Resistance to Chloroquine Unhinges Vivax Malaria Therapeutics

Baird, J. Kevin

doi:10.1128/aac.01296-10

Cited by 57 publications

(58 citation statements)

References 23 publications

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“…3 Plasmodium vivax resistance to CQ in vivo, defined as the persistence of parasites in the blood despite adequate blood levels of CQ and its main metabolite desethylchloroquine, 4 has already reached alarming prevalence rates in Indonesia, East Timor, and Papua New Guinea, and is currently emerging in several countries across southern and Southeast Asia, the Middle East, and the Americas. 3,5 However, only a small proportion of clinical trials of antimalarial drugs worldwide have assessed their efficacy against P. vivax.…”

Section: 2mentioning

confidence: 99%

Single-Nucleotide Polymorphism and Copy Number Variation of the Multidrug Resistance-1 Locus of Plasmodium vivax: Local and Global Patterns

Vargas-Rodríguez

Bastos²,

Menezes³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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Abstract. Emerging resistance to chloroquine (CQ) poses a major challenge for Plasmodium vivax malaria control, and nucleotide substitutions and copy number variation in the P. vivax multidrug resistance 1 ( pvmdr-1) locus, which encodes a digestive vacuole membrane transporter, may modulate this phenotype. We describe patterns of genetic variation in pvmdr-1 alleles from Acre and Amazonas in northwestern Brazil, and compare then with those reported in other malaria-endemic regions. The pvmdr-1 mutation Y976F, which is associated with CQ resistance in Southeast Asia and Oceania, remains rare in northwestern Brazil (1.8%) and its prevalence mirrors that of CQ resistance worldwide. Gene amplification of pvmdr-1, which is associated with mefloquine resistance but increased susceptibility to CQ, remains relatively rare in northwestern Brazil (0.9%) and globally ( 4%), but became common ( 10%) in Tak Province, Thailand, possibly because of drug-mediated selection. The global database we have assembled provides a baseline for further studies of genetic variation in pvmdr-1 and drug resistance in P. vivax malaria.

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Section: 2mentioning

confidence: 99%

Single-Nucleotide Polymorphism and Copy Number Variation of the Multidrug Resistance-1 Locus of Plasmodium vivax: Local and Global Patterns

Vargas-Rodríguez

Bastos²,

Menezes³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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“…However, mounting evidence indicates that resistance to CQ by the asexual blood-stage P. vivax is spreading through Southeast Asia (6). This problem threatens the availability of a safe and effective radical cure against vivax malaria (7).…”

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confidence: 99%

“…While P. vivax CQ resistance has since been documented in many regions (6,13), the problem appeared to be most serious in Indonesia, which led to the change to artemisinin combination therapy (ACT) with PQ for P. vivax therapy in 2009 (7). Despite the ample evidence of CQR parasites in the vast range of P. vivax malaria, the mechanisms of resistance remain unknown and appear to be different from that for CQR P. falciparum (6,14).…”

mentioning

confidence: 99%

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

Yuan

Wang

Parker

et al. 2015

Antimicrob Agents Chemother

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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 ...

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“…Historic examples of likely drug-drug interactions have occurred between pamaquine (a PQ precursor) and mepacrine (structurally similar to CQ) impacting safety, and between quinine and CQ impacting efficacy against relapse. 126 DRUG DEVELOPMENT FOR P. VIVAX Outside of Africa, P. falciparum and P. vivax commonly occur together; mixed infection is very common, and many patients with falciparum malaria harbor P. vivax hypnozoites that commonly cause relapse 3-8 weeks after the acute illness. The emergence of CQ resistance in many endemic regions, along with > 50% prevalence of hypnozoites of P. vivax in patients diagnosed and treated for P. falciparum, provides a strong rationale for a unified policy for therapy of uncomplicated malaria of any species.…”

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confidence: 99%