Efficacy of artesunate-amodiaquine and artemether-lumefantrine fixed-dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria among children aged six to 59 months in Nimba County, Liberia: an open-label randomized non-inferiority trial

Schramm, Birgit; Valeh, Parastou; Baudin, Elisabeth; Mazinda, C S; Smith, Richard A.; Pinoges, Loretxu; Dhorda, Mehul; Boum, Yap; Sundaygar, Timothy; Zolia, Yah; Jones, Joel J.; Comte, Éric; Houzé, Pascal; Jullien, Vincent; Carn, Gwénaëlle; Kiechel, Jean-René; Ashley, Elizabeth A.; Guérin, Philippe J

doi:10.1186/1475-2875-12-251

Cited by 31 publications

(33 citation statements)

References 25 publications

(28 reference statements)

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“…Artemisinin resistance is defined as delayed parasite clearance after treatment with an artemisinin or ACT [11]. In this study a low proportion of patients were parasite positive on day 3 [9], indicating high efficacy of the artesunate compound.…”

Section: Discussionmentioning

confidence: 99%

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Selection of Plasmodium falciparum pfcrt and pfmdr1 polymorphisms after treatment with artesunate–amodiaquine fixed dose combination or artemether–lumefantrine in Liberia

Otienoburu

Maïga-Ascofaré

Schramm³

et al. 2016

Malar J

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BackgroundPlasmodium falciparum uncomplicated malaria can successfully be treated with an artemisinin-based combination therapy (ACT). However resistance is spreading to the different ACT compounds; the artemisinin derivative and the partner drug. Studies of P. falciparum polymorphisms associated with drug resistance can provide a useful tool to track resistance and guide treatment policy as well as an in-depth understanding of the development and spread of resistance.MethodsThe role of P. falciparum molecular markers in selection of reinfections was assessed in an efficacy trial comparing artesunate–amodiaquine fixed-dose combination with artemether–lumefantrine to treat malaria in Nimba County, Liberia 2008–2009. P. falciparum polymorphisms in pfcrt 76, pfmdr1 86, 184 and 1246, and pfmrp1 876 and 1466 were analysed by PCR-RFLP and pyrosequencing.ResultsHigh baseline prevalence of pfmdr1 1246Y was found in Nimba county (38 %). Pfmdr1 1246Y and pfmdr1 86+184+1246 haplotypes NYY and YYY were selected in reinfections in the artesunate–amodiaquine arm and pfcrt K76, pfmdr1 N86 and pfmdr1 haplotype NFD were selected in artemether–lumefantrine reinfections. Parasites harbouring pfmdr1 1246Y could reinfect earlier after treatment with artesunate–amodiaquine and parasites carrying pfmdr1 N86 could reinfect at higher lumefantrine concentrations in patients treated with artemether–lumefantrine.ConclusionsAlthough treatment is highly efficacious, selection of molecular markers in reinfections could indicate a decreased sensitivity or tolerance of parasites to the current treatments and the baseline prevalence of molecular markers should be closely monitored. Since individual drug levels and the day of reinfection were demonstrated to be key determinants for selection of reinfections, this data needs to be collected and taken into account for accurate evaluation of molecular markers for anti-malarial treatments.The protocols for the clinical trial was registered with Current Controlled Trials, under the Identifier Number ISRCTN51688713 on 9 October 2008

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Section: Discussionmentioning

confidence: 99%

“…Recrudescences and reinfections were distinguished by stepwise genotyping msp1 , msp2 and glurp [9]. …”

Section: Methodsmentioning

confidence: 99%

Selection of Plasmodium falciparum pfcrt and pfmdr1 polymorphisms after treatment with artesunate–amodiaquine fixed dose combination or artemether–lumefantrine in Liberia

Otienoburu

Maïga-Ascofaré

Schramm³

et al. 2016

Malar J

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“…Data on age, parasitaemia, haemoglobin (Hb), treatment and treatment outcome were extracted from primary data of nine randomized controlled trials (RCT) conducted in sub-Saharan Africa, of which seven had 28-day [13–20], and two had 42-day follow-up [20, 21]. The RCTs included in this paper were conducted to assess the efficacy and safety of different malaria treatment in sub-Saharan Africa using the WHO protocol (Zwang 2009, Zwang 2014).…”

Section: Methodsmentioning

confidence: 99%

Haemoglobin changes and risk of anaemia following treatment for uncomplicated falciparum malaria in sub-Saharan Africa

