Dataset Information

Association of Impaired Cytochrome P450 2D6 Activity Genotype and Phenotype With Therapeutic Efficacy of Primaquine Treatment for Latent Plasmodium vivax Malaria.

ABSTRACT:

Importance

Latent hepatic Plasmodium vivax hypnozoites provoke repeated clinical attacks called relapses. Only primaquine phosphate kills hypnozoites, and its therapeutic activity may depend on naturally polymorphic cytochrome P450 2D6 isotype (CYP2D6) activity.

Objective

To examine the association of impaired CYP2D6 genotypes and CYP2D6 metabolic phenotypes with therapeutic failure of directly observed high-dose primaquine treatment for P vivax malaria relapse.

Design, setting, and participants

Nested case-control study of patients who, in July 2014, completed a randomized clinical trial of directly observed primaquine treatment for radical cure of acute P vivax malaria in an area of Indonesia where reinfection during 1 year of posttreatment follow-up was improbable. A total of 177 of 180 patients with P vivax malaria completed the clinical trial of primaquine treatment to prevent relapse; 151 were eligible for recruitment as controls. After screening, 59 potential control individuals (no relapse) and 26 potential case patients (relapse) were considered, and 36 controls and 21 cases were enrolled.

Exposures

Cases and controls were exposed to P vivax malaria and primaquine therapy but had variable exposure to the enzymatic activity of CYP2D6, classified as impaired by a genotype-determined qualitative phenotype (poor or intermediate), genotype-determined activity score less than 1.5, or a log of the 24-hour pooled urine dextromethorphan-dextrorphan metabolic ratio greater than -1.0.

Main outcomes and measures

Unadjusted odds ratios (ORs) of relapse with impaired CYP2D6 metabolism determined by genotype or measured by urinary dextromethorphan-dextrorphan metabolic ratio.

Results

Among the 21 cases (mean [SD] age, 30.5 [6.3] years; all male) and 36 controls (mean [SD] age, 29.0 [3.6] years; all male), 6 CYP2D6 alleles (*1, *2, *4, *5, *10, and *41) occurred as 12 distinct genotypes, with model activity scores ranging from 0.0 to 2.0. Among 32 patients with genotypic activity scores of 1.0 or less, 18 had experienced relapse, whereas among the 25 with scores higher than 1.0, 3 had experienced relapse (OR, 9.4; 95% CI, 2.1-57.0; P?=?.001). When the log of the metabolic ratio of dextromethorphan-dextrorphan was -1.0 or less, only 1 of 18 patients experienced relapse, whereas above that threshold (consistent with low metabolic activity), 20 of 39 patients experienced relapse (OR, 18; 95% CI, 2.2-148.0; P?=?.007).

Conclusions and relevance

Genotype-determined and directly measured impaired levels of CYP2D6 activity were associated with elevated risk of therapeutic failure. These findings suggest a natural variability in CYP2D6-dependent metabolism of primaquine as a key determinant of therapeutic efficacy against latent P vivax malaria.

SUBMITTER: Baird JK

PROVIDER: S-EPMC6324265 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Association of Impaired Cytochrome P450 2D6 Activity Genotype and Phenotype With Therapeutic Efficacy of Primaquine Treatment for Latent Plasmodium vivax Malaria.

Baird J Kevin JK Louisa Melva M Noviyanti Rintis R Ekawati Lenny L Elyazar Iqbal I Subekti Decy D Chand Krisin K Gayatri Anggi A Instiaty Soebianto Saraswati S Crenna-Darusallam Chelzie C Djoko Dwi D Hasto Bambang Dwi BD Meriyenes Dubel D Wesche David D Nelwan Erni J EJ Sutanto Inge I Sudoyo Herawati H Setiabudy Rianto R

JAMA network open 20180803 4

<h4>Importance</h4>Latent hepatic Plasmodium vivax hypnozoites provoke repeated clinical attacks called relapses. Only primaquine phosphate kills hypnozoites, and its therapeutic activity may depend on naturally polymorphic cytochrome P450 2D6 isotype (CYP2D6) activity.<h4>Objective</h4>To examine the association of impaired CYP2D6 genotypes and CYP2D6 metabolic phenotypes with therapeutic failure of directly observed high-dose primaquine treatment for P vivax malaria relapse.<h4>Design, setting ...[more]

