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

Malaria represents a severe public health problem in Brazil, being associated with socio-economic problems and failures in preventive measures and social protection actions [35,36]. It presents probable repercussions in the disease-impoverishment-poverty cycle, and is thus considered one of the diseases associated with poverty worldwide, impacting negatively on family income, which then further increases the vulnerability of the affected populations [37,38]. In recent years, the Brazilian Amazon has presented a sharp decline in the incidence of malaria by P. falciparum; however, the number of people infected by P. vivax has not fallen at the same rate [35], perhaps because the parasite is able to provoke relapses weeks or months after the initial infection [39]. Between the years 2009 and 2011, 767,000 cases of vivax malaria were reported, of which 470,000 occurred in male individuals, affecting mainly men of productive age [8]. However, the female population and those in other age categories also suffer from it, especially children between five and 14 years of age, who may do badly at school due to malaria, thus leading to negative economic impacts and a drop in productivity in the long-term [40].

The high number of cases of vivax malaria is particularly important because PQ has been adopted as the strategy for effecting a radical cure of vivax malaria in Brazil, increasing the risk of severe adverse events and of deaths, since the use of PQ at a dose of 0.5 mg/kg/day, for seven days, may cause acute haemolysis among carriers of G6PDd [5,41]. Although the estimates related to the incidence of severe adverse events and to deaths associated with the use of PQ continue to be imprecise [19], evidence obtained from campaigns that used mass treatment in Azerbaijan, Afghanistan, Tajikistan and Korea demonstrates that rigorous management of the risks may minimize their effects on populations with various degrees of G6PDd [42].

The number of hospitalizations and of deaths presented was calculated from the proportion of hospitalizations (94.29%) and of deaths (2.86%) among the carriers of G6PDd attended in the FMT-HVD [10]. Thus, both proportions represent the situation in a reference centre for treatment, and this may differ from what happens in remote areas and small municipalities in the Brazilian Amazon. In the latter case, the proportion of hospitalizations may have been over-estimated and the deaths under-estimated, given that not only are health resources scarce in these places, but they also present problems of accessibility to health services that offer moderate to high-level technology.

Currently, tafenoquine is at an advanced stage of development and that has presented effectiveness in the prevention of relapse with just one dose, may be able to achieve the desired elimination of vivax malaria, but the fact that it is an 8-aminoquilonine means that it presents the same challenge in relation to safety for use with carriers of G6PDd, reinforcing the discussion about the need to detect the deficiency before starting treatment [6,19,43].

The current research estimated a high number of male individuals with G6PDd exposed to the use of PQ and demonstrates that this deficiency may have an important effect on the need for hospitalization, being associated also with a significant number of deaths in individuals infected by vivax malaria. The direct medical and non-medical costs arising from diagnosis and treatment of vivax malaria and from the severe adverse events resulting from the use of PQ are high for the health service. There is a predominance observed of costs related to complications that occur after the use of PQ, especially those linked to hospitalization, indicating that among those suffering from the deficiency the severe adverse events burden the public health system more than the diagnosis and treatment of vivax malaria. As regards hospitalization, although assistance provided in the ward has predominated, the cost arising from 6% of those with G6PDd who go to intensive care corresponded to 19% of the total hospitalization costs, demonstrating the importance of severely ill patients in the context being researched. The high cost of hospitalization of carriers of G6PDd was also confirmed in another context. An economic evaluation of the cost of this deficiency among Lebanese male newborns identified a cost of US$ 1,450.00 per hospitalization [44]. The average cost presented in Table 3 may be considered high in the Brazilian context, where the SUS budget directed towards surveillance, prevention and control of malaria in 2009, 2010 and 2011 was, respectively, US$ 12,115,577.89; US$ 9,622,159.09 and US$ 9,802,395.21 [45].

Although studies were not identified in the literature that evaluate the cost of G6PDd in the context under research, there are recent publications that indicate how urgent it is to carry out economic evaluations on this topic, highlighting especially the need to estimate the costs and effectiveness of incorporating rapid diagnostic tests (RDTs) to detect G6PDd. These should be used at the point of care before applying PQ [4,6,46], similar to what has been described in the Brazilian context in relation to the cost-effectiveness of RDTs for diagnosing malaria itself [30,47], helping in decision-making on the incorporation or not of this technology. Currently, two RDTs to detect G6PDd in field conditions (BinaxNOW® G6PD and CareStartTM G6PD) have been evaluated in malaria endemic areas [48,49]. However, there are still gaps in knowledge about the performance, stability and costs of RDTs [19].

The acute character of the complication under discussion, associated with the constitutional responsibility of the SUS to guarantee universal, complete and equitable assistance, means that the costs falling to the SUS constitute important data. They may be used to help in decision-making and in the development of other economic studies on the topic, especially ones aiming to evaluate the strategies for prevention of severe adverse events, based on the recommendation for diagnosis of G6PDd before using PQ [19]. In this ambit, it is fundamental that research be carried out in Latin America, aiming to study locally the cost and effectiveness of tests to detect G6PDd in field conditions to reduce the cost of hospitalization [46].

Economic evaluations developed in relation to malaria have become increasingly frequent, especially in Sub-Saharan Africa, in Asia and in South America. White et al. identified that the cost of diagnosing a case of malaria ranged from US$ 0.34 to US$ 9.34, the cost of treating a case of uncomplicated malaria from US$ 2.36 to US$ 23.65 and the cost of a case of complicated malaria from US$ 15.64 to US$ 137.87 [50].

This is the first study of the costs of G6PDd in Brazil, and the results presented here are based on sources of epidemiological and secondary economic data. It should be stressed that there is an absence of precise data concerning G6PDd for the whole of the Brazilian Amazon, which may differ because of the diversity in ethnic origin in the region. Furthermore, the data on prevalence of G6PDd, the proportion of individuals hospitalized, the proportion of deaths, the costs of hospital food and salaries for professionals were obtained in the state of Amazonas and generalized for the nine states that make up the Brazilian Amazon. This may have affected the validity of the cost estimates, although the simulation carried out in the analysis of sensitivity has demonstrated that the uncertainties mentioned did not substantially affect the total cost.