Lan;05jun99

Viewpoint
Av e r ting a malaria disaster
N J White, F Nosten, S Looareesuwan, W M Watkins, K Marsh, R W Snow, G Kokwaro, J Ouma, T T Hien, M E Molyneux, T E Taylor, C I Newbold, T K Ruebush II, M Danis, B M Greenwood, R M Anderson, P Olliaro Estimates for the annual mortality from malaria range This approach has since been adopted for cancer from 0·5 to 2·5 million deaths. The burden of this chemotherapy, and, more recently, for the treatment of enormous toll, and the concomitant morbidity, is borne AIDS and early HIV-1 infection. To treat tuberculosis or by the world’s poorest countries. Malaria morbidity and AIDS with a single drug is no longer regarded as ethical.
mortality have been held in check by the widespread We believe the same principle should apply to the availability of cheap and effective antimalarial drugs. The treatment of malaria. The calculation is simple. Resistance loss of these drugs to resistance may represent the single arises from mutations. The chance that a mutant will most important threat to the health of people in tropical emerge that is simultaneously resistant to two different countries. Chloroquine has been the mainstay of antimalarial drugs is the product of the mutation rates antimalarial drug treatment for the past 40 years, but per parasite for the individual drugs, multiplied by the resistance is now widespread and few countries are number of parasites in an infection that are exposed to the drugs. For example, if one in 109 parasites are usually deployed as a successor to chloroquine. Both resistant to drug A and one in 101 3 are resistant to drug these antimalarials cost less than US$0.20 per adult B, and the genetic mutations that confer resistance are treatment course, but the drugs required to treat multi- not linked, only one in 102 2 parasites will be resistant drug-resistant falciparum malaria (quinine, mefloquine, simultaneously to both A and B. Most patients who are halofantrine) are over ten times more expensive and ill with malaria have between 108 and 101 2 parasites at cannot be afforded by most tropical countries— presentation, and a biomass of more than 101 3 p a r a s i t e s especially those in Africa, where it is estimated that more in a single person is physically impossible. In this than 90% of the world’s malaria deaths occur. Resistance example, therefore, most patients will have at least one to chloroquine is widespread across Africa and resistance parasite resistant to drug A, between 0·1% and 1·0% will to PSD is increasing.2 A health calamity looms within the have a parasite resistant to drug B, but a parasite next few years.3 As treatments lose their effectiveness, simultaneously resistant to the two drugs would only morbidity and mortality from malaria will inevitably occur about once every 101 2 treatments (ie, less than continue to rise. Can this disaster be prevented? Can we once a century). Compared with sequential use of single really “roll back malaria”, as the new Director-General drugs, which is current policy, combinations will thus impede the development of resistance substantially.
The rationale for combining drugs with independent modes of action to prevent the emergence of resistance artemether, dihydroartemisinin) are the most potent and was first developed in antituberculous chemotherapy.
