Artemisinin-Naphthoquine Combination Therapy for Uncomplicated Pediatric Malaria: a Tolerability, Safety, and Preliminary Efficacy Study

Abstract

Artemisinin-naphthoquine (ART-NQ) is a fixed-dose coformulated antimalarial therapy recommended as a single-dose treatment and marketed in Papua New Guinea among other tropical countries. We conducted a tolerability, safety, and efficacy study of ART-NQ for Papua New Guinean children aged 5 to 12 years with uncomplicated malaria, comparing single-dose ART-NQ (15 and 6 mg/kg of body weight) given with water (group 1; n = 15), single-dose ART-NQ (22 and 9 mg/kg) given with milk (group 2; n = 17), or two daily doses of 22 and 9 mg/kg given with water (group 3; n = 16). Of the 48 children (45 with Plasmodium falciparum malaria, 2 with Plasmodium vivax malaria, and 1 with mixed-species malaria), 2 in group 2 did not attend all follow-up assessments. All regimens were well tolerated, with no serious adverse events. There were no clinically significant changes in pulse, blood pressure, rate-corrected electrocardiographic QT, routine biochemistry/hematology, or hearing after treatment. Fever clearance was prompt. Mean 50% parasite clearance times were 4, 4, and 5 h for groups 1, 2, and 3, respectively. One group 1 patient had PCR-confirmed P. falciparum recrudescence at day 23; four had PCR-confirmed P. falciparum reinfections on day 28 or 42; and three had P. vivax infections detected on day 42. The only recurrent parasitemia in groups 2 and 3 occurred in a group 2 child who developed a P. vivax infection on day 42. Day 14 gametocyte positivity levels were 20%, 27%, and 9% in groups 1, 2, and 3, respectively. The lower single ART-NQ dose was associated with relatively frequent recurrence of parasitemia, but the prolonged gametocytemia in all three groups has implications for the transmission of malaria.

INTRODUCTION

The World Health Organization (WHO) currently recommends artemisinin combination therapy (ACT) as first-line treatment for uncomplicated Plasmodium falciparum malaria (32). Where there is also transmission of Plasmodium vivax, ACT can be used together with primaquine in non-glucose-6-phosphate dehydrogenase-deficient patients for radical cure. The choice of ACT will depend on the local level of P. falciparum resistance to the longer-half-life partner drug; lumefantrine, amodiaquine, mefloquine, sulfadoxine-pyrimethamine, and piperaquine are all regarded as potentially suitable (32). The WHO stipulates that the artemisinin component of the combination must be given for at least 3 days to ensure optimal effectiveness.

In areas of intense transmission of multiple Plasmodium species, the choice of ACT can be difficult. In a recent randomized trial in Papua New Guinea, for example, artemether-lumefantrine proved superior to dihydroartemisinin-piperaquine for pediatric P. falciparum infections, but dihydroartemisinin-piperaquine was the more efficacious regimen against P. vivax (11). Since P. vivax is increasingly recognized as a potential cause of complications and death (6), there is a need for an ACT that is highly effective against both species in this epidemiologic situation. Two new candidate ACTs are artesunate-pyronaridine and artemisinin-naphthoquine (ART-NQ). Artesunate-pyronaridine appears promising in early-phase trials but is not yet available in tropical countries (20). Despite limited published pharmacologic and efficacy data (9, 10, 28) and the recommendation that it be used as single-dose treatment (13), ART-NQ is currently marketed as the fixed coformulation ARCO (Kunming Pharmaceuticals, Kunming, China) in Oceanic countries, including Papua New Guinea, and also in parts of sub-Saharan Africa (9). It has yet to achieve WHO prequalification status.

Naphthoquine is a tetra-aminoquinoline drug with antimalarial efficacy that was initially demonstrated in in vitro experiments, animal studies, and clinical trials from China that led to its registration in that country in 1993 (28). It has been given as single- and two-dose monotherapy (28), in combination with dihydroartemisinin and trimethoprim in a two-dose regimen (12), and, most recently, combined with ART as either a single- or a two-dose treatment (9). Apart from one Indonesian study with a 28-day adequate clinical and parasitologic response rate (ACPR) of 79% in mixed P. falciparum-P. vivax infections, the ACPRs for NQ given alone and as part of combination therapy for uncomplicated P. falciparum or P. vivax malaria have been ≥94% at doses of 8 to 16 mg/kg of body weight (9, 10, 28).

