Artemether-Lumefantrine May Be a Superior Combination for Malaria Treatment in Resistant Areas CME

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Artemether-Lumefantrine May Be a Superior Combination for Malaria Treatment in Resistant Areas CME

News Author: Laurie Barclay, MDCME Author: Vega, MD, FAAFP

April 25, 2005 — Artemether-lumefantrine is an effective combination for the treatment of malaria in resistant areas, according to the results of a four-group randomized study published in the April 23 issue of The Lancet. A second randomized study in the same issue showed similar cure rates for supervised and unsupervised therapy using this same regimen.

"We found that the artemether-lumefantrine combination is effective taken unsupervised," lead author Theonest Mutabingwa, MD, from the London School of Hygiene and Tropical Medicine, England, U.K., says in a news release. "The cost of the drug means that it is likely to reach only a fraction of those who need it, unless the price is substantially reduced either through market mechanisms or, more realistically, through subsidy."

The authors note that many countries in Africa are considering a change to combination treatment of Plasmodium falciparum malaria because of the increase in drug resistance, but that few data exist about the effectiveness of these combinations.

This four-group randomized trial took place in Muheza, Tanzania, an area with a high prevalence of resistance to sulfadoxine-pyrimethamine and chloroquine. Children aged 4 to 59 months with uncomplicated malaria were randomized to treatment with three days of amodiaquine (n = 270), amodiaquine plus sulfadoxine-pyrimethamine (n = 507), or amodiaquine plus artesunate (n = 515) or to a three-day, six-dose regimen of artemether-lumefantrine (n = 519).

These drugs were taken by mouth, at home, without observation by medical staff. The primary endpoint was parasitologic failure by day 14 assessed by observers blinded to treatment allocation, and secondary endpoints included follow-up on day 28 and gametocyte carriage. Analysis was by intent-to-treat.

Of 3,158 children screened, 1,811 (57.3%) were randomized to one of the treatment groups, and 1,717 (95%) were available for 14-day follow-up. The data and safety monitoring board stopped the amodiaquine group early because interim analysis of parasitologic failure rates. By day 14, these rates were 103 (42%) of 248 for amodiaquine, 97 (20%) of 476 for amodiaquine plus sulfadoxine-pyrimethamine, 54 (11%) of 491 for amodiaquine plus artesunate, and 7 (1%) of 502 for artemether-lumefantrine. By day 28, these rates were 182 (76%) of 239, 282 (61%) of 476, 193 (40%) of 472, and 103 (21%) of 485, respectively.

In every case, the difference between individual treatment groups and the next best treatment combination was significant (P < .001). After correction by genotyping, recrudescence rates by day 28 were 48.4%, 34.5%, 11.2%, and 2.8%, respectively.

"The study shows how few the options are for treating malaria where there is already a high level of resistance to sulfadoxine-pyrimethamine and amodiaquine," the authors write. "The WHO [World Health Organization]-packaged six-dose regimen of artemether-lumefantrine is effective taken unsupervised, although cost is a major limitation."

Study limitations include inability of a trial to completely mimic normal practice, reduced effectiveness if study drugs were sold rather than taken, and lack of packaging of amodiaquine-artesunate for young children and infants.

The authors report no conflict of interest. The Gates Malaria Partnership funded the study, and Sanofi donated amodiaquine-artesunate.

An accompanying article describes the results of a randomized trial from Mbarara, Uganda, that showed high efficacy of the artemether-lumefantrine drug combination, whether given supervised or unsupervised.

"We believe that the six-dose regimen of artemether-lumefantrine is a very promising option for the replacing failing antimalarial therapies in Uganda and other African countries," says lead author Patrice Piola, MD, from Epicentre in Paris, France. "Our experience suggests that providing systematically a short explanation on drug intake to patients at the point of prescription is a simple but important intervention to enhance adherence."

In this study, 313 patients received artemether-lumefantrine in a supervised fashion, with all doses observed with fatty-food intake, and 644 patients received the drug in an unsupervised fashion, with the first dose supervised followed by outpatient treatment with nutritional advice. Patients had acute, uncomplicated P. falciparum malaria; were of all ages; and weighed more than 10 kg. The primary endpoint was 28-day parasitologic cure rate adjusted by polymerase chain reaction, and analysis was by intent-to-treat and evaluability.

One patient withdrew consent, and 38 patients were lost to follow-up. Day-28 cure rates were 97.7% (296/303) in the supervised group and 98.0% (603/615) in the unsupervised group. There were 15 nonsevere, drug-related adverse events, all of which were resolved.

"Artemether-lumefantrine has a high cure rate irrespective of whether given under supervision with food or under conditions of routine clinic practice," the authors write. "If used as first-line treatment, artemether-lumefantrine could make a substantial contribution to malaria control in Africa, though cost is an issue."

Médecins Sans Frontières funded this study, and Novartis Pharma, maker of artemether-lumefantrine, funded the pharmacokinetics analysis. The authors report no conflict of interest.

In an accompanying comment, Gottfried Kremsner, from the Institute of Tropical Medicine in Tübingen, Germany, praises these trials and calls the results "stunning." However, Dr. Kremsner notes three major drawbacks with artemether-lumefantrine: relatively high price; pharmacokinetic mismatch of the two drugs; and safety concerns, particularly audiometric changes.

"Together these two papers convincingly show that the effectiveness of arthemether-lumefantrine is excellent in the artificial real-world condition in a research trial," Dr. Kremsner writes. "How effectively such trials can show the effectiveness of antimalarial drugs in Africa is still an open question."

Dr. Kremsner reports no conflict of interest.

Lancet. 2005;365:1441-1443, 1467-1480