Malaria still claims over one million lives each year and is a risk for some 40% of the world's population [1
]. Most patients with malaria would survive if they had timely access to efficacious medicines that they could afford. With the global spread of drug resistance and the practical difficulties in delivering health care to rural communities, most of those at risk of malaria have not had such access [3
]. However, with the development of artemisinin derivative combination therapy (ACT) and international financial support to allow inexpensive or free distribution to those in need, hope of controlling malaria has been rekindled [3
]. A major obstacle to malaria control, which has received woefully insignificant attention in the past, is the poor quality of antimalarial medicines available in much of the tropics. The available data strongly suggest that antimalarials have been particularly targeted by counterfeiters, who have deliberately and fraudulently produced copies for profit, usually containing no active ingredients and therefore lacking antimalarial activity [4
Artesunate is an antimalarial artemisinin derivative, developed in the People's Republic of China (China), vital for malaria treatment [5
]. It is widely used in South East (SE) Asia and increasingly in Africa for the treatment of Plasmodium falciparum
]. In SE and East Asia there are at least 16 manufacturers of artemisinin and its derivatives [6
] and millions of tablets are produced each year both for consumption in Asia and export to Africa. Artesunate is a crucial component of artemisinin derivative-based combination therapy, but is often used inappropriately as monotherapy outside of national malaria programmes.
Since 1998 an epidemic of multiple types of counterfeit artesunate tablets, both primitive and highly sophisticated copies, have affected patients with malaria in mainland SE Asia (, , and S1
). Ad hoc surveys since 2000 in Burma (Myanmar), the Thai/Myanmar border, the Lao People's Democratic Republic (Lao PDR, Laos), Cambodia, and Vietnam, the most malarious countries in mainland SE Asia, suggested that 33%–53% of bought artesunate was counterfeit, containing either no or subtherapeutic quantities of artesunate () [7
]. In Thailand, which has only a small number of malaria cases, the threat of counterfeit artesunate has been largely averted: such counterfeits have only been described from the central Thai/Myanmar border area around the Western border town of Mae Sot. Counterfeit artesunate has been recently described from southern China [14
]. In Asia the product of one major producer of artesunate, Guilin Pharmaceutical (Guilin, Guangxi autonomous region, China), has been exclusively targeted. The recent description of counterfeit artemisinin derivatives in four sub-Saharan African countries is of enormous public health concern [10
Map of the Distribution of Fake Artesunate, Collected by Wellcome Trust-University of Oxford SE Asian Tropical Medicine Research Programme and Collaborators, in Relation to Packaging Type
Examples of Genuine and Counterfeit Holograms
Counterfeit artesunate containing subtherapeutic quantities of artesunate has recently been described in Asia [10
]. Such counterfeits, which may foil simple screening tests, will engender the selection and spread of artemisinin resistant falciparum parasites, which would be disastrous for malaria control in Asia and thereafter in Africa.
Despite the difficulties of demonstrating in rural Asia that patients die of malaria because of fake drugs, such mortality has been reported [10
]. Malaria remains a public health problem in the countries affected by fake artesunate—with estimates of over 2 million cases/year and over 10,000 deaths/year in the Western Pacific Region of the World Health Organization (2001 data [18
]). With an estimated prevalence of counterfeit artesunate of 33%–53% in mainland SE Asia and a high proportion of patients obtaining antimalarials outside the public health provision of ACTs, the health impact on malaria morbidity and mortality must be considerable—but extremely difficult to quantify.
Since the first description of fake artesunate in 2000, there has been little action in comparison to its public health consequences, apart from surveys [8
], warnings and educational films [10
] with some strengthening of drug regulatory authority (DRA) and malaria programme capacity. With little progress and worsening contamination of the supply of antimalarials in the Greater Mekong Sub-Region, a confidential meeting was held in Manila in May 2005 at the WHO Regional Office for the Western Pacific (WPRO). The meeting brought together WHO officials, physicians, pharmacists, and scientists working in the region with the International Criminal Police Organization (INTERPOL) to discuss what could be done. It was decided that a joint effort be made to investigate where the counterfeits were being manufactured and develop an intelligence document that could be presented to concerned governments with a request that measures be taken to stop the lethal manufacture and trade in counterfeit artesunate.
In the hope that forensic analysis of genuine and counterfeit tablets would provide clues as to the origin of the counterfeits, samples were subjected to high performance liquid chromatography (HPLC), organic mass spectrometry, X-ray diffraction, stable isotope ratio mass spectrometry, gas-chromatographic ‘head space' analysis of the gases surrounding tablets in blister packs, pollen analysis (palynology), and detailed packaging inspection. Further meetings were held in Oxford, UK, and Manila to review the evidence under the umbrella of the Jupiter Operation INTERPOL anti-counterfeiting taskforce chaired by JN. This paper presents the findings of this group relevant to public health.