Neuroauditory Toxicity of Artemisinin Combination Therapies—Have Safety Concerns Been Addressed?

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.


BACKGROUND
Over the past decade, artemisinin-based combination therapies (ACTs) have been deployed as first-and secondline treatments for uncomplicated malaria across malariaendemic regions. Since 2001, this deployment has included the delivery of over 500 million treatments of artemetherlumefantrine (AL), making it one of the most widely prescribed drugs worldwide. 1 Artemisinin derivatives are generally viewed as safe drugs with a very wide therapeutic dose range. However, a number of animal studies conducted before the wide deployment of artemisinins identified their potential ototoxic effects targeting mainly the auditory and vestibular pathways. 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. It was argued that the implications for the use of ACTs in humans were not clear because of the use of lower doses, the use of more water-soluble compounds, and the largely oral route of administration. 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. The possibility of cumulative ototoxicity with repeated use and the specific risk in sub-groups that could be exposed to doses over 5 mg/kg have not been investigated.
Given the considerable number of trials in children 6-59 months of age and their wide-scale use in control programs, one might assume that any specific safety concerns would have been previously identified, which is not necessarily the case. Standard phase III trials generally use the drug of interest at the target dose during a single or a low number of exposures, and they are underpowered for safety end points. Furthermore, there are no standardized guidelines to evaluate ACT ototoxicity or neurotoxicity in clinical trials, both of which are more challenging to assess in young children. Without specific encouragement or recommendation of neuroauditory assessments, few research teams voluntarily opt to conduct such assessments. Pharmacovigilance conducted as part of phase IV or postmarketing safety monitoring largely depends on passive detection of adverse events within regular healthcare systems that often lack the capacity to diagnose changes in auditory function.
Over the past decades, there has been a considerable increase in the reported prevalence of hearing impairment worldwide. This increase has been attributed to better case finding, ageing populations, an increase in noise-induced hearing loss, excessive use of ototoxic drugs, and untreated otitis media. 10 Two-thirds of the cases are from low-income countries, where preventable factors are still the leading cause (World Health Organization [WHO], unpublished data). Data on drug-induced hearing impairment again rely predominantly on relatively weak pharmacovigilance systems. Hearing impairment may not be commonly attributed to recently used drugs, resulting in underreporting. Case reports of hearing loss caused by the use of potentially ototoxic drugs are complicated further by the use of concomitant and different ototoxic drugs over time.
Techniques, such as otoacoustic emissions (OAEs), electrocochleography, and auditory brainstem responses (ABRs), have been used for detecting and monitoring ototoxicity in infants and non-responsive subjects with success. 11,12 Among these techniques, ABR is viewed as the most objective and sensitive method capable of exploring the specific brainstem damage pattern formed by ACTs; the exact clinical implication of changes in the responses is, however, still not known. 13 To assure quality ABR testing, methods are required to rule out external or middle ear disease. Tympanometry provides functional and quantitative information about the middle ear, and its use has been recommended combined with qualitative data provided by otoscopy. Nevertheless, its interpretation and reliability are equivocal in infants because of a highly compliant ear canal. 14 Otoscopy alone, however, allows for the prompt detection of ear canal and middle ear (tympanic membrane) abnormalities before ABR performance, even by non-medically qualified staff, and therefore, it is a feasible tool in low-resource settings. 15 In 2004, a study from Mozambique suggested that AL (Coartem, Novartis Pharma AG, Basel, Switzerland) was associated with hearing impairment in adults being treated for uncomplicated malaria. 16 Although this reopened a global debate on ACT safety, most attention focused on the design weaknesses of the study, detracting from a valid attempt to highlight the need to exclude any safety concerns systematically. Ten years after this debate, we present an update of the published literature on available safety data of ACTs regarding neuro-ototoxicity when treating uncomplicated malaria and identify remaining knowledge gaps.

METHODS
Search strategy. A search of electronic databases was conducted to identify publications on the treatment of uncomplicated malaria with ACTs that included specific reports on neuroauditory safety outcomes. Exclusion criteria were no inclusion of neuroauditory or neurological safety outcomes, studies on treatment of severe malaria, pre-clinical studies, reviews, case reports, and expert opinions. There was no exclusion regarding participants, interventions, comparisons, overall outcomes, or study design.
