Abstract
BackgroundThe World Health Organization recommends regular therapeutic efficacy studies (TES) to monitor the performance of first and second-line anti-malarials. In 2016, efficacy and safety of artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria were assessed through a TES conducted between April and October 2016 at four sentinel sites of Kibaha, Mkuzi, Mlimba, and Ujiji in Tanzania. The study also assessed molecular markers of artemisinin and lumefantrine (partner drug) resistance.MethodsEligible patients were enrolled at the four sites, treated with standard doses of AL, and monitored for 28 days with clinical and laboratory assessments. The main outcomes were PCR corrected cure rates, day 3 positivity rates, safety of AL, and prevalence of single nucleotide polymorphisms in Plasmodium falciparum kelch 13 (Pfk13) (codon positions: 440–600) and P. falciparum multi-drug resistance 1 (Pfmdr1) genes (codons: N86Y, Y184F and D1246Y), markers of artemisinin and lumefantrine resistance, respectively.ResultsOf 344 patients enrolled, three withdrew, six were lost to follow-up; and results were analysed for 335 (97.4%) patients. Two patients had treatment failure (one early treatment failure and one recrudescent infection) after PCR correction, yielding an adequate clinical and parasitological response of > 98%. Day 3 positivity rates ranged from 0 to 5.7%. Common adverse events included cough, abdominal pain, vomiting, and diarrhoea. Two patients had serious adverse events; one died after the first dose of AL and another required hospitalization after the second dose of AL (on day 0) but recovered completely. Of 344 samples collected at enrolment (day 0), 92.7% and 100% were successfully sequenced for Pfk13 and Pfmdr1 genes, respectively. Six (1.9%) had non-synonymous mutations in Pfk13, none of which had been previously associated with artemisinin resistance. For Pfmdr1, the NFD haplotype (codons N86, 184F and D1246) was detected in 134 (39.0%) samples; ranging from 33.0% in Mlimba to 45.5% at Mkuzi. The difference among the four sites was not significant (p = 0.578). All samples had a single copy of the Pfmdr1 gene.ConclusionThe study indicated high efficacy of AL and the safety profile was consistent with previous reports. There were no known artemisinin-resistance Pfk13 mutations, but there was a high prevalence of a Pfmdr1 haplotype associated with reduced sensitivity to lumefantrine (but no reduced efficacy was observed in the subjects). Continued TES and monitoring of markers of resistance to artemisinin and partner drugs is critical for early detection of resistant parasites and to inform evidence-based malaria treatment policies.Trial Registration ClinicalTrials.gov NCT03387631
Highlights
The World Health Organization recommends regular therapeutic efficacy studies (TES) to monitor the performance of first and second-line anti-malarials
The study indicated high efficacy of AL and the safety profile was consistent with previous reports
There were no known artemisinin-resistance Plasmodium falciparum kelch 13 (Pfk13) mutations, but there was a high prevalence of a P. falciparum multi-drug resistance 1 (Pfmdr1) haplotype associated with reduced sensitivity to lumefantrine
Summary
The World Health Organization recommends regular therapeutic efficacy studies (TES) to monitor the performance of first and second-line anti-malarials. Artemisinin-based combination therapy ACT is recommended by the World Health Organization (WHO) for the treatment of uncomplicated malaria caused by Plasmodium falciparum [5]. Studies conducted in the East African countries of Tanzania [9,10,11,12], Kenya [13], Uganda [14], Rwanda [15], Burundi [16], and in other African countries [17,18,19] have shown that AL, as well as other artemisinin-based combinations, such as ASAQ and DP (which are first or second-line therapies in other African countries) have high therapeutic efficacy and are well tolerated with minimal adverse effects. Studies from Southeast Asia have demonstrated resistance to partner drugs, including piperaquine [22, 24], yielding parasites resistant to both components of ACT, a scenario not currently observed in Africa
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