Therapeutic Responses of Plasmodium vivax Malaria to Chloroquine and Primaquine Treatment in Northeastern Myanmar

Abstract

h Chloroquine-primaquine (CQ-PQ) continues to be the frontline therapy for radical cure of Plasmodium vivax malaria. Emergence of CQ-resistant (CQR) P. vivax parasites requires a shift to artemisinin combination therapies (ACTs), which imposes a significant financial, logistical, and safety burden. Monitoring the therapeutic efficacy of CQ is thus important. Here, we evaluated the therapeutic efficacy of CQ-PQ for P. vivax malaria in northeast Myanmar. We recruited 587 patients with P. vivax monoinfection attending local malaria clinics during 2012 to 2013. These patients received three daily doses of CQ at a total dose of 24 mg of base/kg of body weight and an 8-day PQ treatment (0.375 mg/kg/day) commencing at the same time as the first CQ dose. Of the 401 patients who finished the 28-day follow-up, the cumulative incidence of recurrent parasitemia was 5.20% (95% confidence interval [CI], 3.04% to 7.36%). Among 361 (61%) patients finishing a 42-day follow-up, the cumulative incidence of recurrent blood-stage infection reached 7.98% (95% CI, 5.20% to 10.76%). The cumulative risk of gametocyte carriage at days 28 and 42 was 2.21% (95% CI, 0.78% to 3.64%) and 3.93% (95% CI, 1.94% to 5.92%), respectively. Interestingly, for all 15 patients with recurrent gametocytemia, this was associated with concurrent asexual stages. Genotyping of recurrent parasites at the merozoite surface protein 3␣ gene locus from 12 patients with recurrent parasitemia within 28 days revealed that 10 of these were the same genotype as at day 0, suggesting recrudescence or relapse. Similar studies in 70 patients in the same area in 2007 showed no recurrent parasitemias within 28 days. The sensitivity to chloroquine of P. vivax in northeastern Myanmar may be deteriorating. Plasmodium vivax has the widest geographical distribution among the four human-infecting species, stretching from the Korean Peninsula to northern Argentina. An estimated 2.48 billion people lived at risk of P. vivax malaria in 2010, of which a large majority was in Central and Southeast Asia (1). Each year, P. vivax infects an estimated 130 to 391 million people (2, 3). Past eradication campaigns have witnessed the resilience of vivax malaria to control efforts. In areas where P. vivax and P. falciparum are coendemic, intensified control efforts have led to major changes in malaria epidemiology, and the problem of vivax malaria has become more prominent (4). With emerging global interests in malaria elimination (5), many nations in which vivax malaria is endemic will inevitably face greater challenges for the control and elimination of this parasite. For example, among the 34 malariaeliminating countries, 26 have malaria burdens mainly or solely due to P. vivax (4).The relative resilience of vivax malaria may be attributed to the formation of dormant hypnozoites in the livers of patients. These hypnozoites awaken in the weeks and months following a primary attack and cause new attacks, called relapses. Thus, treatment of P. vivax malaria requires drugs that target both the ...

Dynamics of Plasmodium vivax populations in border areas of the Greater Mekong sub-region during malaria elimination

“…Moreover, the parasite populations studied here have undergone apparent population bottlenecks, suggesting population reduction, or limited vectors or human movement within the defined geographic areas. At the CMB, the epidemic malaria transmission documented in the camps for internally displaced people and surrounding villages in 2013 and the detected reduction of effective population size may result from expansion of certain parasite isolates such as those that are resistant to the frontline treatment [77,78]. Interestingly, the TMB 2015 samples were quite genetically distinct, and even differed considerably from the 2012 parasite from the same region, which may suggest population replacement.…”

Seasonal dynamics and microgeographical spatial heterogeneity of malaria along the China–Myanmar border

“…Finally, the increase of malaria incidence in these villages in recent years accompanied the increase of Pv/Pf ratio, indicating increased transmission of vivax malaria in these villages. The emergence of drug-resistant parasites in this region (Yuan et al, 2014) and less stringent uses of primaquine for radical care because the presence of a significant portion of the local ethnic population with glucose-6-phosphate dehydrogenase deficiency (Li et al, 2015) may be partially responsible for the increased vivax cases in this region, which underlines the urgency for implementation of more effective P. vivax control measures (Waltmann et al, 2015; Zhou et al, 2014a). Furthermore, current treatment of P. falciparum was effective, which may contribute to the decrease in falciparum malaria, similar to what has been found in Thailand (Phimpraphi et al, 2008; Wang et al, 2015; Zhou et al, 2005).…”

Limited genetic diversity in the PvK12 Kelch protein in Plasmodium vivax isolates from Southeast Asia

“…In the sample collection areas of this study, CQ/primaquine remains as the primary treatment of vivax malaria with high efficacy. There were only sporadic reports of clinical CQ resistance in P. vivax in western Thailand [51] and the Thai–Myanmar border [52], though recent studies in northeast Myanmar suggested deteriorating CQ efficacy for treatment of P. vivax malaria [53]. …”