The search was not limited by language or year, and it was carried out using the databases of EMBASE and PubMed MEDLINE. The latest search was conducted in January of 2013. The search strategy included seven different MeSH medical subject headings (MeSH) term combinations: artemisinin combination therapy and safety, artemisinins and uncomplicated malaria and safety, artemisinins and auditory safety, artemisinins and neurological safety, artemisinins and ototoxicity, artemisinins and neurological assessment, and artemisinins and hearing assessment.
Neuroauditory and/or neurological assessment methods. Methods currently recommended for auditory measurements Modified from Cunningham and Cox. 45 COR = conditioned-oriented responses; VRA= visual-reinforced audiometry. *Fifteen minutes is very short and can only apply if a click sound is measured at a few decibel levels. It does not explore frequencies over 4 kHz (conventional click). Therefore, it cannot detect early toxicity (ototoxic effects start in very high frequencies of 8-12 kHz). The lengths of IPLs, measured in milliseconds, are the least variable and most independent of subject stimuli and recording parameters compared with other measures derived from ABRs. 19 in infants and children are described in Table 1. In this review, the methods to assess neurological and neuroauditory function varied from subjective reports of hearing loss by participants or caregivers and whispered voice tests to conventional and pure tone audiometry (PTA), OAE, and/or ABR. Tympanometry and otoscopy were also conducted in some studies to rule out ear canal and middle ear disease.
We included neurological and neuropsychiatric assessments when they were reported. They were either reported as general neurological assessments or specifically described as more targeted, such as fine-finger dexterity, hand coordination, audiovestibular tests (Rinne's and Weber's tests), and/or behavioral-developmental assessments adapted for children (tone and behavior-Hammersmith, Bayley). One study reported neuropsychiatric assessments based on questionnaires to caregivers and children over 3.5 years old.
Neuro-ototoxic end points. Neuro-ototoxic end points varied substantially across studies and among methodologies used.
Hearing impairment definition with audiometry. WHO grades of hearing impairment suggest that no impairment is reported at 25 dB, slight impairment is 26-40 dB, moderate impairment is 41-60 dB, severe impairment is 61-80 dB, and profound impairment, including deafness, is 81 dB. Hearing threshold levels are taken for the better ear as the mean of the unaided pure tone threshold levels and the frequencies of 0.5, 1, 2, and 4 kHz (decibels). In addition, hearing threshold levels (decibels) defining disabling hearing impairment are established as being 31 dB in individuals ages 15 years and 41 dB in individuals ages 15 years (audiometric threshold measurements according to the international standards ISO 8253-1).
Ototoxicity with ABR. There are no standardized end points to assess ototoxicity with ABR, although based on animal studies, the wave III-V latency would most likely be affected by artemisinin toxicity, and any cumulative drug exposure and toxicity effect would be expected to produce a bilateral prolongation of the I-V, I-III, and III-V interpeak latencies (IPLs). 17 Hearing failure was defined as an IPL absolute latency in milliseconds above +2.5 SD of the mean for age in this study. McCall and others 18 looked at latencies prolonged 2 SD from baseline. In the study by Hutagalung and others, 19 a difference of 0.30 milliseconds in IPLs with age-matched controls was considered clinically significant. Carrasquilla and others 20 used a wave III latency increase of 0.30 milliseconds at day 7 after treatment. Neurological end points. There were no specified pre-defined general neurological end points in the reviewed papers, and outcome measures consisted of description of main findings, intensity, frequency, age distribution, onset, and resolution.
Risk of bias assessment. A structured data collection sheet was developed to extract data from each selected study. Study design, participants, location, auditory method of assessment, neuro-ototoxic end points reported, and main results were appraised. The reported data were appraised separately by two independent assessors (V.R.M. and C.G.M.) and evaluated for the risk of bias in individuals and across studies using The Cochrane Collaboration's tool for assessing risk of bias in randomized and non-randomized studies combined with the Agency for Healthcare Research and Quality (AHRQ) 2012 recommendations (Table 2). 21,22 The heterogeneity of study end points and methods prevented any meaningful meta-analyses.

