Therapeutic efficacy of fixed dose artesunate-mefloquine for the treatment of acute, uncomplicated Plasmodium falciparum malaria in Kampong Speu, Cambodia
Rithea Leang
1
Sakun Ros
1
Socheat Duong
1
Visweswaran Navaratnam
3
Pharath Lim
1
Frdric Ariey
2
Jean-Ren Kiechel
5
Didier Mnard
2
Walter RJ Taylor
1
4
0
372
,
Monivong Blvd, Corner St. 322, Phnom Penh
,
Cambodia
1
National Centre for Parasitology
,
Entomology and Malaria Control
2
Institut Pasteur du Cambodge
,
Phnom Penh
,
Cambodia
3
Drugs for Neglected Diseases initiative
,
Pulau Pinang
,
Malaysia
4
Centre de Medecine Humanitaire, Hopitaux Universitaires de Geneve
,
Geneva
,
Switzerland
5
Drugs for Neglected Diseases initiative
,
Geneva
,
Switzerland
Background: Cambodia stopped using co-blistered, non-fixed, artesunate-mefloquine (ASMQ) in 2008 when treatment failure rates approximated 20%. Fixed dose combination (FDC) ASMQ is efficacious against acute uncomplicated, drug resistant Plasmodium falciparum malaria in Southeast Asia but has not been tested in Cambodia. Methods: A 42-day WHO therapeutic efficacy study (TES) was conducted in 2010 in Oral, Kampong Speu province, southwest Cambodia, in patients with acute uncomplicated P. falciparum. Daily administered FDC ASMQ for three days was dosed by age. Genotyping of isolates at day 0 and day of recrudescence by polymerase chain reaction (PCR) classified posttreatment recurrent falciparum parasitaemia. Ex vivo drug sensitivity testing ([3H] hypoxanthine method) was performed on baseline parasites and reported as the drug concentration inhibiting 50% parasite growth vs no drug (IC50). Results: Recruited patients numbered 45; five aged <15 years. On day 3, five of 45 [11.1 (3.7-24.05)] % patients were still parasite-positive; one of whom later failed treatment on day 21. There were 5/45 (11.1%) late treatment failures on day 21, 28 and 35; all were PCR diagnosed recrudescent infections. The day 0 MQ IC50s ranged from 11.5-238.9 (median 58.6) nM. Conclusions: This TES demonstrated reasonable efficacy in an area of possible reduced artemisinin sensitivity and high MQ IC50s. Efficacy testing of FDC ASMQ should continue in Cambodia and be considered for reintroduction if efficacy returns.
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Background
The first artemisinin-based combination therapy (ACT) to
be introduced in 2000 by the National Malaria Control
Programme in Cambodia (CNM, Centre National de
Malariologie) to treat drug-resistant Plasmodium
falciparum was non-fixed artesunate-mefloquine (NF-ASMQ).
Prior to this, there had been a long history of anti-malarial
drug resistance, starting with chloroquine [1] in the early
1960s, followed by sulphadoxine-pyrimethamine (SP) [2],
mefloquine (MQ) [3] and SP combined with MQ [4].
NF-ASMQ was co-blistered (i e, both drugs in the same
blister). There were five age-weight dosing categories and
the maximum MQ dose was capped at 1,500 mg because
of its poor tolerability [5]. When dosed by age rather than
weight, a substantial minority of patients (~30% of all
patients, ~43% adults) received less than the total target
doses of AS and MQ over 48 hours, i e, <12 mg/kg of AS
and <20 mg/kg of MQ. Nevertheless, between 2001 to
2004, therapeutic efficacy studies (TESs), conducted
across Cambodia, demonstrated generally PCR-corrected
rates of adequate clinical and parasitological response
(ACPR) exceeding 90% when assessed over 28 days [5,6].
However, as early as 2001, the day 28 ACPR rate in Pailin
was low at 85.7% and was about the same, 90.1%, in 2004.
A subsequent, day 42 follow-up TES in 2004 in Pailin
demonstrated an ACPR of just under 80% [5]. Analyses of
some of the falciparum parasites from these TESs [6]
showed a significantly lower geometric mean MQ IC50
(drug concentration required to inhibit parasite growth by
50% compared to a no-drug control) in parasites with 1
Pfmdr-1 copy number compared with parasites with 2
copies (27.9 nM vs 50.3 nM) and a lower median Pfmdr-1
copy number in patients with ACPR compared those who
failed treatment: 1.5 vs 2.4 [7]. The risk of failing ASMQ
was about eight-fold more likely with 3 Pfmdr-1 copy
numbers [7].
NF-ASMQ TESs conducted in 2007 in Veal Veng
(Pursat province, western Cambodia) and in 200608 in
Chumkiri (Kampot province, south-western Cambodia)
demonstrated day 42 PCR-corrected failure rates of 16%
and just under 19%, respectively [8,9]. Independent risk
factors for treatment failure in Kampot were a high day
0 parasite density, longer time to clear parasites and an
increasing Pfmdr-1 copy number [9].
In vitro drug sensitivity data from Chumkiri showed
that the MQ IC50s ranged from approximately 15 to 180
nM ([3H] hypoxanthine method) and a higher mean
IC50 was reported in resistant infections (90 nM) vs
sensitive (56 nM) infections [9]. These high IC50 values are
consistent with in vitro data from Lim et al. who
reported a geometric mean IC50 of 50.57 nM in MQ
failures vs 23.85 nM in ACPR patients from west and east
Cambodia combined in studies from 2001 to 2007 [10].
Based on these high failure rates and the earlier poor
efficacy of artemether-lumefantrine [6], ASMQ was replaced by
fixed dose dihydroar (...truncated)