Since ART-NQ is already available in Papua New Guinea through the private sector and is likely to be used for pediatric malaria in areas of intense transmission, and given the lack of pharmacokinetic, tolerability, safety, and efficacy data for children, we performed a detailed initial study of single-dose ART-NQ given to Papua New Guinean children aged 5 to 10 years at doses based conservatively on the lower recommended doses (in milligrams per kilogram) for adults (study 1). Because of a significant rate of recrudescence and low plasma NQ concentrations relative to those reported in adults (28), together with the subsequent provision by the manufacturer of a pediatric dosage schedule for body weights down to 16 kg (19), we carried out a further pharmacokinetic, safety, and efficacy study of these higher (in milligrams per kilogram) ART-NQ doses given either as a single dose with fat, to improve the bioavailability of both components, or as a two-dose regimen with water (study 2).

We report here the tolerability, safety, and efficacy data from these two studies, with safety parameters selected to cover potential aminoquinoline-specific effects (blood glucose changes, electrocardiographic QT interval prolongation, postural blood pressure changes, and hearing loss), as well as conventional clinical and laboratory assessments. The pharmacokinetic data are presented elsewhere (1).

MATERIALS AND METHODS

Study site, approvals, and patients.

All components of the present study were conducted at the Alexishafen Health Centre, Madang Province, on the north coast of Papua New Guinea, where there is hyperendemic transmission of P. falciparum and P. vivax (17). Children aged 5 to 10 years who presented with an axillary temperature of >37.5°C or a history of fever in the previous 24 h were screened at the study site for malaria with a Giemsa-stained thick blood film read by a trained microscopist. Those with monoinfections with either Plasmodium falciparum (>1,000 asexual parasites/μl whole blood) or P. vivax, P. ovale, or P. malariae (>250 parasites/μl) were eligible for recruitment provided that (i) they had no features of severe malaria (30), (ii) they had not taken one of the study drugs in the previous 14 days, (iii) there was no history of allergy to artemisinin or aminoquinoline drugs, (iv) there was no clinical evidence of another infection as a possible cause of fever, (v) there were no signs of malnutrition or another significant comorbidity, and (vi) the child's parents or guardians gave written informed consent. Approval for the present studies was obtained from the Papua New Guinea Institute of Medical Research Institutional Review Board and the Medical Research Advisory Committee of the Papua New Guinea Health Department.

Baseline assessment and treatment allocation.

At enrollment, a history and a symptom questionnaire were completed with the assistance of parents/guardians, and a full physical examination was performed, including body weight, height, axillary temperature, lying and standing blood pressure and pulse rate, and respiratory rate. An intravenous cannula was inserted, and a baseline venous blood sample was drawn for hemoglobin (Hemocue, Ängelholm, Sweden), blood glucose (Hemocue), and a white cell count (WCC) using a Neubauer chamber. The remaining blood was centrifuged and the plasma stored at <−20°C for subsequent drug and other assays. The red cell pellet was retained for parasite genotyping.

Each child had a baseline electrocardiogram (ECG) and either audiometry using a Maico MA-40 audiometer at frequencies of 250, 1,000, 2,000, 4,000, 6,000, and 8,000 Hz (study 1) or a whispered voice test (22) as well as Rinne's and Weber's tests (study 2). For study 1, hearing loss was categorized as mild, moderate, moderately severe, or severe if the air conduction thresholds at any tested frequency were ≥25 to 40 dB, 41 to 55 dB, 56 to 70 dB, or 71 to 90 dB, respectively. In the whispered voice test, the examiner stood 0.6 m behind the seated patient and whispered a combination of three numbers and letters twice for each ear, with gentle occlusion of the auditory canal of the opposite ear and rubbing of the tragus with the occluding finger in a circular motion. If a child repeated at least three out of six numbers/letters correctly, hearing was considered normal in that ear. The QT interval was measured from lead II of the 12-lead trace and was corrected for the heart rate using Bazett's method (QT_c = QT/√heart rate).

