Chemoprophylaxis of Malaria—2000
By David R. Hill, MD, DTM&H
For the last decade, the chemoprophylaxis of malaria has relied upon only a few medications—chloroquine, proguanil, mefloquine, and doxycycline. With chloroquine resistance continuing to be a problem in most malarious areas of the world, and an ongoing controversy about the safety and tolerance of mefloquine, travel health advisors have been anticipating new drugs to prevent malaria. Much information addressing prophylaxis was presented at the 48th annual meeting of the American Society of Tropical Medicine and Hygiene. Before focusing on medications, however, it is important to discuss compliance with chemoprophylaxis. No medication will work if it is not taken.
Dr. H. Lobel and colleagues from the CDC, Lufthansa Airlines, and the Kenya Medical Research Institute surveyed returning East African travelers for use of antimalarials (Abstract #511). Noncompliance was most frequent in younger travelers, those who were overseas more than a month, and those who attributed medical problems to their medications. Decreased compliance has also been documented with medications that are taken daily (such as doxycycline and proguanil) or need to be purchased overseas (such as proguanil for U.S. travelers). And, many travelers will discontinue medication when they return home, rather than continuing it for four weeks. Neuropsychiatric side effects were seen in 1%-13% of mefloquine users, depending upon their country of origin, but infrequently led to discontinuation. The message from this study is the need to emphasize to travelers the importance of compliance (with both chemoprophylaxis and mosquito avoidance), and to help them understand the most likely side effects so they do not discontinue drugs based on misconceptions of risk and side effects.
Weekly chloroquine phosphate (500 mg) plus daily proguanil (200 mg) has been advocated, particularly by the British, for chemoprophylaxis in areas of low transmission of resistant malaria, such as India. Dr. R. Behrens from the London School of Hygiene and Tropical Medicine presented a rationale for continued use of this combination. However, several negatives mitigate against wide acceptance. U.S. travelers must purchase proguanil en route to the malarious area, and in our experience 25% fail to do so, leaving them on a single ineffective drug. The combination, although reasonably well tolerated, does have gastrointestinal (GI) side effects, can cause apthous ulceration in the mouth, and has a protective efficacy of about 70% in resistant areas. Thus, if it is used, the traveler should be warned about the possibility of breakthrough malaria while on chemoprophylaxis.
Doxycycline remains an important alternative for persons who are intolerant of mefloquine or who travel to areas where there is both chloroquine and mefloquine resistance, such as the rural hill country in the border areas of Thailand with Myanmar. Dr. C. Ohrt of the Walter Reed Army Institute of Research reviewed data published over the last two decades that document the excellent efficacy of doxycycline against both Plasmodium falciparum and P. vivax. He emphasized that doxycycline cannot be used as a casual prophylactic (i.e., it does not reliably kill parasites that are differentiating and developing in the liver). Therefore, it must be taken for four weeks after leaving the malaria-endemic area. It should also be taken with sufficient liquid or food to ensure complete passage into the stomach because if it remains in the esophagus it can cause erosions. Other well-known side effects include photosensitivity and vaginal yeast infection, and it cannot be used during pregnancy and in children younger than the age of 8 because of teeth staining.
There has been recent interest in another antibiotic, the macrolide azithromycin. It is well tolerated, and is safe in children (available as an oral suspension) and during pregnancy. Because of promising in vitro effects and efficacy as a suppressive agent in challenge studies with sensitive parasites, it was examined in field trials in the late 1990s, usually in a dose of 250 mg/day. Unfortunately, although it demonstrated excellent protection against P. vivax (> 95%), and moderate efficacy against P. falciparum in semi-immunes in Kenya (83%), it had unacceptably low protection in Thailand (69%) (Abstract #25), and in nonimmunes in Indonesia (72%). This has led to azithromycin no longer being developed as a single agent for prevention; it is now being studied in combination with other antimalarials.
