Spread of Artemisinin Resistance in Plasmodium falciparum Malaria

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 in fections (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.)

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

“…The emergence and re‐emergence of infections caused by HIV, Ebola virus and Zika virus has put great pressure on the development of vaccines and new specific therapeutics. The rapid appearances of drug‐resistant pathogens such as drug‐resistant bacteria, fungi, parasites and viruses have been widely reported (Snitkin et al , 2012; Ashley et al , 2014; McCarthy, 2016; Takeda et al , 2017). …”

Elements of effective community engagement: lessons from a targeted malaria elimination study in Lao PDR (Laos)

“…The possibility of these parasites spreading to Africa – a potential public health disaster – has prompted a shift from malaria control to elimination in South East Asia [1–4]. As part of a package of interventions, referred to as Targeted Malaria Elimination (TME), mass antimalarial administration – the presumptive treatment of an entire community to interrupt completely local malaria transmission – is currently under study across the region [5].…”

Genetic markers of artemisinin resistance in Plasmodium spp. parasites

“…Importantly, the latter study demonstrated that slow parasite clearance was observed in malaria patients from western Cambodia irrespective of whether they had been treated with monotherapy, or with artemisinin-based combination therapy (ACT), but this was not observed in patients from the Thailand-Myanmar border to the northwest. Extensive multicentre studies led by the UK-funded TRAC consortium then provided important evidence, just a few years later, that the slow-clearance phenotype was spreading through P. falciparum populations in the Greater Mekong subregion (GMS) in association with certain variants of the pfk13 gene, but that in parallel African studies any treatment failures seen were not associated with this genetic marker [3].…”

“…Alone among these few loci, mutations in pfk13 were also found to correlate with ex vivo DHA susceptibility of Cambodian parasites in the RSA, although the exact mutation identified in mutant F32 parasites has still not been encountered in any wild P. falciparum isolates to date [9]. The identification of key variants of pfk13 that correlate both with slow clearance in patients receiving artesunate monotherapy [3] and with ex vivo RSA data [6] has enabled subsequent research on pfk13. This includes:…”

“…• P. falciparum harbouring variant K13 alleles, and/or demonstrating slow clearance at day 3, are clearly susceptible to extended-duration artemisinin-based treatment, as an ACPR of more than 90% has been achieved in the GMS with 6 days of artesunate monotherapy [23,24] or 3 days of artesunate monotherapy followed by 3 days of ACT [3]. Thus, regimens such as two sequential ACTs with different partner drugs have been postulated as a rational response to signs of falling 3-day ACT efficacy, and a protocol has been developed to evaluate such regimes before ACT failure becomes a serious problem [25].…”