Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an open-label randomised comparison.
BACKGROUND
The burden of Plasmodium vivax infections has been underappreciated, especially in southeast Asia where chloroquine resistant strains have emerged. Our aim was to compare the safety and efficacy of dihydroartemisinin-piperaquine with that of artemether-lumefantrine in patients with uncomplicated malaria caused by multidrug-resistant P falciparum and P vivax.


METHODS
774 patients in southern Papua, Indonesia, with slide-confirmed malaria were randomly assigned to receive either artemether-lumefantrine or dihydroartemisinin-piperaquine and followed up for at least 42 days. The primary endpoint was the overall cumulative risk of parasitological failure at day 42 with a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, trial number 00157833.


RESULTS
Of the 754 evaluable patients enrolled, 466 had infections with P falciparum, 175 with P vivax, and 113 with a mixture of both species. The overall risk of failure at day 42 was 43% (95% CI 38-48) for artemether-lumefantrine and 19% (14-23) for dihydroartemisinin-piperaquine (hazard ratio=3.0, 95% CI 2.2-4.1, p<0.0001). After correcting for reinfections, the risk of recrudescence of P falciparum was 4.4% (2.6-6.2) with no difference between regimens. Recurrence of vivax occurred in 38% (33-44) of patients given artemether-lumefantrine compared with 10% (6.9-14.0) given dihydroartemisinin-piperaquine (p<0.0001). At the end of the study, patients receiving dihydroartemisinin-piperaquine were 2.0 times (1.2-3.6) less likely to be anaemic and 6.6 times (2.8-16) less likely to carry vivax gametocytes than were those given artemether-lumefantrine.


CONCLUSIONS
Both dihydroartemisinin-piperaquine and artemether-lumefantrine were safe and effective for the treatment of multidrug-resistant uncomplicated malaria. However, dihydroartemisinin-piperaquine provided greater post-treatment prophylaxis than did artemether-lumefantrine, reducing P falciparum reinfections and P vivax recurrences, the clinical public-health importance of which should not be ignored.
Ratcliff
A
A
International Health Programme, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.
Siswantoro
H
H
National Institute of Health Research and Development, Ministry of Health, Jakarta, Indonesia.
Kenangalem
E
E
MSHR-NIHRD Malaria Research Programme, Timika, Indonesia; District Ministry of Health, Timika, Papua, Indonesia.
Maristela
R
R
Public Health and Malaria Control Department, PT Freeport, Indonesia, Tembagapura, Papua, Indonesia; International SOS, Tembagapura, Papua, Indonesia.
Wuwung
R M
RM
Public Health and Malaria Control Department, PT Freeport, Indonesia, Tembagapura, Papua, Indonesia.
Laihad
F
F
Directorate General of Centre for Disease Control and Environmental Health, Ministry of Health, Jakarta, Indonesia.
Ebsworth
E P
EP
Public Health and Malaria Control Department, PT Freeport, Indonesia, Tembagapura, Papua, Indonesia; International SOS, Tembagapura, Papua, Indonesia.
Anstey
N M
NM
International Health Programme, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia.
Tjitra
E
E
National Institute of Health Research and Development, Ministry of Health, Jakarta, Indonesia.
Price
R N
RN
International Health Programme, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia; Centre for Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK. Electronic address: rnp@menzies.edu.au.
D000293:Adolescent; D000328:Adult; D000740:Anemia / Q000209:etiology; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D004338:Drug Combinations; D018432:Drug Resistance, Multiple / Q000187:drug effects; D004983:Ethanolamines / Q000627:therapeutic use*; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use*; D006801:Humans; D007214:Indonesia; D007223:Infant; D016778:Malaria, Falciparum / Q000150:complications / Q000188:drug therapy*; D016780:Malaria, Vivax / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects; D012008:Recurrence; D012717:Sesquiterpenes / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D014581:Urticaria / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced; D010879:Piperazines
D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D011804:Quinolines; D012717:Sesquiterpenes; C039060:artenimol; C034759:piperaquine; D010879:Piperazines