Current status of artemisinin-resistant falciparum malaria in South Asia: a randomized controlled artesunate monotherapy trial in Bangladesh

Peter Starzengruber, Paul Swoboda, Hans-Peter Fuehrer, Wasif A Khan, Verena Hofecker, Anja Siedl, Markus Fally, Oliver Graf, Paktiya Teja-Isavadharm, Rashidul Haque, Pascal Ringwald, Harald Noedl, Peter Starzengruber, Paul Swoboda, Hans-Peter Fuehrer, Wasif A Khan, Verena Hofecker, Anja Siedl, Markus Fally, Oliver Graf, Paktiya Teja-Isavadharm, Rashidul Haque, Pascal Ringwald, Harald Noedl

Abstract

Objective: Recent reports indicate that first cases of genuine artemisinin resistance have already emerged along the Thai-Cambodian border. The main objective of this trial was to track the potential emergence of artemisinin resistance in Bangladesh, which in terms of drug resistance forms a gateway to the Indian subcontinent.

Methods: We conducted an open-label, randomized, controlled 42-day clinical trial in Southeastern Bangladesh to investigate the potential spread of clinical artemisinin resistance from Southeast Asia. A total of 126 uncomplicated falciparum malaria patients were randomized to one of 3 treatment arms (artesunate monotherapy with 2 or 4 mg/kg/day once daily or quinine plus doxycycline TID for 7 days). Only cases fulfilling a stringent set of criteria were considered as being artemisinin-resistant.

Findings: The 28-day and 42-day cure rates in the artesunate monotherapy (2 and 4 mg/kg) and quinine/doxycyline arms were 97.8% (95% confidence interval, CI: 87.8-99.8%), 100% (95% CI: 91.1-100%), and 100% (95% CI: 83.4-100%), respectively. One case of re-infection was seen in the artesunate high dose arm, and a single case of recrudescence was observed in the low dose group on day 26. No differences in median parasite and fever clearance times were found between the 2 artesunate arms (29.8 h and 17.9 h vs. 29.5 h and 19.1 h). Not a single case fulfilled our criteria of artemisinin resistance. Parasite clearance times were considerably shorter and ex vivo results indicate significantly higher susceptibility (50% inhibitory concentration for dihydroartemisinin was 1.10 nM; 95% CI: 0.95-1.28 nM) to artemisinins as compared to SE-Asia.

Conclusion: There is currently no indication that artemisinin resistance has reached Bangladesh. However, the fact that resistance has recently been reported from nearby Myanmar indicates an urgent need for close monitoring of artemisinin resistance in the region.

Trial registration: ClinicalTrials.gov NCT00639873.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Flow diagram of the progress…
Figure 1. Flow diagram of the progress through the phase of the trial from enrollment until data analysis for the 3 groups.

References

    1. WHO (2010) Guidelines for the treatment of malaria. Second edition. Geneva, Switzerland: WHO. ISBN: 9789241547925.
    1. Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, et al. (2008) Artemisinin Resistance in Cambodia 1 (ARC1) Study Consortium. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 359: 2619–2620.
    1. Noedl H, Se Y, Sriwichai S, Schaecher K, Teja-Isavadharm P, et al. (2010) Artemisinin resistance in cambodia: a clinical trial designed to address an emerging problem in southeast Asia. Clin Infect Dis 51: e82–89.
    1. Noedl H, Socheat D, Satimai W (2009) Artemisinin-resistant malaria in Asia. N Engl J Med 361: 540–541.
    1. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, et al. (2009) Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 361: 455–467.
    1. Haque R, Thriemer K, Wang Z, Sato K, Wagatsuma Y, et al. (2007) Therapeutic efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Bangladesh. Am J Trop Med Hyg 76: 39–41.
    1. Thriemer K, Haque R, Wagatsuma Y, Salam MA, Akther S, et al. (2006) Therapeutic efficacy of quinine plus sulfadoxine-pyremethamine for the treatment of uncomplicated falciparum malaria in Bangladesh. Am J Trop Med Hyg 75: 645–649.
    1. Thriemer K, Starzengruber P, Khan WA, Haque R, Marma AS, et al. (2010) Azithromycin combination therapy for the treatment of uncomplicated falciparum malaria in Bangladesh: an open-label randomized, controlled clinical trial. J Infect Dis 202: 392–298.
    1. Mita T, Tanabe K, Kita K (2009) Spread and evolution of Plasmodium falciparum drug resistance. Parasitol Int 58: 201–209.
    1. Roper C, Pearce R, Nair S, Sharp B, Nosten F, et al. (2004) Intercontinental spread of pyrimethamine-resistant malaria. Science 305: 1124.
    1. Verdrager J (1986) Epidemiology of the emergence and spread of drug-resistant falciparum malaria in South-East Asia and Australasia. J Trop Med Hyg 89: 277–289.
    1. WHO (2000) Management of severe malaria. A practical handbook. Second edition. Geneva, Switzerland: WHO. ISBN 92 4 154523 2.
    1. WHO (2003) Assessment and Monitoring of Antimalarial Drug Efficacy for the Treatment of Uncomplicated Falciparum Malaria. WHO/HTM/RBM/2003.50. Geneva, Switzerland: WHO.
    1. Snounou G (2001) Genotyping of Plasmodium spp. In: Doolan DL, eds. Methods in Molecular Medicine. Vol. 72. Malaria Methods and Protocols. 103–116.
    1. Noedl H, Attlmayr B, Wernsdorfer WH, Kollaritsch H, Miller RS (2004) A histidine-rich protein 2-based malaria drug sensitivity assay for field use. Am J Trop Med Hyg 71: 711–714.
    1. Noedl H, Bronnert J, Yingyuen K, Attlmayr B, Kollaritsch H, et al. (2005) Simple histidine-rich protein 2 double-site sandwich enzyme-linked immunosorbent assay for use in malaria drug sensitivity testing. Antimicrob Agents Chemother 49: 3575–3577.
    1. Siriyanoda D, Teja-Isavadharm P, Chanarat N, Lim A, Wannaying S, et al.. (2005) LC/MC Analysis of artesunate and dihydroartemisinin in plasma following a single step protein precipitation [abstract 344]. In: Program and abstracts of the 54th annual meeting of the American Society of Tropical Medicine and Hygiene (Washington, DC).
    1. Noedl H (2005) Artemisinin resistance: how can we find it? Trends Parasitol 21: 404–405.
    1. Vijaykadga S, Rojanawatsirivej C, Cholpol S, Phoungmanee D, Nakavej A, et al. (2006) In vivo sensitivity monitoring of mefloquine monotherapy and artesunate-mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003. Trop Med Int Health 11: 211–219.
    1. Krishna S, Woodrow CJ, Staines HM, Haynes RK, Mercereau-Puijalon O (2006) Re-evaluation of how artemisinins work in light of emerging evidence of in vitro resistance. Trends Mol Med 2: 200–205.
    1. Noedl H, Faiz MA, Yunus EB, Rahman MR, Hossain MA, et al. (2003) Drug-resistant malaria in Bangladesh: an in vitro assessment. Am J Trop Med Hyg 68: 140–142.
    1. Stepniewska K, Ashley E, Lee SJ, Anstey N, Barnes KI, et al. (2010) In vivo parasitological measures of artemisinin susceptibility. J Infect Dis 201: 570–579.
    1. WHO (2001) The use of antimalarial drugs. Report of a WHO Informal Consultation, WHO/CDS/RBM/2001.33 Geneva, Switzerland: WHO.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever