The artemisinin resistance containment project started in January 2009 as the result of growing evidence of falciparum resistance to artemisinin on the Thai-Cambodian border . In this area, P. falciparum has developed resistance to almost all anti-malarial drugs except the artemisinins [8, 14]. The emergence of falciparum resistance to artemisinins would not only limit treatment options in border areas, but could compromise the management of uncomplicated malaria cases on other continents, where ACT is widely recommended and supported by international development partners. Enhancing malaria surveillance was one of the major tasks of the containment project to identify and respond to suspected artemisinin-resistant cases. The project monitored anti-malarial drug resistance, not only by strengthening the use of routine data generated from the surveillance system set up under the Thailand containment project, but also by strengthening (via extra staff and incentives) individual follow-up of all falciparum-infected patients until day-28 or 42. The total population in the seven provinces of Thailand along the Cambodian border was targeted. A three-day course of mefloquine-artesunate combination therapy (MAS) was used as first-line treatment in the containment project area, except in three districts bordering Cambodia, in Trat and Chantaburi provinces, where artemisinin resistance has been documented, leading to the choice of a non-artemisinin drug instead of MAS3.
The 28-day and 42-day cure rates of MAS observed in this study were above 90% without PCR correction. However, the situation of MAS resistance at this eastern border of Thailand was more serious, as compared to the north-western border of Thailand, where the efficacy of ACT remained above 95% . There is also growing concern regarding the emergence of artemisinin resistance in an area along the Thai-Myanmar border, especially among migrant workers .
Parasite re-appearance until day-42 was observed in about 5% of patients. Since PCR confirmation was not performed, parasites that were reappearing in this routine monitoring study could not be distinguished either as a recrudescent infection due to drug resistance, or re-infection from new parasites. A study carried out in north-western Thailand from 1995 to 2007 reported PCR-confirmed recrudescence in less than 5% of patients under MAS [5, 16]. Even if the results of this study are not confirmed by PCR, the failure rate with MAS observed during the study period remains less than 10%.
Experience over the past decades has shown that artemisinin can rapidly reduce parasite load, clearing them from blood generally after a two-day intake of treatment . However, in case of suspected P. falciparum resistance to artemisinin, parasites are still observed in blood longer than three days after treatment, which is called “delayed parasite clearance time” . Among patients managed with MAS in this study, about 30% and 15% still had parasitaemia on day-2 and day-3, respectively. Almost all patients were parasite-free on day-7, with about 2% showing parasite re-appearance during 28-day follow-up. In Pailin, western Cambodia, percentages of parasitaemic patients on day-2 and day-3 undergoing artesunate monotherapy or mefloquine-artesunate treatment were as high as 73% and 55%, respectively . A recent study with high-dose artesunate monotherapy conducted in Battambang Province, western Cambodia, also showed, after treatment, a relatively high proportion of parasitaemic patients on day-2 and day-3 (48% on day-2, and 22% on day-3) . The proportion of parasite-positive patients observed in the study area is relatively high compared to other locations in western Thailand and in Vietnam [5,19].
Unlike the resistance patterns of other anti-malarial drugs, the results of clinical and in-vitro studies indicated that artemisinin resistance is suspected by exploring parasite clearance time rather than any sudden change in therapeutic cure rate [7, 9]. On the Thai-Cambodian border, the WHO recommended using the proportion of patients who remain parasitaemic on day-3 as an indicator of suspected artemisinin resistance, to be further confirmed by more sophisticated methods . In this area, delayed parasite clearance on day-3 was observed in about 14% of patients. Significant factors associated with delayed parasite clearance time were people living in seasonal transmission areas or in Srisaket Province, even though the confidence intervals were quite large. The incidence of malaria in Srisaket Province was dramatically increasing during the project period, probably due to the border conflict between Thailand and Cambodia affecting containment operations, with heavy movements of non-immune soldiers. Currently, there is only one vector-borne disease unit located in Srisaket Province with limited staff and healthcare facilities. In addition to the relative inaccessibility to healthcare and malaria services in conflict zones by residents, migrants and soldiers, the overall management of malaria control operations remains difficult in this province, which might have resulted in increasing transmission and, consequently, in the spread of artemisinin-resistant parasites.
Some limitations have to be considered in this study. The pattern of parasite clearance was presented as the cumulative proportion of patients who remained parasitaemic by day after treatment. Parasite clearance curve that shows reduction of parasite load by exploring additional specific periods of time may provide more information on parasite stage-specific response to artemisinins . However, the parasite clearance graph presented here should be considered as a useful tool to monitor parasite resistance in the routine surveillance system, because it is difficult to obtain accurate parasite examination and to count more often than once a day in the field situation. Study results are also subject to bias due to missing follow-up data (50%) and doubtful results, in spite of efforts made to strengthen the routine surveillance system. However, the results of this study were similar, regardless of completion of follow-up data. Additional research-based trials have to be designed to further clarify or complement results such as these. Even though the Ministry of Public Health had attempted to enforce completion and a timely analysis of data as much as possible, missing values were still observed. Approximately 50% of falciparum patients had missing parasitological data between day-1 and day-28 or day-42. The profile of patients not able to be properly followed-up was more likely to be a mobile population, such as young adults and seasonal migrant workers. However, little is known whether the resistance patterns of these two groups are different from other populations. In this study, regardless of missing data, the proportion of delayed parasite clearance on day-3 in these two groups was not significantly different from other age groups and population types. In addition, missing data were mainly (50%) observed in Srisaket Province in the conflict zone. This province was also reported to be at high risk of artemisinin resistance.
About 32% of overall falciparum malaria in this area did not receive MAS treatment. These were a combination of patients who received other second-line drugs, and others who had missing information on anti-malarial drugs received. Since there are no commercial anti-malarial drugs available in Thailand, those missing drug information were likely to have received their treatment in hospitals where standardized reporting forms were not used and computerized, as in peripheral malaria units. Unlike malaria patients who were originally detected at malaria clinics/posts under BVBD supervision, where patients’ details would be directly recorded into eMIS, details of cases at local hospitals were captured later into eMIS after admissions or treatment. Malaria treatment provided at hospital could be either first-line regimen (MAS), or second-line regimens (quinine, tetracycline or doxycycline). Further improvement in the reporting system is needed to assist data sharing between hospitals and public health sectors.
In this study, the follow-up rate on day-42 was relatively high (50%), considering constraints linked to field operation. About 90% of patients who received complete follow-up on day-7 were followed up on day-42. This allowed the study to estimate a 42-day cure rate, which is recommended to be long enough to monitor MAS resistance due to a long elimination half-life of Mefloquine .