Fake antimalarial drugs abound in endemic Asian countries

May 2008

ATLANTA — Although counterfeit drugs are not a new problem, the magnitude of counterfeit antimalarial drug production brings unique challenges.

A team of international scientific and police experts are trying to stop the growth of counterfeit trade through investigation, surveillance and public education. Sophisticated counterfeiters, meanwhile, seem to be just a few steps behind in the market battle for consumers.

“This is a rather depressing subject,” said Paul N. Newton, MD, an infectious disease specialist at the Centre for Tropical Medicine at the University of Oxford and a research physician at Mahoset Hospital in Laos. “The mortality of untreated malaria is very high, and the trade in counterfeit antimalarials must lead to more deaths.” Newton presented an overview of the counterfeit antimalarial drug trade and its implications at the International Conference on Emerging Infectious Diseases, held here recently.

In the WHO Western Pacific region, an estimated 2 million new cases of falciparum malaria are reported each year. Fake antimalarial drugs flood the market in packaging so similar to the original that when Newton informally asked colleagues to identify counterfeits from the originals, none could.

“Keep in mind that if you’re a rice farmer in Southeast Asia, your life would pretty much depend on which one you chose,” Newton said.

Reducing the profit margin is one key to reducing the counterfeit antimalarial drug trade because if genuine antimalarials are readily available at inexpensive prices, counterfeiters will no longer be able to make money.

Unfortunately, many of the countries where malaria is endemic have poor drug regulatory capacity. Most other potential solutions also rely on public health infrastructures, which are also lacking in these regions.

Counterfeit trade assessed

Artesunate is a vital ingredient in the treatment of malaria, particularly in Southeast Asia. The first reports of fake artesunate came from Cambodia in the late 1990s. The counterfeits were revealed when physicians noticed large amounts of antimalarial tablets for sale at prices so low they deemed it impractical. Counterfeit antimalarial drugs were then spotted in Burma, Laos and southern Vietnam soon thereafter.

In an initial survey, experts estimated that one-third of store-bought artesunate was counterfeit and contained no active ingredients except for some trace amounts of chloroquine, which is no longer efficacious for malaria treatment in Southeast Asia.

Counterfeiters have used advanced technology to create product packaging almost indistinguishable from authentic antimalarial drugs.

“One nongovernmental organization bought 100,000 tablets in one shop thinking they were onto a good deal, but all were counterfeit,” Newton said.

A few years later, the results from another survey suggested that about half of all store-bought artesunate was counterfeit. To determine whether tablets contain artesunate, researchers at the CDC developed a rapid test in which a clear liquid would turn yellow if artesunate is present. The test has been used extensively throughout Southeast Asia.

Fake drugs can carry consequences beyond a lack of efficacy. Drug resistance could spread if counterfeit antimalarial tablets contain inadequate amounts of artesunate. Reports of tablets with insufficient amounts of artesunate have already been reported along the Thai–Burma border.

Fake drugs may also contain wrong active ingredients or poisons that may confound appropriate patient treatment. “We’ve recently realized that many of the fake drugs on the market are not just chalk, but contain harmful, potentially toxic ingredients that could be confusing for health care workers when they see unexpected, adverse events in patients,” Newton said.

Manufacturer response

Guilin Pharmaceuticals, a company in southern China that produces most of the antimalarial drugs for the region, has developed several hi-tech security features to derail counterfeiters. The company created a 3-D hologram depicting mountains for its antimalarial drug packaging. The hologram also features Guilin in a microscopic font under the picture in another attempt to stop counterfeiters.

Counterfeiters, however, quickly developed copies.

“Some may be poor copies, but if you’ve never seen the original, it might be reassuring to see some type of security feature on the artesunate,” Newton said.

Guilin also employed an additional security feature, the Chinese registration code X-52, written across the mountain picture in ink visible only under ultraviolet light. When counterfeiters learned of this security feature, some placed X-52 on the fake labels but in an incorrect position.

“It’s been like a cold war between the drug company and the counterfeiters, with the counterfeiters only one or two steps behind the genuine product makers,” Newton said.

Fake tablets analyzed

Counterfeit tablets have been analyzed on several different levels to determine contents and origin. One researcher analyzing the chemical compounds of the tablets found trace amounts of a banned precursor of methylenedioxymethamphetamine, commonly known as ecstasy. Therefore, it is believed that counterfeit tablets and ecstasy may be manufactured at the same sites.

Although it is difficult to link deaths to the use of counterfeit antimalarials, a young man with uncomplicated falciparum malaria died in Burma after he developed cerebral malaria when treated with fake artesunate.

WHO in the Western Pacific Region, INTERPOL and a group of physicians and scientists joined forces to examine counterfeit tablets using novel techniques to look at the chemical and pollen composition of the tablets. About 400 fake artesunate samples collected in seven years were subjected to a range of tests, from examination of the packaging to the tablets. Experts found that the type of calcium carbonate in some tablets is relatively rare but is mined in southern China, suggesting manufacturing could only take place there. The analysis of pollen embedded in the tablets also suggested a source in southern China. Carbon chips found in other tablets suggests that manufacturing occurred in a heavily polluted area. When mites where found in tablets, scientists were hopeful.

“We were hoping that the mites were from a relatively narrow geographic distribution so we could pinpoint where the tablets were coming from; but, unfortunately this mite has global distribution,” Newton said.

Arrests made

The Secretary General of INTERPOL gave the Chinese Ministry of Public Security a dossier of evidence about the counterfeit antimalarial trade, and the Chinese authorites took swift action. Three people were arrested, who are alleged to have traded in 250,000 blister packs of counterfeit artesunate.

“Bear in mind that as the course of therapy for one adult is one blister pack, this [lot] is enough to allow nearly a quarter million people to die,” Newton said.

For more information:

• Newton PN. Counterfeit antimalarials and public health. Presented at: The International Conference on Emerging Infectious Diseases 2008; March 16-19, 2008; Atlanta.
• Newton PN, Fernandez FM, Plancon A, et al. A collaborative epidemiological investigation into the criminal fake artesunate trade in South East Asia. PloS Med. 2008;doi:10.1371/journal.pmed.0050032.