Operational effectiveness of tafenoquine and primaquine for the prevention of Plasmodium vivax recurrence in Brazil: a retrospective observational study.

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.

Operational feasibility of Plasmodium vivax radical cure with tafenoquine or primaquine following point-of-care, quantitative glucose-6-phosphate dehydrogenase testing in the Brazilian Amazon: a real-life retrospective analysis.

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.

Pregnancy outcomes after snakebite envenomations: A retrospective cohort in the Brazilian Amazonia.

Snakebite envenomations (SBEs) in pregnant women can result in adverse maternal or neonatal effects, such as abortion, placental abruption, preterm labor, fetal malformations, and maternal, fetal or neonatal deaths. Despite the high incidence of SBEs in the Brazilian Amazon, there is no literature on the impact of SBEs on pregnancy outcomes. The objective of this study was to describe clinical epidemiology and outcomes associated with SBEs in women of childbearing age and pregnant women in the state of Amazonas, Western Brazilian Amazon, from 2007 to 2021. Information on the population was obtained from the Reporting Information System (SINAN), Mortality Information System (SIM) and Live Birth Information System (SINASC) for the period from 2007 to 2021. A total of 36,786 SBEs were reported, of which 3,297 (9%) involved women of childbearing age, and 274 (8.3%) involved pregnant women. Severity (7.9% in pregnant versus 8.7% in non-pregnant women) (P = 0.87) and case-fatality (0.4% in pregnant versus 0.3% in non-pregnant women) rates were similar between groups (P = 0.76). Pregnant women who suffered snakebites were at higher risk for fetal death (OR: 2.17, 95%CI: 1.74-2.67) and neonatal death (OR = 2.79, 95%CI: 2.26-3.40). This study had major limitations related to the completeness of the information on the pregnancy outcomes. Although SBE incidence in pregnant women is low in the Brazilian Amazon, SBEs increased the risk of fetal and neonatal deaths.

Quantitative G6PD Deficiency Screening in Routine Malaria Diagnostic Units in the Brazilian Amazon (SAFEPRIM): An Operational Mixed-Methods Study.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency testing is not routinely performed before primaquine treatment in most Plasmodium vivax endemic areas, despite the risk of primaquine-associated hemolysis. This is due to the operational challenges associated with pragmatic G6PD testing and as such needs to be addressed. METHODS AND FINDINGS: This mixed-methods operational study was aimed at implementing the quantitative point-of-care StandardTM G6PD (SD Biosensor, Korea) screening test in malaria treatment units (MTUs) in the municipalities of Rio Preto da Eva and Mâncio Lima, in the Brazilian Amazon, between mid-January 2020 and December 2020. In total, 1286 P. vivax cases were treated based on the Standard G6PD test: 1230 had activity equal to or greater than 4.0 U/g Hb, and 56 less than 4.0 U/g Hb. No G6PD deficient (G6PDd) genotypes were found in 96 samples from the 1230, and only 21 of the 56 G6PDd cases had confirmed G6PDd genotypes. Evaluations were conducted on the proficiency of health care professionals (HCPs) training to perform the test, the reliability of testing performed in the field, and the perceptions of HCPs and patients about the implementation. Post-training proficiency was 73.4% after a 4-hour training session. This study revealed that locations with lower malaria caseloads will need regular refresher training. The test was well accepted by both HCPs and patients. Signs and symptoms of hemolysis were not always associated with malaria treatment drugs by HCPs and patients. INTERPRETATION: Point-of-care quantitative G6PD testing can be performed at MTUs in the Brazilian Amazon to inform treatment decisions with primaquine. Limitations related to technical and cultural aspects need to be addressed further when expanding screening to larger areas.

Effect of weekly versus daily primaquine on Plasmodium vivax malaria recurrences: A real-life cohort study.

