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.

G6PD deficiency in Latin America: systematic review on prevalence and variants.

Plasmodium vivax radical cure requires the use of primaquine (PQ), a drug that induces haemolysis in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals, which further hampers malaria control efforts. The aim of this work was to study the G6PDd prevalence and variants in Latin America (LA) and the Caribbean region. A systematic search of the published literature was undertaken in August 2013. Bibliographies of manuscripts were also searched and additional references were identified. Low prevalence rates of G6PDd were documented in Argentina, Bolivia, Mexico, Peru and Uruguay, but studies from Curaçao, Ecuador, Jamaica, Saint Lucia, Suriname and Trinidad, as well as some surveys carried out in areas of Brazil, Colombia and Cuba, have shown a high prevalence (> 10%) of G6PDd. The G6PD A-202A mutation was the variant most broadly distributed across LA and was identified in 81.1% of the deficient individuals surveyed. G6PDd is a frequent phenomenon in LA, although certain Amerindian populations may not be affected, suggesting that PQ could be safely used in these specific populations. Population-wide use of PQ as part of malaria elimination strategies in LA cannot be supported unless a rapid, accurate and field-deployable G6PDd diagnostic test is made available.

Accuracy and reproducibility of a rapid chromatographic immunoassay for the diagnosis of canine visceral leishmaniasis in Brazil.

BACKGROUND: Visceral leishmaniasis is a major public health concern in Brazil and the domestic dog is the main source of infection. In this study, we aimed to evaluate the accuracy and reliability of a rapid chromatographic immunoassay based on a dual-path platform for the diagnosis of canine visceral leishmaniasis (CVL). METHODS: Sampling consisted of 428 domestic dogs selected from two neighborhoods in the municipality of Fortaleza, Ceara state, Brazil. The reference standard was composed of three parasitological tests and was applied samples from 333 dogs. The rapid test was used to analyse whole blood and serum samples. RESULTS: Accuracy of the rapid test in whole blood samples through visual reading (n=305), serum samples through electronic reading (n=333) and serum samples through visual reading (n=333), yielded sensitivities of 87.5% (21/24; 95% CI: 66.5 to 96.7), 88% (22/25; 95% CI: 67.5 to 96.8) and 88% (22/25; 95% CI: 67.5 to 96.8), and specificities of 73.3% (206/281; 95% CI: 67.7 to 78.4), 68.2% (210/308; 95% CI: 62.2 to 74.3) and 69.2% (213/308; 95% CI: 63.7 to 74.3), respectively. Agreement between the visual and electronic readings in 428 serum samples were classified as almost perfect (Kappa Index=0.88; 95% CI: 0.83 to 0.93). The positive predictive value of the test using whole blood samples was 21.9% for the 7.9% prevalence detected by the reference standard in the study sample. A sensitivity analysis of the positive predictive value revealed that it remained below 50% in scenarios with a prevalence of up to 20%. CONCLUSIONS: The similarity of the accuracy values of the rapid test using whole blood or serum samples, together with its reliable performance in sera through visual and electronic reading, suggests that it may contribute as a screening test for routine use under field-conditions. However, future studies need to improve the accuracy of the test so that it can be successfully implemented in public health programs.

Clinical complications of G6PD deficiency in Latin American and Caribbean populations: systematic review and implications for malaria elimination programmes.

BACKGROUND: Although G6PDd individuals are generally asymptomatic throughout their life, the clinical burden of this genetic condition includes a range of haematological conditions, including acute haemolytic anaemia (AHA), neonatal jaundice (NNJ) and chronic non-sphaerocytic anaemia (CNSA). In Latin America (LA), the huge knowledge gap regarding G6PDd is related to the scarce understanding of the burden of clinical manifestation underlying G6PDd carriage. The aim of this work was to study the clinical significance of G6PDd in LA and the Caribbean region through a systematic review. METHODS: A systematic search of the published literature was undertaken in August 2013. Bibliographies of manuscripts were also searched and additional references were identified. Only original research was included. All study designs were included, as long as any clinical information was present. Studies were eligible for inclusion if they reported clinical information from populations living in LA or Caribbean countries or about migrants from these countries living in countries outside this continent. RESULTS: The Medline search generated 487 papers, and the LILACS search identified 140 papers. After applying the inclusion criteria, 100 original papers with any clinical information on G6PDd in LA were retrieved. Additionally, 16 articles were included after reading the references from these papers. These 116 articles reported data from 18 LA and Caribbean countries. The major clinical manifestations reported from LA countries were those related to AHA, namely drug-induced haemolysis. Most of the published works regarding drug-induced haemolysis in LA referred to haemolytic crises in P. vivax malaria patients during the course of the treatment with primaquine (PQ). Favism, infection-induced haemolysis, NNJ and CNSA appear to play only a minor public health role in this continent. CONCLUSION: Haemolysis in patients using PQ seems to be the major clinical manifestation of G6PDd in LA and contributes to the morbidity of P. vivax infection in this continent, although the low number of reported cases, which could be linked to under-reporting of complications. These results support the need for better strategies to diagnose and manage G6PDd in malaria field conditions. Additionally, Malaria Control Programmes in LA should not overlook this condition in their national guidelines.

