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

Tran Tinh Hien, Nguyen Thanh Thuy-Nhien, Nguyen Hoan Phu, Maciej F Boni, Ngo Viet Thanh, Nguyen Thuy Nha-Ca, Le Hong Thai, Cao Quang Thai, Pham Van Toi, Phung Duc Thuan, Le Thanh Long, Le Thanh Dong, Laura Merson, Christiane Dolecek, Kasia Stepniewska, Pascal Ringwald, Nicholas J White, Jeremy Farrar, Marcel Wolbers, Tran Tinh Hien, Nguyen Thanh Thuy-Nhien, Nguyen Hoan Phu, Maciej F Boni, Ngo Viet Thanh, Nguyen Thuy Nha-Ca, Le Hong Thai, Cao Quang Thai, Pham Van Toi, Phung Duc Thuan, Le Thanh Long, Le Thanh Dong, Laura Merson, Christiane Dolecek, Kasia Stepniewska, Pascal Ringwald, Nicholas J White, Jeremy Farrar, Marcel Wolbers

Abstract

Background: By 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.

Methods: From 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.

Results: 166 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).

Conclusions: This 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 registration: NTC01165372.

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Histograms of parasite clearance half-lives by treatment group.
Figure 3
Figure 3
Parasite clearance curves for all 166 patients in the study. Median clearance times are shown in red. Patients who had >0.01% baseline parasitemia at 72 hours are shown in blue.

