Plasmodium Vivax Efficacy Trial in Cruzeiro do Sul, Acre, Brazil
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional

Summary: 
      Background: The World Health Organization recommends that antimalarial treatment policies be
      evaluated every few years to check their efficacy. P. vivax malaria is the most common
      species in Brazil and cases are concentrated in the Amazon Region in Brazil.

      Objectives: Assess the efficacy of chloroquine and primaquine for the treatment of P. vivax
      infections in Cruzeiro do Sul, Acre, Brazil.

      Methods: An in vivo drug efficacy study will be conducted in Cruzeiro do Sul, Acre State,
      Brazil. At least 117 study participants ≥5 years of age with parasitologically confirmed P.
      vivax monoinfections will be treated under supervision with chloroquine (CQ) for three days
      at a daily dose of approximately 25 mg/Kg in accordance with the Brazilian National Malaria
      Control guidelines. For patients with normal glucose 6 phosphate dehydrogenase activity
      levels, investigators will add primaquine at dose of 0.5mg/Kg per day for 7 days. Clinical
      and parasitologic parameters will be monitored over a 28-day follow-up period to evaluate
      drug efficacy and for a total period of 168 days (6 months) to evaluate chances of
      recrudescence, relapse, or reinfection. Blood samples will be taken to measure the CQ levels
      in blood on Day 7 and day of failure, if occurring in the initial 28 days of follow up. In
      addition, a blood sample will be collected on filter paper on first day and on day of
      suspected failure to help differentiate parasite genotypes using techniques based on
      polymerase chain reaction. Results from this drug efficacy study will be used to assist the
      Brazilian Ministry of Health in assessing their national malaria treatment policy for P.
      vivax malaria.
    

Detailed description: 
      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.

      Many malaria cases in the Americas are reported in Brazil (Silveira 2001; Oliveira-Ferreira,
      Lacerda et al. 2010). In 2011, 293,701 malaria cases were reported to the Brazilian National
      Reportable Disease Information System. Most of these cases (99.7%) occurred in the Amazon
      region, which encompasses the states of Acre, Amazonas, Amapa, Para, Maranhao, Mato Grosso,
      Roraima, Rondonia, and Tocantins. In this region, socio-economic and environmental
      conditions, such as presence of natural breeding sites and abundance of Anopheles mosquitoes,
      favor malaria transmission. Amazonas, Rondonia, Para, and Acre states were responsible for
      85.5% of malaria cases in 2011 according to the Brazilian National Reportable Disease
      Information System. As in other regions of the world, malaria is seasonal in Brazil, cases
      increase during or after the rainy season (Costa 2009).

      In 2011, 87,6% of malaria cases in Brazil were due to P. vivax alone, 11,3% to P. falciparum
      alone, and approximately 1.1% due to mixed infections with these two species. P. malariae is
      rarely seen in Brazil. Acre state saw a huge increase in malaria cases from 2003 to 2004 and
      from 2004 to 2005, 153% and 63%, respectively(Cesario and Cesario 2006). The Acre
      municipalities of Cruzeiro do Sul, Rodrigues Alves, and Mancio Lima municipalities were
      responsible for 67.7% of malaria cases in the state in 2006, when a malaria epidemic took
      place in this region. Table 1 shows the absolute number of malaria cases in Brazil and Acre
      state and their respective annual parasitologic index (API), which is the number of positive
      malaria slides per 1,000 residents per year.

      Although currently there is no evidence of CQ-resistant P. vivax in Cruzeiro do Sul, Acre
      State, Brazil, the Ministry of Health would like to assess the efficacy of CQ and primaquine
      for the treatment of uncomplicated P. vivax malaria as part their effort to study
      antimalarial drug resistance within the country. This practice is in accordance with current
      WHO recommendations (WHO 2009).

      Objectives

        -  To assess the therapeutic efficacy of CQ and primaquine for the treatment of P. vivax
           malaria in Cruzeiro do Sul, Acre State, Brazil.

        -  Estimate recrudescence and reinfection rates of P. vivax infection after parasite
           clearance with CQ and primaquine.
    

Intervention name(s): Chloroquine; Primaquine
Intervention type(s): Drug; Drug
Intervention description(s): Patients will receive 3-day treatment with chloroquine in accordance to treatment guidelines in Brazil. All patients will receive the same treatment as there is no comparison arm.; Patients will receive 7-day treatment with primaquine, in conjunction with chloroquine, in accordance to treatment guidelines in Brazil. All patients will receive the same treatment as there is no comparison arm.
Intervention MeSH terms: Chloroquine; Primaquine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment