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

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.

Randomized trial of primaquine hypnozoitocidal efficacy when administered with artemisinin-combined blood schizontocides for radical cure of Plasmodium vivax in Indonesia.

BACKGROUND: Safety and efficacy of primaquine against repeated attacks of Plasmodium vivax depends upon co-administered blood schizontocidal therapy in radical cure. We assessed primaquine (PQ) as hypnozoitocide when administered with dihydroartemisinin-piperaquine (Eurartesim®, DHA-PP) or artesunate-pyronaridine (Pyramax®, AS-PYR) to affirm its good tolerability and efficacy. A third arm, artesunate followed by primaquine, was not intended as therapy for practice, but addressed a hypothesis concerning primaquine efficacy without co-administration of blood schizontocide. METHODS: During March to July 2013, an open-label, randomized trial enrolled Indonesian soldiers with vivax malaria at Sragen, Central Java, after six months duty in malarious Papua, Indonesia. No malaria transmission occurred at the study site and P. vivax recurrences in the 12 months following therapy were classified as relapses. A historic relapse control derived from a cohort of soldiers who served in the same area of Papua was applied to estimate risk of relapse among randomized treatment groups. Those were: 1) AS followed 2d later by PQ (0.5 mg/kg daily for 14d); 2) co-formulated AS-PYR concurrent with the same regimen of PQ; or 3) co-formulated DHA-PP concurrent with the same regimen of PQ. RESULTS: Among 532 soldiers, 219 had vivax malaria during the four months following repatriation to Java; 180 of these were otherwise healthy and G6PD-normal and enrolled in the trial. Subjects in all treatment groups tolerated the therapies well without untoward events and cleared parasitemia within three days. First relapse appeared at day 39 post-enrollment, and the last at day 270. Therapeutic efficacy of PQ against relapse by incidence density analysis was 92 % (95 %CI = 83-97 %), 94 %(95 %CI = 86-97 %), and 95 %(95 %CI = 88-98 %) when combined with AS, AS-PYR, or DHA-PP, respectively. CONCLUSIONS: This trial offers evidence of good tolerability and efficacy of PQ against P. vivax relapse when administered concurrently with DHA-PP or AS-PYR. These offer alternative partner drugs for radical cure with primaquine. The AS arm demonstrated efficacy with a total dose of 7 mg/kg PQ without concurrently administered blood schizontocide, another option when primaquine therapy is removed in time from the treatment of the acute malaria or applied presumptively without an attack. TRIAL REGISTRATION: Current Controlled Trials ISRCTN82366390, assigned 20 March 2013.