@article{fdi:010074078,
  title = {{H}igh-level artemisinin-resistance with quinine co-resistance emerges in {P}. falciparum malaria under in vivo artesunate pressure},
  author = {{T}yagi, {R}. {K}. and {G}leeson, {P}. {J}. and {A}rnold, {L}. and {T}ahar, {R}achida and {P}rieur, {E}. and {D}ecosterd, {L}. and {P}erignon, {J}. {L}. and {O}lliaro, {P}. and {D}ruilhe, {P}.},
  editor = {},
  language = {{ENG}},
  abstract = {{B}ackground: {H}umanity has become largely dependent on artemisinin derivatives for both the treatment and control of malaria, with few alternatives available. {A} {P}lasmodium falciparum phenotype with delayed parasite clearance during artemisinin-based combination therapy has established in {S}outheast {A}sia, and is emerging elsewhere. {T}herefore, we must know how fast, and by how much, artemisinin-resistance can strengthen. {M}ethods: {P}. falciparum was subjected to discontinuous in vivo artemisinin drug pressure by capitalizing on a novel model that allows for long-lasting, high-parasite loads. {I}ntravenous artesunate was administered, using either single flash-doses or a 2-day regimen, to {P}. falciparum-infected humanized {NOD}/{SCID} {IL}-2{R} gamma(-/-) immunocompromised mice, with progressive dose increments as parasites recovered. {T}he parasite's response to artemisinins and other available anti-malarial compounds was characterized in vivo and in vitro. {R}esults: {A}rtemisinin resistance evolved very rapidly up to extreme, near-lethal doses of artesunate (240 mg/kg), an increase of > 3000-fold in the effective in vivo dose, far above resistance levels reported from the field. {A}rtemisinin resistance selection was reproducible, occurring in 80% and 41% of mice treated with flash-dose and 2-day regimens, respectively, and the resistance phenotype was stable. {M}easuring in vitro sensitivity proved inappropriate as an early marker of resistance, as {IC}50 remained stable despite in vivo resistance up to 30 mg/kg ({ART}-{S}: 10.7 n{M} (95% {CI} 10.2-11.2) vs. {ART}-{R}-30: 11.5 n{M} (6.6-16.9), {F} = 0.525, p = 0.47). {H}owever, when in vivo resistance strengthened further, {IC}50 increased 10-fold ({ART}-{R}-240 100.3 n{M} (92.9-118.4), {F} = 304.8, p < 0.0001), reaching a level much higher than ever seen in clinical samples. {A}rtemisinin resistance in this {A}frican {P}. falciparum strain was not associated with mutations in ketch-13, casting doubt over the universality of this genetic marker for resistance screening. {R}emarkably, despite exclusive exposure to artesunate, full resistance to quinine, the only other drug sufficiently fast-acting to deal with severe malaria, evolved independently in two parasite lines exposed to different artesunate regimens in vivo, and was confirmed in vitro. {C}onclusion: {P}. falciparum has the potential to evolve extreme artemisinin resistance and more complex patterns of multidrug resistance than anticipated. {I}f resistance in the field continues to advance along this trajectory, we will be left with a limited choice of suboptimal treatments for acute malaria, and no satisfactory option for severe malaria.},
  keywords = {{M}alaria ; {P}. falciparum ; {A}rtemisinin ; {R}esistance ; {A}rtesunate ; {Q}uinine ; {NSG} mice},
  booktitle = {},
  journal = {{BMC} {M}edicine},
  volume = {16},
  numero = {},
  pages = {art. 181 [19 p.]},
  ISSN = {1741-7015},
  year = {2018},
  DOI = {10.1186/s12916-018-1156-x},
  URL = {https://www.documentation.ird.fr/hor/fdi:010074078},
}