Assessment of drug resistance related genes as candidate markers for treatment outcome prediction of cutaneous leishmaniasis in Brazil.

The great public health problem posed by leishmaniasis has substantially worsened in recent years by the emergence of clinical failure. In Brazil, the poor prognosis observed for patients infected by Leishmania braziliensis (Lb) or L. guyanensis (Lg) may be related to parasite drug resistance. In the present study, 19 Lb and 29 Lg isolates were obtained from infected patients with different treatment outcomes. Translated amino acid sequence polymorphisms from four described antimony resistance related genes (AQP1, hsp70, MRPA and TRYR) were tested as candidate markers for antimonial treatment failure prediction. Possibly due to the low intraspecific variability observed in Lg samples, none of the prediction models had good prognosis values. Most strikingly, one mutation (T579A) found in hsp70 of Lb samples could predict 75% of the antimonial treatment failure clinical cases. Moreover, a multiple logistic regression model showed that the change from adenine to guanine at position 1735 of the hsp70 gene, which is responsible for the T579A mutation, significantly increased the chance of Lb clinical isolates to be associated with treatment failure (OR=7.29; CI 95%=[1.17, 45.25]; p=0.0331). The use of molecular markers to predict treatment outcome presents practical and economic advantages as it allows the development of rapid assays to monitor the emergence of drug resistant parasites that can be clinically applied to aid the prognosis of cutaneous leishmaniasis in Brazil.

Early enlargement of an ulcerated area during leishmaniasis treatment with meglumine antimoniate in Brazil.

BACKGROUND: Cutaneous leishmaniasis is a public health problem in Brazil, where meglumine antimoniate is the drug of choice for treatment. Ulcers treated with pentavalent antimonials show increasing diameters during the first weeks of drug exposure. METHOD: We evaluated data from patients previously enrolled into an open study to compare changes in the ulcerated area of 189 lesions in 101 patients with localized cutaneous leishmaniasis caused by Leishmania braziliensis and L. guyanensis who were treated with i.v. meglumine antimoniate (Glucantime), 20 mg kg(-1) day(-1) for 20 days. RESULTS: An average increase in the ulcerated area of 0.3 cm(2) (95% CI 0.13-0.47 cm(2); p = 0.001) was observed at Day 10 compared with the baseline measurement. Comparison of Day 20 with Day 10 showed a significant decrease of 0.76 cm(2) (95% CI 0.53-0.99 cm(2); p < 0.001) in ulcer size. At Day 50, compared with Day 20, the ulcerated area was decreased by 0.77 cm(2) (95% CI 0.53-1.01 cm(2); p < 0.001). CONCLUSION: We conclude that early enlargement of the ulcerated area during treatment of localized cutaneous leishmaniasis with antimonials in Brazil is a common feature and easily detected by the 10th day of treatment. Following the end of the treatment period (20 days), it would be reasonable to observe a significant decrease in size of the ulcerated area.

Cost-effectiveness of diagnostic for malaria in Extra-Amazon Region, Brazil.

BACKGROUND: Rapid diagnostic tests (RDT) for malaria have been demonstrated to be effective and they should replace microscopy in certain areas. METHOD: The cost-effectiveness of five RDT and thick smear microscopy was estimated and compared. Data were collected on Brazilian Extra-Amazon Region. Data sources included the National Malaria Control Programme of the Ministry of Health, the National Healthcare System reimbursement table, laboratory suppliers and scientific literature. The perspective was that of the Brazilian public health system, the analytical horizon was from the start of fever until the diagnostic results provided to patient and the temporal reference was that of year 2010. Two costing methods were produced, based on exclusive-use microscopy or shared-use microscopy. The results were expressed in costs per adequately diagnosed cases in 2010 U.S. dollars. One-way sensitivity analysis was performed considering key model parameters. RESULTS: In the cost-effectiveness analysis with exclusive-use microscopy, the RDT CareStart™ was the most cost-effective diagnostic strategy. Microscopy was the most expensive and most effective, with an additional case adequately diagnosed by microscopy costing US$ 35,550.00 in relation to CareStart™. In opposite, in the cost-effectiveness analysis with shared-use microscopy, the thick smear was extremely cost-effective. Introducing into the analytic model with shared-use microscopy a probability for individual access to the diagnosis, assuming a probability of 100% of access for a public health system user to any RDT and, hypothetically, of 85% of access to microscopy, this test saw its effectiveness reduced and was dominated by the RDT CareStart™. CONCLUSION: The analysis of cost-effectiveness of malaria diagnosis technologies in the Brazilian Extra-Amazon Region depends on the exclusive or shared use of the microscopy. Following the assumptions of this study, shared-use microscopy would be the most cost-effective strategy of the six technologies evaluated. However, if used exclusively for diagnosing malaria, microscopy would be the worst use of resources. Microscopy would not be the most cost-effective strategy, even when structure is shared with other programmes, when the probability of a patient having access to it was reduced. Under these circumstances, the RDT CareStart™ would be the most cost-effective strategy.

