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Health, International development

Death by Imitation Medicine

In February 2005, a 23-year-old man in eastern Myanmar entered a rural hospital with a fever. A blood test showed that he had malaria. He was given tablets containing artesunate, the most common treatment in that region, but for two days his condition did not improve. On the third day, he became unconscious and slipped into a coma. He was transferred to a different hospital, diagnosed with renal failure, and given intravenous medication. He was then transferred to a third hospital for further treatment, but died within 12 hours when the parasites blocked blood flow to his brain.

The original hospital wondered why its treatment had failed. It sent the artesunate to a laboratory, and was horrified to discover that the medication was counterfeit. Each tablet contained only one-fifth the required amount of artesunate, and instead the main active ingredient was acetaminophen. The man died because he had been treated with little more than Tylenol.

The researchers who documented this case, published in PLoS Medicine in 2006, made no apology for describing the counterfeit medication trade as manslaughter. It is a trade that pays well: global sales in 2010 were about US$75 billion, according to estimates from the US-based Center for Medicines in the Public Interest. Antimalarials seem to have been particularly targeted. At least 40% of the drugs sold in Southeast Asia for malaria are thought to be counterfeit. In some locations, such as along the Thai-Myanmar border, up to 70% of the available medications are fake. Studies from Ghana, Kenya and other African countries have reported that up to one-third of available malaria medication in sub-Saharan Africa is counterfeit. There are no firm statistics on the deaths directly attributable to poor quality medication, but the World Health Organization (WHO) estimates that up to 200,000 deaths from malaria every year could be prevented if all medications were genuine.

Figure 3 from Newton et al. 2011. Genuine artesunate ‘Mekophar Chemical Pharmaceutical Joint-Stock Company’ packet (Mek 10/03).

Counterfeit antimalarials take many forms. Some are made entirely of inactive ingredients, like flour or chalk. Other types are made with active ingredients that are no longer effective. For example, many counterfeit malaria medications are based on chloroquine. But the most lethal form of the malaria parasite, Plasmodium falciparum, has developed widespread resistance to chloroquine. Other counterfeits, like the one analyzed in Myanmar, contain active ingredients that are ineffective at best, and at worst, harmful. A counterfeit based on acetaminophen might help temporarily with a patient’s fever. But counterfeits containing the antibiotic erythromycin cannot kill the parasite and can cause serious side-effects in the patient. Some counterfeits even contain banned substances, such as safrole – a carcinogen and raw material for making the recreational drug ecstasy.

The recommended treatment for malaria in most areas is artesunate or another therapy derived from artemisinin, a compound isolated from the Chinese plant Artemisia annua (annual wormwood). One course of genuine artemisinin-based treatment costs anywhere from US$1 to US$4. This could consume the entire daily income for a family in a developing country, so there is strong incentive to seek out the cheapest option available. Since counterfeits are usually half the price of the genuine article, the chances are high of a mother accidentally buying counterfeit medication for her child. But even if someone was looking for the best treatment available, irrespective of cost, how would she know which products are fake?

Figure 4 from Newton et al. 2011. Counterfeit artesunate packet labelled as made by ‘Mekophar Chemical Pharmaceutical Joint-Stock Company’ (Cam S5/07). Counterfeit hologram in red circle.

The WHO recommends that consumers buy medications only from licensed distributors and check to see that the package lists the batch number and expiry date. But counterfeit medications often contain this type of packaging information too, even though it’s fictional. In the case from Myanmar, the original hospital discovered that its entire stock of artesunate was fake; even reputable dispensaries can be duped.

Holograms are typically used by legitimate manufacturers to verify the authenticity of a product and are usually placed on the medication packet and on each blister pack of tablets. Unfortunately, these are routinely counterfeited. The hologram used by Guilin Pharmaceuticals, a manufacturer in Guangxi province in southern China, is a circle about 15 mm in diameter. A segmented ring surrounds a pair of mountains sitting at the water’s edge, with two Chinese characters written over the top. Guilin Pharmaceuticals currently holds the dubious title of most commonly counterfeited antimalarial brand. At least 14 different imitations of its hologram have been found on counterfeits in Thailand, Myanmar, Laos, Vietnam and Cambodia. The first imitations appeared in 1998 and were obviously flawed – the mountains were the wrong shape, or segments in the outer ring were misaligned. Dr David Pizzanelli, a British product security consultant who specializes in holograms, says that the differences between fake and genuine holograms are now so subtle that it would be almost impossible for a consumer to tell them apart, unless he could compare samples side-by-side. As it turns out, the medication bought by the hospital in Myanmar was an imitation of Guilin Pharmaceutical.

