14 May 2006
New highly active anti-malarial Artemisinin-based Combination Therapy (ACT) protected by phase-out of marketing single-drug artemisinin malaria pills
On May 11 the World Health Organization (WHO) announced that their recommendation to stop marketing single-drug artemisinin malaria pills has been agreed to by 13 pharmaceutical companies. This phase-out of single-drug artemisinin monotherapy for the oral treatment of malaria is a major advance in maximizing the probability that Artemisinin-based Combination Therapies (ACTs) currently recommended as the drugs of choice by WHO for uncomplicated falciparum malaria will remain highly active and effective.
Earlier in 2006 the WHO posted online new "Guidelines for the Treatment of Malaria". This 240-page document contained clear advice on the diagnosis and treatment of all four types of malaria: Plasmodium falciparum ("uncomplicated" and "severe"), Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae.
WHO listed alphabetically the following specific Artemisinin-based Combination therapies (ACTs) (page 21):
A. Artemether-lumefantrine (already available as co-formulated tablets containing 20 mg of artmether plus 120 mg of lumefantrine. The total recommended therapy course is a 6-dose regimen with one tablet being taken orally twice a day for three (3) days.
b. Artesunate plus amodiaquine
c. Artesunate plus mefloquine
d. Artesunate plus sulfadoxine-pyrimethamine
The choice of ACT for uncomplicated falciparum malaria depends on the level of resistance of the partner medicine in the combination. For example, in Africa (page 23) WHO recommends artemether-lumefantrine, OR artesunate plus amodiaquine, OR artesunate plus sulfadoxine-pyrimethamine. In areas of multidrug resistance malaria, such as SE Asia, WHO recommends artemether-lumefantrine OR artesunate and mefloquine.
In Africa WHO notes (page 22) concerns about "insufficient safety and tolerability data on artesunate and mefloquine at the recommended dose of 25mg/kg in African children to support its recommendation there. Trials with mefloquine monotherapy (25mg/kg) have raised concerns of tolerability in African children. Countries may therefore opt instead to use artesunate plus amodiaquine, OR artesunate plus sulfadoxine-pyrimethamine which may have lower cure rates because of resistance".
Monotherapy with amodiaquine, or montherapy with sulfadoxipine-pyrimethamine are widely available and provide continued selection pressure for the P. falciparum malaria parasite to develop resistance.
Lumefantrine has never been available as a monotherapy. Instead, it is only available as a co-formulated tablet with artemether and thus resistance is less likely.
Remarkably, "artemisinin and its derivatives (artesunate, artemether, artemotil, dihydroartemisinin) produce rapid clearance of parasitemia and rapid resolution of symptoms. They reduce parasite numbers by a factor of approximately 10,000 in each asexual cycle, which is more than other current antimalarials (which reduce parasites numbers 100-1,000-fold per cycle)" (page 17).
Artemisinin drugs are eliminated rapidly from the body. Thus, when given in combination with other rapidly eliminated antimalarial compounds (tetracyclines or clindamycin) seven (7) days of the artemisinin medication are required. When given in combination with slowly eliminated antimalarial medications, however, shorter courses of only three (3) days of the artemisinin compounds are required (page 17, WHO 2006).
This important step announced May 11 by the WHO of the phase-out of marketing single-drug artemisinin malaria pills should help preserve Artemisinin-based Combination Therapies (ACTs) as highly effective treatment for uncomplicated falciparum malaria. Combination therapy with several effective medications against the malaria parasite is analogous to combination therapy with highly active antiretroviral drugs for the human immunodeficiency virus, and combination therapy with multiple antibiotics against tuberculosis. In parts of the world where all three infections (malaria, HIV. and TB) can occur in the same patient such combination therapies can increase the probability of successful treatment.
Daniel R. Lucey, MD, MPH
Adjunct Professor of Microbiology and Immunology
Georgetown University Medical Center
Director, Center for Biodefense and Emerging Infectious Diseases
EROne Institutes, Washington Hospital Center