Emerging artemisinin-resistant malaria could bring years of clinical progress to a halt, investigators caution.
Artemisinin-resistant Plasmodium falciparum parasites are prevalent throughout mainland Southeast Asia and have the potential to spread to the Indian subcontinent and Africa, report Elizabeth A. Ashley, MB BS, PhD, from the Mahidol–Oxford Tropical Medicine Research Unit at Mahidol University in Bangkok, Thailand, and colleagues in the Tracking Resistance to Artemisinin Collaboration.
"The spread of artemisinin resistance and the consequent emergence of resistance to the increasingly unprotected partner drugs in artemisinin-based combination regimens may well reverse the substantial recent gains in malaria control. New antimalarial drugs are under development but will not be available for several years," the authors write in an article published in the July 31 issue of the New England Journal of Medicine.
Results from a phase 2 trial of 1 of the antimalarial agents under development, KAE609 (Novartis Institute for Tropical Diseases), are reported in a separate study, by Nicholas J. White, MD, DSc, FRS, from the Mahidol–Oxford Tropical Medicine Research Unit and the Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, United Kingdom, and colleagues, also published in the July 31 issue of the journal.
Potent Agents
Artemisinin and its derivatives are the most potent and rapidly effective antimalarial agents currently available, and their introduction in the mid-1990s helped stem the tide of malaria parasites resistant to older antimalarials such as chloroquine and sulfadoxine-pyrimethamine, Dr. Ashley and colleagues explain.
In an effort to map areas of the world where resistance to artemisinin-based therapy may be emerging, they enrolled 1241 adults and children with acute uncomplicated falciparum malaria in an open-label trial. The patients were treated at 15 sites in 7 Asian and 3 African countries. The researchers gauged artemisinin resistance by measuring the rate of parasite clearance from peripheral blood, with blood sampled at baseline; 4, 6, 8, and 12 hours after the start of therapy; and every 6 hours thereafter.
They defined slow clearance, suggestive of drug resistance, as a clearance half-life of more than 5 hours.
The patients were given the artemisinin derivative artesunate (Guilin Pharmaceutical) in an oral dose of either 2 or 4 mg/kg per day for 3 days. The 4 mg/kg dose was used in western Cambodia and in Sriasket, Thailand, where higher-grade artemisinin-resistant malaria was known to exist. All patients then were administered a standard 3-day course of an artemisinin-based combination therapy (dihydroartemisinin-piperaquine, artemether-lumefantrine, artesunate-sulfadoxine-pyrimethamine, or artesunate-mefloquine, according to local treatment policies).
Half-Life Clearance Varied
Median parasite-clearance half-life, the primary endpoint, ranged from a low of 1.9 hours in the Democratic Republic of Congo to 7.0 hours along the border between Thailand and Cambodia.
The investigators also found a positive association between longer half-life clearance and a single point mutation in the so-called "propeller" domain of the P falciparum kelch protein gene on chromosome 13, supporting evidence for this mutation as a source of artemisinin resistance.
In addition, patients with slow parasite clearance were found to have a higher incidence of gametocytemia (the presence in the blood of parasites in the sexual reproductive stage) than patients with faster clearance rates, suggesting malaria among patients with resistant disease has greater potential for transmission.
"Artemisinin-resistant P. falciparum is now firmly established in eastern Myanmar, western Cambodia and Thailand, and southern Vietnam, and it is emerging in southern Laos and northeastern Cambodia," they write.
Experimental Agent
In the second study, Dr. White and colleagues looked at the use of the investigational synthetic antimalarial spiroindolone analog KAE609 (formerly NITD609) in 10 adults with Plasmodium vivaxmalaria and 11 with P falciparum malaria.
The open-label phase 2 study, conducted at 3 centers in Thailand, was designed to assess the efficacy and safety of the drug, which has been shown to have dose-dependent activity against P falciparum in both the sexual and asexual stages.
Patients were given the oral drug at a dose of 30 mg per day for 3 days.
Median parasite clearance time, the primary endpoint, was 12 hours in each cohort. The clearance half-life was 0.95 hours in the patients with P vivax malaria and 0.90 hours in those with P falciparum malaria. In the 4 patients with P falciparum infections with kelch protein mutations who remained in the study (1 had dropped out), the rapidity of parasite clearance was comparable with that of 6 patients without mutations.
The authors note that the clearance half-life results compare favorably with those of patients in Southeast Asia who were treated with artesunate and similarly evaluated in a different study. Only 19 of 5076 of those patients (less than 1%) had a clearance half-life of less than 1 hour.
Patients appeared to tolerate the drug well, and there were no discontinuations from adverse events, although the authors acknowledge that the study was "too small for us to derive valid conclusion regarding safety and efficacy."
Vigilance Urged
In an accompanying editorial, Brian Greenwood, MD, from the London School of Hygiene and Tropical Medicine, United Kingdom, notes that because spiroindolone-resistant mutations can be induced in vitro, KAE609, if approved for clinical use, will need to be combined with an antimalarial drug that has a different mechanism of action. KAE609 inhibits a parasite plasma membrane enzyme involved in sodium and osmotic homeostasis.
Dr. Greenwood writes that to contain artemisinin resistance, public health authors will need to conduct surveillance for resistant parasites in areas where they have not been previously found.
In addition, "artemisinin monotherapy must be strongly discouraged. Although most national malaria-control programs have heeded the advice of the [World Health Organization] to prohibit the use of artemisinin monotherapy, it is still being used widely in the private sector," he writes. "If resistant parasites are confined to a geographically restricted area, a strong case can be made for a 'blitz' campaign aimed at eliminating the resistant parasites before they can spread. This campaign would involve the use of all available means, including enhanced vector control, mass drug administration, and perhaps vaccination," Dr. Greenwood writes.
He noted that an antimalaria vaccine currently in development (RTS,S/AS01) may become available in 2016.
The study by Dr. Ashley and colleagues was supported by grants from the UK Department for International Development, the Worldwide Antimalarial Resistance Network, the Intramural Research Program of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, and the Bill and Melinda Gates Foundation. The authors have disclosed no relevant financial relationships. The study by Dr. White and colleagues was supported by Novartis. Dr. White and several coauthors disclose receiving grants or personal fees from Novartis, and Dr. White is cochairman of the World Health Organization malaria treatment guidelines committee, but the committee was not involved in the study. The authors have disclosed no other relevant financial relationships. Dr. Greenwood has disclosed no relevant financial relationships.
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