RESUMEN
Effective radical cure of Plasmodium vivax malaria is essential for malaria elimination in Brazil. P. vivax radical cure requires administration of a schizonticide, such as chloroquine, plus an 8-aminoquinoline. However, 8-aminoquinolines cause hemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, requiring prior screening to exclude those at risk. Brazil is pioneering the implementation of tafenoquine, a single-dose 8-aminoquinoline indicated for P. vivax patients with >70% of normal G6PD activity. Tafenoquine implementation in Manaus and Porto Velho, two municipalities located in the western Brazilian Amazon, included comprehensive training of healthcare professionals (HCPs) on point-of-care quantitative G6PD testing and a new treatment algorithm for P. vivax radical cure incorporating tafenoquine. Training was initially provided to higher-level facilities (phase one) and later adapted for primary care units (phase two). This study analyzed HCP experiences during training and implementation and identified barriers and facilitators. In-depth interviews and focus discussion groups were conducted 30 days after each training for a purposive random sample of 115 HCPs. Thematic analysis was employed using MAXQDA software, analyzing data through inductive and deductive coding. Analysis showed that following the initial training for higher-level facilities, some HCPs did not feel confident performing quantitative G6PD testing and prescribing the tafenoquine regimen. Modifications to the training in phase two resulted in an improvement in understanding the implementation process of the G6PD test and tafenoquine, as well as in the knowledge acquired by HCPs. Additionally, knowledge gaps were addressed through in situ training, peer communication via a messaging app, and educational materials. Training supported effective deployment of the new tools in Manaus and Porto Velho and increased awareness of the need for pharmacovigilance. A training approach for nationwide implementation of these tools was devised. Implementing quantitative G6PD testing and tafenoquine represents a significant shift in P. vivax malaria case management. Consistent engagement with HCPs is needed to overcome challenges in fully integrating these tools within the Brazilian health system.
Asunto(s)
Aminoquinolinas , Antimaláricos , Deficiencia de Glucosafosfato Deshidrogenasa , Personal de Salud , Malaria Vivax , Humanos , Brasil , Malaria Vivax/tratamiento farmacológico , Malaria Vivax/prevención & control , Antimaláricos/uso terapéutico , Aminoquinolinas/uso terapéutico , Deficiencia de Glucosafosfato Deshidrogenasa/diagnóstico , Personal de Salud/educación , Femenino , Glucosafosfato Deshidrogenasa , Masculino , Plasmodium vivax/efectos de los fármacos , AdultoRESUMEN
BACKGROUND: Prevention of Plasmodium vivax malaria recurrence is essential for malaria elimination in Brazil. We evaluated the real-world effectiveness of an updated treatment algorithm for P vivax radical cure in the Brazilian Amazon. METHODS: In this non-interventional observational study, we used retrospective data from the implementation of a P vivax treatment algorithm at 43 health facilities in Manaus and Porto Velho, Brazil. The treatment algorithm consisted of chloroquine (25 mg/kg over 3 days) and point-of-care quantitative glucose-6-phosphate dehydrogenase (G6PD) testing followed by single-dose tafenoquine 300 mg (G6PD normal, aged ≥16 years, not pregnant and not breastfeeding), 7-day primaquine 0·5 mg/kg per day (G6PD intermediate or normal, aged ≥6 months, not pregnant, and not breastfeeding or breastfeeding for >1 month), or primaquine 0·75 mg/kg per week for 8 weeks (G6PD deficient, aged ≥6 months, not pregnant, and not breastfeeding or breastfeeding for >1 month). P vivax recurrences were identified from probabilistic linkage of routine patient records from the Brazilian malaria epidemiological surveillance system. Recurrence-free effectiveness at day 90 and day 180 was estimated using Kaplan-Meier analysis and hazard ratios (HRs) by multivariate analysis. This clinical trial is registered with ClinicalTrials.gov, NCT05096702, and is completed. FINDINGS: Records from Sept 9, 2021, to Aug 31, 2022, included 5554 patients with P vivax malaria. In all treated patients of any age and any G6PD status, recurrence-free effectiveness at day 180 was 75·8% (95% CI 74·0-77·6) with tafenoquine, 73·4% (71·9-75·0) with 7-day primaquine, and 82·1% (77·7-86·8) with weekly primaquine. In patients aged at least 16 years who were G6PD normal, recurrence-free effectiveness until day 90 was 88·6% (95% CI 87·2-89·9) in those who were treated with tafenoquine (n=2134) and 83·5% (79·8-87·4) in those treated with 7-day primaquine (n=370); after adjustment for confounding factors, the HR for recurrence following tafenoquine versus 7-day primaquine was 0·65 (95% CI 0·49-0·86; p=0·0031), with similar outcomes between the two treatments at day 180 (log-rank p=0·82). Over 180 days, median time to recurrence in patients aged at least 16 years who were G6PD normal was 92 days (IQR 76-120) in those treated with tafenoquine and 68 days (52-94) in those treated with 7-day primaquine. INTERPRETATION: In this real-world setting, single-dose tafenoquine was more effective at preventing P vivax recurrence in patients aged at least 16 years who were G6PD normal compared with 7-day primaquine at day 90, while overall efficacy at 180 days was similar. The public health benefits of the P vivax radical cure treatment algorithm incorporating G6PD quantitative testing and tafenoquine support its implementation in Brazil and potentially across South America. FUNDING: Brazilian Ministry of Health, Municipal and State Health Secretariats; Fiocruz; Medicines for Malaria Venture; Bill & Melinda Gates Foundation; Newcrest Mining; and the UK Government. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.
