A three-day therapy for malaria caused by the protozoan Plasmodium vivax has proven to be as effective at controlling and preventing the reappearance of parasites in the blood as the treatment traditionally adopted by the Brazilian Unified Health System (SUS), which requires the use of medication for at least seven days. The recent, shorter strategy had another advantage over the prior treatment. It increased the time patients remained free from symptoms, whether caused by reactivation of dormant parasites lingering in the body or by reintroduction through a new infection, as revealed by the results of a study published in March in the medical journal The Lancet Infectious Diseases.
Researchers from the Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), in Amazonas State, an international reference center for the treatment of mosquito-borne diseases, reached these conclusions after one year monitoring the health of 5,554 residents of Manaus, Amazonas, and Porto Velho, Rondônia, who had been diagnosed with P. vivax malaria between September 2021 and August 2022. This species of the parasite is the most widely distributed in the world and accounts for most cases of the disease outside Sub-Saharan Africa. In Brazil, 84% of people with malaria are infected with P. vivax, especially in rural areas of the Amazon, which includes many Indigenous regions and mining sites.
When transmitted by the bite of female Anopheles mosquitoes, P. vivax initially invades liver cells. There, it multiplies asexually, generating thousands of new copies, which are released into the bloodstream. In the bloodstream, the protozoan continues to reproduce after invading red blood cells — responsible for transporting oxygen — and destroying them, which generates episodes of chills, fever, and intense sweating. From time to time, dormant forms of the parasite lodged in the liver reactivate and cause disease symptoms to return.
Since the mid-1990s, P. vivax has been treated at SUS using a combination of two antimalarials: a daily dose of chloroquine for three days, to combat parasites in the blood, combined with a daily dose of primaquine for a minimum of seven days, to eliminate dormant protozoa in liver cells. Children, breastfeeding women, and people with low activity of an enzyme that protects red blood cells — glucose-6-phosphate dehydrogenase (G6PD) — are treated with lower doses of primaquine, which is administered for up to eight weeks. In these patients, especially those with G6PD deficiency (5% of the population in the Brazilian Amazon), primaquine can cause mass destruction of red blood cells, causing anemia and even leading to death.
The success of this strategy is hampered by the lack of monitoring during the medication period, which is even more complicated in the Amazon, where 99% of Brazilian malaria cases occur and the majority of the population lives far from cities. Without the supervision of healthcare professionals, malaria patients often stop taking their medication prematurely.
“The bottleneck in primaquine therapy is adherence to the longer treatment,” says infectious disease specialist Dhelio Pereira, from the Rondônia Tropical Medicine Research Center. “Patients frequently stop taking this medication after the symptoms disappear with the initial action of chloroquine,” explains Pereira, who coauthored the study, which was conducted in collaboration with other institutions in Brazil and abroad. The research received support from Brazil’s Ministry of Health and was financed by the nongovernmental organizations Medicines for Malaria Venture (MMV) and the Bill and Melinda Gates Foundation.
In an attempt to improve the treatment, the ministry proposed a new protocol in 2021 in which primaquine, in appropriate cases, could be replaced by a similar compound, tafenoquine. Due to its longer-acting effects in the blood, tafenoquine can be taken in a single dose by people with normal G6PD activity. It must be avoided by those with G6PD deficiency because, as with primaquine, there is the risk of destruction of red blood cells. Discovered in 1978 at the Walter Reed Army Institute of Research in the United States, tafenoquine was developed by the pharmaceutical companies GlaxoSmithKline and 60° Pharmaceuticals in collaboration with MMV. It is the first alternative to primaquine to emerge in 60 years and was added to the SUS medicine list in June 2023, together with the rapid test for measuring G6PD activity.
Hungry Man (Ian Cheibub e Gualter Pupo) / Medicines for Malaria VenturesAnalyzer for performing rapid test of G6PD enzyme activity, and tafenoquine tabletsHungry Man (Ian Cheibub e Gualter Pupo) / Medicines for Malaria Ventures
In the study conducted in Manaus and Porto Velho, 3,128 people (56% of participants) received traditional therapy with primaquine and chloroquine, while 2,152 were treated using the newer strategy, in which primaquine is replaced by tafenoquine. Ninety days after starting treatment, 89% of those treated with tafenoquine remained symptom-free. This percentage was slightly lower (83.5%) in the primaquine group. At 180 days, the portion of participants who no longer showed signs of malaria was virtually the same in both groups: 75.7% in the tafenoquine group and 77.3% in the primaquine group. The study served as an evaluation of treatments in a real-life situation and as a model for implementing the strategy in the rest of the country.
“Tafenoquine increased the time a person is symptom-free to around 90 days. In those treated with primaquine, symptoms reappeared, on average, after 60 days,” says pharmacist Marcelo Brito, a researcher at FMT-HVD and the study’s lead author. Symptoms can recur as the result of a new infection, the reactivation of dormant parasites in the liver, or multiplication by parasites that were resistant to medications.
This extra period that a patient remains without symptoms, according to researchers, is an important boost to recovery. The delay in recurrence is clinically relevant because patients with P. vivax also suffer from anemia, which worsens with each new malaria episode.
In the opinion of pharmacist José Luiz Vieira, from the Federal University of Pará (UFPA), the new antimalarial is welcome. However, Vieira states that there are issues to be considered before tafenoquine is included in any new version of the Malaria Treatment Guide in Brazil.
“Tafenoquine should facilitate patient adherence, but its effectiveness is very similar to the drug that’s already available, which is lower in cost. Before adopting it, we need to evaluate the cost-benefit, which has to include training professionals to carry out G6PD tests in disease treatment units across the region,” suggests Vieira, who was not involved in the study.
According to the Ministry of Health, for a person weighing 70 kilos with a satisfactory G6PD level, the treatment cycle with chloroquine and tafenoquine — including the test to measure G6PD enzyme activity — costs just over R$46. Chloroquine therapy and seven days of primaquine plus the test cost around R$26. On March 15, the Yanomami territory in Roraima was the first region to receive tafenoquine through the SUS. The health ministry also reported that it has already started training local health professionals to implement the new treatment protocol, which is to be included in an updated edition of the guide to be released later this year.
Scientific article
BRITTO, M. et al. Operational effectiveness of tafenoquine and primaquine for the prevention of Plasmodium vivax recurrence in Brazil: A retrospective observational study. The Lancet Infectious Diseases. mar. 4, 2024.
