Brazil’s Success in Preventing Malaria Relapse Using New Single-Dose Treatment
Raquel da Silva, who lives in Manaus in Brazil’s Amazonas State, had malaria five times in five consecutive months.

Brazil is the first country in the world to introduce tafenoquine, the first new single-dose treatment for P. vivax malaria developed in 70 years, in its public health system.

Raquel da Silva has lived in Manaus in Brazil’s Amazonas State since her childhood. Today she shares her home on the banks of the Rio Negro with her husband Camilo, their three children, her mother-in-law and her grandmother-in-law. 

On the weekends, she works in a restaurant. As a mother of three, Raquel needs her energy to keep up with her children, but living in one of the most malaria-affected areas in the country, she has lost track of how many times she has contracted malaria. 

“My family and I had malaria five times for five consecutive months last year,” Da Silva told Medicines for Malaria Venture (MMV) when she first met them in 2020.

“When I got malaria, my baby was six months old, so I didn’t manage to take the full treatment regimen for seven days. I took just enough so my symptoms would improve, so it always relapsed. My husband works so he had to leave the house and I didn’t have energy to do anything. It was hard.”

Malaria disproportionately impacts the poorest and most vulnerable in society, perpetuating a cycle of poverty. P. falciparum, which is more deadly and prevalent in Africa, has long received the most attention in the malaria world, but P. vivax, known for its frequent relapses, also requires focus if more malaria-endemic countries are to join the 41 nations that have already been declared malaria-free.

Approval of tafenoquine for national rollout

On 5 June, Brazil took an important step in that direction, becoming the first country in the world to approve the new single dose P. vivax treatment, tafenoquine, for nationwide rollout in the public health system.

P. vivax malaria is the most geographically widespread of the two parasites and is the predominant species in most countries in Asia-Pacific and Latin America as well as in other areas on the cusp of malaria elimination.

Transmission is driven by the parasite’s ability to cause relapses – patients suffer recurrent malaria episodes from just one infectious mosquito bite, and human-to-human transmission occurs when a mosquito feeds on the blood of an infected person and transmits the parasite to family members, friends, and neighbours. 

To stop the relapses, both the blood- and liver-stages of the P. vivax infection must be treated, providing what is known as ‘radical cure’.

Until now, this involved blood-stage treatment with chloroquine for three days and liver-stage treatment with primaquine for seven or 14 days. But there are huge issues with treatment adherence. Most patients will not complete the full 7-14 day treatment course, and so risk suffering relapses which in turn fuel further P. vivax malaria transmission.

Turbocharging Brazil’s efforts to eliminate malaria

In Brazil, where over 80% of reported malaria cases in 2021 were caused by P. vivax, the Ministry of Health (MoH) and the country’s malaria research community have been searching for better tools to tackle P. vivax malaria for a long time. 

Between 2014 and 2016, researchers in Manaus and Porto Velho played a pivotal role in the clinical development programme for tafenoquine, the single-dose treatment developed by GSK and MMV.

The same researchers also conducted critical clinical and operational studies on a new point of care test, developed by SD Biosensor and PATH  that could identify a hereditary condition, glucose-6-phosphate-dehydrogenase (G6PD) deficiency, which can cause haemolytic anaemia in those who take either primaquine or tafenoquine. In Brazil around 5% of the population is presumed to be G6PD deficient.

The new G6PD test opened up new opportunities to rapidly diagnose the condition and adapt treatment accordingly. Tracking the development of the diagnostic and treatment in tandem, Brazil’s Ministry of Health recognised their potential to supercharge the country’s malaria elimination efforts.

By the time tafenoquine had been approved as a treatment and registered in Brazil in 2019, plans were already underway to study the drug’s real-world application in Manaus and Porto Velho. The MoH wanted to know whether it would be feasible for health workers, at different levels of the vast network of malaria services within the public system, to perform the quantitative point-of-care G6PD test and provide tafenoquine or primaquine based on the test results.

First real-world study launched with impressive results

Fast forward, past COVID-related delays, to September 2021 when the first real-world study, TRuST, was launched, sponsored by the MoH and MMV. The MoH in coordination with the Municipal and State level health authorities rolled out tafenoquine and G6PD testing in 43 health facilities throughout Manaus and Porto Velho. 

They trained 370 healthcare professionals, and more than 6,000 patients consented to have their data anonymized and collected for analysis by the TRuST study team.

The results were impressive. The level of compliance with the new treatment protocol was above 99%, consistent across all healthcare facilities, showing that routine testing for G6PD activity before providing appropriate radical cure was feasible throughout the Brazilian health system. 

Following the end of patient recruitment into the study in August 2022, a comprehensive dossier was submitted to CONITEC, the country’s health technology assessment body, in December of that year. The dossier included the first and second interim analyses of TRuST; a qualitative research study looking at patient and health worker perceptions; a cost-effectiveness analysis; and a budget impact analysis. 

On reviewing this, CONITEC recommended that the new tools be incorporated into the public health system. On 5 June, the government of Brazil issued a decree on adoption, making it the first malaria-endemic country to introduce single-dose tafenoquine and quantitative point-of-care G6PD testing throughout the health system.

As one of the patients treated with the new shorter treatment during the study, Raquel is optimistic about the new possibilities that the drug provides. She says that, although she also takes preventive measures such as using bed nets, the drug provides a sense of security in case she or her family members do fall ill again.

Regional impact

What does this mean beyond Brazil? Countries in the region are already seeking to learn from Brazil’s experience. A similar tafenoquine and G6PD testing feasibility study, funded by Unitaid, is about to start in Peru with support from MMV and the University of Peru Cayetano Heredia (UPCH). 

The team there received training from the TRuST team in December 2022, enabling them to move more quickly, based on the Brazilian experience. The Ministry of Public Health in Thailand is conducting a similar study with support from MMV, examining routine use of tafenoquine and point-of-care G6PD testing in hospitals and malaria clinics. 

Recruitment in that study is set to conclude in August, providing real-world evidence from a different context. Unitaid is supporting two additional real-world feasibility studies on the use of tafenoquine and G6PD testing in Vietnam and Ethiopia, with support from the international global health non-profit PATH and local research partners. Together this emerging evidence may inform WHO guidelines and support national malaria programmes as they seek to optimise tools for the control and elimination of P. vivax.

Marcus Lacerda was one of the Principal Investigators on both the Tafenoquine Rollout STudy (TRuST) and the Tafenoquine Phase III studies.

Elodie Jambert is senior director at Medicines for Malaria Venture (MMV), the product development partnership that co-developed tafenoquine with GSK and co-sponsored TRuST with the Brazilian Ministry of Health.

Image Credits: Nathalie Brasil, Instagram: @_nathaliebl.

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