rapidly acting of the antimalarial drugs. They reduce theinfecting malaria parasite biomass by roughly 10 0 0 0 - f o l d Lancet 1999; 353: 1965–67
per asexual (2-day) life cycle, compared with 100-fold to Wellcome-Mahidol University Oxford Tropical Medicine Research
1000-fold for other antimalarials.5 Artemisinin and its Programme (Prof N J White FRCP, F Nosten MD), Faculty of Tropical
derivatives are remarkably well tolerated and, to date, no Medicine (Prof S Looareesuwan MD), Mahidol University, Bangkok,
significant resistance has been reported either in clinical Thailand; KEMRI-Wellcome Trust Collaborative Research
isolates or in laboratory experiments. Combinations of Programme (W M Watkins PhD, Prof K Marsh FRCP, R W Snow PhD,
artemisinin, or one of its derivatives, with more slowly G Kokwaro PhD) and National Malaria Control Programme,
eliminated drugs such as mefloquine or lumefantrine Ministry of Health (J Ouma PhD), Kenya; Centre for Tropical
(benflumetol) have proved highly effective, even against Diseases, Cho Quan Hospital, Ho Chi Minh City, Vietnam
multidrug-resistant Plasmodium falciparum.6 , 7 On the (T T Hien MD); College of Medicine, University of Malawi, Malawi
(Prof M E Molyneux
northwest border of Thailand, which harbours the most FRCP, T E Taylor DO); Liverpool School of
Tropical Medicine, Liverpool, UK (Prof M E Molyneux); College of
Osteopathic Medicine, Michigan, USA (T E Taylor); Molecular
chemotherapy has halted the progression of mefloquine Parasitology, Institute of Molecular Medicine, University
resistance. This is attributed to two factors. First, of Oxford, Oxford, UK (C I Newbold PhD); Centers for Disease
combinations ensure high cure rates because treatment Control and Prevention, Atlanta, Georgia, USA (T K Ruebush II MD);
for 3 days with an artemisinin derivative eliminates most Groupe Hospitalier Pitié-Salpetrière, Paris, France
of the infection, and the residuum of parasites remaining (Prof M Danis MD); London School of Hygiene and Tropical
is exposed to maximum concentrations of the more Medicine, London (Prof B M Greenwood FRCP); Department
of Zoology, University of Oxford, Oxford (Prof R M Anderson FRS),
UK; and World Health Organization, Geneva, Switzerland
maximum of 105 parasites or 0·000001% of the asexual parasites present initially) is all that is exposed to Correspondence to: Prof N J White, Faculty of Tropical Medicine,
mefloquine alone. Thus, because of this rapid reduction Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand in the parasite population within each patient, the selective pressure for the emergence of mutants with Copyright 1999. All rights reserved.
reduced mefloquine sensitivity is lessened substantially.8 resistance to date and the rapid elimination of these Second, the artemisinin derivatives decrease gametocyte drugs such that subinhibitory (ie, selective) blood or carriage by roughly 90%.9 Recrudescent (ie, resistant) plasma concentrations occur for only hours, resistance to infections are associated with increased gametocyte this group of drugs will probably develop fairly slowly.1 1 carriage rates, which provide a powerful selection pressure to the spread of resistance.9 , 1 0 This spread is available in many countries, and their use is generally prevented by the artemisinin derivatives. These benefits regulated poorly. Such use is already providing selective are particularly important in areas of low or unstable pressure to the emergence of resistance. If these drugs transmission where morbidity and mortality are high, were used only in combination with other antimalarials, and most malaria is treated. In this context, the artemisinin resistance would develop much more slowly.
antimalarial drugs are under intense selective pressure This mutual protection will result in a longer useful and resistance has, in the past, often developed rapidly.
In areas of high transmission, where infections occur antimalarial chemotherapy than if the two components frequently, and are usually asymptomatic in older children and adults, the rapidly eliminated artemisininderivative will not protect its more slowly eliminated partner during the elimination “tail” of declining blood In animals, intramuscular injections of the oil-based concentrations. Infections newly acquired during this tail compounds arteether and artemether have induced an will therefore be under selection pressure. But, provided unusual and selective pattern of damage to certain brain- the patients with these infections are treated with the combination if they become symptomatic, and provided sustained exposure of the central nervous system, which the combination partner retains some efficacy against is a consequence of the very slow absorption of these any selected mutants, the infections will usually be cured drugs from the intramuscular site. By contrast, in and the resistant parasites will not be transmitted. The animals, the therapeutic ratio is substantially larger after reduction in the risk of selecting resistant mutants in the oral administration of these same drugs, and, for the primary symptomatic infection is not affected by the administration—presumably because of rapid absorption combinations should slow the evolution of drug and elimination (T G Brewer, personal communication).
