The importance of poor-quality anti-tuberculosis drugs cannot be underestimated, as they may disrupt all major complex interventions to ensure treatment efficacy. Not only treatment failure may ensue, but, more importantly, rapid emergence of acquired drug resistances can also be favoured
Poor-quality Anti-tuberculosis Drugs Threaten the Global Disease Control Strategy
by Giorgia Sulis*and Alberto Matteelli**
University Division of Infectious and Tropical Diseases, University of Brescia
Tuberculosis (TB) represents a major public health problem worldwide, with over 8.6 million estimated cases and 1.3 million deaths in 2012. TB remains a global threat in low- and middle-income countries where it represents the paradigm of poverty-related diseases . Undoubtedly, important progresses have been achieved since the first global TB strategy was launched in 1994 and subsequently updated in 2006 in order to better address the needs [2-5], leading to declining trends in incidence and mortality during the recent decades . However, several challenges continue to undermine the way towards control and eventually elimination of the disease.
Quality-assured drug supply is certainly among the most relevant issues under debate, with counterfeits and sub-standards appallingly on the rise [6, 7]. By definition, counterfeit drugs are deliberately and fraudulently mislabelled medicines with respect to identity and/or source . For instance, quantitative and/or qualitative alterations of ingredients and fake packaging all belong to this category. Furthermore, substandard medicines include those lacking quality control requirements, and might probably be even more common than counterfeits .
WHO estimates that counterfeits account for about 10% of the global drug trade, reaching a peak of at least 25% in developing countries, where regulatory and enforcement systems for medicines are weak. However, the real burden of poor-quality medical products on the global market is not exactly known. The very few studies that have been conducted to assess the dimension of the problem of under qualified medicines are limited by the small sample size and are mainly related to a specific drug class in selected geographic areas . Antimicrobials are by far the most frequently involved class of medicines and, coincidentally, they are also the most needed in resource-limited settings which are disproportionately affected by infectious diseases as compared to industrialized countries [11, 12]. Fake pharmaceuticals can be purchased at lower prices thus widening access possibilities especially for the poors. Since most drug stocks do not routinely undergo a proper quality control procedure before usage in several TB high burden countries, the product characteristics vary considerably depending on its final destination. Though usually found on illegal circuits, authorized companies may also be involved in their market .
The mainstay of TB control programs is early diagnosis and proper treatment of patients, principally the contagious ones. Standard short course chemotherapy has been at the centre of any TB control strategy. It is composed of a two-month induction phase with four drugs followed by a four-month continuation phase with two drugs . Treatment adherence is essential for a successful outcome and TB programs devote huge efforts and resources to ensure patient support throughout the entire treatment period. Fixed dose combinations were developed and widely adopted, in order to reduce the number of pills and treatment complexity.
The importance of poor-quality drugs cannot be underestimated, as they may disrupt all major complex interventions to ensure treatment efficacy . Not only treatment failure may ensue, but, more importantly, rapid emergence of acquired drug resistances can also be favoured .
Multidrug resistance tuberculosis (MDR-TB) is currently recognized as one of the most serious challenge to TB control and eventual elimination. Diagnosis is a real challenge for the weak health systems in resource constrained settings: it is estimated that only approximately 10% of the MDR-TB cases estimated to occur in 2012 were enrolled in care . Moreover, in settings where MDR-TB diagnosis is actively promoted, rapidly increasing the number of identified MDR-TB cases, patients start queuing for treatment for the limited availability of second line TB drugs. While treating a TB patient with a short-course standard regimen has an average cost of 19 US dollars, the economic costs of treatment for one single MDR-TB case can reach 10.000 US dollars.
Solutions for the challenge posed by counterfeit medicines are strongly needed, but they are not at reach. In 2001 a targeted strategy to fight this scourge (the Global Drug Facility, GDF) was developed, with the purpose of providing assistance and support to needing countries in terms of affordable supplying of medicines and their management . This is among the most important initiatives within the global TB control program aimed to directly provide drugs to both governments and non-governmental organizations (NGOs) through a well-established and strictly controlled process assuring absolute adherence to quality criteria from the sourcing of raw materials to the final distribution and proper stocking of the packaged product. Today, uncertainty about the quality profile is particularly significant for products coming from outside the GDF channel, which miss the prequalification process and unfortunately still constitute a large proportion of the global drug stock. The consolidation of public funds- and the GDF source – for the purchase of TB drugs has a twofold rationale: it maximises leverage for reduced prices on quality-assured first-line drugs and second-line drugs, thus enabling wider access to them, while also minimising the use of public funds for procurement of drugs of uncertain, potentially substandard, quality.
A relevant proportion of underqualified medicines could be detected through relatively inexpensive and simple assays at destination countries, based on chromatographic techniques, like HPLC and TLC . Such tests are able to identify the type and concentrations of the various components but their execution is not compulsory and then only rarely pursued. In a vicious mechanism, whenever local regulatory authorities fail implementing their controller role not requiring to operate in accordance with basic standards, fraudulent manufacturers are encouraged to enter the market.
The way to fight counterfeit medicines with global efforts is not straight forward and sometimes crosses with political problems. The Indian and Brazilian Governments and some non-governmental organisations, have opposed the work of IMPACT – the International Medical Products Anti-Counterfeiting Taskforce - created by WHO in 2006 . The principal reason is they believe it would confuse quality and intellectual property rights issues and thus undermine access to legitimate and much lower-cost generic medicines consumed mostly in poor areas.
So, once again, the poorest are also the most vulnerable, widely lacking access to adequate healthcare facilities and medications that results in worsening conditions. Putting aside financial responsibilities, our major and definitely unacceptable defeat remains the loss of human lives.
*Giorgia Sulis (Resident in Infectious Diseases since August 2013), was born in Italy in 1986. After graduating from the University of Pavia as a medical doctor in July 2011, she earned a postgraduate research fellowship on HIV/AIDS infection among migrants at the University of Brescia. During the first semester of 2013 she attended a TropEd Course in Tropical Medicine and International Health held in Brescia.
**Alberto Matteelli was born in Italy in 1960. After graduating from the University of Pavia as a medical doctor he got his first job as WHO Junior Professional Officer in 1988 to work in Tanzania. He is employed by the Spedali Civili di Brescia since 1991. Currently he is the head of the Community Infections Unit, head of the Hospital STI centre, and co-Director of the WHO collaborating Center for TB/HIV co-infection.
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