Between July, 2004, and June, 2005, 3473 patients with uncomplicated malaria were treated at the recruitment clinics. For the 2992 (86%) patients meeting the eligibility criteria, age and sex distribution did not differ between the 774 (26%) patients enrolled and the whole clinic workload. There were 20 protocol violations all of which were identified within 24 h, offered alternative treatment, and excluded from further analysis (). Of the remaining 754 patients, 466 (62%) had only P falciparum infection, 175 (23%) had P vivax infection, and 113 (15%) had both species present. shows the baseline characteristics. Overall, follow-up to day 42 or day of failure was achieved in 78% (293/375) of patients given artemether-lumefantrine and 72% (274/379) given dihydroartemisinin-piperaquine (p=0·076).
Patient characteristics at baseline
Seven (1%) of the 754 patients correctly enrolled were unable to tolerate their drug because of recurrent vomiting (). Two patients developed urticaria on day 1, and one developed a non-specific erythematous rash on day 2. These patients were regarded as treatment failures and were given quinine either orally or intravenously. They all had unremarkable recoveries.
Early clinical deterioration that needed hospital treatment was seen in two patients. A 3-year-old boy with only P falciparum infection developed respiratory distress, prostration, and profuse diarrhoea 24 h after his first dose of artemether-lumefantrine. He was admitted, was given intravenous fluids and quinine, and made a full recovery. A 5-year-old girl with mixed parasitaemia and high fever vomited after her first dose of dihyrdoartemisinin-piperaquine and 30 minutes later developed a complex partial seizure. She was transferred to hospital where she was given intravenous quinine and made a full recovery.
73% (254/350) of the remaining patients given dihydroartemisinin-piperaquine had cleared their parasites within 24 h, compared with 57% (192/339) of those who received artemether-lumefantrine (p<0·0001). By day 2, 97% (690/712) of patients were parasite free and 99% (662/671) were afebrile, with no difference between treatment groups.
A total of 163 patients had recurrent parasitaemia during follow-up, of which 34 infections were attributable to P falciparum alone, 102 to P vivax alone, two to P ovale alone, and 25 contained both species. Overall 53% (85/161) of recurrences were symptomatic, 12% (19/159) had documented fever, and 33% (43/131) were anaemic (haemoglobin <100 g/L). These proportions did not differ between treatment groups or infecting species.
The cumulative risk of any parasitological failure was greater after artemether-lumefantrine than after dihydroartemisinin-piperaquine (HR 3·0, 95% CI 2·2–4·1, p<0·0001, ). Reappearance of P falciparum (alone or mixed) was much the same in the two groups (32 patients after artemether-lumefantrine and 27 after dihydroartemisinin-piperaquine, ). Although by day 42 reappearance of P falciparum did not differ between treatment groups, the time to reappearance was longer in patients receiving dihydroartemisinin-piperaquine (median 38 days, range 21–45) than in those receiving artemether-lumefantrine (34 days, 19–43), p=0·018 (). The risk of recurrent P falciparum infections was not dependent on the species of the initial infection. After PCR correction, the risk of true recrudescent P falciparum during follow-up was less than 5% in both treatment groups ().
Cumulative risk of failure at day 42
Cumulative risk of patients failing with P falciparum (upper) and P vivax (lower) parasitaemia (alone or mixed)
Recurrence of P vivax (alone or mixed) was recorded in 127 patients. By day 42, the cumulative risk of P vivax was greater in patients given artemether-lumefantrine than in those given dihydroartemisinin-piperaquine (38% vs 10%, , ). The cumulative risk of P vivax recurrence took place in 36% (95%CI 28–44) of patients initially infected with P vivax, 17% (13–21) of those with P falciparum, and 36% (26–46) of those with mixed infections (p<0·0001). After stratification by the species at presentation, the hazard ratio for P vivax reappearance associated with artemether-lumefantrine was 4·8 (95%CI 3·2–7·2), p<0·0001 ().
On admission, P falciparum gametocytes were present in 21% (122/574) of patients with P falciparum alone or mixed infections. In patients without gametocytes on presentation, the falciparum gametocyte carriage during follow-up was 5·7 per 1000 person-weeks, with no difference between treatment groups.