RESULTS
The literature search process is presented in Figure 1. Sixtyeight full-text articles were assessed for eligibility to identify specific neurological or auditory assessments that were undertaken during the safety evaluation but were not described in the abstract. Fifteen studies were eligible for inclusion in this review (eight randomized controlled trials [RCTs] and seven observational studies). Seven studies looked at multiple exposures. From these multiple exposure studies, four studies included neurological assessment (with or without auditory assessment) in children under 5 years old, and two studies were RCTs. Single exposures were investigated in eight studies: three studies included children under 5 years old, and two studies were RCTs. Seven of eight single-exposure studies conducted a pre-treatment neurological and/or auditory baseline assessment, allowing pre-to-post comparison; however, only The Cochrane Collaboration's tool for assessing risk of bias in RCTs (adapted from Higgins and others 21 ) and AHRQ recommendations (2012) for non-randomized trials (NRTs). 22 NA = not applicable; + = low risk of bias; ? = unclear risk of bias; -= high risk of bias. two of the multiple exposure studies did so. The pooled studies investigated a total of 3,859 participants (including controls) ( Figure 2).
Study characteristics are summarized in Table 3, and results of individual studies are in Table 4. Of three RCTs that assessed efficacy and safety of multiple exposures to ACTs, two RCTs included children under 5 years of age, 23,24 and one RCT assessed auditory safety in children 12 years old. 25 Exposure to several courses of ACTs in these trials was not associated with an increased risk of neuroauditory adverse events. However, in one RCT that included young children conducted by Adjei and others, 23 specific auditory assessments were only conducted in older children ( 5 years old), because the specific auditory test used relied on the cooperation and responses of the tested individual. In this study, hearing thresholds were significantly elevated in treated children compared with those thresholds in age-and sex-matched controls without malaria on days 0, 3, 7, and 28 but not after 9-12 months. 23 Ndiaye and others 25 performed audiometric measurements in children 12 years old during first and second malarial episodes (before treatment and on days 3 and 28) and found no significant variation on hearing thresholds at any point.
Two observational retrospective case-control studies explored the potential ototoxic effect of ACTs after multiple exposures and included children under 5 years old. In children older than 5 years (there were not enough controls under 5 years old to make comparisons), Kissinger and others 17 and Van Vugt and others 26 showed a prolongation in the objective ABR (longer I-III IPLs) compared with the controls without artemisinin treatment. Post-treatment ABR prolongation described by Kissinger and others 17 was, however, only found on the right side. Neither study could correlate those changes to the cumulative dosage of artemisinins administered over periods of 2 and 3 years, respectively. 17, 26 Toovey and Jamieson 16 also conducted an observational retrospective case-control study of 300 adult participants in Mozambique, where audiometry was performed on construction site workers at the start of employment and after repeated diagnosis of malaria and prescription with AL (N = 150). These individuals were compared with controls without drug exposure. Toovey and Jamieson 16 found AL treatment to be associated with irreversible hearing loss. The mean time between exposure to AL and post-exposure audiogram was 163.8 days (range = 3-392 days). 16 Among seven single-exposure studies that included auditory assessment before and after treatment, three studies reported neuroauditory abnormalities after artemisinin treatment. 20,27,28 Gurkov and others 27 undertook an RCT and revealed a prolongation of ABR IPLs I-III on day 28 after a single treatment with AL. This prolongation disappeared by day 90. 27 The study also showed a significant transient cochlear hearing loss in patients treated with quinine, which has been previously reported in the literature. 27 Carrasquilla and others 20 also conducted an RCT assessing single exposure to AL, where 2.6% of participants showed a significant prolongation of ABR latency of wave III at day 7 after treatment (the primary outcome was wave III prolongation in 15% of participants). An additional model-based analysis found no apparent relationship between the drug exposure and the ABR changes. 20 Finally, during a phase IV single-arm study, Frey and others 28 found that, after a single exposure with artesunatemefloquine (AM) in Cameroon, children aged 7 months old to 7 years old were reported to experience a transient drug-related mild to moderate neurological or neuropsychiatric impairment that resolved spontaneously. Eleven events in 8 of 213 children (5.16%) were considered to be related to the study medication 28 ; the most common events were vertigo, dizziness, headache, and sleeping disorders. 28 The study could not rule out that this finding was attributable to mefloquine alone, and despite assessing neurological safety in children below 5 years old, Frey and others 28 did not perform any auditory examination.
Lacking meta-analysis options, we summarize the current available ACT neuroauditory safety data according to the Oxford Center of Evidence Based Medicine (OCEBM) levels of evidence (Table 5). Grades B and C of evidence can be inferred uniquely from studies that tested older age groups (over 5 years old and particularly, young adults). However, in the under 5 years old age group, evidence gaps remain significant and cannot be graded.

