© 2008 American Thoracic Society doi: 10.1164/rccm.200805-788ED
From Threat to RealityThe Real Face of Multidrug-resistant Tuberculosis
World Health Organization Multidrug-resistant tuberculosis (MDR-TB) is affecting all countries and has reached the highest prevalence ever documented worldwide in Eastern Europe and Central Asia, where more than 20% of new cases are multidrug resistant in some settings (1). Its more severe variant, extensively drug-resistant TB, has emerged in high-HIV-prevalence settings in Africa (2). In this issue of the Journal (pp. 306–312), Mak and colleagues show the negative impact of MDR-TB on current TB control efforts. In a well-designed ecological study, the authors have shown that a prevalence of initial MDR-TB of 3% or greater was strongly correlated with higher failure and relapse rates among new cases receiving initial treatment with first-line drugs (3). More importantly, the proportion of cases of TB requiring retreatment doubled where the prevalence of initial MDR-TB was greater than 3%, as compared with 1% or less. Furthermore, the higher the prevalence of MDR-TB in previously treated cases, the higher the failure rate among cases retreated using first-line drugs. Ecological studies are not ideal to derive clear cause–effect relationships. In this case, however, it is entirely plausible and expected that a high prevalence of MDR-TB strains would turn potentially successful treatment outcomes into negative ones. High levels of circulating MDR-TB strains in the community, and incorrect classification of cases as cured based on smear microscopy, when in fact the disease is only temporarily suppressed, are important factors that can explain the findings. Another potential problem with this study relates to the quality of the data used, as TB control varies widely across countries. Finally, as the authors stated, individual patient outcomes were not directly related to drug resistance, although evidence on this matter has been reported previously (4–6). The above considerations notwithstanding, several suggestions can be generated from the data toward improvement of TB control policies and practices. First, the current international retreatment policy for failure cases may need to be fine-tuned (7). Currently, the World Health Organization recommends that failures (that are usually more likely linked to MDR-TB than other retreatment cases) should be addressed considering adequacy of program performance, availability of representative drug resistance information and/or drug susceptibility testing for all cases, and availability of regimens based on second-line drugs. If these conditions are met, specially designed standard or individualized regimens should be used for cases failing initial treatment. These recommendations have been reiterated in the guidelines for programmatic management of drug-resistant TB (8). On the basis of these new findings, an MDR-TB prevalence level among new cases of 3% or more can be used as the cutoff point for revision of recommendations for both initial and retreatment regimens. Concrete measures include early drug susceptibility testing for all new cases, at least by the end of the second month of treatment for those who are still sputum smear positive, to guide choice of treatment regimens. The introduction of line-probe assays to test for isoniazid and rifampicin resistance may result in much more rapid detection of MDR-TB and in the immediate use of second-line drugs. The standard retreatment regimen with five first-line drugs, designed in an era when MDR-TB was unknown as a problem, should be replaced if programs have the capacity to test for drug susceptibility and provide properly designed regimens for every retreatment case, and especially for those who failed the initial treatment. If, on average, the majority of failure cases of initial treatment with first-line drugs have unfavorable outcomes when retreated with first-line drugs, as shown by Mak and colleagues, insisting on old practices will cause further suffering and deaths, as well as the appearance of additional drug resistance. With the new financial mechanisms available today and technical assistance by the Green Light Committee (9), programs can address implementation constraints and scale up management of MDR-TB with regimens containing second-line drugs. Since 2000, the Green Light Committee has facilitated access to low-priced, quality second-line drugs cumulatively to more than 30,000 patients. While this is an achievement compared with the past, the target in 2007 alone was 66,000 patients. The Global Plan to Stop TB calls for treatment of 1.6 million people with MDR-TB between 2006 and 2015 (10). The slow pace toward this goal largely reflects the lack of capacity to implement. It is the result of many bottlenecks: lack of laboratories to diagnose MDR-TB, problems with procurement of expensive second-line drugs, lack of properly trained human resources able to manage MDR-TB, and lack of infection control in high-density settings, as transmission must be stopped especially where HIV prevalence is high. In addition, the current tools are decades old, complex to use, time consuming, and, more importantly, not designed for case management of MDR-TB. The Stop TB Partnership's Global Plan calls for a major investment in research and development of new diagnostics, drugs, and vaccines against TB (11). The strong financial commitment of some donors is an encouraging sign in the right direction. However, a recent report showed that investment on research and development for TB in 2006 was only a meager $400 million, less than half of the need as estimated in the Global Plan to Stop TB (12). Furthermore, the report shows how small the current investment on TB research is when compared with investments in HIV research. The article by Mak and colleagues should serve as a reminder that the fight against TB and MDR-TB is now becoming more complex. MDR-TB needs first to be prevented at all costs by proper practices of TB care and control. For this, the DOTS strategy and its emphasis on strict supervision of treatment are essential. Second, MDR-TB needs to be managed effectively maximizing the use of current tools. Last, research must be urgently intensified to make the diagnosis and treatment of TB more user friendly than they are today. Unless those with the responsibility to boost control and research efforts increase their commitments and their financial investments by several fold, we may never see elimination of this major scourge in the decades to come. FOOTNOTES Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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