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. 2009;4(2):e4551.
doi: 10.1371/journal.pone.0004551. Epub 2009 Feb 23.

Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment

Verena Ilona Carrara  1 , Julien Zwang, Elizabeth A Ashley, Ric N Price, Kasia Stepniewska, Marion Barends, Alan Brockman, Tim Anderson, Rose McGready, Lucy Phaiphun, Stephane Proux, Michele van Vugt, Robert Hutagalung, Khin Maung Lwin, Aung Pyae Phyo, Piyanuch Preechapornkul, Mallika Imwong, Sasithon Pukrittayakamee, Pratap Singhasivanon, Nicholas J White, François Nosten
Affiliations

Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment

Verena Ilona Carrara et al. PLoS One. 2009.

Abstract

Background: Artemisinin combination treatments (ACT) are recommended as first line treatment for falciparum malaria throughout the malaria affected world. We reviewed the efficacy of a 3-day regimen of mefloquine and artesunate regimen (MAS(3)), over a 13 year period of continuous deployment as first-line treatment in camps for displaced persons and in clinics for migrant population along the Thai-Myanmar border.

Methods and findings: 3,264 patients were enrolled in prospective treatment trials between 1995 and 2007 and treated with MAS(3). The proportion of patients with parasitaemia persisting on day-2 increased significantly from 4.5% before 2001 to 21.9% since 2002 (p<0.001). Delayed parasite clearance was associated with increased risk of developing gametocytaemia (AOR = 2.29; 95% CI, 2.00-2.69, p = 0.002). Gametocytaemia on admission and carriage also increased over the years (p = 0.001, test for trend, for both). MAS(3) efficacy has declined slightly but significantly (Hazards ratio 1.13; 95% CI, 1.07-1.19, p<0.001), although efficacy in 2007 remained well within acceptable limits: 96.5% (95% CI, 91.0-98.7). The in vitro susceptibility of P. falciparum to artesunate increased significantly until 2002, but thereafter declined to levels close to those of 13 years ago (geometric mean in 2007: 4.2 nM/l; 95% CI, 3.2-5.5). The proportion of infections caused by parasites with increased pfmdr1 copy number rose from 30% (12/40) in 1996 to 53% (24/45) in 2006 (p = 0.012, test for trend).

Conclusion: Artesunate-mefloquine remains a highly efficacious antimalarial treatment in this area despite 13 years of widespread intense deployment, but there is evidence of a modest increase in resistance. Of particular concern is the slowing of parasitological response to artesunate and the associated increase in gametocyte carriage.

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Conflict of interest statement

Competing Interests: N.J. White is co-chairman of the World Health Organization malaria treatment guidelines committee and is on the editorial board of PloS Medicine. The authors have no other conflict of interest to declare.

Figures

Figure 1
Figure 1. Percentage of patients who had cleared parasitaemia at Day-2 and Day-3 1995–2007.
Figure 2
Figure 2. Relationship between parasite clearance time and gametocyte carriage.
Gametocyte carriage rate is expressed per 1,000 person-gametocyte-week (PGW).
Figure 3
Figure 3. PCR-adjusted parasitological efficacy (95% CI) at Day-42 following MAS3 treatment.
Parasitological efficacy (PCR-adjusted) of the mefloquine-artesunate 3-day combination therapy was evaluated at Day-42 of follow-up between 1995 and 2007. Efficacy is given as a percentage (95% CI).
Figure 4
Figure 4. Drug sensitivity of P. falciparum isolates for artesunate (Figure 4a) and mefloquine (Figure 4b).
Isolates from primary infections were collected at SMRU clinics between 1995 and 2007 and assayed for sensitivity to artesunate and mefloquine, IC50 geometric means are given as nM/l with [95% CI].
Figure 5
Figure 5. Proportion of primary infections with increased Pfmdr1 (≥2) copy number.
Isolates from primary infections were used for genetic analysis between 1996 and 2006. Increase in isolates with 2 or more copy number is given in percentage of the total.
See this image and copyright information in PMC

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