Can Higher Dose Primaquine Shorten Malaria Treatment?

Judy Stone, MD

March 31, 2022

A higher dose of primaquine prevents more relapses from a lingering form of malaria parasite, according to a study from Brazil published in The New England Journal of Medicine.

Venezuela and Brazil have the highest incidences of malaria in Latin America, primarily from Plasmodium vivax. Of the five types of malaria infections, P vivax can be difficult to eradicate, because, in addition to the acute symptomatic blood phase, the parasite can hide quietly in the liver for years in a hypnozoite phase and then reemerge to cause a relapse. Chloroquine is generally used to treat the blood phase of disease. Two drugs treat the liver phase — primaquine, the gold standard, and the newer tafenoquine.

Nathália Chamma-Siqueira, MSc

The main message of the new article, lead author Nathália N. Chamma-Siqueira, MSc, told Medscape Medical News, is that "a higher dose of primaquine has a greater efficacy than a low dose of primaquine."

The research focused on Cruzeiro do Sul, a city in the western Brazilian Amazon with 85,000 residents and 147.5 malaria cases per 1000 residents. In the study, 254 patients with P vivax malaria received three doses of chloroquine (total dose, 25 mg/kg of body weight). Administration of the doses was directly observed. Patients were randomly allocated into three groups.

Group 1 took primaquine as unobserved therapy for a total of 3.5 mg/kg over 7 days (0.5 mg/kg/day).

Group 2 received the same treatment, except primaquine was given as directly observed therapy (DOT).

Group 3 also received DOT primaquine therapy, but for a total dose of 7.0 mg/kg over 14 days (0.5 mg/kg/day).

Patients were evaluated weekly for the first month and then every 4 weeks until day 168. Overall, there were 70 recurrences by day 168.

"The percentage of patients who were recurrence-free was 58% (95% confidence interval, 44 to 70) in group 1, 59% (95% CI, 47 to 69) in group 2, and 86% (95% CI, 76 to 92) in group 3," Chamma-Siqueira and her co-authors write.

"The between-group difference among patients who were recurrence-free by day 168 was 27 percentage points (97.5% CI, 10 to 44) between group 1 and group 3 and 27 percentage points (97.5% CI, 12 to 42) between group 2 and group 3," they add. The differences between groups 1 and 3 and between groups 2 and 3 were significant.

Researchers also genotyped parasites in human blood samples, using seven neutral microsatellites to distinguish between reinfection and relapse. If the genotypes match in the baseline and the recurrence samples, it is called a homologous recurrence and suggests a relapse with the same parasite, rather than a new infection.

Homologous recurrence occurred in 22% of groups 1 and 2 but in only 5% of group 3, further supporting the finding that higher-dose primaquine resulted in fewer relapses.

Co-author Giselle M. R. Viana, PhD, stressed that one of the next steps is to evaluate the efficacy of higher-dose primaquine by conducting a side-by-side comparison of it to tafenoquine. Tafenoquine has the advantage of being a single-dose medication. It has so far shown similar efficacy to low-dose primaquine and has similar problems with hemolysis, a medication side effect in susceptible people that can lead to severe anemia that may require transfusions. Another goal would be to reproduce the trial in other countries to verify the results.

Alexandre Macedo de Oliveira, MD, PhD, a co-author from the US Centers for Disease Control and Prevention, told Medscape Medical News, "This is the kind of research that has the potential to have a direct clinical effect. It's really going to be used — [maybe] to tell us that we need more evidence from other countries before we change policy — but it is something that can drive policy."

Dr Chandy John

Malaria expert Chandy John, MD, professor of pediatrics at Indiana University, suggested to Medscape Medical News another important research question: "Could you actually achieve their goal with the shorter time period if you gave a higher dose every day?"

This is important because it is difficult to give DOT for 14 days. John referred to a large, randomized, controlled study conducted in Afghanistan, Ethiopia, Indonesia, and Vietnam. Patients received DOT primaquine for 7 days (1.0 mg/kg/day), DOT primaquine for 14 days (0.5 mg/kg/day), or a placebo. The shorter, high-dose primaquine was noninferior to the longer course.

John concluded, "The study was very well done. They had excellent follow-up.... It's quite challenging to do follow-up anywhere." He added, "I think it's a practical study, because it will probably affect public health policy in a good way."

N Engl J Med. Published online March 31, 2022. Full text

Judy Stone, MD, is an infectious disease specialist and author of Resilience: One Family's Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide to the topic. You can find her at or on Twitter @drjudystone.

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