The principles of the use of antimalarial drugs for protection against malaria and the treatment of uncomplicated malaria were reviewed in 1995 (16). This section considers the particular requirements for chemoprophylaxis in pregnant women and for chemoprophylaxis and stand-by treatment in travellers. It also comments on the management of severe malaria, the treatment of vivax malaria and the need for antimalarial formulations for paediatric use.

3.1 Guiding principles of chemoprophylaxis and intermittent treatment of malaria during pregnancy

Malaria infection in pregnancy poses a substantial risk to the mother, the fetus and the newborn infant. Pregnant women are less capable of coping with and clearing malaria infections. In areas of low transmission of P. falciparum, where levels of acquired immunity are low, women are susceptible to attacks of severe malaria, which may result in stillbirths or spontaneous abortions, or the death of the mother. In areas of high P. falciparum transmission, levels of acquired immunity tend to be high and women may have asymptomatic infections, which may result in maternal anaemia and placental parasitaemia. Both of these conditions can lead to low birth weight, an important contributor to neonatal mortality.

In programmes for the prevention or treatment of malaria in pregnant women, two major issues are the safety and effectiveness of the antimalarial drug regimen. The programmatic effectiveness of a given drug is determined by the efficacy of that drug against the parasite and by the drug’s characteristics, including affordability, availability, acceptability to the target population, and deliverability in terms of dosing requirements and incorporation into existing antenatal care delivery systems.

Weekly chloroquine chemoprophylaxis and preventive intermittent treatment with sulfadoxine-pyrimethamine during pregnancy have both been shown to reduce the rate of placental parasitaemia and low birth weight (50). Many national antimalarial treatment policies include a recommendation for chloroquine chemoprophylaxis. It is rarely implemented, however, because of problems with compliance, fears about adverse effects of the drug during pregnancy, and the concern of health workers that use of drugs for this purpose may deplete stocks needed for the treatment of acute infections.

An increasing number of countries, e.g. Malawi, are implementing intermittent treatment with 2- or 3-dose treatment regimens of sulfadoxine-pyrimethamine: once in the second and once or twice in the third trimester (51-53) to prevent malaria in pregnancy. In HIV-positive women, the 3-dose treatment is significantly more efficacious than the 2-dose regimen (51). It has been suggested that sulfadoxine-pyrimethamine should ideally be reserved for preventive intermittent treatment in pregnancy (R. Steketee, personal communication, 2000). In many endemic areas where sulfadoxine-pyrimethamine is one of the few replacement therapies for chloroquine, this may not be a viable option.

3.2 Guiding principles of chemoprophylaxis and stand-by treatment in travellers

The spread and intensification of drug resistance worldwide has greatly complicated recommendations for the prevention of malaria in travellers. Travel to malarious areas is on the increase, while many countries are experiencing a resurgence of malaria. As a short-term measure, chemoprophylaxis is recommended for international and national travellers from non-endemic areas, and for soldiers, police and labour forces serving or working in highly endemic areas. Detailed recommendations for the protection of travellers against malaria are updated and published annually by WHO in International travel and health: vaccination requirements and health advice (54).

All travellers to malarious areas should be clearly informed of: the risk of malaria; how they can best protect themselves against mosquito bites; the use of chemoprophylaxis wherever appropriate; and the need to seek early diagnosis and treatment if symptoms suggestive of malaria occur. Malaria must always be suspected if fever, with or without other symptoms, develops at any time between one week after the first possible exposure to malaria and two months (55), or even longer in exceptional cases, after the last possible exposure. Nearly all travellers who acquire a
P. falciparum infection will have developed symptoms within 3 months of exposure (56). Medical attention should be sought and a blood sample examined for malaria parasites. If no parasites are found but symptoms persist, a series of blood samples should be taken and examined at appropriate intervals. Relapses of vivax and ovale malaria are not prevented by chemoprophylaxis with currently used prophylactic regimens.

Malaria chemoprophylaxis should be selected on the basis of an individual risk assessment of the traveller, an assessment of the safety and efficacy of potential chemoprophylactic regimens, and drug resistance and the extent of malaria transmission in the region to be visited. Weekly prophylactic antimalarial regimens should normally be started one week before travel. Daily drugs such as proguanil and doxycycline should be started the day before travel. Drugs should then be taken with unfailing regularity for the duration stay in the area of malaria risk, and continued for 4 weeks after leaving the endemic area. The exception is atovaquone/proguanil, which can be stopped one week after leaving the area with malaria risk. Mefloquine prophylaxis should preferably be started 2-3 weeks before departure, so that adequate blood levels are attained, and adverse reactions can be detected before travel, allowing consideration of alternative drug regimens. Antimalarial drugs should be taken with food and swallowed with plenty of water.