In study 1, all children were administered ARCO tablets (50 mg NQ plus 125 mg ART) orally as a single dose of 2 to 4 whole tablets with water as recommended by the manufacturer (19) (group 1). The dose was based on body weight according to the doses recommended by the manufacturer in milligrams per kilogram for adults (13) and represented dose ranges of 5.0 to 7.5 mg/kg for NQ phosphate and 12.5 to 16.8 mg/kg for ART. Subjects were not required to fast prior to receiving the medication. If a child vomited within 1 h, the same dose was readministered and the time of readministration recorded. In study 2, children were randomized by computer-generated sequence to receive ARCO tablets (50 mg NQ plus 125 mg ART) orally based on body weight as recommended by the manufacturer for children (13) as either (i) a single dose of 3 to 6 tablets given with 250 ml of full-cream cow's milk (containing 8.5 g fat) with dose ranges of 6.1 to 9.5 mg/kg for NQ and 15.3 to 23.8 mg/kg for ART (group 2) or (ii) the same dose given with water on two occasions 24 h apart (group 3). The ART and NQ contents of each batch of ARCO tablets were assayed and were found to be within acceptable levels (1).

Monitoring and follow-up.

Group 1 patients had additional venous blood samples drawn through the cannula at 1, 2, 4, 8, 12, 18, 24, 48, and 72 h and by venesection at 4, 7, 14, 28, 42, and 56 days for subsequent drug assay (1). These children were reassessed clinically at 4 and 24 h and on days 2, 3, 7, 14, 28, 42, and 56. Vital signs and spleen size were recorded; a symptom questionnaire was completed with the assistance of parents/guardians (on an integer scale of 0 to 5, with 0 indicating the absence of symptoms and 5 indicating severe symptoms); and a blood smear was taken on these occasions. Additional monitoring comprised (i) lying/standing blood pressure, ECG, and audiometry at 4 and 24 h and on days 7 and 28 and (ii) blood glucose, hemoglobin, and dipstick urinalysis at 24 h and on days 2, 3, 7, and 28.

Group 2 and 3 patients had further 2.5-ml blood samples for drug assay taken through the sampling cannula at 1, 2, 4, 8, 12, 18, 24, 48, and 72 h and by venesection at 4, 7, 14, 28, and 42 days. Group 3 patients had a second artemisinin-NQ dose given with water at 24 h. Groups 2 and 3 had posttreatment clinical and other monitoring similar to that performed for group 1, except that the whispered voice, Rinne's, and Weber's tests were used instead of audiometry.

All serial blood smears from each patient were reexamined, and parasitemias were quantified independently by two skilled microscopists in a central laboratory, with discrepancies adjudicated by a third microscopist. Parasite densities were calculated from the number of parasites per 200 white cells and an assumed total peripheral white cell count of 8,000/μl, with the final density taken as the geometric mean of the two values (11). Reinfection and recrudescence were distinguished by comparing PCR-restriction fragment length polymorphism-generated genotype patterns of merozoite surface protein 2 and PCR genotype patterns of merozoite surface proteins 1 and 2 and glutamate-rich protein, in pairs of samples obtained at enrollment and on the day of reappearance of parasitemia (11). Treatment response was assessed according to WHO definitions, with follow-up extended to 42 days (31). For groups 2 and 3, plasma was assayed for concentrations of electrolytes, urea and creatinine, albumin and total protein, alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and total bilirubin by using a Cobas Integra 800 platform (Roche Diagnostics, Mannheim, Germany) with reagents supplied by the manufacturer (15).

Statistical analysis.

Data were analyzed using IBM SPSS Statistics (version 19; IBM Corporation, NY). Data are summarized as means ± standard deviations (SD) or as medians and interquartile ranges (IQR) as appropriate to the distribution of each variable. Nonparametric methods were used for between-group comparisons, with a two-tailed level of significance of 0.05 used throughout.

