**4. Chemoprophylaxis**

140 Current Topics in Tropical Medicine

months in duration, can be very difficult as consensus guidelines in this population are not

It has been over ten years since the U.S. Food and Drug Administration has approved an antimalarial chemoprophylactic drug. Lack of market incentive, increasing difficulty in the design and execution of clinical trials, as well as the changing ethical environment after Declaration of Helsinki 2000 have contributed to the lag in continued development for the

Before travel, counseling the individual on the specific risks in the areas they may be visiting is an essential part of trip preparation. When counseling the traveler prior to visiting an endemic area, they must be made aware of the route of transmission of malaria, associated symptoms, variable incubation periods prior to symptom onset, when to seek medical aid, and the risks of contracting the disease, including death, especially in high-risk populations. They need to be aware that recent immigrants to non-malaria endemic areas returning to their home of origin to visit friends and relatives (VFR's) are at high risk for contracting malaria as acquired immunity is not long lasting (Centers for Disease Control and Prevention, 2012). Travelers should be counseled on proper personal protective measures including mosquito bite avoidance, especially during the peak transmission periods of evening and nighttime hours, mechanical and chemical barrier protection, vector control,

Malaria can be effectively treated if suspected and recognized early and appropriate medical intervention is made within a timely manner. Time to symptom onset from initial exposure can vary, ranging as early as 7 days following a mosquito bite to several months or greater following departure from an endemic region. The diagnosis of malaria is a medical emergency since time to definitive treatment is a critical factor in determining clinical outcome. For these reasons, travelers should be counseled to seek medical care as soon as possible if they have any symptoms that may be related to malaria. The clinical presentation of malaria consists of a nonspecific, flu-like illness manifested by fever, chills, malaise, anorexia and headache. In cases of severe illness, altered mental status, seizures, respiratory

Availability of medical care while traveling should be explored prior to travel. There may be rare instances where the chemoprophylaxis regimen is suboptimal or the traveler does not agree to medically advised chemoprophylaxis. In cases when the traveler develops clinical symptoms consistent with malaria and does not have timely access to medical care and definitive parasitological diagnosis, presumptive, self-administered therapy may be considered (WHO, 2010; CDC, 2012). When prescribing presumptive self-treatment, the CDC recommends a consecutive 3-day course of either atovaquone-proquanil or artemetherlumefantrine. One should never use the same drug for treatment that had been prescribed for prophylaxis. It should be stressed to the traveler that even though presumptive

Several measures can be taken by the traveler while in endemic areas to reduce the risk of mosquito bites, thus reducing the risk of contracting malaria. The *Anopheles* mosquito only

treatment may be available, they should seek medical care as soon as possible.

available (Chen et al., 2006).

**2. Education** 

malaria chemoprophylaxis indication (Dow et al., 2008).

and the appropriate use and importance of chemoprophylaxis.

disease (ARDS) and coma may be present (CDC, 2012).

**3. Personal protective measures** 

Educating travelers on the clinical indications, as well as proper use and risks of chemoprophylaxis is an important part of pre-travel counseling. Patients should be told of the options available for the area they are traveling based on CDC recommendations, and when clinically indicated, an appropriate chemoprophylaxis should be chosen and

Malaria Chemoprophylaxis for the International Traveler, Current Options and Future Possibilities 143

because it is one of two current drugs considered safe in pregnant women and children, and because it is fairly well tolerated, it will remain a viable choice for prophylaxis if resistance

Primaquine phosphate is an oral antimalarial agent first approved by the FDA in 1952. The mechanism of action is not well understood, but its plasmodicidal activity is thought to be related to disruption of the parasitic electron transport chain (Castelli et al., 2010). It has a short half-life of approximately seven hours, thus requiring daily dosing. Before the approval of primaquine, there was no available treatment of relapsing malaria because antimalarial drugs available at the time were only effective against the erythrocytic stages of Plasmodium species (Shanks et al., 2001). Primaquine's approval was important because it is effective against both the erythrocytic and exoerythocytic stages of Plasmodium species, making it an effective choice for *P.vivax, P. ovale, or P. falciparum* (WHO, 2010; Shanks, Kain et al., 2001). However, it is only FDA-approved for the treatment of vivax malaria, but has long been used for treatment off-label for other species and is the drug of choice for terminal prophylaxis in travelers at risk for relapsing malaria (Castelli et al., 2010; Hill et al., 2006). Multiple clinical trials have shown the efficacy of primaquine against both vivax and falciparum malaria (Shanks et al., 2001). In two placebo controlled trials on the island of New Guinea it was shown that primaquine had an efficacy of 93 - 95% against *P. falciparum* and 88 - 90% against *P. vivax* (Baird et al., 2001; Fryauff et al., 1995). In two placebo controlled trials done in Columbia good efficacy was also seen, with an overall efficacy of 89% against *P. falciparum* and 88% against *P. Vivax* (Soto et al., 1998, 1999). While good efficacy has been seen in the past, there is emerging evidence of increasing resistance to *P. Vivax* strains in some areas of Oceana, South East Asia, and South America (Baird, 2009). Primaquine is a well-tolerated medication with the most common side effects being nausea, vomiting, and abdominal cramps (Fryauff et al., 1995). It was shown to have better tolerability than chloroquine in Irian Jaya transmigrates, and in a retrospective study of travelers to Ethiopia it had favorable tolerability compared to mefloquine and doxycycline (Schwartz & Regev-Yochay, 1999; Baird et al., 2001). Severe hemolytic anemia can occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and should be avoided in any patient with this enzymopathy. All patients taking primaquine should be

evaluated for G6PD deficiency prior to receiving this drug (Hill et al., 2006).

relapsing malaria is a concern, it makes a good choice for terminal prophylaxis.