When the external appearance of counterfeit medication is virtually impossible to distinguish from the real thing, the only way to be sure is to analyze the ingredients. The most common analysis technique in developing countries is colorimetric testing, such as the Fast Red Dye test. The Fast Red Dye test uses a diazonium salt, an organic nitrogen-based compound with an alkaline pH, which will turn yellow in the presence of artesunate. The test is quick and easy to perform, but it doesn’t specify how much artesunate might be present – a counterfeit product might only contain a little active ingredient and still record a positive result. More sophisticated analysis techniques, such as thin-layer chromatography and near-infrared spectroscopy, could determine the quantity of artesunate in medications. These methods are not that expensive by developed country standards, but laboratories in developing countries typically don’t have the resources to do chromatographic or spectroscopic analysis at every location that receives shipments of medication.

Counterfeits containing low doses of active ingredients, which might fool a Fast Red Dye test, have been found in several countries of Africa and Southeast Asia. They are harmful because they might not kill the parasite and a patient will usually wait a few days for the medication to work before seeking further treatment. Those few days could mean the difference between a patient being cured or going into organ failure. This outcome is tragic for the sick individual, but there are also wider implications. Professor Dyann Wirth, Chair of the Department of Immunology and Infectious Disease at the Harvard School of Public Health, says that counterfeit medications containing low doses of artemisinin-derived ingredients are the most dangerous kind. They could contribute to a public health crisis by pressuring the parasite into developing drug resistance, and it doesn’t need any help from us.

Plasmodium falciparum has proven highly adept at fending off the weapons we throw at it. Within infected red blood cells, the parasite can manipulate the expression of its genes to escape detection by our immune system. The parasite’s genome has inbuilt redundancy – there are hundreds of different genes that can create proteins to perform the same task, so at any given time only one gene is expressed. If our immune system starts to detect the protein created by one gene, the parasite simply switches to another, becoming invisible to the immune system. This ability to switch between different genes is also the reason why a malaria vaccine has been elusive so far, according to Professor Wirth.

Examples of genuine and counterfeit holograms.

The holograms on a genuine Guilin artesunate blister package (top left) and those on three counterfeit products. (E) shows more detail of (C). Credit: Paul Newton, PloS Medicine (2007)

When we’ve attacked the parasite with numerous drugs – chloroquine, mefloquine, sulfadioxine-pyrimethamine, amodiaquine, quinine, atovaquone and halofantrine – it has evolved resistance to these drugs. The mechanism is like a predator picking off the weak members of a herd. In a single infected person, there will be 100 trillion parasites. The chance of an infected person carrying some parasites that are already resistant to a drug is very high, simply due to chance mutation in the parasite’s genes. If that person is given suboptimal treatment, the less sensitive parasites will survive. The patient’s immune system might kill them off on its own, but before that happens a mosquito could transmit these less sensitive parasites to someone else. Over time, the resistant parasites become concentrated, so that any new infections result in transmission of a resistant strain of the disease.

The geographical extent of drug resistance varies: chloroquine resistance is almost universal, while only some locations have reported resistance to quinine. But almost every drug we’ve produced so far has been met with resistance, sooner or later. In another context, if it weren’t intent on killing us, we would marvel at the parasite’s tenacity.

Artemisinin-based products are currently the only malaria treatment available without issues of parasite resistance. For this reason, the WHO now recommends that artemisinin only be taken in combination with other drugs, a form called artemisinin-based combination therapy (ACT). The idea behind ACT is that the parasite will not be able to evolve resistance to artemisinin if it is hit with multiple drugs at one time. When ACT is administered properly, using the correct dosages and combinations of drugs, it is highly effective: there are no reported cases of patients dying after receiving ACT if diagnosed in time for treatment.

But troubling news has come out of the Thai-Cambodia border region in the past two years – cases have been documented where artesunate has taken double or triple the normal time to clear the parasites from a patient’s body. This news is not necessarily a harbinger of artemisinin resistance, but it does not bode well. Should the slow treatment times in Southeast Asia turn into full blown artemisinin failure, the results could be catastrophic. This is the best drug on the market right now. In some parts of the world, it’s the only drug that works. The next generation of drugs is years away. Should artemisinin fail, the consequences will be measured in rising numbers of deaths.

