Early parasite clearance following artemisinin-based combination therapy among Ugandan children with uncomplicated Plasmodium falciparum malaria

Mary K Muhindo, Abel Kakuru, Prasanna Jagannathan, Ambrose Talisuna, Emmanuel Osilo, Francis Orukan, Emmanuel Arinaitwe, Jordan W Tappero, Frank Kaharuza, Moses R Kamya, Grant Dorsey, Mary K Muhindo, Abel Kakuru, Prasanna Jagannathan, Ambrose Talisuna, Emmanuel Osilo, Francis Orukan, Emmanuel Arinaitwe, Jordan W Tappero, Frank Kaharuza, Moses R Kamya, Grant Dorsey

Abstract

Background: Artemisinin-based combination therapy (ACT) is widely recommended as first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide. Artemisinin resistance has now been reported in Southeast Asia with a clinical phenotype manifested by slow parasite clearance. Although there are no reliable reports of artemisinin resistance in Africa, there is a need to better understand the dynamics of parasite clearance in African children treated with ACT in order to better detect the emergence of artemisinin resistance.

Methods: Data from a cohort of Ugandan children four to five years old, enrolled in a longitudinal, randomized, clinical trial comparing two leading ACT, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP), were analysed. For all episodes of uncomplicated P. falciparum malaria over a 14-month period, daily blood smears were performed for three days following the initiation of therapy. Associations between pre-treatment variables of interest and persistent parasitaemia were estimated using multivariate, generalized, estimating equations with adjustment for repeated measures in the same patient.

Results: A total of 202 children were included, resulting in 416 episodes of malaria treated with AL and 354 episodes treated with DP. The prevalence of parasitaemia on days 1, 2, and 3 following initiation of therapy was 67.6, 5.6 and 0% in those treated with AL, and 52.2, 5.7 and 0.3% in those treated with DP. Independent risk factors for persistent parasitaemia on day 1 included treatment with AL vs DP (RR = 1.34, 95% CI 1.20-1.50, p < 0.001), having a temperature ≥38.0°C vs < 37.0°C (RR = 1.19, 95% CI 1.05-1.35, p = 0.007) and having a parasite density >20,000/μL vs <4,000/μL (RR = 3.37, 95% CI 2.44-4.49, p < 0.001). Independent risk factors for having persistent parasitaemia on day 2 included elevated temperature, higher parasite density, and being HIV infected.

Conclusions: Among Ugandan children, parasite clearance following treatment with AL or DP was excellent with only one of 752 patients tested having a positive blood slide three days after initiation of therapy. The type of ACT given, pre-treatment temperature, pre-treatment parasite density and HIV status were associated with differences in persistent parasitaemia, one or two days following therapy.

Trial registration: Current Controlled Trials Identifier NCT00527800.

Figures

Figure 1
Figure 1
Trial profile. AL = artemether-lumefantrine, DP = dihydroartemisinin-piperaquine.