et al. 2017

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BackgroundAnaemia is common in malaria. It is important to quantitate the risk of anaemia and to distinguish factors related to the natural history of disease from potential drug toxicity.MethodsIndividual-patient data analysis based on nine randomized controlled trials of treatments of uncomplicated falciparum malaria from 13 sub-Saharan African countries. Risk factors for reduced haemoglobin (Hb) concentrations and anaemia on presentation and after treatment were analysed using mixed effect models.ResultsEight thousand eight hundred ninety-seven patients (77.0% <5 years-old) followed-up through 28 days treated with artemisinin combination therapy (ACT, 90%, n = 7968) or non-ACT. At baseline, under 5’s had the highest risk of anaemia (77.6% vs. 32.8%) and higher parasitaemia (43,938 μl) than older subjects (2784 μl). Baseline anaemia increased the risk of parasitological recurrence.Hb began to fall after treatment start. In under 5’s the estimated nadir was ~35 h (range 29–48), with a drop of −12.8% from baseline (from 9.8 g/dl to 8.7 g/dl, p = 0.001); in under 15’s, the mean Hb decline between day 0–3 was −4.7% (from 9.4 to 9.0 g/dl, p = 0.001). The degree of Hb loss was greater in patients with high pre-treatment Hb and parasitaemia and with slower parasite reduction rates, and was unrelated to age. Subsequently, Hb increased linearly (+0.6%/day) until day 28, to reach +13.8% compared to baseline.Severe anaemia (<5 g/dl, 2 per 1000 patients) was transient and all patients recovered after day 14, except one case of very severe anaemia associated with parasite recurrence at day 28.There was no systematic difference in Hb concentrations between treatments and no case of delayed anaemia.ConclusionOn presentation with acute malaria young children with high parasitaemia have the highest risk of anaemia. The majority of patients experience a drop in Hb while on treatment as early as day 1–2, followed by a linear increase through follow-up. The degree of the early Hb dip is determined by pre-treatment parasitaemia and parasite clearance rates. Hb trends and rick of anaemia are independent of treatment. Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-017-2530-6) contains supplementary material, which is available to authorized users.

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“…Recent changes suggest that we should reconsider the use of aminoquinolines to treat malaria, including AS-AQ, which showed inferior efficacy to AL in Tanzania (54) and Uganda (55,56) some years ago but excellent recent efficacy in West and Central Africa (57-61); DP, which has shown excellent efficacy (7,(62)(63)(64)(65)(66); and perhaps combinations that include chloroquine (52,67). Further, we should be cautious regarding the long-term antimalarial efficacy of AL, as although both the clinical efficacy of AL (57)(58)(59)(60)(61)(64)(65)(66) and ex vivo activity of DHA and lumefantrine (31,42,(68)(69)(70) ies, current results suggest that the antimalarial potency of lumefantrine is decreasing. Our data show that antimalarial treatment regimens rapidly select for parasites with decreased drug sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Impact of Antimalarial Treatment and Chemoprevention on the Drug Sensitivity of Malaria Parasites Isolated from Ugandan Children

Tumwebaze

Conrad

Walakira

et al. 2015

Antimicrob Agents Chemother

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Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivo drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt 76T, as well as increased lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. Over time, ex vivo sensitivity decreased for lumefantrine and piperaquine and increased for chloroquine, the prevalences of pfcrt K76 and pfmdr1 N86 and D1246 increased, and the prevalences of pfdhfr and pfdhps polymorphisms associated with antifolate resistance were unchanged. In recurrent infections, recent prior treatment with artemether-lumefantrine was associated with decreased ex vivo lumefantrine sensitivity and increased prevalence of pfcrt K76 and pfmdr1 N86, 184F, and D1246. In children assigned chemoprevention with monthly dihydroartemisinin-piperaquine with documented circulating piperaquine, breakthrough infections had increased the prevalence of pfmdr1 86Y and 1246Y compared to untreated controls. The noted impacts of therapy and chemoprevention on parasite polymorphisms remained significant in multivariate analysis correcting for calendar time. Overall, changes in parasite sensitivity were consistent with altered selective pressures due to changing treatment practices in Uganda. These changes may threaten the antimalarial treatment and preventive efficacies of artemether-lumefantrine and dihydroartemisinin-piperaquine, respectively. M alaria, in particular disease caused by Plasmodium falciparum, remains an overwhelming problem in most of subSaharan Africa (1, 2). Malaria control was greatly limited by resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP), leading to adoption of artemisinin-based combination therapy (ACT) as the standard treatment for uncomplicated falciparum malaria in the last decade (3). ACT consists of a rapid-acting artemisinin derivative plus a longer-acting partner drug that clears parasites not eliminated by the artemisinin component and limits selection of artemisinin resistance (4, 5). In nearly all countries in sub-Saharan Africa, either artemether-lumefantrine (AL) or artesunate-amodiaquine (AS-AQ) is recommended to treat uncomplicated malaria (6). Other ACTs are dihydroartemisinin (DHA)-piperaquine (DP), a first-line therapy in some countries in Asia, with particular promise for malaria prevention due to the extended halflife of piperaquine (7), and artesunate-mefloquine (AS-MQ), which is used in some countries in Asia and South America. In Uganda, AL was named the national ma...

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Efficacy of artesunate-amodiaquine and artemether-lumefantrine fixed-dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria among children aged six to 59 months in Nimba County, Liberia: an open-label randomized non-inferiority trial

Cited by 31 publications

References 25 publications

Selection of Plasmodium falciparum pfcrt and pfmdr1 polymorphisms after treatment with artesunate–amodiaquine fixed dose combination or artemether–lumefantrine in Liberia

Selection of Plasmodium falciparum pfcrt and pfmdr1 polymorphisms after treatment with artesunate–amodiaquine fixed dose combination or artemether–lumefantrine in Liberia

Haemoglobin changes and risk of anaemia following treatment for uncomplicated falciparum malaria in sub-Saharan Africa

Impact of Antimalarial Treatment and Chemoprevention on the Drug Sensitivity of Malaria Parasites Isolated from Ugandan Children

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