Clinical trial to determine effective treatment against vivax malaria

Plasmodium vivax is found in the Asia-Pacific, Latin America and the Horn of Africa causing up to 100 million cases of malaria per year. Recent elimination efforts are focused primarily against Plasmodium falciparum, the deadliest form of malaria, and have resulted in major reductions in malaria related deaths and cases, however interventions against P. vivax have been less successful.

P. vivax causes 40% of all clinical malaria In Ethiopia and chloroquine remains the recommended treatment. Artemether-lumefantrine (AL), an artemisinin combination therapy, is used to treat mixed infections of both falciparum and vivax malaria.

"The successful treatment of vivax malaria requires a combination of drugs active against both the blood and liver stages of the parasite,” says Prof Ric Price, senior author from Menzies School of Health Research and Head of the WWARN Clinical Scientific Group. “Although primaquine works well against the liver stages it is usually administered over 14 days and this can lead to patients stopping their treatment early and having relapsing infections.”

In a new study out in PLoS Medicine, funded by the Bill and Melinda Gates Foundation, a team led by Menzies School of Health Research, Darwin, Australia, US President’s Malaria Initiative and ICAP Columbia University’s Mailman School of Public Health, Addis Ababa, with support from the Ethiopian Public Health Institute, the efficacy of AL versus chloroquine for vivax malaria with and without primaquine was compared.

Patients were randomly allocated to one of four treatment arms: group one treated with chloroquine only, group two with chloroquine and primaquine, group three with AL alone and group four with AL and primaquine. All patients were followed for one year and were given the same treatment for every vivax episode they had.

The team found evidence of chloroquine resistance, with almost 20% of patients failing treatment within 42 days. Surprisingly AL alone was not much better than chloroquine, unless it was administered in combination with primaquine.

“Our study demonstrates that resistance to chloroquine has emerged in Ethiopia. However, even though AL works well, it is quickly eliminated from the body and doesn’t suppress vivax malaria at the dormant liver stages,” says Dr Kamala Thriemer, co-lead author of the study from Menzies School of Health Research, Darwin, Australia. “The greater early efficacy of AL over chloroquine was soon overcome by high rates of relapsing infections unless it was combined with primaquine.”

“The study emphasises the importance of primaquine, but when the 14 day regimen was unsupervised the treatment didn’t work so well.  It is possible more patients would be cured if patients were encouraged to adhere to complete treatment,” adds Dr Tesfay Abreha, co-lead author from ICAP at Columbia University’s Mailman School of Public Health, Addis Ababa, Ethiopia.

This study recommends that primaquine treatment should be included in the Ethiopian national treatment guidelines to decrease relapse rates for patients with vivax malaria, malarial anaemia and prevent onward transmission of the parasite to the mosquito vector.

To help monitor the distribution and efficacy of P. vivax resistance to chloroquine, the team at WWARN have developed the Vivax Surveyor. The Vivax Surveyor is an interactive map that summarises the prevalence of Plasmodium vivax antimalarial clinical trials across the world. This tool provides a clear and standardised visualisation of vivax clinical trials to date to inform key international, regional and national monitoring strategies.

Publication details:

Tesfay Abreha, Jimee Hwang, Kamala Thriemer et al.  'Comparison of artemether-lumefantrine and chloroquine with and without primaquine for the treatment of Plasmodium vivax infection in Ethiopia: A randomized controlled trial'. Plos Medicine (2017). Doi: 10.1371/journal.pmed.1002299