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Tafenoquine prevents P. vivax relapse; further study needed
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Tafenoquine is effective for the radical cure of Plasmodium vivax malaria, and a single-dose regimen resulted in a significantly lower risk of P. vivax recurrence, according to two studies published in The New England Journal of Medicine. However, tafenoquine was not shown to be noninferior to another drug in the same class — primaquine.
Based on the results of 13 safety and efficacy studies, the FDA approved tafenoquine for the prevention of P. vivax relapse in adults and teens last summer. WHO currently recommends chloroquine or artemisinin-based combination therapy to treat P. vivax malaria and clear asexual parasites. To kill hypnozites and prevent relapse, the agency also advises treating with the 8-aminoquinoline primaquine for 14 days.
Marcus V. G. Lacerda, MD, PhD, from the Dr. Heitor Vieira Dourado Tropical Medicine Foundation, and Alejandro Llanos-Cuentas, MD, from Universidad Peruana Cayetano Heredia, led two recent studies assessing the ability of tafenoquine to prevent relapse.
“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, Llanos-Cuentas and colleagues wrote. “Hypnozoites can cause multiple clinical relapses, which can increase the disease burden and the potential for onward transmission and impede efforts to eliminate malaria.”
Tafenoquine compared with placebo
The researchers conducted a multicenter, double-blind, double-dummy, parallel-group, randomized, placebo-controlled trial in Ethiopia, Peru, Brazil, Cambodia, Thailand and the Philippines to compare relapse recurrence following a single-dose regimen of tafenoquine and placebo.
The first study enrolled 522 patients with microscopically confirmed P. vivax infection and normal glucose-6-phosphate dehydrogenase (G6PD) activity. According to the study, participants were aged 16 years or older, except in Ethiopia, where the minimum age was 18 years. All patients received a 3-day course of chloroquine. Then, 260 patients received a single 300-mg dose of tafenoquine on day 1 or 2, 133 patients received a placebo and 129 patients received a 15-mg dose of primaquine once daily for 14 days. P. vivax clearance without recurrent parasitemia at 6 months was the primary outcome, according to the first study.
At 6 months, 62.4% (95% CI, 54.9-69) of patients in the tafenoquine group, 27.7% (95% CI, 19.6-36.6) in the placebo group and 69.6% (95% CI, 60.2-77.1) in the primaquine group were free from recurrence. According to Lacerda, Llano-Cuentas and colleagues, the HR for recurrence was 0.30 (95% CI, 0.22-0.4) in the tafenoquine group compared with the placebo group (P < .001). The HR for recurrence in the primaquine group was 0.26 (95% CI, 0.18-0.39) compared with the placebo group (P < .001). Tafenoquine was associated with asymptomatic declines in hemoglobin levels, although this resolved without intervention, they said.
Efficacy of tafenoquine compared with primaquine
The researchers compared the safety and efficacy of tafenoquine with primaquine in a phase 3, prospective, double-blind, double-dummy, randomized controlled trial conducted in Peru, Brazil, Colombia, Vietnam and Thailand.
The researchers cautioned that “both primaquine and tafenoquine cause drug-induced hemolysis in persons with glucose-6-phosphate dehydrogenase (G6PD) deficiency.”
The second study enrolled patients aged 16 years or older with normal G6PD enzyme activity, as well as female patients with moderate G6PD enzyme deficiency. All patients had confirmed P. vivax parasitemia and, like the first study, received a 3-day course of chloroquine. The researchers randomly assigned patients to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days. Patients were followed for 180 days. A protocol-defined decrease in the hemoglobin level was the primary safety outcome, and no recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome. The noninferiority margin was an OR for recurrence of 1.45.
In the tafenoquine group, 2.4% (95% CI, 0.9-6) demonstrated a decrease in hemoglobin levels compared with 1.2% (95% CI, 0.2-6.4) in the primaquine group. When Lacerda, Llanos-Cuentas and colleagues conducted a patient-level meta-analysis, they found that 67% (95% CI, 61-72.3) of patients in the tafenoquine group were free from recurrence at 6 months compared with 72.8% (95% CI, 65.6-78.8) in the primaquine group. Although tafenoquine was effective for the radical cure of P. vivax malaria, it was not shown to be noninferior to primaquine, according to the study.
In a related editorial, Nicholas J. White, FRS, professor of tropical medicine at Mahidol University in Thailand, explained that both studies showed tafenoquine can be administered safely, as long as appropriate G6PD testing occurs. Moreover, long follow-ups are critical to detect relapses, which can happen up to a year after the primary illness. Also, a more reliable method of distinguishing relapses from recrudescences or reinfections is necessary.
Although a single dose of tafenoquine can potentially solve the issue of medication adherence, the drug has restrictions. Unlike primaquine, tafenoquine cannot be stopped at the first sign of hemolysis because of its slow elimination, according to White. Its use is also limited by the need to accurately screen for G6PF deficiency — especially given that point-of-care quantitative tests for G6PD activity “have not yet been tested extensively under field conditions.” White also noted certain prescribing restrictions with tafenoquine, which include pregnancy, lactation, and being aged younger than 16 years.
“The developers of tafenoquine deserve credit for persevering with this potentially valuable antimalarial drug, despite the difficulties, but it is too early to say whether tafenoquine can be used safely on a large scale in routine practice and thus fulfill its promise as a radical improvement in the treatment of malaria,” he concluded. – by Marley Ghizzone
References:
Lacerda MVG, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1710775.
Llanos-Cuentas A, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1802537.
White NJ. N Engl J Med. 2019;doi:10.1056/NEJMe1816383.
Disclosures: Llanos-Cuentas reports receiving grant support and fees from GSK for conducting the tafenoquine clinical program. Lacerda and White report no relevant financial disclosures.
Perspective
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Krutika Kuppalli, MD
The results of the DETECTIVE and GATHER studies are exciting. In patients with appropriate G6PD testing, tafenoquine is a new drug that showed efficacy for the radical cure of P. vivax malaria. Since tafenoquine is taken a one-time dose, it has the potential to solve an important problem of adherence seen with primaquine, which needs to be taken for 14 days in patients who have P. vivax malaria in order to obtain a radical cure.
I think it is too early to say whether tafenoquine is a significant improvement, but it is an exciting potential improvement. From the data in these phase 3 studies, the rates of radical cure were about the same in patients who received tafenoquine versus primaquine. The data we have now look promising. It is too early to say if this can be used on a large scale because, just like primaquine, tafenoquine cannot be used safely in patients with G6PD deficiency. So, this is something we must worry about in patients who we might want to give this medication to.
I think it is always exciting when we have new medications that treat infections that affect millions of people worldwide, especially in low- and middle-income countries. As we find out more information, and as researchers do further studies on the drug, I think this could be potentially very useful, not just for people in developing countries but for the many U.S. citizens who travel abroad yearly and contract malaria.
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