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Drug Resistant Malaria in Papua New Guinea and Molecular Monitoring of Parasite Resistance

Marfurt, J. (2006) Drug Resistant Malaria in Papua New Guinea and Molecular Monitoring of Parasite Resistance. Doctoral thesis, University of Basel.

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Malaria is a serious global health problem and in the absence of an effective vaccine, access to safe and effective treatment still remains the mainstay in the control of the disease. However, the efficacy of this control strategy is hampered by the emergence and spread of drug resistant malaria which may lead to excess of mortality. One of the greatest challenges for health authorities of malaria endemic countries is thus to decide on when and how antimalarial drug policy should be changed, so that most of the patients will fully recover from the disease and will be cleared from parasites. The current ‘gold standard’ for the assessment of antimalarial resistance is the estimation of in vivo drug efficacy, whereas in vitro drug sensitivity tests and the analysis of molecular resistance markers in the parasite serve as complementary tools. In the present study, we assessed the relevance of a new appraisal approach for malaria resistance: community-based cross-sectional surveys versus clinical malaria studies, and the usefulness of a new molecular technology for the identification of molecular markers in different parasite genes. The frequencies of single nucleotide polymorphisms (SNPs) in given resistance marker genes, as well as genotype patterns were analyzed in clinical samples and their role in predicting in vivo treatment response was investigated. Furthermore, community drug resistance profiles were correlated with the incidence risk of clinical treatment failure in order to evaluate the relevance and usefulness of such a novel approach in the management of drug use. In Papua New Guinea (PNG), the 4-aminoquinoline drugs amodiaquine (AQ) and chloroquine (CQ) have been first-line treatment against uncomplicated malaria until the late 1990s. At the same time, resistance of Plasmodium falciparum and P. vivax to these drugs had reached unacceptably high levels and health authorities were prompted to revise antimalarial treatment policy in 1997. First efficacy trials with the combination of AQ or CQ plus SP conducted between 1998 and 1999 showed good efficacy against falciparum and vivax malaria and the PNG Department of Health chose these combination regimens to replace the monotherapy with AQ or CQ as the standard first-line treatment against uncomplicated malaria in 2000. The in vivo studies we conducted between 2003 and 2005 were the first ones to assess the therapeutic efficacy of the newly introduced combination regimen against P. falciparum and P. vivax malaria using the revised WHO standard protocol. In our studies conducted in three different areas over the period of three consecutive years, we observed PCR-corrected treatment failure rates up to 28% for P. falciparum and 12% for P. vivax malaria. Regarding former drug history in PNG (i.e., long lasting 4-aminoquinoline use and sporadic use of SP as mass chemprophylaxis or partner drug with quinine for second-line treatment), we found a genetic background in the parasite population that is associated with high CQ as well as moderate pyrimethamine resistance. We also observed the emergence of mutations concordant with a sulphadoxine resistant phenotype, indicating that the efficacy of the sulpha component is already compromised. Further results that identified key pfdhps mutations to be most relevant in predicting treatment failure with the current first-line regimen corroborated our findings that AQ and CQ as inefficacious partner drugs of SP in the new standard treatment were not able to curb both, the progression of pyrimethamine resistance as well as the emergence of sulphadoxine resistance in PNG. We have shown that our community-based molecular monitoring approach was feasible in PNG and that molecular monitoring of parasite resistance can indeed be a valuable supplementary tool in malaria resistance surveillance. However, our data also clearly highlighted several drawbacks of the presently applied methods for the assessment of resistance, the most important being the lack of standardised methods that are applicable in different epidemiological settings. In addition, our data indicate that currently suggested public health models for the molecular monitoring of parasite resistance are not suitable for universal application in settings which are different with regard to several factors such as malaria endemicity, transmission intensity and drug use patterns. To summarize, decreasing in vivo efficacy of the current first-line regimen in PNG and the molecular drug resistance profile of the parasite population consistent with a CQ and SP resistant phenotype strongly indicate that a policy change to artemisinin-based combination therapy (ACT) has to be considered in the near future. We have shown that a careful baseline evaluation of the molecular resistance background is needed for the identification of the most relevant molecular markers for longitudinal monitoring in a given area. The novel DNA microarray-based method which allows the parallel analysis of multiple drug resistanceassociated SNPs has been proven to be a valuable tool to assess the usefulness of each known molecular marker in a particular region with specific drug use. Moreover, the new technology enabled the assessment of molecular markers on an epidemiological scale and hence opened the avenue for the investigation of a more comprehensive community-based monitoring programme. To conclude, the novel technical tool for the assessment of molecular markers of parasite resistance presented in the current study is cheap, easy to use, and applicable in laboratories with limited infrastructure. Moreover, the technology is highly versatile and allows rapid adaptation to specific monitoring needs, the most important at the moment being the close monitoring of resistance to the highly effective artemisinin derivates and potential partner drugs in ACTs. Though molecular markers have been proven to be useful as an early warning system, their usefulness in predicting treatment response and the progression of resistance is still limited. Hence, currently suggested public health models based on molecular data will have to include additional parameters for important determinants of parasite resistance and to be evaluated in varying epidemiological settings before molecular methods may eventually replace in vivo efficacy studies for the surveillance of resistance.

Item Type: Thesis (Doctoral)
Keywords: Malaria, Papua New Guinea, Vaccine, Mortality, Drugs, Plasmodium Falciparum
Subjects: Malaria > Diagnosis & treatment
Divisions: Other
Depositing User: Mr Joseph Madata
Date Deposited: 19 Feb 2013 08:55
Last Modified: 19 Feb 2013 08:55

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