Editorials
425
Control of Falciparum Malaria Forty years ago, when D D T and Dieldrin were cheap and effective, before mosquitoes started to develop resistance to insecticides, and when the malarial parasites were still susceptible to most of the therapeutic drugs, and before civil wars in so many areas put a stop to efforts at vector control, there seemed to be a real chance that the W H O campaign to eradicate malaria could be successful. Our optimism was misplaced. The prevalence of malaria is rising again. Some territories from which malaria had been eradicated in the 1950s have been recolonised by the parasite, but now by a different type. Where formerly there had been vivax (benign tertian) malaria there is now the more dangerous falciparum variety. In many parts of Asia and sub-Saharan Africa P. falciparurn has become resistant to chloroquine, proguanil and to combinations of pyrimethamine with sulphadoxine (Fansidar) or dapsone (Maloprim).l Even taking double the usual prophylactic dose of both chloroquine and of proguanil fails to protect the traveller to Kenya or Tanzania. Logically we should have expected the development of drug resistance, since the risk was inherent in our policy of giving minimal doses of antimalarial drugs to large numbers of people for prophylaxis, and in particular when we started using the same drug for prophylaxis as we used to treat the disease. Whenever a large number of subjects exposed to an infective agents take low doses of a drug to suppress infection, drug resistance is likely to develop. Variation is an essential feature of all living organisms. Without it they could not have evolved. In any large population of protozoa or bacteria a few deviants will arise which are relatively more tolerant of the drug than the rest. T h e r e will also be a few of the potential hosts who fail to achieve the necessary concentration of the drug, either because of impaired absorbtion, or because undesirable side-effects caused them to stop taking it. In such hosts the more susceptible infecting agents will have been killed, and illness will be due to variants which are relatively more resistant to the drug. Just as the use of antibiotics as a food additive by farmers contributed to the development of antibiotic resistance in some bacteria, so the widespread use of chemoprophylaxis by large numbers of visitors to the tropics has led to the malaria parasite slowly evolving greater tolerance to drugs such as chloroquine until ultimately the drug ceases to be effective. More surprising than the development of resistant strains has been the astonishing speed at which such resistance has spread across the world. Chloroquine resistance is now c o m m o n in Southeast Asia, in large parts of sub-Saharan Africa as well as in a large area of South America. Presumably the growing extent of air travel must have contributed to this, though the same evolutionary pressures could have led to parallel development. Now that we can no longer rely on the old drugs we need to revise our tactics. Fortunately there are some new drugs to which no resistance has yet developed. One of these, mefloquine, (sold by Roche under the name Lariam) is approved for prophylactic use. It has the disadvantage that it causes undesirable side-effects such as dizziness or nausea in a proportion of subjects and it can cause more serious psychiatric problems in those with a history of mental illness. A n o t h e r new drug, halofantrine, currently marketed under the name Halfan by Smith Kline & French, has been approved for treatment but not for prophylaxis. One of the strategies now
426
Editorials
being advocated is the use of this drug as a stand-by treatment, 2 and abandoning the use of prophylactic drugs. Apart from the fact that this would greatly reduce the risk of drug resistance developing, this course of action would benefit those travellers who otherwise put up with side-effects of drugs, and those who take risks because of an unwarranted sense of security. It has been claimed that there has been no rise in incidence of malaria in travellers returning to Switzerland from Thailand since the use of stand-by treatment has been recommended, whereas that in those returning from Kenya, where chemoprophylaxis has been advocated, has risen. This could be due to other factors, as many visitors to Kenya go on safari to view wildlife whereas visitors to Thailand may be more likely to stay in urban areas where vector control is practised. It does, however, suggest that, properly used, stand-by therapy may be at least as good as chemoprophylaxis. It does raise problems for those who go far from the beaten track, in areas where medical care is not readily accessible, as visitors will have difficulty in recognising their first attack of malaria, but for them reliable treatment may be preferable to ineffective prophylaxis. In the near future there is the prospect of a new group of drugs. In China Quinghaosu has been a traditional treatment for ague since the second century BC and its antimalarial action was rediscovered by Chinese scientists in the 1970s. 3 They conducted clinical trials of crude extracts, identified its active principal (artemisinin), synthesised it, and sythesised derivatives (artesunate and artemether) and tested them on over 2000 cases. Subsequent trials in Burma, Thailand, Vietnam and Gambia have confirmed the effectiveness and safety of these preparations. Unfortunately the Chinese preclinical and toxicity data are insufficient to satisfy western licensing authorities, and repeating these studies will take several years. Whether by the time these come into general use 'stand-by therapy' will have replaced chemoprophylaxis remains to be seen. On purely theoretical grounds stand-by therapy would seem the wisest choice for the longer term. As Quinghaosu and its derivatives have short biological half-lives they lend themselves to treatment rather than prevention. They clear parasitaemia more rapidly and appear to have lower toxicity than any of our existing drugs. It is fortunate that they are likely to become available befure the parasite has become resistant to the last of the drugs presently available. J. S. ROBERTSON References
1. WHO (1991). Weekly Epidemiological Record, 66, 157-164. 2. WHO (1992). International Travel and Health: Vaccination Requirements and Health Advice. Geneva: World Health Organisation. 3. Editorial (1992). Rediscovering Wormwood: Quinghaosu for Malaria. Lancet, 339,649-651.