In general, travel areas are classified as:

• Areas with P. vivax transmission only.
• Chloroquine-sensitive--Malarious areas where chloroquine resistance has not been documented or is not widely present; these include Haiti, the Dominican Republic, Central America north-west of the Panama Canal and parts of the Middle East.
• Chloroquine-resistant--Most of Africa, South America, Oceania and Asia.
• Chloroquine-and mefloquine-resistant--Resistance to both chloroquine and mefloquine is not a significant problem except in rural forested regions along the borders between Cambodia, Myanmar and Thailand, which are infrequently visited by tourists; mefloquine resistance in varying degrees has been reported from Brazil, Cambodia, China (in vitro), French Guyana, Myanmar, Thailand and Viet Nam.

Data on the incidence of malaria and the effectiveness and tolerance of currently recommended chemoprophylaxis and self-treatment regimens for long-term travellers are limited. Chloroquine and mefloquine has been shown to be safe for at least 3 years. In chloroquine-resistant regions, mefloquine is more efficacious than the chloroquine plus proguanil combination (57, 58). In one study, chemoprophylaxis with atovaquone-proguanil for 20 weeks and with primaquine for 50 weeks had no significant adverse effects (59, 60).

Malaria prevention in young travellers

Children are at special risk of malaria since they may rapidly become seriously ill. Persuading young children to take antimalarial medications may be difficult because of the lack of paediatric formulations and the bitter taste of many drugs. Furthermore, some chemoprophylactic drugs are contraindicated in children. Chloroquine remains the drug of choice in areas where malaria remains sensitive to this drug, while mefloquine is the preferred agent in chloroquine-resistant areas. Although the manufacturer recommends that mefloquine should not be given to children who weigh less than 5 kg, it should be considered for chemoprophylaxis of all children at high risk of acquiring chloroquine-resistant P. falciparum malaria. Atovaquone- proguanil may be a safe and effective chemoprophylactic alternative to doxycyline for children under 8 years of age who weigh more than 11 kg and are travelling to mefloquine-resistant areas.

Malaria prevention for travellers during pregnancy

In non-immune pregnant travellers, malaria increases the risk of maternal and neonatal death, miscarriage and stillbirth. When travelling to malarious areas, pregnant women should take special care to avoid mosquito bites.

Chloroquine is known to be safe in pregnancy, but its usefulness is limited to a few areas with chloroquine-sensitive strains of P. falciparum. Available data indicate that mefloquine is safe as a chemoprophylactic agent after the first trimester. Becoming pregnant while taking mefloquine chemoprophylaxis is not an indication for termination of the pregnancy. The combination of chloroquine plus proguanil is safe in pregnancy and provides more protection than chloroquine alone in areas with known chloroquine-resistant strains, but is significantly less efficacious than mefloquine (61, 62). Doxycycline and primaquine are contraindicated during pregnancy. Data on the safety of atovaquone-proguanil during pregnancy are insufficient, although studies with this combination are currently under way.

Stand-by emergency treatment for travellers

Most travellers to urban or major tourist areas will be able to obtain prompt and reliable medical attention when malaria is suspected. However, a minority may be travelling to such isolated locations that they will have no access to competent medical attention within 24 h after the onset of symptoms, a week or more after first possible exposure. In such cases, stand-by emergency treatment should be prescribed to the traveller for self-administration should symptoms occur (63-66). Precise instructions should be given on the recognition of malaria symptoms and the need to take the full treatment dose of the drug, and information should be provided on possible adverse reactions. Travellers must also be made aware that they should seek attention as soon as possible after symptoms appear and they begin their stand-by treatment, and that stand-by treatment is not a substitute for diagnosis and treatment by qualified medical personnel.

Because of the potential for additive toxicity and reduced efficacy, individuals who are on chemoprophylaxis should never attempt stand-by-treatment with the same drug. Following completion of the treatment, individuals should resume effective malaria chemoprophylaxis. As a general guide, chemoprophylaxis should be restarted one week after the first treatment dose. When the stand-by-treatment is quinine, however, mefloquine chemoprophylaxis should be restarted one week after the last dose (54).

