Tafenoquine following G6PD screening versus primaquine for the treatment of vivax malaria in Brazil: A cost-effectiveness analysis using a transmission model.

BACKGROUND: Malaria transmission modelling has demonstrated the potential impact of semiquantitative glucose-6-phosphate dehydrogenase (G6PD) testing and treatment with single-dose tafenoquine for Plasmodium vivax radical cure but has not investigated the associated costs. This study evaluated the cost-effectiveness of P. vivax treatment with tafenoquine after G6PD testing using a transmission model. METHODS AND FINDINGS: We explored the cost-effectiveness of using tafenoquine after G6PD screening as compared to usual practice (7-day low-dose primaquine (0.5 mg/kg/day) without G6PD screening) in Brazil using a 10-year time horizon with 5% discounting considering 4 scenarios: (1) tafenoquine for adults only assuming 66.7% primaquine treatment adherence; (2) tafenoquine for adults and children aged >2 years assuming 66.7% primaquine adherence; (3) tafenoquine for adults only assuming 90% primaquine adherence; and (4) tafenoquine for adults only assuming 30% primaquine adherence. The incremental cost-effectiveness ratios (ICERs) were estimated by dividing the incremental costs by the disability-adjusted life years (DALYs) averted. These were compared to a willingness to pay (WTP) threshold of US$7,800 for Brazil, and one-way and probabilistic sensitivity analyses were performed. All 4 scenarios were cost-effective in the base case analysis using this WTP threshold with ICERs ranging from US$154 to US$1,836. One-way sensitivity analyses showed that the results were most sensitive to severity and mortality due to vivax malaria, the lifetime and number of semiquantitative G6PD analysers needed, cost per malaria episode and per G6PD test strips, and life expectancy. All scenarios had a 100% likelihood of being cost-effective at the WTP threshold. The main limitations of this study are due to parameter uncertainty around our cost estimates for low transmission settings, the costs of G6PD screening, and the severity of vivax malaria. CONCLUSIONS: In our modelling study that incorporated impact on transmission, tafenoquine prescribed after a semiquantitative G6PD testing was highly likely to be cost-effective in Brazil. These results demonstrate the potential health and economic importance of ensuring safe and effective radical cure.

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.

Use of anthropophilic culicid-based xenosurveillance as a proxy for Plasmodium vivax malaria burden and transmission hotspots identification.

Vector-borne diseases account for more than 17% of all infectious diseases, causing more than one million deaths annually. Malaria remains one of the most important public health problems worldwide. These vectors are bloodsucking insects, which can transmit disease-producing microorganisms during a blood meal. The contact of culicids with human populations living in malaria-endemic areas suggests that the identification of Plasmodium genetic material in the blood present in the gut of these mosquitoes may be possible. The process of assessing the blood meal for the presence of pathogens is termed 'xenosurveillance'. In view of this, the present work investigated the relationship between the frequency with which Plasmodium DNA is found in culicids and the frequency with which individuals are found to be carrying malaria parasites. A cross-sectional study was performed in a peri-urban area of Manaus, in the Western Brazilian Amazon, by simultaneously collecting human blood samples and trapping culicids from households. A total of 875 individuals were included in the study and a total of 13,374mosquito specimens were captured. Malaria prevalence in the study area was 7.7%. The frequency of households with at least one culicid specimen carrying Plasmodium DNA was 6.4%. Plasmodium infection incidence was significantly related to whether any Plasmodium positive blood-fed culicid was found in the same household [IRR 3.49 (CI95% 1.38-8.84); p = 0.008] and for indoor-collected culicids [IRR 4.07 (CI95%1.25-13.24); p = 0.020]. Furthermore, the number of infected people in the house at the time of mosquito collection was related to whether there were any positive blood-fed culicid mosquitoes in that household for collection methods combined [IRR 4.48 (CI95%2.22-9.05); p<0.001] or only for indoor-collected culicids [IRR 4.88 (CI95%2.01-11.82); p<0.001]. Our results suggest that xenosurveillance can be used in endemic tropical regions in order to estimate the malaria burden and identify transmission foci in areas where Plasmodium vivax is predominant.

