Clinical Pearls & Morning Reports
Approximately 2.5 billion people are at risk for Plasmodium vivax malaria. The treatment and control of P. vivax are complicated by a latent, undetectable form in the liver stage of the parasite lifecycle, known as the hypnozoite. Lacerda et al. conducted a trial that assessed treatment with tafenoquine to prevent recurrence of P. vivax malaria. Read the latest NEJM original article here.
Q: What limits the effectiveness of the current treatment to prevent P. vivax recurrence?
A: The World Health Organization recommends treatment of P. vivax malaria with a blood schizonticide (chloroquine or artemisinin-based combination therapy) to clear asexual parasites, plus treatment with the 8-aminoquinoline primaquine for 14 days to kill hypnozoites and prevent relapse, a treatment termed “radical cure.” Nonadherence to the primaquine regimen jeopardizes the effectiveness of the treatment. Reported nonadherence rates (13.6 to 33.3%) probably underestimate the real-world situation.
Q: How does tafenoquine differ from primaquine?
A: Tafenoquine is a longer-acting 8-aminoquinoline, with a half-life of approximately 15 days, and it has recently been registered with the Food and Drug Administration and Australian Therapeutic Goods Administration as a single-dose treatment for the radical cure of P. vivax. Both primaquine and tafenoquine can cause hemolysis in persons with glucose-6-phosphate dehydrogenase (G6PD) deficiency, and G6PD testing is recommended before treatment with these agents.
A: In the trial by Lacerda et al., the Kaplan–Meier estimates of the percentage of patients who were free from recurrence at 6 months were 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0) and 27.7% in the placebo group (95% CI, 19.6 to 36.6). The hazard ratio for the risk of recurrence with tafenoquine as compared with placebo was 0.30 (95% CI, 0.22 to 0.40; P<0.001). A major limitation of the trial was that P. vivax genotyping cannot differentiate among recrudescence, relapse, and reinfection; all may appear homologous or heterologous to the initial infection. Although this trial was conducted in regions where tropical-type P. vivax strains prevail (with relapses occurring 17 to 45 days after the initial infection), it is possible that not all relapses were observed. Nevertheless, the risk of P. vivax recurrence from any cause was about 70% lower with tafenoquine than with placebo over the 6-month trial period.
A: The CYP2D6 gene has high allelic heterogeneity, with wide variations in enzyme levels and activity. Tafenoquine is metabolized slowly, with no major metabolites in human plasma or urine. In the trial by Lacerda et al., no effect on the efficacy of tafenoquine in preventing recurrence was seen in patients with intermediate CYP2D6 metabolic activity — a finding that is consistent with a previous analysis; however, more data on persons with poor CYP2D6 metabolic activity are required. In contrast, the CYP2D6 enzyme is necessary to convert primaquine to active metabolites, and evidence is emerging that CYP2D6 metabolism can modify primaquine efficacy.