Protease inhibitors used to treat HIV-1 infection may also be effective for treatment or prevention of malaria, according to a study published in the December 1 issue of The Journal of Infectious Diseases, available online.
The study found protease inhibitors inhibited the growth of P. falciparum, the malaria parasite that causes most disease. These findings may also expose a previously unexplored vulnerability in the parasite that could lead to a new class of anti-malarial drug. While the effects of such drugs on co-infection need to be investigated, the study’s findings may be especially significant in sub-Saharan Africa and other areas of the developing world where there are high rates of HIV and malaria co-infection.
Scientists from the Queensland Institute of Medical Research tested the effects of the protease inhibitors saquinavir, ritonavir, nelfinavir, amprenavir, and indinavir, as well as the non-nucleoside reverse transcriptase inhibitor nevirapine, on a drug-resistant line of P. falciparum. Saquinavir, ritonavir, and indinavir all inhibited parasite growth in vitro at levels routinely achieved in human patients, with saquinavir and ritonavir showing the most potent effect on the parasite. Saquinavir was most effective in the study and was equally effective on chloroquine-sensitive and -resistant parasite lines, while nelfinavir and amprenavir did not demonstrate anti-malarial activity. The research builds on a previous study that demonstrated antiretroviral agents can reduce the adhesion of P. falciparum-infected erythrocytes to endothelial surfaces.
The authors believe that the antiretroviral protease inhibitors attack the malaria parasite in ways that current antimalarial treatments do not. While the mode of antimalarial action of the drugs was not uncovered in the study, the authors hypothesize that the antiretrovirals inhibit an aspartyl protease, which helps the parasite digest hemoglobin and is located on the food vacuole of the parasite. Further investigation may not only provide a better knowledge of how to treat co-infected patients with protease inhibitors, but could also lead to a new type of malaria drug that would target the parasite in novel ways.
The World Health Organization’s “3 by 5” program intends to treat three million HIV-infected people, primarily in the developing world, with antiretrovirals by the year 2005. The authors suggest that individuals treated under programs such as this may also gain an anti-parasitic benefit. At the same time, they acknowledge that their study does not address the concern that protease inhibitors may have immunological side effects that could hamper parasite removal.
The authors warn that the clinical application of their novel findings should be made with caution. They are currently carrying out further studies on the interactions of protease inhibitors and current antimalarial agents in order to optimize the drugs’ beneficial effects on both HIV and malaria infections.