Abstract
Background
In Uganda, artemether-lumefantrine (AL) is the first-line therapy and dihydroartemisinin-piperaquine (DP) the second-line therapy for the treatment of uncomplicated malaria. We evaluated the efficacy and safety of AL and DP in the management of uncomplicated Plasmodium falciparum malaria and measured the prevalence of molecular markers of resistance in three sentinel sites from 2018–2019 in Uganda.
Methods
This was a randomized, open-label, phase IV clinical trial. Children aged 6 months to 10 years with uncomplicated falciparum malaria were randomly assigned to treatment with AL or DP and followed for 28 and 42 days, respectively. Genotyping was used to distinguish recrudescence from new infection, and a Bayesian algorithm was used to assign each treatment failure a posterior probability of recrudescence. For monitoring resistance, Pfk13 and Pfmdr1 genes were Sanger sequenced and plasmepsin-2 copy number was assessed by qPCR.
Results
There were no early treatment failures. The uncorrected 28-day cumulative efficacy of AL ranged from 41.2–71.2% and the PCR-corrected cumulative 28-day efficacy of AL ranged from 87.2–94.4%. The uncorrected 28-day cumulative efficacy of DP ranged from 95.8–97.9% and the PCR-corrected cumulative 28-day efficacy of DP ranged from 98.9–100%. The uncorrected 42-day efficacy of DP ranged from 73.5–87.4% and the PCR-corrected 42-day efficacy of DP ranged from 92.1–97.5%. There were no reported serious adverse events associated with any of the regimens. No resistance-associated mutations in the Pfk13 gene were found in the successfully sequenced samples. In the AL arm, the NFD haplotype (N86Y, Y184F, D1246Y) was the predominant Pfmdr1 haplotype, present in 78 of 127 (61%) and 76 of 110 (69%) of the day 0 and day of failure samples, respectively. All the day 0 samples in the DP arm had one copy of the plasmepsin-2 gene.
Conclusions
DP remains highly effective and safe for the treatment of uncomplicated malaria in Uganda. Recurrent infections with AL were common. In Busia and Arua, the 95% confidence interval for PCR-corrected AL efficacy fell below 90%. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended.
Trial registration:
The trail was also registered with the ISRCTN registry with study Trial no PACTR201811640750761.
Efficacy and Safety of Azithromycin-Chloroquine versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment of Plasmodium falciparum Malaria Infection in Pregnant Women in Africa: An Open-Label, Randomized Trial
