**6. Existing challenges and future possibilities**

148 Current Topics in Tropical Medicine

Children and pregnant women are at the highest risk for severe malaria when traveling to endemic areas and increased vigilance should be taken when dealing with these populations. It should be recommend that travel to endemic areas with a risk of transmission be avoided by these populations if possible, however if patients insist, the provider should stress that the traveler or the parents of the traveler insure that both

Contracting malaria while pregnant puts the mother at an increased risk for adverse outcomes. Malaria infection during pregnancy has been associated with premature labor, abortion and stillbirth. The traveler should be counseled that the diagnosis of malaria in pregnancy may be difficult due to relatively low parasitemia at clinical presentation. A very high degree of suspicion should be taken when a pregnant women presents with fever in an endemic area, as missing the diagnosis could have grave consequences (McGready et al., 2004). Appropriate precautions should be followed including mosquito avoidance and control measures discussed previously as well as chemoprophylaxis when clinically indicated. Reviewing label-specific information and current CDC recommendations should be adhered to. There are no published data indicating elevated risks with the use of DEET in pregnant or lactating women, and current U.S. Environmental Protection Agency and CDC sources do not advise additional precautions for using FDA-approved insect repellants in this population (Koren et al., 2003; Zielinski-Gutierrez et al., 2012). Chemoprophylaxis in pregnancy is limited, as both doxycycline and primaquine are contraindicated, and atovoquone/proguanil is not currently recommended due to lack of safety data from clinical studies. Medications considered safe during pregnancy include chloroquine and mefloquine. While data in the past have only recommended mefloquine in the last half of pregnancy, current recommendations state that there is no evidence of adverse outcome if taken in any of

personnel protective measures and chemoprophylaxis are strictly adhered to.

the three trimesters of pregnancy when no other option is available (CDC, 2012).

must be stressed to the traveling parent the importance of these precautions.

Children are at risk of malaria and the associated complications while traveling to endemic areas, and should have the same personal protective measures as adults. DEET has been shown to be safe and effective and is recommended for use by both the CDC and the American Academy of Pediatrics (AAP) for all children over 2 months of age at concentrations between 10-30% based on duration of protection required (Koren et al., 2003; AAP, 2009, 2011; CDC, 2012). Chemoprophylaxis for children is not as restricted as for pregnant women, with contraindications including doxycyline usage in children under 8 and primaquine usage in G6PD deficient patients. Atovaquone/proguanil is FDA approved for children greater than 11kg but recommended for off-label use by the CDC and AAP for children >5 kg. Mefloquine is only FDA approved for children > 5 kg and older than 6 months of age, but when necessary recommend off-label for children < 5kg and any age (AAP, 2009; CDC, 2012). Parents of very young infants should be counseled to avoid areas endemic for malaria given the risk of severe disease in this population. Adherence to personal protective measures and chemoprophylaxis if often poor in children, and thus it

**5. Special populations** 

**5.1 Pregnancy** 

**5.2 Children** 

As outlined in this chapter, there are only five available options for malaria chemoprophylaxis in the United States, one of which, primaquine, is not FDA approved for this indication. Emerging resistance, traveler intolerance, non-adherence, side effects and contraindications to existing options warrant development of newer agents for future chemoprophylactic use.

Resistance to existing drugs is well documented. Wide spread chloroquine resistance has led to the use of this drug in only very limited areas of the world, and mefloquine resistance continues to emerge. Doxycycline resistance has not been established and there is no well accepted definition or validated approach to measuring primaquine resistance (Baird, 2009). Primaquine tolerant or refractory strains of *P. vivax* have been well described, notably the Chesson strain from New Guinea (Collins & Jeffery, 1996). As resistance continues to emerge among existing options for the prevention of malaria, the importance of developing new and effective chemoprophylactic drugs for the international traveler becomes critical.

There are very few candidates currently being developed for malaria chemoprophylaxis, and the last FDA approval for this indication, atovoquone/proquanil, was over ten years ago in 2000. Doxycycline and mefloquine received FDA approval for malaria chemoprophylaxis in the preceding 11 years prior to the atovoquone/proquanil approval. The current lack of development of drugs for this indication is unprecedented and is cause for great concern.

