Artemisinin-based combination therapy (ACT) is considered the best available treatment for uncomplicated Plasmodium falciparum malaria, and is at the heart of the global strategy for malaria control [1]. One of the better documented form of ACT is that combining artesunate (AS) and mefloquine (MQ)(ASMQ) [2].
The use of ASMQ was considered in Asia as a strategy to mitigate resurgence of malaria and the intensifying spread of anti-malarial drug resistance well before the World Health Organization (WHO) recommended using ACT. Over the last 20 years, in the low transmission areas of the Thai Burmese border, the combination of AS and MQ has shown high efficacy and has been of great benefit in considerably reducing the transmission of multidrug resistant malaria, as well as reversing the trend of increasing MQ resistance. [2–8].
Safe, rapid, and reliably effective, the combination of AS and MQ is one of five forms of ACT currently recommended by the WHO as a first-line anti-malarial treatment. The WHO also recommends that fixed-dose combinations (FDC) be used whenever possible [1] to increase compliance to treatment. In 2002, in order to address the treatment needs of people most threatened by malaria and underscoring the need for public leadership, the Fixed-Dose Artesunate-Based Combination Therapies (FACT) Consortium, created by the Drugs for Neglected Diseases initiative (DNDi) and the Special Programme for Research and Training in Tropical Diseases (TDR), developed ASMQ as a (FDC). Within the FACT Consortium, Farmanguinhos was the first manufacturing partner of ASMQ FDC. By developing a FDC of well-established use, DNDi and its partners aimed to improve treatment compliance, extend its use in malaria endemic countries and fight more efficiently against resistance development.[9, 10]. This user-friendly new tablet co-formulation, which simplifies treatment with a single daily dose of 1 or 2 tablets for three days, represents an innovation that could have considerable impact in the treatment of uncomplicated P. falciparum malaria. Fixed-dose combinations eliminate the possibility of patients taking only one component of the combination and are expected to improve patient compliance[1]. With specific presentations for children aged between 6 months and 11 years, ASMQ FDC addresses the needs of children, the primary victims of malaria worldwide.
In 2008, approximately 320,000 cases of P. falciparum malaria were reported in Latin America, where Brazil has the highest malaria burden [11]. In Brazil, 99.8 % of malaria transmission occurs in eight states (Acre, Amapá, Amazonas, Mato Grosso, Pará, Rondônia, Roraima, Tocantins and part of Maranhão) that together form the Legal Amazon [12]. With a mean incidence of 500,000 cases/year, malaria affects all age groups equally, except individuals below one year and older than 60 years of age, for whom incidence is lower. Transmission increases during the seasonal peak, when climatic conditions are favourable to vector proliferation. New urban growth has been related to malaria burden in cities, such as Cruzeiro do Sul [12]. A decrease in malaria cases was observed as of 2006, which has been related to several factors, namely the introduction of ACT for P. falciparum malaria treatment, greater investments, capacity building on prevention and control, and epidemiologic data analyses, which allow a focus on malaria burdens in real time, both from decision makers and the populations involved [12]. Malaria risk in Brazil is classified according to the Annual Parasite Incidence (API). High risk areas have an API of ≥50/1000 inhabitants, intermediate areas of 10–49/1000 inhabitants, and low risk areas have an API <10/1000 inhabitants. From 2003–2007, in the Acre, Amazonas and Roraima states of the Legal Amazon, 79 municipalities were classified as high risk, including eleven with an API >300/1000 inhabitants, three of which were areas in the Juruá valley of the Acre State included in the present study: Rodrigues Alves, Mâncio Lima and Cruzeiro do Sul (Figure 1).
Efficacy studies initiated by the Amazon Network for the Surveillance of Antimalarial Drug Resistance (RAVREDA), created in 2001 to monitor Plasmodium resistance, showed cure rates below 90 % for quinine sulphate and doxycycline (at the time, the first-line regimen) for P. falciparum treatment, and prompted the introduction of ACT in 2006 by the National Malaria Control Programme (PNCM). Chloroquine and primaquine 0,50 mg base/kg during seven days remain the treatment for P. vivax malaria [13].
This article presents the results of a phase IV deployment study investigating the impact of fixed-dose ASMQ combination on P. falciparum incidence, P. vivax and P. falciparum ratio, and on the number of hospital admissions in three municipalities in the Amazon Basin (Brazil), characterized by high malaria incidence and concerns of increasing anti-malarial resistance to quinine-doxycycline. The study aimed to assess the suitability of replacing quinine sulphate and doxycycline as a national first-line treatment policy for children and adults with uncomplicated P. falciparum malaria in Latin America. This study is the largest to date on the programmatic use of ASMQ in Latin America.
