The state of malaria prophylaxis for travelers depends on whom you ask, attendees at the American Society of Tropical Medicine and Hygiene learned last December at the society's annual meeting in Philadelphia, during a session titled “Is Atovaquone/Proguanil the Last Drug to Ever Be Approved for Malaria Chemoprophylaxis?”
“If you look at the current armamentarium, you might come to the conclusion that, looking at both safety and efficacy, [it] might actually be satisfactory,” said Jörg-Peter Kleim, PhD, director of clinical development at GlaxoSmithKline.
Alan J. Magill, MD, FACP, disagreed. “The current options really aren't satisfactory. There are gaps in the chemoprophylaxis strategy and there are different gaps for different drugs,” said Dr. Magill, who is the former director of the Division of Experimental Therapeutics at the Walter Reed Army Institute of Research (WRAIR) in Silver Spring, Md.
There are three commonly used effective drugs that have been approved by the U.S. Food and Drug Administration for people traveling to malaria-prone areas, Dr. Magill acknowledged. However, he highlighted the shortcomings of each.
Mefloquine is highly efficacious and available in four different generic forms, but it is associated with problematic adverse events, including neurotoxicity, psychiatric events and gastrointestinal problems.
“In the U.S., we are required to give an FDA-approved medication guide [with the drug],” said Dr. Magill. “If you read this, you probably wouldn't take the drug. Nor do our patients.”
Compliance is also one of the issues with doxycycline, an antibiotic that was first recommended for malaria prophylaxis in 1987 and subsequently approved by the FDA for this purpose in 1992. Specifically, patients often fail to follow instructions to take the drug for a month after returning from travel, a problem with which Dr. Magill sympathized. “I don't [take the drug long enough] either,” he said.
He used additional personal experience to point to another of the drug's shortcomings. “The efficacy of [doxycycline] is almost certainly weight dependent. ... The standard-dose regimen of 100 mg probably is quite adequate for my wife, who is half my size, but I'm not sure it's good enough for me,” he said.
Doxycycline has also been associated with gastrointestinal effects (although the more expensive monohydrate salt form helps with that) and interactions with many other medications.
“There are a lot of drug-drug interactions. If you prescribe [doxycycline], especially to older patients, who are now traveling much more frequently, this is now a factor that needs to be considered,” Dr. Magill said.
For some destinations and some patients, primaquine (a drug that is recommended by the Centers for Disease Control and Prevention but is not FDA-licensed for prophylaxis) can be a solution. Its most significant adverse effect is hemolytic anemia in any patient with a G6PD deficiency, which is present in 10% of African-American males; all patients need to be screened for this. Because primaquine also lacks activity against falciparum malaria, it is recommended only for destinations with mostly vivax malaria.
The reverse is true of atovaquone-proguanil (Malarone), one of the newer options in malaria prophylaxis. The combination pill, approved in 2000, is well tolerated, efficacious and only has to be taken for a week after return.
“I think many of us in travel medicine now feel that Malarone is clearly the optimal choice for short-term travel (two to three weeks). Usually the only problem with that is actually the cost of the drug,” said Dr. Magill. (Medication for a two-week trip (about 21 tablets) would cost about $100-$200.)
Cost is a major overall obstacle to the advancement of malaria prophylaxis, according to Dr. Kleim. Physicians and patients may have to be satisfied with the current selection of drugs, because development of a new one would face major logistical and financial challenges.
Since the development and approval of the existing options, ethics rules about drug testing were tightened, in an update to the World Medical Association's Declaration of Helsinki.
“Studies undertaken in developing world populations have to be intended to help those populations,” explained Gregory Deye, MD, FACP, another speaker at the session and a medical investigator with the Military Malaria Research Program at WRAIR.
Malarone, for example, was never meant to be marketed for prophylaxis in malaria-endemic countries, given its cost, yet the trials that led to its approval were conducted among local residents of these countries. “We wouldn't do this anymore,” said Dr. Kleim.
However, pharmaceutical researchers have not yet figured out what to do instead. The high efficacy of current prophylaxis options makes it impossible to design a sufficiently powered study among travelers to malaria-prone areas, Dr. Kleim said. Given these challenges, the priority in malaria research at GlaxoSmithKline right now is acute treatment for populations in malaria endemic countries, he concluded.
The shift in malaria research could actually be good news for both residents and visitors of endemic countries, according to Dr. Magill. Although a focus of his talk was the need for a new drug for short-term prophylaxis, he was optimistic that some future medication might also be used for malaria elimination and eradication. “If there were no malaria, we wouldn't have to worry about prophylaxing the short-term traveler,” he said.