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Antimicrobial Agents and Chemotherapy, July 2008, p. 2435-2441, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.00169-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Stronger Activity of Human Immunodeficiency Virus Type 1 Protease Inhibitors against Clinical Isolates of Plasmodium vivax than against Those of P. falciparum

U. Lek-Uthai,^1, R. Suwanarusk,^2,3, R. Ruengweerayut,⁴ T. S. Skinner-Adams,⁵ F. Nosten,^6,7,8 D. L. Gardiner,⁵ P. Boonma,¹ K. A. Piera,² K. T. Andrews,⁵ B. MacHunter,² J. S. McCarthy,⁵ N. M. Anstey,² R. N. Price,^2,7 and B. Russell^2,3*

Department of Parasitology, Faculty of Public Health, Mahidol University, Bangkok, Thailand,¹ International Health Program, Infectious Diseases Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia,² Laboratory for Malaria Immunobiology, Singapore Immunology Network, Biopolis, Agency for Science Technology and Research (A*STAR), Singapore, Singapore,³ Mae Sod Hospital, Tak, Thailand,⁴ Queensland Institute of Medical Research and Australian Centre for International and Tropical Health and Nutrition, Brisbane, Australia,⁵ Shoklo Malaria Research Unit, Mae Sod, Thailand,⁶ Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford OX3 7LJ, United Kingdom,⁷ Faculty of Tropical Medicine, Mahidol University, Rajvithi Road, Bangkok, Thailand⁸

Received 6 February 2008/ Returned for modification 26 March 2008/ Accepted 22 April 2008

Recent studies using laboratory clones have demonstrated that several antiretroviral protease inhibitors (PIs) inhibit the growth of Plasmodium falciparum at concentrations that may be of clinical significance, especially during human immunodeficiency virus type 1 (HIV-1) and malaria coinfection. Using clinical isolates, we now demonstrate the in vitro effectiveness of two HIV-1 aspartic PIs, saquinavir (SQV) and ritonavir (RTV), against P. vivax (n = 30) and P. falciparum (n = 20) from populations subjected to high levels of mefloquine and artesunate pressure on the Thailand-Myanmar border. The median 50% inhibitory concentration values of P. vivax to RTV and SQV were 2,233 nM (range, 732 to 7,738 nM) and 4,230 nM (range, 1,326 to 8,452 nM), respectively, both within the therapeutic concentration range commonly found for patients treated with these PIs. RTV was fourfold more effective at inhibiting P. vivax than it was at inhibiting P. falciparum, compared to a twofold difference in SQV sensitivity. An increased P. falciparum mdr1 copy number was present in 33% (3/9) of isolates and that of P. vivax mdr1 was present in 9% of isolates (2/22), but neither was associated with PI sensitivity. The inter-Plasmodium sp. variations in PI sensitivity indicate key differences between P. vivax and P. falciparum. PI-containing antiretroviral regimens may demonstrate prophylactic activity against both vivax and falciparum malaria in HIV-infected patients who reside in areas where multidrug-resistant P. vivax or P. falciparum is found.

Published ahead of print on 28 April 2008.

Equal contribution authors.