The problem of Plasmodium falciparum drug resistance in Africa south of the Sahara

Bulletin of the World Health Organization, 62 (Suppl.): 55 -62 (1984) © World Health Organization 1984 The problem of Plasmodium falciparum drug resistance in Africa south of the Sahara E. ONORII The resistance of P. falciparum malaria to dihydrofolate reductase inhibitors, to the 4-aminoquinolines (in particular, chloroquine), and to the combination sulfadoxine-pyri- methamine is reviewed in the light ofpast and the most recent findings. Considering the gravity of the situation following the recent discovery of resistance of P. falciparum to chloroquine among the semi-immune populations of Africa south of the Sahara, a few suggestions are madefor a realistic and rational approach to the drug resistance problem. Some questions that may be worthy of applied field research are briefly mentioned and governments are invited to take the necessary action to ensure better control of the pro- curement, distribution, and use of antimalarials. The relatively recent discovery of resistance to chloroquine in Plasmodium falciparum in East Africa, first in the non-immune and more recently among the semi-immune population, is certainly a matter of serious concern. This concern is even more justified by the actions being promoted by African countries for the prevention or reduction of malaria mortality and reduction of morbidity through the use of drugs. An assessment of the present situation with regard to P. falciparum sensitivity to different antimalarials in tropical Africa may provide some guidance for a more correct selection and better utilization of drugs for both chemotherapy and chemoprophylaxis of P. falciparum infections. With this in mind, an attempt has been made to update the available in- formation on the P. falciparum drug resistance problem in tropical Africa and to discuss briefly its implications. RESISTANCE OF P. FALCIPARUM TO DIHYDROFOLATE REDUCTASE INHIBITORS This group of compounds includes proguanil, chlorproguanil, pyrimethamine, and cycloguanil embonate. These drugs have been used mainly for prophylaxis or presumptive treatment; for radical treatment, pyrimethamine is given in combination with long-acting sulfonamides, especially in chloro- I Chief Medical Officer, Epidemiological Methodology and Evaluation, Malaria Action Programme, World Health Organiz- ation, Geneva, Switzerland. quine-resistant P. falciparum malaria. Another member of this group is trimethoprim, which has been used very rarely for the radical treatment of P. falciparum, in combination with sulfa drugs. Resistance of P. fakciparum to pyrimethamine in tropical Africa was detected as early as 1954 (1). In subsequent years, P. falciparum resistance to di- hydrofolate reductase inhibitors was discovered in several countries of West and East Africa, to the ex- tent that in 1970 it was possible to talk of the "saga of pyrimethamine resistance in Africa" (2). A map (Fig. 1) showing the distribution of resist- ance to dihydrofolate reductase inhibitors in tropical Africa has been drawn on the basis of published in- formation on P. fakciparum resistance to proguanil, chlorproguanil, pyrimethamine, and cycloguanil embonate up to 1970. More recently, pyrimethamine resistance has been reported from northern Liberia (Bjorkman, personal communication) and Kenya (3) and this is also shown in the map. In Liberia, the distribution of pyrimethamine resistance was found to be patchy; in the absence of pyrimethamine re- sistance, chlorproguanil was given as a prophylactic for a few years without the parasite becoming resist- ant to the drug, whereas chlorproguanil resistance developed quickly in the presence of pyrimethamine resistance. This is an interesting experience, since cross-resistance among different dihydrofolate re- ductase inhibitors is a very common, even though not a constant, phenomenon. In conclusion, P. falciparum resistance to di- hydrofolate reductase inhibitors is a widespread phenomenon in subtropical Africa and perhaps much more common than the map would indicate if anec- dotal evidence is taken into account. 4468 -55- E. ONORI Fig. 1. Countries in tropical Africa where P. falciparum resistance to one or more dihydrofolate reductase inhibitors has been documented. RESISTANCE OF P. FALCIPARUM TO 4-AMINOQUINOLINES In 1970, it was possible to state that P. falciparum resistance to chloroquine had never been convin- cingly demonstrated in the African continent (4). In the following years, however, reports from Ethiopia (5), Nigeria (6), the Sudan (7), and Zambia (8) raised very strong suspicions that chloroquine- resistant P. falciparum malaria had emerged in those countries. They were not accepted as definite proof simply because the criteria established by WHO for the confirmation of resistance had not been fully respected. The first well documented case of P. falciparum resistance to chloroquine