Study area description and population selection
The study included data collected between July 2004 and December 2008. The ASMQ intervention was carried out between July 2006 and December 2008 in three municipalities in the Juruá valley, within the state of Acre in Brazil: Cruzeiro do Sul, Mancio Lima and Rodrigues Alves (Figure 1). The municipalities were selected because they had recorded more than 20 P. falciparum malaria cases per month between 2003 and 2004, and had a stable population (defined by < 15 % proportion of imported cases), as well as supportive and cooperative local health authorities.
Acre state, situated in the most occidental region of Legal Amazon (Figure 1) has a population of 680,073 inhabitants; 15.2 % (103,371) of the population live in Cruzeiro do Sul, Mâncio Lima and Rodrigues Alves, and account for 86 % of Acre’s malaria cases. The state of Acre has a tropical climate, with temperatures ranging between 22–34 °C (72–93 °F), relative humidity of 60–85 %, and a rainy season that lasts from October through to April.
Malaria epidemiology in Acre
Anti-malarial drug resistance has not been investigated in this region for almost two decades [14, 15]. Acre borders Peru and Bolivia, where until recently first-line treatment regimens for P. falciparum malaria differed from those used in Brazil [13, 16, 17]. As a result, sustained population influx from these countries may affect the local patterns of drug-resistance [14, 15].
Malaria incidence in some areas of the Amazon Basin rose between 2003 and 2005, which was attributed to several environmental and socio-economic factors, including climatic changes, new urban growth, cattle ranching and agricultural practices associated with deforestation) [16, 18]. Public health strategies promoted by the PNCM were not fully implemented. The Ministry of Health initiated a collaborative task force of health managers in the Amazon region to coordinate population movements and to prioritize malaria surveillance, prevention and control[12, 19].
In the Juruá Valley of Acre, Brazil, P. vivax predominates in urban populations, but in 2009, P. falciparum still accounted for more than half of the malaria burden in isolated river communities [16].
The most important malaria vector in Brazilian endemic areas is Anopheles darlingi, and the most vulnerable group consists of low-income workers (fishermen and gold miners) [20–22]. Anopheles darlingi is the main species captured outside and inside the homes of inhabitants of the Juruá valley, in a proportion of 4:1, respectively. The mean rate of An. darlingi per person/hour was 3.2 indoors and 11.5 outdoors. Both inside and outside feeding preferences are from ~8:00 p.m. until ~0:00 a.m. (Izanelda Magalhães, personal communication).
Malaria and vector control programme
The control strategy of the Brazilian National Malaria Control Programme (Programa Nacional de Controle da Malária, PNCM) is based on early diagnosis and treatment, selective vector control interventions, early epidemic detection and involvement of local government and concerned populations. Malaria is diagnosed by rapid tests based on the immunochromatographic method or Giemsa-stained thick blood smears, according to PNCM training recommendations and quality control guidelines. Malaria treatment in Brazil is free of charge, as per government policy.
In 2000, malaria control programmes were decentralized to individual states of Brazil. In Acre state, as 90 % of total cases of malaria occur in the Juruá valley, a regional coordination body for malaria control was created. This organization includes support teams (diagnosis, epidemiology, vector control, health education and social mobilization), information systems as well as administrative and pharmaceutical assistance. In November 2005, intensified malaria control activities included active systematic screening of the population as routine practice, with weekly screenings performed by healthcare workers. Health surveillance workers in each locality collected thick blood smears, administered therapy and provided health education. These agents also prevented prescription mistakes and sought to improve treatment compliance. Local health facilities supported diagnosis and drug distribution. Drug supply was planned according to the number of cases reported for each type of malaria infection (P. falciparum vs. P. vivax). The Brazilian Ministry of Health regulated drug distribution and provided epidemiological data by mapping drugs received, distributed, and consumed.
By 2006–2007, the studied municipalities had a network of 73 diagnostic laboratories, 475 health surveillance workers, and 229 hospital beds. The private sector was also involved. Control strategy results were monitored by the Epidemiological Surveillance Information System Malaria module online database (SIVEP-malaria). Epidemiological and service indicators were evaluated on a weekly basis by the management team and all supervisors, ensuring that all information was disseminated widely.
Vector control strategies included outdoor thermo-nebulization and indoor chemical residual spraying with cipermetrine, and environmental management of larvae control until 2006. Biolarvicide was used in water tanks from December 2005 to July 2007. As of October 2006, the strategy focused mainly on vector control, with the goal of using indoor chemical spraying in 80 % of the highest risk area homes. In December 2007, an intervention with long lasting impregnated bed nets was initiated, where 7,000 insecticide-treated bed nets were distributed to cover 100 % of the population in 13 localities selected on the basis of epidemiological criteria: high disease burden, high proportion of P. falciparum infections, population age range, continuous access to treatment and diagnosis, good management of information systems, evidence of transmission inside the homes, and acceptability of bed nets to the population. These localities also had the least reduction in malaria incidence in previous years compared with other localities in the Juruá valley. Adequate anti-malarial drug control and supplies were available through the cooperation of health authorities and malaria control programs.