Overcoming challenges to tackle malaria relapse

Prof. Alejandro Llanos-Cuentas, Universidad Peruana Cayetano Heredia, Lima, Peru

Half the world’s population lives at risk of the Plasmodium vivax malaria parasite. Once it has infected the human body, it can lie dormant in the liver, hidden from standard antimalarial medicines, and reawaken at regular intervals causing a malaria bouts in the absence of a mosquito bite.

Over the last decade, MMV and GSK have partnered to develop a new, single-dose cure to prevent the relapse of P. vivax malaria. This cure, tafenoquine, was approved by the US Food and Drug Administration and Australian Therapeutic Goods Administration in 2018 and in early 2019 the phase III data was published in two articles in the New England Journal of Medicine. The medicine is yet to be approved elsewhere.

Prof. Llanos, one of the principal investigators for the Phase III trials of tafenoquine in Peru and co-author of the two publications, explains the challenges in treating malaria and how tafenoquine could help.

1. What is the burden of malaria in Peru and how is it treated?

Acording to figures from the Ministry of Health, over the last 6 years, an average of 54,910 cases per year of malaria have been diagnosed in Peru, of which 73–84% were due to P. vivax. The MoH also estimates that 96% of malaria in Peru occurs in the Peruvian Amazon. It is basically a rural disease, affecting remote populations. The current treatment schedule for P. vivax malaria is chloroquine (3 days) to treat the symptomatic malaria attack and primaquine (7 days) to target the dormant relapsing forms of the parasite in the liver. The efficacy of this treatment regimen is still high, although resistance studies are limited.

2. What are the biggest challenges in the management and treatment of malaria in Peru?

The main challenge we have in the management of vivax malaria is adherence to treatment, which is only 62% at the moment.1 Part of this is owing to the beliefs and cultural practices of the population, especially the indigenous population, who do not accept prolonged treatment. These populations have the highest rate of malaria relapse.

A second challenge is the reservoir of malaria, which we usually do not treat. Data from our investigations show that for each symptomatic case of vivax malaria (case confirmed by positive blood smear) in the Peruvian Amazon there are between 7–10 asymptomatic cases (people infected with P. vivax but without symptoms). To eliminate malaria, we need to treat and eliminate this reservoir. Therefore, in the near future, in addition to treating symptomatic patients, we must also treat asymptomatic patients (reservoirs), which involves treating infected populations in the places where they live. Moving forward this will be part of Peru’s efforts to work towards malaria elimination.2

3. If approved in Peru, what role could a new medicine like tafenoquine have in this context?

Tafenoquine’s efficacy and rate of adverse effects are similar to primaquine, with the great advantage that it can be administered in a single dose. This would significantly increase adherence to treatment, consequently increasing the cure rate in endemic areas, and reducing the relapse rate. Incomplete adherence to treatment with primaquine can lead to a suboptimal total dose of drug  taken by the patients, and affect its efficacy against hypnozoites. Additional studies are needed to measure the real impact of tafenoquine in malaria treatment programmes.

A second role of tafenoquine will be the treatment of the P. vivax malaria dormant reservoir in endemic areas, where asymptomatic  people should be treated in the villages, and where the current strategies have a very limited effect. In these places, effective, short and highly adherent treatment schedules are required.

4. What was the main challenge you faced in the phase III trial of tafenoquine and how did you overcome it?

The biggest challenge was to recruit a large number of patients into the trial in a relatively short time. We tapped into the Ministry of Health’s network of health facilities situated less than 2 hours (by river or road) from the city of Iquitos, to establish our own network for patient recruitment. When a patient diagnosed with malaria was reported in these establishments, a field worker from the study team went to the place and transported the patient to the clinic so that the doctor could explain the study, obtain informed consent, and conduct the corresponding baseline exams.

5. With the medicine now approved in the US and in Australia, what are the next steps to support its uptake in Peru?

Tafenoquine is currently not approved in Peru, so we first need it to be registered in the country in the shortest possible time. GSK and MMV are planning the regulatory submission. Furthermore, GSK and MMV have already initiated a series of actions to support the future uptake. For example, several scientific events have been organized where the results have been shown to members of the National Academy of Medicine, the Ministry of Health and opinion leaders in communicable diseases.

 1. Grietens KP et al. Adherence to 7-day primaquine treatment for the radical cure of P. vivax in the Peruvian Amazon. Am J Trop Med Hyg. 82(6):1017-23 (2010).

2. Quispe AM et al. Accelerating to Zero: Strategies to Eliminate Malaria in the Peruvian Amazon. Am J Trop Med Hyg. 94(6): 1200–1207 (2016).