425
Control of Falciparum Malaria Forty years ago, when D D T and Dieldrin were cheap and effective, before mosquitoes started to develop resistance to insecticides, and when the malarial parasites were still susceptible to most of the therapeutic drugs, and before civil wars in so many areas put a stop to efforts at vector control, there seemed to be a real chance that the W H O campaign to eradicate malaria could be successful. Our optimism was misplaced. The prevalence of malaria is rising again. Some territories from which malaria had been eradicated in the 1950s have been recolonised by the parasite, but now by a different type. Where formerly there had been vivax (benign tertian) malaria there is now the more dangerous falciparum variety. In many parts of Asia and sub-Saharan Africa P. falciparurn has become resistant to chloroquine, proguanil and to combinations of pyrimethamine with sulphadoxine (Fansidar) or dapsone (Maloprim).l Even taking double the usual prophylactic dose of both chloroquine and of proguanil fails to protect the traveller to Kenya or Tanzania. Logically we should have expected the development of drug resistance, since the risk was inherent in our policy of giving minimal doses of antimalarial drugs to large numbers of people for prophylaxis, and in particular when we started using the same drug for prophylaxis as we used to treat the disease. Whenever a large number of subjects exposed to an infective agents take low doses of a drug to suppress infection, drug resistance is likely to develop. Variation is an essential feature of all living organisms. Without it they could not have evolved. In any large population of protozoa or bacteria a few deviants will arise which are relatively more tolerant of the drug than the rest. T h e r e will also be a few of the potential hosts who fail to achieve the necessary concentration of the drug, either because of impaired absorbtion, or because undesirable side-effects caused them to stop taking it. In such hosts the more susceptible infecting agents will have been killed, and illness will be due to variants which are relatively more resistant to the drug. Just as the use of antibiotics as a food additive by farmers contributed to the development of antibiotic resistance in some bacteria, so the widespread use of chemoprophylaxis by large numbers of visitors to the tropics has led to the malaria parasite slowly evolving greater tolerance to drugs such as chloroquine until ultimately the drug ceases to be effective. More surprising than the development of resistant strains has been the astonishing speed at which such resistance has spread across the world. Chloroquine resistance is now c o m m o n in Southeast Asia, in large parts of sub-Saharan Africa as well as in a large area of South America. Presumably the growing extent of air travel must have contributed to this, though the same evolutionary pressures could have led to parallel development. Now that we can no longer rely on the old drugs we need to revise our tactics. Fortunately there are some new drugs to which no resistance has yet developed. One of these, mefloquine, (sold by Roche under the name Lariam) is approved for prophylactic use. It has the disadvantage that it causes undesirable side-effects such as dizziness or nausea in a proportion of subjects and it can cause more serious psychiatric problems in those with a history of mental illness. A n o t h e r new drug, halofantrine, currently marketed under the name Halfan by Smith Kline & French, has been approved for treatment but not for prophylaxis. One of the strategies now
426
Editorials
being advocated is the use of this drug as a stand-by treatment, 2 and abandoning the use of prophylactic drugs. Apart from the fact that this would greatly reduce the risk of drug resistance developing, this course of action would benefit those travellers who otherwise put up with side-effects of drugs, and those who take risks because of an unwarranted sense of security. It has been claimed that there has been no rise in incidence of malaria in travellers returning to Switzerland from Thailand since the use of stand-by treatment has been recommended, whereas that in those returning from Kenya, where chemoprophylaxis has been advocated, has risen. This could be due to other factors, as many visitors to Kenya go on safari to view wildlife whereas visitors to Thailand may be more likely to stay in urban areas where vector control is practised. It does, however, suggest that, properly used, stand-by therapy may be at least as good as chemoprophylaxis. It does raise problems for those who go far from the beaten track, in areas where medical care is not readily accessible, as visitors will have difficulty in recognising their first attack of malaria, but for them reliable treatment may be preferable to ineffective prophylaxis. In the near future there is the prospect of a new group of drugs. In China Quinghaosu has been a traditional treatment for ague since the second century BC and its antimalarial action was rediscovered by Chinese scientists in the 1970s. 3 They conducted clinical trials of crude extracts, identified its active principal (artemisinin), synthesised it, and sythesised derivatives (artesunate and artemether) and tested them on over 2000 cases. Subsequent trials in Burma, Thailand, Vietnam and Gambia have confirmed the effectiveness and safety of these preparations. Unfortunately the Chinese preclinical and toxicity data are insufficient to satisfy western licensing authorities, and repeating these studies will take several years. Whether by the time these come into general use 'stand-by therapy' will have replaced chemoprophylaxis remains to be seen. On purely theoretical grounds stand-by therapy would seem the wisest choice for the longer term. As Quinghaosu and its derivatives have short biological half-lives they lend themselves to treatment rather than prevention. They clear parasitaemia more rapidly and appear to have lower toxicity than any of our existing drugs. It is fortunate that they are likely to become available befure the parasite has become resistant to the last of the drugs presently available. J. S. ROBERTSON References
1. WHO (1991). Weekly Epidemiological Record, 66, 157-164. 2. WHO (1992). International Travel and Health: Vaccination Requirements and Health Advice. Geneva: World Health Organisation. 3. Editorial (1992). Rediscovering Wormwood: Quinghaosu for Malaria. Lancet, 339,649-651.
