Author
Andreas Mårtensson
Other affiliations: Uppsala University, Karolinska University Hospital
Bio: Andreas Mårtensson is an academic researcher from Karolinska Institutet. The author has contributed to research in topics: Plasmodium falciparum & Malaria. The author has an hindex of 38, co-authored 69 publications receiving 5334 citations. Previous affiliations of Andreas Mårtensson include Uppsala University & Karolinska University Hospital.
Papers published on a yearly basis
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TL;DR: Following deployment of ACT in Zanzibar 2003, malaria-associated morbidity and mortality decreased dramatically within two years and indicated that the Millennium Development Goals of reducing mortality in children under five and alleviating the burden of malaria are achievable in tropical Africa with high coverage of combined malaria control interventions.
Abstract: BACKGROUND
The Roll Back Malaria strategy recommends a combination of interventions for malaria control. Zanzibar implemented artemisinin-based combination therapy (ACT) for uncomplicated malaria in late 2003 and long-lasting insecticidal nets (LLINs) from early 2006. ACT is provided free of charge to all malaria patients, while LLINs are distributed free to children under age 5 y ("under five") and pregnant women. We investigated temporal trends in Plasmodium falciparum prevalence and malaria-related health parameters following the implementation of these two malaria control interventions in Zanzibar.
METHODS AND FINDINGS
Cross-sectional clinical and parasitological surveys in children under the age of 14 y were conducted in North A District in May 2003, 2005, and 2006. Survey data were analyzed in a logistic regression model and adjusted for complex sampling design and potential confounders. Records from all 13 public health facilities in North A District were analyzed for malaria-related outpatient visits and admissions. Mortality and demographic data were obtained from District Commissioner's Office. P. falciparum prevalence decreased in children under five between 2003 and 2006; using 2003 as the reference year, odds ratios (ORs) and 95% confidence intervals (CIs) were, for 2005, 0.55 (0.28-1.08), and for 2006, 0.03 (0.00-0.27); p for trend < 0.001. Between 2002 and 2005 crude under-five, infant (under age 1 y), and child (aged 1-4 y) mortality decreased by 52%, 33%, and 71%, respectively. Similarly, malaria-related admissions, blood transfusions, and malaria-attributed mortality decreased significantly by 77%, 67% and 75%, respectively, between 2002 and 2005 in children under five. Climatic conditions favorable for malaria transmission persisted throughout the observational period.
CONCLUSIONS
Following deployment of ACT in Zanzibar 2003, malaria-associated morbidity and mortality decreased dramatically within two years. Additional distribution of LLINs in early 2006 resulted in a 10-fold reduction of malaria parasite prevalence. The results indicate that the Millennium Development Goals of reducing mortality in children under five and alleviating the burden of malaria are achievable in tropical Africa with high coverage of combined malaria control interventions.
621 citations
Mahidol University1, University of California, San Francisco2, University of Cape Town3, Wellcome Trust4, University of Tübingen5, University of Western Australia6, University of Oxford7, University of Paris8, World Health Organization9, University of Bamako10, Swiss Tropical and Public Health Institute11, University of Lausanne12, Pasteur Institute13, Novartis14, Liverpool School of Tropical Medicine15, Karolinska Institutet16, Walter and Eliza Hall Institute of Medical Research17, Drugs for Neglected Diseases Initiative18, University of Southern Denmark19, National University of Laos20, Mahosot Hospital21, International Military Sports Council22, Muhimbili University of Health and Allied Sciences23, Yale University24, Uppsala University25, University of Washington26, University of Amsterdam27
TL;DR: Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia, as well as patients in very low transmission intensity areas with emerging parasite resistance.
Abstract: Background: Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the 'therapeutic' day 7 lumefantrine concentration threshold needs to be defined better, particularly for important patient and parasite sub-populations. Methods: The WorldWide Antimalarial Resistance Network (WWARN) conducted a large pooled analysis of individual pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on study design, methodology and missing data. Results: Of 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21 studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations (HR 1.59 (95 % CI 1.36 to 1.85) per halving of day 7 concentrations) and high baseline parasitemia (HR 1.87 (95 % CI 1.22 to 2.87) per 10-fold increase). Adjusted for mg/kg dose, day 7 concentrations were lowest in very young children (98 % cure rates (if parasitemia <135,000/μL). Conclusions: Current artemether-lumefantrine dosing recommendations achieve day 7 lumefantrine concentrations ≥200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.
