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December 6, 2000

The New White Plague

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JAMA. 2000;284(21):2789. doi:10.1001/jama.284.21.2789-JMS1206-6-1

Multidrug-resistant Mycobacterium tuberculosis (MDRTB) came to attention in the 1980s, when a number of scattered outbreaks occurred in North America and Europe. In subsequent decades, these gave way to a more widespread problem. In 1997, the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease found resistance to first-line drugs in every country they assayed.1 Basing their calculation on data from several developing countries, the WHO estimated that, by 1996, some 50 million persons were already infected with MDRTB. This disease has arisen as a significant global health problem in the space of a single generation.

Pioneered in the 1960s, the directly observed therapy, short-course (DOTS) strategy has been central to the WHO-recommended TB-control strategy since 1991. The primary therapeutic innovation of DOTS is directly observed administration of short-course chemotherapy (SCC).

What is to be done about MDRTB in resource-poor settings? In 1996, the WHO offered a grim view: "In developing countries people with multidrug-resistant TB usually die."2 Until recently, WHO guidelines recommended that DOTS treatment failures—of whom over 93% have been shown to have drug-resistant disease in some series3—be given an empirical regimen consisting of the same 4 first-line drugs—isoniazid, rifampin, pyrazinamide, ethambutol—plus an additional agent, streptomycin.

It has been repeatedly demonstrated that DOTS alone is ineffective against MDRTB. This has recently been acknowledged by the WHO, which published a 6-country study of the use of SCC among patients with MDRTB. SCC failed in most patients, with cure rates varying between 20% and 60%.4 Even lower cure rates have been demonstrated in other settings. The CDC, working in Russia's Ivanovo Oblast, cured only 5% of primary MDRTB cases with SCC.5 These lower cure rates are closer to what would be expected given that many patients who have negative smears after treatment, and are thus declared "cured" by DOTS criteria, in fact only experience transient suppression and would actually have positive culture results throughout therapy. In the setting of underlying drug resistance, standardized DOTS retreatment regimens constitute ineffective therapy.

Given the success of DOTS in settings in which resistance to first-line drugs is rare, the concept of "DOTS-Plus" has been proposed.6 Two approaches to DOTS-Plus have been advanced: individualized treatment regimens and standardized MDRTB regimens utilizing second- and third-line drugs. Individualized treatment regimens are designed for each patient according to the drug-susceptibility pattern of the infecting isolate. Therefore, such regimens tend to be more efficacious, making amplification of resistance less likely. Standardized DOTS-Plus treatment regimens can also be used in the treatment of MDRTB. If patients failing DOTS are presumed to have MDRTB, and if drug-susceptibility testing is unavailable, they might be placed on an empirical re-treatment regimen consisting of second-line drugs. This regimen could be tailored to the local epidemiology of TB using population surveillance data and resistance patterns commonly encountered in an outbreak.

Many have argued against treating MDRTB in resource-poor settings. Some have claimed that drug-susceptibility testing and second-line drugs required to treat MDRTB are cost-ineffective and unsustainable. Drug-susceptibility testing, however, can be performed for as little as $2 per patient.7 Almost all second-line drugs are off-patent, and many of them are regarded incorrectly as "orphan drugs"—drugs for which there is exceedingly low demand—by their manufacturers. Pooled procurement through central agencies such as the WHO could lower drug prices dramatically.

It is strikingly ironic that 50 years after the introduction of effective chemotherapy, TB remains the leading infectious cause of adult mortality in the world, causing as many as 2 million deaths in a single year.8 In 1997 the WHO warned, "Once MDRTB is unleashed, we may never be able to stop it."9 We believe that MDRTB has already been unleashed, and effective therapy that cures drug-resistant TB in infectious patients is the only acceptable way to interrupt the transmission of new infections.

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