Therapeutic efficacy of fixed dose artesunate-mefloquine for the treatment of acute, uncomplicated Plasmodium falciparum malaria in Kampong Speu, Cambodia

Malaria Journal, Sep 2013

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, south-west 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 post-treatment 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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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. - 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)


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Rithea Leang, Sakun Ros, Socheat Duong, Visweswaran Navaratnam, Pharath Lim, Frédéric Ariey, Jean-René Kiechel, Didier Ménard, Walter RJ Taylor. Therapeutic efficacy of fixed dose artesunate-mefloquine for the treatment of acute, uncomplicated Plasmodium falciparum malaria in Kampong Speu, Cambodia, Malaria Journal, 2013, pp. 343, 12, DOI: 10.1186/1475-2875-12-343