Chloroquine, sulfadoxine-pyrimethamine, mefloquine, quinine plus tetracycline, atovaquone-proguanil and artemether-lumefantrine can be prescribed as stand-by treatments, depending on the drug-resistance status of the parasites in the areas to be visited. Halofantrine is not recommended owing to the fact that it can result in ventricular dysrhythmias and prolongation of QTc intervals in susceptible individuals. While the antimalarial drugs described above are all used for stand-by treatment, artemether plus lumefantrine is the only therapy registered by a national drug regulatory authority for this purpose (67). Efficacy, safety and ease of administration should be considered for the selection of stand-by treatment, but there is some concern about the use of drugs for this purpose in travellers who may have access to medical facilities.

3.3 Management of severe malaria

Treatment with antimalarial drugs has a major role to play in preventing severe malaria and death. It reduces fever promptly and effectively to interrupt the progression of infection or mild illness to severe disease, and reduces fatality rates in severe malaria. Since the great majority of patients with fever or other symptoms suggestive of malaria receive their initial treatment at home, improving home management of fever is a critical component of this process. Patients and their families need up-to-date and practical guidance on when and how to use antimalarial drugs at home, on how to recognize when a patient is not responding to therapy in order to seek medical attention, and on the importance of correctly following, at home, the recommendations and treatments that are given in health centres and hospitals. This guidance should be complemented with more user-friendly treatment regimens, improved formulations, especially for the treatment of children, and pre-packaging of antimalarial tablets.

At the health post or health centre level, availability of effective drugs is crucial. Health workers need clear guidelines on how antimalarial drugs should be used and how to deal with potential adverse reactions. In addition, there should be facilities to administer fluids, glucose, antibiotics, and anticonvulsants to severely ill patients. In suspected cases of severe malaria, rectal formulations of the artemisinin drugs and other preparations can be used as an emergency pre-referral treatment when parenteral antimalarial therapy is not available, and have the potential to reduce early mortality. In hospitals, prompt confirmation of diagnosis, rapid assessment of the severity of disease and the administration of prompt specific and supportive treatment, including safe blood for transfusion, are all critical. These issues are covered thoroughly elsewhere (15).

3.4 Vivax malaria

P. vivax is the predominant malaria species in most of Asia (including the Indian subcontinent), Oceania, North Africa, and Central and South America and is estimated to account for about 55% of the total malaria incidence outside subtropical Africa. In recent years, there has been a major resurgence of vivax malaria in eastern Europe and central Asia, areas which had been free of malaria for several decades. The major threat to the control of P. vivax today is the emergence and spread of chloroquine-resistant strains in Guyana, India, Indonesia (Irian Jaya), Myanmar and Papua New Guinea (68).

The existence of strains of P. vivax that differ in their relapse patterns and their innate sensitivity to primaquine influences the choice of regimen for radical cure. For strains of P. vivax from Papua New Guinea, Solomon Islands and Vanuatu, and parts of Indonesia, a total dose of primaquine base of 7 mg/kg (equivalent to 420 mg in an adult) given as 30 mg of primaquine base daily for 14 days, is required to achieve 100% cure rates. Strains from China, South-East Asia, central Asia, the Middle East, northern Africa, and Central and South America can be cured with half this dose. There is limited evidence that strains from the Indian subcontinent may respond to a 5-day course of 15 mg of primaquine base (69, 70).

3.5 Formulations for paediatric use

In Africa, particularly in areas of high transmission, children under 5 years of age are the most affected by malaria, leading to a high case fatality rate in this age group. In spite of the importance of the disease in children and the fact that they are the major targets for antimalarial drugs, there are problems with existing paediatric formulations and regimens:

• Many tablet formulations are not scored, making it difficult to break the tablets into halves and quarters as required by current treatment regimens.
• Confusion arises from the availability on the market of some drugs at more than one strength (e.g. chloroquine as tablets of 100 mg and 150 mg base).
• Different spoon sizes lead to inconsistencies in the dosing of syrups.
• Syrups are often dispensed in volumes of 100-120 ml, tempting mothers to continue administering until finished, or to save the medication for administration to other children.
• Confusion arises because there are four different age groups for treatment with chloroquine in children under 5 years.

These and similar problems influence patient adherence and result in both underdosing and overdosing. Increasing attention to this area through operational research is beginning to suggest some solutions. Appropriate packaging and labelling improves compliance, enhances acceptability (71-74) and greatly reduces the risk of overdosing (74-77). Adherence to prepackaged tablets is much better than to syrup, and the cost of prepackaged treatments is much lower (76). Training health facility workers and equipping them with packaged treatments have been shown to reduce case fatality rates (78). Prepackaging of drugs for specific age and weight ranges (76) can improve home management of malaria. It now remains to translate these research findings into practice.