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

Abstract

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

“…The treatment failure rates reported in the current and previous study are most likely due to resistance to SP. As all patients cleared their parasitemia by day 3, the presence of artemisinin resistance is unlikely.…”

“…The high prevalence of dhfr/dhps quintuple mutations detected in Bosaso, together with the high rates of quadruple/quintuple mutations previously found in two study sites in the southern zone in 2011 , indicates widespread resistance to SP in Somalia. It is interesting to note that in the current study, there was a high prevalence of the dhps 581G mutation occurring in combination with the dhps double (437G and 540E) mutation.…”

“…Subsequently, in 2015, to evaluate the geographical extent of AS + SP treatment failure, as well as the efficacy and safety of AL, studies were conducted in a new study site, Bosaso, located in the north‐east (Puntland). The findings from these and previous studies provided the evidence needed for the National Malaria Control Program of Somalia to make an informed decision to change the malaria treatment policy in 2016.…”

“…We are reporting a PCR‐corrected AS + SP treatment failure rate of 12% in Bosaso, located in the north‐eastern zone. Given that a high treatment failure rate (22%) with AS + SP was previously reported from Jamame in the southern zone of the country , P. falciparum resistance to this ACT is likely to be widespread. The treatment failure rate exceeds the WHO‐recommended 10% threshold for changing antimalarial treatment policy .…”

“…In accordance with WHO recommendations, Somalia adopted AS + SP as the first‐line treatment for uncomplicated malaria in 2006 , and AL as the recommended second‐line drug in 2011. However, in 2011, studies conducted in Somalia's southern zone detected a high proportion of treatment failures (22%) with AS + SP in the study site Jamame, and high levels of dhfr/dhps quadruple and quintuple mutations in the study sites Jamame and Jowhar .…”