Malaria in Brazil, Colombia, Peru and Venezuela: current challenges in malaria control and elimination.

In spite of significant progress towards malaria control and elimination achieved in South America in the 2000s, this mosquito-transmitted tropical disease remains an important public health concern in the region. Most malaria cases in South America come from Amazon rain forest areas in northern countries, where more than half of malaria is caused by Plasmodium vivax, while Plasmodium falciparum malaria incidence has decreased in recent years. This review discusses current malaria data, policies and challenges in four South American Amazon countries: Brazil, Colombia, Peru and the Bolivarian Republic of Venezuela. Challenges to continuing efforts to further decrease malaria incidence in this region include: a significant increase in malaria cases in recent years in Venezuela, evidence of submicroscopic and asymptomatic infections, peri-urban malaria, gold mining-related malaria, malaria in pregnancy, glucose-6-phosphate dehydrogenase (G6PD) deficiency and primaquine use, and possible under-detection of Plasmodium malariae. Some of these challenges underscore the need to implement appropriate tools and procedures in specific regions, such as a field-compatible molecular malaria test, a P. malariae-specific test, malaria diagnosis and appropriate treatment as part of regular antenatal care visits, G6PD test before primaquine administration for P. vivax cases (with weekly primaquine regimen for G6PD deficient individuals), single low dose of primaquine for P. falciparum malaria in Colombia, and national and regional efforts to contain malaria spread in Venezuela urgently needed especially in mining areas. Joint efforts and commitment towards malaria control and elimination should be strategized based on examples of successful regional malaria fighting initiatives, such as PAMAFRO and RAVREDA/AMI.

Cost-effectiveness analysis of rapid diagnostic tests for G6PD deficiency in patients with Plasmodium vivax malaria in the Brazilian Amazon.

BACKGROUND: The use of primaquine (PQ) for radical treatment of Plasmodium vivax in carriers of G6PD deficiency (G6PDd) constitutes the main factor associated with severe haemolysis in G6PDd. The current study aimed to estimate the incremental cost-effectiveness ratio of using a rapid diagnostic test (RDT) to detect G6PDd in male patients with P. vivax malaria in the Brazilian Amazon, in comparison with the routine indicated by the Programme for Malaria Control, which does not include this evaluation. METHODS: A cost-effectiveness analysis of estimated RDT use was carried out for the Brazilian Amazon for the year 2013, considering the perspective of the Brazilian Public Health System. Using decision trees, estimates were compared for two different RDT strategies for G6PDd in male individuals infected with P. vivax before being prescribed PQ, with the routine indicated in Brazil, which does not include prior diagnosis of G6PDd. The first strategy considered the combined use of RDT BinaxNOW(®) G6PD (BX-G6PD) in municipalities with more than 100,000 inhabitants and the routine programme (RP) for the other municipalities. Operational limitations related to the required temperature control and venous blood collection currently restrict the use of RDT BX-G6PD in small municipalities. The second strategy considered the use of the RDT CareStart™ G6PD (CS-G6PD) in 100 % of the municipalities. The analysis was carried out for the outcomes: "adequately diagnosed case" and "hospitalization avoided". RESULTS: For the outcome "adequately diagnosed case", comparing the RDT strategies based on RDT with the routine control programme (RP), the CS-G6PD strategy was the most cost-effective, with BX-G6PD extendedly dominating (the ICER of BX-G6PD compared with RP was higher than the ICER of CS-G6PD compared with RP). CS-G6PD dominated the other strategies for the "hospitalization avoided" outcome. CONCLUSION: The CS-G6PD strategy is cost-effective for adequately diagnosing cases and avoiding hospitalization. This information can help in decision-making, both in incorporating prior diagnosis in the use of PQ and to promote greater safety among G6PD deficient individuals in the Brazilian Amazon P. vivax endemic areas.