References

    1. Hien TT. An overview of the clinical use of artemisinin and its derivatives in the treatment of falciparum malaria in Vietnam. Trans R Soc Trop Med Hyg. 1994;88(Suppl 1):S7–S8.
    1. Hien TT, Dolecek C, Pham PM, Nguyen TD, Nguyen TT, Le HT, Dong TH, Tran TT, Stepniewska K, White NJ, Farrar J. Dihydroartemisinin-piperaquine against multidrug-resistant Plasmodium falciparum malaria in Vietnam: randomised clinical trial. Lancet. 2004;363:18–22. doi: 10.1016/S0140-6736(03)15163-X.
    1. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N, Socheat D, White NJ. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361:455–467. doi: 10.1056/NEJMoa0808859.
    1. Noedl H, Socheat D, Satimai W. Artemisinin-resistant malaria in Asia. N Engl J Med. 2009;361:540–541. doi: 10.1056/NEJMc0900231.
    1. Rogers WO, Sem R, Tero T, Chim P, Lim P, Muth S, Socheat D, Ariey F, Wongsrichanalai C. Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria in southern Cambodia. Malar J. 2009;8:10. doi: 10.1186/1475-2875-8-10.
    1. Carrara VI, Zwang J, Ashley EA, Price RN, Stepniewska K, Barends M, Brockman A, Anderson T, McGready R, Phaiphun L, Proux S, van Vugt M, Hutagalung R, Lwin KM, Phyo AP, Preechapornkul P, Imwong M, Pukrittayakamee S, Singhasivanon P, White NJ, Nosten F. Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment. PLoS One. 2009;4:e4551. doi: 10.1371/journal.pone.0004551.
    1. Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, McGready R, ler Moo C, Al-Saai S, Dondorp AM, Lwin KM, Singhasivanon P, Day NP, White NJ, Anderson TJ, Nosten F. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet. 2012;379:1960–1966. doi: 10.1016/S0140-6736(12)60484-X.
    1. WHO. Update on artemisinin resistance. 2012. .
    1. Stepniewska K, Ashley E, Lee SJ, Anstey N, Barnes KI, Binh TQ, D'Alessandro U, Day NP, de Vries PJ, Dorsey G, Guthmann JP, Mayxay M, Newton PN, Olliaro P, Osorio L, Price RN, Rowland M, Smithuis F, Taylor WR, Nosten F, White NJ. In vivo parasitological measures of artemisinin susceptibility. J Infect Dis. 2010;201:570–579. doi: 10.1086/650301.
    1. WHO. Methods for surveillance of anti-malarial drug efficacy. .
    1. Bereczky S, Martensson A, Gil JP, Farnert A. Short report: Rapid DNA extraction from archive blood spots on filter paper for genotyping of Plasmodium falciparum. AmJTrop Med Hyg. 2005;72:249–251.
    1. Moll K, Ljungström I, Perlmann H, Scherf A, Wahlgren M. Methods in malaria research. 2008. (MR4/ATCC (Manassas, Virginia and BioMalPar (Paris, France))).
    1. WHO. Methods and techniques for clinical trials on anti-malarial drug efficacy: genotyping to identify parasite populations: informal consultation organized by the Medicines for Malaria Venture and cosponsored by the World Health Organization, 29–31 May 2007, Amsterdam, The Netherlands. .
    1. US-NIH. .
    1. Flegg JA, Guerin PJ, White NJ, Stepniewska K. Standardizing the measurement of parasite clearance in falciparum malaria: the parasite clearance estimator. Malar J. 2011;10:339. doi: 10.1186/1475-2875-10-339.
    1. Phu NH, Tuan PQ, Day N, Mai NT, Chau TT, Chuong LV, Sinh DX, White NJ, Farrar J, Hien TT. Randomized controlled trial of artesunate or artemether in Vietnamese adults with severe falciparum malaria. Malar J. 2010;9:97. doi: 10.1186/1475-2875-9-97.
    1. Fraley C, Raftery AE, Murphy TB, Scrucca L. mclust Version 4 for R: Normal Mixture Modeling for Model-Based Clustering, Classification, and Density Estimation Technical Report No. 597. University of Washington: Department of Statistics; 2012.
    1. Anderson TJ, Nair S, Nkhoma S, Williams JT, Imwong M, Yi P, Socheat D, Das D, Chotivanich K, Day NP, White NJ, Dondorp AM. High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in western Cambodia. J Infect Dis. 2010;201:1326–1330. doi: 10.1086/651562.
    1. Cheeseman IH, Miller BA, Nair S, Nkhoma S, Tan A, Tan JC, Al Saai S, Phyo AP, Moo CL, Lwin KM, McGready R, Ashley E, Imwong M, Stepniewska K, Yi P, Dondorp AM, Mayxay M, Newton PN, White NJ, Nosten F, Ferdig MT, Anderson TJ. A major genome region underlying artemisinin resistance in malaria. Science. 2012;336:79–82. doi: 10.1126/science.1215966.
    1. WHO. Global plan for artemisinin resistance containment (GPARC ) .
    1. Amaratunga C, Sreng S, Suon S, Phelps ES, Stepniewska K, Lim P, Zhou C, Mao S, Anderson JM, Lindegardh N, Jiang H, Song J, Su XZ, White NJ, Dondorp AM, Anderson TJ, Fay MP, Mu JDuong S, Fairhurst RM. Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study. Lancet Infect Dis. 2012;12:851–858. doi: 10.1016/S1473-3099(12)70181-0.
    1. O'Riordan S, Hien TT, Miles K, Allen A, Quyen NN, Hung NQ, Anh do Q, Tuyen LN, Khoa DB, Thai CQ, Triet DM, Phu NH, Dunstan S, Peto T, Clegg J, Farrar J, Weatherall D. Large scale screening for haemoglobin disorders in southern Vietnam: implications for avoidance and management. Br J Haematol. 2010;150:359–364. doi: 10.1111/j.1365-2141.2010.08237.x.
    1. Hien TT. Anti-malarial drug treatment in Vietnam. PhD Thesis. Open University UK: Oxford University Clinical Research Unit; 2004.
    1. Thanh NV, Toan TQ, Cowman AF, Casey GJ, Phuc BQ, Tien NT, Hung NM, Biggs BA. Monitoring for Plasmodium falciparum drug resistance to artemisinin and artesunate in Binh Phuoc Province, Vietnam: 1998–2009. Malar J. 2010;9:181. doi: 10.1186/1475-2875-9-181.
    1. Teuscher F, Gatton ML, Chen N, Peters J, Kyle DE, Cheng Q. Artemisinin-induced dormancy in Plasmodium falciparum: duration, recovery rates, and implications in treatment failure. J Infect Dis. 2010;202:1362–1368. doi: 10.1086/656476.
    1. Boni MF, Buckee CO, White NJ. Mathematical models for a new era of malaria eradication. PLoS Med. 2008;5:e231. doi: 10.1371/journal.pmed.0050231.
    1. Boni MF, Smith DL, Laxminarayan R. Benefits of using multiple first-line therapies against malaria. Proc Natl Acad Sci U S A. 2008;105:14216–14221. doi: 10.1073/pnas.0804628105.
    1. Hastings I. How artemisinin-containing combination therapies slow the spread of anti-malarial drug resistance. Trends Parasitol. 2011;27:67–72. doi: 10.1016/j.pt.2010.09.005.
    1. Editorial. New estimates of malaria deaths: concern and opportunity. Lancet. 2012;379:385. doi: 10.1016/S0140-6736(12)60169-X.
    1. Murray CJ, Rosenfeld LC, Lim SS, Andrews KG, Foreman KJ, Haring D, Fullman N, Naghavi M, Lozano R, Lopez AD. Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet. 2012;379:413–431. doi: 10.1016/S0140-6736(12)60034-8.

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