- First trial of its kind finds that treatment with triple artemisinin-based combination therapies (TACTs) is effective.
- TACTs were safe and well tolerated, but showed slightly higher rates of vomiting and some minor changes in the electrical activity of the heart compared to existing treatment that uses two drugs.
- Drug resistance is a major threat to malaria control and elimination. The authors say that triple therapies are potentially an immediately available new treatment option that could improve outcomes in countries with multidrug resistant malaria.
The first clinical trial of two triple artemisinin-based combination therapies for malaria finds that the combinations are highly efficacious with no safety concerns.
Published in The Lancet, the study of 1,100 people with uncomplicated falciparum malaria from eight countries compared people receiving the current national first-line treatment combining two drugs, with two forms of triple therapy (dihydroartemisinin-piperaquine plus mefloquine and artemether-lumefantrine plus amodiaquine).
The triple therapies (known as triple artemisinin-based combination therapies - TACTs), combine existing treatment consisting of two drugs (artemisinin-based combination therapies - ACTs) with a second partner drug that remains present in the blood to target the malaria parasites for longer. TACTs add additional antimalarial activity and provide mutual protection for the partner drugs, and researchers believe that it might provide effective treatment and could potentially delay the emergence of antimalarial drug resistance.
ACTs have contributed substantially to the reduction in the global burden of malaria. However, progress is now threatened by the emergence and spread of artemisinin and artemisinin partner-drug resistance in southeast Asia. Emerging multidrug resistance in the malaria parasite has led to a series of treatment policy changes, but this means fewer treatments are available and new compounds are not becoming available quickly enough in countries facing drug resistant malaria.
With the risk of the spread of multidrug resistant malaria to India and sub-Saharan Africa, it is important to find new treatments to treat drug-resistant infections and help prevent the emergence of multidrug resistance.
"With the increasing failure of conventional ACTs, the use of TACTs might soon become essential for treatment of malaria in the Greater Mekong subregion in southeast Asia. This region is aiming for accelerated malaria elimination before the growing drug resistance renders Plasmodium falciparum malaria close to untreatable. The TACTs we studied here could prevent a resurgence of malaria that often accompanies spreading antimalarial drug resistance." says senior author Professor Arjen Dondorp, Mahidol-Oxford Research Unit, Bangkok, Thailand. 
Co-author, Dr Chanaki Amaratunga, Mahidol-Oxford Research Unit, Bangkok, Thailand, says: "Because two well-matched partner drugs provide mutual protection against resistance, deployment of TACTs is expected to extend the useful life of the few effective available and affordable antimalarial drugs. Fortunately, to date, artemisinin resistance has not worsened in southeast Asia and has not spread to sub-Saharan Africa, so these drugs still provide useful antimalarial treatment when used in combination. To ensure we reduce resistance as much as possible, it is important that we avoid waiting for resistance to emerge and spread before changing malaria therapies." 
The new study was an open-label randomised controlled trial including 1,100 patients aged 2-65 years from 18 hospitals in eight countries (Thailand, Cambodia, Vietnam, Myanmar, Laos, Bangladesh, India and the Democratic Republic of the Congo). Participants were included if they had acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37.5°C or higher, or a history of fever in the past 24 hours. People who had been treated with artemisinins in the past week, and people with a history of problems with the electrical activity of their heart were not included in the study.
The ACTs and TACTs assigned in the trial depended on the first-line ACTs used in the country where the participant was being treated. In some cases, where a country's first-line treatment changed during the trial (due to that treatment beginning to fail due to resistance), the comparison treatment in the trial was also changed. Doses varied by drug combination and location, and all drugs were administered orally.
Participants in Thailand, Cambodia, Vietnam, and two sites in Myanmar were assigned to either dihydroartemisinin-piperaquine or dihydroartemisinin-piperaquine plus mefloquine. Due to changes in Cambodia's first-line treatment, at three sites participants were later assigned to either artesunate-mefloquine or dihydroartemisinin-piperaquine plus mefloquine. In Laos, one site in Myanmar, Bangladesh, India, and the Democratic Republic of the Congo, participants were assigned to either artemether-lumefantrine or artemether-lumefantrine plus amodiaquine.
