Atovaquone

U.S. military aviators are currently restricted to the use of chloroquine or doxycycline for malaria prophylaxis. Ground forces are allowed the additional option of taking mefloquine. These medications are begun before deployment, must be taken for 4 weeks after leaving the malarious area, and primaquine must be added to the regimen the last 2 of those 4 weeks. Compliance with this regimen is often poor, especially in populations who travel abroad frequently for short periods of time. Causal malaria prophylaxis offers potential benefits of decreased length of postdeployment regimens and obviates the need for a second medication for terminal prophylaxis. Potential obstacles include adverse drug reactions, cost, and rapid development of resistance to new medications by Piasmodium species, which should be weighed against the risks to health and mission success in each deployment.

Introduction

As the incidence of malaria rises in parts of the world,1 the World Health Organization estimates 300 to 500 million cases of malaria occur annually, resulting in 1.5 to 2.7 million deaths.2,3 Approximately 30,000 of the annual cases are from European and American travelers,4-7 with a case fatality rate approaching 3.6%.8 In the United States, the military has accounted for 90% of cases imported into the United States, presenting a challenge to U.S. clinicians, even rarely resulting in transfusion-related deaths from military donors.9,10 Even for cases not manifesting overseas, malaria treated by U.S. and U.K. civilian physicians is accompanied by a 5.7% mortality rate.11

Preventing malaria in deployed personnel hinges on anticipating the risk as well as using effective countermeasures. In World War II, U.S. forces suffered greatly from malaria (694,935 cases, 377 deaths); some units had rates as high as 84%.10 Early in the Vietnam conflict, whole infantry battalions were decimated by malaria, even though almost complete protection was available.10

It can be difficult to accurately predict the threat: 9% of the more than 200 malaria cases in the U.S. Marines from Somalia (1993) were in individuals who never left Mogadishu, which had previously been reported as free of malaria.12 More often, however, the failure lies in not providing or using appropriate prophylactic measures. One-half of the Somalia cases occurred in a single Marine battalion whose commander did not enforce recommended countermeasures. The majority of the cases developed after the Marines had returned to the United States, which most likely resulted from the medical decision not to provide terminal primaquine prophylaxis and, in 70 cases, self-discontinuing mefloquine after deployment.10,12

This is not a new problem for the military, as the rate of compliance with terminal prophylaxis during the Vietnam war was only 30%.13 More recently, five special operations troops contracted malaria during operations this past year in western Africa, which was attributed largely to problems with compliance and perceived risk (M. Coatsworth, Air Force Special Operations Command Surgeon General's Office, unpublished data). Civilian sources have reported equally disappointing, if not worse, antimalarial compliance.14

A primary reason for noncompliance is length and complexity of postdeployment prophylaxis. Current Department of Defense-authorized prophylactic medications require 1 month of usage after deployment with primaquine added the last 2 weeks for terminal prophylaxis, targeting hepatic hypnozoites of Piosmodium vivax and Plasmodium ovale. Primaquine is needed because most currently used antimalarials are "suppressive" prophylactic agents that act on Piosmodium parasites in the blood after merozoites have emerged from the liver.

Individuals who deploy frequently for short periods of time (flight crews, special operations forces) would find the current regimens particularly burdensome. A medicine that would eliminate the month-long postdeployment part of the regimen and require no additional medications would likely be well-received in these communities. This article will review such a class of medications, "causal" malaria prophylactics, after briefly mentioning the three currently authorized medications (chloroquine, mefloquine, and doxycycline).

Suppressive Prophylactic Agents

Chloroquine

Chloroquine (Aralen, Sanofi-Sandoz, New York, NY) is a 4-aminoquinoline given as 500 mg (300-mg base) once per week, which is usually begun 1 week before arrival in a malarious area. Chloroquine acts as a blood schizonticide. As chloroquine-sensitive Plasmodium falciparum is increasingly uncommon (now found only in Mexico, Haiti, the Dominican Republic, Central America north of the Panama Canal, Argentina, Paraguay, Iraq, Syria, Turkey, North and South Korea, and parts of North Africa, China, and the Philippines), mefloquine or doxycycline are the only two viable options left for deploying military members.15 Chloroquine-resistant P. vivax reported in Papua New Guinea, Man Jaya, Vanuatu, Burma, and Guyana.3 Overall, Chloroquine is a safe medication, and although in pregnancy safety class "C," it remains the safest to use during pregnancy and is considered safe for breastfeeding.15-17 Side effects are rare but include nausea, vomiting, headache, blurry vision (retinopathy has been reported with high doses), and itching; chloroquine may also worsen the symptoms of psoriasis.18 Chloroquine as well as mefloquine may interfere with the rabies vaccine.19 Like most antimalarials, it should be taken on a full stomach to minimize gastrointestinal upset. Although the Physician's Desk Reference states primaquine should be given with caution to glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals, the Centers for Disease Control and Prevention make no mention of this in their advisories.

