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Molecular surveillance for drug-resistant Plasmodium falciparum in clinical and subclinical populations from three border regions of Burma/Myanmar: cross-sectional data and a systematic review of resistance studies

Tyler Brown12, Linda S Smith2, Eh Kalu Shwe Oo3, Kum Shawng4, Thomas J Lee26, David Sullivan5, Chris Beyrer7 and Adam K Richards28*

Author Affiliations

1 Johns Hopkins University School of Medicine, Broadway Research Building, 733 N. Broadway, Suite 147, Baltimore, MD, 21205, USA

2 Global Health Access Program, 2550 Ninth Street, Ste 111, Berkeley, CA, 94710, USA

3 Karen Department of Health and Welfare, PO Box 189, Mae Sot, Tak, 63110, Thailand

4 Office of the Director of the Health Department, Kachin Baptist Convention 135/Shan Su (South), Myitkyina, Kachin State, Myanmar

5 Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health 615 North Wolfe St, Room E5628, Baltimore, MD, 21205, USA

6 School of Medicine, University of California at Los Angeles, 924 Westwood Blvd, Suite 300, Los Angeles, CA, 90024, USA

7 Department of Epidemiology Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Suite E7152, Baltimore, MD, 21205, USA

8 Department of General Internal Medicine and Health Services Research, University of California at Los Angeles, 911 Broxton Ave, Los Angeles, CA, 90025, USA

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Malaria Journal 2012, 11:333  doi:10.1186/1475-2875-11-333

Published: 19 September 2012

Abstract

Background

Confirmation of artemisinin-delayed parasite clearance in Plasmodium falciparum along the Thai-Myanmar border has inspired a global response to contain and monitor drug resistance to avert the disastrous consequences of a potential spread to Africa. However, resistance data from Myanmar are sparse, particularly from high-risk areas where limited health services and decades of displacement create conditions for resistance to spread. Subclinical infections may represent an important reservoir for resistance genes that confer a fitness disadvantage relative to wild-type alleles. This study estimates the prevalence of resistance genotypes in three previously unstudied remote populations in Myanmar and tests the a priori hypothesis that resistance gene prevalence would be higher among isolates collected from subclinical infections than isolates collected from febrile clinical patients. A systematic review of resistance studies is provided for context.

Methods

Community health workers in Karen and Kachin States and an area spanning the Indo-Myanmar border collected dried blood spots from 988 febrile clinical patients and 4,591 villagers with subclinical infection participating in routine prevalence surveys. Samples positive for P. falciparum 18 s ribosomal RNA by real-time PCR were genotyped for P. falciparum multidrug resistance protein (pfmdr1) copy number and the pfcrt K76T polymorphism using multiplex real-time PCR.

Results

Pfmdr1 copy number increase and the pfcrt K76 polymorphism were determined for 173 and 269 isolates, respectively. Mean pfmdr1 copy number was 1.2 (range: 0.7 to 3.7). Pfmdr1 copy number increase was present in 17.5%, 9.6% and 11.1% of isolates from Karen and Kachin States and the Indo-Myanmar border, respectively. Pfmdr1 amplification was more prevalent in subclinical isolates (20.3%) than clinical isolates (6.4%, odds ratio 3.7, 95% confidence interval 1.1 - 12.5). Pfcrt K76T prevalence ranged from 90-100%.

Conclusions

Community health workers can contribute to molecular surveillance of drug resistance in remote areas of Myanmar. Marginal and displaced populations under-represented among previous resistance investigations can and should be included in resistance surveillance efforts, particularly once genetic markers of artemisinin-delayed parasite clearance are identified. Subclinical infections may contribute to the epidemiology of drug resistance, but determination of gene amplification from desiccated filter samples requires further validation when DNA concentration is low.

Keywords:
Malaria; Plasmodium falciparum; Artemisinin resistance; Genetic; Subclinical infection; Conflict; Myanmar