DISCUSSION
This review is the first comprehensive and systematic review on specific human neuroauditory safety concerns of ACTs for the treatment of uncomplicated malaria since these concerns were raised a decade ago. Unfortunately, this review reveals a lack of collective effort to obtain the required safety data in a structured way, although ACTs have become some of the most widely used drugs in Africa over the past decade.
This review highlights the technical challenges involved in determining this specific safety concern properly, but more importantly, it questions if the scientific community has      neglected the opportunity and its responsibility for ongoing targeted assessment of the safety of widely used antimalarials in real-life settings during the post-marketing period. Most of the studies aimed to assess efficacy and general safety of a single exposure. Only 15 studies looked at specific neuroauditory and/or general neurological safety outcomes. The lack of a standardized approach to drug adverse event monitoring hampered the ability to compare data collected in different studies and prevented any meaningful meta-analysis.
Systematic assessments for adverse events in efficacy-safety studies generally followed the International Conference of Harmonization Good Clinical Practice guidelines. These assessments, however, did not focus on the existence of systemspecific adverse events and could not rule out neuroauditory toxicity of ACTs in humans. The reviewed studies that were looking at multiple and single exposures to ACTs identified some changes in the hearing assessments performed after treatment but collectively failed to accurately and objectively ( 500 mg/kg) Ar/As cumulative dosage. However, when correcting for age, no significant differences regarding cumulative dosage in IPLs. Van Vugt and others, 2000 26 Neurologic examination: all normal except for hearing test in one case and two controls (PTA and ABR). Very small but significant difference between controls and cases (longer; 2.08 vs. 2.14 milliseconds; SD = 0.19) for the IPLs I-III only in the right side (P = 0.049). No correlation between the total dose (milligrams per kilogram) of artemisinin administered and IPLs. Adjei and others, 2008 23 Neurologic examination: no abnormal findings in children without previous pathologies. PTA: hearing thresholds significantly elevated in treated children on days 0, 3, 7, and 28 but not at 9-12 months.
No additional details. Maiteki-Sebuguzi and others, 2008 24 Neurological examination: children 5 years who received AQ-SP were at higher risk of anorexia (RR = 3.82, 95% CI = 1.59-9.17, P = 0.003) and weakness (RR = 5.40, 95% CI = 1.86-15.7, P = 0.002) than those children treated with AL. No reported results on hearing loss. Toovey and Jamieson, 2004 16 PTA: hearing threshold loss was significantly greater in the treatment group at all except the very lowest frequencies of 250 and 500 Hz. The mean threshold change was negative in the treatment group, ranging from −6.50 dB (95% CI = −8.19 to −4.81) to −0.07 dB (95% CI= −2.19-2.05). Hutagalung and others, 2006 19 High proportion of subjects with hearing loss overall related to age. PTA: no differences between the groups in MEP and the median PTA conduction thresholds. ABR: no differences in wave length or the IPLs. Ndiaye and others, 2011 25 Audiograms in 167 patients during the first malaria episode and 12 patients during the second episode. Hearing thresholds on days 3 and 28 showed no significant variation compared with pre-Rx on day 0 and no difference between AS-AQ and LA. Single exposures Abdulla and others, 2008 41 Neurological examination: isolated cases of somnolence, convulsion, dyskinesia, epilepsy, dizziness, and tremor reported as unrelated adverse events. No patient reported hearing loss. Ambler and others, 2009 47 Neurological examination: coordination, behavior, and tone not significantly changed by either treatment. Frey and others, 2010 28 Neurological and neuropsychiatric examinations: among 213 children, 3.8% of the children had a transient drug-related mild to moderate neurological or neuropsychiatric impairment, which resolved spontaneously. The most common neurological disorders were sleeping disorders, insomnia, nightmares, vertigo, dizziness, and headache. No report on hearing impairment. McCall and others, 2006 18 Tymp, OAE, PTA, ABR: no prolongations of peak latencies or I-V IPLs were seen. No statistically significant differences after the treatment (day 8 for PTA and day 21/22 for ABR + PTA) compared with before the infection. Carrara and others, 2008 48 Hearing loss on admission was common (57%) and associated with age. Day 7 vs. 0 showed no threshold change 10 dB and no shift in wave III latency 0.30 milliseconds. Gurkov and others, 2008 27 PTA and DP-OAE revealed transient significant cochlear hearing loss in patients treated with Q on day 7 that disappeared on day 28. ABR: the prolongation of I-III IPLs between LA and the other groups on day 28 disappeared by day 90 (only right ear). In all groups, IPLs I-V was shorter on day 0. One patient in