<i>Plasmodium</i><i>falciparum</i>Clearance Is Rapid and Pitting Independent in Immune Malian Children Treated With Artesunate for Malaria

Ndour, Papa Alioune; Lopera-Mesa, Tatiana M.; Diakité, Seidina A. S.; Chiang, Serena; Mouri, Oussama; Roussel, Camille; Jauréguiberry, Stéphane; Biligui, Sylvestre; Kendjo, Éric; Claessens, Antoine; Ciceron, Liliane; Mazier, Dominique; Thellier, Marc; Diakité, Mahamadou; Fairhurst, Rick M.; Buffet, Pierre

doi:10.1093/infdis/jiu427

Cited by 51 publications

(56 citation statements)

References 29 publications

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“…The proportion of patients cured paralleled the prevalence of kelch13 mutations (77% vs 34% vs 11%). Treatment failures were not associated with patient age, initial parasite density, or piperaquine plasma concentration at 7 days, suggesting that they did not result from lower levels of age-dependent, parasite-clearing immunity, 34,35 higher parasite load, or lower plasma exposure to piperaquine. Although patients in Ratanakiri had significantly lower piperaquine concentrations at 7 days than those in other provinces (probably due to the greater proportion of children, who clear piperaquine more rapidly than do adults), 3,36 recrudescences in Ratanakiri were rare.…”

Section: Discussionmentioning

confidence: 93%

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

Amaratunga

Lim

Suon

et al. 2016

The Lancet Infectious Diseases

418

430

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Background Artemisinin resistance in Plasmodium falciparum threatens to reduce the efficacy of artemisinin combination therapies (ACTs), thus compromising global efforts to eliminate malaria. Recent treatment failures with dihydroartemisinin-piperaquine, the current first-line ACT in Cambodia, suggest that piperaquine resistance may be emerging in this country. We explored the relation between artemisinin resistance and dihydroartemisinin–piperaquine failures, and sought to confirm the presence of piperaquine-resistant P falciparum infections in Cambodia. Methods In this prospective cohort study, we enrolled patients aged 2–65 years with uncomplicated P falciparum malaria in three Cambodian provinces: Pursat, Preah Vihear, and Ratanakiri. Participants were given standard 3-day courses of dihydroartemisinin–piperaquine. Peripheral blood parasite densities were measured until parasites cleared and then weekly to 63 days. The primary outcome was recrudescent P falciparum parasitaemia within 63 days. We measured piperaquine plasma concentrations at baseline, 7 days, and day of recrudescence. We assessed phenotypic and genotypic markers of drug resistance in parasite isolates. The study is registered with ClinicalTrials.gov, number NCT01736319. Findings Between Sept 4, 2012, and Dec 31, 2013, we enrolled 241 participants. In Pursat, where artemisinin resistance is entrenched, 37 (46%) of 81 patients had parasite recrudescence. In Preah Vihear, where artemisinin resistance is emerging, ten (16%) of 63 patients had recrudescence and in Ratanakiri, where artemisinin resistance is rare, one (2%) of 60 patients did. Patients with recrudescent P falciparum infections were more likely to have detectable piperaquine plasma concentrations at baseline compared with non-recrudescent patients, but did not differ significantly in age, initial parasite density, or piperaquine plasma concentrations at 7 days. Recrudescent parasites had a higher prevalence of kelch13 mutations, higher piperaquine 50% inhibitory concentration (IC50) values, and lower mefloquine IC50 values; none had multiple pfmdr1 copies, a genetic marker of mefloquine resistance. Interpretation Dihydroartemisinin–piperaquine failures are caused by both artemisinin and piperaquine resistance, and commonly occur in places where dihydroartemisinin–piperaquine has been used in the private sector. In Cambodia, artesunate plus mefloquine may be a viable option to treat dihydroartemisinin–piperaquine failures, and a more effective first-line ACT in areas where dihydroartemisinin–piperaquine failures are common. The use of single low-dose primaquine to eliminate circulating gametocytes is needed in areas where artemisinin and ACT resistance is prevalent. Funding National Institute of Allergy and Infectious Diseases.