RESULTS

Patient characteristics.

The baseline characteristics of the children are summarized in Table 1. The three groups of children were well matched for a variety of demographic, anthropometric, and clinical characteristics. With regard to available biochemical data, no child in group 2 or 3 had a value for plasma electrolytes, urea, creatinine, albumin, total protein, ALT, ALP, GGT, or total bilirubin at baseline that was outside the local reference ranges for these analytes (15). Group 1 children had significantly lower hemoglobin levels than those in groups 2 and 3, but only two group 1 subjects were anemic based on local laboratory reference ranges (15), compared with one in each of the other two groups.

Table 1.

Admission details for the children in each dosing regimen group^a

Characteristic	Group 1 (single dose with water) (n = 15)	Group 2 (single dose with milk) (n = 17)	Group 3 (double dose with water) (n = 16)	Pb
Age (mo)	83 (67–101)	89 (76–113)	75 (65–94)	0.22
No. (%) male	8 (53)	11 (65)	12 (75)	0.45
Wt (kg)	17.9 ± 3.5	18.9 ± 5.2	16.8 ± 3.2	0.44
Ht (cm)	110.3 ± 9.7	116.8 ± 12.0	110.0 ± 8.8	0.15
Axillary temp (°C)	37.0 ± 1.4	37.3 ± 0.8	37.8 ± 1.3	0.18
Supine blood pressure (mm Hg)
Systolic	100 (91–103)	94 (80–101)	99 (70–100)	0.37
Diastolic	60 (50–62)	54 (50–61)	53 (50–61)	0.70
Standing blood pressure (mm Hg)
Systolic	100 (90–104)	97 (80–108)	95 (80–104)	0.57
Diastolic	60 (53–64)	59 (50–63)	60 (50–61)	0.77
Postural blood pressure change (mm Hg)
Systolic	0 (−6 to 4)	3 (0 to 9)	3 (−4 to 10)	0.33
Diastolic	0.0 (−2 to 6)	3 (−1 to 9)	4 (0 to 10)	0.51
Respiratory rate (breaths/min)	34 ± 29	24 ± 2	29 ± 6	0.16
Supine pulse rate (beats/min)	105 ± 23	96 ± 31	113 ± 16	0.13
Mean upper arm circumference (cm)	15.8 ± 1.3	16.1 ± 1.6	15.6 ± 1.3	0.69
No. of parasites/μl
Plasmodium falciparumc	44,560 (2,890–90,220)	4,200 (2,040–41,780)	28,480 (9,670–127,060)	0.19
Plasmodium vivaxd	160	440	200
Hemoglobin concn (g/liter)	87 ± 14	104 ± 18*	114 ± 18**	<0.001
Blood glucose concn (mmol/liter)	6.9 ± 1.0	7.6 ± 2.1	7.1 ± 1.7	0.87
QTc (ms0.5)	424 (415–452)	429 (418–440)	427 (416–442)	0.95
Serum alanine transaminase concn (U/liter)		12 (9–18)	10 (8–13)	0.85
Total serum bilirubin concn (μmol/liter)		10 (4–13)	8 (5–18)	0.64
Serum creatinine concn (μmol/liter)		46 (44–55)	46 (43 ± 52)	0.64

^aData are means ± SD or medians (IQR). Asterisks indicate significant differences from group 1, as follows: *, P = 0.01; **, P < 0.001.

^bBy the Kruskal-Wallis test.

^cThe number of patients tested was 15 for group 1, 12 for group 2, and 11 for group 3.

^dOne patient was tested for each group.

All 15 group 1 children had detectable baseline P. falciparum parasitemia, and 1 child had a mixed infection with P. vivax at low density (160 parasites/μl of blood). Four children in group 2 and four in group 3 were considered to have low-grade parasitemia on screening microscopy at the study site but were subsequently found to be slide negative on confirmatory expert microscopy. For two of the group 2 and one of the group 3 slide-negative children, PCR was positive for P. falciparum. All recruited children were included in the tolerability and safety analyses.

Efficacy.