The researchers assessed the efficacy of the treatment based on the complete cure of the infection assessed after 42 days of follow-up (comprised of absence of malaria parasites as well as clinical symptoms). They also recorded any adverse events associated with the treatments.
Overall, 17% of participants were given dihydroartemisinin-piperaquine (183/1,100 people), a quarter were given dihydroartemisinin-piperaquine plus mefloquine (269 people), 7% were given artesunate-mefloquine (73), 26% were given artemether-lumefantrine (289), and 26% were given artemether-lumefantrine plus amodiaquine (286).
In 15 sites, the study was stopped before target recruitment was reached because of a sharp decrease in malaria cases in those study sites, but their data still contributed to the analysis. In addition, 113 patients were excluded from the more strict "per protocol" analysis.
Six patients discontinued the study drug and started standard antimalarial treatment due to abnormal baseline laboratory results or extension of the QTc-interval. Their results were included in the trial.
In Cambodia, Thailand, and Vietnam, efficacy of the TACT dihydroartemisinin-piperaquine plus mefloquine was greater than for the ACT dihydroartemisinin-piperaquine (98% [successful treatment in 149 of 152 people] vs 48% efficacy [67/141 people], respectively). While in Myanmar, which used the same treatments, the efficacy of the ACT was similar to the efficacy of the TACT (91% [42 of 46 people] vs 100% [42 of 42 people], respectively).
In the three Cambodian sites where the drugs tested were changed during the trial, the efficacy of the TACT dihydroartemisinin-piperaquine plus mefloquine and the ACT artesunate-mefloquine were comparable (95% [69/73] vs 96% [68/71], respectively).
Comparing the TACT artemether-lumefantrine plus amodiaquine and the ACT artemether-lumefantrine in five countries, the authors found that their efficacies were similar (98% [281/286] vs 97% [279/289], respectively).
Both TACTs were well-tolerated and safe, although vomiting within an hour of treatment was more common after dihydroartemisinin-piperaquine plus mefloquine than after dihydroartemisinin-piperaquine (3.8% [30/794 people] vs 1.5% [8/543 people]), and adding amodiaquine to artemether-lumefantrine led to some changes in the electrical activity of the heart (ie, extended the electrocardiogram corrected QT interval - mean increase at 52 hours was 8.8 milliseconds for the triple therapy vs 0.9 milliseconds for the double therapy), which does not have clinical importance.
The incidence of serious adverse events was similar after treatment with ACTs or TACTs. Overall, 24 serious adverse events were reported in 1,100 patients, of which 11 were judged to be possibly (n=10) or probably (n=1) drug related.
"The TACTs used in this study combine existing antimalarial drugs and could be made available in the near future and might buy important time before new antimalarial compounds become available. In areas not yet affected by antimalarial resistance, TACTs might have the potential to delay the emergence and spread of antimalarial resistance and could help prevent importation of drug resistance from the Greater Mekong subregion, but we will need more research to confirm this." Concludes Dr Rob van der Pluijm, lead author of the paper, from the Mahidol-Oxford Research Unit, Bangkok, Thailand. 
The authors note some limitations in their study, including that it did not include many children - who are the main group affected by malaria. Since the study was open-label (ie, patients knew which drug they were receiving), this may have affected reporting of symptoms and adverse effects but the authors say it is unlikely to have affected efficacy.
Writing in a linked Comment, Professor Philip Rosenthal (who was not involved in the study), University of California, San Francisco, USA, says: "These new results suggest that TACTs might replace ACTs. The addition of mefloquine to dihydroartemisinin-piperaquine rescued the regimen from unacceptably poor efficacy, and mefloquine might additionally restrict selection of resistance to piperaquine. If safety and tolerability remain acceptable in follow-up studies, use of optimally dosed and formulated TACTs to treat P falciparum malaria might soon be appropriate in regions with artemisinin resistance. However, most cases of P falciparum malaria occur in regions without established artemisinin resistance... Thus, this study offers promise for TACTs in regions with artemisinin resistance, but whether we should implement TACTs in other areas is uncertain. In any event, TACTs should be seen as a stopgap; novel combination therapies to treat malaria are greatly needed."
NOTES TO EDITORS
This study was funded by UK Department for International Development, with additional contributions from Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health. A full list of authors institutions is available in the Article.
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