Spatial and Temporal Analyses of\ud Sulphadoxine Pyrimethamine\ud Resistance in African Plasmodium\ud falciparum malaria

Sulphadoxine pyrimethamine resistance (SPR) emerged soon after SP was introduced as\ud first line therapy for malaria in Africa during the 1990s. This thesis presents the first\ud attempt to describe the spatio-temporal distribution of SPR in sub-Saharan Africa.\ud Molecular and in vivo SPR data were gathered from primarily published sources onto a\ud handwritten and digital template, recording the precise geo-location of every data point.\ud The most commonly used methods were the World Health Organisation 1973 and 1996\ud protocols to measure in vivo efficacy and PCR-RFLP for molecular studies. Consistent\ud data gaps with both SPR measures were found in Botswana, Burundi, Cape Verde,\ud Eritrea, Somalia, Togo and Mauritius (chapter two). Three broad categories of molecular\ud resistance emerged, reflecting the distribution patterns of dhfr and dhps point mutation\ud prevalence: (1) scarce partially resistant mutations namely dhps 436A and 613S which are\ud not increasing significantly over time, (2) emerging resistance mutations such as dhfr 164L\ud and dhps 581G which are rare but increasing within distinct geographical foci and (3)\ud major resistance mutations namely dhps 437G and 540E, which are widespread with\ud significantly increased prevalence over time and regional differences (chapter three).\ud Statistical analysis showed that the sensitive dhfr allelic haplotype frequencies decreased\ud over time in all regions whilst the triple mutant increased. The models developed for dhps\ud haplotypes showed a clear East-West divide with the double mutant dominating East\ud Africa and the single mutant occurring mainly in West Africa (chapter four). Standardised\ud in vivo efficacy data were matched with dhfr and dhps haplotypes using the nearest\ud geographic location and study year and then modelled. These analyses showed for the\ud first time, a clear effect of the frequency of dhps allelic haplotypes on SP efficacy (chapter\ud five). These findings are important in the context of continued use of SP in sub-Saharan\ud Africa for intermittent preventive treatment and support the use of molecular surveillance to\ud inform policy on SP use.