Two new and exciting areas are the development and imminent release of Malarone (Glaxo Wellcome), a fixed combination of atovaquone (250 mg) and proguanil (100 mg), and the rebirth of the 8-aminoquinolines as prophylactics. Malarone is already available for treatment of malaria in Canada and in many countries of the European Union. Dr. D. Shanks of the U.S. Army Medical Research Unit in Kenya reviewed the clinical experience with Malarone. When used as a therapeutic agent for multi-drug-resistant P. falciparum, it has an excellent efficacy ranging from 95% to 100%. Studies from Kenya, Zambia, and Gabon document its effectiveness as a prophylactic in both children and adults, with efficacy rates of 95% to 100% against P. falciparum. Malarone can be discontinued soon after exposure because of its ability to kill exo-erythrocytic organisms of P. falciparum. Thus, it is a causal prophylactic for P. falciparum. It is generally well tolerated; GI effects are most common, and reversible elevation of liver enzymes can occur when used for treatment (at a dose 4 times that of prophylaxis). It also appears safe in persons with G-6-PD deficiency (Abstract #424).
The addition of malarone to drugs available for prevention of malaria is welcome and provides an alternative for persons intolerant of mefloquine and young children who cannot take doxycycline. It can be targeted for those going on short trips who would only need to take chemoprophylaxis for several days, for travel to multi-drug-resistant areas, and for those who prefer a daily regimen. It should be started one to two days before travel, taken daily during exposure, and continued for seven days after leaving the malarious area. It will not kill hypnozoites (dormant liver-phase parasites) of P. vivax or P. ovale, so persons who are at high risk for these species will need to take terminal prophylaxis with primaquine. Concerns raised with malarone’s efficacy studies are that they have been carried out in semi-immune persons and that there has been only limited experience in prevention of P. vivax and P. ovale malaria. However, preliminary information indicates it has a high degree of efficacy in nonimmunes, and information from treatment studies indicates that it should be effective in areas endemic for nonfalciparum species.
A new role for 8-aminoquinolines is in chemoprophylaxis. The best known agent, primaquine, is currently limited to terminal prophylaxis or radical cure of P. vivax and P. ovale malaria because of its ability to eradicate the hypnozoites of these species. Dr. Baird of the Naval Medical Research Center and Dr. Prescott of the Walter Reed Army Institute of Research discussed these agents. Studies in the last five years have demonstrated that a dose of 30 mg base daily (or equivalent) is effective in protecting against both P. falciparum (85%-95% protective efficacy) and P. vivax (85%-90%). It can also be used as a causal prophylactic, which allows discontinuation of the drug within a week after leaving the malarious region. With the dose of 30 mg daily, however, tolerance is an issue; about 15% of persons report side effects. Taking the drug with food may decrease the incidence of gastrointestinal upset.
Because primaquine is an oxidant stress it can cause hemolysis in G-6-PD-deficient persons. The mild deficiency variant occurs in about 10% of Africans; there is a rare variant among Caucasians (particularly those of Mediterranean descent) and Asians, which may result in life-threatening hemolysis. Thus, a G-6-PD level needs to be obtained before prescribing the drug. This also precludes its use in pregnant women in whom the G-6-PD status of the unborn child cannot be determined. Methemoglobinemia is another concern, and increases in severity with longer use of the drug. Thus, primaquine has good potential as a causal prophylactic in persons on short-term trips who have normal G-6-PD levels. This indication, however, needs to be submitted to the FDA for review.
Another promising 8-aminoquinoline is tafenoquine (WR 238605). It has excellent efficacy in achieving radical cure (eradication of liver hypnozoites) following treatment of P. vivax malaria (Abstract #314). When used in chemoprophylaxis, its long half-life is likely to allow long-interval dosing: following a loading dose there are protective levels for 10 weeks. In semi-immune Thai soldiers, a loading dose of 500 mg daily for three days followed by a monthly dose of 500 mg was highly effective in preventing both P. vivax and multi-drug-resistant P. falciparum (Abstract #845). The drug acts as a causal prophylactic and is schizonticidal and gametocidal. The issues of hemolysis in G-6-PD deficiency and development of methemoglobinemia also apply to tafenoquine. While more Phase III trials are needed, this agent has promise particularly for prophylaxis of malaria, and could lead to a prophylactic regimen that would only need to be administered before travel.
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Which of the following drugs has exhibited reliable causal prophylactic activity (killing of exo-erythrocytic parasites) against Plasmodium falciparum?