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Section: Discussionmentioning

confidence: 93%

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

Amaratunga

Lim

Suon

et al. 2016

The Lancet Infectious Diseases

418

430

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“…Exposure of wild-type ring-stage parasites to artemisinin derivatives damages and kills the parasite, with the spleen rapidly removing damaged intraerythrocytic ring-stage parasites (a process termed "pitting"), returning the once-infected erythrocytes to circulation (34,35). Pitting is the main mechanism of parasite clearance after artesunate treatment in nonimmune children in high-transmission areas, whereas in older semi-immune children, immune-mediated parasite clearance mechanisms predominate and parasite clearance by pitting is reduced (36). Therefore, both immune-independent and immune-dependent mechanisms of parasite clearance will result in fast-clearance of wild-type infections regardless of immune status.…”

Section: Kelch13 Mutation Prevalencementioning

confidence: 99%

Host immunity to Plasmodium falciparum and the assessment of emerging artemisinin resistance in a multinational cohort

Ataíde

Ashley

Powell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Artemisinin-resistant falciparum malaria, defined by a slow-clearance phenotype and the presence of kelch13 mutants, has emerged in the Greater Mekong Subregion. Naturally acquired immunity to malaria clears parasites independent of antimalarial drugs. We hypothesized that between-and within-population variations in host immunity influence parasite clearance after artemisinin treatment and the interpretation of emerging artemisinin resistance. Antibodies specific to 12 Plasmodium falciparum sporozoite and blood-stage antigens were determined in 959 patients (from 11 sites in Southeast Asia) participating in a multinational cohort study assessing parasite clearance half-life (PCt 1/2 ) after artesunate treatment and kelch13 mutations. Linear mixed-effects modeling of pooled individual patient data assessed the association between antibody responses and PCt 1/2. P. falciparum antibodies were lowest in areas where the prevalence of kelch13 mutations and slow PCt 1/2 were highest [Spearman ρ = −0.90 (95% confidence interval, −0.97, −0.65), and Spearman ρ = −0.94 (95% confidence interval, −0.98, −0.77), respectively]. P. falciparum antibodies were associated with faster PCt 1/2 (mean difference in PCt 1/2 according to seropositivity, −0.16 to −0.65 h, depending on antigen); antibodies have a greater effect on the clearance of kelch13 mutant compared with wild-type parasites (mean difference in PCt 1/2 according to seropositivity, −0.22 to −0.61 h faster in kelch13 mutants compared with wild-type parasites). Naturally acquired immunity accelerates the clearance of artemisininresistant parasites in patients with falciparum malaria and may confound the current working definition of artemisinin resistance. Immunity may also play an important role in the emergence and transmission potential of artemisinin-resistant parasites.malaria | artemisinin | drug resistance | immunity | serology

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“…In the first study [19], parasite clearance half-lives decreased significantly as age increased, suggesting that age-dependent immunity is involved in clearing ring-infected RBCs within hours of artesunate exposure. In the second study [20], younger children cleared their parasites mostly by pitting, suggesting they lacked immune responses that rapidly clear ring-infected RBCs, while older children cleared their parasites mostly by a non-pitting, artemisinin-independent mechanism, suggesting they possessed such immune responses. Since parasite clearance half-lives are likely influenced by immunity in many areas of Africa, site-specific, age-stratified data are needed to define baseline cut-off values for suspected artemisinin resistance in the future.…”

Section: What Is the Definition Of Artemisinin Resistance?mentioning

confidence: 99%

Understanding artemisinin-resistant malaria

Fairhurst

2015

Current Opinion in Infectious Diseases

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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.

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PlasmodiumfalciparumClearance Is Rapid and Pitting Independent in Immune Malian Children Treated With Artesunate for Malaria

Cited by 51 publications

References 29 publications

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

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

Host immunity to Plasmodium falciparum and the assessment of emerging artemisinin resistance in a multinational cohort

Understanding artemisinin-resistant malaria

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