BACKGROUND: Although primaquine (PQ) is indicated for G6PD-deficient patients, data on weekly PQ use in Brazil are limited. METHODS: We aimed to investigate malaria recurrences among participants receiving daily and weekly PQ treatments in a real-life setting of two municipalities in the Amazon between 2019 and 2020. RESULTS: Patients receiving weekly PQ treatment had a lower risk of recurrence than those receiving daily PQ treatment (risk ratio: 0.62, 95% confidence interval: 0.41-0.94), using a model adjusted for study site. CONCLUSIONS: Weekly PQ use did not increase the risk of malaria recurrence. Further studies with larger populations are warranted.

Real-life quantitative G6PD screening in Plasmodium vivax patients in the Brazilian Amazon: A cost-effectiveness analysis.

BACKGROUND: As quantitative glucose 6-phosphate dehydrogenase deficiency (G6PDd) screening tools are evaluated in operational studies, questions remain as to whether they are cost-effective. Here, a cost-effectiveness analysis (CEA) was performed to estimate the Incremental Cost-effectiveness Ratio (ICER) of the introduction of quantitative screening test to detect G6PDd among P. vivax carriers in two municipalities in the Brazilian Amazon. METHODOLOGY/PRINCIPAL FINDINGS: This cost-effectiveness analysis evaluated the use of the Standard G6PD quantitative screening test in vivax malaria treatment units in two municipalities of the Brazilian Amazon. Using the perspective of the Brazilian public health system, the analysis was performed for the outcome 'PQ-associated hospitalization avoided', based on a decision tree model. The results indicated that the G6PDd screening strategy compared with the routine strategy was highly cost-effective, with an ICER of US$495 per additional hospitalization avoided, which represented less than 8% of one Brazilian gross domestic product per capita (US$6,822). The uncertainties evaluated in the sensitivity analysis did not significantly affect the ICER identified in the base-case. CONCLUSIONS/SIGNIFICANCE: This cost-effectiveness analysis showed the quantitative G6PD testing was effective in avoiding PQ-associated hospitalizations. The incorporation of G6PD screening is of paramount importance towards P. vivax malaria elimination in the Amazon to promote the safe use of primaquine and tafenoquine.

Prevalence of glucose 6-phosphate dehydrogenase deficiency in highly malaria-endemic municipalities in the Brazilian Amazon: A region-wide screening study.

Background: Difficulties associated with the assessment of glucose-6-phosphate dehydrogenase deficiency (G6PDd), particularly in remote areas, hinders the safe use of 8-aminoquinolines such as primaquine (PQ) and tafenoquine against Plasmodium vivax malaria due to the risk of haemolysis. Methods: This cross-sectional study was conducted in 41 malaria-endemic municipalities of six states in the Brazilian Amazon, between 2014 and 2018. Male individuals were screened for G6PDd using the qualitative Fluorescent Spot Test using fingerpick-collected whole blood samples. Point and interval estimates of the G6PDd prevalence were calculated for each state. Deficient samples were genotyped for the most prevalent variants in the Amazon. Frequencies of P. vivax malaria recurrences were estimated for G6PDd and non-G6PDd patients. Interpretation: This is one of the largest surveys ever conducted in Latin America, covering the entire malaria endemic area in the Brazilian Amazon. These results indicate that an important proportion of the population is at risk of hemolysis if exposed to PQ and its congener drug tafenoquine. The adoption of G6PDd screening protocols is essential to ensure the safety of individuals treated with those drugs and should also be considered when implementing malaria elimination strategies. Findings: A total of 14,847 individuals were included, of which 5.6% presented G6PDd. The state of Acre had the highest G6PDd prevalence (8.3%), followed by Amapá (5.8%), Pará (5.7%), Rondônia (5.4%), Roraima (4.2%) and Amazonas (4.0%). From 828 genotyped samples, African A+ (6.2%), African A- (39.3%) and wild-type (non-African non-Mediterranean; 54.2%) variants were found. A greater proportion of malaria recurrences was found among G6PD deficient individuals [16.7% vs 4.1%, Risk ratio 3.52 (2.16-5.74) p < 0.01]. Funding: Brazilian Ministry of Health; Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM).