Positive symptoms recorded on the questionnaire at presentation resolved in all cases over the next 2 days. In all 20 children (42%) with fever (axillary temperature, >37.3°C) at baseline, the fever cleared within 48 h. For the 39 children with microscopically confirmed parasitemia at study entry, response to treatment was assessed by group.

(i) Group 1.

There was a rapid decline in P. falciparum parasitemia in all cases, with a mean time to 50% parasite clearance (PCT₅₀) of 4 h. Thirteen children (87%) were slide negative by 24 h, and all were slide negative at 48 h. The sole P. vivax parasitemia, part of a mixed infection, cleared within 24 h. Eight children (53%) had recurrent parasitemia by microscopy and PCR during the 42-day follow-up period. One was a P. falciparum recrudescence on day 23; four were P. falciparum reinfections (two on day 28 and two on day 42); and three were low-grade P. vivax parasitemias detected by microscopy on day 42. The P. falciparum ACPR was, therefore, 93% (95% confidence interval [CI], 70% to 98%) at 28 days and 42 days. This ACPR is below the ≥95% WHO-recommended range for adoption of a new antimalarial therapy (32). Forty percent of patients were positive for P. falciparum gametocytes by microscopy at day 7, and 20% were still positive at day 14. All children with recurrent asexual parasitemia were treated with chloroquine plus sulfadoxine-pyrimethamine, according to Papua New Guinea guidelines (21).

(ii) Group 2.

The 11 children with P. falciparum parasitemia in group 2 also exhibited a rapid decline in parasitemia, with a mean PCT₅₀ of 4 h. Seven children (58%) were slide negative by 24 h, and all but one (92%) were slide negative at 48 h. The child with P. vivax parasitemia cleared parasites within 24 h. Two children in this group withdrew because they were unable to attend the follow-up assessment, but they remained well up to the time of withdrawal. Apart from one child with P. vivax parasitemia detected on day 42, there were no recurrences in the remaining subjects during the 42-day follow-up period (ACPR, 100%). Sixty-four percent of patients were positive for P. falciparum gametocytes by microscopy at day 7, and 27% were still positive at day 14.

(iii) Group 3.

The 11 children with P. falciparum parasitemia in group 3 also exhibited a rapid decline in parasitemia, with a mean PCT₅₀ of 5 h. Six children (55%) were slide negative by 24 h, and all (100%) were slide negative at 48 h. The sole P. vivax parasitemia cleared within 24 h. There were no recurrent parasitemias during the 42-day follow-up period (APCR, 100%). Eighteen percent of patients were positive for P. falciparum gametocytes by microscopy at day 7, and 9% were still positive at day 14.

Safety and tolerability.

No significant adverse events were reported for any of the 48 children during the 42 day follow-up. Integer scores for symptoms were consistently ≤2 on the 5-point scale in all cases.

(i) Hemodynamic stability and electrocardiographic changes.

There was no significant postural decrease in mean systolic or diastolic blood pressure at baseline (Table 1), and no individual child had a systolic decrease of >20 mm Hg at this time. Similarly, there were no significant changes in postural blood pressure during follow-up to day 3 (P > 0.05) (Fig. 1).

Fig 1.

Changes in postural blood pressure during follow-up to day 7 in the three groups of children treated with artemisinin-naphthoquine. Data are medians (filled circles) and ranges (error bars).

Changes in the QT_c in each of the three groups are shown in Fig. 2. The QT_c increased from baseline to 4 h after the first dose by an overall median (IQR) of 14 (−5 to 26) ms^0.5 (P, 0.004 by the Wilcoxon signed-rank test), but there was no significant difference between the groups (P, 0.83 by the Kruskal-Wallis test), and values for most patients had returned toward baseline at 24 h, with a prolongation of only 5 (−9 to 21) ms^0.5 at that time (P, 0.044 by the Wilcoxon test). Twenty-six of 48 children (54%) had a QT_c of >440 ms^0.5 at 4 h postdose, and the longest QT_c recorded at this time point was 487 ms^0.5, for a group 1 child.

Fig 2.

Changes in the electrocardiographic QT_c interval during follow-up to day 7 in the three groups of children treated with artemisinin-naphthoquine. Data are medians (filled circles) and ranges (error bars). Asterisks indicate significant differences from the baseline value (P < 0.01).

