The A581G Mutation in the Gene Encoding Plasmodium falciparum Dihydropteroate Synthetase Reduces the Effectiveness of Sulfadoxine-Pyrimethamine Preventive Therapy in Malawian Pregnant Women

Gutman, J., Kalilani, L., Taylor, S., Zhou, Z., Wiegand, R. E., Thwai, K. L., Mwandama, D., Khairallah, Carole, Madanitsa, M., Chaluluka, E., Dzinjalamala, F., Ali, D., Mathanga, D. P., Skarbinski, J., Shi, Y. P., Meshnick, S. and terKuile, Feiko ORCID: https://orcid.org/0000-0003-3663-5617 (2015) 'The A581G Mutation in the Gene Encoding Plasmodium falciparum Dihydropteroate Synthetase Reduces the Effectiveness of Sulfadoxine-Pyrimethamine Preventive Therapy in Malawian Pregnant Women'. Journal of Infectious Disease, Vol 211, Issue 12, pp. 1997-2005.

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Abstract

Background

The A581G mutation in the gene encoding Plasmodium falciparum dihydropteroate synthase (dhps), in combination with the quintuple mutant involving mutations in both dhps and the gene encoding dihydrofolate reductase (dhfr), the so-called sextuple mutant, has been associated with increased placental inflammation and decreased infant birth weight among women receiving intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) during pregnancy.

Methods

Between 2009 and 2011, delivering women without human immunodeficiency virus infection were enrolled in an observational study of IPTp-SP effectiveness in Malawi. Parasites were detected by polymerase chain reaction (PCR); positive samples were sequenced to genotype the dhfr and dhps loci. The presence of K540E in dhps was used as a marker for the quintuple mutant.

Results

Samples from 1809 women were analyzed by PCR; 220 (12%) were positive for P. falciparum. A total of 202 specimens were genotyped at codon 581 of dhps; 17 (8.4%) harbored the sextuple mutant. The sextuple mutant was associated with higher risks of patent infection in peripheral blood (adjusted prevalence ratio [aPR], 2.76; 95% confidence interval [CI], 1.82–4.18) and placental blood (aPR 3.28; 95% CI, 1.88–5.78) and higher parasite densities. Recent SP use was not associated with increased parasite densities or placental pathology overall and among women with parasites carrying dhps A581G.

Conclusions

IPTp-SP failed to inhibit parasite growth but did not exacerbate pathology among women infected with sextuple-mutant parasites. New interventions to prevent malaria during pregnancy are needed urgently.

Item Type:	Article
Additional Information:	Presented in part: 62nd Annual Meeting of the American Society of Tropical Medicine and Hygiene, Washington, D.C., 13–17 November 2013 [abstract 1268]; 6th MIM Pan-African Malaria Conference, Durban, South Africa, 6–11 October 2013. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Subjects:	QU Biochemistry > Genetics > QU 460 Genomics. Proteomics QX Parasitology > Protozoa > QX 135 Plasmodia WA Public Health > Health Problems of Special Population Groups > WA 310 Maternal welfare WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria WC Communicable Diseases > Tropical and Parasitic Diseases > WC 765 Prevention and control WQ Obstetrics > Pregnancy Complications > WQ 256 Infectious diseases
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):	https://doi.org/10.1093/infdis/jiu836
Depositing User:	Lynn Roberts-Maloney
Date Deposited:	30 Oct 2015 11:24
Last Modified:	07 Dec 2018 10:12
URI:	https://archive.lstmed.ac.uk/id/eprint/5385

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