was reported in 1979 in an American tourist who had contracted the disease in Kenya (9). Since then, cases of P. falciparum resist- ant to chloroquine have continued to be found at an unrelenting speed among non-immune persons visit- ing East Africa (10-12). Chloroquine resistance of P. falciparum at the RI 56 PLASMODIUM FALCIPARUM DRUG RESISTANCE 57 ' ; 9 : X $ tS'cI;IN * 1 0ooecssio-mue0 O Less than 10 cases in non-immunes A10 or more cases in non-immunes * Less than 10 cases in semi-immunes A 10 or more cases in semi-immunes Fig. 2. Distribution of P. falciparum chloroquine resistance in tropical Africa: status as at October 1 983. level was found among semi-immune persons in the United Republic of Tanzania from 1981 onwards' (13, 14) and in Kenya (15). Resistance at the RII and RIII levels among semi-immune persons has been found more recently in Gabon (16), Madagascar (17), the Sudan,b the United Republic of Tanzania (Zanzibar) (18), Zaire (19), and Zambia (20), and a VERNAJ, F. ET AL. Chloroquine-resistant malaria cases imported from Tanzania. Unpublished document, WHO/MAL.81.943 (1981). b AL TAWIL, N. & AKOOD, M. A. Response offalciparum mal- aria to a standard regimen of chloroquine in Khartoum Province, Sudan. Unpublished document, WHO/MAL.83.991 (1983). among non-immune persons in Kenya (22) and the United Republic of Tanzania (22-24). The latest re- ports of P. falciparum resistance to chloroquine have come from Mozambiquec and Malawi (25). Of im- portance is the presence of P. falciparum resistance to amodiaquine (RII level) in Zanzibar (46). In recent years, we have thus witnessed a rapid development of chloroquine-resistant P. falciparum and its spread from East Africa to other countries of the continent (Fig. 2). However, although the phenomenon ALMEIDA FRANCO, L. T. WHO unpublished report (no num- ber), 1983. 58 E. ONORI requires further investigation, especially in West Africa, and continuous monitoring, the distribution of resistant parasites and their degree of resistance is far from being uniform. From published and unpublished information, an evaluation has been made of in vitro tests for chloro- quine sensitivity in P. falciparum by probit analysis of log/dose response from 3-8 point assaydand the results are summarized in Table 1 and Fig. 3. The regression lines indicate that, on the basis of the micro in vitro tests carried out in different areas, the P. falciparum populations showed significant differ- ences with regard to chloroquine sensitivity. Highly sensitive populations prevailed at Shirati (United Re- public of Tanzania) in 1979-80 and at Buyo (Ivory Coast) in 1983, whilst incipient resistance was found at Mto-wa-Mbu (United Republic of Tanzania) in 1981 and by 1982 resistant populations were well rep- resented at Shirati and Lambarene (Gabon) and even more so in Zanzibar (United Republic of Tanzania). d GRAB B. & WERNSDORFER, W. H. Evaluation of in vitro tests for drug sensitivity in Plasmodium falciparum: probit analysis of log/dose response test from 3-8 point assay. Unpublished docu- ment, WHO/MAL.83.990 (1983). RESISTANCE OF P. FALCIPARUM TO PYRIMETHAMINE-SULFADOXINE P. falciparum malaria resistant to the combination pyrimethamine-sulfadoxine (Fansidar) has recently been reported from East Africa. It has been detected among non-immune persons visiting Kenya (26, 27) and the United Republic of Tanzania (27-30) and in a semi-immune person in the latter country (31). One case of P. falciparum resistant to pyrimetha- mine-dapsone (Maloprim) has also been found in a non-immune person visiting Kenya (32). These preliminary reports on P. falciparum resistance to pyrimethamine-sulfadoxine and pyrimethamine- dapsone should be viewed with great concern. These drug combinations have never been widely used in Africa for the treatment of malaria and the distri- bution of the resistant parasites and their degree of resistance is little known because of the lack of ex- tensive surveys and of suitable in vitro test methods. The resistance of P. falciparum to pyrimethamine is quite widespread on the African continent and it would appear that, once established, it can remain 99.9 SENSITIVE RESISTANT 99.0 c 95.0 1 E 80.0 ON 70.0 60.0 --~ 0 50.0 .2 40.0 -~ ~ -C20.0 - cL 5.0 1.0 0.01 0.10 0.20 0.40 0.80 .1.14 1.60 3.20 6.40 10.00 Threshold at EC x 1O-6 mol chloroq uine/litre blood WHO 84686 Fig. 3. Inhibition of schizont maturation in the in vitro chloroquine microtest, showing probit regression lines for six different studies. PLASMODIUM FALCIPARUM DRUG RESISTANCE 59 Table 1. Results of an evaluation of in vitro tests for chloroquine sensitivity in P. falciparum by probit analysis of log/dose response from 3-8 point assays. Plotting points at various levels of Number Variance effective concentration of chloroquine of of Country/location Year isolates Slope slopes EC10 EC50 EC90 EC95 EC9 U. Rep. of Tanzania/Shirati (1) 1979-80 73 