PMID: 30646129

Similar Datasets

Project description:BACKGROUND:Plasmodium vivax malaria is characterized by the presence of dormant liver-stage parasites, called hypnozoites, which can cause malaria relapses after an initial attack. Primaquine, which targets liver hypnozoites, must be used in combination with a schizonticidal agent to get the radical cure. However, relapses can sometimes occur in spite of correct treatment, due to different factors such as a diminished metabolization of primaquine. CASE PRESENTATION:In January 2019, a 21 years old woman with residence in Madrid, returning from a trip to Venezuela with clinical symptoms compatible with malaria infection, was diagnosed with vivax malaria. Chloroquine for 3 days plus primaquine for 14 days was the elected treatment. Two months later and after a second trip to Venezuela, the patient presented a second P. vivax infection, which was treated as the previous one. A third P. vivax malaria episode was diagnosed 2 months later, after returning from a trip to Morocco, receiving chloroquine for 3 days but increasing to 28 days the primaquine regimen, and with no more relapses after 6 months of follow up. The genotyping of P. vivax in the three malaria episodes revealed that the same strain was present in the different relapses. Upon confirmation of correct adherence to the treatment, non-description of resistance in the infection area and the highly unlikely re-infection on subsequent trips or stays in Spain, a possible metabolic failure was considered. CYP2D6 encodes the human cytochrome P450 isoenzyme 2D6 (CYP2D6), responsible for primaquine activation. The patient was found to have a CYP2D6*4/*1 genotype, which turns out in an intermediate metabolizer phenotype, which has been related to P. vivax relapses. CONCLUSIONS:The impairment in CYP2D6 enzyme could be the most likely cause of P. vivax relapses in this patient. This highlights the importance of considering the analysis of CYP2D6 gene polymorphisms in cases of P. vivax relapses after a correct treatment and, especially, it should be considered in any study of dosage and duration of primaquine treatment.

Project description:BackgroundTafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed "radical cure."MethodsWe performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter). Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin.ResultsA protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, -4.2 to 5.0). In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group. The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96).ConclusionsAmong patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine. Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123 .).

Project description:BackgroundPrimaquine and tafenoquine are the only licensed drugs that effectively kill the hypnozoite stage and are used to prevent Plasmodium vivax malaria relapse. However, both primaquine and tafenoquine can cause acute hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient people with varying degrees of severity depending on G6PD variants. Additionally, primaquine efficacy against malaria parasites was decreased in individuals with impaired cytochrome P450 2D6 (CYP2D6) activity due to genetic polymorphisms. This study aimed to characterize G6PD and CYP2D6 genetic variations in vivax malaria patients from Yala province, a malaria-endemic area along the Thai-Malaysian border, and determine the biochemical properties of identified G6PD variants.Methodology/principle findingsMultiplexed high-resolution melting assay and DNA sequencing detected five G6PD variants, including G6PD Kaiping, G6PD Vanua Lava, G6PD Coimbra, G6PD Mahidol, and G6PD Kerala-Kalyan. Biochemical and structural characterization revealed that G6PD Coimbra markedly reduced catalytic activity and structural stability, indicating a high susceptibility to drug-induced hemolysis. While Kerala-Kalyan had minor effects, it is possible to develop mild adverse effects when receiving radical treatment. CYP2D6 genotyping was performed using long-range PCR and DNA sequencing, and the phenotypes were predicted using the combination of allelic variants. Decreased and no-function alleles were detected at frequencies of 53.4% and 14.2%, respectively. The most common alleles were CYP2D6*36+*10 (25.6%), *10 (23.9%), and *1 (22.2%). Additionally, 51.1% of the intermediate metabolizers showed CYP2D6*10/*36+*10 as the predominant genotype (15.9%).Conclusions/significanceOur findings provide insights about genetic variations of G6PD and CYP2D6 in 88 vivax malaria patients from Yala, which may influence the safety and effectiveness of radical treatment. Optimization of 8-aminoquinoline administration may be required for safe and effective treatment in the studied population, which could be a significant challenge in achieving the goal of eliminating malaria.

Dataset Information

Association of Impaired Cytochrome P450 2D6 Activity Genotype and Phenotype With Therapeutic Efficacy of Primaquine Treatment for Latent Plasmodium vivax Malaria.

Importance

Objective

Design, setting, and participants

Exposures

Main outcomes and measures

Results

Conclusions and relevance

Publications

Association of Impaired Cytochrome P450 2D6 Activity Genotype and Phenotype With Therapeutic Efficacy of Primaquine Treatment for Latent Plasmodium vivax Malaria.

Similar Datasets

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