(ii) Hemoglobin.

There was a significant decline in the median hemoglobin concentration between day 0 and day 1 in each of the three groups (P < 0.02), with an overall median (IQR) decline in the groups combined of 13 (7 to 23) g/liter. There was a subsequent gradual rise in the hemoglobin concentration in each group such that the day 28 concentration was a median (IQR) 6 (−6 to 23) g/liter higher than baseline. No child developed severe anemia (hemoglobin concentration, <50 g/liter) during follow-up.

(iii) Capillary blood glucose.

No child was hypoglycemic at presentation (minimum blood glucose concentration, 4.4 mmol/liter). Similarly, no child became hypoglycemic during the first 3 days after treatment was started; the lowest blood glucose concentration recorded was 3.8 mmol/liter.

(iv) Other biochemical tests.

There were no children in groups 2 and 3 whose assay results were outside local reference ranges for any analyte (15) on days 3 and 7 after treatment. There were no changes in plasma ALT concentrations over time (P = 0.25), but total bilirubin and creatinine levels fell significantly over the first 3 days in both groups (P, <0.01 for the combined groups) (Fig. 3).

Fig 3.

Changes in plasma bilirubin and creatinine concentrations in children treated with artemisinin-naphthoquine from groups 2 and 3 combined during follow-up to day 7. Data are medians (filled circles) and ranges (error bars). Asterisks indicate significant differences from the baseline value (P < 0.05).

(v) Hearing.

In study 1, children had responses at frequencies of 500, 6,000, and 8,000 Hz at baseline that were categorized as either normal or mild hearing loss (≥25 to 40 dB), with averages of 22, 26, and 25 dB, respectively. Due to ambient noise (no soundproof booth was available) and problems with ensuring cooperation, especially during the acute phase of the illness, these baseline values were difficult to interpret, but there were no subsequent significant changes over time in this group (P > 0.05), implying no drug-specific auditory toxicity. In study 2, 25 of the 33 children (76%) cooperated with the whispered voice, Rinne's, and Weber's tests at baseline. No abnormalities were detected in this group by any of these tests at baseline or subsequently at 4 h and on days 1, 7, and 28.

DISCUSSION

The present study shows that a 1- or 2-day course of ART-NQ is well tolerated and safe for treatment of uncomplicated malaria in a Papua New Guinea pediatric setting. Group 1 subjects were studied at a time when there was no recommended dose regimen for children, and the conservative doses (in milligrams per kilogram) employed were likely to have been responsible for the relatively high recurrence rate. The higher doses in study 2 were associated with a 100% ACPR, but there was prolonged carriage of gametocytes in a significant proportion of children in both the single- and double-dose groups. These data have implications for the use of this ACT, especially in settings in which interruption of malaria transmission is an important consideration.

The early ACT trials showed that at least 3 days of treatment with an artemisinin derivative combined with a long-half-life partner, such as mefloquine, were required to achieve ≥90% cure (16). Recent WHO recommendations for ACT treatment of uncomplicated P. falciparum malaria reflect this finding (32). Although it is the least expensive of the drugs in its class, ART is seldom chosen to form part of a 3-day course of ACT. Unlike its semisynthetic derivatives artesunate and artemether, it is not metabolized to the more-active dihydroartemisinin, while its oral bioavailability falls progressively during daily dosing to <30% of baseline after 3 days of treatment (8, 25). Initial parasite clearance was prompt in the three groups of children in the present study. However, ACTs have not been used other than in clinical trials in the Madang area, implying that local strains of P. falciparum should be fully sensitive. In view of the development of resistance to artemisinin derivatives in areas of endemicity with a history of subtherapeutic drug use (5), and in view of the pharmacologic shortcomings of ART relative to other derivatives, the introduction of an ACT containing ART appears inappropriate in a country such as Papua New Guinea, especially as a single-dose regimen.

