CYP2D6 polymorphism and the risk of Plasmodium vivax recurrences following chloroquine-primaquine treatment in Brazil and Colombia

• Grant number: 20/03611-4
• Support type: Regular Research Grants
• Duration: February 01, 2021 - January 31, 2023
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Cooperation agreement: Universidad de Antioquia (UdeA)
• Principal researcher: Marcelo Urbano Ferreira
• Grantee: Marcelo Urbano Ferreira
• Principal researcher abroad: Tatiana María Lopera Mesa
• Institution abroad: Universidad de Antioquia (UdeA), Colombia
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Despite the major recent progress towards malaria elimination in Latin America and the Caribbean, focal transmission persists mostly across the Amazon Basin and the Pacific and Atlantic Coast of Colombia and Central America, where Plasmodium vivax accounts for nearly 80% if the cases. One distinctive feature of P. vivax associated with its increased resilience is the ability to stay in the liver as a dormant stage, the hypnozoite, following a primary infection and reactivate over the next weeks or months, causing relapses. Primaquine (PQ), the only widely available hypnozoitocidal drug, is essentially an inactive pro-drug that requires biotransformation by the cytochrome P450 (CYP) enzyme CYP2D6 for its antirelapse effect. Here we hypothesize that individuals with low-activity CYP2D6 variants who are treated with chloroquine (CQ)-PQ regimens are at increased risk of P. vivax relapses in major malaria hotspots of South America, with major public health implications. To test this hypothesis, we will genotype CYP2D6 variants in: (a) participants in an ongoing cohort of 2,000 malaria-exposed individuals in Juruá Valley, in the Amazon Basin of Brazil, and (b) participants of a therapeutic efficacy study of supervised CQ-PQ treatment on the Caribbean Coast of Colombia that showed a P. vivax recurrence rate of 24.1% over 6 months of follow-up. The primary outcomes are: (a) the incidence of laboratory-confirmed clinical vivax malaria in subjects with varying CYP2D6 activity levels over two years of follow-up in Brazil and (b) the time of the first recurrent vivax malaria episode confirmed by microscopy, among study subjects with varying CYP2D6 activity levels, over 180 days of follow-up after supervised CQ-PQ therapy in Colombia. (AU)