Rosiglitazone for Adjunctive Treatment of Malaria
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Synopsis: Rosiglitazone was studied in a randomized, double-blind, placebo-controlled trial for adjunctive therapy of Plasmodium falciparum malaria in Thailand. Seventy patients received rosiglitazone 4 mg BID for four days and 70 patients received placebo. All patients received standard antimalarial therapy with atovaquone/proguanil. For the rosiglitazone-treated patients, parasite clearance from the peripheral blood was enhanced, and reduced inflammatory responses to infection were demonstrated. Rosiglitazone was well tolerated.
Source: Boggild AK, et al. Use of peroxisome proliferator-activated receptor gamma agonists as adjunctive treatment for Plasmodium falciparum malaria: A randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2009;49:841-849.
In this randomized, double-blind, placebo-controlled trial, 140 patients with uncomplicated falciparum malaria were randomized to rosiglitazone 4 mg BID for four days vs. placebo, in addition to atovaquone/proguanil. In the rosiglitazone-treated patients, parasite clearance from the peripheral blood was significantly enhanced vs. placebo (19 hours vs. 24.6 hour). In addition, levels of pro-inflammatory cytokines (IL-6 and monocyte chemoattractant protein-1) were significantly lower in the group treated with rosiglitazone. No ICU admissions or deaths were observed in either group. Rosiglitazone was well tolerated, with no significant differences in adverse effects observed between the two groups.
Commentary
Malaria due to P. falciparum is a major cause of global morbidity and mortality and is especially lethal in young children and non-immune individuals, including travelers to malaria-endemic areas. The pathogenesis of falciparum malaria includes a number of factors, including: 1) the high level of parasitemia seen in falciparum vs. other species of malaria, 2) sequestration of parasitized erythrocytes within organ microvasculature due to the abnormal rheologic characteristics of the parasitized RBCs, and 3) the dysregulated inflammatory response in the host contributing to immune-mediated tissue injury and further up-regulation of vascular receptors involved in erythrocyte sequestration.
The innate immune system has been shown to be the critical component of the inflammatory response to malaria infection. Pattern-recognition receptors (including Toll-like receptors and scavenger receptors) sense microbial molecules and activate pro-inflammatory responses, including release of proinflammatory cytokines such as TNF-alpha. CD36 has been shown to mediate macrophage clearance of P. falciparum-parasitized RBCs and contributes to survival in rodent models of malaria.1 Since CD36 transcription is regulated by the nuclear receptor heterodimer peroxisome proliferator-activated receptor gamma (PPAR-gamma)-retinoic X receptor,2 Boggild et al postulated that currently available PPAR-gamma antagonists (used for treatment of diabetes) might be beneficial as adjunctive therapy of malaria by their immunomodulatory effects on CD36, Toll-like receptors, and other pathways within the innate immune system.
The clinical trial reported in this paper is an important pilot study with potentially significant clinical implications for the use of PPAR-gamma agonists in the adjunctive treatment of malaria (and potentially other infections). An editorial accompanying this paper in the same issue of Clinical Infectious Diseases points out some of the sad realities and difficulties associated with performing a follow-up trial of rosiglitazone (or any other agent) in patients with severe falciparum malaria in the developing world. This is, unfortunately, the subset of patients for whom better treatment is so urgently needed.3
References
- Patel SN, et al. Disruption of CD36 impairs cytokine response to Plasmodium falciparum GP1 and confers susceptibility to severe and fatal malaria in vivo. J Immunol. 2007:178: 3954-3961.
- Serghides L, et al. Peroxisome proliferator activated receptor gamma-retinoid X receptor agonists increase CD36-dependent phagocytosis of Plasmodium-falciparum-parasitized erythrocytes and decrease malaria-induced TNF-alpha secretion by monocytes/macrophages. J Immunol. 2001;166:6742-6748.
- Shanks GD. Are studies on severe malaria still possible? Clin Infect Dis. 2009;850-851.
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