Primaquine ineligibility in anti-relapse therapy of Plasmodium vivax malaria: the problem of G6PD deficiency and cytochrome P-450 2D6 polymorphisms

Abstract

The hypnozoite reservoir of Plasmodium vivax represents both the greatest obstacle and opportunity for ultimately eradicating this species. It is silent and cannot be diagnosed until it awakens and provokes a clinical attack with attendant morbidity, risk of mortality, and opportunities for onward transmission. The only licensed drug that kills hypnozoites is primaquine, which attacks the hypnozoite reservoir but imposes serious obstacles in doing so—at hypnozoitocidal doses, it invariably causes a threatening acute haemolytic anaemia in patients having an inborn deficiency in glucose-6-phosphate dehydrogenase (G6PD), affecting about 8% of people living in malaria endemic nations. That problem excludes a large number of people from safe and effective treatment of the latent stage of vivax malaria: the G6PD deficient, pregnant or lactating women, and young infants. These groups were estimated to comprise 14.3% of populations resident in the 95 countries with endemic vivax malaria. Another important obstacle regarding primaquine in the business of killing hypnozoites is its apparent metabolism to an active metabolite exclusively via cytochrome P-450 isozyme 2D6 (CYP2D6). Natural polymorphisms of this allele create genotypes expressing impaired enzymes that occur in over 20% of people living in Southeast Asia, where more than half of P. vivax infections occur globally. Taken together, the estimated frequencies of these primaquine ineligibles due to G6PD toxicity or impaired CYP2D6 activity composed over 35% of the populations at risk of vivax malaria. Much more detailed work is needed to refine these estimates, derive probabilities of error for them, and improve their ethnographic granularity in order to inform control and elimination strategy and tactics.

Genetic Polymorphism of human CYP2D6 gene coding region from vivax malaria cases in Yunnan Province, China

“…Its CDS is 1338~1491bp in length and encodes 446 497 amino acids. The heterogeneity of CYP2D6 monooxygenase activity varies from complete dysfunction to ultra-rapid enzyme metabolism, depending on the various genotypes of CYP2D6 [14]. Among the 150 identi ed alleles, multiple mutations such as CYP2D6*3, CYP2D6*4, CYP2D6*5 and CYP2D6*6 are considered to contribute to compromised CYP2D6 enzyme activity [32,33].…”

“…Studies have found that the heterogeneity of CYP2D6 activity is predominantly governed by its genetic variation [13], and that decreased CYP2D6 isoenzyme activity caused by genetic polymorphisms would obstruct the generation of 5-hydroxy-primaquine, making large doses or repeated use of primaquine necessary to compensate for the declined e cacy of primaquine. Meanwhile, primaquine can cause life threatening hemolysis in patients with Glucose-6-Phosphate Dehydrogenase (G6PD) de ciency, subsequently in icting dual hazards, including low e cacy of anti-relapse and acute hemolysis, on the patients [9,[14][15]. So the patient's G6PD gene type should be identi ed by care workers prior to receiving anti-relapse treatment of vivax malaria and based on our and others' ndings, it should be considered to test for CYP2D6 genotype and predicted enzyme activity as well [14,[16][17].…”

“…Meanwhile, primaquine can cause life threatening hemolysis in patients with Glucose-6-Phosphate Dehydrogenase (G6PD) de ciency, subsequently in icting dual hazards, including low e cacy of anti-relapse and acute hemolysis, on the patients [9,[14][15]. So the patient's G6PD gene type should be identi ed by care workers prior to receiving anti-relapse treatment of vivax malaria and based on our and others' ndings, it should be considered to test for CYP2D6 genotype and predicted enzyme activity as well [14,[16][17].…”

Challenges in the Control and Elimination of Plasmodium vivax Malaria

“…We do not yet know the extent of this problem with regard to the frequencies of CYP2D6 alleles associated with PQ therapeutic failure, but the significantly impaired CYP2D6 *10 allele (a particular genetic variant of CYP2D6 gene) is relatively common among Southeast Asians, at about 35% frequency [44]. It may be that many Asians will be unable to adequately metabolize PQ and achieve successful radical cure [45].…”

Genetic Polymorphism of Cyp2d6 Gene Coding Region and Association Between Them With Vivax Malaria Relapse in Yunnan Province, China

“…Studies have found that the heterogeneity of CYP2D6 activity is predominantly governed by its genetic variation [13], and that decreased CYP2D6 isoenzyme activity caused by genetic polymorphisms would obstruct the generation of 5-hydroxy-primaquine, making large doses or repeated use of primaquine necessary to compensate for the declined e cacy of primaquine. Meanwhile, primaquine can cause life threatening hemolysis in patients with Glucose-6-Phosphate Dehydrogenase (G6PD) de ciency, subsequently in icting dual hazards, including low e cacy of anti-relapse and acute hemolysis, on the patients [9,[14][15]. So the patient's G6PD genotype should be identi ed by care workers prior to receiving anti-relapse treatment of vivax malaria and based on our and others' ndings, it should be considered to test for CYP2D6 genotype and predicted enzyme activity as well [14,[16][17].…”