In vivo efficacy of artemether-lumefantrine and artesunate-amodiaquine for the treatment of uncomplicated falciparum malaria in children: a multisite, open-label, two-cohort, clinical trial in Mozambique

Abstract

BackgroundMozambique adopted artemisinin-based combination therapy (ACT) for the treatment of uncomplicated Plasmodium falciparum malaria in the year 2006, and since 2009 artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) have been proposed as alternative first-line treatments. A multicentre study was conducted in five sites across the country to assess the in vivo efficacy and tolerability of these two drugs.MethodsChildren aged six to 59 months with uncomplicated malaria were recruited between June 2011 and January 2012 in five sites across Mozambique (Montepuez, Dondo, Tete, Chokwe, and Manhiça), and treated with AL or ASAQ in a non-randomized study. Follow-up was organized following standard WHO recommendations for in vivo studies, and included daily visits during the three-day-long supervised treatment course, followed by weekly visits up to day 28. The study primary outcome was the day 28 PCR-corrected early treatment failure (ETF), late clinical failure (LCF), late parasitological failure (LPF), and adequate clinical and parasitological response (ACPR). PCR was performed centrally for all cases of recurrent parasitaemia from day 7 onwards to distinguish recrudescence from re-infection.ResultsFour-hundred and thirty-nine (AL cohort; five sites) and 261 (ASAQ cohort, three sites) children were recruited to the study. Day 28 PCR-corrected efficacy for AL was 96.0% (335/339; 95% CI: 93.4-97.8), while for ASAQ it was 99.6% (232/233; 95% CI: 97.6-99.9). The majority of recurring parasitaemia cases throughout follow-up were shown to be re-infections by PCR. Both drugs were well tolerated, with the most frequent adverse event being vomiting (AL 4.5% [20/439]; ASAQ 9.6% [25/261]) and no significant events deemed related to the study drugs.ConclusionThis study confirms that both AL and ASAQ remain highly efficacious and well tolerated for the treatment of uncomplicated malaria in Mozambican children. Studies such as these should be replicated regularly in the selected surveillance sentinel sites to continuously monitor the efficacy of these drugs and to rapidly detect any potential signs of declining efficacy to ACT, the mainstay of malaria treatment.

In vivo efficacy of artemether-lumefantrine and artesunate-amodiaquine for uncomplicated Plasmodium falciparum malaria in Malawi, 2014

“…Overall, the corrected efficacies for both AL and ASAQ are consistent with findings from other studies conducted in Malawi and elsewhere in the region [ 3 , 5 , 11 – 13 ]. In a therapeutic efficacy study conducted in 2010 in six study sites across Malawi, the combined PCR-corrected ACPR for AL was 93.4 % [ 3 ].…”

Therapeutic efficacy of artesunate-amodiaquine and artemether-lumefantrine combinations in the treatment of uncomplicated malaria in two ecological zones in Ghana

“…The study showed that PCR-uncorrected cure rates for AS-AQ were 98 % (95 % CI 89.4, 99.9) in the forest zone and 97.3 % (95 % CI 90.7, 99.7) in the savannah zone whilst AL showed PCR-uncorrected cure rates of 85 % (95 % CI 77.5, 90.9) in the forest zone and 56.3 % (95 % CI 37.7, 73.6) in the savannah zone. Although the study was not a comparative study, the findings compare well with the observation of higher PCR-uncorrected cure rate for AS-AQ, compared with AL, in Mozambique [ 20 ]. This observation may be explained by the longer terminal half-life of amodiaquine (approximately 10 days) over lumefantrine (approximately 4 days) resulting in a higher post-treatment prophylactic effect of AS-AQ [ 21 , 22 ].…”

Polymorphisms of the artemisinin resistant marker (K13) in Plasmodium falciparum parasite populations of Grande Comore Island 10 years after artemisinin combination therapy

“…Our observation is consistent with those in previous reports from Kenya [ 36 ], Angola [ 37 ], Mozambique [ 37 ], Senegal [ 39 ], Ugandan [ 40 ] as well as other areas of Sub-Saharan Africa [ 30 ], Caribbean’s Haiti [ 41 ], and South Asia’ Bangladesh [ 42 ], where the K13-propeller gene mutations associated with artemisinin resistance were absent. Additionally, trials of ACT for treating uncomplicated P. falciparum malaria in Uganda [ 43 ], Kenya [ 44 ], and Mozambique [ 45 ] have found 28-day PCR-corrected cure rates of 89 % or greater. Thus, our data is strongly suggesting that many Grande Comore P. falciparum isolates collected in 2013–2014 are likely still sensitive to artemisinin even under the drug selective pressure from introduction of ACT as the first-line treatment since 2004.…”