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A triple artemisinin-based combination therapy (TACT) of artemether-lumefantrine plus amodiaquine (AL+AQ) for uncomplicated falciparum malaria in areas with a high prevalence of artemisinin resistance is a well-tolerated, effective treatment for multidrug-resistant parasites, say a team of MORU-led researchers.

Composite photo, with a doctor and a patient, and a view over the river in the Sekong Province, Lao PDR © Nature & James Callery
Left: A TACT-CV study doctor examines a patient. Right: The Sekong River in Cambodia, near the location of a TACT study site.

Published in The Lancet Infectious Diseases, the results of the MORU-led TACT-CV study demonstrate that AL+AQ  provides an alternative first-line treatment for multidrug-resistant P falciparum malaria in the Greater Mekong subregion (GMS), and could prolong the therapeutic lifetime of artemether–lumefantrine in malaria-endemic populations in SE Asia and elsewhere, with an expected longer therapeutic lifetime than current artemisinin combination therapies.

“This is an important study, showing that artemether-lumefantrine-amodiaquine is efficacious and safe for the treatment of falciparum malaria in an area of multidrug resistance. It is currently the most advanced triple ACT, which will become available as a fixed dose drug combination later this year.,” said Professor Arjen Dondorp, Head of Malaria at MORU and TACT-CV Principal Investigator (PI).

Artemisinin-based combination therapies (ACTs) are the first-line treatment for falciparum malaria, but parasites that are resistant to artemisinin and the partner drugs used in ACTs have emerged, with high levels of resistance noted in the Greater Mekong subregion in countries such as Cambodia and Vietnam. Resistance to artemisinin and ACT partner drugs has been reported widely from Cambodia and Vietnam since 2009, with a single artemisinin-resistant parasite lineage carrying the C580Y pfkelch13mutation becoming the predominant artemisinin-resistant strain by 2016-17. Artemisinin could be given with two partner drugs, lumefantrine and amodiaquine (AQ), as a triple ACT to improve cure rates and extend the useful therapeutic lifetimes of these available drugs.

The first randomised trial of artemether-lumefantrine (AL) alone versus artemether-lumefantrine plus amodiaquine (AL+AQ) for uncomplicated falciparum malaria in areas with a high prevalence of artemisinin resistance, the TACT-CV study was funded by the Bill & Melinda Gates Foundation and Wellcome, and undertaken from 2018-20 at two sites in Cambodia and one in Vietnam. Led by PI Prof Arjen Dondorp, TACT-CV was coordinated by Lorenz von Seidlein, Tom Peto, James Callery and Rupam Tripura, in collaboration with colleagues from the Cambodian malaria control programme (led by Dr Soley and Dr Chea) and OUCRU in Vietnam (led by Dr Hien and Dr Nghia).

The study showed that although AL alone cleared the initial artemisinin-resistant infections, it had only about 90% efficacy against recrudescence; for such infections, triple therapy with AL+AQ is a safe option that might be about 96% effective against recrudescence. The addition of AQ to AL did not affect plasma lumefantrine concentrations but, as in a previous trial (TRACII), it slightly increased the incidence of vomiting and mild bradycardia.

The TACT-CV team wish to thank and extend a big appreciation to everyone who was involved in successfully completing the TACT-CV study.

- Text and photos courtesy of James Callery,
on behalf of Tom Peto, Rupam Tripura and the TACT-CV team.

Read the publication 'Triple therapy with artemether–lumefantrine plus amodiaquine versus artemether–lumefantrine alone for artemisinin-resistant, uncomplicated falciparum malaria: an open-label, randomised, multicentre trial' on the Lancet Infectious Diseases website

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