Artemether-Lumefantrine versus Dihydroartemisinin-Piperaquine for Treating Uncomplicated Malaria: A Randomized Trial to Guide Policy in Uganda

Abstract

BackgroundUganda recently adopted artemether-lumefantrine (AL) as the recommended first-line treatment for uncomplicated malaria. However, AL has several limitations, including a twice-daily dosing regimen, recommendation for administration with fatty food, and a high risk of reinfection soon after therapy in high transmission areas. Dihydroartemisinin-piperaquine (DP) is a new alternative artemisinin-based combination therapy that is dosed once daily and has a long post-treatment prophylactic effect. We compared the efficacy and safety of AL with DP in Kanungu, an area of moderate malaria transmission.Methodology/Principal FindingsPatients aged 6 months to 10 years with uncomplicated falciparum malaria were randomized to therapy and followed for 42 days. Genotyping was used to distinguish recrudescence from new infection. Of 414 patients enrolled, 408 completed follow-up. Compared to patients treated with artemether-lumefantrine, patients treated with dihydroartemisinin-piperaquine had a significantly lower risk of recurrent parasitaemia (33.2% vs. 12.2%; risk difference = 20.9%, 95% CI 13.0–28.8%) but no statistically significant difference in the risk of treatment failure due to recrudescence (5.8% vs. 2.0%; risk difference = 3.8%, 95% CI −0.2–7.8%). Patients treated with dihydroartemisinin-piperaquine also had a lower risk of developing gametocytaemia after therapy (4.2% vs. 10.6%, p = 0.01). Both drugs were safe and well tolerated.Conclusions/SignificanceDP is highly efficacious, and operationally preferable to AL because of a less intensive dosing schedule and requirements. Dihydroartemisinin-piperaquine should be considered for a role in the antimalarial treatment policy of Uganda.Trial RegistrationControlled-Trials.com ISRCTN75606663

Prevalence of Pfmdr 1 N86Y and Y184F Alleles is Associated with Recurrent Parasitemia following Treatment of Uncomplicated Malaria with Artemether-Lumefantrine in Nigerian Patients

“…In this study, Pfmdr 1 S1034C allele was also observed but occurred at a lower frequency compared to Pfmdr 1 N86Y and Y184F while Pfmdr 1 N1042D allele was not observed in any of the patients tested. The absence of N1042D allele within the study group could not be explained, however a similar finding has been reported in other studies Dokomajila et al, 2006;Happi et al,2009 while our result differs from another study carried out in Ghana, where the prevalence of Pfmdr 1 N1042D allele was found to increase from 2003(Duah et al, 2013. It is worthy of note that it is the cumulative rather than individual effect of these Pfmdr 1 SNPs that contributed significantly (P<0.001) to artemether-lumefantrine resistance.…”

“…The role of genes such as Plasmodium falciparum chloroquine resistance transporter (Pfcrt), Pfmdr1 and Dihydrofolate reductase (dhfr) in antimalarial drug resistance has been studied (Falade et al, 2005). The efficacy and effectiveness of AL as an antimalarial drug has been reported (Falade et al, 2005;Yeka et al 2008;Zurovac et al, 2008). Recent reports from Africa have shown some evidence of clinical and parasitological failure after treatment with AL (Yang et al, 2003;Jambou et al, 2005;Noedl et al, 2010).…”

Clinical Efficacy of Dihydroartemisinin–Piperaquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria at the China–Myanmar Border

“…Nevertheless, clinical trials in Africa and southeast Asia have documented excellent efficacy of DP for treatment of falciparum malaria. [25][26][27] More importantly, several comparative trials of DP versus AL in Africa revealed another advantage of DP in reducing the risk of recurrent parasitemia within 4-9 weeks of treatment. [26][27][28][29] However, clinical failure with DP was recently reported from Cambodia.…”

Increased Risk of Early Vomiting among Infants and Young Children Treated with Dihydroartemisinin-Piperaquine Compared with Artemether-Lumefantrine for Uncomplicated Malaria

“…2 Dihydroartemisinin-piperaquine (DP) is emerging as a favorable antimalarial option with comparable clinical efficacy to AL, prolonged post-treatment prophylaxis, and a simple once a day dosage regimen. [3][4][5][6] The ACTs appear to be well-tolerated and serious toxicities are rare. 1,4,5,7 Early vomiting (vomiting within one hour of dosing) has been reported in 3% of courses of AL 4 and DP 4,6 in adults.…”

“…[3][4][5][6] The ACTs appear to be well-tolerated and serious toxicities are rare. 1,4,5,7 Early vomiting (vomiting within one hour of dosing) has been reported in 3% of courses of AL 4 and DP 4,6 in adults. However, this rate increased to 10% 6 or 11% 4 in children.…”