Asunto(s)
Aminoquinolinas , Antimaláricos , Malaria Vivax , Plasmodium vivax , Primaquina , Humanos , Malaria Vivax/tratamiento farmacológico , Malaria Vivax/prevención & control , Primaquina/uso terapéutico , Primaquina/administración & dosificación , Estudios Retrospectivos , Antimaláricos/uso terapéutico , Antimaláricos/administración & dosificación , Femenino , Masculino , Adulto , Brasil/epidemiología , Aminoquinolinas/uso terapéutico , Aminoquinolinas/administración & dosificación , Adolescente , Niño , Adulto Joven , Persona de Mediana Edad , Plasmodium vivax/efectos de los fármacos , Preescolar , Lactante , Prevención Secundaria/métodos , Cloroquina/uso terapéutico , Cloroquina/administración & dosificación , Recurrencia , Resultado del Tratamiento , AncianoRESUMEN
BACKGROUND: To achieve malaria elimination, Brazil must implement Plasmodium vivax radical cure. We aimed to investigate the operational feasibility of point-of-care, quantitative, glucose-6-phosphate dehydrogenase (G6PD) testing followed by chloroquine plus tafenoquine or primaquine. METHODS: This non-interventional, observational study was done at 43 health facilities in Manaus (Amazonas State) and Porto Velho (Rondônia State), Brazil, implementing a new P vivax treatment algorithm incorporating point-of-care quantitative G6PD testing to identify G6PD status and single-dose tafenoquine (G6PD normal, aged ≥16 years, and not pregnant or breastfeeding) or primaquine (intermediate or normal G6PD, aged ≥6 months, not pregnant, or breastfeeding >1 month). Following training of health-care providers, we collated routine patient records from the malaria epidemiological surveillance system (SIVEP-Malaria) retrospectively for all consenting patients aged at least 6 months with parasitologically confirmed P vivax malaria mono-infection or P vivax plus P falciparum mixed infection, presenting between Sept 9, 2021, and Aug 31, 2022. The primary endpoint was the proportion of patients aged at least 16 years with P vivax mono-infection treated or not treated appropriately with tafenoquine in accordance with their G6PD status. The trial is registered with ClinicalTrials.gov, NCT05096702, and is completed. FINDINGS: Of 6075 patients enrolled, 6026 (99·2%) had P vivax mono-infection, 2685 (44·6%) of whom were administered tafenoquine. G6PD status was identified in 2685 (100%) of 2685 patients treated with tafenoquine. The proportion of patients aged at least 16 years with P vivax mono-infection who were treated or not treated appropriately with tafenoquine in accordance with their G6PD status was 99·7% (95% CI 99·4-99·8; 4664/4680). INTERPRETATION: Quantitative G6PD testing before tafenoquine administration was operationally feasible, with high adherence to the treatment algorithm, supporting deployment throughout the Brazilian health system. FUNDING: Brazilian Ministry of Health, Municipal and State Health Secretariats; Fiocruz; Medicines for Malaria Venture; Bill & Melinda Gates Foundation; Newcrest Mining; and the UK Government. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.