445 citations
TL;DR: An follow-up clinical trial in Zanzibar points to 86N as a potential marker of lumefantrine resistance in vivo, while suggesting that Coartem is not robust enough to avoid selection of resistance-associated mutations in some malarial settings.
Abstract: Artemisinin derivative-based combination therapy is expected to suppress the development of Plasmodium falciparum drug resistance in Africa. We have performed an artemether-lumefantrine (Coartem; Novartis) follow-up clinical trial in Zanzibar, in which pfcrt K76T and pfmdr1 N86Y frequencies were determined before drug administration and in all recurrent parasites during a follow-up period of 42 days. A significant increase in pfmdr1 86N was observed after exposure to the drug. This points to 86N as a potential marker of lumefantrine resistance in vivo, while suggesting that Coartem is not robust enough to avoid selection of resistance-associated mutations in some malarial settings.
365 citations
Duke University1, University of North Carolina at Chapel Hill2, Liverpool School of Tropical Medicine3, University of Ouagadougou4, University of London5, Kwame Nkrumah University of Science and Technology6, Medical Research Council7, Centers for Disease Control and Prevention8, Kenya Medical Research Institute9, University of Malawi10, Karolinska Institutet11, University of Health and Allied Sciences12, University of California, San Francisco13, University of Kinshasa14, University of Massachusetts Amherst15
TL;DR: An assay to quantify rare polymorphisms in parasite populations that uses a pooled deep-sequencing approach to score allele frequencies is developed and validated by evaluating mixtures of laboratory parasite strains, and used to screen P. falciparum parasites from >1100 African infections collected since 2002.
Abstract: Plasmodium falciparum parasites that are resistant to artemisinins have been detected in Southeast Asia. Resistance is associated with several polymorphisms in the parasite's K13-propeller gene. The molecular epidemiology of these artemisinin resistance genotypes in African parasite populations is unknown. We developed an assay to quantify rare polymorphisms in parasite populations that uses a pooled deep-sequencing approach to score allele frequencies, validated it by evaluating mixtures of laboratory parasite strains, and then used it to screen P. falciparum parasites from >1100 African infections collected since 2002 from 14 sites across sub-Saharan Africa. We found no mutations in African parasite populations that are associated with artemisinin resistance in Southeast Asian parasites. However, we observed 15 coding mutations, including 12 novel mutations, and limited allele sharing between parasite populations, consistent with a large reservoir of naturally occurring K13-propeller variation. Although polymorphisms associated with artemisinin resistance in P. falciparum in Southeast Asia are not prevalent in sub-Saharan Africa, numerous K13-propeller coding polymorphisms circulate in Africa. Although their distributions do not support a widespread selective sweep for an artemisinin-resistant phenotype, the impact of these mutations on artemisinin susceptibility is unknown and will require further characterization. Rapid, scalable molecular surveillance offers a useful adjunct in tracking and containing artemisinin resistance.
253 citations
TL;DR: An individual patient data meta-analysis of the associations between parasite clearance half-life (PC1/2) and pfk13 genotype based on a large set of individual patient records from Asia and Africa demonstrates that 15 additional pfK13 alleles are associated strongly with the slow-clearing phenotype in Southeast Asia.
Abstract: Background: Plasmodium falciparum infections with slow parasite clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow cleara ...
216 citations
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TL;DR: The overall median clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours in Wang Pha (P<0.001) in each of the two locations as discussed by the authors.
Abstract: We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate–mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P = 0. 31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco–endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups. CONCLUSIONS P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)
3,010 citations
TL;DR: Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing, and the incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission.
Abstract: BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).
1,777 citations
01 Jan 2011
TL;DR: The World Health Organization (WHO) World Malaria Report 2021 estimates that there were 241 million malaria cases, including 627,000 deaths, worldwide in 2020, which represents around 14 million more cases, and 69,000 more deaths, than 2019.
