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Effects of Host Genetic Polymorphisms on the Efficacy of the Radical Cure Malaria Drug Primaquine

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  • 1 National Institute of Malaria Research, New Delhi, India;
  • | 2 Molecular Medicine, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
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ABSTRACT.

Malaria is a major cause of death in low-income countries. Malaria relapses are caused by Plasmodium vivax–induced latent liver stage hypnozoites, and relapses contribute significantly to the total disease burden. The goal of malaria elimination is threatened in countries where P. vivax is endemic and relapses remain a key aspect of concern. Targeting of the hypnozoites is crucial for radical cure and this is achieved by primaquine (PQ). In addition to its anti-hypnozoite effects, PQ also possesses gametocidal activity against all malaria causing Plasmodium species and is hence a useful tool to curtail malaria transmission. It is well known that host glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with hemolysis after treatment with PQ. Multiple other host polymorphisms impact on PQ metabolism, potentially affecting drug efficacy. Being a prodrug, PQ requires host factors cytochrome P450 2D6 (CYP2D6), cytochrome P450 NADPH: oxidoreductase (CPR) and monoamine oxidase (MAO) for its metabolism and conversion to active form. The efficacy of PQ in the host is therefore dependent on genetic polymorphisms of these three host genes. The efficacy of PQ is important for clearing reservoirs of P. vivax infection. Here, we have analyzed the known spectrum of genetic polymorphisms for host genes that enable PQ metabolism. It is vital to delineate the polymorphisms that determine the ultimate efficacy of PQ for formulating better malaria elimination strategies in countries with severe malaria burden. Thus population-based studies of these gene variants will provide new insights into the role of host genetics on PQ treatment outcomes.

Author Notes

Address correspondence to Amit Sharma, National Institute of Malaria Research, Group Leader, Molecular Medicine, International Centre for Genetic Engineering and Biotechnology, Sector 8, Dwarka, New Delhi, Delhi 110077, India. E-mail: directornimr@gmail.com

Authors’ addresses: Minu Nain and Mradul Mohan, National Institute of Malaria Research, New Delhi, India, E-mails: minu345r@gmail.com and mradul_mohan@yahoo.com. Amit Sharma, Molecular Medicine, International Centre for Genetic Engineering and Biotechnology, New Delhi, India, E-mail: directornimr@gmail.com.

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