Efficacy of Chloroquine and Primaquine for the Treatment of Plasmodium Vivax Malaria in Cruzeiro do Sul, Acre, Brazil

Background The impact of malaria on the health and economic development of human populations is greatest in the tropics and subtropics. The World Health Organization (WHO) has estimated 216 million episodes of malaria in 2010, of which 174 million (81%) were in Africa. There were a total of 655,000 malaria deaths worldwide, approximately 86% of which in children under 5 years of age (WHO 2011). Although the majority of deaths occur among children in sub-Saharan Africa, malaria accounts for considerable morbidity in the Americas, particularly in the Amazon Basin.

Most countries in the Americas have adopted the WHO Global Strategy for Malaria Control, which relies on prompt and effective antimalarial treatment as the major means of reducing malaria morbidity and mortality (WHO 2008). The ultimate success of this strategy rests on the ability of ministries of health to provide antimalarial drugs with proven efficacy. Although a wide variety of methods have been used to assess resistance to antimalarial drugs in vivo methods, in vitro drug sensitivity testing, and molecular analyses, most national malaria control programs rely on data from in vivo efficacy trials to assess the efficacy of the current first- and second-line drugs and to decide if charges in malaria treatment policy are needed.

The most widely used approach to conduct in vivo drug efficacy trials in the Americas follows the guidelines of the WHO (WHO 2009) with the modifications recommended by the Pan American Health Organization for studies in the Americas (PAHO 2003). The goal of such studies is to assess antimalarial drugs currently being used for first-line treatment of uncomplicated malaria. Much of the effort to monitor antimalarial efficacy in the Americas has been done as part of the Amazon Network of Antimalarial Resistance Monitoring and the Amazon Malaria Initiative (PAHO 2012). This information is critical for guiding the development of rational antimalarial drug policies in endemic areas.

Chloroquine-resistant P. vivax was first reported from Papua New Guinea in 1989 in two Australian soldiers (Rieckmann, Davis et al. 1989). In 1995, a study in Irian Jaya, Indonesia showed resistance in at least 44% of the P. vivax patients treated with chloroquine (CQ) (Baird, Basri et al. 1995). Several investigators have reported cases of CQ-resistant P. vivax in South America. In 1996, in Guyana, Phillips et al. reported three patients in whom 25 mg/kg of CQ failed to eliminate parasitemia despite adequate therapeutic blood levels of CQ (Phillips, Keystone et al. 1996). Three years later, in the Brazilian Amazon region, Alecrim et al. reported a 12-year old girl with P. vivax malaria who continued to have parasitemia after receiving a supervised course of 25mg/kg of CQ (Alecrim, Alecrim et al. 1999). More recently, Soto et al. reported three cases of CQ-resistant P. vivax in Colombia (Soto, Toledo et al. 2001). In these last two studies, CQ blood levels were not measured and it is not possible to confirm that adequate therapeutic levels were achieved.

Because of the serious public health implications of CQ-resistant P. vivax in the Americas, it is critically important to limit reports to well-confirmed cases. In most cases, this will require measurement of CQ blood levels and genotyping of parasites from the initial infection and any suspected recrudescence. P. falciparum in vivo trials take advantage of well-established molecular markers that help differentiate cases of recrudescence and reinfection, by polymerase chain reaction (PCR) techniques. Although no universally accepted technique for this purpose exists for P. vivax, investigators plan to use the microsatellites, base pair repeats in the parasite genome, described by Imwong et al (Imwong, Sudimack et al. 2006). Investigators believe that having PCR-corrected analysis is especially important in the context of the long follow-up period, six months, investigators aim for this study.