Abstract: The World Health Organization (WHO) World Malaria Report 2021 < https://www.who.int/publications/i/item/9789240040496 > estimates that there were 241 million malaria cases, including 627,000 deaths, worldwide in 2020, which represents around 14 million more cases, and 69,000 more deaths, than 2019. Approximately two-thirds of these additional deaths were linked to disruptions in the provision of malaria prevention, diagnosis and treatment during the COVID-19 pandemic. Sub-Saharan Africa continues to carry the heaviest malaria burden, accounting for about 95% of all cases and 96% of all deaths in 2020, with around 80% of deaths in the region among children under five years old. Since 2015, the baseline date for the WHO's global malaria strategy, registered increases in malaria deaths were reported in 24 countries. In the 11 countries that carry the highest burden of malaria worldwide, cases increased from 150 million in 2015 to 163 million cases in 2020, and malaria deaths increased from 390,000 to 444,600 over that same period. As in previous years, the report includes an up-to-date assessment on the burden of malaria at global, regional, and country levels, and tracks investment in malaria programmes and research, as well as detailing progress across the four intervention areas of prevention, diagnosis, treatment and surveillance. There are also dedicated chapters on malaria elimination and key threats, such as insecticide and drug resistance.
1,181 citations
TL;DR: This 2007 global P. falciparum malaria endemicity map is the first of a series with which it will be possible to monitor and evaluate the progress of this intervention process, and shows significant opportunities for malaria control in Africa and for malaria elimination elsewhere.
Abstract: Transmission intensity affects almost all aspects of malaria epidemiology and the impact of malaria on human populations. Maps of transmission intensity are necessary to identify populations at different levels of risk and to evaluate objectively options for disease control. To remain relevant operationally, such maps must be updated frequently. Following the first global effort to map Plasmodium falciparum malaria endemicity in 2007, this paper describes the generation of a new world map for the year 2010. This analysis is extended to provide the first global estimates of two other metrics of transmission intensity for P. falciparum that underpin contemporary questions in malaria control: the entomological inoculation rate (Pf EIR) and the basic reproductive number (PfR). Annual parasite incidence data for 13,449 administrative units in 43 endemic countries were sourced to define the spatial limits of P. falciparum transmission in 2010 and 22,212 P. falciparum parasite rate (Pf PR) surveys were used in a model-based geostatistical (MBG) prediction to create a continuous contemporary surface of malaria endemicity within these limits. A suite of transmission models were developed that link Pf PR to Pf EIR and PfR and these were fitted to field data. These models were combined with the Pf PR map to create new global predictions of Pf EIR and PfR. All output maps included measured uncertainty. An estimated 1.13 and 1.44 billion people worldwide were at risk of unstable and stable P. falciparum malaria, respectively. The majority of the endemic world was predicted with a median Pf EIR of less than one and a median PfRc of less than two. Values of either metric exceeding 10 were almost exclusive to Africa. The uncertainty described in both Pf EIR and PfR was substantial in regions of intense transmission. The year 2010 has a particular significance as an evaluation milestone for malaria global health policy. The maps presented here contribute to a rational basis for control and elimination decisions and can serve as a baseline assessment as the global health community looks ahead to the next series of milestones targeted at 2015.
1,161 citations
01 Jan 2008
TL;DR: The number of malaria cases and deaths in sub-Saharan Africa has increased significantly in recent years, with the number of cases and number of deaths more than trebling in the past five years.
Abstract: Estimated burden of malaria Estimated cases and deaths (2006) Estimated cases and deaths per 1000 (2006) Age group Numbers Lower Upper Per 1000 Lower Upper Fever suspected of being malaria All ages 18 848 000 2 823 000 39 076 000 390 58 808 < 5 years 2 214 000 332 000 4 590 000 534 80 1 107 Malaria cases All ages 4 209 000 867 000 8 529 000 87 18 176 < 5 years 494 000 102 000 1 002 000 119 25 242 Malaria deaths All ages 9 100 2 400 17 000 0.19 0.05 0.35 < 5 years 2 300 590 4 400 0.56 0.14 1.1 Malaria case-fatality rate (%) All ages 0.22 — — — < 5 years 0.47 — — —
1,012 citations