First indications of high failure rates associated with the extensive use of ACTs in Thailand were reported in a paper published in 2006 suggesting the possibility of poor clinical response to ACTs along the Thai-Cambodian border and coincide with the first reports of the experimental induction of in vitro
artemisinin resistance 
. Recent studies have shown that the first cases of genuine artemisinin resistance have already emerged in the region 
raising the question of how far artemisinin resistance has already spread.
This study using a systematic in vivo-ex vivo approach was conducted in Southeastern Bangladesh in close proximity to the borders of India and Myanmar and was specifically designed to answer the question of whether clinical artemisinin resistance has already spread to the region. As compared to Southeast Asia the major difference in terms of exposure of malaria parasites to artemisinins is the fact that in Bangladesh ACTs have only been introduced very recently and that the local parasite populations have therefore not been exposed to artemisinins on any significant scale. The parasite phenotype seen in Bangladesh is therefore likely to be representative of Asian P. falciparum populations before the introduction of artemisinins. Historical data suggest that in terms of the spread of resistance from Southeast Asia the malaria-endemic regions of Bangladesh may represent an important gateway to the Indian Subcontinent.
Our data clearly indicate that in this region there is currently no evidence for spreading or de novo
emerging artemisinin resistance. Although a single case of recrudescence was observed, this case did not fulfill our stringent criteria for artemisinin resistance 
. Even 7 days of artesunate monotherapy with a total dose much higher than the one commonly used in artemisinin-based combinations typically result in a certain proportion of failures. The one patient who developed a recrudescence received 700 mg total dose (2.04 mg/kg) as compared to a typical artesunate dose of 300 mg in artemisinin-based combinations. All other parameters, however, indicate that this case was a drug failure rather than a failure due to drug resistance. As compared to the Thai-Cambodian border PCTs were considerably shorter (28.2 vs. 57.6 in a recently published study from Cambodia; P<0.001) 
. Our ex vivo
data confirm earlier published data suggesting a continuous and significant decrease in ex vivo
artemisinin susceptibility from Bangladesh throughout western to eastern Thailand and Cambodia 
. There was also no increase in the IC50
for artemisinins as compared to our earlier studies in the same region suggesting the absence of a temporal trend towards reduced sensitivity 
The discussion of the role and importance of poor clinical response and failures with 7 days of high-dose artemisinins along the Thai-Cambodian border has largely been focusing on the question of whether innately resistant clones occur naturally as a fixed subset of parasite populations from different locales. Our data from an area in Asia where artemisinins have as yet not been deployed on any significant scale would suggest that this is not the case.
In its early stages reduced drug susceptibility is not necessarily reflected in an increased proportion of treatment failures. Clinical response parameters (particularly parasite clearance) and intrinsic ex vivo
drug sensitivity therefore play a crucial role in detecting early stages of compromised drug sensitivity 
. In this study all indicators seem to suggest as yet uncompromised drug sensitivity to artemisinins in southeastern Bangladesh. The comparison of ex vivo
drug sensitivity between Bangladesh and Cambodia seems to closely match the major differences in treatment response 
The obvious advantage of artemisinins is their capacity to quickly reduce the initial parasite burden making them highly successful even in combination treatment courses as short as 3 days (as typically used in ACTs). However, with parasite clearance times reaching 100 hours or more in selected patients in Cambodia 
artemisinins cannot fulfill their main function.
Both, the prolongation in parasite clearance and persisting parasitemia 72 hours after initiation of treatment are strong indicators for reduced susceptibility or artemisinin resistance 
. In our study neither were PCTs prolonged nor did a single patient have detectable parasites after 72 hours. Our findings are an obvious contrast to recent findings in western Thailand and Cambodia, where the positivity rate at 72 h was as high as 21.9% and where PCTs were almost twice as high as in our study with individual times reaching values close to the traditional classification of RII resistance 
In summary, there is currently no indication of compromised drug sensitivity to artemisinin derivatives in the region. The rapid reduction in parasite densities as well as the high efficacy seen with 7 days artesunate monotherapy in Bangladesh suggests that the phenomenon seen in Cambodia and along the eastern borders of Myanmar is likely to be based on the selection of parasite populations with reduced sensitivity under drug pressure rather than due to innately resistant clones occurring naturally as a fixed subset of parasite populations. So far artemisinins have not been used on any significant scale in Bangladesh but the situation is likely to change in the future, either due to resistance spreading from Southeast Asia or due to de novo emergence of resistance under drug pressure. These data therefore also provide an important baseline for future assessments of temporal and geospatial trends in artemisinin resistance in the region.