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Resistance to pyrimethamine and proguanil is due to a single point mutation in the gene that codes for dihydrofolate reductase. A single mutation gives rise to resistance to only one of the drugs. Resistance to both drugs results from several mutations. Chloroquine resistance phenotype is due to a rapid efflux of the drug from the parasite's digestive vacuole. This efflux is associated with a transmembrane permeability glycoprotein, or P-gp, which is similar to the protein implicated in the multidrug resistant phenotype of some cancer cells. However, one or several other poorly understood major gene(s) may be involved. Drugs which can inhibit the supposed affinity of P-gp for chloroquine are under study.

Plasmodium falciparum chloroquine-resistance occurred initially in 1978 in East Africa. Its step by step propagation towards West Africa is due to several factors which coincide with a high increase of population migration and urbanization since the seventies. Several maps show the dynamics of chloroquine-resistance in Africa during that era.

Resistance of Plasmodium falciparum to antimalarial drugs is a growing worldwide problem in endemic areas. This is particularly obvious with chloroquine resistance which has been spreading throughout Africa since 1978. Initially localized on the Eastern coast of the continent, it has recently reached the Atlantic coast although Western Africa is as yet unaffected. This resistance has most probably arisen in the autochtonous population under the selective pressure of insufficient curative treatments as a result of self medication. It is most prevalent in children of urban areas but is often revealed in non immune expatriates. In addition, moderately resistant parasites in expatriates under chemoprophylaxis may lead to an insidious clinical form with a low or even negative parasitemia which raises diagnostic problems. Prophylactic and therapeutic schemes must take this new situation into account.

Twelve recent cases of Plasmodium falciparum malaria presented with unusual clinical and laboratory features. All patients had regularly been taking adequate doses of amino-4-quinolines as prophylaxis. In most cases the symptoms were mild as compared with those in a group of 20 control patients with typical malaria. More surprisingly, parasitaemia was either negative or very weakly positive (less than 1000 infested erythrocytes per mm3). All cases occurred in people returning from areas in which resistance of P. falciparum to these drugs is endemic. Diagnostic problems could be solved in most patients by new immunological techniques relying on the detection of parasitized erythrocytes and plasmodium antigens using a battery of monoclonal antibodies. A physiopathological model explaining why parasitaemia is negative in such cases is suggested.

In a patients with P. falciparum malaria contracted in Thailand, the course of the disease under treatment suggested resistance to both chloroquine and pyrimethamine-sulfadoxine, as well as reduced sensitivity to quinine. This was confirmed by in vitro tests on continuous culture of the strain. Therapeutic success was obtained with a quinine-cycline combination. The problems raised by the emergence of P. Falciparum strains resistant to polychemotherapy are emphasized.

Between April and June 1984, eight chloroquine-resistant P. falciparum malaria cases were observed in non-immune patients after their emergency sanitary return from NE Mozambique. In vivo resistance to amodiaquine and pyrimethamine were demonstrated from two isolates. Radical cure was obtained with mefloquine in all cases. These patients came from an expatriate community of 35 adult men among which six other chloroquine-resistant malarial cases were probable. The epidemic pattern of this chloroquine-resistant focus is underlined.

The duration of action of the drug Antemal, a combination of Pyrimethamine and Sulfametopyrazine, was eveluated in Bobo-Dioulasso, Upper Volta, West Africa, and endemic zone for Plasmodium falciparum malaria. The study was held during the season of maximum malaria transmission. 79 persons presenting with an acute attack of malaria were studied; 37 persons received a single dose of chloroquine sulfate (Nivaquine), at a dose of 15 mg./kg.; 42 persons received a single dose of Antemal at a dose of one tablet (75 mg. of Pyrimethamine and 25 mg. of Sulfametopyrazine) per 10 kg. Clinical and parasitological studies of all subjects occurred on days one, two, three, 10, 17, 24 and 31. Only one of 37 (2.7%) subjects on Antemal had a reappearance of trophozoites, occurring on day 17. Eight of 42 (19.0%) patients taking nivaquine had reappearance of trophozoites, observed between day 23 and 31. Gametocytes were observed in eight of 37 (21.6 %) persons on Antemal and in only one of 42 (2.3 %) persons on Nivaquine. These observations suggest an extended duration of protection from Antemal in semi-immune individuals. Nivaquine appeared as a potent inhibitor of gametocytogenesis.

34 case-reports of type RI resistance of P. falciparum to chloroquine published between 1975 and 1982 are reviewed. The patients were non-immune travellers infected in East Africa and in the neighbouring islands, especially Tanzania, Kenya and Madagascar. The increase in number and level of resistance might be a problem in Africa. A monitoring system of the patient and in the field is proposed and the possibilities of prevention and control are discussed.

In vitro testing of P. falciparum chemosensitivity was assessed from 2 severe malaria cases in which the parasite was thought to be resistant to chloroquine. The 3 following methods were compared in both cases. 1.--Maturation test, carried out before and from the outset of treatment, is a rapid and simple method. Primary efficiency of therapeutic procedures can be estimate and the eventually adjust. 2.--Rieckmann test, on patient blood, measure chemosensitivity of host strain modulated by hosts factors. Initially proposed for epidemiological trials, this method is of interest for the choice of treatment at the end of acute phase in individuals cases. 3.--Strain chemosensitivity measurement, require one or more weeks of Plasmodium cultivation. This value will be very helpful to estimate the sensitivity level of P. falciparum to chloroquine in the outcoming strain area.

After recalling the biochemical and genetic mechanisms of P. falciparum chemo-resistance, the authors report on an analytic study of the factors ruling the apparition and diffusion of resistant strains. The phenomenon is of chromosomic origin. The repetitive and high doses of drugs exert a pressure on the strains which is the main factor for revealing the selecting resistant mutants. Other facilitating factors may operate such as a lack of immunity of the considered population, a possible particular efficiency of some anopheles (more specially A. balabacencis) in the transmission of chloroquino-resistant strains, transfers of population acting either by a massive arrival of persons receptive or carrying resistant plasmodia. The most serious concern is the recent apparition of polyresistant cases in the Indochina Peninsula. The geographical distribution of chloroquino-resistance suggests the existence of two distinct stocks of P. falciparum: one indigenous to Africa and the Atlantic skirt of the American continent, the other to south-est Asia and deep tropical America. Prophylactif consequences, though difficult to apply, are proposed.

We present two cases of Plasmodium falciparum malaria contracted in Douala despite adequate prophylaxis by Fansidar for one and by chloroquine for the other. Failure of curative treatment by Fansidar for the first case (in vitro chloroquine-resistant strain) and by amodiaquine plus erythromycin for the second. After these therapeutic failures, both patients presented without fever, but with splenomegaly and anaemia. The successful therapeutic was mefloquine.