Understanding artemisinin-resistant malaria

Abstract

Purpose of review The emergence of artemisinin resistance in Southeast Asia, where artemisinin combination therapies (ACTs) are beginning to fail, threatens global endeavors to control and eliminate Plasmodium falciparum malaria. Future efforts to prevent the spread of this calamity to Africa will benefit from last year’s tremendous progress in understanding artemisinin resistance. Recent findings Multiple international collaborations have established that artemisinin resistance is associated with slow parasite clearance in patients; increased survival of early ring-stage parasites in vitro; single-nucleotide polymorphisms (SNPs) in the parasite’s ‘K13’ gene; parasite ‘founder’ populations sharing a genetic background of four additional SNPs; parasite transcriptional profiles reflecting an “unfolded protein response” and decelerated parasite development; and elevated parasite phosphatidylinositol-3-kinase activity. In Western Cambodia, where the K13 C580Y mutation is approaching fixation, the frontline ACT is failing to cure nearly half of patients, likely due to partner drug resistance. In Africa, where dozens of K13 mutations have been detected at low frequency, there is no evidence yet of artemisinin resistance. Summary In Southeast Asia, clinical and epidemiological investigations are urgently needed to stop the further spread of artemisinin resistance; monitor ACT efficacy where K13 mutations are prevalent; identify currently-available drug regimens that cure ACT failures; and rapidly advance new antimalarial compounds through clinical trials.

Dihydroartemisinin–piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study

“…We did a cohort study to identify piperaquine-resistant P falciparum infections in Cambodia. We postulated that such infections would be associated with artemisinin resistance, 19 dihydroartemisinin–piperaquine failures, adequate piperaquine exposure, and decreased susceptibility of P falciparum isolates to piperaquine in vitro. We also postulated that dihydroartemisinin–piperaquine would fail more often in areas where artemisinin resistance is prevalent than where it is emerging.…”

Emergence of Mutations in the K13 Propeller Gene of Plasmodium falciparum Isolates from Dakar, Senegal, in 2013-2014

“…In Comoros (Grande Comore and Anjouan) in 2013, two isolates (6.9%) were found to carry the N554H and N554K mutations (16). A mutation in the corresponding codon (resulting in N554S) was found in one isolate from Ungoye, Kenya, in 2012 (11) and in one isolate from Mali in 2011 (17). A mutation in this codon has never been found in an isolate from Southeast Asia (18).…”

Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Ugandan Schoolchildren Selects for Plasmodium falciparum Transporter Polymorphisms That Modify Drug Sensitivity

“…Piperaquine is a bisaminoquinoline related to chloroquine and amodiaquine. Resistance to piperaquine was widely reported during the preartemisinin era in China (20), and recently clinically relevant resistance, with frequent recrudescences after therapy with DP, has been noted in Cambodia (21)(22)(23). However, mechanisms of resistance to piperaquine are uncertain.…”