Mefloquine

Mefloquine (Lariam, Roche Laboratories, Nutley, NJ) is a 4-quinolinemethanol derivative analog of quinine usually given as 250 mg weekly, which is started 1 week before travel and then for 4 weeks after return.3 To more rapidly achieve acceptable blood levels, some recommend starting daily mefloquine at 5 mg/kg salt 3 days before travel and then 250 mg in weekly doses.17,20,21 A blood schizonticide, mefloquine is reported as 90% efficacious against drug-resistant P. falciparum and P. vivax in most regions of the world and is listed by the Centers for Disease Control and Prevention as a drug of choice for travel in high-risk, drug-resistant areas.3 The only regions of the world known for mefloquine resistance are Thailand's borders with Burma and Cambodia.

Mefloquine's primary limitation for aviator usage stems from potential neuropsychiatric reactions.14,22 One study of trainee civilian pilots showed 4% withdrawing from the study because of dizziness and other symptoms.23

Its manufacturer recommends caution for drivers, pilots, and machine operators because of concerns with spatial orientation and fine motor coordination. Most often nausea, strange dreams, dizziness, mood changes, insomnia, headache, or diarrhea are reported, whereas severe reaction such as psychosis or convulsions occur in ~1/10,000 users.24 The 2002 Physician's Desk Reference states the most common prophylactic problem at a rate of 3% is vomiting.

Field studies on mefloquine provide varying conclusions regarding mefloquine's side effects. One recent study reported most discontinuation was from neuropsychiatric events,25 whereas others state gastrointestinal events and dizziness are most problematic; the largest reports indicate that 25% to 50% of users report side effects (rates roughly double if the 3-day accelerated dosing schedule is used), although most are mild and self-limited.3 Very rarely, mefloquine-associated neuropsychiatric events have led to deployed troops being temporarily removed from useful service or sent home.23

Contraindications for usage include: history of psychiatric illness, seizure disorder, or past reaction to the medication. Mefloquine should be used with caution in pregnancy, especially during the first trimester (pregnancy category C), and in children

Doxycycline

Doxycycline (Vibramycin, Vibra-Tabs, Pfizer, New York, NY) is a broad-spectrum antibiotic given as a 100-mg tablet taken daily, which is begun 1 to 2 days before travel. In multiple trials, doxycycline has been shown to be equivalent or superior to mefloquine with >90% efficacy as prophylaxis.21,26 It is also effective for mefloquine-resistant P. falciparum and is recommended by the Centers for Disease Control and Prevention for this along with Malarone (vide infra).15 Pfizer states it is indicated for use up to 4 months; although not widely regarded as dangerous, beyond this period of time some may wish to draw complete blood counts before continuing with doxycycline. Doxycycline acts to suppress asexual blood stages of Piosmodia not gametocytes.

Doxycycline is contraindicated in pregnancy (category D) and for children

Causal Prophylactic Agents

In contrast with "suppressive" agents that target only blood stages of Plasmodium, "causal" prophylactic agents act on the hepatic schizonts and hypnozoites; this activity allows it to be withdrawn after only 1 week postexposure vs. 4 weeks.28 Tetracycline has been reported to exert some causal prophylactic activity against P. falciparum but not P. vivax or P. ovale.29 Several causal prophylactic agents have been developed, however, with activity against all Plasmodium species and thus offer unique advantages. The three most important causal medications are primaquine, tafenoquine, and atovaquone-proguanil (Malarone).

Primaquine

History and Mechanism of Action

Primaquine (Sanofi-Winthrop, New York, NY) was first introduced over 50 years ago, synthesized during World War II from research on 8-aminoquinolines for malaria treatment, not prophylaxis,30 and was widely used as the drug of choice for treatment of P. vivax during the Korean War31,32 Primaquine acts on schizonts in liver for apparently all Plasmodium species, as well as (with efficacy dependent somewhat upon species) gametocytes, erythrocytic blood stages, sporozoites, P. vivax/ovale hypnozoites, and possibly mosquito oocysts.14,30 With the advent of chloroquine, primaquine was dropped largely because of G6PD-deficiency-related hemolysis and methemoglobinemia.

