In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam

Abstract

BackgroundBy 2009, there were worrying signs from western Cambodia that parasitological responses to artesunate-containing treatment regimens for uncomplicated Plasmodium falciparum malaria were slower than elsewhere which suggested the emergence of artemisinin resistance. Vietnam shares a long land border with Cambodia with a large number of migrants crossing it on a daily basis. Therefore, there is an urgent need to investigate whether there is any evidence of a change in the parasitological response to the artemisinin derivatives in Vietnam.MethodsFrom August 2010 to May 2011, a randomized controlled clinical trial in uncomplicated falciparum malaria was conducted to compare two doses of artesunate (AS) (2mg/kg/day versus 4 mg/kg/day for three days) followed by dihydroartemisinin-piperaquine (DHA-PPQ) and a control arm of DHA-PPQ. The goal was characterization of the current efficacy of artesunate in southern Vietnam. The primary endpoint of this study was the parasite clearance half-life; secondary endpoints included the parasite reduction ratios at 24 and 48 hours and the parasite clearance time.Results166 patients were recruited into the study. The median parasite clearance half-lives were 3.54 (AS 2mg/kg), 2.72 (AS 4mg/kg), and 2.98 hours (DHA-PPQ) (p=0.19). The median parasite-reduction ratio at 24 hours was 48 in the AS 2mg/kg group compared with 212 and 113 in the other two groups, respectively (p=0.02). The proportions of patients with a parasite clearance time of >72 hours for AS 2mg/kg, AS 4mg/kg and DHA-PPQ were 27%, 27%, and 22%, respectively. Early treatment failure occurred in two (4%) and late clinical failure occurred in one (2%) of the 55 patients in the AS 2mg/kg group, as compared with none in the other two study arms. The PCR-corrected adequate clinical and parasitological response (APCR) rates in the three groups were 94%, 100%, and 100% (p=0.04).ConclusionsThis study demonstrated faster P. falciparum parasite clearance in southern Vietnam than in western Cambodia but slower clearance in comparison with historical data from Vietnam. Further studies to determine whether this represents the emergence of artemisinin resistance in this area are needed. Currently, the therapeutic response to DHA-PPQ remains satisfactory in southern Vietnam.Trial registrationNTC01165372

Delayed Parasite Clearance after Treatment with Dihydroartemisinin-Piperaquine in Plasmodium falciparum Malaria Patients in Central Vietnam

“…Earlier studies from southern Vietnam reported a 48-h PCT after 3 days of DHA-PPQ treatment (DHA, 2.4 mg/kg/day; PPQ, 19.2 mg/kg/day) and a clearance half-life of 2.98 h (13). This is considerably shorter than the PCT and clearance half-life found in our study, in which we used the dosage recommended by the Vietnamese Ministry of Health (14).…”

“…In addition, there were no differences in dosage between patients with delayed clearance and the others (data not shown). When considering that our dosing scheme resulted in a higher total dosage per patient than in a previous study carried out in Binh Phuoc Province (13), it is unlikely that underdosage was the cause of the observed delayed parasite clearance.…”

“…However, in 2010 and 2011 in the same area, the parasite clearance time was slower than in previous years (13). Even though artemisinin combination therapies are still efficacious in treating malaria patients, prolonged clearance rates may indicate reduced susceptibility.…”

Clinical Efficacy of Dihydroartemisinin–Piperaquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria at the China–Myanmar Border

“…[4][5][6] Since the time when clinical artemisinin resistance was first documented in western Cambodia, 5,7,8 intensive monitoring in the GMS has detected artemisinin resistance in at least six areas because of spread, independent emergence, or both. [9][10][11][12] In vision of a potential catastrophic spread of artemisinin resistance to Africa, the World Health Organization (WHO) developed a containment plan. 13 One critical component to deter the spread of artemisinin resistance is to monitor the efficacy of ACTs.…”

Role of K13 Mutations in Artemisinin-Based Combination Therapy

“…Unsurprisingly, ASMQ efficacy in 5 Cambodian provinces where DP was failing in 2014-2016 was 100% at day 42 (n = 305), even though 94.2% (278/295) of parasites carried the K13 C580Y mutation (Amaratunga et al, unpublished data; Rithea et al, unpublished data). High ACT efficacy despite high K13 mutation prevalence has also been reported in neighboring countries [4][5][6][7].…”