Prevalence of CYP2D6 Genotypes and Predicted Phenotypes in a Cohort of Cambodians at High Risk for Infections with Plasmodium vivax

Abstract

Clinical failure of primaquine (PQ) has been demonstrated in people with CYP450 2D6 genetic polymorphisms that result in reduced or no enzyme activity. The distribution of CYP2D6 genotypes and predicted phenotypes in the Cambodian population is not well described. Surveys in other Asian countries have shown an approximate 50% prevalence of the reduced activity CYP2D6 allele *10, which could translate into increased risk of PQ radical cure failure and repeated relapses, making interruption of transmission and malaria elimination difficult to achieve. We determined CYP2D6 genotypes from 96 volunteers from Oddor Meanchey Province, Cambodia, an area endemic for Plasmodium vivax. We found a 54.2% frequency of the *10 allele, but in approximately half of our subjects, it was paired with a normal activity allele, either *1 or *2. The prevalence of *5, a null allele, was 9.4%. Overall predicted phenotype percentages were normal metabolizers, 46%; intermediate metabolizers, 52%; and poor metabolizers, 1%.

Figure 1.

Percentages of CYP2D6 genotypes and predicted phenotypes. Pie charts for each location show percentages of each CYP2D6 diplotype activity score: 0, 0.25, 0.5, 0.75, 1, 0.25, 1.5, and 2. Poor metabolizer (PM, activity score-A [AS-A] of 0) is shaded in white with black border, intermediate metabolizers (IMs) are shades of yellow depending on AS-A (0.25, 0.5, 0.75, and 1), and normal metabolizers (NMs) are shaded in blues depending on AS-A (1.25, 1.5, and 2), and ultrarapid metabolizers (UMs) are shaded in purple. Volunteers with allele duplications that led to dual phenotype interpretations are in patterned slivers. Listed adjacent to each AS-A sliver are the corresponding diplotypes with the number of subjects typed. Bar graph insets show overall percentages of PMs, IMs, NMs, and UMs. (A) The current Cambodia study in Oddor Meanchey Province, (B) data adapted from reference 11 at Ramathibodi Hospital in Bangkok, (C) data adapted from references and with Thai subjects taking part in clinical trials in Tak Province in northwestern Thailand, (D) data adapted from reference 13 with subjects from Hanoi, Vietnam, and (E) data adapted from reference 12 with Karen subjects living at the Thai–Myanmar border area in Tak Province.

Figure 2.

Pattern of vivax malaria recurrences in 44 Cambodian adults over an 18-week study period. Recurrences of malaria during the Study A active cohort are shown in which each primary case of malaria (all-species) was treated with dihydroartemisinin–piperaquine monotherapy and subsequent vivax recurrences with chloroquine. Each space represents 1 week. Black boxes represent Plasmodium vivax infections, gray boxes represent Plasmodium falciparum infections, and gray box with black border represents mixed P. falciparum/vivax. “E” stands for the one subject in this group who was enrolled in December, and thus had a shorter follow-up time. At conclusion of the active cohort, primaquine (PQ) radical cure was given. In PQ column, the predicted phenotype of that subject is listed: IM = intermediate metabolizer; NM = normal metabolizer; PM = poor metabolizer. The longer PQ boxes represent subjects who are glucose-6-phosphate dehydrogenase deficient and received 8 weeks of PQ. The diagonal line through one box represents a subject who did not complete the 2-week PQ course and dropped out. In the 6-month follow-up period, malaria recurrences are indicated, and each box represents 1 month.