Treatment Efficacy and Malaria TRANSmission After Artemisinin Combination Therapy (TRANSACT)

2.1 MALARIA AND ITS TRANSMISSION TO MOSQUITOES Malaria is the most important parasitic disease in the world. Approximately one fourth of the world population is at risk of contracting the disease, and every year more than 2 million people, mainly young children in sub-Sahara Africa, die of malaria. Malaria is caused by single-cell (protozoan) parasites of the genus Plasmodium. Four species can cause human disease: P. falciparum, P. vivax, P. ovale and P. malariae. The parasites are transmitted between humans by the bite of an infected female mosquito (Anopheles). Inside the human body, the malaria parasites multiply rapidly in the liver cells. After approximately six days, parasites leave this organ and subsequently infect red blood cells (erythrocytes). A next wave of Plasmodium replication takes place in the erythrocytes, then the red blood cell bursts, followed by infection of new red blood cells by the parasites. Since this part of the malaria life cycle involves asexual replication, parasites in this phase are referred to as asexual parasites. A small fraction of these asexual parasites develop into sexual stage parasites (gametocytes). Asexual parasites are responsible for malaria morbidity and mortality, while gametocytes ensure transmission of the parasite from humans to mosquitoes. Malaria transmission takes place when mature gametocytes are ingested by mosquitoes that are taking a blood meal. Once ingested, male and female gametocytes merge to form a zygote that develops though an ookinete stage into an oocyst that can be detected on the mosquito midgut within one week after feeding. The oocyst will burst and sporozoites are released that migrate to the mosquito salivary glands. Once the salivary glands are infected with sporozoites, the mosquito is capable of infecting new human beings.

2.2 MALARIA TREATMENT WITH ARTEMISININ COMBINCATION THERAPY (ACT) Accurate diagnosis followed by prompt and efficacious treatment is the backbone of any malaria control programme. However, malaria treatment has been facing huge challenges in recent years. A number of affordable antimalarial drugs have been used to cure malaria since the 1940s: these include chloroquine (CQ), sulphadoxine-pyrimethamine (SP; Fansidar®), mefloquine, amodiaquine (AQ) and quinine. The emergence and spread of resistance to these commonly-used drugs has been largely responsible for the worsening of the malaria situation observed in the past few years.

Across the African continent, guidelines have recently been changed. The World Health Organization (WHO) recommends for falciparum malaria the use of combination therapies, preferably those containing artemisinin derivatives (ACTs - artemisinin-based combination therapies). Artemisinin derivatives, e.g. artesunate, artemether and dihydroartemisinin, being extremely potent antimalarial agents are the ideal partners in combinations with other antimalarials. ACTs have three demonstrable advantages over conventional therapy, i) they are efficacious in treating malaria patients, ii) substantially reduce post-treatment gametocyte carriaga and iii) "protect" the partner drug from selecting resistant parasites.

In Tanzania, both CQ and SP have lost clinical efficacy. CQ was replaced by SP in 2001 and in the year 2006, SP was officially replaced by Artemether-Lumefantrine (AL: Coartem®). The policy change to the artemisinin-based drug AL is in line with the WHO recommendations to shift to ACT as first line antimalarial treatment.

2.3 RESISTANT PARASITES, MALARIA TRANSMISSION AND ACT Parasite resistance against SP has a genetic background in mutations in the parasite dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes. Single nucleotide polymorphisms (SNPs) in these genes are associated with clinical treatment failure. There is now also accumulating evidence that these mutant parasite strains also have a transmission advantage compared to wildtype parasites. Gametocyte carriage is higher for parasite with mutations in the dhfr and dhps genes, even if parasites are successfully cleared due to a longer parasite clearance time. Importantly, these mutant parasites are also more infectious to mosquitoes. These are worrying findings that may explain the rapid spread of parasite resistance in the population. The findings also indicate that gametocytes may be used as an early warning system to indicate the development of parasite resistance: parasite strains that produce most gametocytes are likely to have a reduced susceptibility to the drug.