Many reasons have been postulated for the lack of candidates in the developmental pipeline for the chemoprophylaxis indication. Obvious barriers are the lack of market incentive for this indication, although it is clear that the number of international non-immune travelers visiting endemic malarious regions has increased substantially in the last few decades, with case fatality rates ranging from 1-3% for falciparum malaria (Chen & Keystone, 2005). One challenge that has been attributed to stalled development in this area is the 5th Amendment to the Declaration of Helsinki (DH2000). First adopted by the World Medical Association (WMA) in 1964, the Declaration of Helsinki was an attempt to formally identify core ethical principles and guidelines for physicians and others involved in the design, execution and oversight of clinical research (Carlson et al., 2004). Principles relating to the use of placebo in clinical trials, post-trial access to investigational drugs, and social benefit as defined in DH2000, have presented challenges to existing models and development strategies for antimalarial chemoprophylactic drugs. Strategies to address these challenges in clinical development have been proposed (Dow et al., 2008).

Azithromycin, piperaquine, and tafenoquine have all been suggested as possible future chemoprophylactic drugs (Dow et al., 2008). Azithromycin has shown some promise, however future study is needed with combination agents to clarify its role for this indication (Chen & Keystone, 2005).

Tafenoquine, an 8-aminquinolone is a synthetic analogue of primaquine. First developed by the Walter Reed Army Institute of Research as WR238605 or etaquine, tafenoquine has a very long elimination half-life of approximately 14 days allowing weekly dosing. This novel compound shows promise for causal chemoprophylaxis against *P. falciparum* and *P. vivax*, as well as radical cure of *P. vivax.* It has been shown in rhesus monkeys to have 10x higher potency than primaquine for causal prophylaxis, and has demonstrated greater activity against blood and liver-stage parasites *in vitro.* (Cooper et al., 1994; Shanks et al., 2001).

Malaria Chemoprophylaxis for the International Traveler, Current Options and Future Possibilities 151

Addressing malaria chemoprophylaxis for the international traveler can be challenging and should be done within the context of a comprehensive medical evaluation well before visiting the endemic region. Malaria is a life-threatening illness and requires a multidimensional, individually tailored approach to ensure the most appropriate measures, including non-drug strategies, are taken to prevent infection if the traveler is exposed. Existing chemoprophylactic drugs offer effective options for the international traveler, however emerging resistance, side effect profiles and contraindications limit use in many circumstances. Future effort is needed to identify and develop new effective and safe

The views expressed in this chapter are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Army or Air Force, the

AAP. (2011). "American Academy of Pediatrics." Retrieved July 10, 2011, 2011, from

Andersen, S. L., A. J. Oloo, et al. (1998). "Successful double-blinded, randomized, placebo-

Badolo, A., E. Ilboudo-Sanogo, et al. (2004). "Evaluation of the sensitivity of Aedes aegypti

Baird, J. K. (2009). "Resistance to Therapies for Infection by *Plasmodium vivax*." Clinical

Baird, J. K., M. D. Lacy, et al. (2001). "Randomized, parallel placebo-controlled trial of

Brueckner, R. P., K. C. Lasseter, et al. (1998). "First-Time-In-Humans Safety and

Carlson, R. V., K. M. Boyd, et al. (2004). "The revision of the Declaration of Helsinki: past, present and future." British Journal of Clinical Pharmacology 57(6): 695-713. Castelli, F., S. Odolini, et al. (2010). "Malaria prophylaxis: A comprehensive review."

CDC (2012). Infectious Disease Related to Travel, Malaria. Atlanta, U.S. Department of

Chen, L. H. and J. S. Keystone (2005). "New Strategies for the Prevention of Malaria in Travelers." Infectious Disease Clinics of North America 19: 185-210. Chen, L. H., M. E. Wilson, et al. (2006). "Prevention of malaria in long-term travelers."

