of Microbiology and Infectious Diseases, PathWest Laboratory Medicine WA, QEII Medical Centre, Western Australian Department of Health, Nedlands, Western Australia. 6 Medical Entomology, Centre for Disease Control, Health Protection Division, Northern Territory Department of Health, Royal Darwin Hospital, Casuarina, Northern Territory; 7 Communicable Disease Prevention and Control, Department of Health, Melbourne, Victoria; 8 Agriculture Victoria Research, AgriBio Centre for AgriBioscience, 5 Ring Road, Bundoora, Victoria, 3083, Australia; 9 Health Protection, Public Health, South Australian Department of Health, Adelaide, South Australia; 10 Department of Agriculture and Water Resources, Compliance Division, Eagle Farm, Queensland; 11 Medical Entomology, Environmental Health Directorate, Department of Health, Western Australia; 12 Royal Darwin Hospital Northern Territory; Menzies School of Health Research, Darwin, Northern Territory

 

Abstract

This report describes the epidemiology of mosquito-borne diseases of public health importance in Australia during the 2014–15 season (1 July 2014 to 30 June 2015) and includes data from human notifications, sentinel chicken, vector and virus surveillance programs. The National Notifiable Diseases Surveillance System received notifications for 12,849 cases of disease transmitted by mosquitoes during the 2014–15 season. The Australasian alphaviruses Barmah Forest virus and Ross River virus accounted for 83% (n=10,723) of notifications. However, over-diagnosis and possible false positive diagnostic test results for these two infections mean that the true burden of infection is likely overestimated, and as a consequence, revised case definitions were implemented from 1 January 2016. There were 151 notifications of imported chikungunya virus infection. There were 74 notifications of dengue virus infection acquired in Australia and 1,592 cases acquired overseas, with an additional 34 cases for which the place of acquisition was unknown. Imported cases of dengue were most frequently acquired in Indonesia (66%). There were 7 notifications of Zika virus infection. No cases of locally-acquired malaria were notified during the 2014–15 season, though there were 259 notifications of overseas-acquired malaria and one notification for which no information on the place of acquisition was supplied. Imported cases of malaria were most frequently acquired in southern and eastern Africa (23%) and Pacific Island countries (20%). In 2014–15, arbovirus and mosquito surveillance programs were conducted in most of the states and territories. Surveillance for exotic mosquitoes at international ports of entry continues to be a vital part of preventing the establishment of vectors of mosquito-borne diseases such as dengue to new areas of Australia. In 2014-15, there was a sharp increase in the number of exotic mosquitoes detected at the Australian border, with 36 separate exotic mosquito detections made, representing a 280% increase from the 2013-14 period where there were 13 exotic mosquito detections.

KEYWORDS: arbovirus; Barmah Forest virus; chikungunya; dengue; Zika; disease surveillance; epidemiology; flavivirus; Japanese encephalitis; West Nile virus; Kunjin virus; malaria; mosquito-borne disease; mosquitoes; Murray Valley encephalitis virus; Ross River virus; yellow fever; exotic mosquitoes

PMID: 30982295

Keywords: Arbovirus; Alphavirus; Flaviviru; Barmah forest virus; Chikungunya fever; Zika virus; WNV; Malaria; Australia.

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Efficacy and #risk of #harms of repeat #ivermectin mass drug administrations for control of #malaria (#RIMDAMAL): a cluster-randomised trial (Lancet, abstract)

[Source: The Lancet, full page: (LINK). Abstract, edited.]

Efficacy and risk of harms of repeat ivermectin mass drug administrations for control of malaria (RIMDAMAL): a cluster-randomised trial

Prof Brian D Foy, PhD., Haoues Alout, PhD, Jonathan A Seaman, BSc, Sangeeta Rao, PhD, Tereza Magalhaes, PhD, Martina Wade, BSc et al.

Open Access / Published: March 13, 2019 / DOI: https://doi.org/10.1016/S0140-6736(18)32321-3

 

Summary

Background

Ivermectin is widely used in mass drug administrations for controlling neglected parasitic diseases, and can be lethal to malaria vectors that bite treated humans. Therefore, it could be a new tool to reduce plasmodium transmission. We tested the hypothesis that frequently repeated mass administrations of ivermectin to village residents would reduce clinical malaria episodes in children and would be well tolerated with minimal harms.

Methods

We invited villages (clusters) in Burkina Faso to participate in a single-blind (outcomes assessor), parallel-assignment, two-arm, cluster-randomised trial over the 2015 rainy season. Villages were assigned (1:1) by random draw to either the intervention group or the control group. In both groups, all eligible participants who consented to the treatment and were at least 90 cm in height received single oral doses of ivermectin (150–200 μg/kg) and albendazole (400 mg), and those in the intervention group received five further doses of ivermectin alone at 3-week intervals thereafter over the 18-week treatment phase. The primary outcome was cumulative incidence of uncomplicated malaria episodes over 18 weeks (analysed on a cluster intention-to-treat basis) in an active case detection cohort of children aged 5 years or younger living in the study villages. This trial is registered with ClinicalTrials.gov, number NCT02509481.

Findings

Eight villages agreed to participate, and four were randomly assigned to each group. 2712 participants (1333 [49%] males and 1379 [51%] females; median age 15 years [IQR 6–34]), including 590 children aged 5 years or younger, provided consent and were enrolled between May 22 and July 20, 2015 (except for 77 participants enrolled after these dates because of unavailability before the first mass drug administration, travel into the village during the trial, or birth), with 1447 enrolled into the intervention group and 1265 into the control group. 330 (23%) participants in the intervention group and 233 (18%) in the control group met the exclusion criteria for mass drug administration. Most children in the active case detection cohort were not treated because of height restrictions. 14 (4%) children in the intervention group and 10 (4%) in the control group were lost to follow-up. Cumulative malaria incidence was reduced in the intervention group (648 episodes among 327 children; estimated mean 2·00 episodes per child) compared with the control group (647 episodes among 263 children; 2·49 episodes per child; risk difference −0·49 [95% CI −0·79 to −0·21], p=0·0009, adjusted for sex and clustering). The risk of adverse events among all participants did not differ between groups (45 events [3%] among 1447 participants in the intervention group vs 24 events [2%] among 1265 in the control group; risk ratio 1·63 [1·01 to 2·67]; risk difference 1·21 [0·04 to 2·38], p=0·060), and no adverse reactions were reported.

Interpretation

Frequently repeated mass administrations of ivermectin during the malaria transmission season can reduce malaria episodes among children without significantly increasing harms in the populace.

Funding

Bill & Melinda Gates Foundation.

Keywords: Malaria; Ivermectin.

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