Because of reputation of the more toxic pamaquine, its use as a causal prophylactic never caught on, even though it was shown to be effective and well-tolerated in single doses against strains of P. vivax and P. falciparum.30 Although a few studies have demonstrated efficacy with a daily dosage of 15 mg of base (the same given for terminal prophylaxis), the majority of researchers have administered 30 mg of base per day.

The causal prophylactic activity of primaquine was established in 1954 by Arnold et al.33, who went on to demonstrate that the tissue forms of P. falciparum are most susceptible to primaquine 72 hours after inoculation.34 His team concluded that the optimal single dose was 15 mg of primaquine given on the third day after the bite; if given on the same day or 5 days after inoculation, the intervention is not effective. These findings correspond well with earlier studies that showed complete protection against P. falciparum and P. vivax, James35 also found giving primaquine the day before inoculation to be effective. Although most researchers emphasize a 24- to 48-hour window,36,37 others relate 48 to 96 hours after exposure still viable for intervention.34 Such findings may partially explain disappointment with "C-P pill" (single weekly tablet of 300 mg of chloroquine and 45 mg of primaquine base) used in Vietnam.38

Efficacy

Multiple, independent controlled studies report primaquine's efficacy as comparable to doxycycline and mefloquine (85%-95%) in several parts of the world (Kenya, Ethiopia, Indonesia, Man Jaya, Colombia) in both semi-immune and nonimmune individuals.14,38-42 In selected studies, primaquine appeared especially effective against P. vivax in sub-Saharan Africa and Indonesia and Thailand.14,30 Other reports suggest greater efficacy against P. falciparum (in Irian-Jaya/Indonesia/southeast Asia and Colombia);25,41 however, hypnozoites in some regions have been reported as relatively insensitive.30 Although not Food and Drug Administration (FDA)-approved for this indication, the current Sanford Guide to Antimicrobial Therapy lists primaquine as alternative prophylactic agent for adults, and other infectious disease authorities have advocated its usage with appropriate precautions.38

Safety

Most G6PD-normal people tolerate primaquine about as well as suppressive agents,39 and in subjects taking it for up to 1 year, no significant side effects have been found.40 Its side effects revolve chiefly around G6PD deficiency, gastrointestinal upset, and methemoglobinemia. Primaquine is contraindicated in G6PD-deficient individuals because of the risk of hemolysis. Primaquine's gastrointestinal side effects are comparable in incidence and severity with most other agents, reportedly better tolerated than mefloquine, doxycycline, and even chloroquine, and greatly diminish if given on a full stomach.14,39 Up to 240 mg of primaquine can be tolerated well if given with food.40 One often-cited study reported nonstatistically significant increased gastrointestinal complaints, but that study administered primaquine before, not after, meals.41 Primaquine given for 1 year to 126 volunteers in Irian-Jaya getting 0.5 mg/kg base resulted in a methemoglobin of 5.8% (1.4%-13%), which declined by one-half after 1 week of ending medication; complete blood count, hepatic, and renal function in all participants remained normal.40 Methemoglobinemia

Taefenoquine

History and Mechanism of Action

Developed at Walter Reed in 1963 (also known as WR 238605) for radical cure of P. vivax, taefenoquine is a synthetic primaquine analogue with an improved therapeutic index and safety profile.30,38,43 Taefenoquine is produced by GlaxoSmithKline and is currently in advanced field testing as 1 tablet of 250 mg of salt (200-mg base) per week.38 Taefenoquine's half-life is 14 days, much longer than primaquine's half-life (6 hours).43 This drug may provide use as a causal prophylactic for both P. falciparum and P. vivax as well as an agent of radical cure for P. vivax/ovale (a single dose of 500 mg achieved radical cure of P. vivax in Thailand) or treatment for multidrug-resistant P. falciparum and chloroquine-resistant P. vivax.30 As one author has commented, it may be of most use ". . . in planning short-term visits (

Efficacy

Taefenoquine has been shown in the laboratory to be approximately 10 times more effective as a prophylactic in rhesus monkeys than primaquine, being more potent against both liver and blood stages of Piosmodium.38,43

Human studies in western Kenya where participants received daily doses for 3 days (200-400 mg) and then weekly doses of either 200 or 400 mg yielded 86% to 89% efficacy.30,38 In Ghana, participants who took daily doses for 3 days and then 200 mg per week also achieved a protection efficacy of 86% for P. falciparum.44 For ease and compliance, even more interesting are studies of taefenoquine given on a monthly basis.

