Antimalarial resistance: is vivax left behind?
Authors: Frédéric Ariey, Richard E Paul
Journal: The Lancet Infectious Diseases (2014)

Despite the necessary and major goal of containment of artemisinin resistance in Plasmodium falciparum,1WHOWorld Malaria Report 2013.http://www.who.int/malaria/publications/world_malaria_report_2013/en/Google Scholar, 2Dondorp AM Nosten F Poravuth Y et al.Artemisinin resistance in Plasmodium falciparum malaria.N Engl J Med. 2009; 361: 455-467Crossref PubMed Scopus (2520) Google Scholar, 3Ariey F Witkowski B Amaratunga C et al.A molecular marker of artemisinin-resistant Plasmodium falciparum malaria.Nature. 2014; 505: 50-55Crossref PubMed Scopus (1319) Google Scholar, 4Ashley EA Dhorda M Fairhurst RM et al.Spread of artemisinin resistance in Plasmodium falciparum malaria.N Engl J Med. 2014; 371: 411-423Crossref PubMed Scopus (1462) Google Scholar not all malaria is caused by P falciparum and outside of Africa the greatest malaria burden is attributable to Plasmodium vivax.1WHOWorld Malaria Report 2013.http://www.who.int/malaria/publications/world_malaria_report_2013/en/Google Scholar In The Lancet Infectious Diseases, Ric Price and colleagues5Price RN von Seidlein L Valecha N Nosten F Baird JK White NJ Prevalence of chloroquine-resistant Plasmodium vivax: a systematic review.Lancet Infect Dis. 2014; (published online Sept 9.)http://dx.doi.org/10.1016/S1473-3099(14)70855-2PubMed Google Scholar report a systematic review of the resistance of P vivax to chloroquine, examining published studies from 1960 to 2014. They conclude that chloroquine-resistant P vivax is now present across most of vivax-endemic regions. In addition to containing their high-quality analysis, their Article proposes a set of methods to explore resistance to antimalarial drugs in vivax malaria and highlights a surprising scarcity of data and methods available to work on P vivax. Many national control programmes are quite insensitive to concerns about vivax elimination in the face of the threat of falciparum. However, vivax, and the threat of resistance in that organism, needs to be considered in its own right. The P vivax lifecycle has important differences to that of P falciparum, which are expected to slow down the development of resistance to chloroquine.6Garnham PCC Malaria parasites and other haemosporidia. Blackwell, Oxford1966: 1132Google Scholar The parasite stays as latent forms (hypnozoites) in the liver, from which regular relapses can occur. Treatment with chloroquine alone cannot prevent relapses and hence the interest in hypnozoiticidal drugs such as primaquine. Vivax can produce gametocytes (stages that are infectious to mosquitoes) rapidly after emergence from the liver and invasion of the blood. This contrasts with falciparum, which not only does not have latent liver stages, but also takes a minimum of 10 days to generate infectious gametocytes in the blood.7Talman AM Domarle O McKenzie FE et al.Gametocytogenesis: the puberty of Plasmodium falciparum.Malar J. 2004; 3: 24Crossref PubMed Scopus (144) Google Scholar Both these lifecycle differences should expose vivax parasites to less selection pressure from drug treatment. However, vivax parasites might have been exposed to sublethal concentrations of chloroquine after treatment for falciparum malaria during coinfection; treatment of falciparum cases in Thailand was often followed by a clinical case of vivax malaria.8Looareesuwan S White NJ Chittamas S et al.High rate of Plasmodium vivax relapse following treatment of falciparum malaria in Thailand.Lancet. 1987; 2: 1052-1055Summary PubMed Scopus (120) Google Scholar Now that chloroquine is no longer the first-line drug for treating falciparum malaria, this collateral effect will be alleviated. Thus, the probability of the spread of resistance is expected to be lower for vivax than that for falciparum. Lower but not null, and this risk must be taken into account when considering vivax national treatment policies. Obstacles specific to addressing of P vivax chloroquine resistance need to be overcome: it is very difficult to do standardised in-vitro culture (and therefore have a reproducible phenotype of drug sensitivity); it is impossible to distinguish between relapse and recrudescence; we have little information on the population genetic structure of P vivax (gene flow, selfing rate, etc); and so far no molecular marker of resistance has been proposed for large epidemiological studies. The absence of molecular markers is, of course, a major obstacle for use in the assessment of the spread of resistance and, thus, optimisation of therapeutic strategies. A key step for the identification of a molecular marker is development of a clear-cut phenotype of resistance. Price and colleagues propose parasite clearance time as a proxy to study antimalarial resistance. Indeed, accurate characterisation of this clearance time would enable differentiation of clinical resistance from relapse.9Pukrittayakamee S Imwong M Looareesuwan S et al.Therapeutic responses to antimalarial and antibacterial drugs in vivax malaria.Acta Trop. 2004; 89: 351-356Crossref PubMed Scopus (72) Google Scholar There has been much conjecture on whether P vivax and P falciparum affect one another and thus whether targeting one species might lead to the emergence of the other.10Sattabongkot J Tsuboi T Zollner GE et al.Plasmodium vivax transmission: chances for control?.Trends Parasitol. 2004; 20: 192-198Summary Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 11Snounou G White NJ The co-existence of Plasmodium: sidelights from falciparum and vivax malaria in Thailand.Trends Parasitol. 2004; 20: 333-339Summary Full Text Full Text PDF PubMed Scopus (102) Google Scholar Focus is now on the fight against P falciparum, which seems to have had little effect on the vivax burden.1WHOWorld Malaria Report 2013.http://www.who.int/malaria/publications/world_malaria_report_2013/en/Google Scholar For public health care, vivax malaria must be considered as a disease distinct from falciparum malaria,12Vogel G The forgotten malaria.Science. 2013; 342: 684-687Crossref PubMed Scopus (13) Google Scholar, 13Cotter C Sturrock HJ Hsiang MS et al.The changing epidemiology of malaria elimination: new strategies for new challenges.Lancet. 2013; 382: 900-911Summary Full Text Full Text PDF PubMed Scopus (432) Google Scholar and will benefit from a dedicated control programme strategy. Malaria elimination will not be able to ignore vivax, which should no longer be the least of our worries. We declare no competing interests. Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysisHeterogeneity of study design and analysis has confounded global surveillance of chloroquine-resistant P vivax, which is now present across most countries endemic for P vivax. Improved methods for monitoring of drug resistance are needed to inform antimalarial policy in these regions. Full-Text PDF Open Access