Improved malaria case management in under-fives in the era of Artemisinin-based combination therapy in Tanzania

Early parasite-based diagnosis of malaria prior to treatment is critical for rational drug use, optimal outcome of febrile illness, patient adherence, prevention of parasite drug resistance, and reduced costs of health services. However, most primary health care (PHC) facilities in subSaharan Africa have no laboratory support and malaria diagnosis is based on clinical symptoms and signs, which are nonspecific. This results in over-diagnosis of malaria, overuse of antimalarial drugs, and failure to identify and treat other causes of fever appropriately. Artemether-lumefantrine (AL) is the most widely adopted artemisinin-based combination therapy (ACT) for treatment of uncomplicated malaria in Africa. However, there is still limited data on its efficacy, effectiveness and safety during extended follow-up and after repeated treatment. Importantly, the effectiveness when used in the home management of malaria (HMM) strategy needs to be assessed. The main aim of this thesis is to improve the quality of malaria case management in government health facilities and specifically to assess the efficacy, effectiveness and safety of AL in under-five children with acute uncomplicated Plasmodium falciparum malaria in Tanzania. In a diagnostic intervention study, antimalarial drug prescriptions were significantly reduced in microscopy-based diagnosis arm (61%) compared to clinical algorithm arm (95%) and no training arm (100%) (both p < 0.001). Of the patients with positive blood smears, 99% were prescribed antimalarial drugs and so were 11% of children with negative readings. Those with positive blood smear readings were less likely to be prescribed antibiotics than those with negative results (relative risk = 0.66, 95% confidence interval: 0.55, 0.72). However, the training did not improve accuracy of microscopy at PHC level when compared to the reference level. In a randomized study on the efficacy of AL and sulphadoxine-pyrimethamine, including methodological objectives regarding the use of PCR-corrected cure rates in antimalarial drug trials, PCR analysis from blood samples collected on consecutive days both at study inclusion and parasite recurrence during follow-up improved identification of recrudescences by about 20% compared with the WHO recommended standard single-day blood sampling protocol. In a randomized trial of supervised versus unsupervised AL intake, the PCR-corrected cure rates were similarly high in both groups, i.e. 98% versus 96% by day 56 after initial treatment, and 93% versus 98% by day 42 after retreatment, respectively, despite that the median blood lumefantrine concentrations on day 7 were significantly higher in the supervised compared with the unsupervised group (after initial treatment [304 versus 194 ng/mL; p<001] and after retreatment [253 versus 164 ng/mL; p=001]). Both regimens were safe and well tolerated after both initial and retreatment. In a single arm effectiveness study of unsupervised AL intake in the context of HMM, the PCRcorrected cure rate by day 42 was 93 %. In conclusion, microscopy-based diagnosis of malaria at PHC facilities reduced prescription of antimalarial drugs and appeared to improve appropriate management of non-malaria fevers. Interpretation of PCR-corrected cure rates in high endemic areas is influenced by methodological aspects such as the blood sampling protocol. AL was highly efficacious and safe for the treatment of uncomplicated malaria. The high effectiveness of AL provides evidence for scaling-up its use within the HMM strategy in Tanzania.