High therapeutic efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Somalia.

BACKGROUND: Artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA/PPQ) are the recommended first- and second-line treatments, respectively, for uncomplicated falciparum malaria in Somalia. The studies reported here were conducted to assess the efficacy of these artemisinin-based combinations and the mutations in Plasmodium falciparum K13-propeller (Pfk13) domain and amplification in Pfplasmepsin 2 (Pfpm2) gene in Somalia. METHODS: One-arm prospective studies were conducted to assess the clinical and parasitological responses to DHA/PPQ and AL at two sites in 2016 and 2017, respectively, using the standard WHO protocol. The patterns of molecular markers associated with artemisinin and PPQ resistance were investigated for the first time in Somalia. RESULTS: A total of 339 patients were enrolled with 139 for AL and 200 for DHA/PPQ. With AL, no parasite recurrence was observed among patients treated at either site, corresponding to 100% clinical and parasitological responses. For DHA-PPQ, an adequate clinical and parasitological response rate > 97% was observed. All study patients on both treatments at both sites were parasite-free on day 3. Of the 138 samples with interpretable results for the polymorphism in Pfk13, only one (0.7%), from Bosaso, contained a non-synonymous mutation (R622I), which is not one of the known markers of artemisinin resistance. No Pfpm2 amplification was observed among the 135 samples with interpretable results. CONCLUSIONS: AL and DHA/PPQ were highly effective in the treatment of uncomplicated falciparum malaria, and there was no evidence of resistance to artemisinin or PPQ. These two combinations are thus relevant in the chemotherapeutic strategy for malaria control in Somalia. Trial registration ACTRN12616001005448 (Jowhar DP study), ACTRN12616000553471 (Bosaso DP study), ACTRN12617001055392 (AL study in Bosaso and Jowhar).

Efficacy of artesunate + sulphadoxine/pyrimethamine and artemether + lumefantrine and dhfr and dhps mutations in Somalia: evidence for updating the malaria treatment policy.

OBJECTIVE: To determine the therapeutic efficacy of artesunate + sulphadoxine/pyrimethamine (AS + SP) and artemether + lumefantrine (AL), and to investigate the presence of molecular mutations associated with resistance, to inform national malaria treatment policy. METHODS: One-arm prospective studies were conducted in three study sites in Somalia in 2013 and 2015 to evaluate the efficacy of AS + SP and AL among patients with uncomplicated falciparum malaria. Outcomes included clinical and parasitological response over 28 days, and the presence of dihydrofolate reductase (dfhr) and dihydropteroate synthase (dhps) and mutations. RESULTS: Among patients treated with AS + SP, the PCR-corrected treatment failure rate was 12.3%. The majority of patients (89%) carried either the quintuple mutations (51I/108N + 437G/540E/581G or 51I/59R/108N + 437G/540E) or the quadruple mutation (51I/108N + 437G/540E). All patients who failed treatment with AS + SP carried the quintuple mutation (51I/108N + 437G/540E/581G). In the studies of AL, the PCR-corrected treatment failure rate was <6%. All patients in both treatment groups cleared their parasitaemia by day 3. CONCLUSIONS: The findings demonstrate a failing first-line treatment (AS + SP), with a failure rate above the threshold (10%) for policy change, and a high prevalence of quintuple mutations. In contrast, AL was highly efficacious. Based on these findings and the results from a previous AS + SP study, AL was selected to replace AS + SP as the first-line treatment for uncomplicated malaria in Somalia in 2016. Dihydroartemisinin + piperaquine (DHA + PPQ) has been recommended as the second-line treatment. Routine monitoring of recommended ACTs should continue to inform treatment policy.

Treatment of uncomplicated malaria with artesunate plus sulfadoxine-pyrimethamine is failing in Somalia: evidence from therapeutic efficacy studies and Pfdhfr and Pfdhps mutant alleles.

OBJECTIVE: Artesunate plus sulfadoxine-pyrimethamine (AS + SP) has been Somalia's national treatment policy since 2006. Routine monitoring of first-line malaria treatment is needed to ensure appropriate national malaria treatment policy and early detection of drug resistance. For this purpose, we conducted therapeutic efficacy studies of AS + SP for the treatment of uncomplicated malaria in Somalia in 2011. METHODS: Studies were conducted in three sentinel sites. Eligible patients were evaluated for clinical and parasitological outcomes according to the WHO standard protocol. Molecular surveillance was conducted on resistance conferring mutations in the P.falciparum dihydrofolate reductase (dfhr) and dihydropteroate synthase (dhps) genes. RESULTS: The proportion of PCR-corrected treatment failures was high in Jamame (22%, 95% CI: 13.7-32.8%) and low (<5%) in Janale and Jowhar. All patients cleared parasites by day 3. Molecular markers associated with SP resistance were detected in all three sites. Treatment failure was associated with the presence of the double mutant dhps A437G/K540E (OR = 22.4, 95% CI: 5.1-98.1), quadruple mutant dhfr N51I/S108N+dhps A437G/K540E (OR = 5.5, 95% CI: 2.3-13.6), quintuple mutant dhfr N51I/C59R/S108N+dhps A437G/K540E (OR = 3.5, 95% CI: 1.4-8.8) and younger age (OR=0.86, 95% CI: 0.76-0.96). CONCLUSIONS: The high treatment failure rate observed in Jamame, together with the presence of molecular mutations associated with SP resistance, indicates P. falciparum resistance to SP. In Jowhar, high treatment failure rates were absent despite the presence of molecular mutations; signs of resistance in vivo may have been masked by the stronger immunity of the older study population. The study underscores the need to update Somalia's national malaria treatment policy.

Efficacy of monotherapies and artesunate-based combination therapies in children with uncomplicated malaria in Somalia.

In order to guide the antimalarial treatment policy of Somalia, we conducted therapeutic efficacy studies of routinely used antimalarial monotherapies as well as artemisinin-based combination therapies (ACTs) for uncomplicated malaria in three sentinel sites during 2003-2006. Therapeutic efficacy of chloroquine (CQ), amodiaquine (AQ) and sulfadoxine/pyrimetahmine (SP) monotherapies, and artesunate plus SP (AS+SP) or AQ (AS+AQ) were evaluated in children 6 months to 10 years old with uncomplicated malaria. For the assessment of the monotherapies, 2003 WHO protocol with 14-day follow-up was used while the 2005 WHO protocol with 28-day follow-up was used for testing the ACTs. Of the monotherapies, CQ performed very poorly with treatment failures varying from 76.5% to 88% between the sites. AQ treatment failure was low except for Janale site with treatment failure of 23.4% compared to 2.8% and 8% in Jamame and Jowhar, respectively. For SP, treatment failures from 7.8% to 12.2% were observed. A 28-day test of artemisinin-based combinations, AS+SP and AS+AQ, proved to be highly efficacious with cure rates of 98-100% supporting the choice of AS+SP combination as first line treatment for uncomplicated malaria for Somalia.