There has been no evidence of any adverse neurological effects in a clinical experience extending to several combinations. The rapid therapeutic response ensures million patients, detailed prospective studies in over that patients are able to return to school or work earlier 10 000 patients, and neurophysiological assessments in and, in the unlikely event of complete resistance to the more than 300 individuals who have received multiple combination partner, a therapeutic response will stilloccur—ie, there will not be a high-grade or dangerous treatment courses (FN, TTH, unpublished). The failure to respond to treatment. Thus, for several artemisinin derivatives are well-tolerated antimalarials reasons, combination therapy with artemisinin or a individually but combinations of drugs may lead to unexpected adverse effects. There is no evidence for Current practice is to deploy antimalarial drugs serious adverse effects resulting from combinations of individually in sequence. When one drug fails, another is artemisinin derivatives with mefloquine, lumefantrine, introduced. Unfortunately, there are few antimalarials and in a small study with atovaquone-proguanil.5 , 6 and, as for many microbial pathogens, the evolution of However, studies of pharmacokinetics and tolerability resistance in P falciparum seems to be outstripping the are needed on combinations with other available development of new drugs. There are compelling reasons to believe that resistance to the available antimalarial amodiaquine), and also on the safety of combinations in drugs would be slowed or prevented by the addition of artemisinin or one of its derivatives, as has been the casewith mefloquine. Combination of an artemisinin derivative with chloroquine and PSD in areas where Cost is usually the major factor that determines the use partial sensitivity to these compounds is still retained of antimalarial drugs. Combinations with artemisinin should extend their useful life. So what are the derivatives would, in general, be expected to double the objections to combination antimalarial chemotherapy? treatment cost for individual patients. But increasedshort-term costs should result in overall savings in the Will artemisinin resistance be encouraged? longer term. If combination treatment translates into a Some have argued that artemisinin derivatives are so 3–5 year extension in the useful lifespan of chloroquine, effective in the management of severe malaria that they amodiaquine, or PSD (as it has done for mefloquine on should be withheld from use in uncomplicated malaria in the western border of Thailand), the overall cost would those areas where they are not needed, so as to protect be less than that of deploying the next, more expensive them from the development of resistance. However, alternatives (mefloquine, quinine). Since chloroquine combination chemotherapy does protect the artemisinin and PSD are already failing in many areas, combination derivatives from the development of resistance. If the treatment would be expected to improve cure rates with drug is always used in combination with another a reduction in the morbidity (and therefore costs) unrelated antimalarial drug, then, provided they are at associated with treatment failure. In areas of low least partially susceptible to the second drug, parasites transmission, use of the artemisinin derivatives may have are never exposed to the antimalarial activity of the the added benefit of reducing the incidence of malaria.
artemisinin derivative alone. Given the reassuring lack of In parts of Vietnam and Thailand, where these drugs Copyright 1999. All rights reserved.
have been used systematically, there has been a both these disasters could be averted if the approach we reduction in the incidence of falciparum malaria, thus have outlined were adopted widely. To buy 5 or 10 years’ extra life for the available affordable antimalarialdrugs will allow time for new drugs to be developed and other interventions to be deployed. We recognise that To ensure compliance with drug combinations, the there are formidable logistic and political barriers to individual components should ideally be formulated rapid action on the scale required, but we believe that together in a single tablet or liquid preparation.
this is now the single most important issue for malaria in However, such formulations would need the expensive Africa. Our purpose in writing this paper has been to place this subject at the top of the agenda for every studies required for regulatory approval—and who will individual, organisation, and funding body concerned pay for these? A less satisfactory but simpler alternative initially would be to combine separate components inblister packs, as is done for the multiple-drug treatmentof tuberculosis and leprosy. The successes of directly R e f e r e n c e s
observed therapy in these infections may be relevant to Bloland PB, Lackritz EM, Kazembe PN, Were JB, Steketee R, antimalarial treatment. The use of combinations should Campbell CC. Beyond chloroquine: implications of drug resistance be accompanied by new initiatives to facilitate for evaluating malaria therapy efficacy and treatment policy in Africa.