the LA group had a potentially clinically relevant interaural difference of IPLs I-III 10% on day 28 (disappeared by day 90). Benjamin and others, 2012 46 PTA: At baseline, children had normal or mild hearing loss ( 25-40 dB) with no subsequent changes on audiometry over time in group 1 (P 0.05). In groups 2 and 3, 76% of children cooperated with the tests. Whispered test, audiovestibular tests: no abnormalities were detected by any of the tests at baseline or subsequently. Carrasquilla and others, 2012 20 ABR: 2.6% of patients on LA (95% CI = 0.7-6.6) exceeded 0.30 milliseconds at day 7 wave III latency, statistically significant below 15% (P 0,0001). No patient receiving AM or AP revealed day 7 III IPLs increases of 0.30 milliseconds. None of the latency increases were sustained, bilateral, or associated with significant PTA thresholds deteriorations. PTA: no notable changes were observed for any treatment group at any frequency. A model-based analysis found no apparent relationship between drug exposure and ABR change. CI = confidence interval; RR = relative-risk.
investigate this finding, particularly in children under 5 years of age, most likely for very pragmatic reasons. The investigation of hearing impairment in infants and young children can be particularly challenging, especially when trying to detect subtle and early toxicity in remote settings where trained audiologists and equipment are not available. There is a need to provide objective auditory measurements to predict the pure tone audiogram in young children that cannot report reliable behavioral responses to sound. OAEs and/or ABRs are widely used to detect sensory or conductive hearing loss in this age group (Joint Committee on Infant Hearing, unpublished data). ABR measurements are particularly well-suited in detecting and estimating a magnitude of hearing loss in young children, with click-evoked ABRs providing several advantages: they assist in determining whether auditory neuropathy exists and can be obtained in a relatively brief amount of time. 29 However, ototoxicity tends to start at high frequencies (8-12 kHz) before speech frequencies are affected. 13 Because conventional ABR only explores speech frequencies of 1-4 kHz, it does not detect early ototoxicity before clinical significance. The studies by McCall and others 18 and Ndiaye and others 25 were the only studies to explore frequencies over 8 kHz, but they involved only 12 adult patients with a single treatment of experimental human malaria and only participants 12 years old after two exposures (on day 0 before dosing, day 3, and if abnormality was detected, day 28), respectively. Neither study provided a definitive answer about ACT safety at high frequencies. 18,25 The variations in study designs and auditory assessment methods used (Table 3) prevented systematic investigation of an association between neuroauditory changes and ACT use. Studies that showed impaired auditory assessments in older children, adolescents, and adults generally failed to explore the association in detail and did not examine adequately the presence of possible confounding factors. Single-exposure studies in Ethiopia and on the Thailand-Burma border, which performed pre-treatment hearing assessments to account for an influence of malaria on hearing impairment, were reassuring in their conclusions but lacked evidence. In both studies, similar improvements on hearing were detected 7 days after treatment that were correlated to a learning effect (with the use of behavioral audiometric assessments) or a fever resolution, but they failed to show or rule out an association and potential ototoxic effect of the drugs. 19,27 However, the study that raised the safety concern on humans and opened a global safety discussion of ACTs reported an association between artemether and irreversible hearing impairment in construction workers. Nevertheless, the study could not establish if the association was caused by the drug, the malaria episode, or the prolonged occupational noise exposure of the study participants. 16 Causes of hearing damage are multifactorial, and therefore, potential confounders need to be taken into account. A challenging one in this context is the potential disease-specific damage caused by malaria itself. Hearing loss is a recognized complication of cerebral malaria, 30 but the evidence regarding an association between uncomplicated malaria and hearing impairment remains inconclusive. Some authors have hypothesized that the presence of malaria may contribute to hearing loss by lowering resistance to ototoxic drugs or vascular disruption in the end arteries of the cochlea. 31,32 A recent study has assessed the impact of malaria on hearing in mice. ABRs were performed before the infection and at the peak of Table   5 Level of evidence of ACT neuroauditory safety  = case series; 5 = expert opinion. 41 the disease (between days 5 and 11 after the infection without the administration of antimalarials). Hearing impairment was found in mice with both cerebral and uncomplicated malaria compared with a control group that was not infected with malaria. 