Multi-centric prospective evaluation of rk39 rapid test and direct agglutination test for the diagnosis of visceral leishmaniasis in Brazil.

The diagnosis of visceral leishmaniasis (VL) is still a major problem in Brazil and several other countries where the disease is endemic. The use of an easy-to-use and interpret, sensitive, and specific method that requires no complex infrastructure or specialized professionals, such as direct agglutination test (DAT) and the rK39-based rapid immunochromatographic test may enhance the diagnosis of disease. This study evaluated the performance of a rapid test (DiaMed- IT-LEISH®) and the DAT for the diagnosis of VL in 213 parasitologically confirmed cases and 119 controls with clinical suspicion of VL and confirmation of another etiology. The sensitivities and specificities of the rapid test were 93% and 97%, respectively and those of the DAT were 90% and 96%, respectively. The positive predictive values of the rapid test and the DAT were 98% and 97%, respectively and the negative predictive values were 89% and 84%, respectively. The Kappa index showed agreement between both methods classified as substantial (0.77). This study showed that the DAT and the rapid test can be used to diagnose VL in Brazil, following a pilot study for implementation of the rapid test in the health services.

Targeted gene expression profiling in Leishmania braziliensis and Leishmania guyanensis parasites isolated from Brazilian patients with different antimonial treatment outcomes.

In Brazil, cutaneous leishmaniasis represents a serious public health problem, and chemotherapy is an important element of the clinical management of this disease. However, treatment efficacy is variable, a phenomenon that might be due to host and parasite (e.g., drug resistance) factors. To better understand the possible contribution of parasite factors to this phenomenon, we characterised 12 Leishmania braziliensis (LB) and 25 Leishmania guyanensis (LG) isolates collected from patients experiencing different antimonial treatment outcomes. For each isolate, promastigote cultures were grown in duplicate and were harvested at the late-log and stationary phases of growth. The RNA expression profiles of six genes encoding proteins with roles in antimony metabolism (AQP1, MRPA, GSH1, GSH2, TRYR and TDR1) were assessed by means of real-time quantitative PCR. Molecular data were compared to the clinical phenotypes. Within LB, we did not find statistically significant differences in the expression levels of the examined genes among isolates from patients with different treatment outcomes. In LG, GSH1 (encoding gamma-glutamylcysteine synthetase, gamma-GCS) was overexpressed in therapeutic failure isolates regardless of the growth curve phase. This finding reveals the predictive potential of promastigote expression curves for the prognosis of cutaneous leishmaniasis caused by LG in Brazil.

Control of visceral leishmaniasis in latin america-a systematic review.

BACKGROUND: While three countries in South Asia decided to eliminate anthroponotic visceral leishmaniasis (VL) by 2015, its control in other regions seems fraught with difficulties. Is there a scope for more effective VL control in the Americas where transmission is zoonotic? We reviewed the evidence on VL control strategies in Latin America-diagnosis, treatment, veterinary interventions, vector control-with respect to entomological and clinical outcomes. METHODOLOGY/PRINCIPAL FINDINGS: We searched the electronic databases of MEDLINE, LILACS, and the Cochrane Central Register of Controlled Trials, from 1960 to November 2008 and references of selected articles. Intervention trials as well as observational studies that evaluated control strategies of VL in the Americas were included. While the use of rapid diagnostic tests for VL diagnosis seems well established, there is a striking lack of evidence from clinical trials for drug therapy and few well designed intervention studies for control of vectors or canine reservoirs. CONCLUSION: Elimination of zoonotic VL in the Americas does not seem a realistic goal at this point given the lack of political commitment, gaps in scientific knowledge, and the weakness of case management and surveillance systems. Research priorities and current strategies should be reviewed with the aim of achieving better VL control.

Estudo terapêutico aberto com sulfato de aminosidine na leishmaniose mucosa causada por Leishmania (Viannia) braziliensis / Open therapeutic study with aminosidine sulfate in mucosal leishmaniasis due to Leismania (Viannia) braziliensis

From September to November 1994. 21 patients with active mucosal leishmaniasis were treated with aminosidine sulphate 16 mg/kg/day by intramuscular injection for 20 days. They were principally adult male agricultural workers. Thirteen patients had not received specific treatment and eight had failed to respond to Glucantime therapy. Diagnosis was based on clinical and epidemiological observations, a search for the parasite, leishmanin skin sensitivity and indirect fluorescent antibody serological tests. Sixty seven percent of patients had leishmania parasites isolated from inoculated hamsters or visualized in imprints or histopathological sections. The mean follow-up period was 12.6 months. All patients completed treatment. Side effects were pain at the injection site (86 per cent); mild proteinuria (24 per cent), elevated serum creatinine (.5 per cent) and subclinical bearing loss in one of two patients who did audiometric tests. Clinical cure was achieved in 48 per cent and the accumulated relapse rate was 29 per cent(4/14).