Triple Therapies Safe, Effective Against Malaria And May Curb Resistance

Two triple artemisinin-based combination therapies (ACTs) for malaria were effective and safe in a multi-center open-label trial, investigators say.

Triple ACTs combine existing co-formulated ACTs with a second partner drug that is eliminated more slowly, thereby targeting malaria parasites longer.

"In areas where resistance is clearly established, we think triple ACTs could provide a good option for the treatment of multiresistant malaria," Dr. Rob W. van der Pluijm of Mahidol University in Bangkok, Thailand and the University of Oxford, UK, told Reuters Health by email. "Deployment of antimalarials in areas where resistance is not yet established could potentially prevent the emergence or importation of resistance."

Dr. van der Pluijm and colleagues recruited children and adults with acute, uncomplicated Plasmodium falciparum malaria alone or mixed with non-falciparum species, at 18 hospitals and health clinics in 8 countries.

As reported in The Lancet Infectious Diseases, 1,100 patients (median age: 23; 78% male) were randomly assigned to either dihydroartemisinin-piperaquine (17%); dihydroartemisinin-piperaquine plus mefloquine (25%); artesunate-mefloquine (7%); artemether-lumefantrine (26%); or artemether-lumefantrine plus amodiaquine (26%).

The 42-day PCR-corrected efficacy after dihydroartemisinin-piperaquine plus mefloquine was 98%, versus 48% after dihydroartemisinin-piperaquine in Cambodia, Thailand, and Vietnam.

The efficacy of dihydroartemisinin-piperaquine plus mefloquine in three sites in Myanmar was 91%, versus 100% after dihydroartemisinin-piperaquine.

In three sites in Cambodia, the 42-day PCR corrected efficacy of dihydroartemisinin-piperaquine plus mefloquine (96%) was non-inferior to that of artesunate-mefloquine (95%).

The overall 42-day PCR-corrected efficacy of artemether-lumefantrine plus amodiaquine (98%) was similar to that of artemether-lumefantrine (97%).

From a safety perspective, both triple ACTs were well tolerated, although early vomiting (within 1 hour) was more frequent after dihydroartemisinin-piperaquine plus mefloquine (3.8%) than after dihydroartemisinin-piperaquine (1.5%). Vomiting was infrequent after artemether-lumefantrine plus amodiaquine (1.3%) and artemether-lumefantrine (0.6%).

Further, adding amodiaquine to artemether-lumefantrine extended the electrocardiogram-corrected QT interval, but not to the extent associated with cardiac arrhythmias (mean increase of 8.8 ms at 52 h compared with baseline vs 0.9 ms without amodiaquine); however, adding mefloquine to dihydroartemisinin-piperaquine did not (mean increase of 22.1 ms for dihydroartemisinin-piperaquine vs 20.8 ms for dihydroartemisinin-piperaquine plus mefloquine).

The authors conclude that the triple ACTS "are efficacious, well tolerated, and safe treatments of uncomplicated P. falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance."

Dr. van der Pluijm said, "Before triple ACTs can be widely deployed in Sub-Saharan Africa, additional data on the efficacy, safety and tolerability in children (there) are needed. Therefore, a follow-up trial will start next month in which 5,000 patients, predominantly children in Sub-Saharan Africa, will be treated with either the standard treatment or the triple ACTs."

Dr. Philip Rosenthal of the University of California, San Francisco, author of a related editorial, commented in an email to Reuters Health, "This study offers a novel strategy...for addressing resistance to artemisinin-based combination therapies. If safety and tolerability remain acceptable in follow-up studies, use of optimally dosed and formulated triple ACTs to treat P. falciparum malaria may soon be appropriate in regions with artemisinin resistance."

"However," he noted, "most cases of P. falciparum malaria occur in areas without artemisinin resistance, and it's not clear whether triple ACT is feasible or even desirable in those regions, as adding a third drug to any regimen is likely to raise issues of tolerability, safety, and potential drug interactions, and as implementing any change in treatment policy is difficult."

"Ultimately, we need novel combination therapies to treat malaria globally," he added, "and in that context, triple ACTs should be viewed as a stopgap measure."

—Marilynn Larkin

Source