An international effort has recently been coordinated by the WHO and INTERPOL to tackle the counterfeit medication trade. Operation Mamba targeted counterfeiters and distributors in East Africa. During Mamba I, in October 2008, officers in Uganda and Tanzania inspected 226 pharmacies, wholesalers and hospitals, seizing 100 different counterfeit products. During Mamba II, in August 2009, officers raided 270 premises in Kenya, Tanzania and Uganda, seizing thousands of counterfeit tablets and resulting in the prosecution of several individuals. Operation Storm focused on Southeast Asia and was a longer campaign: between April and September 2008, more than 16 million counterfeit tablets with a market value of US$6.65 million were seized from 186 raids all over the region.

The international effort is encouraging, but seems like the proverbial drop in the bucket. National-level efforts are also limited, since counterfeiting is greatest in countries with poor regulatory environments and weak legal enforcement: counterfeiting is most pervasive precisely where people are most vulnerable. With visual detection of counterfeit antimalarials so difficult, and official medication dispensaries unintentionally stocking up on fake drugs, there is presently little recourse for the average person who simply wants to buy good quality medicine.

But a promising innovation could give citizens some control. In a short video viewed over the internet, a young woman walks into a pharmacy in Accra,Ghana, and asks for a single course of ACT medication sold under the name Easadol. She scratches off a panel on the front of the packet, revealing a 9-digit code. She sends the code via text message to the number 1393 and waits for a reply that will tell her if the medicine is genuine or counterfeit.

Checking the quality of medication using mPedigree’s phone service. Photo from mpedigree.net

This video was made by the company mPedigree to demonstrate the cell phone-based service it developed, whereby a consumer can check the authenticity of her medication for free. Participating drug manufacturers generate unique, time-sensitive IDs for every packet of medication, then upload the codes to a database maintained jointly by mPedigree and Hewlett Packard. The cost of the text message service is borne by the drug manufacturer, but mPedigree has negotiated with telecommunication companies to provide the service for almost cost price. The consumer experience was intentionally designed to mimic the process for topping up cell phone minutes, so that anyone who can work a cell phone can use the service.

Nine drug manufacturers in Africa are currently participating in the service, which is publicly available in Ghana and Nigeria. Trials are being conducted in Kenya and Tanzania, and mPedigree is in negotiations with manufacturers in East Asia. Bright Simons, the founder and president of mPedigree, says that the system took two years to set up in Ghana and Nigeria because of the unusual partnerships required, between drug manufacturers and computing and telecommunication companies. But the manufacturers see the benefits of the service, for recovering market share lost to counterfeiters, so the process of establishing the service in a new location is becoming easier with time. “We will definitely be [operating] outside Africa by the end of the year,” Simons asserts.

For now the names of the participants remain confidential, as is the data generated by the users of the service. But once participants have grown comfortable enough with the service, mPedigree hopes to publish the user data and help organizations like the WHO generate better statistics on the presence of counterfeits in the market. Widespread use of the service should also start squeezing some of the counterfeit medications out of the market, though it will by no means be a complete solution.

Six seconds after she hit the ‘send’ button, the woman in the video receives a text message. It reads: “OK Easadol (LOT: 12035, MFD: NOV 2008, EXP: OCT 2013)”, informing her that the packet of medicine is a genuine Easadol product, with verification of the batch number and the manufacturing and expiry dates. She can breathe easy knowing that the medicine, at least this time, is the real thing.

This essay was researched and written in May 2011 for a class I took at MIT: Science Writing and New Media, under the instruction of Robert Kanigel. For more recent and detailed documentation of the counterfeit antimalarial trade, please see work by Paul Newton and colleagues, for example: http://www.malariajournal.com/content/10/1/352. This article is freely available. For more information on the mPedigree network, please see: http://www.mpedigree.net/mpedigree/index.php

Discussion

One thought on “Death by Imitation Medicine

  1. A good story. unfortunately a common happening in the poorer nations in Asia. I would liek to draw yoru attention teo teh sale of expired medicine. A serious problem in India. There will be unscrupulous people to exploit any situation. Wonderingw hether WHO or any such organisation can bring a legoslation that would make the insituiatution that discards old medicine to teh responsible for the destruction of such items.
    In India, some medical institution actually sells expired items to vendors..!!!
    Sive Sivandran Indonesia.

    Posted by Dr Sive Sivandran | December 1, 2012, 8:44 pm

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