33 There is also real potential for confounding by ototoxic effects of the partner drug in the ACT, especially from quinoline-based drugs such as mefloquine, piperaquine, and amodiaquine. Mefloquine, in particular, is recognized as a central and peripheral neurotoxic, with several human reports documenting a range of neuropsychiatric effects as well as both reversible and irreversible hearing loss when used at prophylactic concentrations in adult patients. 34,35 The peripheral ototoxicity of mefloquine follows a dose-dependent mechanism of cochlear hair cells and spiral ganglion neurons loss different from the artemisinin derivatives. 36 However, animal models and a recent human case report have provided additional insight into the clinical significance and plausible pathophysiology of mefloquine focal brainstem, limbic, and thalamic cortical toxicity that needs to be emphasized and further elucidated when investigating the potential neurotoxicity of ACTs. 37,38 Cognizant of this information, the US Food and Drug Administration announced label changes for the approved mefloquine hydrochloride in July of 2013 to specifically warn of the risk of permanent neurological effects, including vestibular symptoms and tinnitus. 39 Neuroauditory events could be associated with the use of cumulative high-dose exposure in young children, and more emphasis needs to be given to the potential of dose-and agedependent adverse events. Drugs are assessed at very narrow dose ranges during the drug development stages, and considerable developmental changes in early childhood affect the pharmacokinetic profile of drugs. With the current recommended weight-based dosing regimens in sub-Saharan Africa, children under 5 years of age could receive oral artemether ranging from 2 to 6 mg/kg per dose and from 8 to 24 mg/kg per course of treatment. 40 In settings where age-based dosing regimens are used (e.g., treatment by village health workers or in health centers that do not have functional scales), children can be exposed to 5 mg/kg per dose. These unintended high doses could have a detrimental neuroauditory impact that has not yet been investigated. Better knowledge and targeted studies to determine safety around the upper therapeutic intake dose threshold are urgently needed to support their programmatic use, including the development of evidencebased age-based regimens.
The main limitations of this review are the varying quality and descriptive nature of the neuroauditory findings reported by most studies and the lack of robust data from the most vulnerable groups. The risk of bias was unclear or likely for the majority of studies. Of the RCTs, only the study by Abdulla and others 41 showed a low risk of bias in selective reporting of results. The others were classified as unclear risk of bias in this item, because safety end points were reported as secondary results without detail (Table 2). To summarize our findings, we present a summary table of results (Table 5) graded according to widely used medicine-based evidence levels (OCEMB) to help identify specific remaining neuroauditory safety gaps in the most vulnerable populations. 42 This information highlights two important issues. First, there is a need for an appropriate standardized method to detect early ototoxicity and other adverse effects in young children. Second (and more generic), there is an urgent need to collect and compile study safety data in a more standardized way, similar to the data compilation and analyses of antimalarial efficacy data conducted by the Worldwide Antimalarial Resistance Network (WWARN). 43 In conclusion, after a decade of use, there remains a lack of high-quality evidence on the neuroauditory safety of ACTs. There is no reported evidence to rule out the occurrence of any ototoxicity in those individuals who have been mentioned over and over again as the most vulnerable subgroup: young children who are treated repeatedly during a potentially vulnerable phase of brain development and may be exposed to some of the highest intake doses. Early evaluation and prevention of hearing impairment in childhood are essential, because hearing impairment can have severe adverse effects on speech, behavior, linguistic understanding, and language acquisition, contributing to global disability and mortality. Early-onset hearing loss detection programs are successful and increasingly implemented in the developing settings. 44 More efforts should be made to improve this evaluation through not only universal infant hearing screening programs but also, monitoring of neuroauditory adverse events from potential ototoxic agents that are given repeatedly over time.
With the current exploration of the use of ACTs for mass drug administration programs (conducting multiple full treatment courses per year) in an attempt to reduce transmission and the potential need to increase artemisinin dosing in the near future to slow the spread of emerging artemisinin resistance, this knowledge gap should not merely be accepted after a decade of widespread use but addressed as soon as possible.