Persistent Submicroscopic Plasmodium falciparum Parasitemia 72 Hours after Treatment with Artemether-Lumefantrine Predicts 42-Day Treatment Failure in Mali and Burkina Faso

Abstract

A recent randomised controlled trial, WANECAM, conducted at seven centres in West Africa, found that artemether-lumefantrine, artesunate-amodiaquine, pyronaridine-artesunate and dihydroartemisinin-piperaquine all displayed good efficacy. However, artemether-lumefantrine was associated with a shorter interval between clinical episodes than the other regimens. In a further comparison of these therapies, we identified cases of persisting sub-microscopic parasitaemia by qPCR at 72h post-treatment among WANECAM participants from 5 sites in Mali and Burkina Faso, and compared treatment outcomes for this group to those with complete parasite clearance by 72h. Among 547 evaluable patients, 17.7% had qPCR-detectable parasitaemia at 72h during their first treatment episode. This proportion varied among sites, reflecting differences in malaria transmission intensity, but did not differ among pooled drug treatment groups. However, patients who received artemether-lumefantrine and were qPCR positive at 72h were significantly more likely to have microscopically-detectable recurrent Plasmodium falciparum parasitaemia by day 42 than those receiving other regimens, and experienced on average a shorter time-interval before the next clinical episode. Haplotypes of pfcrt and pfmdr1 were also evaluated in persisting parasites. These data identify a possible threat to the parasitological efficacy of artemether-lumefantrine in West Africa, over a decade since it was first introduced on a large scale.

Parasite clearance dynamics in children hospitalised with severe malaria in the Ho Teaching Hospital, Volta Region, Ghana

“…There have been some reports of delayed parasite clearance in Africa. The distributions observed do not yet support a widespread selective sweep for an ACT-resistant phenotype, but does warrant continued surveillance ( Beshir et al, 2013 , Beshir et al, 2021 ; Taylor et al, 2015 ; Lu et al, 2017 ; Sutherland et al, 2017 ). Recent in vitro studies have greatly expanded our understanding of reduced artemisinin susceptibility in P. falciparum and identified important K13-independent resistance phenotypes mediated in vitro by variants of other cellular proteins, including Coronin, trafficking adaptin subunit AP-2μ and ubiquitin binding protein 1 (UBP-1) ( Sutherland et al, 2020 ).…”

“…qPCR reactions for each sample were run in duplicate alongside a calibrator, the WHO international standard for P. falciparum DNA, as previously described ( Robinson et al, 2019 ). This method has an estimated limit of detection of 0.05 parasites per μL of whole blood ( Beshir et al, 2013 , Beshir et al, 2021 ; Lubis et al, 2020 ).…”

“…Artemisinin-based combination therapy (ACT) is recommended for the management of uncomplicated malaria in African countries, whereas parenteral artesunate monotherapy is the recommended regimen for hospitalised SM cases ( Dondorp et al, 2010 ). Reduced susceptibility to artemisinin in P. falciparum manifests as slower parasite clearance in vivo , commonly measured as parasite clearance half-life in patients treated with artesunate monotherapy and monitored by microscopy of closely-spaced (6–12 h apart) blood samples ( Ashley et al, 2014 ) or by qPCR estimation of parasite density in daily finger-prick blood samples ( Beshir et al, 2021 ). The emergence in the Mekong countries of P. falciparum parasites displaying reduced susceptibility threatens ACT treatment efficacy ( Noedl et al, 2008 ; Dondorp et al, 2009 ; Ashley et al, 2014 ; Spring et al, 2015 ).…”

“…In the African setting, with large paediatric patient population, and in remote areas of Asia qPCR estimation of changes in parasite density in daily blood samples at 24 h, 48 h and 72 h provides an alternative to the frequent blood sampling deployed by studies in the Mekong countries ( Beshir et al, 2010 , Beshir et al, 2013 , Beshir et al, 2021 ; Lubis et al, 2020 ). Declining ACT efficacy would not only jeopardize malaria eradication but may also result in a surge in African childhood morbidity and mortality rates.…”

Impact of Drug Exposure on Resistance Selection Following Artemether‐Lumefantrine Treatment for Malaria in Children With and Without HIV in Uganda

“…[6][7][8][9][10][11][12] Artemisinins may also exert selective pressure at pfmdr1. 10,[13][14][15] AL has remained the ACT least impacted by the emergence and spread of artemisinin resistance, but efficacy concerns are being raised in a handful of SSA countries. 15,16 Following rapid artemisinin clearance, partner drugs persist as a monotherapy for weeks to months.…”