Effect of weekly versus daily primaquine on Plasmodium vivax malaria recurrences: A real-life cohort study

ABSTRACT Background: Although primaquine (PQ) is indicated for G6PD-deficient patients, data on weekly PQ use in Brazil are limited. Methods: We aimed to investigate malaria recurrences among participants receiving daily and weekly PQ treatments in a real-life setting of two municipalities in the Amazon between 2019 and 2020. Results: Patients receiving weekly PQ treatment had a lower risk of recurrence than those receiving daily PQ treatment (risk ratio: 0.62, 95% confidence interval: 0.41-0.94), using a model adjusted for study site. Conclusions: Weekly PQ use did not increase the risk of malaria recurrence. Further studies with larger populations are warranted.

Correction: Social, demographic, health care and co-morbidity predictors of tuberculosis mortality in Amazonas, Brazil: a multiple cause of death approach.

[This corrects the article DOI: 10.1371/journal.pone.0218359.].

Social, demographic, health care and co-morbidity predictors of tuberculosis mortality in Amazonas, Brazil: a multiple cause of death approach.

OBJECTIVES: Estimate TB mortality rates, catalogue multiple causes on death certificates in which TB was reported and identify predictors of TB from reporting on death certificates in the State of Amazonas, Brazil, based on a multiple cause of death approach. METHODS: The death records of residents in the Amazonas state between 2006-2014 were analyzed and separated into three categories: TB not reported on the death certificate (TBNoR), TB reported as the underlying cause of death (TBUC) and TB reported as an associated cause of death (TBAC). Age standardized annual mortality rates for TBUC, TBAC and with TB reported (TBUC plus TBAC) were estimated for the State of Amazonas using the direct standardization method and World Health Organization 2000-2025 standard population. Mortality odds ratios (OR) for reporting of TBUC and TBAC were estimated using multinomial logistic regression. RESULTS: Age standardized annual TBUC and TBAC mortality rates ranged between 5.9-7.8/105 and 2.7-4.0/105, respectively. TBUC was associated with being a resident in the State capital (OR = 0.66), of female gender (OR = 0.87), having an education level of 8 to 11, or 12 or more school years (OR = 0.67 and 0.50 respectively), non-white race/skin color (OR = 1.38) and place of death reported as in the State capital (OR = 1.69). TBAC was related to the triennium in which death occurred (OR = 1.21 and 1.22 for the years 2009-2011 and 2012-2014 respectively), age (OR = 36.1 and 16.5 for ages 15-39 and 40-64 years respectively) and when death occurred in the State capital (OR = 5.8). CONCLUSIONS: TBUC was predominantly associated with predictors of unfavorable socioeconomic conditions and health care access constraints, whereas TBAC was mainly related to ages which were typical of high HIV disease incidence.

Fatores associados à mortalidade por causas inespecíficas e mal definidas no estado do Amazonas, Brasil, de 2006 a 2012 / Factors associated with unspecified and ill-defined causes of death in the State of Amazonas, Brazil, from 2006 to 2012

Resumo Objetivou-se investigar fatores associados à mortalidade por causas inespecíficas e mal definidas no estado do Amazonas (AM). Desenvolveu-se um estudo seccional incluindo 90.439 registros de óbitos não fetais, com residência e ocorrência no AM entre 2006 e 2012. Foram estimadas razões de chances de causas inespecíficas e mal definidas por meio de regressão logística multinomial hierárquica. A proporção de causas mal definidas e inespecíficas foi, respectivamente, 16,6% e 9,1%. A ocorrência de causas mal definidas diminuiu ao longo dos anos e a de causas inespecíficas somente no último biênio. As causas inespecíficas associaram-se com residência e ocorrência do óbito fora da capital, via pública, sexo feminino, dos 10 aos 49 anos, cor parda e quando atestadas por legistas. As causas mal definidas associaram-se com residência e ocorrência fora da capital, em domicílios, a partir de 40 anos, cor não branca, não ser solteiro, baixa escolaridade, assistência médica e falta de informação sobre o atestante. A mortalidade por causas mal definidas e inespecíficas no AM declinou entre 2006 e 2012, associando-se às dimensões espacial e temporal, fatores demográficos, socioeconômicos e à assistência médica na ocasião do óbito.

