Where chloroquine still works: the genetic make-up and susceptibility of Plasmodium vivax to chloroquine plus primaquine in Bhutan

Abstract

BackgroundBhutan has made substantial progress in reducing malaria incidence. The national guidelines recommend chloroquine (CQ) and primaquine (PQ) for radical cure of uncomplicated Plasmodium vivax, but the local efficacy has not been assessed. The impact of cases imported from India on the genetic make-up of the local vivax populations is currently unknown.MethodsPatients over 4 years of age with uncomplicated P. vivax mono-infection were enrolled into a clinical efficacy study and molecular survey. Study participants received a standard dose of CQ (25 mg/kg over 3 days) followed by weekly review until day 28. On day 28 a 14-day regimen of PQ (0.25 mg/kg/day) was commenced under direct observation. After day 42, patients were followed up monthly for a year. The primary and secondary endpoints were risk of treatment failure at day 28 and at 1 year. Parasite genotyping was undertaken at nine tandem repeat markers, and standard population genetic metrics were applied to examine population diversity and structure in infections thought to be acquired inside or outside of Bhutan.ResultsA total of 24 patients were enrolled in the clinical study between April 2013 and October 2015. Eight patients (33.3 %) were lost to follow-up in the first 6 months and another eight patients lost between 6 and 12 months. No (0/24) treatment failures occurred by day 28 and no (0/8) parasitaemia was detected following PQ treatment. Some 95.8 % (23/24) of patients were aparasitaemic by day 2. There were no haemolytic or serious events. Genotyping was undertaken on parasites from 12 autochthonous cases and 16 suspected imported cases. Diversity was high (HE 0.87 and 0.90) in both populations. There was no notable differentiation between the autochthonous and imported populations.ConclusionsCQ and PQ remains effective for radical cure of P. vivax in Bhutan. The genetic analyses indicate that imported infections are sustaining the local vivax population, with concomitant risk of introducing drug-resistant strains.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1320-8) contains supplementary material, which is available to authorized users.

Higher Complexity of Infection and Genetic Diversity of Plasmodium vivax Than Plasmodium falciparum Across All Malaria Transmission Zones of Papua New Guinea

“…30 This may be in part due to lower transmission areas having increasing proportions of imported infections, which reflects the MOI and diversity of the infection origin, 22,69,70 and this effect would be enhanced for P. vivax by the fact that relapse can occur 1-3 years after the primary infection. 71 The high complexity of infection for P. vivax regardless of parasite prevalence is also comparable to other studies where high infection complexity and diversity were found even with sustained low parasite prevalence such as in South America 33,72,73 and Sri Lanka. 74,75 Polyclonal infections are common in malariaendemic areas of different countries for both species and can arise from a single mosquito bite carrying multiple clones or from inoculation by different mosquitoes carrying single clones.…”

Molecular Epidemiology of P. vivax in Iran: High Diversity and Complex Sub-Structure Using Neutral Markers, but No Evidence of Y976F Mutation at pvmdr1

“…Cumulative data from different endemic settings indicates that transmission intensity and geographical isolation are important determinants shaping diversity and structure in P . vivax populations [23, 42–53]. In this respect, the trends observed here infer that the K 1 sub-population may reflect a low intensity and moderately isolated reservoir of infection.…”

“…In the K 2 sub-population, a moderately high I A S of 0.2 was observed, with no evidence of epidemic transmission dynamics. Relative to other studies applying the same markers, the K 2 sub-population was most comparable to the meso-endemic setting of West Timor ( I A S = 0.19) [50], and to Bhutan ( I A S = 0.16) [53]. Over 60% of the infections in the Bhutanese study were imported from India, but epidemiological and molecular evidence of local transmission was also demonstrated; the resulting LD was postulated to reflect the composite of local inbreeding and imported infection transmission dynamics.…”

“…Previous studies using the APMEN markers have demonstrated equivocally high diversity ( H E > 0.8) in a range of endemic settings including stable endemic settings in Indonesia [50] and Ethiopia [44], and the contrastingly low endemic, pre-elimination setting of Bhutan [53]. Similar to the situation in Iran, malaria elimination efforts in Bhutan have been undermined by cross-border malaria.…”

A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

“…Our results show that the historically oldest antimalarial substance (QN) has the greatest anti-cancer activity on dimerization. The effectiveness of these dimeric compounds in cancer models suggests that they should be investigated in other disorders where CQ has shown efficacy, including rheumatoid arthritis (33), malaria (34), prion disease (35) and viral disorders (36). …”