Abstract
Although artemisinin-based combination therapies (ACTs) are widely viewed as safe drugs with a wide therapeutic dose range, concerns about neuroauditory safety of artemisinins arose during their development. A decade ago, reviews of human data suggested a potential neuro-ototoxic effect, but the validity of these findings was questioned. With 5–10 years of programmatic use, emerging artemisinin-tolerant falciparum malaria in southeast Asia, and the first calls to consider an increased dose of artemisinins, we review neuroauditory safety data on ACTs to treat uncomplicated falciparum malaria. Fifteen studies reported a neurological or auditory assessment. The large heterogeneity of neuro-ototoxic end points and assessment methodologies and the descriptive nature of assessments hampered a formal meta-analysis and definitive conclusions, but they highlight the persistent lack of data from young children. This subgroup is potentially most vulnerable to any neuroauditory toxicity because of their development stage, increased malaria susceptibility, and repeated ACT exposure in settings lacking robust safety monitoring.
Highlights
Over the past decade, artemisinin-based combination therapies (ACTs) have been deployed as first- and secondline treatments for uncomplicated malaria across malariaendemic regions
With 5–10 years of programmatic use, emerging artemisinin-tolerant falciparum malaria in southeast Asia, and the first calls to consider an increased dose of artemisinins, we review neuroauditory safety data on ACTs to treat uncomplicated falciparum malaria
In programmatic settings, where malaria incidence is highest among the youngest children, individual doses of 5–10 mg/kg will occur where ACTs are dosed by age rather than weight
Summary
Artemisinin-based combination therapies (ACTs) have been deployed as first- and secondline treatments for uncomplicated malaria across malariaendemic regions. Damage to specific brainstem nuclei was reported when administering high and parenteral doses of the lipophilic artemisinin molecules arteether and artemether.[2,3,4,5,6,7,8] A drug treatment safety study in rats showed the drugs’ toxicities during a critical neurodevelopmental stage and their potential long-term cumulative effect.[9] This study showed that repeated treatment (up to eight cycles) with lower parenteral doses of B-arteether (5–10 mg/kg) was associated with brainstem damage after five cycles, whereas higher single doses (60–90 mg/kg) caused death without brainstem pathology.[9] These findings suggest that repeated treatment of these oil-based artemisinin components could cause similar neurological and ototoxic damage in young children. The possibility of cumulative ototoxicity with repeated use and the specific risk in sub-
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