Antimalarial Drug Resistance in Mali
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional

Summary: 
      Resistance of Plasmodium falciparum (malaria) to current antimalarial drugs and the
      continuing development of resistance to new antimalarial formulations is one of the major
      obstacles to effective malaria control and case management. Efficient, comprehensive and
      validated methods for monitoring drug resistance in advance of the development of resistance
      to the antimalarial drugs that are in use are urgently needed. Molecular markers of genetic
      polymorphisms that give rise to resistant P. falciparum parasites and methods in population
      genetics for evaluating the data can be valuable tools for monitoring drug resistance in the
      field. This study aims to:

        1. Prospectively measure the in vivo response of P. falciparum malaria in Mali to several
           different antimalarial drugs and drug combinations: chloroquine (CQ),
           sulfadoxine-pyrimethamine (SP), amodiaquine (AQ), sulfadoxine-pyrimethamine in
           combination with amodiaquine (SP/AQ), amodiaquine in combination with artesunate
           (AQ/AS), sulfadoxine-pyrimethamine in combination with artesunate (SP/AS), and
           artemether-lumefantrine (Co-artem). In one site with preliminary data showing a high
           rate of P. falciparum resistance to mefloquine (MQ), this drug will also be tested.

        2. Measure the frequencies of molecular markers for antimalarial drug resistance, and
           examine how those results relate to the efficacy of these drugs in treating clinical
           malaria

        3. Measure drug levels at 3 days and correlate with efficacy results.

        4. Examine early clinical, parasitologic, and clinical predictors of late treatment
           failure.

        5. Use the knowledge gained in Aims 1-3 to develop a molecular tool for a countrywide
           resistance surveillance system for antimalarial drugs.
    

Detailed description: 
      Resistance of Plasmodium falciparum to current antimalarial drugs and the continuing
      development of resistance to new antimalarial formulations is one of the major obstacles to
      effective malaria control and case management. Parasite populations are highly resistant to
      chloroquine on an almost worldwide basis (Central America and Haiti being the exceptions) and
      resistance to the next line of treatment, SP, is widespread in Asia and large parts of East
      Africa and South America. SP is also now recommended for use as intermittent preventative
      treatment (IPT) in pregnancy, which adds to concerns about the development and spread of SP
      resistance. More expensive combination drug therapy using artesunate and other antimalarials
      in combination is increasingly being recommended in an effort to extend the useful life of
      drugs and to slow the spread of antimalarial drug resistance. In all likelihood, resistance
      will eventually emerge for any new single drug or combination formulation that we deploy in
      the field.

      Given the above, efficient, comprehensive and validated methods for monitoring drug
      resistance in advance of the development of resistance to the antimalarial drugs that are in
      use are urgently needed. Such methods would help malaria control and prevention programs in
      guiding national treatment recommendations and policies. Integrating laboratory expertise,
      analytic methods based on population genetics, and more traditional methods of surveillance
      for anti-malarial drug resistance (e.g. in vivo drug efficacy studies) and networking with
      national and international partners will result in a multidisciplinary, geographically
      diverse team approach to assessing and monitoring drug resistant malaria, as well as
      developing and validating molecular methods. This type of effort will greatly assist in
      maximizing the useful life span of antimalarial drugs and in providing evidence-based
      guidance for drug policy decisions.

      Specific Aims:

        1. Prospectively measure the in vivo response of P. falciparum malaria in Mali to CQ, SP,
           AQ, SP/AQ in combination, AQ/artesunate (AS) in combination, SP/AS, and
           artemether-lumefantrine (Co-artem). In one site with preliminary data showing a high
           rate of P. falciparum resistance to MQ, MQ will also be tested.

        2. Measure the frequencies of dihydrofolate reductase (dhfr), dihydropteroate synthetase
           (dhps), P. falciparum chloroquine resistance transporter (pfcrt) and P. falciparum
           multi-drug resistant (pfmdr 1) genotypes and establish their relationship with in vivo
           resistance to SP (dhfr and dhps), CQ, AQ, SP/AQ, AQ/AS, SP/AS, and MQ.

        3. Measure drug levels at 3 days and correlate with in vivo efficacy results.

        4. Examine early clinical, parasitologic, and clinical predictors of late treatment
           failure.

        5. Use the knowledge gained in Aims 1-3 to develop a molecular tool for a countrywide
           resistance surveillance system for SP, AQ, and MQ.

      Study Design:

      The study will entail two consecutive years of prospective 28 day in vivo drug efficacy
      studies carried out during the rainy season in three different malaria transmission sites:
      Koro (rural town with 71% of resistance to MQ at a lower dose of 15 mg/kg), Pongono (rural
      town with little exposure to antimalarials) and Faladje (rural village with > 30% of
      chloroquine resistance). Children aged 6-59 months with clinical symptoms consistent with
      malaria will be enrolled in the study after screening for fever (axillary temperature >=37.5
      C) and malaria asexual parasites identified by microscopic examination of thick blood films.

      Blood spotted onto filter papers will be collected prior to treatment and during follow up.
      These filter paper samples will be used for the molecular detection of drug
      resistance-conferring gene polymorphisms as well as the HPLC detection and quantification of
      the respective drugs and their relevant metabolites. In vivo data interpretation will be done
      using the WHO 28-day protocol (WHO, 2003) and molecular markers will be used for the
      determination of the genotype resistance index (GRI). Venous blood will be collected at
      enrollment and at the time of in vivo failure to measure in vitro drug efficacy and
      cryopreserve parasites to search for novel molecular markers to new antimalarial drugs.
    

Intervention name(s): chloroquine; sulfadoxine-pyrimethamine; amodiaquine; amodiaquine+artesunate; amodiaquine+sulfadoxine-pyrimethamine; sulfadoxine-pyrimethamine+artesunate; artemether-lumefantrine; mefloquine
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention MeSH terms: Artesunate; Chloroquine; Lumefantrine; Pyrimethamine; Artemether; Sulfadoxine; Artemether, Lumefantrine Drug Combination; Fanasil, pyrimethamine drug combination; Amodiaquine; Mefloquine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: malaria; Plasmodium falciparum; drug resistance; antimalarials; genotype; treatment outcome