title: Therapeutic efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria from three highly malarious states in India.
abstract: Anti-malarial drug resistance continues to be a leading threat to malaria control efforts and calls for continued monitoring of waning efficacy of artemisinin-based combination therapy (ACT). Artesunate + sulfadoxine/pyrimethamine (AS + SP) is used for the treatment of uncomplicated Plasmodium falciparum malaria in India. However, resistance against AS + SP is emerged in northeastern states. Therefore, artemether-lumefantrine (AL) is the recommended first line treatment for falciparum malaria in north eastern states. This study investigates the therapeutic efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in three malaria-endemic states in India. The data generated through this study will benefit the immediate implementation of second-line ACT as and when required.
  
  
  
  This was a one-arm prospective evaluation of clinical and parasitological responses for uncomplicated falciparum malaria using WHO protocol. Patients diagnosed with uncomplicated mono P. falciparum infection were administered six-dose regimen of AL over 3 days and subsequent follow-up was carried out up to 28 days. Molecular markers msp-1 and msp-2 were used to differentiate recrudescence and re-infection and K13 propeller gene was amplified and sequenced covering the codon 450-680.
  
  
  
  A total of 402 eligible patients were enrolled in the study from all four sites. Overall, adequate clinical and parasitological response (ACPR) was 98 % without PCR correction and 99 % with PCR correction. At three study sites, ACPR rates were 100 %, while at Bastar, cure rate was 92.5 % on day 28. No early treatment failure was found. The PCR-corrected endpoint finding confirmed that one late clinical failure (LCF) and two late parasitological failures (LPF) were recrudescences. The PCR corrected cure rate was 96.5 %. The mean fever clearance time was 27.2 h ± 8.2 (24-48 h) and the mean parasite clearance time was 30.1 h ± 11.0 (24-72 h). Additionally, no adverse event was recorded. Analysis of total 186 samples revealed a mutation in the k13 gene along with non-synonymous mutation at codon M579T in three (1.6 %) samples.
  
  
  
  AL is an efficacious drug for the treatment of uncomplicated falciparum malaria. However, regular monitoring of AL is required in view of malaria elimination initiatives, which will be largely dependent on therapeutic interventions, regular surveillance and targeted vector control.
authors.affiliation: National Institute for Research in Tribal Health (NIRTH), Jabalpur, Madhya Pradesh, 482003, India.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Bharti
authors.affiliation: National Institute for Research in Tribal Health (NIRTH), Jabalpur, Madhya Pradesh, 482003, India.
authors.forename: Man M
authors.initials: MM
authors.lastname: Shukla
authors.affiliation: Global Malaria Programme World Health Organization, Geneva, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Ringwald
authors.affiliation: National Institute for Research in Tribal Health (NIRTH), Jabalpur, Madhya Pradesh, 482003, India.
authors.forename: Sri
authors.initials: S
authors.lastname: Krishna
authors.affiliation: National Institute for Research in Tribal Health (NIRTH), Jabalpur, Madhya Pradesh, 482003, India.
authors.forename: Pushpendra P
authors.initials: PP
authors.lastname: Singh
authors.affiliation: National Institute for Research in Tribal Health (NIRTH), Jabalpur, Madhya Pradesh, 482003, India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Yadav
authors.affiliation: National Institute for Research in Tribal Health (NIRTH), Jabalpur, Madhya Pradesh, 482003, India.
authors.forename: Sweta
authors.initials: S
authors.lastname: Mishra
authors.affiliation: Community Health Centre Ranapur, District Jhabua, Madhya Pradesh, India.
authors.forename: Usha
authors.initials: U
authors.lastname: Gahlot
authors.affiliation: Community Health Centre Rajendragram, District Anuppur, Madhya Pradesh, India.
authors.forename: Jai P
authors.initials: JP
authors.lastname: Malaiya
authors.affiliation: Community Health Centre Jaldega, District Simdega, Jharkhand, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Community Health Centre Bano, District Simdega, Jharkhand, India.
authors.forename: Shambhu
authors.initials: S
authors.lastname: Prasad
authors.affiliation: Community Health Centre Kilepal, District Bastar, Chhattisgarh, India.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Baghel
authors.affiliation: Satpura Bhawan, Bhopal, Madhya Pradesh, India.
authors.forename: Mohan
authors.initials: M
authors.lastname: Singh
authors.affiliation: Indravati Bhawan, Raipur, Chhattisgarh, India.
authors.forename: Jaiprakash
authors.initials: J
authors.lastname: Vadadi
authors.affiliation: National Institute of Malaria Research (NIMR) Field Station, Jabalpur, MP, India.
authors.forename: Mrigendra P
authors.initials: MP
authors.lastname: Singh
authors.affiliation: World Health Organization, Country Office for Thailand, Bangkok, Thailand.
authors.forename: Maria Dorina G
authors.initials: MD
authors.lastname: Bustos
authors.affiliation: Global Malaria Programme World Health Organization, Geneva, Switzerland.
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Ortega
authors.affiliation: World Health Organization, Regional Office for South-East Asia, New Delhi, India.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Christophel
authors.affiliation: National Vector Borne Disease Control Programme (NVBDCP), New Delhi, India.
authors.forename: Sher S
authors.initials: SS
authors.lastname: Kashyotia
authors.affiliation: National Vector Borne Disease Control Programme (NVBDCP), New Delhi, India.
authors.forename: Gagan S
authors.initials: GS
authors.lastname: Sonal
authors.affiliation: National Institute for Research in Tribal Health (NIRTH), Jabalpur, Madhya Pradesh, 482003, India. neeru.singh@gmail.com.
authors.forename: Neeru
authors.initials: N
authors.lastname: Singh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000953:Antigens, Protozoan / Q000235:genetics; D000962:Antimalarials / Q000009:adverse effects / Q000627:therapeutic use*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions; D004983:Ethanolamines / Q000009:adverse effects / Q000627:therapeutic use*; D005449:Fluorenes / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007194:India; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D020066:Merozoite Surface Protein 1 / Q000235:genetics; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000145:classification / Q000235:genetics / Q000302:isolation & purification; D011446:Prospective Studies; D015800:Protozoan Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000953:Antigens, Protozoan; D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D020066:Merozoite Surface Protein 1; D015800:Protozoan Proteins; C065974:merozoite surface protein 2, Plasmodium
keywords: Artemether–lumefantrine; India; Malaria; Plasmodium falciparum; Therapeutic efficacy