Collins, W. E. and G. M. Jeffery (1996). "Primaquine Resistance in *Plasmodium Vivax*." American Journal of Tropical Medicine and Hygiene 55(3): 243-249.

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and Anopheles gambiae complex mosquitoes to two insect repellents: DEET and

primaquine for malaria prophylaxis in Papua, Indonesia." Clin Infect Dis 33(12):

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**7. Conclusion** 

**8. References** 

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http://www.aap.org/.

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Department of Defense, nor the U.S. Government

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In phase I studies of tafenoquine the drug is well tolerated with single doses up to 600mg and with chronic dosing (6 months) at 200mg weekly following a load of 200mg daily for 3 days (Brueckner et al., 1998; Leary et al., 2009) with no dose-limiting adverse events. The most common side effects observed are gastrointestinal, including heartburn, nausea and gas, usually associated with higher (>200mg) dosing. The most significant toxicity associated with tafenoquine is the potential to induce hemolysis in G6PD deficient individuals and methemoglobinemia (Crockett & Kain, 2007). GlaxoSmithKline, in partnership with Medicines for Malaria Venture, are undertaking an ascending-dose safety study of tafenoquine in G6PD heterozygous patients to identify the maximum safe dose in this population (MMV, 2011).

There have been several placebo-controlled trials evaluating tafenoquine as a causal antimalarial chemoprophylactic drug. In a study of non and semi-immune Thai soldiers, tafenoquine was administered monthly at 400mg, following a 1200mg loading dose (given as 400mg/day for 3 days) for a total of 6 months and demonstrated a protective efficacy 96% for *P. vivax* and 100% for multidrug-resistant *P. falciparum* (Walsh et al., 2004).

In a dose ranging prophylactic trial of tafenoquine to prevent *P. falciparum* in Gabon semiimmunes, which included children, doses of 25mg, 50mg, 100mg or 200mg/day for three consecutive days were tested. Tafenoquine was given one week following treatment with halofantrine. Subjects were actively followed for positive blood smears at day 56 and day 77 following tafenoquine dosing. Notwithstanding the 25mg dose, which uniformly failed, tafenoquine demonstrated 100% protective efficacy (PE) at all doses of 50mg or greater at day 56 and had PE of 80%, 93% and 100% at day 77 for doses of 50mg, 100mg and 200mg, respectively (Lell et al., 2000).

In a 13-week prophylactic trial in Kenyan semi-immune adults, tafenoquine was evaluated at weekly doses of 200mg and 400mg followed by a 600mg and 1200mg 3-day load, respectively. A third group consisted of a loading dose (1200mg load), followed by weekly placebo and a fourth group received placebo only throughout the 13-week period. The 200mg and 400mg weekly doses demonstrated PE of 91% and 93%, respectively. The loading dose only group had a PE of 80% (Shanks et al., 2001).

A large randomized, non-placebo controlled trial of non-immune Australian soldiers evaluated tafenoquine, dosed at 200mg weekly for 6 months following a loading dose (200mg/day for 3 days) while deployed to East Timor. Study participants were randomized 3:1 to receive either tafenoquine (n=492) or mefloquine (n=162) throughout their deployment. Although treatment-emergent adverse events were similar between the two groups and tafenoquine was well-tolerated during the study, there were no cases of malaria in any group. Exposure to malaria could not be assessed and therefore efficacy was not established (Nasveld et al., 2010).

In a subset of subjects (n=74) in the East Timor study who received tafenoquine, detailed safety assessments were conducted which detected vortex keratopathy. This finding had no effect on visual acuity and was fully resolved within one year following cessation of therapy (Nasveld et al., 2010). More extensive clinical ophthalmic evaluation of tafenoquine in a subsequent phase 1 safety trial further supports the vortex keratopathy seen with tafenoquine is not clinically significant (Leary et al., 2009).

Tafenoquine shows promise as a causal prophylactic drug and is currently being developed for a radical cure indication for *P. vivax* through a joint collaboration between GlaxoSmithKline and Medicines for Malaria Venture (MMV, 2011).