In the present study, group 1 patients received an average of 75% of the ART-NQ administered to group 2 children, due to the deliberate adoption of an initially conservative dose regimen. Although the number of children in each group was relatively small, the fact that more than half of those in group 1 developed some form of recurrent parasitemia during the 42 days of follow-up suggests that even relatively minor degrees of underdosing may have implications both for the patient and for the selection of resistant parasite strains (14). In contrast to groups 1 and 2, none of the children in group 3 developed recurrent parasitemia (recrudescence or reinfection). This suggests that two daily doses of ART-NQ should be the minimum if this ACT is introduced in Papua New Guinea as a recommended treatment.

It has long been recognized that artemisinin and its derivatives, in contrast to 4-aminoquinolines and related drugs, can reduce transmission through effects on gametocyte maturation (3, 23). However, the rates of posttreatment gametocyte carriage by microscopy were particularly high in the single-dose groups (groups 1 and 2) in our study. Group 3 children had a lower rate of carriage: 18% were still positive at day 7, and this proportion declined to 9% at day 14. In a previous comparative trial of different ACTs in the Madang area (11), only 4% of children treated with artemether-lumefantrine (soon to be implemented as first-line treatment for uncomplicated malaria in Papua New Guinea) were still carrying P. falciparum gametocytes at day 14. The present data suggest a dose-response relationship such that a 3-day course of ART-NQ, if safe and well tolerated, might be the best way to promote the eradication of both gametocytes and asexual forms, especially through greater exposure of the parasite to the ART component. A potent gametocytocidal effect is especially important, since the high incidence of glucose-6-phosphatase deficiency in Papua New Guinea (7) precludes the routine use of primaquine in this context.

Although ART has been studied relatively extensively, there are few safety data on NQ. Available data from healthy volunteers (24) and clinical studies (9, 10, 28) suggest that the drug is safe apart from short-lived abdominal distension (28), occasional mild and transient elevations in serum ALT concentrations that appear unrelated to the dose (24), one episode of hypoglycemia and associated psychiatric disturbance in a Papua New Guinean adult with uncomplicated malaria treated with ART-NQ (10), and dizziness (which was relieved by oral glucose) in two Chinese adults who received ART-NQ (26). We found no evidence that NQ in combination with ART was hepatotoxic at the recommended doses, and none of our children developed hypoglycemia. There were also no reports of abdominal distension or discomfort, no significant hemodynamic changes, and no detectable effects on renal function, hearing, or hemoglobin.

Many antimalarial drugs are associated with QT_c prolongation (29), which might theoretically increase the risk of significant arrhythmias, such as torsade de pointes. Artemisinin derivatives appear safe in this regard, but questions have been raised concerning chloroquine and chemically related drugs. Chloroquine has been reported to increase the QT_c by a mean of 14 to 30 ms^0.5 (2, 4), but no cases of malignant arrhythmias or sudden death have been reported with the chloroquine doses recommended for acute malarial infection. Our children exhibited a median increase in QT_c that was at the lower end of the range for chloroquine and similar to that observed with piperaquine (18), a drug soon to be available in Papua New Guinea in a fixed combination with dihydroartemisinin as an alternative to artemether-lumefantrine.

The interpretation of QT_c prolongation in children is, however, problematic. In a recent U.S. study of children and adolescents presenting to an emergency department without structural heart disease, arrhythmias, electrolyte abnormalities, or exposure to QT interval-prolonging medications and who had an ECG for any indication, one-third had significant QT_c prolongation (>440 ms^0.5), while 11% had a QT_c of >460 ms^0.5, and in 3% the QT_c was >480 ms^0.5 (27). Even at 4 h postdose, there was only a comparatively mild right shift of the QT_c distribution in our children, and as in the U.S. study (27), all children showed either reversion to normal or significant reductiond in QT_c at later time points.

In conclusion, ART-NQ combination therapy was well tolerated and safe when given as treatment for uncomplicated malaria to Papua New Guinean children. This applied to the recommended single-dose treatment given daily for 2 days. The present efficacy data, including those relating to gametocyte persistence, suggest that the 2-day regimen is preferable to single-dose therapy but that a 3-day regimen, if safe, may prove even more efficacious and conform with current WHO recommendations for ACT.