Abstract This study aimed to investigate factors associated with unspecified and ill-defined causes of death in the State of Amazonas (AM), Brazil. This is a cross-sectional study on 90,439 non-fetal deaths of residents in AM from 2006 to 2012. The hierarchical multinomial logistic model estimated odds ratios of unspecified and ill-defined causes of death. Ill-defined and unspecified causes of death proportional mortality was, respectively, 16.6% and 9.1%. Ill-defined causes showed a decreasing trend over the years, while unspecified causes only decreased in the last two years. Unspecified causes of death were associated with residence and death outside the capital, public roads, female gender, age group 10-49 years, brown skin color and when certified by forensic doctors. Ill-defined causes of death were associated with residence and occurrence outside capital, at home, ages 40 years and older, non-whites, not being single, low schooling, under medical care and when examiner was unknown. Ill-defined and unspecified cause mortality in the State of Amazonas decreased between 2006 and 2012 in AM and was associated with space and time, demographic and socioeconomic factors and medical care at the moment of death.

Factors associated with unspecified and ill-defined causes of death in the State of Amazonas, Brazil, from 2006 to 2012. / Fatores associados à mortalidade por causas inespecíficas e mal definidas no estado do Amazonas, Brasil, de 2006 a 2012.

This study aimed to investigate factors associated with unspecified and ill-defined causes of death in the State of Amazonas (AM), Brazil. This is a cross-sectional study on 90,439 non-fetal deaths of residents in AM from 2006 to 2012. The hierarchical multinomial logistic model estimated odds ratios of unspecified and ill-defined causes of death. Ill-defined and unspecified causes of death proportional mortality was, respectively, 16.6% and 9.1%. Ill-defined causes showed a decreasing trend over the years, while unspecified causes only decreased in the last two years. Unspecified causes of death were associated with residence and death outside the capital, public roads, female gender, age group 10-49 years, brown skin color and when certified by forensic doctors. Ill-defined causes of death were associated with residence and occurrence outside capital, at home, ages 40 years and older, non-whites, not being single, low schooling, under medical care and when examiner was unknown. Ill-defined and unspecified cause mortality in the State of Amazonas decreased between 2006 and 2012 in AM and was associated with space and time, demographic and socioeconomic factors and medical care at the moment of death.

Objetivou-se investigar fatores associados à mortalidade por causas inespecíficas e mal definidas no estado do Amazonas (AM). Desenvolveu-se um estudo seccional incluindo 90.439 registros de óbitos não fetais, com residência e ocorrência no AM entre 2006 e 2012. Foram estimadas razões de chances de causas inespecíficas e mal definidas por meio de regressão logística multinomial hierárquica. A proporção de causas mal definidas e inespecíficas foi, respectivamente, 16,6% e 9,1%. A ocorrência de causas mal definidas diminuiu ao longo dos anos e a de causas inespecíficas somente no último biênio. As causas inespecíficas associaram-se com residência e ocorrência do óbito fora da capital, via pública, sexo feminino, dos 10 aos 49 anos, cor parda e quando atestadas por legistas. As causas mal definidas associaram-se com residência e ocorrência fora da capital, em domicílios, a partir de 40 anos, cor não branca, não ser solteiro, baixa escolaridade, assistência médica e falta de informação sobre o atestante. A mortalidade por causas mal definidas e inespecíficas no AM declinou entre 2006 e 2012, associando-se às dimensões espacial e temporal, fatores demográficos, socioeconômicos e à assistência médica na ocasião do óbito.