G6PD deficiency in male individuals infected by Plasmodium vivax malaria in the Brazilian Amazon: a cost study.

BACKGROUND: Deficiency of the enzyme G6PD (G6PDd) is caused by mutations in the gene G6PD, which plays an important role in protecting the red blood cell against oxidizing agents; it is linked to chromosome X, and it may affects both sexes. The clinically relevant manifestations, such as acute haemolytic anaemia, mainly occur in men, however. The 8-aminoquinoline primaquine, which is the medication used in the radical treatment of malaria caused by Plasmodium vivax, represents the main factor that triggers complications associated with G6PDd. The current study aims to estimate the costs of G6PDd among male individuals infected by P. vivax in the Brazilian Amazon. METHODS: This is an economic analysis developed within the Brazilian National Health System perspective for the years of 2009, 2010 and 2011. Direct medical and non-medical costs were estimated for G6PDd in the Brazilian Amazon, considering among those suffering from the deficiency the costs of diagnosing infection by P. vivax, its treatment and severe adverse events that require hospitalization and were connected to the use of primaquine. RESULTS: The estimates of the average costs of diagnosing vivax malaria, of its treatment and of severe adverse events after using primaquine among the carriers of G6PDd, over the three evaluated years, corresponded to US$ 739,410.42; US$ 2,120.04 and US$ 4,858,108.87, respectively. The results indicate that the average total cost in the study period corresponded to US$ 5,599,639.33, varying in accordance with the sensitivity analysis between US$ 4,439,512.14 and US$ 6,702,619.24. CONCLUSION: The results indicate that the use of primaquine among men with G6PDd who are infected by P. vivax represents a heavy burden on the public health service of Brazil.

Integrated vector management targeting Anopheles darlingi populations decreases malaria incidence in an unstable transmission area, in the rural Brazilian Amazon.

BACKGROUND: Studies on vector behaviour should be conducted in order to evaluate the effectiveness of vector control measures on malaria protection in endemic areas of Latin America, where P. vivax predominates. This work aims to investigate the fauna of anopheline mosquitoes and verify the impact of integrated vector management in two colonization projects in the Careiro Municipality, Western Brazilian Amazon. METHODS: Four mosquitoes' captures were carried out from August 2008 to March 2010, with an interval of six months between each collection. Since September 2009 a large programme to reduce the burden of malaria has started in the two communities by distribution of insecticide-treated bed nets (ITN) and intensification of indoor residual spraying (IRS). Human biting rates (HBRs), entomological inoculation rates (EIRs), malaria incidence rate (MIR) and Plasmodium carrier's prevalence were used as outcomes to estimate the impact of the control measures. RESULTS: A total of 3,189 anophelines were collected, belonging to 13 species. Anopheles darlingi was the predominant species in the period (42.6%), followed by Anopheles albitarsis (38.4%). An. darlingi HBRs showed a notable decreasing trend from the start to the end of the study. Conversely, An. albitarsis increased its contribution to overall HBRs throughout the study. For An. darlingi there was a significant positive correlation between HBRs and MIR (p = 0.002). Anopheles albitarsis HBRs showed a significant negative correlation with the corresponding MIR (p = 0.045). EIR from total anophelines and from An. darlingi and An. albitarsis presented decreasing patterns in the successive collections. Four species of anophelines (An. darlingi, An. albitarsis, Anopheles braziliensis and Anopheles nuneztovari) were naturally infected with Plasmodium, albeit at very low infection rates. There were a decrease in the MIR for both vivax and falciparum malaria and in the prevalence of Plasmodium vivax and Plasmodium falciparum carriers during the period of study. CONCLUSIONS: There is strong evidence of association between the density of An. darlingi and the incidence of malaria in the studies sites, further highlighting the importance of this vector in malaria transmission in this region. An. darlingi susceptibility to control using ITN and IRS is likely to be high in the rural settlements studied.