Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study

Abstract

Summary Background Artemisinin-resistant Plasmodium falciparum has been reported in Pailin, western Cambodia, detected as a slow parasite clearance rate in vivo. Emergence of this phenotype in western Thailand and possibly elsewhere threatens to compromise the effectiveness of all artemisinin-based combination therapies. Parasite genetics is associated with parasite clearance rate but does not account for all variation. We investigated contributions of both parasite genetics and host factors to the artemisinin-resistance phenotype in Pursat, western Cambodia. Methods Between June 19 and Nov 28, 2009, and June 26 and Dec 6, 2010, we enrolled patients aged 10 years or older with uncomplicated falciparum malaria, a density of asexual parasites of at least 10 000 per μL of whole blood, no symptoms or signs of severe malaria, no other cause of febrile illness, and no chronic illness. We gave participants 4 mg/kg artesunate at 0, 24, and 48 h, 15 mg/kg mefloquine at 72 h, and 10 mg/kg mefloquine at 96 h. We assessed parasite density on thick blood films every 6 h until undetectable. The parasite clearance half-life was calculated from the parasite clearance curve. We genotyped parasites with 18 microsatellite markers and patients for haemoglobin E, α-thalassaemia, and a mutation of G6PD, which encodes glucose-6-phosphate dehydrogenase. To account for the possible effects of acquired immunity on half-life, we used three surrogates for increased likelihood of exposure to P falciparum: age, sex, and place of residence. This study is registered with ClinicalTrials.gov, number NCT00341003. Findings We assessed 3504 individuals from all six districts of Pursat province seeking treatment for malaria symptoms. We enrolled 168 patients with falciparum malaria who met inclusion criteria. The geometric mean half-life was 5.85 h (95% CI 5.54–6.18) in Pursat, similar to that reported in Pailin (p=0.109). We identified two genetically different parasite clone groups: parasite group 1 (PG1) and parasite group 2 (PG2). Non-significant increases in parasite clearance half-life were seen in patients with haemoglobin E (0.55 h; p=0.078), those of male sex (0.96 h; p=0.064), and in 2010 (0.68 h; p=0.068); PG1 was associated with a significant increase (0.79 h; p=0.033). The mean parasite heritability of half-life was 0.40 (SD 0.17). Interpretation Heritable artemisinin resistance is established in a second Cambodian province. To accurately identify parasites that are intrinsically susceptible or resistant to artemisinins, future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation. Funding Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Clinical Efficacy of Dihydroartemisinin–Piperaquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria at the China–Myanmar Border

“…However, the recent emergence and/or spread of artemisinin resistance in Plasmodium falciparum in parts of GMS pose a serious threat to regional malaria control and elimination campaign. [4][5][6] Since the time when clinical artemisinin resistance was first documented in western Cambodia, 5,7,8 intensive monitoring in the GMS has detected artemisinin resistance in at least six areas because of spread, independent emergence, or both. [9][10][11][12] In vision of a potential catastrophic spread of artemisinin resistance to Africa, the World Health Organization (WHO) developed a containment plan.…”

Étude de la résistance dePlasmodium falciparumaux antipaludiques au sein du réseau international des Instituts Pasteur (RIIP-Palu)

“…Les dérivés des artémisinines ont une place à part dans l'arsenal thérapeutique, car ils sont les seuls à agir sur toutes les formes de développement du parasite et ont une action remarquablement rapide. Malheureusement, ces médicaments sont maintenant menacés par l'apparition de parasites présentant une sensibilité diminuée aux artémisinines en Asie du Sud-Est [9][10][11][12]. Pour faire face à cette menace, un plan a été élaboré par l'OMS début 2011 [34] qui vise à endiguer et à prévenir la dissémination des souches résistantes aux artémisinines.…”

“…Ces combinaisons sont maintenant recommandées dans la plupart des pays d'endémie, mais leur accès est encore loin d'être général. Aujourd'hui, une des préoccupations majeures est que l'on assiste en Asie du Sud-Est aux premiers signes d'émergence de parasites résistants aux dérivés des artémisinines [9][10][11][12]. Aucune solution thérapeutique de remplacement n'est actuellement disponible.…”

Making the Most of Clinical Data: Reviewing the Role of Pharmacokinetic-Pharmacodynamic Models of Anti-malarial Drugs

“…The development and evaluation of reliable within-host PK-PD models are becoming increasingly relied upon to optimize anti-malarial treatment regimens to maximize the impact of policy and elimination efforts and contain the emergence of anti-malarial resistance (23)(24)(25)(26). In this review, we describe the within-host PK-PD models for anti-malarial drugs that have been developed over the last two decades and discuss the challenges of applying them to clinical data within a formal statistical framework.…”