2.229 0.008 0.017 0.066 0.247 0.359 0.726 U. Rep. of Tanzania/Mto-wa-Mbu 1981 21 3.920 0.051 0.163 0.345 0.733 0.907 1.354 U. Rep. of Tanzania/Shirati (2) 1982 30 2.169 0.099 0.054 0.210 0.819 1.204 2.483 U. Rep. of Tanzania/Zanzibar 1982 30 1.652 0.007 0.160 0.955 5.695 9.449 24.442 Gabon/Lambarene 1982 14 2.485 - 0.0774 0.2537 0.8317 1.1645 2.1907 Ivory Coast/Buyo 1983 1 9 2.1 9 0.11 0.017 0.066 0.255 0.373 0.776 and spread even many years after the withdrawal of the drug.e The resistance of P. falciparum to pyri- methamine-sulfadoxine seems to be linked to the presence of parasites highly resistant to pyrimetha- mine, as the presence of a medium level of pyrimetha- mine resistance per se does not seem to preclude the curative effect of the combination of drugs (33). It may also be a necessary condition for the develop- ment of resistance to the combination that P. fal- ciparum parasites should be resistant to both pyri- methamine and sulfadoxine, a likely event since sulfonamides have been widely used in Africa for other bacterial diseases. The reservations expressed in 1969 concerning the use of long-acting sulfonamides in association with pyrimethamine for the treatment of P. falciparum malaria in Africa (34) have now become more relevant in the light of recent findings. It is also important to remember that pyrimetha- mine-sulfadoxine should not be given during the first three months of pregnancy or to infants and that cases of agranulocytosis associated with pyri- methamine-dapsone (35-37) and cases of Stevens- Johnson syndrome following pyrimethamine-sul- fadoxine prophylaxis (38-39) have been reported recently. RESISTANCE OF P. FALCIPARUM TO QUININE In Africa south of the Sahara, P. falciparum has always proved to be highly sensitive to quinine and there do not appear to be any reports of quinine resistance from this part of the world. However, variations in the response of P. falciparum to quinine may occasionally be encountered and, since there may be some association between quinine resistance and chloroquine resistance (40), the sensitivity of e KOUZNETSOV, R. L. ET AL. Spread of pyrimethamine-resistant strains of Plasmodium falciparum into new areas of north-east Tanzania in the absence of drug pressure. Unpublished document, WHO/MAL/80.926 (1980). P. falciparum to quinine should be monitored in those areas where chloroquine resistance is already established. DISCUSSION Large-scale vector control operations are at present not feasible for malaria control programmes in tropi- cal Africa, owing to the magnitude of the adminis- trative, operational, technical, and logistic problems encountered in the area. The most recent attempt to reduce specific mortality and morbidity by making drugs available to the rural African population is being greatly jeopardized by the appearance and rapid spread of drug-resistant P. falciparum malaria. At this stage, what seems to be urgently required is a judicious selection and proper use of the available compounds and the promotion of research activities that may answer some outstanding questions. Some elements that may be worthy of consider- ation are summarized below. Antimalarials are used for prophylaxis and treat- ment. From what has been said above about the resistance of P. falciparum to chloroquine, it would appear that this drug should no longer be used for chemoprophylaxis in the tropical African environ- ment. Despite the widespread P. falciparum resistance to dihydrofolate reductase inhibitors, some clinicians still recommend proguanil at the increased daily dosage of 200 mg (adult dosage) as a prophylactic (41, 42). This view is not unchallenged. Proguanil is not recommended in WHO-supported programmes because of the lack of sufficient documented evidence of the efficacy of proguanil in the presence of pyri- methamine resistance and the ease with which resist- ance to dihydrofolate reductase inhibitors develops under drug pressure. Chlorproguanil may have some advantages over proguanil since it is retained in the E. ONORI human body much longer than proguanil. From recent experiences, it would appear that its adminis- tration at regular intervals for the protection of vulnerable groups of the population may be recom- mended, but only in the absence of pyrimethamine resistance; this greatly limits its use on a large scale. Long-acting sulfonamides with pyrimethamine cannot be recommended for chemoprophylaxis and their use should be reserved for the radical treatment of P. falciparum infections resistant to chloroquine (43). Primaquine has a sporontocidal and gametocyto- cidal effect. It can be added to the drugs used for the radical treatment of P. falciparum infections, especially if treatment facilities become more easily available. This may curtail the transmission of drug- resistant parasites. Appropriate studies may be indi- cated, even in areas where the transmission potential is very high. The