In another study of western Kenyans, participants who received 400 mg per day for 3 days followed by placebo were afforded equal protection to those who took weekly taefenoquine up to 7 weeks with efficacy still at 68% by 12 weeks and with some residual prophylactic benefit at 15 weeks.45 In a separate study, 400 Gabonese received 3 days of 31.25, 62.5, 125, or 250 mg of salt. None of the 84 patients who received 250 mg for 3 days had developed malaria by day 77, and even 125 mg resulted in 93% efficacy up to 77 days.38 A study in northeast Thailand with participants taking 400 mg of base daily for 3 days, followed by a single monthly dose of 400 mg, demonstrated 95% efficacy after 6 months (1 case of P. vivax with tafenoquine vs. 20 cases of P. vivax and 8 cases of P. falciparum with placebo).46

Safety

Toxicity concerns are similar to those of primaquine and other 8-aminoquinolines: G6PD deficiency-related hemolysis and methemoglobinemia. Neither seems to be a significant problem in early clinical studies, as overall taefenoquine appears better tolerated than primaquine.30,38 With regard to hemolysis, one researcher has noted the A variant of G6PD deficiency of some Africans, which is characterized by low-grade deficiency, might not lead to major hemolysis and that usual doses can be given to individuals with this variant without monitoring.43 Given in doses up to 600 mg, taefenoquine as been found to be safe and well-tolerated; when taken with food, absorption increases 50% and gastrointestinal upset decreases in incidence.38,43

Malarone

History and Mechanism of Action

Atovaquone-proguanil (AP) or Malarone is a fixed dose combination of 250 mg of atovaquone and 100 mg of proguanil hydrochloride. Produced by GlaxoWellcome (Research Triangle Park, NC), Malarone is licensed in 35 countries for treatment of P. falciparum and for malaria prophylaxis in the United States and Denmark.47 AP is active against both asexual and sexual forms of the parasite (and against the formation of ookinetes in the mosquito vector) as well as against liver stages.48 In fact, both atovaquone and proguanil are independently effective against liver forms.47 Atovaquone belongs to the family of hydroxynaphthoquinones, known for over 50 years to be active against P. falciparum, its causal prophylactic activity is well-established.48,3 Proguanil acts to lower the effective concentration at which atovaquone collapses the mitochondrial membrane potential.49

As with other causal agents, AP should be started 1 day before travel, continued while in a malarious area, and for 7 days after leaving the area of risk.3,25 In a trial of 16 volunteers, 12 took AP and 4 took placebo days 1 through 8 and were exposed to P. falciparum on day 2. Patent parasitemia developed in all of those who took placebo, but no subpatent or patent parasitemia developed in the AP group, affirming hepatic action not blood schizonticidal activity.47

Resistance to atovaquone is associated with mutation in the cytochrome b gene.3 Single point mutations in the gene encoding this cytochrome confer complete resistance to atovaquone and proguanil.48 Probability of selecting for resistance has been calculated at one per three cases treated with atovaquone and 1 per 500 cases treated with AP.50 Protection against resistance can be achieved by combining with an arteminisin derivative.48

Efficacy

AP has been extensively tested in both semi-immune and nonimmune (malaria naive) populations. Three double-blind, randomized placebo-controlled chemoprophylaxis trials have been conducted in semi-immunes in various malarious regions with overall efficacy 95% to 98%.47 Additionally, AP has been shown to be useful in P. falciparum mefloquine-resistant areas such as Thailand.51

Studies in nonimmune populations have yielded consistently encouraging results as well with reported 86% to 100% efficacy.47 In a study of >2,000 nonimmune travelers taking mefloquine, AP, or chloroquine-proguanil (CP), no diagnosis of malaria was reported from those taking mefloquine or AP, although those on CP did develop clinical disease.3,25 In a similar study, 1,083 nonimmune travelers were randomized to take AP or CP, having blood drawn for enzyme-linked immunosorbent assay of malarial circumsporozoite protein (CSP) antibody before and after travel. Of 501 individuals taking AP, 7 developed CSP antibody but none developed cases, whereas of the 507 travelers on CP, 8 developed CSP antibody and 3 developed clinical malaria at days 3, 6, and 11 after travel.8 In a separate study of AP vs. mefloquine in >900 nonimmunes travelers to malarious areas, no malaria was reported in either group 60 days after travel, although 5 in each group developed antibodies to CSP.25 Two other studies of >1,000 travelers total showed 12 developing CSP antibodies, but none developed malaria.47