P vivax gametocytes on admission were present in 56% (160/284) of patients with P vivax alone or mixed infections. After day 7, P vivax gametocytaemia was always associated with recurrence of the organism's asexual stages, with carriage occurring at a rate of 3·7 per 1000 patient-weeks after dihydroartemisinin-piperaquine compared with 24·6 after artemether-lumefantrine (rate ratio [RR]=6·6, 95%CI 2·8–16·0, p=0·0002) ().
P vivax gametocyte carriage in all patients studied after treatment with artemether-lumefantrine or dihydroartemisinin-piperaquine.
Baseline haemoglobin concentrations were assessed in 99% (750/754) of patients, 387 (52%) of whom had anaemia (haemoglobin <100 g/L). Haemoglobin concentrations were available in 42% (1403/3326) of the subsequent reviews of patients, with no difference between treatment groups. Although the mean haemoglobin concentrations initially rose after treatment (), by the end of the study the mean haemoglobin in patients with a recurrent parasitaemia was 10·2 g/L (95% CI 4·4–16·0) lower than those successfully treated (p<0·0001). The corresponding risk of anaemia was 33% (45/135) in patients failing therapy compared with 19% (21/111) in those successfully treated (RR=1·8, 95% CI 1·1–2·8, p=0·02). By day 42, 35% (24/68) of patients given artemether-lumefantrine were anaemic, compared with 17% (15/86) of those who received dihyrdoartemisinin-piperaquine (relative risk 2·0, 1·2–3·6, p=0·019).
Haematological recovery after treatment for patients receiving dihydroartemisinin-piperaquine and artemether-lumefantrine
Early vomiting within the first hour of drug administration was recorded in 2·7% (ten of 375) of patients given artemether-lumefantrine and 2·9% (11/379) of patients given dihydroartemisinin-piperaquine. 11% (11/96) of children less than 5 years of age vomited the drug, compared with 3% (seven of 227) in older children, and 1% (three of 431) in adults (p<0·0001).
Adverse events were assessed in patients without the symptom at enrolment (). The only difference between the two treatment groups was a two-fold (95% CI 1·3–3·3) increased risk of diarrhoea on days 1 and 2, which arose in more patients receiving dihydroartemisinin-piperaquine than in those given artemether-lumefantrine. By day 7, the risk of diarrhoea was 5% in both treatment groups. Although 35% (12/34) of patients developed a headache on days 1 and 2 after dihydroartemisinin-piperaquine (compared with 23% [nine of 40] of patients given artemether-lumefantrine), the difference was not significant since headache was a common symptom at presentation.
Adverse events on day 1 or 2 in patients without symptoms on admission
The three patients who developed urticaria (two on day 1 and one on day 2 [after his final dose and not included as treatment failure]) were treated with antihistamines and all made a complete recovery. A 3-year-old child who developed an erythematous rash on day 1 was treated with antihistamines and the rash had resolved by day 4. A 32-year-old man died suddenly and unexpectedly 60 days after treatment with artemether-lumefantrine. He had been assessed on day 28 and was reported as being well—analysis of his blood on day 28 revealed no haematological or biochemical abnormalities. No further details were available.
Of the 163 patients with recurrent parasitaemia, 139 (85%) agreed to be retreated and followed up for a further 28 days. Of the 48 patients representing with P falciparum (alone or mixed infections), who were given an unsupervised course of quinine with or without doxycycline, the risk of failure at day 28 rose to 83% (95% CI 70–96). Of the 91 patients with a recurrence of P vivax alone, 26 patients were retreated with an unsupervised course of quinine plus primaquine with or without doxycycline, with a subsequent risk of failure of 57% (36–79). The remaining 65 patients with P vivax were retreated with a supervised course of amodiaquine plus primaquine. Two patients had recurrent vomiting, four failed to complete therapy, and 18 had recurrent parasitaemia by day 28 (one with P falciparum, nine with P vivax, and eight with mixed infections). By day 28, the cumulative risk of recurrence with P vivax was 26% (12–40).