Artemether-lumefantrine most effective combination therapy for uncomplicated malaria in Ugandan children

The fixed drug combination artemether-lumefantrine is the most efficacious treatment for uncomplicated malaria in Ugandan children, according to the findings of a randomized trial published in the May 23-30th edition of the Journal of American Medical Association.

In the wake of escalating treatment failures associated with chloroquine and sulfadoxine pyrimethamine (SP), the World Health Organization (WHO) has recommended five regimens including four artemisinin-based combination therapies (ACTs) and 1 non-ACT regimen for treating uncomplicated malaria in Africa. The ACTs include artesunate + mefloquine (AS/MQ), artesunate + SP (AS/SP), artemether-lumefantrine (ART/LUM), and amodiaquine+artesunate (AQ/AS).

Two of these ACTs have important limitations; AS/MQ is too costly with poor tolerability due to MQ and AS/SP has poor efficacy. The remaining ACTs have been adopted as first-line therapy in many Sub-Saharan African countries where the availability of ACTs is still hampered by logistical and economic constraints.

AQ/SP is a non-ACT regimen which is paradoxically efficacious in Uganda despite high resistance to the individual drugs. The long term viability of AQ/SP is uncertain because of increasing resistance to AQ and SP and poor effectiveness.

African countries must make policy decisions about the best combination regimens to adopt for malaria control based on a number of considerations. Scientific evidence to support policy decisions comes from comparative assessments of various drug combinations. But what is the best way to assess the comparative efficacies of candidate drugs in endemic countries? This issue has been addressed by a team of US and Ugandan investigators using a longitudinal study design in a single-blind randomized clinical trial.

The objective was to compare the efficacy and safety of the three leading combination therapies for the treatment of uncomplicated malaria in children from an urban community in Kampala. The study took place in Mulago III Parish between November 2004 and June 2006. A total of 601 eligible healthy children aged 1-10 years were randomly selected and followed up for 13-19 months while receiving medical care at the study clinic.

In order to evaluate malaria episodes diagnosed only during the period of observation and to minimize the effect of antimalarial medications taken before enrollment, children with asymptomatic malaria on the day of screening were treated with quinine and enrolled only after showing a negative blood smear result seven days after the initiation of therapy. Malaria was diagnosed if a child had complicated malaria or fever and any parasitemia.

Children underwent routine assessment and blood smears to check for adherence to the study protocol and asymptomatic malaria. Routine complete blood cell count and a liver function test were carried out quarterly. Medications with antimalarial activity for treatment of non-malaria illnesses were avoided. Anthelmintics, iron sulfate, and vitamin A were routinely provided according to national guidelines.

Study participants were randomised to receive either AQ/SP, AQ/AS, or ART/LUM when diagnosed with their first episode of uncomplicated malaria. The same treatments were given for all subsequent episodes. Patients with confirmed malaria diagnoses were asked to return on days 1, 2, 3, 7, 14, and 28 or any other day they felt ill. Follow up evaluation consisted of a standardized medical history-taking and physical examination. Finger-prick blood samples were collected for thick blood smears and spotted onto filter papers for parasite genotyping.

Treatment outcomes were defined according to the 2005 WHO guidelines. Patients with early treatment failure or late clinical failure within 14 days of treatment initiation received quinine and began another 28-day follow up period. Adverse events were monitored and study treatments were withheld until the cause was established. If the cause was not related to the study drug, participation in the study continued.

The main outcome measure was the 28-day risk of parasitological failure (unadjusted and adjusted by genotyping to distinguish between recrudescence from new infections) for each episode of uncomplicated malaria treated with study drugs. Molecular genotyping was by a polymerase chain reaction-based method.

Three hundred and twenty nine of 601 enrolled children were diagnosed with at least 1 episode of uncomplicated malaria. In all, 687 episodes of P. falciparum malaria were treated with study drugs. The 28-day risk of treatment failure (unadjusted) for individual episodes of malaria were 26.1% (95% CI, 21.1-32.1%) for AQ/SP, 17.4 % (95% CI, 13.1-23.1) for AQ/AS, and 6.7% (95% CI, 3.9-11.2%) for ART/LUM (P < 0.05 for all pair-wise comparisons).

When only recrudescent failures were considered, the risks of treatment failures were 14.1% (95% CI, 10.3-19.2%), 4.6 (95% CI, 2.5—8.3%), and 1.0 % (95% CI, 0.3%-4.0 %) for AQ/SP, AQ/AS, and ART/LUM, respectively (P < 0.008 for all pair-wise comparisons except for AQ/AS versus ART/LUM for which P < 0.05).

There were no deaths or cases of severe malaria. There was a significant reduction in anemia (9.3% at enrolment versus 2.3% during the last two months of follow up; P < 0.001) and asynmptomatic parasitemia (18.6% at enrolment versus 2.3% during the last two months of follow up, P < 0.001).

The findings of Dorsey et al clearly established the superiority of ART/LUM over other combination drugs for treating uncomplicated malaria in children from a region of low malaria transmission in Uganda. Similar studies need to be carried out in other African countries in order to identify optimal combination therapies for malaria control. These studies must employ standardized protocols and study end-points in order to allow comparisons between study sites with different malaria prevalence and drug resistance profiles.

While ART/LUM is the most efficacious in Uganda, it has several shortcomings. First, it is expensive and continued availability will depend on sustained donor funding. Second, the pill burden for complete treatment is awfully high and might result in poor adherence which is a harbinger for drug resistance. Third, studies in other countries and by the same group in a region of high malaria transmission in Uganda demonstrated a high rate of re-infections within a relatively short time. Finally, there are concerns about the supply of ART/LUM not meeting the demands of endemic countries. These are equally important considerations for policy decisions.