discovery of chloroquine-resistant P. falci- parum among the semi-immune populations of Africa is an undeniable proof of the potential gravity of the present situation. However, there is no reason for generalizing from only a few, though well estab- lished, facts. Studies on the distribution of chloro- quine resistance in P. falciparum in Africa are still fragmentary and from these reports (some shown in Fig. 3) and others that have appeared in the literature (44, 45), it is evident that there are still large areas in Africa where chloroquine is highly effective. The situation may be in an evolutionary phase, hence the necessity to study chloroquine sensitivity of P. falci- parum in different geographical areas of tropical Africa and to monitor it in subsequent years. Con- currently, proper guidance in the use of 4-amino- quinolines should be derived from past and more recent epidemiological experiences. From the knowledge at present available it would appear that chloroquine resistance has been selected and enhanced by drug pressure. In P. falciparum chloroquine resistance has been found in Madagascar where the drug has been used for chemoprophylaxis in schoolchildren since 1949; it has also been found in the United Republic of Tanzania where enormous quantities of the drug have been imported in recent years and used for both chemoprophylaxis and treat- ment. The evolution of P. falciparum chloroquine sensitivity in the Shirati area in the north of the United Republic of Tanzania is also interesting and informative (Fig. 3): chloroquine was introduced in this area in 1978 and continued to be administered at regular intervals up to the end of 1982 as a chemo- suppressant in schoolchildren up to 10 years of age. There is certainly a need for a more rational use of chloroquine. In endemic areas where P. falciparum is still sensitive to 4-aminoquinolines, these drugs can and must still be used for the radical treatment of the disease, but they must be given at sufficiently high doses to obtain radical cure. In many areas of tropical Africa, a radical cure is no longer attainable with a single-dose treatment (10 mg base per kg body weight) as was the case a few years ago. Great diffi- culties are to be expected if the single dose has to be replaced by the 3-day treatment (25 mg total dose of base per kg) and simple trials may be required in dif- ferent countries. Cases not responding to the 3-day chloroquine treatment should be given quinine for five days or a single dose of 1500 mg of sulfadoxine and 75 mg pyrimethamine (adult dose). Under no circumstances should pyrimethamine-sulfadoxine (Fansidar) be used for radical treatment of P. falci- parum infections in areas where the parasites are still fully sensitive to the 4-aminoquinolines. There is an urgent need for African governments to formulate and implement a malaria drug policy aimed at controlling the importation and production of antimalarial drugs, their distribution to the private and public sectors, and their utilization. RESUME LE PROBLEME DE LA RESISTANCE AUX MEDICAMENTS DE PLASMODIUMFALCIPARUM EN AFRIQUE SUBSAHARIENNE La situation actuelle en ce qui concerne la sensibilite de P. falciparum aux inhibiteurs de la dihydrofolate-reductase, aux amino-4 quinoleines (notamment la chloroquine), a l'association sulfadoxine-pyrimethamine et a la quinine en Afrique tropicale est examinee a la lumiere de l'experience anterieure comme des resultats les plus recents. La resis- tance largement repandue de P. falciparum aux antifoliques et, ce qui est plus important, l'implacable propagation de la resistance de ce meme parasite aux amino-4 quinoleines, constituent les traits les plus marquants et les plus in- qui6tants qui se degagent de cette etude. L'examen de la litterature sur le sujet montre que l'on assiste a une modification de la reponse a la chloroquine chez des souches de P. falciparum preleves dans plusieurs pays d'Afrique. D'oii l'urgence de mener d'autres etudes sur la distribution de ce phenomene dans differentes regions geographiques du continent et d'en surveiller l'evolution dans les annees a venir. Le probleme de la resistance a la chimiotherapie est sans doute preoccupant, mais l'affole- ment n'est pas de mise. Ce dont on a besoin de toute urgence, c'est d'une selection judicieuse et d'une bonne utilisation des produits existants. A cet effet on peut tirer des donnees epidemiologiques, ou mieux, des recherches de terrain esquissees dans l'article, de precieuses indications. 60 PLASMODIUM FALCIPARUM DRUG RESISTANCE 61 REFERENCES 1. AVERY-JONES, S. Resistance of Plasmodiumfalciparum and Plasmodium malariae to pyrimethamine follow- ing mass treatment with this drug. A preliminary note. E. Afr. med. j., 31: 47-49 (1954). 2. PETERS, W. Chemotherapy and drug resistance in malaria. London & New York, Academic Press, 1970. 3. NGUYEN-DINH, P. ET AL. 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