Despite unprecedented decline in global malaria burden due to increased interventions, malaria infections still claims over 400,000 people annually, most of them being vulnerable children in sub-Saharan Africa. Among other factors, the deployment of artemisinin-based combination therapies (ACTs) as the first-line treatment was shown to have substantial contribution in averting the malaria disease incidence and mortality in the continent. Malaria treatment depends heavily on artemisinin-based combination therapies (ACTs) for treatment, which synergistic action of an artemisinin-based derivative and partner antimalarial component. The ACTs are widely used in endemic settings in sub-Saharan Africa as the first line drugs.
Recently, the drug were also recommended as rescue option for patients with recurrent malaria infections. However, it is unclear if (re-)treatment with ACTs could lead to drug-mediated selection of resistant strains in clinical settings. In addition, the emergence and spread of ACT resistance in the Great Mekong sub-region is alarming as it could imperil the gains in malaria control. In ensuring the ACTs remains effective in achieving adequate clinical and parasitological response, it is crucial that both the artemisinin derivatives and partner component remain potent. To date, de-facto artemisinin resistance is yet to be confirmed in Africa; however, continued efforts are needed to track parasite resistance or reduced susceptibility to both artemisinin derivatives and the partner components.
In addition, sulphadoxine-pyrimethamine (SP) is still recommended by WHO for intermittent preventive treatment (IPTp) and seasonal malaria chemoprevention (SMC) strategies. However, emerging and spread of high-grade resistant haplotypes due to step-wise accumulation of mutations in P. falciparum dihydropteroate synthase (Pfdhps) could compromise the effectiveness of SP in chemoprevention strategies in the region.
In this thesis, we provide molecular evidence on the impact of ACTs in (re-)treatment approach on selection for parasite genetic signatures (and human genetic variation) associated with P. falciparum resistance or decreased sensitivity in clinical settings (paper III-V). Furthermore , we describe SP-resistance pattern in Tanzania where novel Pfdhps A581G was first described (paper I) and highlights the parasite genetic structure and dispersal of high-grade Pfdhps resistant haplotypes in East and Central Africa (paper II) . The results are important to guide implementation ACTs and of SP in malaria control and elimination strategies in the region. Continued monitoring of genetic signatures of resistance is warranted to maintain
the efficacy of ACTs and guide SP-based chemoprevention strategies in the region.