Vivax malaria: the challenges towards malaria elimination

Plasmodium vivax is a less widely studied form of the malaria parasite but it still infects over 20 million people with malaria each year. Most of these cases occur in the Asia Pacific region where more than 2.2 billion people are at risk of infection. National malaria control programmes in the past have prioritised the containment of Plasmodium falciparum malaria, as it is considered more pathogenic and has been easier to detect and treat. However, as many countries progress towards the elimination of malaria, it is now imperative to focus greater resources on tackling vivax malaria to achieve this major public health goal.

P. vivax parasites can remain dormant in the liver for several months and even up to a year or more. When these dormant parasites reactivate they can cause relapses of febrile illness. Because of this, vivax requires a combination of drugs active against both the blood stages of the parasite and the dormant liver stages. Primaquine is currently the only licensed drug that targets the liver stage of the malaria lifecycle. However, widespread use of primaquine is limited by a genetic condition found in up to 40 per cent of some populations - a deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD), which increases the risk of rupturing red blood cells.

Lack of available and reliable diagnostics make it difficult to confirm G6PD deficiency in patient populations, and therefore the extent of potential drug toxicity. This means that clinicians prescribe primaquine erratically even when national policy recommends its use. Furthermore, primaquine is prescribed over seven to 14 days and there are concerns that reduced adherence may reduce the efficacy of preventing liver stage relapse.

In addition to killing the parasite dormant liver stages, treatment of P. vivax also requires killing the blood stages of the parasites. Drug resistance has forced most malaria endemic countries to abandon chloroquine for the treatment of blood stages of P. falciparum, but it still remains the drug of choice for P. vivax. This strategy is now under threat from the emergence and spread of chloroquine resistant P. vivax, which is now present in many endemic areas. Several countries are now changing national policy to artemisinin combination therapy for both P. falciparum and P. vivax malaria.

A recent study published in PLoS Medicine, 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, found that the addition of primaquine to treatment for vivax malaria in Ethiopia could decrease risk of malaria recurrence.

In recent years, the scientific scope of WWARN has evolved to place greater emphasis on improving treatment of vivax malaria, and the team is currently undertaking two related collaborative study groups. The Vivax Recurrence Study Group aims to determine the risk factors that lead to vivax recurrence, such as chloroquine dose and primaquine co-administration. The Vivax Anaemia Study Group which will define the haematological effects of vivax infection with and without primaquine. Together these projects aim to provide the evidence which will inform treatment policy and improve the treatment strategies for vivax malaria.

As the P. vivax resistance profile is less well defined than P. falciparum, WWARN collaborators Dr Marcus Lacerda and Dr Wuelton Monteiro at the Doctor Heitor Vieira Dourado Foundation for Tropical Medicine (FMT-HVD), Brazil, are exploring the potential to identify molecular markers associated with P. vivax resistance. The team hopes to estimate the expression of markers pvcrt and pvmdr1 in distinct P. vivax isolates from sites in the Brazilian Amazon and French Guiana, with comparison to clinical failures to validate the markers. Identifying markers for P. vivax resistance will help identify regions at highest risk of resistance and to implement strategies to maintain the efficacy of existing treatments.

Earlier this year, WWARN also launched an interactive tool that summarises P. vivax antimalarial clinical trials across the world. This Vivax Surveyor provides a clear and standardised visualisation of vivax clinical trials to date in order to inform key international, regional and national organisations about where and how to focus efforts, to understand the spread and emergence of chloroquine-resistant vivax malaria parasites. This tool builds on a systematic review of the literature that assessed the extent of chloroquine resistant P. vivax and the different methodologies used to quantify therapeutic efficacy, which was published in the Lancet Infectious Diseases in 2015.

The Malaria Atlas Project (MAP), a WWARN collaborator, is working on mapping populations at risk of P. vivax and associated haemolytic risk from G6PD deficiency. This mapping project will generate global estimates of the burden of P. vivax malaria and show how the clinical burden of P. vivax varies both across space and time by generating pixel-level maps from the year 2000 to 2016. Unlike with P. falciparum in Africa, there is not the same wealth of cross-sectional parasite rate survey data, so they are developing new methods that leverage routine surveillance data that is more widely available throughout the P. vivax endemic world.

The Asia-Pacific Malaria Elimination Network (APMEN) is at the forefront of the challenge of vivax malaria across Asia. The Network is supporting research and advocacy to address the challenge of vivax malaria, through reviewing the existing evidence for effective surveillance diagnosis and treatment, identifying key knowledge gaps and priorities, and implementing a process to translate relevant evidence into policy and practice.

MAP and the APMEN Vivax Working Group will soon undertake a collaborative project to update MAP’s database of G6PD deficiency surveys and make these available through an online database portal. The database update will also allow for updates to be made to the G6PD deficiency prevalence and variants maps and offer the potential to compare the prevalence of G6PD deficiency in malaria patients and healthy individuals.

Elimination efforts across many endemic regions have intensified over recent years. Vivax malaria is now the predominant cause of malaria transmission outside Africa and it is therefore vital that it receives adequate political attention and resources.

• Commons, RJ et al. (2017). “The Vivax Surveyor: online mapping database for Plasmodium vivax clinical trials.” International Journal for Parasitology: Drugs and Drug Resistance. Volume 7, Issue 2, 2017, Pages 181–190. https://doi.org/10.1016/j.ijpddr.2017.03.003
• Price RN, von Seidlein L, Valecha N, et al. The global extent of chloroquine resistant Plasmodium vivax: a systematic review and meta-analysis. Lancet Infectious Diseases; DOI S1473-3099(14)70855-2 
• 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