References

    1. WHO. Guidelines for the treatment of malaria. Second. Geneva, Switzerland: World Health Organization; 2010.
    1. WHO. World Malaria Report 2011. Geneva, Switzerland: World Health Organization; 2011.
    1. Bethell D, Se Y, Lon C, Tyner S, Saunders D, Sriwichai S, Darapiseth S, Teja-Isavadharm P, Khemawoot P, Schaecher K. Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial. PLoS One. 2011;6:e19283. doi: 10.1371/journal.pone.0019283.
    1. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361:455–467. doi: 10.1056/NEJMoa0808859.
    1. Noedl H, Se Y, Sriwichai S, Schaecher K, Teja-Isavadharm P, Smith B, Rutvisuttinunt W, Bethell D, Surasri S, Fukuda MM. Artemisinin resistance in Cambodia: a clinical trial designed to address an emerging problem in Southeast Asia. Clin Infect Dis. 2010;51:e82–e89. doi: 10.1086/657120.
    1. Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, McGready R, ler Moo C, Al-Saai S, Dondorp AM, Lwin KM. 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. Ariey F, Fandeur T, Durand R, Randrianarivelojosia M, Jambou R, Legrand E, Ekala MT, Bouchier C, Cojean S, Duchemin JB. Invasion of Africa by a single pfcrt allele of South East Asian type. Malar J. 2006;5:34. doi: 10.1186/1475-2875-5-34.
    1. Mita T, Venkatesan M, Ohashi J, Culleton R, Takahashi N, Tsukahara T, Ndounga M, Dysoley L, Endo H, Hombhanje F. Limited geographical origin and global spread of sulfadoxine-resistant dhps alleles in Plasmodium falciparum populations. J Infect Dis. 2011;204:1980–1988. doi: 10.1093/infdis/jir664.
    1. Roper C, Pearce R, Nair S, Sharp B, Nosten F, Anderson T. Intercontinental spread of pyrimethamine-resistant malaria. Science. 2004;305:1124. doi: 10.1126/science.1098876.
    1. Fairhurst RM, Nayyar GM, Breman JG, Hallett R, Vennerstrom JL, Duong S, Ringwald P, Wellems TE, Plowe CV, Dondorp AM. Artemisinin-resistant malaria: research challenges, opportunities, and public health implications. Am J Trop Med Hyg. 2012;87:231–241. doi: 10.4269/ajtmh.2012.12-0025.
    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. Das D, Price RN, Bethell D, Guerin PJ, Stepniewska K. Early parasitological response following artemisinin-containing regimens: a critical review of the literature. Malar J. 2013;12:125. doi: 10.1186/1475-2875-12-125.
    1. Stepniewska K, Ashley E, Lee SJ, Anstey N, Barnes KI, Binh TQ, D’Alessandro U, Day NP, de Vries PJ, Dorsey G. In vivo parasitological measures of artemisinin susceptibility. J Infect Dis. 2010;201:570–579. doi: 10.1086/650301.
    1. Okello PE, Van Bortel W, Byaruhanga AM, Correwyn A, Roelants P, Talisuna A, D’Alessandro U, Coosemans M. Variation in malaria transmission intensity in seven sites throughout Uganda. Am J Trop Med Hyg. 2006;75:219–225.
    1. Arinaitwe E, Sandison TG, Wanzira H, Kakuru A, Homsy J, Kalamya J, Kamya MR, Vora N, Greenhouse B, Rosenthal PJ, Tappero J, Dorsey G. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for falciparum malaria: a longitudinal, randomized trial in young Ugandan children. Clin Infect Dis. 2009;49:1629–1637. doi: 10.1086/647946.
    1. Sandison TG, Homsy J, Arinaitwe E, Wanzira H, Kakuru A, Bigira V, Kalamya J, Vora N, Kublin J, Kamya MR, Dorsey G, Tappero JW. Protective efficacy of co-trimoxazole prophylaxis against malaria in HIV exposed children in rural Uganda: a randomised clinical trial. BMJ. 2011;342:d1617. doi: 10.1136/bmj.d1617.
    1. White N. Antimalarial drug resistance and combination chemotherapy. Philos Trans R Soc Lond B Biol Sci. 1999;354:739–749. doi: 10.1098/rstb.1999.0426.
    1. White NJ. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother. 1997;41:1413–1422.
    1. Borrmann S, Sasi P, Mwai L, Bashraheil M, Abdallah A, Muriithi S, Fruhauf H, Schaub B, Pfeil J, Peshu J, Hanpithakpong W, Rippert A, Juma E, Tsofa B, Mosobo M, Lowe B, Osier F, Fegan G, Lindegårdh N, Nzila A, Peshu N, Mackinnon M, Marsh K. Declining responsiveness of Plasmodium falciparum infections to artemisinin-based combination treatments on the Kenyan coast. PLoS One. 2011;6:e26005. doi: 10.1371/journal.pone.0026005.
    1. Whitworth J, Morgan D, Quigley M, Smith A, Mayanja B, Eotu H, Omoding N, Okongo M, Malamba S, Ojwiya A. Effect of HIV-1 and increasing immunosuppression on malaria parasitaemia and clinical episodes in adults in rural Uganda: a cohort study. Lancet. 2000;356:1051–1056. doi: 10.1016/S0140-6736(00)02727-6.
    1. Kamya MR, Gasasira AF, Yeka A, Bakyaita N, Nsobya SL, Francis D, Rosenthal PJ, Dorsey G, Havlir D. Effect of HIV-1 infection on antimalarial treatment outcomes in Uganda: a population-based study. J Infect Dis. 2006;193:9–15. doi: 10.1086/498577.
    1. Birku Y, Mekonnen E, Bjorkman A, Wolday D. Delayed clearance of Plasmodium falciparum in patients with human immunodeficiency virus co-infection treated with artemisinin. Ethiop Med J. 2002;40(Suppl 1):17–26.
    1. Lopera-Mesa TM, Doumbia S, Chiang S, Zeituni AE, Konate DS, Doumbouya M, Keita AS, Stepniewska K, Traore K, Diakite SA, Ndiaye D, Sa JM, Anderson JM, Fay MP, Long CA, Diakite M, Fairhurst RM. Plasmodium falciparum clearance rates in response to artesunate in malian children with malaria: effect of acquired immunity. J Infect Dis. 2013;207:1655–1663. doi: 10.1093/infdis/jit082.

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