Off-label dosing recommendations are 30mg base per day for 14 days for terminal prophylaxis, and 30mg per day 1-2 days before travel and continued for 7 days after travel for prophylaxis (CDC, 2012). It should be taken with food to limit side effects. Dosing for children is 0.5 mg/kg base per day. It has been shown safe in studies up to one year with no labeled restrictions on duration of use (Fryauff et al., 1995; Chen et al., 2006). Primaquine is contraindicated in pregnant women, making prevention or treatment of malaria in areas with *P.vivax* difficult in this population. If used as a primary prophylaxis, it negates the need for terminal prophylaxis, however, if another primary chemoprophylaxis is chosen, and

Mefloquine hydrochloride is a methanol-quinoline oral antimalarial agent whose mechanism of action is not completely understood, but is thought to be similar to quinine

patterns are taken into account when prescribing.

**4.2 Primaquine** 

**4.3 Mefloquine** 

prescribed based on the patient's medical history, tolerability of side effects, compliance, and known resistance in the area (Table 1). Resistance to antimalarial drugs is growing, and is a major public health concern (WHO, 2010). Resistance of *P. falciparum* to chloroquine, the most widely available and least expensive chemoprophylaxis agent, is now widespread, except in a few limited areas of the Caribbean, Central and South America, and a few countries in the Middle East. Resistance to mefloquine is spreading and has been confirmed in areas of SE Asia including along the borders of Burma and China, Laos and Burma, Thailand and Burma, Thailand and Cambodia, and in southern Vietnam (CDC, 2012).

#### **4.1 Chloroquine**

Chloroquine is a 4-aminoquinoline oral antimalarial agent first introduced in the 1940's. It has good bioavailability, is rapidly absorbed and appreciably concentrated in tissues such as the liver, spleen, and to a lesser extent in the CNS (WHO, 2010). Its plasmodicidal activity is thought to be related to its interaction with malarial DNA, specifically haem detoxification (Castelli et al., 2010; WHO, 2010). Chloroquine is dosed once weekly and is effective against the erythrocytic stages of sensitive plasmodium species.

Chloroquine has long shown its efficacy against malaria, and was a cornerstone of treatment until growing resistance became a problem in the 1980's (Castelli et al., 2010). *P. falciparum*  resistance to chloroquine is widespread, thus making it an acceptable choice only in chloroquine sensitive areas. There is some evidence of mutations making non-falciparum strains resistant, with resistance of *P. vivax* to chloroquine reported in areas of Papua New Guinea, West Papua, Guyana, Vanuatu, Myanmar, Indonesia, and India (WHO, 2010; Kain et al., 2001; Davis et al., 2003).

Chloroquine has a generally mild side effect profile with the most common events being nausea, headache, blurred vision, insomnia, and pruritis (Castelli et al., 2010). Serious side effects, although rare, include myopathy, hepatitis, hearing loss, Stevens-Johnson Syndrome, seizures, and irreversible retinopathy (WHO, 2010). Retinopathy is usually seen after 100g cumulative dose, which is equivalent to what a long-term traveler may ingest in 5-6 years of weekly dosing (Chen et al., 2006). Chloroquine-induced retinopathy is rare in patients taking malaria prophylaxis and is more frequently seen in the higher doses administered for the treatment of rheumatoid arthritis (CDC, 2012). In a large (N=2701) trial of peace corps volunteers undergoing malaria prophylaxis it was found that chloroquine was better tolerated and had fewer serious side effects than mefloquine or doxycycline, however prophylaxis in general was not tolerated well with 9% reporting severe events and 23% at some point changing their prophylactic medication (Korhonen et al., 2007).

Chloroquine is considered safe for use in children and pregnancy, however strict adherence to weight-based dosing must be adhered to for children since serious adverse events have been reported in children receiving as little as 1 gram of chloroquine (Chen et al., 2006). While chloroquine is safe for breast-feeding mothers, the infant should receive separate prophylaxis as the amount of chloroquine secreted in breast milk is not sufficient for protection.

Chloroquine is available in 500mg tablets, which is equivalent to 300mg chloroquine base. Dosing is done weekly starting 2 weeks before travel into an endemic area and for 4 weeks after leaving the area. Pediatric dosing is 5mg/kg base, never to exceed adult dosing.

While generally considered a safe and efficacious drug, the growing resistance to chloroquine is making it a choice only available in limited areas of the world. However, because it is one of two current drugs considered safe in pregnant women and children, and because it is fairly well tolerated, it will remain a viable choice for prophylaxis if resistance patterns are taken into account when prescribing.