Safety

Malarone is tolerated as well as if not better than other medications for malaria prophylaxis. Its rate of discontinuance from side effects is less than with mefloquine.3,25 Compared with doxycycline and even CP, AP usage is associated with significantly fewer gastrointestinal adverse events and, like most antimalarials, is even better tolerated when taken with food.3,8 Most studies report side effects comparable with placebo.3,8 Because of the few side effects, compliance is exceptionally good while in malarious areas.2 Because it is a causal prophylactic and thus only requires 1 week usage after deployment, its post-travel compliance is also outstanding, significantly better than with mefloquine (p = 0.001).25 Malarone is not recommended during pregnancy (pregnancy category "C"), while breastfeeding children

Relative Cost of Malaria Prophylaxis Medications

Both the cost of the medications per pill and the dosing schedule affect the relative cost of the various antimalarials, which changes with length of deployment. Using data from the 2001 U.S. Defense Medical Logistics Standard Support Universal Data Repository, the following medications' costs are listed per tablet/capsule: chloroquine ($0.83); doxycycline ($0.032); mefloquine ($5.71); primaquine ($0.115); Malarone ($2.91). No cost is published for the U.S. Department of Defense yet for taefenoquine because it is not yet FDA approved.

Cost analysis of malaria prophylaxis for deployments of 3 days, 1 week, 2 weeks, and 1 month is provided in Table I. Analysis was performed using standard protocols as mentioned in the text above, including standard terminal prophylaxis with 2 weeks of primaquine for suppressive agents.

Conclusions

Decisions about appropriate malaria chemoprophylaxis must consider the malaria risk of the geographic area and mission, the potential impact of side effects on the deployed individual's ability to safely perform his/her mission, the likelihood of compliance, and cost of the regimen. For most deployments involving large numbers of personnel and long stays abroad (>30 days), current suppressive agents (chloroquine, doxycycline, and mefloquine) are appropriate prophylactic agents. However, for small units that deploy frequently to malarious areas for only days to weeks at a time, causal offer a less cumbersome alternative. Taefenoquine may eventually combine the advantages of chloroquine and mefloquine (weekly or perhaps even monthly dosing) with those of primaquine and Malarone (minimal post-deployment doses).

Primaquine must not be used in the G6PD-deficient individual, and despite advocacy in some publications, it is not yet FDA approved for field prophylaxis, possibly because it would cost its producer considerable time and money to procure this additional approval. Fortunately, it is an inexpensive medication and is already approved for individuals on flight status when taken as 15 mg for terminal prophylaxis. Command approval may be required for a 30-mg usage for those on flight status, and prescribing physicians would need to understand implications of using primaquine for an "off-label" indication. Although a legal, common practice, off-label prescribing may increase liability in the case of a negative outcome, although this is significantly decreased if published data support the indication.52 Fortunately, since 1998, the FDA has allowed pharmaceutical companies to provide physicians with more reliable information about the efficacy, risks, side-effects, and dosing of drugs used for off-label indications.53 The American Medical Association recommends off-label prescribing for indications with sound scientific evidence and estimates that 40% to 60% of all prescription are for non-FDA-approved usage.54 Physicians are not required to disclose to their patients that a drug is being used off-label, although this would certainly be a sound practice.

Malarone is FDA-approved for field prophylaxis and causes remarkably few side effects. Although its widespread usage and distribution in the developing world has been criticized for fear of inducing rapid resistance, more concerning to most military pharmacies is its high cost relative to suppressive agents. This would be less of an issue for small units on short trips. Malarone is not yet approved for individuals on flying status in any of the armed services. This may be an appropriate subject for discussion and research at the services' medical commands and aeromedical research establishments.

Despite the obstacles to usage of causal prophylactics, their payoff in compliance should be seriously considered by military medical planners. Commanders in World War II learned the importance of malaria prevention, and those in Korea, Vietnam, Somalia, and more recently in western Africa all learned specifically about compliance and terminal prophylaxis. Meanwhile, continued research into new medications as well as novel applications of current ones (i.e., a 1993 Australian Army study suggested reasonable efficacy against P. falciparum and P. vivax using 100 mg of doxycycline plus 7.5 mg of primaquine daily, stopping 3 days after deployment)55 will continue to contribute to our evolving defense against the world's most significant parasitic disease.

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Guarantor; Maj James A. Chambers, USAF MC FS HMO

Contributor: Maj James A. Chambers, USAF MC FS HMO

Headquarters Air Force Special Operations Command, Office of the Command Surgeon, Hurlburt Field, FL 32544.

This manuscript was received for review in May 2002. The revised manuscript was accepted for publication in February 2003.

Reprint & Copyright © by Association of Military Surgeons of U.S., 2003.

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