J Infect Dis 1993; 1 6 7 : 9 3 2 – 3 7 .
compliance and to encourage dispensers and retailers to Ronn A, Msangeni HA, Mhina J, Wernsdorfer WH, Bygbjerg IC.
educate their patients on the need to complete a full High level of resistance of Plasmodium falciparum to sulfadoxine- course of treatment.1 3 Single-dose treatments should be pyrimethamine in children in Tanzania. Trans R Soc Trop Med Hyg monitored. More effective surveillance should also be 1996; 9 0 : 1 7 9 – 8 1 .
Marsh K. Malaria disaster in Africa. L a n c e t 1998; 3 5 2 : 9 2 4 – 2 5 .
encouraged in tropical countries, both to monitor Harlem Brundtland G. Speech to the fifty-first World Health efficacy and to document adverse reactions.
White NJ. Assessment of the pharmacodynamic properties of antimalarial drugs in-vivo. Antimicrob Agents Chemother 1997; 4 1 :
1 4 1 3 – 2 2 .
Normally, the answer is more research, and more Price RN, Nosten F, Luxemburger C, et al. Artesunate/mefloquine research is certainly required. However, with a concerted treatment of multi-drug resistant falciparum malaria. Trans R Soc effort, this research could be completed within 2 years.
Trop Med Hyg 1997; 9 1 : 5 7 4 – 7 7 .
Van Vugt M, Brockman A, Gemperli B, et al. Randomized Critical decisions often need to be taken with incomplete comparison of artemether-benflumetol and artesunate-mefloquine in knowledge. Time is running out in Africa; four treatment of multidrug-resistant falciparum malaria. A n t i m i c r o b Agents Chemother 1998; 4 2 : 1 3 5 – 3 9 .
Africa—have already been forced to use PSD as their White NJ. Preventing antimalarial drug resistance through
combinations. Drug Resis Update 1998; 1 : 3 – 9 .
first-line antimalarial. When this happened in southeast Price RN, Nosten F, Luxemburger C, et al. Effects of artemisinin Asia, high-level resistance developed within a few years derivatives on malaria transmissibility. L a n c e t 1996; 3 4 7 : 1 6 5 4 – 5 8 .
and mefloquine had to be substituted. But there is so 1 0 Handunnetti SM, Gunewardena DM, Pathirana PPSL, Ekanayake K, much more malaria in Africa and so much less money.
Weerasinghe S, Mendis KN. Features of recrudescent chloroquine-resistant Plasmodium falciparum infections confer a survival advantage For the vast majority who cannot afford a US$1 or more on parasites and have implications for disease control. Trans R Soc for antimalarial treatment, widespread resistance to PSD Trop Med Hyg 1996; 9 0 : 5 6 3 – 6 7 .
or its analogues will be a disaster. Time is short.3 In east 1 1 Watkins WM, Msobo M. Treatment of Plasmodium falciparum malaria with pyrimethamine-sulfadoxine: selective pressure for Africa, parasites with up to three mutations in the D H F R resistance is a function of long elimination half-life. Trans R Soc Trop gene, conferring antifolate resistance, are already Med Hyg 1993; 8 7 : 7 5 – 7 8 .
prevalent in some areas. Acquisition of the 164 D H F R 1 2 Brewer TG, Grate SJ, Peggins JO, et al. Fatal neurotoxocity of mutation, found in southeast Asia, would render PSD arteether and artemether. Am J Trop Med Hyg 1994; 5 1 : 2 5 1 – 5 9 .
1 3 Snow RW, Peshu N, Forster D, Mwenesi H, Marsh K. The role of ineffective. The development of artemisinin resistance shops in the treatment and prevention of childhood malaria on the would also be a health-care catastrophe. We believe that coast of Kenya. Trans R Soc Trop Med Hyg 1992; 8 6 : 2 3 7 – 3 9 .
Copyright 1999. All rights reserved.

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