HIV-1 protease inhibitors and clinical isolates of Plasmodium: Greater activity against P. vivax than P. falciparum

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

^* To whom correspondence should be addressed. Email: bruce_russell{at}immunol.a-star.edu.sg.

	Abstract

Recent studies using laboratory clones have demonstrated that several antiretroviral protease inhibitors inhibit the growth of Plasmodium falciparum at concentrations that may be of clinical significance, especially during HIV-1 and malaria co-infection. Using clinical isolates, we now demonstrate the in vitro effectiveness of two HIV-1 aspartic protease inhibitors (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 Thai-Burmese border. The median IC₅₀ values of P. vivax to RTV and SQV were 2233nM (range; 732-7738nM) and 4230nM (range; 1326-8452nM) respectively, both within the therapeutic concentration range commonly found in patients treated with these PIs. RTV was four fold more effective at inhibiting P. vivax than P. falciparum compared to a two fold difference in SQV sensitivity. Increased Pfmdr1 copy number was present in 33% (3/9) of isolates and that of Pvmdr1 in 9% (2/22), but neither was associated with PI sensitivity. The inter-Plasmodium spp. 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 resident in areas where multi-drug resistant P. vivax or P. falciparum is found.