Tracking antimalarial resistance in P vivax

As efforts to treat Plasmodium falciparum have seen increasing success, the proportion of P vivax cases may rise. The Malaria Atlas Project (MAP) estimates that some 2.85 billion people were at risk of contracting the illness in 2009.¹ While less lethal than P falciparum, P vivax is a major source of morbidity, particularly amongst women and children in poorly-resourced communities, with an estimated net annual cost of between 1.4 and 4 billion USD. Despite this tremendous disease burden, less than 3.1% of global funding for malaria research was committed to P vivax during 2007-2009.^2,3

Whereas most malaria endemic countries have turned to Artemisinin Combination Therapies (ACTs) to reduce the risk of multidrug resistant strains of P falciparum, chloroquine remains the first line treatment for P vivax in most of the world. This approach is threatened by the emergence and spread of chloroquine resistant parasite strains, first documented over 20 years ago in Papua New Guinea.⁴  There is now evidence that the efficacy of chloroquine against P vivax is declining in many endemic areas, the highest percentage of resistant parasites being found on the island of New Guinea.^5,6

Unlike P falciparum, P vivax forms hypnozoites. These remain in the patient’s liver and are capable of reactivating and initiating recurrent blood stage infections months after the initial infection. This complex life cycle makes it difficult to differentiate these relapses from emergent drug resistance.

A number of research groups, including that of WWARN Scientific Advisory Committee member Dr Marcelo Urbano Ferreira from the Instituto de Ciencias Biomedicas in São Paulo, Brazil, are working to identify molecular markers to differentiate P vivax strains. Dr Ferreira’s laboratory is currently standardising molecular markers to help physicians identify P vivax recrudescences resulting from drug failure, which exhibit the same parasite genotypes found in the primary infection. This differs from parasite relapses or reinfections, which may be due to either similar or different parasite genotypes.

Professor Ric Price, Head of WWARN’s Clinical Scientific Group, stresses the importance of early warning: “In the 1990s, the use of crude tools to define drug resistant P falciparum — clinical studies with short follow up and no molecular analysis — led to a significant delay before we realised how far chloroquine resistant malaria had progressed. We can’t afford to make the same mistake again, either with P vivax or artemisinin resistance.”

From the outset, WWARN planned a standardised approach for pooling and analysing clinical data from P falciparum studies. The challenge of defining drug resistance in P vivax is similar but requires adaptation to the biology of the parasite. Prof Price and Dr Ferreira, along with leading scientists in the field, are now developing protocols and automated efficacy analyses to create a global map of drug resistant P vivax on the WWARN Explorer. 

“In the last 60 years, less than 15% of published trials assessed P vivax drug efficacy. It is now crucial that researchers address this gap,” adds Prof Price. The malaria community is indeed rising to the challenge. Documentation of high-grade chloroquine resistance has already resulted in several countries changing national antimalarial guidelines to recommend ACT treatment for both P falciparum and P vivax.

The 12 countries of the Asia Pacific Malaria Elimination Network (APMEN) have identified P vivax as one of the greatest challenges for the elimination of malaria. WWARN is working with APMEN to facilitate studies that will gather better evidence with which to optimise the treatment of P vivax.

WWARN recently appointed Lígia Gonçalves as Liaison Scientist for Latin America, marking an intention to become more active in the region. Based in São Paulo with Dr Ferreira, Dr Gonçalves will coordinate WWARN activities in the region, which includes a P vivax hotspot in the Western Amazon, mostly in Brazil but extending into parts of Peru, Colombia and Venezuela.

Arguably the most common form of malaria with its unique biology, P vivax has the potential to be the one of the most formidable challenges in eliminating malaria. With its global collaborators, WWARN is building crucial resources and tools to identify and track P vivax antimalarial resistance.

¹ Guerra CA, Howes RE, Patil AP, Gething PW, Van Boeckel TP, et al. The International Limits and Population at Risk of Plasmodium vivax Transmission in 2009. PLoS Negl Trop Dis 2010; 4(8): e774. doi:10.1371/journal.pntd.0000774

² Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM. Vivax Malaria: Neglected and Not Benign. American Journal of Tropical Medicine and Hygiene 2007; 77 (Suppl 6): 79–87.
³ Carlton JM, Sina BJ, Adams JH. Why Is Plasmodium vivax a Neglected Tropical Disease? PLoS Negl Trop Dis 2011; 5(6): e1160.
⁴ Rieckmann KH, Davis DR, Hutton DC. Plasmodium vivax resistance to chloroquine? The Lancet1989; 2(8673):1183-4.
⁵ Price RN, Douglas NM, Anstey NM. New developments in Plasmodium vivax malaria: severe disease and the rise of chloroquine resistance. Current Opinion in Infectious Diseases. June 2009.
⁶ Douglas NM, NM Anstey, Angus BJ, Nosten F, Price RN. Artemisinin combination therapy for vivax malaria.  Lancet ID 2010; 10: 405–16.