ABSTRACT
The majority of malaria rapid diagnostic tests (RDTs) detect Plasmodium falciparum histidine-rich protein 2 (PfHRP2), encoded by the pfhrp2 gene. Recently, P. falciparum isolates from Peru were found to lack pfhrp2 leading to false-negative RDT results. We hypothesized that pfhrp2-deleted parasites in Peru derived from a single genetic event. We evaluated the parasite population structure and pfhrp2 haplotype of samples collected between 1998 and 2005 using seven neutral and seven chromosome 8 microsatellite markers, respectively. Five distinct pfhrp2 haplotypes, corresponding to five neutral microsatellite-based clonal lineages, were detected in 1998-2001; pfhrp2 deletions occurred within four haplotypes. In 2003-2005, outcrossing among the parasite lineages resulted in eight population clusters that inherited the five pfhrp2 haplotypes seen previously and a new haplotype; pfhrp2 deletions occurred within four of these haplotypes. These findings indicate that the genetic origin of pfhrp2 deletion in Peru was not a single event, but likely occurred multiple times.
Subject(s)
Antigens, Protozoan/genetics , Gene Deletion , Parasites/genetics , Plasmodium falciparum/genetics , Protozoan Proteins/genetics , Animals , Bayes Theorem , Cluster Analysis , Haplotypes/genetics , Humans , Microsatellite Repeats/genetics , Peru , Phenotype , PrevalenceABSTRACT
BACKGROUND: Artemisinin-based combination therapy (ACT) is recommended as a means of prolonging the effectiveness of first-line malaria treatment regimens. Different brands of mefloquine (MQ) have been reported to be non-bioequivalent; this could result in sub-therapeutic levels of mefloquine with decreased efficacy. In 2002, mefloquine-artesunate (MQ-AS) combination therapy was adopted as the first-line treatment for uncomplicated Plasmodium falciparum malaria in the Amazon region of Peru. Although MQ resistance has yet to be reported from the Peruvian Amazon, it has been reported from other countries in the Amazon Region. Therefore, continuous monitoring is warranted to ensure that the first-line therapy remains efficacious. This study examines the in vivo efficacy and pharmacokinetic parameters through Day 56 of three commercial formulations of MQ (Lariam, Mephaquin, and Mefloquina-AC Farma) given in combination with artesunate. METHODS: Thirty-nine non-pregnant adults with P. falciparum mono-infection were randomly assigned to receive artesunate in combination with either (1) Lariam, (2) Mephaquin, or (3) Mefloquina AC. Patients were assessed on Day 0 (with blood samples for pharmacokinetics at 0, 2, 4, and 8 hours), 1, 2, 3, 7, and then weekly until day 56. Clinical and parasitological outcomes were based on the standardized WHO protocol.Whole blood mefloquine concentrations were determined by high-performance liquid chromatography and pharmacokinetic parameters were determined using non-compartmental analysis of concentration versus time data. RESULTS: By day 3, all patients had cleared parasitaemia except for one patient in the AC Farma arm; this patient cleared by day 4. No recurrences of parasitaemia were seen in any of the 34 patients. All three MQ formulations had a terminal half-life of 14-15 days and time to maximum plasma concentration of 45-52 hours. The maximal concentration (Cmax) and interquartile range was 2,820 ng/ml (2,614-3,108) for Lariam, 2,500 ng/ml (2,363-2,713) for Mephaquin, and 2,750 ng/ml (2,550-3,000) for Mefloquina AC Farma. The pharmacokinetics of the three formulations were generally similar, with the exception of the Cmax of Mephaquin which was significantly different to that of Lariam (p = 0.04). CONCLUSION: All three formulations had similar pharmacokinetics; in addition, the pharmacokinetics seen in this Peruvian population were similar to reports from other ethnic groups. All patients rapidly cleared their parasitaemia with no evidence of recrudescence by Day 56. Continued surveillance is needed to ensure that patients continue to receive optimal therapy.
Subject(s)
Antimalarials/pharmacokinetics , Artemisinins/pharmacokinetics , Malaria, Falciparum/drug therapy , Mefloquine/pharmacokinetics , Plasmodium falciparum/drug effects , Administration, Oral , Adolescent , Adult , Animals , Antimalarials/administration & dosage , Antimalarials/therapeutic use , Artemisinins/administration & dosage , Artemisinins/therapeutic use , Artesunate , Chromatography, High Pressure Liquid , Drug Administration Schedule , Female , Humans , Malaria, Falciparum/parasitology , Male , Mefloquine/administration & dosage , Mefloquine/therapeutic use , Middle Aged , Parasitemia/drug therapy , Peru , Plasmodium falciparum/isolation & purification , Time Factors , Treatment Outcome , Young AdultABSTRACT
The frequency of alleles with triple mutations conferring sulfadoxine-pyrimethamine (SP) resistance in the Peruvian Amazon Basin has declined (16.9% for dhfr and 0% for dhps compared to 47% for both alleles in 1997) 5 years after SP was replaced as the first-line treatment for Plasmodium falciparum malaria. Microsatellite analysis showed that the dhfr and dhps alleles are of common origin.
